And Pediatric Dermatology Is Now an Integral Part of Most Dermatological and Pediatric Meetings

Arnold P. Oranje Nawaf Al-Mutairi Tor Shwayder Editors Practical Pediatric Dermatology

Controversies in Diagnosis and Treatment

123 Practical Pediatric Dermatology

Arnold P. Oranje • Nawaf Al-Mutairi Tor Shwayder Editors

Practical Pediatric Dermatology

Controversies in Diagnosis and Treatment Editors Arnold P. Oranje Nawaf Al-Mutairi Kinderhuid.nl, Rotterdam Dermatology Unit Dermicis Huidziekenhuis Alkmaar Faculty of Medicine The Netherlands Kuwait University Kuwait Tor Shwayder Department of Dermatology Henry Ford Hospital Detroit , Michigan USA

ISBN 978-3-319-32157-8 ISBN 978-3-319-32159-2 (eBook) DOI 10.1007/978-3-319-32159-2

Library of Congress Control Number: 2016946031

© Springer International Publishing Switzerland 2016 This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of the material is concerned, specifi cally the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfi lms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specifi c statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. The publisher, the authors and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, express or implied, with respect to the material contained herein or for any errors or omissions that may have been made.

Printed on acid-free paper

This Springer imprint is published by Springer Nature The registered company is Springer International Publishing AG Switzerland Pref ace

Pediatric dermatology is a young fi eld that combines dermatologic and pediatric skills and expertises. Knowledge of dermatology and pediatrics is necessary for optimal care of children with skin diseases. A multidisciplinary approach in which there is cooperation between dermatologists and pediatricians is essential and makes that 1 + 1 (dermatologist + pediatrician) equals 2 but is actually more than 2. This has always been the slogan of our Dutch courses in pediatric dermatology that were organized for more than 20 years. Pediatric dermatology is offi cially started as a subspeciality in many countries and recognized as a terminology beginning in 1972 in Mexico. The number of pediatric dermatologists started small and has been growing quickly in the last several decades. Pediatric dermatology was earlier called dermatology of the child. Since the 1980s, developments have been impressive with several specifi c pediatric dermatology textbooks, as well as world, European, regional, and national congresses. The interest in this fi eld has grown, and pediatric dermatology is now an integral part of most dermatological and pediatric meetings. The (US) American Board of Medical Specialties, which oversees all medical specialties, has demanded that specifi c pediatric dermatology teaching criteria be included in the training of all US trained general dermatologists. In this book, subjects were chosen based on practical controversial problems in pediatric dermatology, so the content is not structured after basic classifi cation or subgrouping of dermatological disorders but according to controversies in diagnosis and treatment of childhood dermatological disorders. It will help the authors and readers to think about and evaluate pediatric dermatology dilemmas. In this way it will help you to perform a critical and well-balanced and most evidence-based diagnosis, approach, and treatment of the disease involved.

Arnold P. Oranje Rotterdam , The Netherlands Nawaf Al-Mutairi Farwaniya , Kuwait Tor Shwayder Detroit , MI , USA

Contents

Part I Introduction

1 Pediatrics, “Dermatopediatrics”, and Pediatric Dermatology ...... 3 Arnold P. Oranje and Flora B. de Waard-van der Spek

Part II Inﬂ ammation

2 Proactive Therapy in Atopic Dermatitis ...... 11 Arnold P. Oranje 3 Contact Allergy in Children: Diagnosis and Treatment ...... 17 Flora B. de Waard-van der Spek 4 Allergy Tests in Atopic Dermatitis ...... 31 Flora B. de Waard-van der Spek 5 Childhood Psoriasis ...... 37 Nawaf Al-Mutairi 6 Childhood Pityriasis Rubra Pilaris ...... 51 Nawaf Al-Mutairi 7 Neonatal Acne Controversies Versus Pityrosporum Folliculitis...... 61 Nawaf Al-Mutairi

Part III Tumors

8 Controversies in the Treatment of Infantile Haemangiomas with β-Blockers ...... 69 Sherief R. Janmohamed , Nisha Suyien Chandran , and Arnold P. Oranje 9 Multiple Cutaneous Infantile Hemangioma and the Risk of Internal Hemangioma ...... 79 Astrid D. Vredenborg , Sherief R. Janmohamed , Peter C. J. de Laat , Gerard C. Madern , and Arnold P. Oranje 10 Congenital Melanocytic Nevi: What to Do? ...... 91 Linda De Raeve

vii viii Contents

Part IV Immune Disorders and Autoimmunity

11 Alopecia Areata ...... 101 Abdullah Alkhalifah 12 Therapy of Juvenile Immune Bullous Disorders ...... 113 Sultan Al-Khenaizan and Luluah Al Mubarak 13 Childhood Sweet Syndrome ...... 125 Marla Jahnke , Devika Patel , and Tor Shwayder 14 Childhood Vitiligo ...... 133 Rashmi Sarkar and Shuchi Bansal

Part V Psychology

15 Childhood Trichotillomania: Diagnostic Algorithm and Systematic Problem-Solving Management Using the 5W1H (Kipling’s Principle) ...... 143 Nisha Suyien Chandran , Jeroen Novak , Matilde Iorizzo , Ramon Grimalt , and Arnold P. Oranje 16 Child Abuse: More Than Skin Deep ...... 155 Robert A.C. Bilo

Part VI Miscellaneous

17 Solar Protection Policy in School Children: Proposals for Progress ...... 165 Yi Chun Lai , Edmund J. Janniger , and Robert A. Schwartz 18 Adolescent Tanning Practices: Understanding the Popularity of Excessive Ultraviolet Light Exposure ...... 177 Thomas J. Jasterzbski , Edmund J. Janniger , and Robert A. Schwartz 19 Androgenetic Alopecia in Adolescents...... 187 Rubina Alves and Ramon Grimalt 20 Classification of Mastocytosis ...... 197 Dirk Van Gysel 21 Mastocytosis in Children: What to Do? ...... 205 Dirk Van Gysel 22 Erythema Multiforme, Stevens- Johnson Syndrome and Toxic Epidermal Necrolysis ...... 213 Lea Solman and John Harper 23 Kawasaki Disease ...... 221 Katherine Johnson and Tor Shwayder 24 Retinoids ...... 233 Dirk Van Gysel Contents ix

25 Cyclosporine in Pediatric Dermatology ...... 241 Nawaf Al-Mutairi 26 Laser Therapy: When, Where, and Why ...... 251 Jasem Alshaiji 27 Photography in Pediatric Dermatology: More Important than Many Physicians Think ...... 259 Frans Bel and Arnold P. Oranje

Index ...... 263

Contributors

Luluah Al Mubarak , MD Department of Dermatology , Prince Sultan Military Medical City-Riyadh Military Hospital , Riyadh , Saudi Arabia Abdullah Alkhalifah , MD Department of Dermatology , Prince Sultan Military Medical City , Riyadh , Saudi Arabia Sultan Al-Khenaizan , MD King Abdulaziz Medical City-Ministry of National Guard , Riyadh , Saudi Arabia College of Medicine, King Saud Bin Abdulaziz University for Health Sciences , Riyadh , Saudi Arabia Nawaf Al-Mutairi , MD Dermatology Unit, Department of Medicine , Faculty of Medicine, Kuwait University , Kuwait Jasem Alshaiji , MD Department of Dermatology , Amiri Hospital, Ministry of Health , Al-surra , Kuwait Rubina Alves , MD Department of Dermatology and Venereology , Universitat Internacional de Catalunya , Barcelona , Spain Shuchi Bansal , MD Department of Dermatology and Venereology , Maulana Azad Medical College and Lok Nayak Hospital , New Delhi , India Frans Bel , RMF Department of Medical Photography , Erasmus MC , Rotterdam , The Netherlands Robert A.C. Bilo , MD Department of Forensic Medicine, Section of Forensic Pediatrics , Netherlands Forensic Institute , The Hague , The Netherlands Nisha Suyien Chandran , MRCP (UK) Division of Dermatology , University Medicine Cluster, National University Hospital , Singapore , Singapore Ramon Grimalt , MD, PhD Department of Dermatology , Universitat Internacional de Catalunya , Barcelona , Spain Dirk Van Gysel , MD, PhD Department of Pediatrics , O. L. Vrouw Hospital , Aalst , Belgium John Harper , MBBS, MD, FRCP, FRCPCH Department of Paediatric Dermatology , Great Ormond Street Hospital for Children , London , UK Matilde Iorizzo , MD Private Dermatology practice , Bellinzona , Switzerland xi xii Contributors

Marla Jahnke , MD Department of Pediatric Dermatology , Children’s Hospital of Michigan , Detroit , MI , USA Department of Dermatology , Henry Ford Hospital , Detroit , MI , USA Sherief R. Janmohamed , MD, PhD, MHS, MSc Department of Dermatology , University Hospital Brussels , Brussels , Belgium Edmund J. Janniger Rutgers University School of Public Affairs and Administration , Newark , NJ , USA Thomas J. Jasterzbski , BS Department of Dermatology , Rutgers New Jersey Medical School , Newark , NJ , USA Katherine Johnson , DO Department of Pediatric Dermatology , Henry Ford Hospital , Detroit , MI , USA Peter J. C. de Laat , MD, PhD Department of Pediatrics , Erasmus MC , Rotterdam , The Netherlands Yi Chun Lai , MPH Department of Dermatology , Rutgers New Jersey Medical School , Newark , NJ , USA Gerard C. Madern , MD, MSc Department of Pediatric Surgery , Erasmus MC , Rotterdam , The Netherlands Jeroen Novak , MD PsyQ, Parnassiagroep , Breda/Rotterdam , The Netherlands Arnold P. Oranje , MD, PhD Department of Dermatology , Dermicis Skin Hospital – Alkmaar , Kinderhuid.nl – Rotterdam , Rotterdam , The Netherlands Devika Patel , MD Department of Dermatology , Henry Ford Hospital, Wayne State University , Detroit , MI , USA Linda De Raeve , MD, PhD Department of Dermatology , UZ Brussel, Vrije Universiteit Brussel , Brussels , Belgium Rashmi Sarkar , MD, MNAMS Department of Dermatology and Venereology , Maulana Azad Medical College and Lok Nayak Hospital , New Delhi , India Robert A. Schwartz , MD, MPH, DSc (Hon), FRCP Edin Departments of Dermatology, Pediatrics and Pathology, and Rutgers New Jersey Medical School , Newark , NJ , USA Department of Dermatology , Rutgers University School of Public Affairs and Administration , Newark , NJ , USA Tor Shwayder , MD Department of Pediatric Dermatology , Henry Ford Hospital , Detroit , MI , USA Lea Solman , MD, FRCPCH Department of Paediatric Dermatology , Great Ormond Street Hospital for Children , London , UK Astrid D. Vredenborg , MD, MSc Department of Dermatology , Catharina Hospital , Eindhoven , The Netherlands Flora B. de Waard-van der Spek , MD, PhD Department of Dermatology , Franciscus Gasthuis and Vlietland , Rotterdam / Schiedam , The Netherlands Part I Introduction

Pediatrics, “Dermatopediatrics”, and Pediatric Dermatology 1

Arnold P. Oranje and Flora B. de Waard-van der Spek

Abstract Pediatric dermatology is a specialty that is dealt with by pediatricians and dermatologists. Knowledge of dermatology as well as a solid basic knowledge of pediatrics is necessary. In the USA, pediatric dermatology is a recognized term and an ofﬁ cial specialty with its own board exam. But there are also physicians who call themselves pediatric dermatologists though they are not board certiﬁ ed in pediatric dermatology. However, in the rest of the world, much more physicians call themselves pediatric dermatologists while they are not all experienced and educated in diagnosing and treating children with skin diseases.

Keywords Pediatric dermatology • “Dermatopediatrics” • Pediatrics • Training in pediatric dermatology • Status of pediatric dermatology

Pediatric dermatology is a specialty that is dealt with by pediatricians and dermatologists. Knowledge of dermatology as well as a solid basic knowledge of pediatrics is necessary. About 10–30% of the pediatric primary care visits in the USA include skin-related problems (Prindaville et al. 2015 ). Skin diseases in children are thus A. P. Oranje , PhD, MD (*) Department of Dermatology , common and represent a spectrum of diseases Dermicis Skin Hospital – Alkmaar , completely or partly in detail different from that Kinderhuid.nl – Rotterdam, Rotterdam, in adults. Only in some countries, in particular in The Netherlands the USA, pediatric dermatology is an offi cial e-mail: [email protected] subspecialty. Formal training in pediatric F. B. de Waard-van der Spek , MD, PhD dermatology and certifi cation of the subspe- Department of Dermatology , Franciscus Gasthuis and Vlietland, Rotterdam / Schiedam , The Netherlands cialty must be defi ned. This has been illustrated e-mail: [email protected] by the publication of the American Academy

© Springer International Publishing Switzerland 2016 3 A.P. Oranje et al. (eds.), Practical Pediatric Dermatology, DOI 10.1007/978-3-319-32159-2_1 4 A.P. Oranje and F.B. de Waard-van der Spek for Dermatology, entitled “Dermatology Core Tertiary Pediatric Dermatology Curriculum: Pediatric Dermatology” (Appendix ) and Requirements (Kanzler et al. 2001 ). Pediatric dermatology is different from European Society for Pediatric “dermatology of the child” (see in particular the Endocrinology report in the White Book Dermatology , 2005) (Oranje et al. 2005). There is a great need for cer- This chapter summarizes the minimum require- tifi cation of pediatric dermatology and for spe- ments for training in tertiary care pediatric cialized training both for dermatologists and dermatology center. Tertiary care pediatric der- pediatricians. In the USA, initial informal train- matology is not yet recognized as such by the ing in pediatric dermatology evolved into formal Confederation of European Specialists in 1–2-year programs sponsored by the American Paediatrics (CESP). The situation with respect Board of Dermatology (ABD). Certifi cation to national bodies varies within the European should be instituted by the European Society for Union (EU) as follows. Pediatric Dermatology (ESPD) and become valid In many countries, there are different for 5 years, commencing with the fi rst certifying categories: evaluation offered by the Certifi cation Board of the ESPD. • General dermatologists and pediatricians with a special interest. • Pediatric dermatologist as a subspecialist. Role of the Training • A pediatric dermatologist could be originally and Certifi cation Committee a dermatologist or pediatrician. in Pediatric Dermatology • Some societies in pediatric dermatology are led by non-pediatric dermatologists perhaps There is an urgent demand for training and cer- because of these physicians’ eagerness to lead tifi cation programs in pediatric dermatology in any society. It is known to the authors some of Europe and all other countries in which there is these physicians do not even practice pediatric no protected status of pediatric dermatology. dermatology. A certifi cation committee needs to (1) ensure that all trainees entering the pediatric dermatol- A tertiary specialist in pediatric dermatology ogy program have access to European and must have a good knowledge in dermatology, as national-based programs, (2) specify the train- defi ned in this document. He or she must be able ing program in pediatric dermatology, (3) “to read the skin” (statement of Ruggero Caputo, supervise and monitor training and certifi cation MD, personal communication). standards in the EU in pediatric dermatology in The training program should: conjunction with the European Board of Pediatrics and the European Academy of • Harmonize training programs in pediatric der- Dermatology and Venereology (EADV), and matology between different European coun- (4) liase with the European Board of Pediatrics tries and other countries. and EADV and the national bodies so that train- • Establish clearly defi ned standards of knowl- ing programs and assessments meet the agreed edge and skill required to practice pediatric standards and provide for the national bodies as dermatology at the secondary and tertiary care an independent reference for internal disagree- level. ments over training and training center accredi- • Foster the development of a European net- tation. Till now, conservatism restricted the work of competent tertiary care centers for evolvement of a subspecialty in pediatric der- pediatric dermatology. matology, as well as that pediatric dermatology • Improve the level of care for children with com- is not a money-making activity. plicated or chronic dermatological disorders. 1 Pediatrics, “Dermatopediatrics”, and Pediatric Dermatology 5

Pediatric Dermatology Training Autoimmune diseases Allergology The CESP is the specialist section of pediatrics of There will be a structured quality review of the the European Union of Medical Specialists recognized centers every 5 years based on (UEMS). Represented are the member countries UEMS guidelines. of the European Union and the European Free A training center can be a single institution or a Trade Association. In addition, CESP has admit- group of related establishments. ted subspecialties to their meetings. The European Society for Pediatric Dermatology also has the Full Training Center intention to become a member of the CESP. For The center must provide adequate experience in pediatric dermatology, there exists no certifi cation all fi elds of pediatric dermatology including all (offi cial and nonoffi cial) and no specialization in aspects of care. It is expected to provide all train- any country except in the USA. Anybody may ing modules. A full component of the foundation call himself/herself a pediatric dermatologist and and advanced courses must be provided. The that is what is actually happening at present. number of activities must be suffi cient to provide at least a minimum experience for a trainee. A group of related establishments can be consid- Requirements for Training ered a center and each component considered as Institutions a unit contributing one or more modules to either the foundation or advanced course. Training centers in pediatric dermatology should The center must have easy access and close cover the whole fi eld of pediatric dermatology in relationships with other relevant specialities in an excellent way and medical research. In these pediatrics. The center must provide evidence of institutes, pediatric dermatology is a major fi eld ongoing clinical research and access to basic of interest. Postgraduate courses on a national or research. Textbooks should be immediately avail- international level should be organized periodi- able, and there should be easy access to a com- cally. The mission is to lead a national and inter- prehensive reference library either in paper or national effort on the European level to improve electronic format. the knowledge in the fi eld of pediatric dermatology through clinical research and training pro- Training Units grams to understand the causes of childhood skin Training units are institutions that provide train- disease; prevent, detect, diagnose, treat, and con- ing in one or more aspects of basic dermatology trol skin disease in early stages; and disseminate and advanced pediatric dermatology. Two to information to the practitioner, patient, and pub- three training units can in combination fulfi ll the lic. Such training centers should be located in a requirements of a “full training center.” high-standard pediatric hospital setting. Language should be limited to English, Spanish, and French. The language will be chosen based on the national Delivery of the Training Program origin of the candidates for training. The following are fi elds closely integrated The delivery of the training program relies on the into pediatric dermatology: recognition of centers and teachers as described above along with the process required for trainee Neonatal diseases assessment. In order to facilitate these processes, Genetic diseases. The Human Genome Project, a modular approach to the program is outlined. a worldwide research effort designed to ana- The modular approach allows for: lyze the structure of human DNA, must be supported. • Trainee assessment in either the foundation or Ophthalmology advanced courses or both. 6 A.P. Oranje and F.B. de Waard-van der Spek

• Assessment of training centers or units in Granuloma annulare terms of what they can deliver. Hair anomalies (hair dysplasia and hair anomalies • Development of CME in the true sense of the associated with genetic syndromes) concept with post-accreditation in add-on Hemangiomas of infancy (nowadays termed as modules. This will allow ﬂ exibility between infantile hemangioma) secondary and tertiary care to develop. Herpes simplex Histiocytosis (Langerhans and non-Langerhans cell histiocytosis) Hypomelanosis of Ito List of Controversies Ichthyosis Impetigo • Pediatric dermatology is not the same as der- Incontinentia pigmenti matology of the child. The latter term is a mis- Insect bites nomer illustrating the lack of insight in Keratosis pilaris pediatric skin problems. Lice • Pediatric dermatology should not be practiced Lichen planus by general dermatologists who are not trained Mastocytosis – urticaria pigmentosa, mastocytoma in pediatrics or lack any experience. Metabolic diseases and skin symptoms • The same is true for pediatricians who are Molluscum inadequately trained or not trained in derma- Nail alterations (20-nail disease, trachyonychia, tology at all (“dermatopediatrics”). nail-biting, nail alteration in genetic syndromes, • Pediatric dermatology societies should always i.e., ectodermal dysplasia) be chaired by physicians who are trained pedi- Neonatal lesions atric dermatologists. Nevi – congenital, acquired, halo • Pediatric dermatology has been its own board Palmoplantar keratoderma Pigmented (Café au lait macula (CALM), Mongolian) for over a decade in the USA. In Europe, the and hypopigmented lesions (pityriasis alba, nevus description is not protected, so anyone can call depigmentosus) himself/herself a pediatric dermatologist. Pityriasis rosea Pityriasis rubra pilaris Porphyrias Appendix Psoriasis Scabies Basic knowledge list of pediatric dermatology Seborrheic dermatitis for pediatricians and dermatologists Sexually transmitted diseases Skin signs of internal diseases (Crohn's disease Acanthosis nigricans and others) Acne Skin signs of child abuse Acrodermatitis enteropathica Sunburn Alopecia (alopecia areata, congenital alopecia, Steroid potency (cream use) trichotillomania, syndromic alopecia) Syphilis Atopic dermatitis Trichotillomania (trichophagia) Blistering disorders – SSSS, TEN Vascular malformations – Sturge-Weber Syndrome, Diaper rashes Klippel-Trenaunay syndrome, Kasabach-Merritt Drug eruptions syndrome, CMTC (syndrome of Lohuizen, cutis marmorata telangiectatica congenita) Erythema nodosum Urticaria Fungal infections – body, scalp, groin, feet, kerion, P. versicolor Viral exanthems Genetic syndromes (among the most common ones are Vitiligo neuroﬁ bromatosis, tuberous sclerosis complex, Warts incontinentia pigmenti, ichthyosis, epidermolysis bullosa) 1 Pediatrics, “Dermatopediatrics”, and Pediatric Dermatology 7

Classiﬁ cation according to morphology (selec- Nevi tion of disorders) Neuroﬁ broma Milia Acneiform eruptions Molluscum contagiosum Acne infantum Adnex tumor Acne neonatorum Verruca Acne vulgaris Keloid/scar Juvenile dermatitis perioralis Histiocytosis Folliculitis Xanthoma Keratosis pilaris atrophicus faceii Mucinosis Milia Pilomatrixoma Atrophy Hamartoma Aplasia cutis Gianotti-Crosti syndrome Atrophy after injection or vaccination Connective tissue nevus Atrophoderma Mastocytosis Juvenile dermatomyositis Red-colored Juvenile discoid lupus erythematosus Vasculitis Focal dermal hypoplasia Insect bite Lipoatrophy/lipodystrophy Scabies nodules Lichen sclerosus Xanthoma Morphea Gianotti-Crosti syndrome Necrobiosis lipoidica Granuloma annulare Poikiloderma Pityriasis lichenoides Striae Spitz nevus Blisters Hemangioma Allergic contact dermatitis Granuloma telangiectaticum Aplasia cutis Vascular malformation Bullous impetigo Lymphomatoid papulosis Bullous lichen planus Histiocytosis Bullous ichthyosiform erythroderma Mastocytosis Bullous drug eruptions Brown-colored Congenital syphilis Melanocytic nevus Epidermolysis bullosa Spitz nevus Herpes simplex infection Mastocytosis Histiocytosis Malignant melanoma Incontinentia pigmenti Blue-/black-colored Hydroa aestivale Blue nevus Hydroa vacciniforme Comedo (open) Staphylococcal scalded skin syndrome (SSSS) Congenital melanocytic nevus Toxic epidermal necrolysis (TEN) Malignant melanoma Eczematous eruptions Pilomatrixoma Atopic dermatitis (eczema) Hemangioma (deep) Infantile seborrheic dermatitis Vascular malformation Pityriasis rosea Yellow-colored Asymmetric exanthem of childhood Xanthoma Diaper dermatitis (napkin dermatitis, nappy rash) Xanthogranuloma Langerhans cell histiocytosis Nevus sebaceous Papules, plaques, nodules, and tumors Pseudoxanthoma elasticum Skin-colored Nevus lipomatosis 8 A.P. Oranje and F.B. de Waard-van der Spek

Nodules and tumors Painful tumors/nodules Cysts Eccrine spiradenoma Epidermoid cyst Glomus tumor Dermoid cyst Angiolipoma Pilomatrixoma Leiomyoma Ganglion cyst Erythema nodosum Branchial cleft cyst Infl ammatory nodules Bronchogenic cyst Erythema nodosum Thyroglossal cyst Polyarteritis nodosa Brown/black-colored Nodular vasculitis Melanocytic nevi Deep fungal infections Malignant melanoma Leishmaniasis Skin-colored Sweet syndrome Keloid/scar Milker’s nodule Spitz nevus Sporotrichosis Lipoma Orf Xanthoma Furuncle Neurofi broma Tuberculosis Leiomyoma Atypical mycobacteriosis Fibroma Lipoma Some data from Kanzler et al. (2001 ) Vascular Bold advanced knowledge (dermatologists), non-bold Hemangioma basic knowledge (pediatricians) Vascular malformations Lymphangioma Angiokeratoma References Glomus tumor Granulomas Kanzler MH, Davidson LS, Nordlund JJ, Mallory SB. Dermatology core curriculum: pediatric dermatology Foreign body granuloma (American Academy of Dermatology). Dubuque, Granuloma annulare Iowa, US: Kendall Hunt Publishing Company; 2001. Rheumatoid nodule Oranje AP, Taieb A, Grimalt R, Happle R. Pediatric der- Appendix tumors matology. In: White book dermatology. 2005. Prindaville B, Antaya RJ, Siegfried EC. Pediatric derma- Syringocystadenoma papilliferum tology: past, present and future. Pediatric Dermatology. Pilomatrixoma 2015;32:1–12. Part II I n fl ammation

Proactive Therapy in Atopic Dermatitis 2

Arnold P. Oranje

Abstract Atopic dermatitis (AD) is a common pruritic genetically based dermatitis and a part of the Atopic March. Treatment is started based on the severity of AD with a multidisciplinary approach in complicated cases. In the last 15 years, an alternative treatment strategy approach was proposed in which physicians almost never stop with the treatment, but continue with the application of the creams or the ointments twice weekly at sites of treated eczema with a combined application of emollients or bland vehicles. At the end of the 1990s, it was referred to as “step-down” therapy by Glazenburg, van der Meer, and Oranje (1999). Later this was called proactive treatment in 2009 with the major difference that healed spots also were continuously treated at a low frequency. Proactive treatment, emollient supplementation, and bleach baths in cases of overt secondary infection are now the key steps in the modern treatment of AD. Wet wraps with diluted corticosteroids are excellent as a crisis intervention in severe childhood atopic dermatitis. Wet wraps with diluted corticosteroids for severe AD is an effective therapy option for at least a period of 4 weeks. For longer term, proactive approach with wet wrap treatment (WWT) is very useful and safe if supervised by a nurse practitioner.

Keywords Atopic dermatitis • Proactive treatment of atopic dermatitis • Crisis intervention in atopic dermatitis • Long-term intervention atopic dermatitis • Cutaneous disease

A. P. Oranje , PhD, MD Atopic dermatitis (AD) is a common itching der- Department of Dermatology , matitis with a strong genetic basis characterized Dermicis Skin Hospital – Alkmaar , by exacerbations and remissions that need multi- Kinderhuid.nl – Rotterdam, Rotterdam, disciplinary and varied treatment strategies The Netherlands e-mail: [email protected] (Oranje 2014 ). Treatment is started based on the

© Springer International Publishing Switzerland 2016 11 A.P. Oranje et al. (eds.), Practical Pediatric Dermatology, DOI 10.1007/978-3-319-32159-2_2 12 A.P. Oranje severity of AD. Systemic therapy is necessary in roids (Huang et al. 2009 ; Paller et al. 2012 ). More only 10 % of severe and recalcitrant AD. The severe cases may require allergen avoidance and scoring atopic dermatitis (SCORAD) index, the more intense education and psychological sup- objective SCORAD, and the EASI are the most port for the family. Therefore, written instruction validated systems for evaluating the severity. plans and eczema school settings are important Follow-up may be evaluated by the target or the tools. A “fourth generation” of topical steroids, global scoring of the scratches, the edema, and including both mometasone and fl uticasone, the erythema, the so-called Three-Item Severity appears to have an improved therapeutic index (TIS) score (Oranje et al. 2007 ; Wolkerstorfer with less adverse effects noted after use for more et al. 1999 ). than 2 weeks. In the last 15 years, an alternative treatment Different variations of wet wrap techniques strategy was proposed that of continuous or proac- may be used in erythrodermic or severe refrac- tive therapy. Proactive therapy is an alternative, tory AD. The wet wrap technique is a modifi ed evidence-based, immunologically founded treat- occlusive treatment. The absorption of the topical ment approach based on the fact that the normal- corticosteroid is increased to 10 % under occlu- looking, non-lesional skin of patients with AD is sion, while hydration of the skin leads to a four- not normal (Gelmetti and Wollenberg 2014 ). In to fi vefold increase in absorption (Oranje et al. this approach the physicians do not stop the treat- 2006 ). This therapy with a potent diluted cortico- ment, but continue applying the creams or oint- steroid cream with minor systemic adverse ments twice weekly to sites where eczema was effects is not only an interesting and promising previously treated using a combined application of option in children but also in adults. The WWT is emollients or vehicles of the active drugs. At the usually more effective than treatment with the end of the 1990s, it was referred to as “step-down” topical immunomodulators (TIM) including therapy by Glazenburg, van der Meer, and Oranje. tacrolimus and pimecrolimus creams or oint- In these studies, a target screening test for severity ments. Both of these immunomodulatory drugs was introduced, named TIS by Wolkerstorfer and have demonstrated effi cacy when used in the Oranje (Van Der Meer et al. 1999 ). treatment of moderate and severe atopic dermati- Wet wrap treatment (WWT) for severe retract- tis. Toxicity has thus far been minimal with the able AD was also recently described as a proac- use of either agent. tive manner for long-term treatment (Janmohamed et al. 2014 ). Both the general and the specifi c aspects of topical management related to the pro- Bathing active treatment and the use of emollients in AD are described. There is no evidence-based information on the positive or negative effects of bathing and on the manner in which it should be done. In the Dutch General Aspects of Therapy guidelines for atopic eczema, it is stated that one should bathe shortly in lukewarm water 3 times The current therapy of AD is directed at sup- weekly [NHG standard text, 2014]. pressing the infl ammation and reducing the trig- I recommend daily bathing (maximum time of gering factors. Goals of the current standard 5 min), application of emollients, and the use of therapy are an improvement in the skin barrier synthetic soap substitutes (so-called syndets). function, the blocking of receptors, and a reduc- The use of diluted bleach baths in patients with tion of the infl ammatory infi ltrate. Most patients overt secondary skin infection in AD is very use- with AD respond to a regimen that consists of ful and diminishes the need for WWT [own obser- bleach baths at least 2–3 times weekly, antibiotic vations]. Diluted bleach baths with intermittent ointment for the nose, emollients, and topical ste- intranasal application of mupirocin ointment 2 Proactive Therapy in Atopic Dermatitis 13 decreased the clinical severity of atopic eczema in then 4 days per week for 4 weeks and then patients with clinical secondary skin infections attempt to reduce the frequency based on skin (Huang et al. 2009 ). clearance and symptoms. This treatment is currently still the approach used at our clinic also in WWT (Oranje 2014 ). Emollients and Atopic Dermatitis

Skin dryness is a highly important aspect of Proactive Therapy AD. The skin barrier function is impaired, allowing an easy penetration of bacteria, other micro- Proactive therapy as a term and a concept was organisms, allergens, and toxic substances into introduced in 2009 by Wollenberg and Bieber the skin. The role of the microbiome has become (Wollenberg and Bieber 2009 ). This is an alter- more and more relevant. native treatment that includes an intensive topi- Hydration of the skin may be improved by at cal anti-infl ammatory therapy until all lesions least twice daily or even more applications of have mostly cleared, followed by long-term, emollients (up to 6 times daily, although this is low-dose intermittent application of anti-infl am- often practically diffi cult for parents) with a matory therapy to the former affected areas com- hydrophilic base or containing approximately bined with daily applications of emollients to 5 % urea and/or lactic acid, if tolerated. unaffected areas (Tang et al. 2014; Thaçi et al. Emollients can be defi ned as bland moisturiz- 2008 ). This is completely different from reactive ers without active ingredients (Harcharik and treatment in which the treatment consists of Emer 2014 ). daily application of emollients and antiseptics Today, more and more moisturizers with dif- and topical anti-infl ammatory drugs if needed ferent added components are available in an (Darsow et al. 2013; Oranje 2014 ). Proactive attempt to repair the disrupted skin barrier func- therapy is in reality basically a little bit different tion. It is diffi cult to distinguish these products from the step-down therapy described earlier from active topical drugs. Direct topical use of (Hanifi n et al. 2002 ; Berth-Jones et al. 2003 ; emollients or moisturizers on actively infl amed Glazenburg et al. 2009; Van Der Meer et al. skin is poorly tolerated in AD (Gelmetti and 1999 ). Wollenberg 2014 ). Flares of AD need to be treated with wet dressings, topical corticosteroids, or topical calcineurin Education of the Parents inhibitors (Oranje 2014 ). A steroid- sparing effect by the use of emollients was claimed in two dif- Treatment with a proactive strategy demands ferent studies (Giordano-Labadie et al. 2006 ; much discipline from the parents and the patients Grimalt et al. 2007 ). (Wollenberg and Ehmann 2012 ; Tang et al. 2014 ). It means that you have to spend a lot of time training the parents: how to cope with pruritus, Step-Down (Step-Up) Therapy how to apply the creams or the ointments, and not in Maintenance Phase to stop the treatment early. There are four ways to manage this: teaching At the start of the treatment, a potent topical ste- programs for parents and patients, support by a roid preparation is applied daily for approxi- nurse practitioner, being readily available by mately 3–14 days; then a weaker topical steroid e-mail or via a website, and written instruction preparation is applied as needed to maintain plans. It is also essential that the parents under- eczema-free skin. An alternative is to apply the stand that AD cannot be cleared completely potent steroid preparation daily for 2 weeks and (Barbarot and Stalder 2014 ). 14 A.P. Oranje

Discussion impaired skin barrier function and hyperreactivity to irritant stimuli enhancing contact reactions. Reactive therapy was always the “golden stan- A positive effect of combining proactive treat- dard.” However, proactive treatment and step- ment with emollients may be that emollients down treatment changed this concept completely limit the use of therapies such as topical cortico- as reported in several studies (Oranje 2014 ; steroid creams/ointments and calcineurin inhibi- Wollenberg and Bieber 2009 ; Wollenberg et al. tor cream or ointments only to when they are 2009 ). A recent review on all these concepts of actually needed. It is also still unclear which induction of remission and treatment of a sub- emollients are the most effective and whether it is clinical or non-visible eczema showed that in 20 important to have a choice of different emollients of the 26 included studies, there was evidence of for different body sites. a subclinical infl ammation with a change from The skin of AD patients is highly colonized by normal-appearing skin or posttreatment lesion Staphylococcus aureus and other staphylococcal skin to active skin lesions in patients with species persisting in areas of dry skin as well in AD. Such subclinical infl ammation was reported mildly affected skin. The current hypothesis is to improve with proactive treatment aimed at that staphylococcal exotoxins are thought to act maintaining remission. Failure to achieve control as superantigens causing exacerbations of of AD symptoms with initial therapy was associ- eczema. Therefore, increased staphylococci col- ated with a higher risk of relapse in 14 random- onization/infection may be responsible for fl ares. ized controlled trials both with fl uticasone Reducing bacterial load will result in clinical propionate cream or ointment and with tacroli- improvement. mus ointment (Wollenberg et al. 2009 ; Oranje The human cutaneous microbiome is an eco- 2014 ; Tang et al. 2014 ). system composed of trillions of microorganisms Topical corticosteroids or topical calcineurin (bacteria, yeast, viruses, fungi, etc.), which colo- inhibitors are necessary to suppress and control nize the stratum corneum. Recently, it was AD, since fl ares only respond adequately to these reported (Grice 2014 ) that the microbiome or anti-infl ammatory drugs. For maintenance and to biofi lm in AD differs from that in normal skin. prevent recurrences, emollients and moisturizers Staphylococci form a biofi lm and play a domi- are highly important because of their nant role in the occlusion of sweat ducts leading corticosteroid- sparing or calcineurin inhibitor- to infl ammation and pruritus. sparing effects. Today, emollients are more Severe childhood AD was reported to be suc- sophisticated and attempt to restore the epider- cessfully treated with wet wraps (“wet pajamas”) mal barrier dysfunction and to supplement or and not only with diluted corticosteroids but also alter the shortcomings in the epidermis. with antiseptics illustrating once again the impor- Proactive treatment, emollient supplementa- tance of the biofi lm in AD (Allen et al. 2014 ; tion, and bleach baths in cases of overt secondary Oranje 2014 ). Possible future developments of infections are the key steps now in the modern moisturizers will include products with antibac- treatment of AD. terial activities that will restore a balanced micro- Emollients are widely used and are inexpen- biome in the damaged skin in AD. sive in most cases, but there are ever-increasing dangers of contact sensitization because of their complicated composition. Bulleted List of Controversies Contact sensitization or irritation by components of the emollients/moisturizers may worsen • Proactive treatment showed better results than the skin condition in AD and infl uence the course reactive treatment in which only a small num- and the severity of eczema, especially by the use of ber of patients experienced a long-term remis- complex composed moisturizers. Moreover, sensi- sion of eczema. tized atopic subjects may respond to very low con- • Proactive therapy in contrast to reactive centrations of contact allergens because of their therapy is an alternative, evidence-based, 2 Proactive Therapy in Atopic Dermatitis 15

immunologically founded treatment approach, Barbarot S, Stalder JF. Therapeutic patient education in based on the fact that normal-looking, atopic eczema. Br J Dermatol. 2014;170 Suppl 1:44–8. Berth-Jones J, Damstra RJ, Golsch S, Livden JK, Van non-lesional skin of patients with AD is not Hooteghem O, Allegra F, Parker CA, Multinational normal. Study Group. Twice weekly fl uticasone propionate • Proactive topical therapy is preferred above all added to emollient maintenance treatment to reduce other topical treatment schedules. It is a varia- risk of relapse in atopic dermatitis: randomised, double blind, parallel group study. BMJ. 2003;326:1367. tion of the step-up/step-down strategy (Van Darsow U, Wollenberg A, Simon D, Taïeb A, Werfel T, Der Meer et al. 1999 ; Glazenburg et al. 2009 ; Oranje A, Gelmetti C, Svensson A, Deleuran M, Calza Oranje 2014 ) that starts with intensive and AM, Giusti F, Lübbe J, Seidenari S, Ring J; European aggressive topical anti-infl ammatory therapy Task Force on Atopic Dermatitis/EADV Eczema Task Force. Diffi cult to control atopic dermatitis. World until control is achieved. Proactive treatment Allergy Organ J. 2013;6:1–6. is defi ned as “long-term, low dose intermittent Glazenburg EJ, Wolkerstorfer A, Gerretsen AL, Mulder topical anti-infl ammatory therapy for previ- PG, Oranje AP. Effi cacy and safety of fl uticasone pro- ously affected areas with subclinical infl am- pionate 0.005% ointment in the long-term maintenance treatment of children with atopic dermatitis: mation” (Wollenberg et al. 2009 ). differences between boys and girls? Pediatr Allergy • Both visible and non-visible eczemas are Immunol. 2009;20:59–66. treated with at least twice weekly application. Gelmetti C, Wollenberg A. Atopic dermatitis–all you can Aggressive active treatment is started again in do from the outside. Br J Dermatol. 2014;170 Suppl 1:19–24. case of recurrence. Giordano-Labadie F, Cambazard F, Guillet G, Combemale • Wet wraps with diluted corticosteroids are P, Mengeaud V. Evaluation of a new moisturizer excellent as a crisis intervention in severe child- (Exomega milk) in children with atopic dermatitis. hood cases and do not enhance the chances of J Dermatolog Treat. 2006;17(2):78–81. Grice EA. The skin microbiome: potential for novel diag- infections as suggested in a Cochrane review. nostic and therapeutic approaches to cutaneous dis- • Wet wraps improve the microbiome in AD by ease. Semin Cutan Med Surg. 2014;33:98–103. reducing the staphylococcal count and thus Grimalt R, Mengeaud V, Cambazard F, Study Investigators’ also improve eczema. Wet wraps with diluted Group. The steroid-sparing effect of an emollient therapy in infants with atopic dermatitis: a randomized corticosteroids for severe AD are an effective controlled study. Dermatology. 2007;214:61–7. therapy option for at least a period of 4 weeks. Hanifi n J, Gupta AK, Rajagopalan R. Intermittent dosing For longer-term proactive approach with of fl uticasone propionate cream for reducing the risk WWT is very useful and safe if supervised by of relapse in atopic dermatitis patients. Br J Dermatol. 2002;147:528–37. a nurse practitioner. Harcharik S, Emer J. Steroid-sparing properties of emol- • Emollients have become increasingly impor- lients in dermatology. Skin Therapy Lett. 2014; tant in the treatment of AD. In earlier years, 19:5–10. there were simply prepared creams or oint- Huang JT, Abrams M, Tlougan B, Rademaker A, Paller AS. Treatment of Staphylococcus aureus colonization ments. However, today there are more sophis- in atopic dermatitis decreases disease severity. ticated creams and ointments available in an Pediatrics. 2009;123:e808–14. attempt to repair the skin barrier function in Janmohamed SR, Oranje AP, Devillers AC, et al. The pro- AD. It is better to refer to these moisturizers. active wet-wrap method with diluted corticosteroids versus emollients in children with atopic dermatitis: a Future emollients or moisturizers are expected prospective, randomized, double-blind, placebo- to have specifi c properties to restore the bar- controlled trial. J Am Acad Dermatol. 2014;70: rier function even more effi ciently in AD. 1076–82. Oranje AP, Devillers AC, Kunz B, Jones SL, DeRaeve L, Van Gysel D, de Waard-van der Spek FB, Grimalt R, Torrelo A, Stevens J, Harper J. Treatment of patients with atopic dermatitis using wet-wrap dressings with References diluted steroids and/or emollients. An expert panel’s opinion and review of the literature. J Eur Acad Allen HB, Vaze ND, Choi C, Hailu T, Tulbert BH, Cusack Dermatol Venereol. 2006;20:1277–86. CA, Joshi SG. The presence and impact of biofi lm- Oranje AP, Glazenburg EJ, Wolkerstorfer A, de Waard- van producing staphylococci in atopic dermatitis. JAMA der Spek FB. Practical issues on interpretation of scor- Dermatol. 2014;150:260–5. ing atopic dermatitis: the SCORAD index, objective 16 A.P. Oranje

SCORAD and the three-item severity score. Br Van Der Meer JB, Glazenburg EJ, Mulder PG, Eggink J Dermatol. 2007;157:645–8. HF, Coenraads PJ. The management of moderate to Oranje AP. Evidence–based pharmacological treatment of severe atopic dermatitis in adults with topical fl uti- atopic dermatitis: an expert opinion and new expecta- casone propionate. The Netherlands Adult Atopic tions. Indian J Dermatol. 2014;59:140–2. Dermatitis Study Group. Br J Dermatol. 1999;140: Paller AS, Simpson EL, Eichenfi eld LF, Ellis CN, Mancini 1114–21. AJ. Treatment strategies for atopic dermatitis: opti- Wolkerstorfer A, de Waard van der Spek FB, Glazenburg mizing the available therapeutic options. Semin Cutan EJ, Mulder PG, Oranje AP. Scoring the severity of Med Surg. 2012;31(3 Suppl):S10–7. atopic dermatitis: three item severity score as a rough Tang TS, Bieber T, Williams HC. Are the concepts of system for daily practice and as a pre-screening tool induction of remission and treatment of subclinical for studies. Acta Derm Venereol. 1999;79:356–9. infl ammation in atopic dermatitis clinically useful? Wollenberg A, Bieber T. Proactive therapy of atopic der- J Allergy Clin Immunol. 2014;133:1615–25. matitis–an emerging concept. Allergy. 2009;64:276–8. Thaçi D, Reitamo S, Gonzalez Ensenat MA, Moss C, Wollenberg A, Ehmann LM. Long term treatment con- Boccaletti V, Cainelli T, van der Valk P, Buckova H, cepts and proactive therapy for atopic eczema. Ann Sebastian M, Schuttelaar ML, Ruzicka T, European Dermatol. 2012;24:253–60. Tacrolimus Ointment Study Group. Proactive disease Wollenberg A, Frank R, Kroth J, Ruzicka T. Proactive management with 0.03% tacrolimus ointment for chil- therapy of atopic eczema--an evidence-based concept dren with atopic dermatitis: results of a randomized, with a behavioral background. J Dtsch Dermatol Ges. multicentre, comparative study. Br J Dermatol. 2009;7:117–21. 2008;159:1348–56. Contact Allergy in Children: Diagnosis and Treatment 3

Flora B. de Waard-van der Spek

Abstract Sensitization to contact allergens can develop already at an early age. Neither sex nor the presence or absence of atopic dermatitis appeared to inﬂ uence the risk of ACD in children. ACD in children is not rare and should always be considered in children with recalcitrant eczema. Atopic dermatitis, skin barrier defects and intense or repetitive contact with allergens may play a role in the onset of early sensitization. A diagnosis of contact dermatitis is based on clinical examination and patch testing, requiring careful evaluation of a patient’s clinical history, physical examination and various types of skin testing (patch testing, photopatch testing, repeated open application test (ROAT)). It is important to test strictly based on the indication, using a standardized procedure, keeping in mind the limited surface available in children and the (low) potential risk of active sensitization. After reading the tests, patients require a clear explanation on positive tested allergens, where the allergen is likely to be encountered and, last but not least, the relevance of any positive test. Preventive strategies should be developed and optimized if new information becomes available, to reduce the incidence of ACD in children.

Keywords Allergic contact dermatitis • Contact allergy • Children • Patch tests • Allergens • ROAT • Repeated open application test • Sensitization

Contact dermatitis is a type of skin inﬂ ammation caused by contact with exogenous substances. Allergic contact dermatitis results from exposure to allergens, irritant contact dermatitis from F. B. de Waard-van der Spek , MD, PhD exposure to irritants. In this chapter the term Department of Dermatology , ‘allergen’ (referring also to ‘hapten’) will indi- Franciscus Gasthuis and Vlietland , cate substances causing the allergic response. Rotterdam/Schiedam , The Netherlands e-mail: [email protected] Phototoxic dermatitis occurs when the allergen

© Springer International Publishing Switzerland 2016 17 A.P. Oranje et al. (eds.), Practical Pediatric Dermatology, DOI 10.1007/978-3-319-32159-2_3 18 F.B. de Waard-van der Spek or irritant has to be activated by sunlight, to Diagnosis induce an infl ammatory skin reaction. Allergic contact dermatitis (ACD) corresponds to a If contact dermatitis is considered after a careful delayed-type hypersensitivity response. ACD is evaluation of a patient’s clinical history and the result of primary sensitization and secondary physical examination, various types of skin test- elicitation by allergy-provoking haptens. The ing are available (patch tests, photopatch tests, skin infl ammation is mediated by hapten-specifi c repeated open application tests (ROATs)). Patch T cells (Nosbaum et al. 2009 ). testing is the gold standard diagnostic test. ACD in children is not uncommon, and increasing (Simonsen et al. 2011 ; de Waard-van der Spek et al. 2013 ). Sensitization to contact Careful Evaluation of a Patient’s allergens can start in early infancy and continues Clinical History and Physical to be more common in older children. Likewise, Examination in adults, patch testing is the gold standard diagnostic test (Hammonds et al. 2009 ; Belloni Fortina A detailed history of the patients and information et al. 2011 ; de Waard-van der Spek et al. 2015 ). regarding the several forms of exposure are very The epidermal barrier has a crucial role in the important to obtain including domestic or leisure development of sensitization and elicitation of activities, personal or family history of eczema, ACD. Filaggrin (FLG) has a key role in maintain- asthma and hay fever, known allergies, exposure to ing an effective skin barrier against the external medications (topical or systemic) and skin care prod- environment. Thyssen et al. reported individuals ucts. The clinical symptoms and the localization of with FLG mutations and an increased risk of the lesions should be examined carefully. Localized nickel sensitization (Thyssen et al. 2013 ). dermatitis, uncontrolled or deteriorating (atopic) der- The onset of early sensitization in children matitis or a history of reacting to a specifi c allergen may be infl uenced by several factors, like atopy, give rise to suspicion of infl uence of an external trig- in particular atopic dermatitis, skin barrier ger. The patient usually thinks the dermatitis to be of defects and intense or repetitive contact with an allergic nature; however, most contact dermatitis allergens (Thyssen et al. 2014 ). The most fre- is caused by irritating factors (Nosbaum et al. 2009 ). quent contact allergens in children are metals, A constitutionally compromised skin may be more fragrances, preservatives, neomycin, rubber easily infl uenced by external allergens or irritants. chemicals and, more recently, also colourings (Mortz and Andersen 1999; Mortz et al. 2002 ; Barros et al. 1991 ; Dotterud and Falk 1995 ; Skin Testing Weston et al. 1986 ; Simonsen et al. 2014; de One has to realize that only an allergen that Waard-van der Spek et al. 2013 , 2015; Admani is tested can be detected. and Jacob 2014 ). Selection of Patch Test Materials Children with a suspicion of allergic contact der- The European Environmental Contact matitis, for example, because of recalcitrant eczema, Dermatitis Research Group (EECDRG) should be patch-tested with a selection of allergens recommends a European baseline series for having the highest proportion of positive, relevant adults (Andersen et al. 2011 ; Bruze et al. patch test reactions, taking into account allergen 2008 ; Johansen et al. 2015 ). exposure pattern that differs between age groups. The Task Force Allergic Contact It is of great importance that children are Dermatitis in Children of the European patch-tested using a standardized protocol. Keep Academy of Allergy and Clinical in mind that negative patch test results do not Immunology (EAACI) produced, based on fully exclude allergic contact dermatitis: false- consensus, a baseline series of test aller- negative reactions can, among others, be due to a gens to be tested in children with suspected ‘missed’ allergen. Detailed further questioning ACD (de Waard-van der Spek et al. 2015 ) may make this apparent. 3 Contact Allergy in Children: Diagnosis and Treatment 19

The history and examination of a patient patches (in most clinics on day 2, after occlusion may provide clues to the possible causative for 48 h) and the second 2–5 days later (Lindberg external factors or sensitizers. These should and Matura 2011; Rietschel et al. 1988). The guide the choice of (supplementary) patch test internationally accepted recording system for materials. reading patch tests was originally developed by In addition to the commercially available test the International Contact Dermatitis Research materials, it is useful to test samples of own mate- Group (ICDRG) (Wilkinson et al. 1970 ) and is rials brought in by the patients. However, this shown in Table 3.1 . Some allergens are ‘late requires additional information about the con- reactors’ and may induce a delayed positive tents. One has to avoid testing with irritants and reaction. Patients are to be instructed to report corrosive compounds. back any additional positive reaction appearing Supplementary patch tests are advised to be after the test. undertaken on indication. Leave-on products can Some allergens, like cinnamaldehyde, are be tested as is and rinse-off products have to be responsible for immediate urticarial reactions. diluted to prevent irritating reactions. If the history suggests an immediate-type reac- Although it is not common, one of the most tion, it is useful to remove the tests shortly serious adverse reactions from patch testing is sen- after 20 min application and reapply immedi- sitization induced by the procedure itself (active ately at the same site. A positive (urticarial) sensitization). reaction after 20 min may reﬂ ect the existence of a contact urticaria syndrome that may eventually coexist with allergic contact dermatitis Test Technique (Goossens 2011).

A small amount of the suspected allergen in a suitable concentration and vehicle is applied on the skin, usually at the back. Avoid patch Diffi culties in Interpretation and testing at skin sites presenting currently or Complications in Patch Testing recently any type of dermatitis. The patient is In the fi nal decision, the patch test reac- instructed not to bath or shower for the durations must be related to the clinical history. tion of the test, to avoid wetting the test site, Assessing (current or past) relevance is a and to avoid other activities that are likely to diffi cult but intricate part of the test proce- dislodge the discs or cause sweating. Several dure. A patch test may also be positive circumstances may interfere with the patch test because of cross-reaction with another results, like acute dermatitis, intensive UV allergen that is of clinical relevance. exposure or long-term pretreatment with topi- Diffi culties in distinguishing allergic from cal corticosteroids. Immunosuppressive or irritant reactions and ascribing the rele- immunomodulating drugs may also infl uence vance of an allergic reaction have to be patch test results. Patch testing should prefer- dealt with. ably not be performed under circumstances False-positive reactions are positive that may interfere with the results. If it is not patch test reactions in the absence of con- possible to interrupt the use of certain medica- tact allergy. These are mainly related to tion, interpretation of the test results needs misinterpretation of the results, for exam- great caution. ple, by using inadequate concentrations of allergens or irritating vehicles, by testing despite current or recent dermatitis at Reading Patch Tests the test site or by interpreting adhesive tape reactions as positive patch test At least two readings of the patch test reactions reactions. are recommended, the fi rst after removal of the 20 F.B. de Waard-van der Spek

Table 3.1 Recording of patch test reactions according to There is a risk of active sensitization by the the International Contact Dermatitis Research Group tested allergens; however, this risk is considered ± Doubtful reaction, faint erythema only to be very uncommon. A fl are-up reaction at the + Weak positive reaction, erythema and homogenous test site 10 days after application could be infi ltration, possibly papules induced by active sensitization (Cronin 1980 ). ++ Strong positive reaction, erythema, infi ltration, On repeated testing, the reaction is usually papules and vesicles already positive by days 2–4. However, late reac- +++ Extreme positive reaction, intense erythema, infi ltration and coalescing vesicles tions may occur, appearing after day 7, being IR irritant reaction of different types explained by a delayed immune response (Jensen NT not tested et al. 2006; Gawkrodger and Paul 2008). It is NTS not tested, previously documented positive important to avoid patch testing with unknown reaction substances or formulations (Bygum and Data from Wilkinson et al. (1970 ) Andersen 1998 ). It is still very important to test the patient’s own materials (including cosmet- False-negative reactions can be defi ned as ics) because these may contain relevant sensitiz- negative patch test reactions, while a contact ers. Of course, necessary precautions have to be allergy is present. Common causes are use of too taken (Uter et al. 2005 ; de Waard-van der Spek low concentration or insuffi cient amount applied et al. 2013 ). of the allergen tested, present adjuvant factors (insuffi cient occlusion, poor adhesion, sweating, friction), pretreatment of the test site (UV light, Use Test/Repeated Open Application corticosteroids or immunomodulators) or failure Test (ROAT) to include late readings. Multiple (false-positive) patch test reactions Patch tests are vastly different from normal use may be caused by enhanced skin reactivity, in conditions. The tests can be completed by the patients with both active dermatitis as well as provocative use testing of sensitized subjects. strong positive allergic patch test reactions. These When dermatitis occurs after repeated exposure reactions are not reproducible. Mitchell (1975 ) or after the use of products such as cosmetics on coined the term ‘angry back syndrome’ also sensitive skin areas such as the face and a nega- known as ‘excited skin syndrome’. It is recom- tive patch test result is obtained, use tests and/or mended to retest each allergen, preferably on a ‘repeated open application tests’ (ROATs) are different skin site (Andersen et al. 1993 ; Bruynzeel recommended, to approximate the use situation and Maibach 1990 ). as nearly as possible. Compound allergy is an allergic contact der- With ROATs, approximately 0.1 ml of the test matitis in which a formulated product is believed material is applied twice daily to the fl exor aspect to be allergenic on patch testing, for example, of the forearm near the cubital fossa, to an area of cosmetic creams or topical medicaments, with approximately 5 × 5 cm. The results are inter- negative patch test results to its individual ingre- preted after 1 week; however, at times, ROATs dients. Some or all of those ingredients must have must be performed up to 21 days, particularly interacted to form a new reactive allergen, or the with low-concentrated allergens to reveal an ingredients were patch-tested at concentrations allergic reaction (Goossens 2007 ). that were too low to elicit a true-positive reaction (Kelett et al. 1986 ; Smeenk et al. 1987 ; Bashir et al. 2000 ). The actual manufacturing grade ACD in Children: Some Specifi c ingredients directly from the company may be Conditions and Presentations preferably used for patch testing in specifi c cases (Orton and Shaw 2001 ; Clemmensen et al. 2007 ; Factors that may infl uence early sensitization in Stausbøl-Grøn and Andersen 2007 ). children are factors and skin diseases inducing 3 Contact Allergy in Children: Diagnosis and Treatment 21 skin barrier defects, like atopic dermatitis, and followed by cobalt (2.3 %), colophony (2.0 %), thi- contact at an early age with several allergens. merosal (1.4 %) and p-phenylenediamine (1.1 %). Next to many persistent nickel reactions, a signifi - cant number of new nickel sensitizations were Atopic Dermatitis found. Nickel was still the most common contact allergen. New sensitizations do occur despite the ACD is not rare in children with atopic dermatitis EU nickel regulation (Mortz et al. 2013b ). (AD) (Oranje et al. 1994 ; Clayton et al. 2006 ; de Antiseptics, like chlorhexidine, and emol- Waard-van der Spek and Oranje 2009 ; de Waard- lients may be causes of contact allergy to topical van der Spek et al. 2013 , 2015). The role of contact treatment in children with atopic dermatitis allergy in AD patients is frequently underesti- (Mailhol et al. 2009). Topical corticosteroids mated. Several studies have indicated a similar may be sensitizing. If topical corticosteroids are prevalence of ACD in patients with AD and non- tested by patch tests, the readings after 48 and atopics (Goon and Goh 2006 ; Roul et al. 1999 ; de 72 h may be negative, due to the initial anti- Waard-van der Spek et al. 2013 ; Vender 2002 ; Zug infl ammatory effect of the steroids. Therefore a et al. 2008 ; Duarte et al. 2003 ). However, evidence delayed reading at day 7 or even later is recom- to support lower rates of ACD in atopics has been mended (Mailhol et al. 2009 ; Uter et al. 2009 ; mentioned too (Rystedt 1985 ). A higher rate of Kränke et al. 1996 ). In patients with atopic der- false-positive reactions (Lammintausta et al. 1992 ) matitis, sensitization to bufexamac, a non- and increased irritancy in patients with chronic steroidal anti-infl ammatory drug with limited (atopic) dermatitis has been reported. The fre- evidence for effectiveness, has been observed quency of irritant reactions seemed to correlate (Heine et al. 2006 ; Mailhol et al. 2009 ). The both with higher numbers of ACD responses and European Medicines Agency’s Committee for with the presence of atopy (Klas et al. 1996 ). The Medicinal Products for Human Use (CHMP) has impaired skin barrier function and hyper-reactivity recommended that bufexamac-containing medi- to irritant stimuli in patients with atopic dermatitis cines should be taken off the market across the may enhance contact reactions in sensitized atopic European Union (Uter and Schnuch 2011 ). subjects and induce a response to very low con- Atopic patients are at a signifi cant risk of centrations of contact allergens (Seidenari and developing allergic and irritant contact dermatitis. Giusti 2006 ). ACD in childhood may affect decisions regarding The frequency of contact sensitization in chil- future occupations in adulthood. That is why it is dren 5 years and older and adults with AD ranged very important to develop and optimize preven- from 41 to 64 % according to observations, sup- tive strategies to reduce the incidence of occupa- porting the importance of systematic patch testing tional dermatitis in AD patients (Paulsen et al. in atopic patients, adults and children, from age 5 2008 ; Darsow et al. 2010 ; de Waard-van der Spek and, if suspected, earlier at any age. Common et al. 2013 ). contact sensitizers are, among others, metals and fragrance, neomycin and lanolin. Preventive measures from an early age should be introduced to Emollients and Skin Care Products avoid contact with common contact sensitizers in children, like nickel-containing objects, perfumed Emollients or moisturizers help reducing water cosmetics and products or topical medication loss from the epidermis. Emollients keep the skin including lanolin and neomycin in AD patients moist and supple by providing a protective fi lm. (Heine et al. 2006 ). For patients with dry skin, for example, patients A follow-up study in 1206 young adults from a with atopic dermatitis, emollients are an essential cohort of 1501 unselected 8th-grade schoolchil- part of daily skin care. Emollients are considered dren established 15 years ago showed that nickel as the mainstay of maintenance therapy and are was the most common contact allergen (11.8 %), also used as an additional in-between supportive 22 F.B. de Waard-van der Spek therapy in ACD. Correct use of emollients may Natural Remedies reduce the amount of corticosteroids necessary for effective treatment (Grimalt et al. 2007 ). Plant extracts and herbal remedies have become Certain moisturizers could improve skin barrier very popular. The use of herbal medicinal products, function in atopics and reduce their skin suscep- ‘natural remedies’ and supplements is increasing. tibility to irritants (Lodén et al. 1999 ). These products are generally considered to be safe. An emollient consists of carrier-containing It is important to realize that some of these products lipophilic components (oils or waxes) and/or contain potential sensitizers and may induce allergic hydrophilic components (water, moisturizer, gels) contact dermatitis (Kütting et al. 2004 ). One and other ingredients (like moisturizers, emulsifi - example is tea tree oil. This oil has to be kept in the ers and preservatives). Glycerin seems to be well dark, and ‘older’ tea tree oil becomes a strong tolerated in younger children (Lodén et al. 1999 ). sensitizer due to oxidation. Urea causes a burning sensation in infants and Other examples of natural remedies with sensi- very young children. Propylene glycol is fre- tizing properties are balsam of Peru, a resin of quently irritating in children younger than 2 years exotic plant Myroxylon pereirae, a quite common and can cause irritant contact dermatitis, allergic component of natural remedies, next to its use as contact dermatitis and non- immunologic contact fragrance and food fl avouring agent, and propolis urticaria (Funk and Maibach 1994 ). (bee glue), advocated for decades as natural Many additives are potential contact remedy for all kinds of dermatological diseases, sensitizers (Wolf 2009 ). which contains many potential contact sensitizers Only emollient preparations devoid of pro- (Hausen 2005 ; Bonitsis et al. 2011 ; Piętowska teins and allergens should be used, especially in et al. 2008 ; Czarnobilska et al. 2011 ). young children. Apart from the specifi c hypersensitivity, mari- Skin care products contain leave-on and rinse- gold (Calendula offi cinalis ), belonging to the off products. Most cases of ACD to skin care prod- Compositae family, is also known to cause irritant ucts are caused by leave-on cosmetics. Causative as well as phototoxic reactions (Hausen 2004 ; allergens are, among others, formaldehyde- Jacob et al. 2008 ). releasers, methyldibromoglutaronitrile (MDBGN), There is a considerable risk that the sensitiza- cocamidopropyl betaine and methylchloroisothia- tions to natural remedies in children remain zolinone/methylisothiazolinone (MCI/MI), pre- undiagnosed, if natural remedies used by the servatives which are added to water-containing patients, like balsam of Peru and propolis, are not cosmetics (personal care products and toiletries) to included into patch testing. It is important to prevent the growth of microorganisms (Jensen always ask about recently used natural remedies. et al. 2004 , 2005 ; de Groot et al. 2010 ). The risk of Patients and their parents often neglect to mention developing ACD from rinse-off products such as this spontaneously (Kütting et al. 2004 ). soaps, shampoos and shower foams has been less studied (Uter et al. 2005 ). Especially in case of rinse-off products, one Juvenile Plantar Dermatosis and Foot has to be aware of false-positive reactions. These Eruptions rinse-off products remain on the body for a very short period of time. For patch testing, a 1 % dilu- Foot eruptions in children are usually self- tion in water is commonly recommended, or a limiting. If symptoms persist and are resistant to dilution series in a reasonable concentration treatment, allergic contact dermatitis must be range. It is usually safe to patch test leave-on considered (Teixeira et al. 2005 ). In children with products as is. Emollients should be included into plantar dermatoses, a mixed clinical picture of the series whenever personal care products are atopy associated with ACD may be present. patch-tested (Fonacier and Aquino 2010 ; de Many patients referred to the clinic because of a Waard-van der Spek et al. 2013 ). suspected ACD to shoe materials are ultimately 3 Contact Allergy in Children: Diagnosis and Treatment 23 diagnosed with infantile plantar dermatosis. The shoes or identifi ed allergens is often suffi cient to high prevalence of this atopic manifestation may alleviate the symptoms of ACD to materials from lead to a misdiagnosis in some cases. In a study shoes. evaluating the relevance of all patch tests performed in children with dermatoses of the soles between 1997 and 2009, rubber additives and Shin Guards potassium dichromate were the most frequent allergens identifi ed in these children (<18 years). Playing soccer or hockey is very popular among Forty-eight percent of children with infl amma- children and adolescents, and protective shin tory dermatitis of the sole and 29 % of children guards are used by many people worldwide. with JPD had at least one relevant reaction However, reports of allergy to shin guards are (Darling et al. 2012 ). sparse, while these shin protectors are often made Contact dermatitis to shoes has not been studied of materials known to cause allergies. Friction extensively in children (de Waard-van der Spek and moisture from the use of shin guards during et al. 2013 ). The anatomical site of primary sport activities would seem to predispose soccer dermatosis may point on the source of eliciting players to the development of an allergic response sensitizers, e.g. rubber chemicals found in modern (Powell and Ahmed 2010 ). Weston has published footwear. a retrospective analysis of eight children aged The prevalence of ACD because of shoes 9–16 years evaluated for a persistent or recurrent seems low; however, irritant contact dermatitis dermatitis that appeared under soccer shin and infantile plantar dermatitis are frequent, so guards. Irritant contact dermatitis (ICD) seemed the need for differential diagnosis and patch tests to be the diagnosis in these subjects, induced is high (Roul et al. 1996 ). mainly by sweating and friction (Weston and Eczema of the dorsal feet in atopic patients Morelli 2006 ). However, some of the patients requires patch testing for possible ACD; in more with suspected ICD also showed allergic sensiti- exceptional cases, ACD may present as eczema zation in another study on soccer shin guard on the plantar surfaces. In a prospective study of eruptions (Powell and Ahmed 2010 ). De Waard- 79 children with suspected ACD, material from van der Spek ( 2009) reported positive allergic own shoes together with other frequent sensitizers patch test reactions in fi ve boys aged 9–10 years was tested in atopic and non-atopic children with to contact material from shin guards. All suffered foot eczema. Six children showed an allergic from shin eczema, three of them had atopic der- patch test reaction to their own shoes; three of matitis (de Waard-van der Spek 2009 ). In shin them were atopic. One child wore a blue leather guards, rubber components and thiourea deri- case around his lower leg because of walking vates were the most common sensitizers. problems, which caused a positive allergic patch test reaction. Other positive allergic patch test reactions in these children were to potassium Tattoos dichromate (3 children), p -tert-butylphenol formaldehyde resin (2 children), formaldehyde (1 Temporary black henna tattooing is popular child), p -phenylenediamine (PPD; 2 children), among children and young adults in some regions. diethyl urea (1 child) and disperse red (1 child) Henna is a greenish brown vegetable dye that (de Waard-van der Spek 2009 ). Together with pre- rarely causes allergic contact dermatitis. The vious studies, these data demonstrate that contact addition of products to darken the colour of pure allergy to shoe materials can be found in both henna has been the cause of many dermatoses due atopic and non-atopic children with foot eczema. to the so-called black henna. P- phenylenediamine The most common sensitizers present in shoes (PPD) is added to increase the intensity of the resulting in ACD are potassium dichromate, PPD, colour and may cause severe hypersensitivity PTBF resin and nickel. Avoiding the causative reactions. Temporary tattoos painted with 24 F.B. de Waard-van der Spek

PPD-contaminated henna may have perma- dye, cyclohexylthiopthalimide, PTBF resin and nent consequences. Extreme patch test reactions sorbitan sesquioleate. Heat and humidity may play to PPD are not uncommon. PPD is also used as a a role in the potential release of chemicals from the permanent hair-colouring agent and as an product or absorption of chemicals into the skin accelerator for rubber vulcanization. Cross- (Giusti et al. 2002 ; Smith and Jacob 2009 ; Roul reactive chemical compounds are azo dyes, sul- et al. 1998; Karlberg and Magnusson 1996 ). phonamides, p-aminobenzoic acid sunscreens and Allergic contact dermatitis may result from poten- local anaesthetics such as benzocaine or procaine. tial sensitizers in the diaper itself but can also be Exposure to ‘black henna’ tattoos and to hair dyes caused by products applied to the skin of the dia- are the main cause of strong patch test reactions to per area by caregivers (Table 3.2 ). The caregivers PPD in children aged 14 years and younger themselves may also develop ACD to these (Spornraft-Ragaller et al. 2012 ). The application products. Such diaper-associated dermatitis could, of temporary henna tattoos in children should be for example, be caused by sorbitan sesquioleate discouraged because of the potentially serious used as an emulsifi er in topical preparations (emol- consequences of sensitization to PPD in the lients, bottom balms), fragrances and preservatives future, including severe ACD from hair dyes and (iodopropylcarbamate and bronopol) found in cross-reactive chemical compounds (de Waard- baby wipes (Smith and Jacob 2009 ). van der Spek et al. 2009 , 2013 ; Neri et al. 2002 ; Alberta et al. reported fi ve patients aged 9 Marcoux et al. 2002 ; Sosted et al. 2006 ; Jacob months to 3 years with suspected ACD in response et al. 2008 ; Almeida and Borrego 2009 ). to the various blue, pink and green dyes in diapers (Alberta et al. 2005 ). Patch testing was performed in two patients, resulting in positive reactions Diapers (erythema, oedema and papules) to different disperse dyes. The diaper rash resolved in all the fi ve Diaper dermatitis is a common cutaneous condi- patients upon the use of dye-free diapers. tion characterized by an acute infl ammatory ‘Lucky Luke’ dermatitis, a particular pattern eruption of the skin in the diaper area. Irritant of diaper dermatitis, reminiscent of a cowboy’s diaper dermatitis is caused by friction and gun belt holsters, develops because of the sensiti- maceration of the nappy area, prolonged contact zation to rubber components in diapers. This with urine, faeces and faecal enzymes and the variant is localized on the outer buttocks and the secondary development of ammonia by faecal hips (Roul et al. 1998 ; Landro et al. 2002 ; bacterial fl ora and may be complicated by the Belhadjali et al. 2001 ). presence of Candida albicans and infl ammatory Allergic contact dermatitis should be considered bacteria. In irritant diaper dermatitis, the skin in the differential diagnosis of therapy-resistant folds are usually spared (Pigatto et al. 2010 ). The exact prevalence of diaper ACD is unknown but is seems to be very low. Table 3.2 Causes of allergic contact dermatitis in the diaper region Allergic contact dermatitis is rarely a differential diagnostic problem in the spectrum of diaper Sensitizers in Disperse dyes (in coloured diapers) the diaper Rubber components (e.g. dermatitis, but it may be considered in children itself mercaptobenzothiazole, cyclohexyl who are not responsive to the usual treatment for thiophthalimide) irritant diaper dermatitis. It was suggested that Glue (e.g. paratertiary butyl sensitization to an allergen can be enhanced by a formaldehyde resin) wet environment such as that under a diaper (Smith Sensitizers in Emollients or bottom balms: topical used emulsifi ers (e.g. sorbitan and Jacob 2009 ). Allergic contact dermatitis to products sesquioleate) diaper-associated chemicals has been reported in Baby wipes: fragrances, children, with the most common allergens being preservatives (e.g. mercaptobenzothiazole, fragrance mix, disperse iodopropylcarbamate, bronopol) 3 Contact Allergy in Children: Diagnosis and Treatment 25 diaper dermatitis. Improved product design, pro- corticosteroid side effects such as the face and duction of dye-free diapers, using superabsorbent body folds. Topical coal tar (TCT) preparations polymers and vapour permeable back sheets may form another alternative or adjuvants to topical explain the decline in observed diaper dermatitis corticosteroids (Roelofzen et al. 2007 ). among infants (Runeman 2008 ).

Prognosis Toys There is currently very little data on the natural Toys are a commonly overlooked source allergen history of ACD in children. exposure and sensitization. Examples are toy The course of nickel allergy and clinically cosmetic products, such as perfumes, lipstick relevant nickel dermatitis over 15 years from and eye shadow. Fragrances are important aller- adolescence to adulthood has been studied in gens in toys (Rastogi et al. 1999 ). Toys may also Denmark. A high prevalence and a high inci- release nickel and be a potential source in the dence rate of nickel allergy have been found in manifestation of allergic contact dermatitis. The the study population, despite implementation of presence of nickel, chromium and cobalt in cos- the nickel regulation in Denmark. Most reac- metics is prohibited by European Law. However, tions from childhood could be reproduced and toy make-up such as lipstick, lip gloss and pow- were clinically relevant (Mortz et al. 2013a , b ). dery eye shadow has been occasionally found to A long-term follow-up study to uncover the contain nickel, chromium and cobalt at sensiti- course of skin symptoms and the impact of per- zation levels, exceeding the recommended sistent eczema on life quality in children referred 5 ppm limit (Rastogi et al. 1999). Nickel is also for patch testing indicated a signiﬁ cant risk of found in more conventional toys such as cos- childhood eczema becoming chronic and affect- tume jewellery (Hsu and Jacob 2009; Fischer ing life quality considerably. Patch testing did et al. 2005 ). not affect the course of eczema, highlighting the difﬁ culties of avoidance behaviour (Simonsen et al. 2015 ). Treatment

The symptomatic treatment is aimed at reducing Conclusion and Advice skin infl ammation, as well as restoring the epidermal barrier defect. Emphasis has to be put on Sensitization to contact allergens can develop at the proper use of topical medication as well as an early age. The risk of ACD in children is not avoidance of factors that may negatively infl u- being infl uenced by sex or the presence or ence the disease. The defi nitive treatment of absence of atopic dermatitis. ACD in children is allergic contact dermatitis is the identifi cation not rare and should always be considered in chil- and removal of any potential causal agents. If that dren with recalcitrant eczema. Factors that may cannot be achieved, the patient is at increased infl uence the onset of early sensitization in chil- risk for chronic or recurrent dermatitis. Topical dren are skin barrier defects in atopic dermatitis. corticosteroids are the mainstay of treatment. Contact allergens have to penetrate the epidermal Emollients are used to alleviate skin dryness and barrier to be able to elicit a specifi c immune restore part of the defective epidermal barrier. An response. Intense or repetitive contact with aller- alternative to topical corticosteroids became gens can lead to ACD. Patch testing is indicated available after the discovery of topical calcineu- to confi rm ACD. Negative patch test results do rin inhibitors (Ashcroft et al. 2005 ). Their unique not fully exclude allergic contact dermatitis. safety profi le makes them a valid treatment False-negative reactions may be due to a missing alternative, especially on body areas prone to causative allergen. Further detailed history taking 26 F.B. de Waard-van der Spek may help to identify an important supplementary Consider the role of toys in the evaluation of allergen to be tested. children with dermatitis. Toys are another impor- A diagnosis of contact dermatitis requires care- tant source allergen exposure in children, espe- ful evaluation of a patient’s clinical history, physi- cially from toy cosmetic products. cal examination and various types of skin testing The defi nitive treatment of allergic contact (patch testing, photopatch testing, repeated open dermatitis is the identifi cation and removal of any application test (ROAT)). A basic list of allergens potential causal agents. If that cannot be achieved, is advised to be tested in children with suspected the patient is at increased risk for chronic or allergic contact dermatitis, partly dependant on recurrent dermatitis. Topical corticosteroids are suspected history. Additional tests should be per- the mainstay of treatment. Emollients are used to formed only on indication (special history or clini- alleviate skin dryness and restore part of the cal fi ndings, age). The list may be extended with defective epidermal barrier. Alternatives to topi- environment/country-based common allergens. cal corticosteroids are topical calcineurin inhibi- The internationally accepted recording system tors and topical coal tar. for reading patch tests was originally developed ACD in children is not rare, and children by the ICDRG. In the fi nal decision, the test should be tested strictly based on the indication, results must also be related to the clinical history, using a standardized procedure, keeping in mind taking into account the possibility of cross- the limited surface available and the potential risk reactions. Patients require a clear explanation on of active sensitization. Patients require a clear any allergies, where the allergen is likely to be explanation on any allergies, where the allergen is encountered and the relevance of any positive test. likely to be encountered, and the relevance of any The role of contact allergy in AD patients is fre- positive test. Good information on preventing the quently underestimated. Additives in emollients development of ACD in children is important, not contain potential contact sensitizers. Children with only for health care workers but also for the care- moderate-to-severe atopic dermatitis whose condi- givers. It is still better to prevent than to cure. tion is refractory to treatment or whose history is suggestive of allergic contact dermatitis have a clear indication for systematic patch testing. Bulleted List of Controversies Furthermore, prevention through exposure avoidance from an early age to the most frequent con- • Allergic contact dermatitis in children is not tact sensitizers, like fragrances and nickel in rare and the prognosis is unclear. patients with atopic dermatitis, is very important. • Sensitization to contact allergens can develop Contact dermatitis to shoe materials has not already at an early age. been extensively described in children, and • Neither sex nor the presence or absence of reports of allergy to shin guards are sparse. atopic dermatitis appears to infl uence the risk Irritant contact dermatitis is in most cases men- of ACD in children. tioned as the cause of the sharply demarcated • Children should be tested strictly based on the dermatitis on the lower legs. True contact sensiti- indication, using a standardized procedure. zation has also been observed. Rubbers and thio- • Only an allergen that is tested can be detected. ureas are the most common allergens. • Negative patch test results do not fully exclude Temporary tattoos painted with PPD- allergic contact dermatitis. contaminated henna may have permanent conse- • The fashion of having temporary henna tat- quences. The application of temporary henna toos in children should be discouraged because tattoos in children needs to be discouraged. There of the potentially serious consequences of are also risks of serious consequences in the future sensitization to PPD in the future. of sensitization to PPD. Diaper allergic contact • The defi nitive treatment of allergic contact dermatitis may be considered in the differential dermatitis is the identifi cation and removal of diagnosis of persisting diaper dermatitis. any potential causal agents. 3 Contact Allergy in Children: Diagnosis and Treatment 27

References Clemmensen A, Thorman J, Andersen KE. Allergic contact dermatitis from retinyl palmitate in polycaprolac- tone. Contact Dermatitis. 2007;56:288–9. Admani S, Jacob SE. Allergic contact dermatitis in chil- Cronin E. Contact dermatitis. Edinburgh: Churchill dren: review of the past decade. Curr Allergy Asthma Livingstone; 1980. p. 15. Rep. 2014;14(4):421. Czarnobilska E, Obtulowicz K, Dyga W, Spiewak R. The Alberta L, Sweeney SM, Wiss K. Diaper dye dermatitis. most important contact sensitizers in Polish children Pediatrics. 2005;116(3):e450–2. and adolescents with atopy and chronic recurrent Almeida PJ, Borrego L. Temporary henna tattoos with eczema as detected with the extended European long-term consequences. Med J Aust. 2009;191:11–2. Baseline Series. Pediatr Allergy Immunol. 2011; Andersen KE, Liden C, Hansen J, Vølund AA. Dose- 22(2):252–6. response testing with nickel sulphate using TRUE test Darling MI, Horn HM, McCormack SKA, Schofi eld in nickel-sensitive individuals. Multiple nickel sul- OMV. Sole dermatitis in children: patch testing revis- phate patch-test reactions do not cause an “angry ited. Pediatr Dermatol. 2012;29(3):254–7. back”. Br J Dermatol. 1993;129:50–6. Darsow U, Wollenberg A, Simon D, et al. ETFAD/EADV Andersen KE, White IR, Goossens A. Chapter 31. eczema task force 2009 position paper on diagnosis Allergens from the European baseline series. In: and treatment of atopic dermatitis. J Eur Acad Johansen JD, Frosch PJ, Lepoittevin JP, editors. Dermatol Venereol. 2010;24:317–28. Contact dermatitis. 5th ed. Berlin/Heidelberg: Springer; Dotterud LK, Falk ES. Contact allergy in relation to hand 2011. p. 545–90. eczema and atopic diseases in north Norwegian Ashcroft DM, Dimmock P, Garside R, et al. Effi cacy and schoolchildren. Acta Paediatr. 1995;84:402–6. tolerability of topical pimecrolimus and tacrolimus in Duarte I, Lazzarini R, Kobata CM. Contact dermatitis in the treatment of atopic dermatitis: meta-analysis of adolescents. Am J Contact Dermat. 2003;14:200–2. randomised controlled trails. BMJ. 2005;330(7490):516. Fonacier LS, Aquino MR. The role of contact allergy in Barros MA, Baptista A, Correia TM, Azevedo F. Patch atopic dermatitis. Immunol Allergy Clin North Am. testing in children: a study of 562 schoolchildren. 2010;30(3):337–50. Contact Dermatitis. 1991;25:156–9. Fischer LA, Menné T, Johansen JD. Experimental nickel Bashir SJ, Kanerva L, Jolanki R, Maibach HI. Occupational elicitation thresholds—a review focusing on occluded and non-occupational compound allergy. In: Kanerva nickel exposure. Contact Dermatitis. 2005;52:57–64. L, Elsner P, Wahlberg JE, Maibach HI, editors. Funk JO, Maibach HI. Propylene glycol dermatitis: re- Handbook of occupational dermatology. Berlin: evaluation of an old problem. Contact Dermatitis. Springer; 2000. p. 351–5. 1994;31(4):236–41. Belhadjali H, Giordano-Labadie F, Rance F, Bazex Gawkrodger DJ, Paul L. Late patch test reactions: delayed J. ‘Lucky Luke’ contact dermatitis from diapers a new immune response appears to be more common than allergen? Contact Dermatitis. 2001;44(4):248. active sensitization. Contact Dermatitis. Belloni Fortina A, Romano I, Peserico A, Eichenfi eld 2008;59:185–7. LF. Contact sensitization in very young children. J Am Giusti F, Mantovani L, Martella A, Seidenari S. Hand der- Acad Dermatol. 2011;65(4):772–9. matitis as an unsuspected presentation of textile dye Bonitsis NG, Tatsioni A, Bassioukas K, Ioannidis contact sensitivity. Contact Dermatitis. 2002;47:91–5; JP. Allergens responsible for allergic contact dermati- 994; 31(4): 236–241. tis among children: a systematic review and meta- Goon AT, Goh CL. Patch testing of Singapore children analysis. Contact Dermatitis. 2011;64(5):245–57. and adolescents: our experience over 18 years. Pediatr Bruynzeel DP, Maibach HI. Excited skin syndrome and the Dermatol. 2006;23:117–20. hyporeactive state: current status. In: Menne T, Maibach Goossens A. Art and science of patch testing. Indian HI, editors. Exogenous dermatoses: environmental der- J Dermatol Venereol Leprol. 2007;73:289–91. matitis. Boca Raton: CRC; 1990. p. 141–50. Goossens A. Contact-allergic reactions to cosmetics. Bruze M, Andersen KE, Goossens A. Recommendation to J Allergy. 2011, Article ID 467071:1–6. include fragrance mix 2 and hydroxyisohexyl Grimalt R, Mengeaud V, Cambazard F, Study Investigators’ 3- cyclohexene carboxaldehyde (Lyral1) in the Group. The steroid-sparing effect of an emollient ther- European baseline patch test series. Contact apy in infants with atopic dermatitis: a randomized Dermatitis. 2008;58:129–33. controlled study. Dermatology. 2007;214:61–7. Bygum A, Andersen KE. Persistent reactions after patch de Groot AC, White IR, Flyvholm MA, Lensen G, testing with TRUE Test panels 1 and 2. Contact Coenraads PJ. Formaldehyde-releasers in cosmetics: Dermatitis. 1998;38:218–20. relationship to formaldehyde contact allergy. Contact Clayton TH, Wilkinson SM, Rawcliffe C, Pollock B, Dermatitis. 2010;62:2–17. Clark SM. Allergic contact dermatitis in children: Hammonds LM, Hall VC, Yiannias JA. Allergic contact should pattern of dermatitis determine referral? A ret- dermatitis in 136 children patch tested between 2000 rospective study of 500 children tested between 1995 and 2006. Int J Dermatol. 2009;48:271–4. and 2004 in one U.K. centre. Br J Dermatol. Hausen BM. Evaluation of the main contact allergens in 2006;154:114–7. oxidized tea tree oil. Dermatitis. 2004;15(4):213–4. 28 F.B. de Waard-van der Spek

Hausen BM. Evaluation of the main contact allergens in Mailhol C, Lauwers-Cances V, Rancé F, Paul C, propolis (1995 to 2005). Der matitis. 2005;16(3): Giordano-Labadie F. Prevalence and risk factors for 127–9. allergic contact dermatitis to topical treatment in Heine G, Schnuch A, Uter W, Worm M, Information atopic dermatitis: a study in 641 children. Allergy. Network of Departments of Dermatology (IVDK), 2009;64:801–6. German Contact Dermatitis Research Group (DKG). Marcoux D, Couture-Trudel P-M, Riboulet-Delmas G, Type-IV sensitization profi le of individuals with Sasseville D. Sensitization to para-phenylenediamine atopic eczema: results from the Information Network from a street side temporary tattoo. Pediatr Dermatol. of Departments of Dermatology (IVDK) and the 2002;19:498–502. German Contact Dermatitis Research Group (DKG). Mitchell JC. The angry back syndrome: eczema creates Allergy. 2006;61(5):611–6. eczema. Contact Dermatitis. 1975;1:193–4. Hsu JW, Jacob SE. Children’s toys as potential sources of Mortz CG, Andersen KE. Allergic contact dermatitis in nickel exposure. Dermatitis. 2009;20:349–50. children and adolescents. Contact Dermatitis. 1999; Jacob SE, Zapolanski T, Chayavichitsilp P, Connelly EA, 41:121–30. Eichenfi eld LF. p-Phenylenediamine in black henna Mortz CG, Lauritsen JM, Bindslev-Jensen C, Andersen tattoos: a practice in need of policy in children. Arch KE. Nickel sensitization in adolescents and associa- Pediatr Adolesc Med. 2008;162(8):790–2. tion with ear piercing, use of dental braces and hand Jensen CD, Johansen JD, Menné T, Andersen eczema. The Odense Adolescence Cohort Study on KE. Methyldibromoglutaronitrile in rinse-off products Atopic Diseases and Dermatitis (TOACS). Acta Derm causes allergic contact dermatitis: an experimental Venereol. 2002;82:359–64. study. Br J Dermatol. 2004;150:90–5. Mortz CG, Kjaer HF, Eller E, Osterballe M, Norberg LA, Jensen CD, Johansen JD, Menne T, Andersen Høst A, Bindslev-Jensen C, Andersen KE. Positive KE. Methyldibromo glutaronitrile contact allergy: nickel patch tests in infants are of low clinical relevance effect of single versus repeated daily exposure. Contact and rarely reproducible. Pediatr Allergy Immunol. Dermatitis. 2005;52:88–92. 2013a;24(1):84–7. Jensen CD, Paulsen E, Andersen KE. Retrospective evalu- Mortz CG, Bindslev-Jensen C, Andersen KE. Nickel ation of the consequence of alleged patch test sensiti- allergy from adolescence to adulthood in the TOACS zation. Contact Dermatitis. 2006;55:30–5. cohort. Contact Dermatitis. 2013b;68(6):348–56. Johansen JD, Aalto-Korte K, Agner T, Andersen KE, Bircher Neri I, Guareschi E, Savoia F, Patrizi A. Childhood aller- A, Bruze M, Cannavó A, Giménez-Arnau A, Gonçalo M, gic contact dermatitis from henna tattoo. Pediatr Goossens A, John SM, Lidén C, Lindberg M, Mahler V, Dermatol. 2002;19:503–5. Matura M, Rustemeyer T, Serup J, Spiewak R, Thyssen Nosbaum A, Vocanson M, Rozieres A, Hennino A, JP, Vigan M, White IR, Wilkinson M, Uter W. European Nicolas J-F. Allergic and irritant contact dermatitis. Society of Contact Dermatitis guideline for diagnostic Eur J Dermatol. 2009;19(4):325–32. patch testing – recommendations on best practice. Oranje AP, Bruynzeel DP, Stenveld HJ, Dieges Contact Dermatitis. 2015;73:195–221. PH. Immediate- and delayed-type contact hypersensi- Karlberg A-T, Magnusson K. Rosin components identi- tivity in children older than 5 years with atopic derma- fi ed in diapers. Contact Dermatitis. 1996;34:176–80. titis: a pilot study comparing different tests. Pediatr Kelett JK, King CM, Beck MH. Compound allergy to Dermatol. 1994;11(3):209–15. medicaments. Contact Dermatitis. 1986;14:45–8. Orton DI, Shaw S. Allergic contact dermatitis from phar- Klas PA, Corey G, Storrs FJ, Chan SC, Hanifi n maceutical grade BHA in Timodine®, with negative JM. Allergic and irritant patch test reactions and atopic results to analytical grade BHA. Contact Dermatitis. disease. Contact Dermatitis. 1996;34:121–4. 2001;44:191–2. Kränke B, Derhaschnig J, Komericki P, Aberer Paulsen E, Otkjae A, Andersen KE. Sesquiterpene lactone W. Bufexamac is a frequent contact sensitizer. Contact dermatitis in the young: is atopy a risk factor? Contact Dermatitis. 1996;34(1):63–4. Dermatitis. 2008;59:1–6. Kütting B, Brehler R, Traupe H. Allergic contact dermati- P i ętowska J, Czarnobilska E, Spiewak R. The most fre- tis in children – strategies of prevention and risk man- quent contact sensitizers and atopic diseases among agement. Eur J Dermatol. 2004;14:80–5. consecutive patients of a Polish patch test clinic. Lammintausta K, Kalimo K, Fagerlund VL. Patch test Allergy. 2008;63 Suppl 88:320. reaction in atopic dermatitis. Contact Dermatitis. Pigatto P, Martelli A, Marsili C, Fiocchi A. Contact der- 1992;26:234–40. matitis in children. Ital J Pediatr. 2010;36:2. Landro AD, Greco V, Valsecchi R. ‘Lucky Luke’ contact Powell D, Ahmed S. Soccer shin guard reactions: allergic dermatitis from diapers with negative patch tests. and irritant reactions. Dermatitis. 2010;21:162–6. Contact Dermatitis. 2002;46:48–9. Rastogi SC, Johansen JD, Menné T, Frosch P, Bruze M, Lindberg M, Matura M. Patch testing. In: Johansen JD, Andersen KE, Lepoittevin JP, Wakelin S, White Frosch PJ, Lepoittevin J-P, editors. Contact dermatitis. IR. Contents of fragrance allergens in children’s 5th ed. Berlin: Springer; 2011. p. 439–69. cosmetics and cosmetic-toys. Contact Dermatitis. Lodén M, Andersson AC, Lindberg M. Improvement in 1999;41:84–8. skin barrier function in patients with atopic dermatitis Rietschel RL, Adams RM, Maibach HI, et al. The case for after treatment with a moisturizing cream (Canoderm). patch test readings beyond day 2. J Am Acad Dermatol. Br J Dermatol. 1999;140(2):264–7. 1988;18:42–5. 3 Contact Allergy in Children: Diagnosis and Treatment 29

Roelofzen JH, Aben KK, van der Valk PG, et al. Coal tar Thyssen JP, Linneberg A, Ross-Hansen K, Carlsen BC, in dermatology. J Dermatol Treat. 2007;18(6):329–34. Meldgaard M, Szecsi PB, Stender S, Menné T, Roul S, Ducombs G, Leaute-Labreze C, Labbe L, Taïeb Johansen JD. Filaggrin mutations are strongly associ- A. Footwear contact dermatitis in children. Contact ated with contact sensitization in individuals with der- Dermatitis. 1996;35:334–6. matitis. Contact Dermatitis. 2013;68(5):273–6. Roul S, Ducombs G, Leaute-Labreze C, Taieb A. ‘Lucky Thyssen JP, McFadden JP, Kimber I. The multiple factors Luke’ contact dermatitis due to rubber components of affecting the association between atopic dermatitis diapers. Contact Dermatitis. 1998;38:363–4. and contact sensitization. Allergy. 2014;69(1):28–36. Roul S, Ducombs G, Taieb A. Usefulness of the European Uter W, Balzer C, Geier J, Frosch PJ, Schnuch A. Patch standard series for patch testing in children. A 3-year testing with patient’s own cosmetics and toiletries: single-centre study of 337 patients. Contact Dermatitis. results of the IVDK, 1998–2002. Contact Dermatitis. 1999;40:232–5. 2005;53:226–33. Runeman B. Skin interaction with absorbent hygiene Uter W, de Pádua CM, Pfahlberg A, Nink K, Schnuch A, products. Clin Dermatol. 2008;26(1):45–51. Lessmann H. Contact allergy to topical corticoste- Rystedt I. Atopic background in patients with occupational roids – results from the IVDK and epidemiological risk hand eczema. Contact Dermatitis. 1985;12:247–54. assessment. J Dtsch Dermatol Ges. 2009;7(1):34–41. Seidenari S, Giusti F. Skin sensitivity, interindividual fac- Uter W, Schnuch A. EMA revokes marketing authorization tors: atopy. In: Van Der Valk PMG, Maibach H, edi- for bufexamac. Contact Dermatitis. 2011;64:235–6. tors. The irritant contact dermatitis syndrome. Boca Vender RB. The utility of patch testing children with Raton: CRC Press; 2006. p. 266. atopic dermatitis. Skin Ther Lett. 2002;7:4–6. Simonsen AB, Deleuran M, Johansen JD, Sommerlund de Waard-van der Spek FB, Oranje AP. Patch tests in chil- M. Contact allergy and allergic contact dermatitis in dren with suspected allergic contact dermatitis: a pro- children – a review of current data. Contact Dermatitis. spective study and review of the literature. Dermatology. 2011;65:254–65. 2009;218:119–25. Simonsen AB, Deleuran M, Mortz CG, Johansen JD, de Waard-van der Spek FB, Andersen KE, Darsow U, Sommerlund M. Allergic contact dermatitis in Danish Mortz CG, Orton D, Worm M, Muraro A, Schmid- children referred for patch testing – a nationwide multi- Grendelmeier P, Grimalt R, Spiewak R, Rudzeviciene centre study. Contact Dermatitis. 2014;70(2): O, Flohr C, Halken S, Fiocchi A, Borrego LM, Oranje 104–11. AP. Allergic contact dermatitis in children: which fac- Simonsen AB, Sommerlund M, Deleuran M, Mortz CG, tors are relevant? (review of the literature). Pediatr Johansen JD. Course of skin symptoms and quality of Allergy Immunol. 2013;24(4):321–9. life in children referred for patch testing – a long-term de Waard-van der Spek FB, Darsow U, Mortz CG, Orton D, follow-up study. Acta Derm Venereol. 2015;95(2): Worm M, Muraro A, Schmid-Grendelmeier P, Grimalt 206–10. R, Spiewak R, Rudzeviciene O, Flohr C, Halken S, Sosted H, Kohansen JD, Andersen KE, et al. Severe aller- Fiocchi A, Borrego LM, Oranje AP. EAACI position gic hair dye reactions in 8 children. Contact Dermatitis. paper for practical patch testing in allergic contact der- 2006;54:87–91. matitis in children. Pediatr Allergy Immunol. Smeenk G, Kerckhoffs HPM, Schreurs PHM. Contact 2015;26:598–606. allergy to a reaction product in Hirudoid® cream: an Weston WL, Weston JA, Kinoshita J, et al. Prevalence of example of compound allergy. Br J Dermatol. 1987; positive epicutaneous tests among infants, children 116:223–31. and adolescents. Pediatrics. 1986;78:1070–4. Smith WJ, Jacob SE. The role of allergic contact dermati- Weston WL, Morelli JG. Dermatitis under soccer shin tis in diaper dermatitis. Pediatr Dermatol. 2009;26: guards: allergy or contact irritant reaction? Pediatr 369–70. Dermatol. 2006;23(1):19–20. Spornraft-Ragaller P, Schnuch A, Uter W. Extreme patch Wilkinson DS, Fregert S, Magnusson B, et al. Terminology test reactivity to p-phenylenediamine but not to other of contact dermatitis. Acta Dermatol Venereol. 1970; allergens in children. J Dtsch Dermatol Ges. 2012; 50:287–92. 10(4):258–64. Wolf G, Höger PH. Hypoallergenic and non-toxic emol- Stausbøl-Grøn B, Andersen KE. Allergic contact dermati- lient therapies for children. J Dtsch Dermatol Ges. tis to ethylhexylglycerin in a cream. Contact Dermatitis. 2009;7:50–60. 2007;57:193–4. Zug KA, McGinley-Smith D, Warshaw EM, et al. Contact Teixeira M, Machado S, Teixeira A, et al. Severe contact allergy in children referred for patch testing: north allergy to footwear in a young child. Contact Dermatitis. American Contact Dermatitis Group data 2001-2004. 2005;52:159–60. Arch Dermatol. 2008;144:1329–36. Allergy Tests in Atopic Dermatitis 4 Flora B. de Waard-van der Spek

Abstract Atopic dermatitis (AD) is one of the most common diseases, with a prevalence of 20 % in several studies. The diagnosis of AD is made using evaluated clinical criteria. Depending upon the severity of AD, type and strength of management is started. The severity of AD is made using evaluated clinical systems such as SCORAD and EASI. The TIS score shows promise for future use in routine clinical practice. Allergic management of AD may be worthwhile, since allergy may trigger the disease. However, there is not one allergy that is causing the disease. Skin testing is a common diagnostic procedure in food allergy. The skin prick test is the test of fi rst choice for investigating the immediate IgE-mediated reaction. Based on the mechanism of the contact urticaria syndrome (CUS), imitating provocation tests have been developed. The fi nal proof for establishing the diagnosis of food allergy is the double-blind placebo- controlled oral challenge. The role of diet in the cause and treatment of AD is very controversial. Dietary recommendations should be very specifi c and only prescribed in those children with diagnosed food allergy. Clinical observations indicate that aeroallergens may be trigger factors in AD patients. Infl uence of aero-allergy on AD is very limited.

Keywords Allergy tests • Atopic dermatitis • Children • Atopy patch test • Prick test • Food allergy • Contact allergy • Allergic contact dermatitis

Atopic dermatitis (AD) is one of the most common diseases, with a prevalence of 20 % in F. B. de Waard-van der Spek , MD, PhD several studies. AD like many other atopic dis- Department of Dermatology , eases has increased in occurrence in the last cou- Franciscus Gasthuis and Vlietland , ple of decades (Spergel 2010). Epidemiological Rotterdam/Schiedam , The Netherlands e-mail: [email protected] studies are not easy to compare. The International

Study of Asthma and Allergies in Childhood is aimed at long-term stabilization, fl are preven- (ISAAC) was designed to allow international tion, and avoidance of side effects (Darsow et al. comparison of epidemiological data on atopic 2010). Depending upon the severity of AD, type conditions in childhood. The global ISAAC and strength of management is started. Therefore results on the prevalence of AD showed much measuring the severity of AD as objectively as variation in different countries, partly explained possible is extremely important in clinical practice by nonvalidated translations of the question- and for research purposes. For the measurement naires (Williams et al. 1999 ). of disease severity, many systems have been AD is a chronic dermatosis with typical intense developed. Twenty-eight different scales were pruritus. It starts primarily in infants in the fi rst identifi ed by Eichenfi eld et al. without a single year of life in 80 % of the cases. The clinical gold standard emerging (Eichenfi eld et al. 2014). manifestations result from a complex interplay of The SCORAD system has been developed based genetic, immune, infectious, and environmental on consensus by the European Task Force on factors. Atopic Dermatitis (ETFAD) (European Task AD is a common health problem for children Force on Atopic Dermatitis 1993 ). Confusion and adolescents but also for adults throughout the exists about the correct use of the SCORAD index world (Oranje and de Waard-van der Spek 2002 ). and the objective SCORAD. Terms and interpretation are used incorrectly and lead to mistakes The available literature suggests that the Diagnosis of AD SCORAD index, the Eczema Area and Severity Index (EASI) score, and the Patient-Oriented The diagnosis of AD is made using evaluated Eczema Measure (POEM) severity scale have clinical criteria. Hanifi n and Rajka stated three of been adequately tested and validated. At present, four main criteria to be necessary: pruritus, typi- the use of these scales is recommended in cal morphology and distribution, chronic relaps- clinical trials and everyday practice (Schmitt ing course, and atopic personal or family history, et al. 2007 ). in addition to the three minor criteria among a list The SCORAD and EASI systems take time. of 21 (Hanifi n and Rajka 1980 ). The Three-Item Severity score (TIS score) is a According to the UK working party, who simple scoring system using three of the inten- developed criteria especially suitable for epide- sity items of the SCORAD index. The TIS miological purposes but not in small children, score evaluates the intensity of erythema (red- itchy skin changes have to be diagnosed in the last ness), oedema, and excoriations (scratches). It 12 months, in addition to at least three of the fol- can be regarded as a simple and quick scoring lowing criteria: onset of the disease under the age system that correlates very well with the of 2 years, history of involvement of skin folds, objective SCORAD (Wolkerstorfer et al. 1999 ; generalized dry skin, other atopic diseases, and Oranje et al. 2007). The TIS score shows visible fl exural eczema (Williams et al. 1996 ). In promise for future use in clinical practice very young children (younger than 2 years), we (Eichenfield et al. 2014 ). propose the slightly modifi ed criteria of Sampson After the diagnosis has been made and the (Sampson 1990 ). severity has been scored, it is important to give advice about basic therapy for atopic dermatitis and skin care. The application of moisturizers Management of AD should be an integral part of the treatment of patients with AD. There is strong evidence that Management of AD and exacerbated AD is their use can reduce disease severity and the a therapeutic challenge. It requires effi cient need for pharmacologic intervention (Eichenfi eld short- term control of (acute) symptoms without et al. 2014). Topical anti-infl ammatory treatment compromising the overall management plan that will reduce the infl ammatory skin lesions. 4 Allergy Tests in Atopic Dermatitis 33

Allergy Tests in AD also begins early but generally does not disappear as quickly. Commonly occurring allergens are Allergic management of AD may be worthwhile, vegetables, fruits, peanuts, and fi sh. If a relation since allergy may trigger the disease. However, between food allergy and exacerbation of eczema there is not one allergy that is causing the disease. is found, among food allergens, cow’s milk, hen’s There is much controversy on this subject. In our egg, wheat, soy, tree nuts, and peanuts are most opinion, allergic exploration may be useful in frequently responsible in infancy. In older chil- severe cases without response to classical topical dren, adolescents, and adults, pollen-related food treatment. allergy should be taken into account (Ring et al. 2012b ). The most important symptoms of food allergy in AD are, in addition to vomiting and Food diarrhea, itch and skin eruptions such as the contact urticaria syndrome, urticaria, and, to a lesser The role of diet in the cause and treatment of AD extent, angioneurotic edema. Respiratory prob- is very controversial: several investigators believe lems occur less frequently. Food allergy may ini- that foods play a major part in young children tially manifest as urticarial redness around the with AD, whereas others state that food allergy mouth and on the hands. The children may cry and intolerance occur in patients with AD but after food intake or may reject the food. When have no infl uence on eczema. We believe that diet older, the child sometimes complains of pain or has a place in the therapy of young children with itch in the mouth or the throat. One should check AD. Adverse reactions to foods may infl uence whether these reactions are based on contact urti- the severity of AD in children younger than 5 caria syndrome or on irritation. years. In older children, reactions may occur but hardly have any effect on AD. Food additives Immediate Type Food Allergy rarely play a part in exacerbating AD. If a child Skin testing is a common diagnostic procedure in reacts adversely to foods, AD does not necessar- food allergy. The skin prick test is the test of fi rst ily improve when the specifi c food is avoided. In choice for investigating the immediate IgE- contrast, if sensitivity to a certain food has been mediated reaction. Based on the mechanism of proved, improvement of AD is not necessarily the contact urticaria syndrome (CUS), imitating because of dietary restriction. Elimination diets provocation tests have been developed (Oranje and preventive diets are benefi cial in a small per- 1991 ; de Waard-van der Spek et al. 1998 ). These centage of young children with AD. In our opin- tests are specially performed in young children ion, food allergy plays a part in 20 % of the with AD suspected of food allergy. This test was children younger than 4 years with AD. A direct initially called skin application food test (SAFT), effect on eczema is observed in about four of ten and later the term direct atopy patch test (dAPT) children with AD and proven food allergy (Oranje has been introduced. and de Waard-van der Spek 2000 ). We use the dAPT in young children. The test One distinguishes three types of food allergy is read after 10–20–30 min and ended as soon as reactions in AD: a type I (immediate type) reac- the test result is positive (Oranje et al. 1994 ; de tion (immunoglobulin E [IgE] mediated), which Waard-van der Spek et al. 1998 ; Devillers et al. is accompanied by urticaria; a combined type 1 2009 ). Similar to that used by most physicians, and type IV (delayed type) reaction predomi- we use the prick test in children older than 2 nated by urticaria; and a type that is more diffi - years. Extracts may differ in many aspects. cult to diagnose and produces late reactions. We studied the relevance of the skin test, then Cow’s milk allergy generally begins in the called SAFT, in children younger than 4 years fi rst months of life and as a rule disappears spon- with atopic dermatitis and (suspected) food taneously around the second to the fourth year of allergy as compared with the prick-prick test, life (95 % of the cases). Hen’s egg-white allergy the radioallergosorbent test (RAST), and the oral 34 F.B. de Waard-van der Spek challenge. In the skin tests, we used fresh food, in et al. 2009 ; Lipozencić and Wolf 2010 ; Darsow the same state as it was consumed. et al. 2010 ). This test must be performed by a der- There was a good agreement between the matologist who is familiar with the test. The SAFT and the prick-prick test. A moderate agree- practical value has appeared to be limited thus ment was observed between the SAFT and the far. The standardization of the test system is inad- serologic test (RAST). Signifi cantly more posi- equate, since the results can be ambiguous and tive results in the RAST were observed than in the clinical relevance leaves much to be desired. the SAFT. There was very good agreement We do not use this test in our daily practice. between the SAFT and the oral challenge (kappa Based on adequate diagnostic procedures and = 0.86). We concluded that the SAFT is a reliable oral provocations, dietary recommendations and child-friendly skin test for evaluating (sus- should be very specifi c and only prescribed in pected) food allergy in children younger than 4 those children with diagnosed food allergy. years with atopic dermatitis. The very good correlation with the oral challenge indicates that one may probably consider the SAFT a “skin provo- Aeroallergen Allergy cation” in children younger than 4 years (de Waard-van der Spek et al. 1998 ). Clinical observations indicate that aeroallergens Determination of total IgE has no value at all are relevant trigger factors in AD patients. (Oranje and de Waard-van der Spek 2002 ). If one Exacerbation of eczematous lesions after skin only relies on serological testing, much overdiag- contact or inhalation has been described, and nosis and overtreatment will occur. improvement can be observed after allergen Since several years, component-resolved diag- avoidance, especially with regard to house dust nostics (CRD) are developed, being a possible mites (Darsow et al. 2010 ). potential breakthrough in food allergy testing. Aeroallergens may elicit active eczematous The detection of specifi c IgE (sIgE) to individual skin lesions in patients of different ages with allergens in diagnostic extracts could signifi cantly AD. In at least 30 % of children older than 2 years improve diagnosing food allergy. The real risk of with AD, one observes positive atopy patch tests either a mild or severe reaction could be estab- (APT) (Devillers et al. 2009 ; Lipozencić and lished using these tests. Improvement of the diag- Wolf 2010 ). Some selected patients show exacer- nostic accuracy of microarray-immunoassay, bation of AD during contact with house dust mite combined with interpreting its results next to clin- (HDM) and grass pollen. There is some evidence ical information, could lead to changes in clinical that HDM avoidance strategies may reduce HDM practice in food allergy (Antonicelli et al. 2014 ). content in indoor air and lead to improvement of The fi nal proof for establishing the diagnosis AD (Darsow et al. 2010 ; Ring et al. 2012a , b ). In of food allergy is the double-blind placebo- spring and summertime, pollen exposure may controlled oral challenge. Elimination and provo- exacerbate AD in the air-exposed skin areas. It is cation may be used in mild manifestations of uncertain if avoidance measures are helpful. suspected food allergy. It is very important to use Infl uence of aero-allergy on AD is very limited. a validated objective scoring system to evaluate the effect. One should suspect food allergy in those cases nonresponding to therapy, those with Contact Allergy moderate to severe AD, and those with urticarial fl are-ups. The role of contact allergy in AD patients is frequently underestimated. Allergic contact derma- Delayed Type Allergy titis is not rare in children with atopic dermatitis It is possible in some patients to demonstrate (de Waard-van der Spek and Oranje 2009 ; de allergy to food and aeroallergen of the delayed Waard-van der Spek et al. 2013 , 2015 ). Children type with the atopy patch test (APT) (Devillers should be tested strictly based on the indication 4 Allergy Tests in Atopic Dermatitis 35 using a standardized protocol. In Chap. 3 , Contact Devillers AC, de Waard-van der Spek FB, Mulder PG, Allergy in Children: Diagnosis and Treatment, Oranje AP. Delayed- and immediate-type reactions in the atopy patch test with food allergens in young chil- you can read more about this topic. dren with atopic dermatitis. Pediatr Allergy Immunol. 2009;20:53–8. Eichenfi eld LF, Tom WL, Chamlin SL, Feldman SR, Bulleted List of Controversies Hanifi n JM, Simpson EL, Berger TG, Bergman JN, Cohen DE, Cooper KD, Cordoro KM, Davis DM, Krol A, Margolis DJ, Paller AS, Schwarzenberger K, • The severity of AD is best made using evalu- Silverman RA, Williams HC, Elmets CA, Block J, ated clinical systems such as SCORAD and Harrod CG, Smith Begolka W, Sidbury R. Guidelines EASI. of care for the management of atopic dermatitis: section 1. Diagnosis and assessment of atopic dermatitis. • Allergic exploration is only useful in severe J Am Acad Dermatol. 2014;70(2):338–51. cases without response to classical topical European Task Force on Atopic dermatitis. Severity scor- treatment. ing of atopic dermatitis: the SCORAD index (consen- • In young children (<2 years of age), the direct sus report of the European Task Force on Atopic Dermatitis). Dermatology. 1993;186:23–31. atopy patch test (dAPT), formerly termed Hanifi n JM, Rajka G. Diagnostic features of atopic der- SAFT, is a reliable test for the diagnosis matitis. Acta Derm Venereol. 1980;92(Suppl):44–7. food allergy, though controversial and not Lipozencić J, Wolf R. The diagnostic value of atopy patch supported by many allergologists because of testing and prick testing in atopic dermatitis: facts and controversies. Clin Dermatol. 2010;28:38–44. limited sensitivity. Oranje AP. Skin provocation test SAFT based on contact • One may consider the dAPT as a “skin provo- urticaria: a marker of dermal food allergy. In: Vermeer cation” in children younger than 2 years. J, editor. Proceedings of metabolic disorders and nutri- • Determination of total IgE and serologic tests tion related to the skin. Basel: Karger; 1991. Oranje AP, de Waard-van der Spek FB, van Oostende L, (RAST) have very limited value in the diag- Aarsen RSR, Toorenenbergen AW, Dieges PH. Food- nostic process in children with AD. induced contact urticarial syndrome (CUS) in young • If one only relies on serological testing in children with atopic dermatitis: practical consequences. diagnosing food allergy, much overdiagnosis J Eur Acad Dermatol Venereol. 1994;3:295–301. Oranje AP, de Waard-van der Spek FB. Atopic dermatitis and overtreatment will occur. and diet. J Eur Acad Dermatol Venereol. 2000;14: • Component-resolved diagnostics (CRD) are 437–8. developed, being a possible potential break- Oranje AP, de Waard-van der Spek FB. Atopic dermatitis: through in food allergy testing. review 2000-January 2001. Curr Opin Pediatr. 2002; 14:410–3. • Infl uence of aero-allergy on AD is very lim- Oranje AP, Glazenburg EJ, Wolkerstorfer A, de Waard- ited and probably not existing or in a small van der Spek FB. Practical issues on interpretation of subset of AD. scoring atopic dermatitis: the SCORAD index, objec- • Improved education and support for children tive SCORAD and the three-item severity score. Br J Dermatol. 2007;157:645–8. with AD and their families may improve qual- Ring J, Alomar A, Bieber T, Deleuran M, Fink-Wagner ity of life. A, Gelmetti C, Gieler U, Lipozencic J, Luger T, Oranje AP, Schäfer T, Schwennesen T, Seidenari S, Simon D, Ständer S, Stingl G, Szalai S, Szepietowski JC, Taïeb A, Werfel T, Wollenberg A, Darsow References U. Guidelines for treatment of atopic eczema (atopic dermatitis) part I. J Eur Acad Dermatol Venereol. Antonicelli L, Massaccesi C, Braschi MC, Cinti B, Bilò 2012a;26:1045–60. MB, Bonifazi F. Component resolved diagnosis in real Ring J, Alomar A, Bieber T, Deleuran M, Fink-Wagner A, life: the risk assessment of food allergy using Gelmetti C, Gieler U, Lipozencic J, Luger T, Oranje microarray-based immunoassay. Eur Ann Allergy AP, Schäfer T, Schwennesen T, Seidenari S, Simon D, Clin Immunol. 2014;46(1):30–4. Ständer S, Stingl G, Szalai S, Szepietowski JC, Taïeb Darsow U, Wollenberg A, Simon D, et al. for the European A, Werfel T, Wollenberg A, Darsow U. Guidelines for Task Force on Atopic Dermatitis/EADV Eczema Task treatment of atopic eczema (atopic dermatitis) part II. J Force. ETFAD/EADV eczema task force 2009 posi- Eur Acad Dermatol Venereol. 2012b;26(9):1176–93. tion paper on diagnosis and treatment of atopic derma- Sampson HA. Pathogenesis of eczema. Clin Exp Allergy. titis. J Eur Acad Dermatol Venereol. 2010;24:317–28. 1990;20:459–67. 36 F.B. de Waard-van der Spek

Schmitt J, Langan S, Williams HC, European Dermato- de Waard-van der Spek FB, Darsow U, Mortz CG, Orton Epidemiology Network. What are the best outcome D, Worm M, Muraro A, Schmid-Grendelmeier P, measurements for atopic eczema? A systematic review. Grimalt R, Spiewak R, Rudzeviciene O, Flohr C, J Allergy Clin Immunol. 2007;12(6):1389–98. Halken S, Fiocchi A, Borrego LM, Oranje AP. EAACI Spergel JM. Epidemiology of atopic dermatitis and atopic position paper for practical patch testing in allergic march in children. Immunol Allergy Clin North Am. contact dermatitis in children. Pediatr Allergy 2010;30:269–80. Immunol. 2015;26:598–606. de Waard-van der Spek FB, Elst EF, Mulder PGH, Munte Williams HC, Burney PJG, Pembroke AC, et al. Validation K, Devillers ACA, Oranje AP. Diagnostic tests in chil- of the UK diagnostic criteria for atopic dermatitis in a dren with atopic dermatitis and food allergy. Allergy. population setting. Br J Dermatol. 1996;135:12–7. 1998;53:1–5. Williams HC, Robertson C, Stewart A, et al. Worldwide de Waard-van der Spek FB, Oranje AP. Patch tests in chil- variations in the prevalence of symptoms of atopic dren with suspected allergic contact dermatitis: a pro- dermatitis in the international study of asthma and spective study and review of the literature. Dermatology. allergies in childhood. J Allergy Clin Immunol. 2009;218:119–25. 1999;103:125–38. de Waard-van der Spek FB, Andersen KE, Darsow U, Wolkerstorfer A, de Waard-van der Spek FB, Glazenburg Mortz CG, Orton D, Worm M, Muraro A, Schmid- AJ, et al. Scoring the severity of atopic dermatitis: Grendelmeier P, Grimalt R, Spiewak R, Rudzeviciene three item severity (TIS) score as a rough system for O, Flohr C, Halken S, Fiocchi A, Borrego LM, Oranje daily practice and as a prescreening tool for studies. AP. Allergic contact dermatitis in children: which fac- Acta Derm Venereol. 1999;79:356–9. tors are relevant? (review of the literature). Pediatr Allergy Immunol. 2013;24(4):321–9. Childhood Psoriasis 5 Nawaf Al-Mutairi

Abstract Psoriasis is a chronic immune-mediated inﬂ ammatory disorder characterized clinically by erythematous papules and plaques covered with silvery scales. Pediatric psoriasis is a well-recognized entity having profound psychosocial and life-altering impact. Psoriasis in children differs in clinical features, natural history, epidemiology, triggering factors, treatment choices, and long-term outcome. Diagnosis and management of pediatric psoriasis focusing on controversial aspects of disease and treatment unique to the pediatric patients have been discussed in this chapter.

Keywords Childhood psoriasis • Psoriasis in childhood • Pediatric psoriasis • Phototherapy for pediatric psoriasis • Topical therapy for pediatric psoriasis

Psoriasis is a common chronic immune-medi- altering impact. Psoriasis in children differs in ated inﬂ ammatory dermatological disorder char- clinical features, natural history, epidemiology, acterized clinically by erythematous papules and triggering factors, treatment choices, and long- plaques covered with silvery scales due to com- term outcome. Diagnosis and management of plex alterations in epidermal proliferation and pediatric psoriasis focusing on controversial differentiation. Pediatric psoriasis, surrounded aspects of disease and treatment unique to the by many controversies, is a well-recognized pediatric patients have been discussed in this entity having profound psychosocial and life- chapter.

Etiology and Pathogenesis

N. Al-Mutairi , MD Psoriasis is a T-cell-mediated hyperproliferative Dermatology Unit, Department of Medicine , Faculty of Medicine, Kuwait University , Kuwait disorder characterized by keratinocyte prolifera- e-mail: [email protected] tion, vascular endothelial proliferation, and

© Springer International Publishing Switzerland 2016 37 A.P. Oranje et al. (eds.), Practical Pediatric Dermatology, DOI 10.1007/978-3-319-32159-2_5 38 N. Al-Mutairi infl ammatory cell infi ltration. Activated T cells children. Stressful life events can pose as a risk and activated dendritic cells release tumor necro- factor for acute guttate psoriasis (Naldi et al. sis factor-α (TNF-α) and interferon-γ (IFN-γ) in 2001). The role of stressful events in having a psoriatic plaques. TNF increases infl ammatory causal infl uence on psoriasis is clear (Picardi and cytokines (interleukin (IL)-1, IL-6, NFkB) and Abeni 2002 ). triggers cytokine (IL-6, IL-8) synthesis. These Streptococcal pharyngitis and perianal strep- cytokines participate in blood vessel synthesis, tococcal dermatitis are often associated with gut- vasodilatation, and keratinocyte proliferation, tate psoriasis in children. Staphylococcal leading to psoriasis. superantigens and HPV DNA are the other asso- Research in the fi eld of pediatric psoriasis ciated infections found in psoriatics. Children continue to throw light on its controversial multi- can also present with psoriasis in areas of trauma factorial etiology with both genetic and environ- (Koebner phenomenon). Corticosteroid with- mental infl uences. Up to 70 % of the children drawal and antimalarial drugs can also induce with psoriasis may have a family history of pso- pediatric psoriasis. riasis (Silverberg 2009 ). The lifetime risk of psoriasis with no parent, one parent, or both parents having psoriasis amounts to 4 %, 28 %, and 65 %, Epidemiology respectively (Swanbeck et al. 1997 ). An affected sibling further raises the risk higher. The PSORS Psoriasis affects about 3.5 % of the population, I gene is the major genetic determinant of early- with about a third having a disease onset in the onset type I psoriasis with HLA-Cw6 being the fi rst two decades of life. An estimated 10 % of the major disease allele at PSORS I focus. HLA-B57 patients develop psoriasis before the age of 10 and DRT are also associated with type I disease, years (Busch et al. 2012). Both childhood and whereas HLA-CW2 represents type II late-onset adult psoriases have the highest incidence among psoriasis. Pediatric psoriatic arthritis patients the white people and less among East Asian, have increased prevalence of HLA-A2 and a sig- black, and Native American population. Girls nifi cant rate of paternal transmission (Swanbeck slightly outnumber boys in childhood psoriasis. et al. 1997 ). Pediatric psoriatic arthritis has also been found to Psoriasis has been found to occur along with be more common among females, with age of other autoimmune skin conditions like morphea onset between 7 and 13 years (Al-Fouzan et al. and vitiligo vulgaris in many patients (Al-Mutairi 1994 ). Napkin psoriasis which was before con- and Al-Doukhi 2009; Sawchuk et al. 2012 ). sidered a controversial entity is now the most Pathogenesis of psoriasis vulgaris is now under- common presentation (especially in children less stood as a T-cell-mediated systemic autoimmune than 2 years of age) (Busch et al. 2012 ). Excluding disease; hence, the awareness for the potential it, childhood psoriasis manifests most often as systemic implications of the chronic active plaque psoriasis followed by guttate disease. infl ammation has grown (Wohlrab et al. 2013 ). Psoriatic arthritis is less prevalent in childhood Now there is a clear consensus that when chil- disease as compared to adults. dren with psoriasis also present with other autoimmune disorders such as vitiligo, which has association with thyroid disease or psoriatic Clinical Features of Psoriasis arthritis, then screening for autoimmune thyroid in Children disease is warranted (Antonelli et al. 2006 ). Apart from genetic and autoimmune factors, Generally, psoriasis presents an erythematous many environmental triggers have been proposed well-demarcated plaques or papules with silvery to play a role in etiology. Triggers such as upper scales. Childhood psoriasis differs from psoria- respiratory infection, emotional stress, skin sis in adults in being more frequently pruritic, trauma, and drugs can precipitate psoriasis in relatively thinner, softer, and less scaly lesions. 5 Childhood Psoriasis 39

Sometimes an atypical presentation can make tions can sometimes be confused with tinea cor- the diagnosis diffi cult. However, some valuable poris, pityriasis rosea, nummular dermatitis, or clues that can aid in settling the controversies in pityriasis rubra pilaris. Scalp psoriasis needs to diagnosis are (1) Auspitz sign, pinpoint bleed- be differentiated from seborrheic dermatitis, ing at the base of the scale that has been atopic dermatitis, or tinea capitis. KOH prepara- removed;(2) Koebner phenomenon, occurrence tion, fungal culture, and skin biopsies can be of the lesions in the areas of trauma; and (3) nail helpful, when needed. changes, such as oil spots, onycholysis, subungual hyperkeratosis, and nail pitting being frequently observed, especially in adolescents Guttate Psoriasis (Busch et al. 2012 ). Facial, fl exural, and intertriginous areas are Small, scaly, salmon-colored papules and plaques more often involved in children. Diaper area on the trunk and proximal extremities represent involvement is prevalent during infancy, whereas guttate “drop-like” psoriasis (Fig. 5.4 ). anogenital distribution is more common among Streptococcal pharyngitis and perianal strepto- older children. Although rare and often debated, coccal disease (PSD) have been frequently docu- congenital and naevoid forms of psoriasis have mented to precede the onset of guttate psoriasis been recognized (Busch et al. 2012 ). Infections in children. Previously controversial, genetic link and physical or psychological trauma are the to Cw-0602 allele on HLA-C locus and strep pro- main precipitating factors in childhood psoriasis. teins acting as superantigens have now been con- Frequency of remissions is higher in pediatric- fi rmed to play a role in pathogenesis (Lewkowicz onset psoriasis than in adult-onset. But being a and Gottlieb 2004 ; Zvulunov et al. 1994 ). chronic disfi guring skin disease, it can lead to Swabbing both pharynx and perianal areas and profound emotional and psychological conse- treating with appropriate antibiotics is benefi cial. quences in this tender age and hence requires A signifi cant portion of the affected patients can special attention. eventually land up in chronic plaque psoriasis. At times guttate psoriasis may morphologically sim- ulate pityriasis rosea, nummular dermatitis, or Patterns of Presentation in Children secondary syphilis.

Plaque Psoriasis Napkin Psoriasis Plaque psoriasis is the most common form of childhood psoriasis, presenting as sharply Napkin psoriasis also known as psoriatic diaper demarcated, erythematous lesion with silvery rash was surrounded by many controversies and and white scales (Fig. 5.1 ) most often involving is now recognized as the most prevalent pattern the extensor surfaces, knees, buttocks, elbows, in children under the age of 2 years. It presents as and scalp. Scalp is the most frequent site of onset bright red, well-demarcated, glazed patches in and involvement in childhood disease. Scalp the diaper area (Fig. 5.3d ) poorly responding to psoriasis in the form of thick, adherent white the standard treatment of diaper dermatitis. It scales called pityriasis amiantacea can lead to may be followed by appearance of small dissemi- temporary alopecia (Fig. 5.2). Face and inter- nated psoriasis-like lesions elsewhere on the triginous areas (Fig. 5.3a–c) such as axillae, body. Bacterial and fungal growth in the occluded genital, perianal, and retroauricular are other fre- diaper area may initiate psoriatic lesions in pre- quently affected areas in children. Shiny, well- disposed children. Napkin psoriasis is less com- deﬁ ned, erythematous plaques with ﬁ ssuring and mon in parts of the world where western-type absence of scales is a common presentation in diapers are not used by most parents for their genital and perianal areas. Atypical presenta- children (Dogra and Kaur 2010 ). 40 N. Al-Mutairi

Fig. 5.1 ( a , b ) Sharply demarcated, erythematous psoriatic plaques involving the trunk and limbs

Pustular Psoriasis adults. Von Zumbusch variant is more common during infancy, whereas annular variant is the Pustular psoriasis is relatively rare in children. It most common manifestation in older children, presents as sterile pustules on erythematous base, although mixed forms can also exist. Though and four patterns have been described: general- localized variant is extremely rare in this age ized (GPP or Von Zumbusch), annular (APP), group, parakeratosis pustulosa is often a manifes- exanthematic, and localized. GPP can present tation of childhood psoriasis (Busch et al. 2012 ). with sheets of pustules on erythematous base Pustular psoriasis needs to be differentiated from with fever and systemic toxicity but usually fol- folliculitis, impetigo, and viral, dermatophyte, or lows a benign course in children compared to candidal infection. 5 Childhood Psoriasis 41

Psoriatic Erythroderma

Psoriatic erythroderma is a rare form of psoriasis in children. It presents as erythema involving more than 90 % of body surface area with scaling being less prominent than plaque psoriasis. Skin biopsy can be performed if history or clinical signs are not conclusive.

Mucosal Involvement

Mucosal involvement can be seen in up to 7 % of Fig. 5.2 Scalp psoriasis the children with psoriasis (Al-Fouzan et al.

a c

Fig. 5.3 ( a – d ) Facial and ﬂ exural psoriasis common in childhood presenting as axillae, genital, perianal, and retroauricular 42 N. Al-Mutairi

a b

Fig. 5.4 (a , b ) Small, scaly, salmon-colored papules and plaques of guttate “drop-like” psoriasis on the back

a b

Fig. 5.5 ( a – c ) Nail pitting, the most frequent manifestation of nail psoriasis in childhood

1994 ). Erythematous lesions or erosions on the Nail Psoriasis genital or oral mucosa, including geographic tongue, are the main manifestations. Incidence of Nail changes manifest in the form of subungual mucosal involvement has been reported to be 7 % debris, oil or yellow spots, onycholysis, and lon- in Kuwait but exceptionally rare in India gitudinal striations, with nail pitting (Fig. 5.5 ) (Al-Fouzan et al. 1994 ; Dogra and Kaur 2010 ). being the most frequent especially in adolescents 5 Childhood Psoriasis 43

(Al-Mutairi et al. 2007 ; Busch et al. 2012 ). Nail the management of pediatric psoriasis should changes, predominantly pitting and longitudi- also consider minimizing the impact of disease nal striations, may also be seen among psoriatic on psychosocial development leading to a better arthritis patients. Observing nail changes can quality of life and limiting the adverse effects of serve as valuable clue in establishing diagnosis in drugs on growth and future health of the child. complex cases. The choice of therapeutic modality depends on the type severity, extent, and sites of psoriasis measured by Psoriasis Area severity Index Psoriatic Arthropathy (PASI) score, patient’s age, quality of life factors, as well as safety and accessibility of treatment. Psoriatic arthritis (PsA) is defi ned as a chronic Fortunately, majority of the childhood cases infl ammatory arthropathy affecting the distal are mild and hence adequately manageable with interphalangeal joints (DIP) of hands, metatar- topical treatment modalities. The controversial sophalangeal joints (MTP) of feet, and spine in systemic options are considered only in children association with psoriasis. Skin lesions precede with severe, rapidly evolving, debilitating, and the onset of PsA by about 5–10 years in 80 % of frequently relapsing psoriasis, which presents the patients (Lewkowicz and Gottlieb 2004). PsA true challenge. The disease is chronic and visible is less prevalent in younger patients and may be and can have a signifi cant impact on the child’s diffi cult to differentiate from juvenile rheuma- psychosocial development especially through toid arthritis (JRA). Bluish discoloration over the school years and adolescence. In such a situ- affected joints, spinal involvement, and uveitis ation when it is causing severe psychological associated with PsA may be helpful to settle the and social sequel, childhood psoriasis should controversies in diagnosis (Antonelli et al. 2006 ). be treated more aggressively, and these children Oligoarticular asymmetrical arthritis (≤4 joints) may require substantial family and professional is the most common manifestation which can support. Management is also infl uenced by pres- overtime progress to polyarthritis. The onset of ence of comorbid conditions like PsA and hema- disease seems to be earlier in females, and those tological, liver, and renal function parameters as with early disease can have a greater body surface well as with the level of functional, emotional, area involved, frequent relapses, unstable psoria- or social disability (Silverberg 2009). The treat- sis and higher incidence of guttate psoriasis, and ment options available for pediatric psoriasis are nail involvement (Lewkowicz and Gottlieb 2004 ). the same as for adults. Formulations and strength Early recognition in childhood and aggressive but need to be appropriately adjusted for the patient’s safe treatment in early stages to induce remission age. Although many of these modalities are still can prevent further damage and disabilities. surrounded by controversies and not yet FDA approved for children, they are being successfully used as off-label treatments. The treatment Controversies in Management of pediatric psoriasis still remains a challenge, as safety profi le of many of these modalities is yet Psoriasis is a chronic skin disorder with remis- to be established, mainly because of lack of pedi- sions and relapses and without permanent cure. atric therapeutic studies. The goal of treatment is, therefore, to establish disease control and prolong periods of remission and the period in between fl ares. Proper patient Topical Therapy and parent education is necessary, emphasizing the need to control versus cure, as setting real- Topical treatment is suffi cient to manage major- istic expectations often enhances compliance. ity of childhood patients presenting with mild Apart from improving the physical symptoms, forms of psoriasis. Topical corticosteroids, coal 44 N. Al-Mutairi tar, anthralin, vitamin D analogues, calcineurin acceptable creams are recommended during the inhibitors, and a range of emollients and kerato- day and greasy ointments during the night, and lytics are available. The choice of topical agent foams, lotions, and shampoos are selected for depends on the morphology, site of involvement, scalp psoriasis. The choice of topical cortico- patient’s tolerability, and side effect profi le. steroids for the childhood psoriasis is similar to recommendations given for the lichenifi ed atopic dermatitis. Low- to mid- potency (classes 5–7) Emollients and Keratolytics agents are preferred for the face, neck, and intertriginous areas, while the scalp and extremities are Emollients and keratolytics play an adjunc- generally treated with mid-potency (classes 2–4) tive role in the topical management of psoria- topical corticosteroids (Silverberg 2010 ). Class I sis. Emollients and moisturizers are essential corticosteroids or steroids under occlusion rapidly to normalize epidermal hyperproliferation and fl atten psoriasis lesions but are associated with differentiation and improve the barrier func- atrophy and a host of the other side effects. Hence, tion and stratum corneum hydration, making the prescribing steroid creams in pediatric psoriasis epidermis supple and strong enough to prevent has been a matter of controversy. Clobetasol pro- koebnerization from trauma or stress. They are pionate emulsion aerosol foam 0.05 % used for a especially supportive in scaly plaque lesions and maximum of 2 weeks is the only class I agent that in the maintenance of remission of psoriasis. has been approved in the treatment of children of Emollients like clear mineral oil penetrate the 12 years and older. Mometasone furoate and fl uo- intercellular spaces, allowing an optical match- cinolone in children older than 2 years and alclo- ing effect, which increases the UV transmission metasone dipropionate in children 1 year or older and hence therapeutic effect of UVB photother- are the other FDA-approved agents. apy. Mild emollient such as petrolatum is suit- Topical corticosteroids are widely used for able for children of all ages. In older children, the treatment of chronic plaque psoriasis on the emollients with keratolytics can be considered. face, ears, fl exures, and genitals, as monother- Salicylic alone as 3 and 6 % ointment or sham- apy or in combination. Side effects of long use poo is benefi cial for softening small, thick, local- of corticosteroids like skin atrophy and striae ized scaly plaques on the scalp, palms, and soles are especially common on the face and fl exures. in older children. It should be avoided in chil- Prolonged widespread application of potent topi- dren under 6 years especially infants because cal corticosteroids in children can rarely lead to of risk of percutaneous salicylate intoxication hypothalamic- pituitary-adrenal axis suppression (Dogra and Kaur 2010 ). due to their high body surface to mass ratio (Dogra and Kaur 2010 ). Combination with calcipotriol or tazarotene can to some extent overcome these Corticosteroids side effects, and at the same time, corticosteroids can reduce their irritation potential. Intermittent Anti-infl ammatory and antiproliferative properties exposure by pulse therapy, weekend therapy, or of topical corticosteroids help to reduce erythema, rotational therapies can further limit these side scaling, and pruritus in psoriasis. Faster onset of effects. Corticosteroids need slow tapering off to action, wide availability, easy usage, odorless, and prevent any rebound of psoriasis. nonstaining properties lead to high acceptability of corticosteroids among patients, affi rming their status as fi rst-line agents of topical treatment of Coal Tar psoriasis in all ages. An array of potencies and vehicles are available to choose from including Coal tar is antiproliferative and antipruritic and cream, ointment, gel, spray, lotion, solution, nail can modulate infl ammatory events in psoriasis. It lacquer, tape, and foam. Usually cosmetically is an effective and benefi cial treatment for 5 Childhood Psoriasis 45

childhood psoriasis, particularly plaque-type of psoriasis in ≥12-year-old patients. It acts by lesions either alone or in combination with ultra- restoring normal epidermal differentiation and violet light, as in the Goeckerman regimen. It proliferation and suppressing infl ammation. It is should be used with caution due to controversial available in 0.05 and 0.1 % gel and cream for- reports of genomic alterations and chromosomal mulations to treat mild to moderate psoriasis. aberrations, leading to their ban in Germany, sec- Dose- related skin irritation often necessitates its ondary to their carcinogenic potential (Lewkowicz use as short-contact, alternate-day, or weekend and Gottlieb 2004 ). Crude coal tar and tar extracts applications. Combining with topical steroids such as liquor carbonis detergens (LCD) have has improved its effi cacy as well as tolerance. been used topically, in the form of shampoos, Its use should preferably be limited to thicker bath oils, creams, and liquid form or may be plaques, non-intertriginous sites, and thicker combined with topical corticosteroids. However, areas such as nails. its strong odor, dark color, and side effects including acne, folliculitis, and irritant/contact dermatitis limit its frequent usage. Educating the patient Vitamin D Analogues about its effi cacy, good safety profi le, and its place as steroid-sparing agent increase compli- Calcipotriol, tacalcitol, maxacalcitol, and cal- ance of this underutilized topical option. citriol are vitamin D analogues that stimulate keratinocyte differentiation and inhibit DNA synthesis and proliferation. Calcipotriene (calci- Anthralin potriol), FDA approved in adults, is an effi cient nonsteroidal alternative treatment in mild to Anthralin (dithranol) is the synthetic version of moderate plaque psoriasis. It is comparable to or chrysarobin, a natural product from Araroba tree better than class II corticosteroid ointments or introduced for treatment of psoriasis in 1852 from anthralin and is preferred cosmetically over the Gao on the west coast of India. Anthralin being latter. UVB phototherapy has shown to increase a potent anti-infl ammatory and antiproliferative its effi cacy. Burning sensation or irritation are agent has been used as an adjunctive therapy for the most frequent side effects predominantly on large and thick localized plaques. Anthralin has fl exural or facial use. Combining it with topical shown effi cacy of 81 % in a study on 5–10-year- corticosteroids improve the effi cacy and reduce old children (Zvulunov et al. 1994). It has been the side effects of cutaneous atrophy caused by associated with side effects like irritation, tem- corticosteroids and irritation caused by calcipot- porary perilesional staining of the skin, and per- riene. Signifi cant systemic absorption is thought manent staining of the clothes. “Short contact” to have the potential to cause hypervitaminosis therapy or “minute” therapy used in outpatient D and alteration in calcium levels. However, clinic helps to reduce side effects and improve treatment for children with mild to moderate patient compliance. Currently, it holds FDA plaque psoriasis involving <30 % of body sur- approval for adult use. It can be combined with face area is considered safe and can thin or clear other topical therapies or with UVB phototherapy psoriatic lesions (Benoit and Hamm 2007 ). It is as Ingram regimen. It is a safe and easy treatment available in cream, liquid, gel, and ointment for children, but application on the face, fl exures, forms. Gel and liquid forms are preferred for and genitals is not recommended. scalp psoriasis. For plaque psoriasis, creams are pleasant but ointments are more effective. Dovonex (calcipotriol 50 mg/g) cream and oint- Tazarotene ment are licensed in the UK for use in children with a maximum dose of 75 g/week for children Tazarotene is a retinoic acid receptor-specifi c >12 years and 50 g/week for those aged 6–12 topical retinoid, FDA approved for treatment years (Dogra and Kaur 2010 ). 46 N. Al-Mutairi

Topical Calcineurin Inhibitors oral psoralens when PUVA is used in children, to avoid the 24 h strict eye protection and gas- Tacrolimus (0.03 %, 0.1 %) ointment and trointestinal side effects associated with oral pimecrolimus (1 %) cream are nonsteroidal psoralens (Cordoro 2008). NB-UVB is now immunomodulating macrolactams. They inhibit considered the fi rst-line phototherapy in chil- the production and release of IL-2 and subse- dren as it is equally effective, more convenient, quent T-cell activation and proliferation, by and less carcinogenic. Combination with topical blocking the enzyme calcineurin. Both topical calcipotriene, tazarotene, anthralin, or systemic agents are FDA approved for second-line ther- acitretin can reduce the cumulative UVB dose apy of atopic dermatitis in children. Their off- and hence its carcinogenic risk. label use in pediatric psoriasis is controversial, but they have been found to be safe and effective, especially for thin lesions in areas prone to atro- Systemic Therapy phy or steroid acne, such as the face, fl exures, and intertriginous and anogenital region (Busch Treatment with systemic agents in pediatric pso- et al. 2012 ). riasis has been controversial and is reserved for severe, refractory, widespread, or incapacitating disease with psychological effect, pustular or Phototherapy erythrodermic forms, and psoriatic arthropathy. Many of adult treatments have been extrapolated Phototherapy is an effective and safe therapeu- for use in children, but are not licensed in this age tic modality in carefully selected patients with group. The most documented experience is with refractory disease, diffuse (>15–20 % BSA) retinoids which are now probably considered as involvement, or focal debilitating palmoplantar second-line drug of choice for children. psoriasis. Broadband UVB (BB-UVB, 290– Methotrexate and cyclosporine are effective in 320 nm), narrowband (NBUVB 311 ± 2 nm), and children, but the safety data is available mainly UVA (320–400 nm) are the three main types of from pediatric studies on juvenile RA and trans- therapeutic lights useful in psoriasis, due to their planted organs, respectively. The lower tolerabil- action of inhibiting DNA synthesis, keratinocyte ity and cumulative toxicities of systemic agents proliferation, and induction of T-cell apoptosis limit their use in children and are preferably used and immunosuppressive and anti-infl ammatory over short periods in rotational or sequential ther- cytokines. BB-UVB is the most biologically apy, when indicated. Oral antibiotics are the sys- active radiation from sun to which guttate pso- temic therapy of choice in early disease because riasis responds best. Children with refractory of their superior safety and side effect profi le as plaque psoriasis usually require higher dose compared to other systemic agents. and a longer duration of treatment. NB-UVB is safer and effective in children as it is less ery- themogenic than BB-UVB (Silverberg 2009 ). Oral Antibiotics Delivery systems include hand/foot units, generalized phototherapy booths, and excimer laser Oral antibiotics can be used in rapid-onset gut- systems. Excimer (308 nm) laser is especially a tate or pustular psoriasis in children with posi- safe and effective option for localized psoriasis tive history or cultures of pharyngeal psoriasis or in children as it reduces the risk of photoaging perianal streptococcal disease. Amoxicillin, pen- and carcinogenesis associated with wide and icillin, and azithromycin are among the various long-term exposure in UVB therapy (Dogra and antibiotics used without any ideal recommended Kaur 2010 ). Psoralen + UVA (PUVA) therapy regimen. Tonsillectomy may be considered in is not generally recommended in young chil- refractory psoriasis and recurrent tonsillitis, but dren, but can be used in ≥12-year-olds with their role is controversial because of the lack of caution. Topical psoralens are preferred over controlled studies (Wison et al. 2003 ). 5 Childhood Psoriasis 47

Acitretin synthesis. It has been FDA approved for severe, recalcitrant psoriasis in non-immunocompromised Acitretin, a retinoid, is FDA approved for the adult adults and in treatment of transplant rejection in psoriasis only. It is an off-label but effective treat- children >6 months of age. It is an off-label, short- ment option for cutaneous disease in erythroder- term crisis management drug producing rapid mic, plaque, and pustular psoriasis in adolescents clinical response in children within 4–8 weeks (Sarkar et al. 1999 ). Combining it with topical (Mendiratta et al. 2012 ). Its use is limited by a agents and NB-UVB phototherapy can improve dose-dependent risk of nephrotoxicity, hyper- their effi cacy. Its side effects include cheilitis, pru- tension, and immunosuppression. Hence, close ritus, hair loss, elevated serum lipids, elevation of monitoring of the dose based on clinical response, liver enzymes, and skeletal toxicity. Hence, base- blood pressure, serum creatinine levels, and other line and follow-up monitoring are essential. Long- blood parameters is required. Doses of 3–5 mg/ term use in children is controversial because of kg/day generally produce rapid clearing of pus- concern about the growth potential of the child, tular or erythrodermic psoriasis (Dogra and Kaur due to associated premature epiphyseal closure, 2010 ). The dose needs to be reduced if the base- apart from other bone changes. Hence, periodic line creatinine increases by a third. Risk of malig- radiological bone evaluations are required. It nancy is observed to be minimal at 5 mg/kg/day should be used with caution in girls of childbear- or less, in patients who are not on concomitant ing age due to associated teratogenic risk. immunosuppressive drugs. Gradual tapering of dose should start after 1–3 months of clinical stability, but psoriasis rebounds are common during Methotrexate taper or withdrawal of the drug. Hence, either it needs to be effectively used in sequential therapy Methotrexate is an antimetabolite having immu- with acitretin or combined with other systemic nomodulatory and anti-infl ammatory properties. and topical therapies to prevent rebound, increase It has been FDA approved for treatment of severe effi cacy, and decrease end-organ toxicity. adult psoriasis and juvenile rheumatoid arthritis for more than three decades. Methotrexate in a dose of 0.2–0.7 mg/kg/week can provide excellent Biologics reduction (>75 % PASI) in most children (Cordoro 2008). Monitoring blood counts and liver func- Targeted biologic therapies aim at specifi c compo- tion test are recommended, with rare observation nents of infl ammatory cascade involved in patho- of liver function alteration especially in obese due genesis of psoriasis. Tumor necrosis factor to fatty liver changes. Hence, methotrexate should inhibitors are the latest in the armamentarium be avoided in children with immunosuppressive against psoriasis. Etanercept and infl iximab are conditions, liver disease, obesity, diabetes, and TNF-α inhibitors that have been used for treatment alcoholism. Folic acid supplementation helps alle- of pediatric autoimmune disease such as juvenile viate the gastrointestinal symptoms and anemia. rheumatoid arthritis (JRA) for over a decade now. Methotrexate has the advantage of clearing or FDA approved etanercept for treatment of JRA at improving psoriatic arthritis apart from the cuta- a dose of 0.4 mg/kg twice weekly or 0.8 mg/kg neous disease. Its intramuscular or subcutaneous once weekly. Etanercept has been approved for the forms have fewer gastrointestinal adverse effects use in pediatric psoriasis under the European and require lower dose as compared to oral tablets. guidelines. It has been found to improve both cutaneous psoriasis and psoriatic arthritis. It is prudent to update all immunizations and perform PPD Cyclosporine prior to starting treatment. Long-term usage up to 1 year has been found to be safe in children with Cyclosporin is an immunosuppressant that acts by rheumatoid arthritis. Hence, etanercept provides a inhibiting T-cell functions and interleukin (IL-2) good balance of safety and effi cacy in children and 48 N. Al-Mutairi adolescents with moderate to severe plaque psoria- • Previously controversial, genetic link to sis (Al-Mutairi et al. 2010 ). Infl iximab, another Cw-0602 allele on HLA-C locus and strep TNF-α inhibitor, appears to have a promising role proteins acting as superantigens have now in the treatment of refractory plaque psoriasis and been confi rmed to play a role in pathogenesis generalized pustular psoriasis in children. The of guttate psoriasis. benefi ts of these new therapeutic agents have to • Stressful life events have a clear causal infl u- outweigh their potential for the risk of infection, ence and can pose as a risk factor for precipi- lymphoma, demyelinating disorders, and cost. tating psoriasis. Napkin psoriasis, also known as psoriatic diaper rash, was surrounded by many controversies, is now recognized as the Diet and Supportive Care most prevalent pattern in children under the age of 2 years. Although rare and often Whether dietary changes or supplement can debated, congenital and naevoid forms of pso- improve their child’s skin condition is a matter of riasis have been recognized. debate and a common concern of parents with • Controversies continue to challenge treatment children having psoriasis. Fish meals four to six strategies for pediatric psoriasis. Based on times per week, oral supplement of fi sh oil that is published literature (Silverberg 2010 ), limited rich in omega-3 fatty acid, and oral and intrave- disease should be treated preferably with topi- nous supplementation of omega-3 fatty acid have cal calcipotriene-steroid combination as fi rst- been found to be effective in psoriasis possibly line therapy. Topical calcineurine inhibitors through effects on a variety of cytokines includ- should be reserved for fl exures and face. The ing IL-1, IL-6, and TNF (Silverberg 2009 ). approved potent topical steroids for pediatric use must be limited to short term for up to 2 Conclusion weeks. Targeted phototherapy can be employed Children with psoriasis face a lifelong illness for plaques resistant to topical treatments. that can cause considerable stress or fear of • Generalized pediatric psoriasis not responding being stigmatized and other psychosocial to topical treatments should be treated with issues. Besides providing proper treatment of safer UVB phototherapy alone or in combina- disease after considering the clinical presentation with methotrexate, before considering tion and the age of patient, management of other controversial systemic treatment these patients presents a special challenge to options. dermatologists in dealing with psychological ramifi cations and providing supportive care to the child as well as the family. At times, refer- References ral for psychological counseling to develop coping skills for their cosmetically diffi cult Al-Fouzan AS, et al. A survey of childhood psoriasis in disease may be necessary. Kuwait. Pediatr Dermatol. 1994;11(2):116–9. Al-Mutairi N, Al-Doukhi A. Familial coexisting and colo- calised psoriasis and vitiligo responding to alefacept. J Cutan Med Surg. 2009;13(3):172–5. Al-Mutairi N, et al. Nail changes in childhood psoriasis: a Bulleted List of Controversies study from Kuwait. Pediatr Dermatol. 2007;24:7–10. Al-Mutairi N, et al. Etanercept in childhood psoriasis: an • Psoriasis is now being considered an autoim- experience from Kuwait. Gulf J Dermatol Venereol. 2010;17(2):35–40. mune disorder. When children with psoriasis Antonelli A, et al. High prevalence of thyroid autoimmu- also present with other autoimmune disorders nity and hypothyroidism in patients with psoriatic such as vitiligo, which has association with arthritis. J Rheumatol. 2006;33(10):2026–8. thyroid disease or psoriatic arthritis, then Benoit S, Hamm H. Childhood psoriasis. ClinDermatol. 2007;25(6):555–62. screening for autoimmune thyroid disease is Busch AL, et al. Pediatric psoriasis. Skin Therapy Lett. warranted. 2012;17(1):4–7. 5 Childhood Psoriasis 49

Cordoro KM. Systemic and light therapies for the man- Sawchuk M, et al. The coexistence of psoriasis and agement of childhood psoriasis: part II. Skin Therapy vitiligo:a review. J Cutan Med Surg. 2012;16(5):300–5. Lett. 2008;13(4):1–3. Silverberg NB. Pediatric psoriasis: an update. Therapeutic Dogra S, Kaur I. Childhood psoriasis. In J Dermatol Risk Manag. 2009;5:849–56. Venereol Leprol. 2010;76(4):357–65. Silverberg NB. Update on pediatric psoriasis, part 2: ther- Lewkowicz D, Gottlieb AB. Pediatric psoriasis and psori- apeutic management. Cutis. 2010;86:172–6. atic arthritis. Dermatol Ther. 2004;17:364–75. Swanbeck G, et al. Genetic counseling in psoriasis: Mendiratta V, et al. Management of childhood psoriasis. empirical data on psoriasis among fi rst degree rela- In J Paedia Dermatol. 2012;13:12–6. tives of 3095 psoriatic probands. Br J Dermatol. 1997; Naldi L, et al. Family history of psoriasis, stressful life 137:939–42. events and recent infectious disease are risk factors for Wison JK, et al. Treatment of psoriasis in children: is a fi rst episode of acute guttate psoriasis: results of a there a role for antibiotic therapy and tonsillectomy? case-control study. J Am Acad Dermatol. 2001;44(3): Pediatr Dermatol. 2003;20(1):11–5. 433–8. Wohlrab J, et al. Recommendations for detection of indi- Picardi A, Abeni D. Stressful life events and skin dis- vidual risk for comorbidities in patients with psoriasis. eases: disentangling evidence from myth. Psychother Arch Dermatol. 2013;305(2):91–8. Psychosom. 2002;70(3):118–36. Zvulunov A, et al. Effi cacy of short-contact therapy with Sarkar R, et al. Erythroderma in children: a clinic- dithranol in childhood psoriasis. Int J Dermatol. etiological study. J Dermatol. 1999;26:507–11. 1994;33:808–10. Childhood Pityriasis Rubra Pilaris 6 Nawaf Al-Mutairi

Abstract Pityriasis rubra pilaris (PRP), characterized by the appearance of follicular hyperkeratotic papules, erythematosquamous plaques, and palmoplantar keratoderma, is an uncommon disorder of corniﬁ cation in children. Most cases of PRP are sporadic and acquired, but a familial type with an autosomal mode of inheritance has been recognized in children. There is bimodal age distribution of the disease onset in children, with almost equal sex distribution. PRP is an uncommon disease with prevalence varying from 1 in 5000 to 1 in 50,000 in different populations, but incidence as high as about 1 case in every 500 new pediatric dermatology patients has been reported.

Keywords Pityriasis rubra pilaris • PRP • Childhood • Pediatric • Controversies • Corniﬁ cation disorder • Epidermal hyperactivity

Pityriasis rubra pilaris (PRP), characterized by cornifi cation in children (Griffi ths 1980 ). It was the appearance of follicular hyperkeratotic pap- fi rst described in 1828 by Tarral, but he did not ules, erythematosquamous plaques, and palmo- recognize the dermatosis as a distinct entity. plantar keratoderma, is an uncommon disorder of Besnier named it pityriasis rubra pilaris in 1889 (Albert and Mackool 1999 ). Pityriasis rubra pilaris (PRP) is an uncommon disorder of cornifi cation in children, occurring in both sporadic and familial forms. Griffi ths type III, IV, and V have been described exclusively in N. Al-Mutairi , MD children. Controversies in its pathogenesis, clas- Dermatology Unit, Department of Medicine , Faculty of Medicine , Kuwait University , Kuwait sifi cation, clinical presentations, and treatment e-mail: [email protected] have been discussed in this chapter.

Epidemiology of it being a form of an atypical ichthyosis with a follicular element. PRP patients frequently have Most cases of PRP are sporadic and acquired, but normal serum vitamin A levels, although vitamin a familial type with an autosomal mode of inheri- A defi ciency has been controversially incrimi- tance has been recognized in children. There is nated as its etiology in the past. Low levels of bimodal age distribution of the disease onset in serum retinol-binding proteins or an abnormal children, namely, early childhood (0–10 years) vitamin A metabolism in the form of altered and late childhood (11–19 years), with almost intracellular retinol signaling in the skin has not equal sex distribution. PRP is an uncommon dis- been excluded as a possible pathological ease with prevalence varying from 1 in 5000 to mechanism. 1 in 50,000 in different populations, but incidence as high as about 1 case in every 500 new pediatric dermatology patients has been reported (Griffi ths Controversies in Classifi cation 1980 ; Vijayalakshmi and Mallika 2003 ). In 1980, Griffi ths classifi ed PRP into fi ve categories based on age at onset, behavior, clinical Pathogenesis appearance, and prognosis (Griffi ths 1980 ). Griffi ths type III (juvenile classical), type IV The pathogenesis of PRP is controversial, but it is (juvenile circumscribed), and type V (juvenile a state of epidermal hyperactivity approaching atypical) have been described exclusively in chil- that of psoriasis. The postulated etiologies dren (Table 6.1 ), whereas type I and II occur in involve dysfunction in keratinization or vitamin adults. Miralles et al. added a new category of A metabolism, an underlying immunological PRP (type VI) characterized by the presence of abnormality, or a superantigen-mediated derma- HIV infection, resistant to the standard PRP tosis. The precipitating events in the form of pretreatment associated sometimes with HIV- ceding trauma, infection, or a febrile illness have follicular syndrome and a poor prognosis been identifi ed especially in children. History of (Miralles et al. 1995 ). a preceding infection and fl are-ups coinciding Gelmetti et al. presented an alternative classifi - with episodes of infection hypothesize that cation, categorizing childhood PRP based only on superantigen- mediated reaction triggered by a duration of disease: acute form (resolves in less previous infection may cause acute PRP. The than 6 months), acute form with prolonged course association of hypogammaglobulinemia, isolated (resolves within 1 year), and a chronic form (per- IgA defi ciency, vitiligo, and hypoparathyroidism sists for more than 1 year) (Gelmetti et al. 1986 ). with PRP hints toward a possible underlying Larregue introduced a new subgroup of acute immunologic abnormality. Onset of PRP shortly postinfectious PRP. It is morphologically same as after or at the time of HIV (human immunodefi - Griffi ths type III but is characterized by a previ- ciency virus) seroconversion, responsiveness to ous infectious episode, appearance of scarlatini- antiviral therapy, and relapse when therapy was form erythema followed by follicular papules, stopped support the hypothesis that HIV infec- acute course with good prognosis, and no ten- tion could induce PRP. dency to recur (Larrègue et al. 1983 ). Familial cases mostly belong to the atypical juvenile form (type V) of PRP, with up to 6.5 % of PRP patients reported to have a positive family Clinical Features history (Sehgal, and Srivastava 2006 ). This form is usually inherited as an autosomal A typical PRP lesion consists of follicular and/or dominant trait with variable expression and perifollicular verrucous papules with central ker- reduced penetrance. It has been associated with atotic plug on an erythematous base. an abnormality in keratin (K) 17 with speculation Circumscribed juvenile form (type IV) is the 6 Childhood Pityriasis Rubra Pilaris 53

Table 6.1 Working diagnosis of juvenile PRP based on Griffi ths classifi cation Type Age at onset Lesional distribution Typical features Natural course Type III juvenile 5–10 years Generalized Large zones of confl uent Most clear in 1–3 classical follicular hyperkeratosis with years cephalocaudal spread and islands of spared skin Type IV juvenile Prepubertal Localized on the Sharply demarcated areas of Variable circumscribed elbows, knees, follicular hyperkeratosis and palms and soles erythema Type V juvenile First few years Generalized Follicular hyperkeratosis but Chronic atypical of life erythema not prominent, atypical ichthyosiform dermatitis Type VI HIV Any age Generalized Similar to type III. HIV- May respond to associated associated follicular antiretroviral therapy syndrome may be present From Goldsmith et al. ( 1982 ) most common expression of PRP among chil- tion. Nails and rarely oral mucosa may be dren. Some studies reported type III, the classical affected. Most of them have an excellent progno- juvenile form, to be more common. Different eth- sis with an acute course culminating in resolu- nic or genetic backgrounds may underlie this tion within 6 months. Few may follow a controversy, as Asian children tend to develop a prolonged course but self-limit within a year, more localized (type IV) form of PRP. with almost 90 % resolving in 3 years (Gelmetti et al. 1986 ). Partial healing of type III form may transform it to type IV form and follow a pro- Juvenile Classical (Type III) tracted course.

The onset of type III juvenile classical PRP is seen at around 5–10 years of age with clinical Juvenile Circumscribed (Type IV) features same as of adult (type I) form. The disease usually starts on the head, neck, or upper Type IV juvenile circumscribed PRP is the torso, in the form of an erythematous scaly mac- most common type of PRP in children with ule that gradually develops characteristic follicu- onset usually seen in prepubertal years. It is lar and/or perifollicular papules with central characterized by well-circumscribed, erythe- acuminate plug which gives it the characteristic matosquamous plaques studded with follicular nutmeg grater feel (Fig. 6.1). Within few weeks and/or non- follicular papules with prominent these papules coalesce to form large zones of central plugs. These typical PRP lesions are erythematosquamous plaques studded with acu- most often sharply demarcated and localized to minate papules, generalizing in cephalocaudal elbows and knees (Fig. 6.3 ), but occasionally direction and typically sparing islands of unaf- they can be seen on the dorsum of hands or fected skin (Fig. 6.2). Scaling is ﬁ ne bran-like on feet, distal arms or legs, and rarely on trunk or the upper torso, including the scalp, and coarser scalp. More than three fourth of patients may on the lower body. Occasionally, it can progress show palmoplantar involvement with over half to erythroderma with or without ectropion, but of them showing nail changes. The clinical classical islands of spared skin and hyperkerato- course of type IV PRP is marked by remissions sis of palms and soles may be helpful signs, if and exacerbations, with no tendency to gener- the diagnosis is controversial. A preceding acute alize and ultimately may disappear in the late infection or trauma can precipitate this condi- teens. 54 N. Al-Mutairi

a b

c d

Fig. 6.1 ( a – d ) Juvenile classical (type III) PRP starting on the upper torso as erythematous scaly macule with characteristic follicular and/or perifollicular papules 6 Childhood Pityriasis Rubra Pilaris 55

a b

Fig. 6.2 (a , b ) Juvenile classical (type III) PRP papules coalesce to form large zones of erythematosquamous plaques sparing islands of unaffected skin

Juvenile Atypical (Type V) shortly after or at the same time when the patient tested positive for HIV infection. It differs from Type V is a relatively rare and atypical expres- the classical disease by the presence of HIV sion of PRP observed mainly in children. It infection usually without evidence of immuno- appears either in the 1st year of life or at birth. It suppression, poor response to systemic retinoids, presents as mild to severe erythema, follicular and variable association with HIV-follicular syn- hyperkeratosis, and keratoderma. Ichthyosiform drome. Apart from fi liform keratosis of the face features, sclerodermatous changes of the digits, and trunk, acne conglobate, hidradenitis suppura- or seborrheic dermatitis-like scaling of the scalp tiva, and lichen spinulosus are the other features observed over the course of disease may pose dif- of HIV-associated follicular syndrome. HIV fi culty in diagnosing it with full confi dence. It is infection has been contemplated to induce PRP often resistant to treatment, but can clear sponta- in genetically predisposed individuals with modi- neously after following a chronic course. Most fi cation of its clinical features. Response of type cases of familial PRP belong to this type V dis- VI disease to antiretroviral therapy and relapse ease tend to persist throughout life. after stoppage support the role of HIV infection in this form of PRP.

Type VI PRP Associated Features Type VI PRP associated with HIV infection is a recent addition to the classiﬁ cation, as proposed Palmoplantar keratoderma presents an evenly thick by Miralles et al. (1995 ); usually, the onset occurs yellow-orange keratoderma with a sharply demar- 56 N. Al-Mutairi

a intense erythema. PRP has been described in association with various autoimmune diseases like vitiligo, alopecia universalis, hypothyroidism, celiac sprue, etc. Association with internal malignancies or signs of internal malignancies such as eruptive seborrheic keratosis (sign of Leser-Trelat) have been reported in adults with PRP (Albert and Mackool 1999 ).

Differential Diagnosis

Juvenile PRP may often need differentiation from psoriasis. The bimodal age at onset, bran- like fi ne scaling on the scalp, islands of sparing in generalized involvement, characteristic pale- colored palmoplantar keratoderma, and histopathology can help to distinguish juvenile PRP from psoriasis. Other follicular disorders common in childhood which may pose controversy in diagnosis are keratosis pilaris, characterized by a b coiled hair within horny plug and sometimes association with atopy; follicular psoriasis, having Munro microabscesses on histology or accompanying nail pitting or thick scalp scales; lichen spinulosus, a self-limiting childhood dis- Fig. 6.3 ( a , b ) Juvenile circumscribed (type IV) PRP: order with crops of follicular papules with kerati- Sharply demarcated and well-circumscribed erythemato- nous spines; phrynoderma, characterized by squamous plaques localized to elbows ( b ) and knees (a ) monomorphic pigmented follicular papules on the elbows and thighs, curable with vitamin A cated border, delimited by the dorsal aspect of the supplementation; lichen scrofulosorum, a form limbs (Fig. 6.4 ). Griffi ths described this so- called of cutaneous tuberculosis presenting as grouped PRP sandal as a characteristic feature of type III acuminate, scaly, lichenoid follicular papules. PRP. It is found to occur in more than three fourths Atypical presentation of type V PRP may be of the PRP cases involving all subtypes. At times it tough to differentiate from follicular ichthyosis, can be associated with deep fi ssures or hard nonpit- erythrokeratodermas, and other ichthyotic disor- ting edema causing functional disability. ders. Histopathology helps to solve the contro- Nails are affected in more than one third of the versies and confi rm the diagnosis, whenever the children with PRP in the form of thickening of clinical presentation is atypical. nail plates, yellow-brown discoloration, subungual hyperkeratosis, and punctiform hemor- rhages (Allison et al. 2002 ). Mucous membranes Histopathology may be occasionally involved in the form of white lacy plaques of buccal mucosa or ectro- The classical histology of juvenile PRP is same pion. Koebner phenomenon is rare but can occur as that of adults. On light microscopy, the three on the bony prominences. The disease is some- most common features are hyperkeratosis with times accompanied by photosensitivity or pruri- alternating orthokeratosis and parakeratosis tus with a burning sensation due to associated forming a checkerboard pattern in the stratum 6 Childhood Pityriasis Rubra Pilaris 57

a b

Fig. 6.4 ( a – d) Palmoplantar keratoderma presenting an evenly thick yellowish keratoderma associated with deep fi s- sures (a ) corneum, focal or confl uent hypergranulosis, and PRP. Focal acantholytic dyskeratosis in biopsy, follicular plugging with perifollicular parakera- specifi c pattern of keratin components on gel tosis giving a shoulder effect. These and other electrophoresis, and familial PRP having keratin features like thick suprapapillary plates, broad 17 expression on Western blot analysis are more rete ridges, narrow dermal papillae, and sparse diagnostic of PRP. The presence of acantholysis, superfi cial dermal lymphocytic perivascular infi l- hypergranulosis, and follicular plugging and the trate are representative but not pathognomic of absence of Munro microabscesses and dilated 58 N. Al-Mutairi capillaries may help to distinguish PRP from noids are discontinued, although long-term remis- psoriasis. Occasional areas of plasma exudates, sions are possible. The extent of involvement in neutrophilic infi ltrate, and bacterial colonies may post-therapy recurrence is observed to be signifi - indicate an acute infective episode. cantly less than the pretreatment presentation, reinforcing their prolonged effect on the disease (Goldsmith et al. 1982 ). Controversies in Treatment Resistant familial PRP patients with chronic disease extending into their adulthood may Juvenile PRP frequently present as limited require immunosuppressants such as cyclospo- involvement and often has good overall progno- rine and azathioprine in later life. sis. Hence, it generally requires conservative The use of methotrexate is debated in adult management with topical agents, alone or in com- and in pediatric ages. Authors mainly criticize bination. Topical corticosteroids with or without the toxic effects of the drug on the liver and the keratolytics like salicylic acid, urea, 0.05 % treti- apparently high rate of recurrence after cessation noin, and emollients can be helpful to contain of therapy. However, it showed good response in localized disease. They can provide comfort but some reported cases. have little long-term therapeutic effect in manage- There are previous reports of juvenile PRP ment of PRP. Calcipotriol, a vitamin D analogue; treated with a tumor necrosis factor alpha (TNFα) tazarotene, a topical retinoid; tar with anti-infl am- inhibitor. Ruzzetti et al. demonstrated successful matory and antiproliferative properties, and topi- treatment of juvenile PRP with infl iximab cal vitamin A are the other topical agents reported (Ruzzetti et al. 2008 ). to be effective in treating the limited disease. Gomez et al. reported clinical improvement Children with generalized disease, which is with efalizumab in a pediatric patient. Etanercept unresponsive to topical treatments, might require was also successfully tried in juvenile PRP both systemic agents to control their disease. The use with and without acitretin (Gomez et al. 2007 ). of oral retinoids with known delirious effects on Although its use is still off-labeled, bones in the growing phase of childhood has been ustekinumab was used in the treatment of resis- a matter of controversy. Nevertheless, literatures tant cases of juvenile PRP. It showed rapid effi - support the use of short-term oral retinoids effec- cacy, easy way of administration, with no tively in such cases as a fi rst-line systemic ther- hospitalization, and a prolonged time gap apy. Oral isotretinoin in a dose of 1–2 mg/kg/day between subsequent administrations. for 4–6 months demonstrated signifi cant improve- Hoefnagel et al. believed that fumaric acid ment in more than 90 % of the treated patients esters are safe for long-term use as the adverse (Goldsmith et al. 1982 ). Etretinate has also been effects were mostly mild and transient, although found to be effective in a dose of 0.5–1.0 mg/kg/ results in children are sparse (Hoefnagel et al. day for 4–5 months resulting in slightly faster 2003 ; Coras et al. 2005 ). clearance than isotretinoin (Borok and Lowe Stanozolol, penicillin, cloxacillin, antitubercu- 1990 ). Etretinate is often avoided in girls of child- lar drugs, and phototherapy have been also tried in bearing age because of its teratogenic potential anecdotal reports. Highly active triple antiretrovi- and long half-life (etretinate was removed from ral drug therapy has been found to be effective in the US market in 1998). There have been contro- HIV-associated PRP resistant to other therapies. versial reports of high-dose vitamin A therapy to treat PRP, which often leads to liver toxicity. However, oral treatment with carotene, cod or Bulleted List of Controversies halibut liver oil, vitamin E with vitamin A, and aqueous emulsifi ed oral vitamin A in place of oil- • The pathogenesis of PRP is controversial, based vitamin A have been variably successful involving dysfunction in keratinization or (Albert 2002). PRP may return after systemic reti- vitamin A metabolism, an underlying immu- 6 Childhood Pityriasis Rubra Pilaris 59

nological abnormality, or superantigen- Borok M, Lowe NJ. Pityriasis rubra pilaris: further obser- mediated dermatosis as postulated etiologies, vations of systemic retinoid therapy. J Am Acad Dermatol. 1990;22:792–5. resulting in a state of epidermal hyperactivity Coras B, Vogt TH, Ulrich H, Landthaler M, Hohenleutner approaching that of psoriasis. U. Fumaric acid esters therapy: a new treatment • Although vitamin A defi ciency has been con- modality in pityriasis rubra pilaris? Br J Dermatol. troversially incriminated as its etiology in the 2005;152:368–403. Gelmetti C, et al. Pityriasis rubra pilaris in childhood – a past, PRP patients frequently have normal long-term study of 29 cases. Pediatr Dermatol. serum vitamin A levels. Low levels of serum 1986;3:446–51. retinol-binding proteins or an abnormal vita- Goldsmith LA, et al. Pityriasis rubra pilaris response to min A metabolism in the form of altered intra- 13-cis-retinoic acid (isotretinoin). J Am Acad Dermatol. 1982;6:710–5. cellular retinol signaling in the skin has been Gomez M, Ruelas ME, Welsh O, Arcaute HD, Ocampo- suggested as possible pathological mecha- Candiani J. Clinical improvement of pityriasis rubra nisms, requiring further research. pilaris with efalizumab in a pediatric patient. J Drugs • The use of oral retinoids, which has been a mat- Dermatol. 2007;6:337–9. Griffi ths WA. Pityriasis rubra pilaris. Clin Exp Dermatol. ter of controversy, is now considered fi rst- line 1980;5:105–12. systemic therapy, demonstrating signifi cant Hoefnagel JJ, Thio HB, Willemenze R, Bouwes Bavinck outcome and safety, as short-term intervention. JN. Longterm safety aspects of systemic therapy with • Therapy with methotrexate is also controver- fumaric acid esters in severe psoriasis. Br J Dermatol. 2003;149:363–9. sial but works well in a number of cases. Larrègue M, et al. Acute pityriasis rubra pilaris in the • Biologicals could be used in treatment of child. Apropos of 4 cases. Ann Dermatol Venereol. refractory cases of juvenile PRP although 1983;110:221–8. their use is still off-label. Miralles ES, et al. Pityriasis rubra pilaris and human immunodefi ciency virus infection. Br J Dermatol. 1995;133:990–3. Ruzzetti M, Saraceno R, Carboni I, Papoutsaki M, Chimenti S. Type III juvenile pityriasis rubra pilaris: a References successful treatment with infl iximab. J Eur Acad Dermatol Venereol. 2008;22:117–8. Sehgal VN, Srivastava G. (Juvenile) Pityriasis rubra pila- Albert MR, Mackool BT. Pityriasis rubra pilaris. Int ris. Int J Dermatol. 2006;45:438–46. J Dermatol. 1999;38:1–11. Vijayalakshmi AM, Mallika A. Pityriasis rubra pilaris. Allison DS, et al. Pityriasis rubra pilaris in children. J Am Indian Pediatr. 2003;40(5):432–3. Acad Dermatol. 2002;47:386–9. Neonatal Acne Controversies Versus Pityrosporum Folliculitis 7

Nawaf Al-Mutairi

Abstract Neonatal acne is considered to be a common condition of newborns. The major controversy in this age group is whether the lesions truly represent acne or one of a number of heterogeneous papulopustular acneiform conditions typically without comedones, such as transient neonatal pustular melanosis or colonization with Malassezia species as neonatal cephalic pustulosis or pityrosporum folliculitis. Controversies in neonatal acne pathogenesis, clinical presentation, and treatment will be discussed in this chapter.

Keywords Neonatal acne • Neonatal cephalic pustulosis • Pityrosporum folliculitis • Follicular pustules • Malassezia overgrowth

Neonatal acne is not rare but has high chance of Etiology being overlooked or misdiagnosed in this age. It is important to consider and treat. Neonatal acne must Neonatal acne is believed to be caused by stimula- be distinguished from other cutaneous disorders tion of the sebaceous glands by maternal or neona- seen in newborns and from neonatal cephalic pustu- tal androgens that lead to increase sebum excretion losis or pityrosporum folliculitis caused by increased (Kim 2013). Increased production of dehydroepi- colonization with Malassezia species. Persistence androsterone (DHEA) in neonates occurs in asso- of neonatal acne beyond 12 months of age may rep- ciation with a large androgen-producing zona resent a virilization syndrome (such as congenital reticularis in the fetal adrenal glands (Eichenﬁ eld adrenal hyperplasia or adrenal tumor) and may pre- and Mancini 2013 ). DHEA levels drop off at dict development of severe adolescent acne. around 1 year of age as a consequence of involution of the neonatal adrenal gland (Lucky 1998 ). Testicular production of androgens is the second factor believed to cause neonatal acne. Boys have N. Al-Mutairi , MD, FRCPC pubertal levels of testosterone during the ﬁ rst 12 Dermatology Unit, Department of Medicine, Faculty of Medicine , Kuwait University , Kuwait months of age which might explain why acne is e-mail: [email protected] more common in male infants than in female infant

(Jansen et al. 1997 ). There is also transplacental passage of maternal androgens, which stimulate sebaceous glands. An abnormal sensitivity of pilosebaceous follicles to normal levels of circulating hormones has also been postulated to explain the occurrence of neonatal and infantile acne. The observation that some infants have a family history of severe acne or hyperandrogenism suggests possible role of genetic factors (Katsambas et al. 1999 ). A more pustular presentation of neonatal acne has been described and termed neonatal cephalic pustulosis. A relationship between this condition and Malassezia furfur and M. sympodialis has been suggested (Kim 2013).

Fig. 7.1 Neonatal acne Controversies in Etiology

The etiology of neonatal acne is controversial. It may be due to stimulation of the sebaceous glands by maternal or neonatal androgens that lead to increase sebum excretion or due to increased colonization with Malassezia species (normal commensal ﬂ ora of infant skin) or may represent an inﬂ ammatory reaction to Malassezia overgrowth during neonatal period.

Clinical Presentation Fig. 7.2 Neonatal acne: closed comedones, papules, and Acne neonatorum occurs in up to 20 % of new- pustules on the face primarily on the cheeks, chin, and borns. The lesions of neonatal acne may pres- forehead ent from birth to age 4 weeks. The lesions are primarily on the face on the cheeks (Fig. 7.1 ), exclusion of virilization as its underlying cause, chin, eyelids, and forehead (Cantatore-Francis and the possible implication of severe acne in and Glick 2006 ). The lesions seen are also sim- adolescence (Antoniou et al. 2009 ). In infants ilar to adolescent acne including open and and children under 7 years of age with signifi cant closed comedones, papules, pustules (Fig. 7.2), acne vulgaris, evaluate for signs of sexual pre- and occasionally nodules. All of the lesions are cocity, virilization, and/or growth abnormalities in similar stage. Most infants exhibit few that may indicate an underlying systemic abnor- lesions; only a minority has disease severe mality (Eichenfi eld et al. 2013 ). enough to prompt medical attention (White 1998). Persistence of neonatal acne beyond 12 months of age should arouse suspicion of Controversy in Clinical Presentation endocrine abnormalities (Eichenfi eld and Mancini 2013 ). Many acneiform eruptions can be misdiagnosed The clinical importance of neonatal acne lies as neonatal acne. The main controversy lies in in its differentiation from infectious diseases, the differentiating from colonization with Malassezia 7 Neonatal Acne Controversies Versus Pityrosporum Folliculitis 63 yeast species. It presents as either neonatal The infl ammation and occlusion of hair follicles cephalic pustulosis or pityrosporum folliculitis. may be the result of the ability of Malassezia lipase to hydrolyze triglycerides into free fatty Neonatal Cephalic Pustulosis (NCP) acid (Gupta et al. 2004 ). It was also reported that It is actually not acne and is much more common Malassezia species induce the production of than acne. It presents in newborns, in the fi rst few infl ammatory cytokines on human epidermal weeks of life, as papules and pustules on the keratinocytes (Baroni et al. 2006 ). Several factors cheeks, chin, eyelids, and forehead (Cantatore- can lead to changes in immunity, sebum produc- Francis and Glick 2006 ) Comedones are absent. tion, and humidity. These factors help to produce NCP represents follicular or poral colonization favorable conditions for growth of these yeasts with Malassezia sympodialis and Malassezia and allow it to become an opportunistic pathogen globosa (Bernier et al. 2002 ). It is usually self- (Ayers et al. 2005 ). limiting and does not require any treatment. Pityrosporum folliculitis manifest as chronic, Reassuring the parent is usually the only man- erythematous, pruritic papules, and pustules, agement needed (Eichenfi eld et al. 2013 ). which occur in a follicular pattern with perifol- Cephalic pustulosis is actually almost identical to licular erythema. These lesions are usually pres- pityrosporum folliculitis. ent on the back and chest and, occasionally, on the neck, shoulders, upper arms, and face. Often, Pityrosporum Folliculitis patients have been treated with medication appro- This acneiform eruption is often misdiagnosed as priate for acne vulgaris, resulting in no improve- acne vulgaris caused by Malassezia yeast over- ment or worsening of their condition (Levy growth secondary to occlusion of hair follicle or 2007 ). Recalcitrant acne should be reevaluated disturbance of normal cutaneous fl ora (Fig. 7.3 ). for potential pityrosporum infection (Rubenstein and Malerich 2014). Pityrosporum folliculitis is recognized as one that affects youths and young and middle-aged adults. However, three cases of pityrosporum folliculitis occurred in an ICU setting in older individuals who were in consecutive beds, who received care from the same nursing staff, and who all received high-dose antibiotics (Archer-Dubon et al. 1999 ). The very young can also be affected. In 2013, Anane described an unusual case of Malassezia folliculitis occurring in a 3-month-old immunocompetent boy (Anane 2013 ). On clinical examination, 1–2 mm superfi - cial follicular pustules were observed on his face, neck, and upper trunk. Malassezia folliculitis is diagnosed on the basis of clinical picture, microscopy, and response to therapy. Microscopic examination of pustules with a potassium hydroxide preparation shows budding yeast forms and spores. Based on the clinical and mycological data, the diagnosis of Malassezia folliculitis was made. The prognosis of pityrosporum folliculitis is good. Pityrosporum folliculitis can completely resolve without treatment. In severe cases, appli- Fig. 7.3 Pityrosporum folliculitis: erythematous papules and pustules occurring in a follicular pattern with perifol- cation of ketoconazole 0.2 % solution (dilute the licular erythema on the chest, shoulder, face, and back 2.0 % shampoo) by cotton bud to the affected 64 N. Al-Mutairi area twice daily leads to rapid clearing (Jelinek versy to use anti-acne medication like erythro- and Cameron 2011 ). mycin solution 2 % and benzoyl peroxide gel 2.5 % or to use the antifungal medication clotrimazole as another possible treatment Differential Diagnosis option. of Neonatal Acne

There are a number of acneiform eruptions that Bulleted List of Controversies should be considered in the differential diagnosis including bacterial folliculitis, herpes simplex • Acne is defi ned by pustules, papules, comedo- virus, and varicella zoster virus (Antoniou et al. nes, and scars. So-called neonatal acne 2009 ). Other neonatal eruptions such as erythema lacks comedos and is considered by some toxicum neonatorum, transient neonatal pustular experts as cephalic pustulosis or pityrosporum melanosis, milia, pustular miliaria, and skin colo- folliculitis. nization by fungi of Malassezia species, as well • It is therefore diffi cult to confi rm the diagnosis as a drug eruption associated with hydantoin, of neonatal acne. There is controversy over lithium, or halogens, should be considered whether it is truly acne or whether it repre- (Morgan et al. 2009 ; Borton and Schwartz 1981 ; sents a form of papulopustular conditions Kufl ick and Schwartz 2000 ). (e.g., erythema toxicum neonatorum, eosino- philic folliculitis, transient neonatal pustular melanosis, milia, miliaria) that occur during Treatment the newborn period. • So-called neonatal acne also must be distin- Parents should be reassured that neonatal acne is guished from acne that is induced by topical mild, self-limiting and generally resolves sponta- application of oils and ointments (acne vene- neously without scarring in approximately 1–3 nata) and from acneiform eruptions induced months (Antoniou et al. 2009 ). In most cases, no by acnegenic maternal medications such as treatment is needed. If necessary, comedones may hydantoin (fetal hydantoin syndrome) and be treated with azelaic acid cream 20 % or treti- lithium. noin cream 0.025–0.05 % (Antoniou et al. 2009 ). • The relationship between neonatal acne and For infl ammatory lesions, erythromycin solution neonatal cephalic pustulosis, which is charac- 2 % and benzoyl peroxide gel 2.5 % may be used terized by papules and pustules without com- (Van Praag et al. 1997 ). Twice-daily erythromycin edones, is controversial; some like Antoniou 125–250 mg is the treatment of choice when oral et al. (2009 ) consider them to be two different antibiotics are indicated. Tetracyclines are contra- entities, while others like Mancini et al. do not indicated in the treatment of neonatal and infantile (Mancini et al. 2011 ). acne (Kim and Mancini 2013 ). Severe or recalci- • The treatment of neonatal acne is still a con- trant disease warrants a workup for congenital troversy, as it might resolve alone without adrenal hyperplasia, a virilizing tumor, or underly- treatment ,or treating it with acne medication ing endocrinopathy (Katsambas et al. 1999 ). versus antifungal medication needs to be considered. • Evaluation for hyperandrogenism, such as Controversy of Treatment congenital adrenal hyperplasia or adrenal tumor, should be reserved for those infants The disease is self-limited, so many families and with severe or persistent typical disease with physicians chose not to treat with medication. all the cornerstones of acne according to the For those who prefer treatment, there is a contro- defi nition. 7 Neonatal Acne Controversies Versus Pityrosporum Folliculitis 65

References Eichenfi eld LF, Krakowski AC, Piggott C, Del Rosso J, Baldwin H, et al. Evidence-based recommendations for the diagnosis and treatment of pediatric acne. Anane S, Chtourou O, Bodemer C, Kharfi M. Malassezia Pediatrics. 2013;131(S):163–86. folliculitis in an infant. Med Mycol Case Rep. Gupta AK, Batra R, Bluhm R, Boekhout T, Dawson 2013;2:72–4. TL. Skin diseases associated with Malassezia species. Antoniou C, Dessinioti C, Stratigos AJ, et al. Clinical and J Am Acad Dermatol. 2004;51:785–98. therapeutic approach to childhood acne: an update. Jansen T, Burgdorf WH, Plewig G. Pathogenesis and Pediatr Dermatol. 2009;26:373–80. treatment of acne in childhood. Pediatr Dermatol. Archer-Dubon C, Icaza-Chivez ME, Orozco-Topete R, 1997;14:17–21. Reyes E, Baez-Martinez R, Ponce de Leon S. An epi- Jelinek G, Cameron P. Text book of pediatric emergency demic outbreak of Malassezia folliculitis in three adult medicine. Medical Ian Event; 2011. patients in an intensive care unit: a previously unrec- Katsambas AD, Katoulis AC, Stavropoulos P. Acne neo- ognized nosocomial infection. Int J Dermatol. natorum: a study of 22 cases. Int J Dermatol. 1999;38(6):453–6. 1999;38:128–30. Ayers K, Sweeney SM, Wiss K. Pityrosporum folliculitis: Kim W, Mancini AJ. Acne in childhood: an update. diagnosis and management in 6 female adolescents Pediatr Ann. 2013;42(10):418–27. with acne vulgaris. Arch Pediatr Adolesc Med. K u fl ick JH, Schwartz RA. Acneiform eruptions. Cutis. 2005;159(1):64–7. 2000;66:97–100. Baroni A, Orlando M, Donnarumma G, Farro G, Iovene Levy A, Feuilhade de Chauvin M, Dubertret L, Morel P, MR, Tufano MA, et al. Toll-like receptor 2 (TLR2) Flageul B. [Malassezia folliculitis: characteristics and mediates intracellular signalling in human keratino- therapeutic response in 26 patients]. Ann Dermatol cytes in response toMalassezia furfur. Arch Dermatol Venereol. 2007;134(11):823–8. Res. 2006;297:280–8. Lucky AW. A review of infantile and pediatric acne. Bernier V, Weill FX, Hirigoyen V, Elleau C, Feyler A, Dermatol (Basel Switzerland). 1998;103:643–9. Labrèze C, et al. Skin colonization by Malassezia spe- Mancini AJ, Baldwin HE, Eichenfi eld LF, et al. Acne life cies in neonates: a prospective study and relationship cycle: the spectrum of pediatric disease. Semin Cutan with neonatal cephalic pustulosis. Arch Dermatol. Med Surg. 2011;30(3):2–5. 2002;138:215–8. Morgan AJ, Steen CJ, Schwartz RA, et al. Erythema toxi- Borton LK, Schwartz RA. Pityrosporum folliculitis: cum neonatorum revisited. Cutis. 2009;83:13–6. acommon acneiform condition of middle age. Ariz Rubenstein RM, Malerich SA. Malassezia (pityrosporum) Med. 1981;38:598–601. folliculitis. J Clin Aesthet Dermatol. 2014;7(3): Cantatore-Francis JL, Glick SA. Childhood acne: evalua- 37–41. tion and management. Dermatol Ther. 2006;19: Van Praag MC, Van Rooij RW, Folkers E, et al. Diagnosis 202–9. and treatment of pustular disorders in the neonate. Eichenfi eld LF, Mancini AJ. PedAcne resource guide: a Pediatr Dermatol. 1997;14:131–43. comprehensive overview of pediatric acne & compan- White GM. Recent fi ndings in the epidemiologic evi- ion to the online self-assessment exam. New York: dence, classifi cation, and subtypes of acne vulgaris. Education Testing & Assessment Systems; 2013. J Am Acad Dermatol. 1998;39:S34–7. Part III Tumors

Controversies in the Treatment of Infantile Haemangiomas 8 with β-Blockers

Sherief R. Janmohamed , Nisha Suyien Chandran , and Arnold P. Oranje

Abstract The management and therapy of infantile haemangioma (IH) have changed greatly over the years, especially after 2008 with the observation that propranolol, a non-selective β-blocker, inﬂ uences IH growth and regression. Beta-blocking agents, in particular propranolol, are now widely used, both orally and topical. However, a uniform strategy is not yet available and currently a lot of patients with alarming and non-alarming IHs are being treated with different β-blockers, different dosages and different durations. Also management before and during treatment differs and side effects are not clear. We conclude that there are a lot of controversies in the treatment of IHs with β-blockers, and in this chapter, we discuss these controversies and substantiate these with the available evidence.

Keywords Atenolol • β -Adrenergic receptors • β -Blockers • Haemangioma • Hemangiol • Infantile haemangioma • Nadolol • Propranolol • Timolol • Treatment • Tumour of infancy

S. R. Janmohamed , MD, PhD, MHS, MSc The incidence of infantile haemangioma (IH) Department of Dermatology , Universitair Ziekenhuis varies greatly in the literature but it is the most Brussel (UZB), Vrije Universiteit Brussel (VUB) , frequent occurring tumour of infancy with inci- Laarbeeklaan 101, 1090 Brussels , Belgium dences of 5–10 % up to 20 % in prematures e-mail: [email protected] (Bruckner and Frieden 2003 , 2006 ; Chiller et al. N. S. Chandran , MRCP (UK) 2002 ). IHs occur predominantly in the Caucasian Division of Dermatology , University Medicine Cluster, National University Hospital , population (Mulliken and Enjolras 2004 ). They Singapore , Singapore follow a typical course: they arise within the ﬁ rst A. P. Oranje , MD, PhD (*) few days to weeks after birth and grow exponen- Department of Dermatology , tially for up to 6–9 months. Thereafter, regres- Dermicis Skin Hospital – Alkmaar , sion follows with approximately 10 % per year, Kinderhuid.nl – Rotterdam, Rotterdam, meaning that at the age of 5 years 50 % of IHs The Netherlands e-mail: [email protected] have disappeared, at the age of 7 years 70 %, and

© Springer International Publishing Switzerland 2016 69 A.P. Oranje et al. (eds.), Practical Pediatric Dermatology, DOI 10.1007/978-3-319-32159-2_8 70 S.R. Janmohamed et al. most IHs have gone at the age of 10 years (Luu near the eye, rapid growth of internal haemangi- and Frieden 2013 ). However, scarring may oma, e.g. near the trachea or in the liver). In these remain in more than half of the regressed IH cases, oral therapy is indicated without delay. (Bauland et al. 2011 ; Luu and Frieden 2013 ). Some non-alarming IHs, especially those in the Although IHs are benign and self-limiting, severe face, can be treated topically, e.g. for cosmetic complications can arise due to localisation and reasons or given the fact that IHs leave scars in accelerated tumour growth (Chiller et al. 2002 ; >50 % of cases. It is also possible to treat deeper Haggstrom et al. 2006 ; Janmohamed et al. IHs with a visible superﬁ cial part topically in 2012b ). In these cases, therapy is necessary. The order to diminish the visible discoloration. management of IH can vary from conservative (watchful waiting) to radical (surgery/excision), and management and therapy have changed Working Mechanism of Β-Blockers greatly over the years, especially after 2008. Propranolol is a non-selective β-blocker and its The autonomic nervous system consists of the effect on IHs was serendipitously discovered in parasympathetic nervous system and the sympa- 2008 in France (Leaute-Labreze et al. 2008 ). An thetic nervous system. Important receptors of infant with an IH was given corticosteroids, and these systems are the α-adrenergic receptors and because of cardiac side effects, propranolol was the β-adrenergic receptors. Beta-blockers bind to administered. After propranolol, quick regression β-adrenergic receptors and antagonise the sym- was observed. The authors thereupon began treat- pathetic effects of epinephrine/norepinephrine. ing IHs with propranolol and a follow-up study There are several β-adrenergic receptors: β1 - showed good results (Sans et al. 2009 ). adrenergic receptors are found in the heart and

Propranolol then soon became the ﬁ rst choice of kidneys, and β 2 -adrenergic receptors are located treatment, even though it has to be administered in the lungs, gastrointestinal tract, liver, uterus, for some time and often is not fully effective. vascular smooth muscle and skeletal muscle. Fat

Still, more and more patients are now treated cells also have β 3 -adrenergic receptors, which are with both orally and topically administered not further discussed here. Beta-blocking agents β-blockers for its good and fast results (Frieden are mainly used for their effects on heart and and Drolet 2009 ; Lawley et al. 2009 ; Manunza blood vessels. The ﬁ rst β-blocker, propranolol, et al. 2010 ; Schiestl et al. 2011 ). Clinicians would was discovered in 1964 by Sir James W. Black. do well, however, to consider whether treatment Beta-blockers can be non-selective, acting on β1 - is really necessary. Treatment may have changed and β 2-adrenergic receptors, e.g. propranolol, and over the last years, but IHs are still self-limiting. selective, acting only on β 1 -adrenergic receptors, e.g. atenolol. However, β-receptor selectivity is dose dependent: at higher concentrations, selec- Alarming Versus Non-alarming IHS tive β-blockers lose their selective capabilities. Furthermore, β-blockers are either more lipo- IHs are very heterogeneous and therefore require philic or more hydrophilic. More lipophilic individual assessment. Some are very small and β-blockers will pass the blood-brain barrier, giv- superﬁ cial, and relatively slowly growing, but ing wanted and unwanted effects. Stimulation of others may be very big, with a part under the skin β1 -adrenergic receptors by epinephrine/norepi- and growing very rapidly. It would be helpful to nephrine induces a positive chronotropic and ino- distinguish between two groups: non-alarming tropic effect on the heart and increases cardiac IHs and alarming IHs. Non-alarming IHs do not conduction velocity and automaticity. Stimulation cause immediate danger and a ‘watch and wait’ of β 1-adrenergic receptors on the kidney causes management is adequate. Alarming IHs are IHs renin release. Stimulation of β 2 -adrenergic recep- that give immediate problems or are expected to tors induces smooth muscle relaxation, induces give problems at the short term (rapid growth tremor in skeletal muscle and increases glycoge- 8 Controversies in the Treatment of Infantile Haemangiomas with β-Blockers 71 nolysis in the liver and skeletal muscle. Safety and Side Effects

Stimulation of β3 -adrenergic receptors induces of Β-Blockers lipolysis. Thus selective β-blockers reduce excitement/physical exertion on heart rate and Side effects, however rare, have to be considered force of contraction (β1 -adrenergic receptors). (Lawley et al. 2009). The most common serious Non-selective β-blockers have additional effects, side effects include bradycardia and hypotension. namely, vasoconstriction of blood vessels, con- Bronchospasm can be seen in patients with reac- striction of bronchi, reduction of tremor and tive airway diseases. Furthermore, dyspnoea, reduction of breakdown of glycogen (β2 - cold acral surfaces, provocation of decompensa- adrenergic receptors) (Rang et al. 2011 ; Jänig tio cordis (congestive heart failure) or hypogly- 2006 ; Perez 2006 ). caemia, nightmares and decreased cardiac output are described (Table 8.1 ) (Reiter 2004 ). Therefore, important contraindications in chil- Working Mechanism of β-Blockers dren are sinus bradycardia, AV block, hypoten- in IH sion, asthma and decompensatio cordis, among other things (Table 8.2 ). Furthermore, even caries Very little is known about the mechanism of is described as a side effect of propranolol treat- action of propranolol in IH (Li et al. 2015 ). In ment, resulting from the sweetened solution in 2010, Storch and Hoeger presented an overview which propranolol suspension is being produced of how propranolol interferes with endothelial by some pharmacists (Giron-Vallejo et al. 2010 ). cells, vascular tone, angiogenesis and apoptosis This will be less of a problem nowadays with the (Storch and Hoeger 2010). They distinguished recent availability of Hemangiol, which is EMA three stages, with immediate (early), intermedi- and FDA approved. ate and long-term effects. These effects of pro- Real side effects are rare, but there are some pranolol on IH can be attributed to three different publications reporting hypoglycaemia and hypo- pharmacological targets. Early effects (lightening tension (Breur et al. 2011 ; de Graaf et al. 2011 ; of the colour of the IH surface within 1–3 days Holland et al. 2010 ) in patients receiving pro- after start of therapy) are attributable to vasocon- pranolol. However, these are rarely directly striction due to decreased release of nitric oxide. related to propranolol. Beta-blockers do not com- Intermediate effects are due to the blocking of monly induce hypotension, but there is a miscon- proangiogenic signals (vascular endothelial ception with regard to the mechanism of action of growth factor, basic ﬁ broblast growth factor, propranolol, in particular, concerning its effect matrix metalloproteinases 2 and 9) and result in on blood pressure. Beta-blockers act on β1 - growth arrest. Long-term effects of propranolol adrenoceptors in the heart, thereby preventing the are characterised by induction of apoptosis in positive chronotropic and inotropic effects medi- proliferating endothelial cells, which results in ated by these receptors. Non-selective beta- tumour regression (Storch and Hoeger 2010 ). blockers (like propranolol) will also antagonise Kum and Khan further differentiated between the vasorelaxant effect that occurs following

IH-derived endothelial cells and IH-derived stem stimulation of vascular β 2 -adrenoceptors. An cells (Kum and Khan 2014 ). They were the fi rst increase in peripheral vascular resistance will to fi nd that there was no apoptosis in IH-derived occur, both due to the direct vascular effects of stem cells. Apoptosis was however seen in propranolol and to activation of the baroreceptor IH-derived endothelial cells. It can be hypothe- refl ex. Blood pressure is therefore unlikely to fall sised that early effects, due to vasoconstriction, acutely, but usually only after several weeks of might be more pronounced when using non- treatment when these compensatory mechanisms selective β-blockers such as propranolol, as have disappeared. Obviously, the effects of beta- selective β-blockers have no effect on β 2 - blockade will be particularly apparent in patients adrenergic receptors. in whom the sympathetic nervous system has 72 S.R. Janmohamed et al.

Table 8.1 Side effects of oral β-blockers Very common (>10 %) Common (1–10 %) Uncommon (>0.1 %) Unknown frequency Bronchitis Bronchiolitis, bronchospasm, AV block, decreased Bradycardia, symptomatic Sleep disorders slightly decreased blood heart rate hypotension Diarrhoea, vomiting pressure Decreased blood Vasoconstriction, Raynaud’s Nightmares, irritability, glucose phenomenon somnolence Hypoglycaemic seizures Constipation, acrocyanosis/ cold extremities

Table 8.2 Contraindications for oral β-blockers Contraindications Specifi cations, reference values Neonates 0–4 weeks Exceptions for rapidly growing, immediately life-threatening infantile haemangioma Potential drug interactionsa Calcium channel blockers and other antihypertensive agents, antiarrhythmic agents (propafenone, quinidine, amiodarone, lidocaine), digitalis glycosides, dihydropyridines, NSAID, lipid lowering drugs, rifampicin, phenobarbital, corticosteroids, etc. Bronchial asthma AV block II–III° sick sinus syndrome Bradycardia, hypotension Reference values (lower limits of normal for age) Age [months] HR [bpm] RR [mmHg] 0–3 100 65/45 3–6 90 70/50 6–12 80 80/55 Cardiac failure Proneness to hypoglycaemia Metabolic diseases, e.g. glycogenosis Hypersensitivity to propranolol hydrochloride Phaeochromocytoma Raynaud’s syndrome a Drug intake history also refers to lactating women been activated, and little or no effect on blood number of case reports published after 2008 pressure is expected in healthy, normotensive describe hypoglycaemia as a side effect in chil- people (Rang et al. 2011 ; Janmohamed et al. dren with IH treated with propranolol (Breur 2012a ). However, these case reports of adverse et al. 2011 ; Lawley et al. 2009 ). However, on effects can result in doctors being over cautious close reading, it appears that most patients who and lead to recommendations and requests for were hypoglycaemic had an underlying condi- unnecessary blood pressure measurements. tion; often they were ill or feverish (rectal tem- Hypotension is not a frequent side effect of pro- perature <36 or >38.5 °C) and were in a fasting pranolol in the treatment of IH. In reporting state (Puttgen et al. 2013). This observation has hypotension, only values below p5 should be been summarised by Holland et al. (Holland et al. regarded to as too low (or symptomatic patients). 2010 ). The mechanism by which hypoglycaemia Hypoglycaemia is another side effect. develops, aside from less oral intake, is not com- However, it is well known that this occurs mostly pletely understood. Also, normal glucose homeo- in the neonatal period. Older infants and children stasis is thought to be impaired through inhibition are considered to be low risk and IH therapy is of adrenergic-mediated glycogenolysis, gluco- generally started after the neonatal period. A neogenesis and lipolysis. Children (and infants) 8 Controversies in the Treatment of Infantile Haemangiomas with β-Blockers 73 seem to be at a higher risk for this adverse effect et al. 2013). Blood pressure and glucose are because their glucose use is higher while fasting closely monitored and an ECG is taken. Relapses (attributed partly to their greater brain mass rela- were commonly seen and therefore therapy lasted tive to their body weight). In addition, glycogen for more than 1 and even 2 years (Marqueling stores are lower in infants and children compared et al. 2013 ). Nowadays most infants start with with adults, leading to a reduced fasting ability propranolol in a day-care unit. Just recently, (Fonseca 2010 , Janmohamed et al. 2011 ). Thus, results from an international study were pub- when treating healthy infants with beta-blockers, lished regarding the optimal dosage and duration hypoglycaemia normally does not occur. of propranolol therapy in the treatment of IH Therefore, it is not necessary to check the glu- (Drolet et al. 2013 ; Leaute-Labreze et al. 2015 ). cose level frequently. Especially when treating It seemed that propranolol therapy with 3 mg/kg/ with topical beta-blockers, there is a minimal use day (to be administered twice daily) is superior and the penetration through the skin is also mini- with no extra side effects. In most patients, thermal (see Chap. 8 ). apy can then be stopped after 6 months. Propranolol has been used in IH since 2008 Guidelines have recently also been proposed by a and therefore it has been widely used in paediat- European expert group in a consensus meeting ric cardiology. There are numerous reports show- and are summarised in Fig. 8.1 (Hoeger et al. ing its effi cacy and safety, and there are a lot of 2015 ). Blood glucose is not advised as a stan- trials running currently. This is not true for other dard, and pretreatment ECG is of limited value β-blockers (Table 8.3 ). However, it remains for patients with an unremarkable cardiovascular uncertain that the effects on cardiovascular, gross history and a normal heart rate and blood pres- motor or neurocognitive systems in the long term sure (Raphael et al. 2015 ). will be of early (and prolonged) exposition to a Bronchial hyperreactivity is a relative contra- lipophilic β-blocker that passes the blood-brain indication for propranolol treatment due to the barrier. However, evidence-based propranolol effect of propranolol on the β2 -receptors in the remains the fi rst choice. Selective β-blockers that airways. Some authors have considered, for do not cross the blood-brain barrier might have example, atenolol, a selective β-blocker (Raphael less central side effects such as nightmares or et al. 2011 ; Sharma et al. 2013 ). However, there sleep disturbances, but on the other hand, they is not enough evidence of the results. Given the might also work less effectively in terms of cen- good effect and few side effects of propranolol, tral effects and peripheral vasoconstriction. other (selective) β-blockers are generally not Finally, with the availability of Pierre Fabre’s advised in the treatment of IH. Table 8.3 shows Hemangiol, which has been FDA and EMA all β-blockers used in the treatment of IH with approved, off-label treatment of IH with other comments and their (dis)advantages. Note that β-blockers (under normal conditions) is normally because of a different half-time, some β-blockers not allowed in most countries. can be administered once daily. Figure 8.2 shows the evolution of a patient with an IH, treated with oral propranolol. Systemic Therapy of IH with β-Blockers Topical Therapy of Small Superfi cial Although used in IH since 2008 and many years IH with β-Blockers before in paediatric cardiology, a uniform recommendation on dosage, starting up and duration of Before 2008, topical treatment of IH was rare, propranolol is not yet available. Most physicians mainly from fear of side effects of the available tended to start very carefully, for example, at a options. After 2008, topical β-blockers were pro- dosage of 1 mg/kg/day and increasing this to duced and superfi cial IHs were more easily 2 mg/kg/day during hospitalisation (Marqueling treated by these drugs. Bonifazi and colleagues 74 S.R. Janmohamed et al.

Table 8.3 Beta-blockers used in the treatment of infantile haemangioma (IH) with comments and their (dis)advantages (2015 06 06) β-Blocker Comments Advantages Disadvantages Oral propranolol Non-selective More experience 2 or 3 times daily Lipophilic FDA/EMA-approved solution Passes blood-brain barrier 0.5–3 mg/kg/day available (Hemangiol/Hemangeol) (?) PubMeda : 525 Not selective (cave Trials b : 15 bronchial hyper-reactivity) Oral atenolol Selective Once daily Less experience Hydrophilic Does not pass the blood-brain barrier No uniform formulation 0.5–3 mg/kg/day (less central side effects?) Selective: no peripheral PubMed a : 2 groups Selective: can be used in children vasoconstriction (?) Trials b : 1 with bronchial hyper-reactivity Oral nadolol Non-selective Once daily Less experience Hydrophilic Does not pass the blood-brain barrier No uniform formulation 0.5–3 mg/kg/day Not selective (note: PubMed a : 3 groups bronchial hyper-reactivity) Trials b : 1 Topical propranolol 1–2 % Cheap Case reports of irritations PubMed a : 20 Good penetration through the skin with higher concentrations Trials b : 1 No uniform formulation Topical timolol 0.1–0.5 % In theory more potent Higher concentration only PubMed a : 67 in ophthalmic solution Trials b : 8 Expensive a Number of publications in PubMed ( www.pubmed.com ) b From trial registers of Europe and the USA ( www.clinicaltrials.gov and www.clinicaltrialsregister.eu )

Fig. 8.1 Recommendations for oral therapy with international randomised controlled trial (Data from β-blockers for infantile haemangioma, based on recom- Hoeger et al. 2015 ; Leaute-Labreze et al. 2015 ) mendations from a European expert group and a large 8 Controversies in the Treatment of Infantile Haemangiomas with β-Blockers 75

a b

Fig. 8.2 A 7-week-old girl with an infantile haemangioma at baseline (a ) and after 5 months of oral propranolol (b )

a b

Fig. 8.3 Small, superfi cial infantile haemangioma at baseline (a ) and after 4 weeks of timolol 0.1 % gel (b ) were the fi rst to use propranolol 1 % cream and shown that (more lipophilic) β-blockers, espe- they described favourable results (Bonifazi et al. cially propranolol, permeate through the skin and 2010 ). Nowadays even case reports of proprano- therefore can be used in IH (Chantasart et al. lol 2 % are published (Mouhari-Toure et al. 2013 ; Zhang et al. 2015 ). On the other hand, 2013). Timolol is a β-blocker that already existed when comparing simple posology schemes, in a gel (0.1 %) and an ophthalmic solution timolol seems to be up to ten times more potent (0.5 %). It is being used in ophthalmology for than propranolol. However, a comparative study glaucoma. Guo et al. and Pope et al. were the fi rst has not been performed until now. Side effects to use timolol for superfi cial IH (Guo and Ni are generally not seen because only (small) 2010 , Pope and Chakkittakandiyil 2010 ). A superfi cial IHs are treated. Dr. Lisa Weibel (per- recent, large randomised controlled trial on timo- sonal communication; not published) and the lol showed that the ophthalmic solution worked previously mentioned authors showed that both better due to a higher concentration, although this propranolol and timolol are indeed systemically may seem illogical as it is an ophthalmic solu- absorbed, but in very small harmless amounts, tion. It is advised to use these topical β-blockers compared to the use in ophthalmology. Timolol 3–4 times daily, consistent with the half-time of has to be used with caution in elderly people with these β-blockers (6 (Chan et al. 2013 ; Oranje pre-existing heart problems (Munroe et al. 1985 ) et al. 2011). Chantasart and colleagues have or when used with occlusion (Zhang et al. 2015 ). 76 S.R. Janmohamed et al.

Figure 8.3 shows the evolution of a patient with a brain barrier. Besides, propranolol has been small, superfi cial IH, treated with timolol gel used in paediatric cardiology long before 0.1 %. 2008. Oral β-Blockers • There is no uniform strategy in treating IHs Bulleted List of Controversies with oral β-blockers. The most recent publications suggest that pretreatment evalua- Indication for Treatment tion should only consist of a full physical • Do all patients with infantile haemangio- examination including heart rate and blood mas (IHs) need treatment? Generally it is pressure. ECG and blood glucose is only accepted to treat only those patients with necessary when indicated (Fig. 8.1 ). alarming IHs with oral β-blockers. For top- • At initiation of propranolol therapy, only ical β-blockers, no uniform guidelines exist heart rate and blood pressure are necessary. at the moment. Small, superfi cial IHs in the Propranolol should be started in a dose of face can be easily treated topically. 1 mg/kg/day (twice daily) and raised in the Working Mechanism of β-Blockers second week to 2 mg/kg/day (twice daily) • It is still not completely understood how and in the third week to 3 mg/kg/day (twice propranolol works in IHs. Early peripheral daily). Propranolol can be stopped after vasoconstriction seems important, as well 6 months depending on the clinical as intermediate (blocking of proangiogenic response. signals) and long-term (induction of • For monitoring during therapy, only heart apoptosis in proliferating endothelial cells) rate every 4 weeks is necessary. effects. • It is not regularly necessary to consult a • Theoretically, selective β-blockers do not paediatric cardiologist prior to initiating give peripheral vasoconstriction and there- therapy. fore cannot give quick results. Topical β-Blockers Side Effects • Do you have to treat topically? Alarming • Are β-blockers really safe? Beta-blockers IHs should be treated orally; therefore, top- are relatively safe: hypoglycaemia nor- ical treatment is not strictly necessary. But mally does not occur in healthy infants and for smaller but cosmetically disturbing hypoglycaemia occurs only in state of fast- IHs, topical treatment may be a good ing (feverish child, diarrhoea). Therefore choice. There are several controversies. inform the parents that in case of an illness • Propranolol and timolol are both used and or fever their child is not allowed to fast. both show good effects. An RCT compar- Parents have to see to it that their child has ing timolol versus propranolol has not been a suffi cient intake or else they have to stop performed yet. Also, concentrations are propranolol. Pay special attention on con- debatable (timolol gel 0.1 % versus timolol comitant medication also causing hypogly- ophthalmic solution 0.5 % versus propran- caemia! Bronchial hyper-reactivity is a olol 1 % and 2 %). contraindication as are some other cardiac • Given the half-life of the drug, it can be diseases. advised to apply the cream 3–4 times daily • There have been numerous publications on but there is a great variation in use. Some safety and effi cacy of propranolol. patients show quick effects and others • The long-term effect on, e.g. memory loss show slower effects after 4–6 months of cannot be predicted at this moment. treatment. But indeed it seems to accelerate • Given the current evidence, there is how- IH regression. ever no indication for using hydrophilic • The safety is not fully clarifi ed but despite β-blockers, which do not pass the blood- systemic absorption, topical use seems 8 Controversies in the Treatment of Infantile Haemangiomas with β-Blockers 77

safe. The surface is normally small and Frieden IJ, Drolet BA. Propranolol for infantile hemangi- concentrations in the blood are much lower omas: promise, peril, pathogenesis. Pediatr Dermatol. 2009;26(5):642–4. than compared to, for example, ophthalmic Giron-Vallejo O, Lopez-Gutierrez JC, Fernandez-Pineda I, use of timolol. Therefore blood glucose Mendez NA, Ruiz Jimenez JI. Dental caries as a side controls are not necessary. effect of infantile hemangioma treatment with propranolol solution. Pediatr Dermatol. 2010;27(6):672–3. Guo S, Ni N. Topical treatment for capillary hemangioma of the eyelid using beta-blocker solution. Arch Ophthalmol. 2010;128(2):255–6. doi: 10.1001/ References archophthalmol.2009.370 . Haggstrom AN, Drolet BA, Baselga E, Chamlin SL, Bauland CG, Luning TH, Smit JM, Zeebregts CJ, Garzon MC, Horii KA, Lucky AW, Mancini AJ, Metry Spauwen PH. Untreated hemangiomas: growth pattern DW, Newell B, Nopper AJ, Frieden IJ. Prospective and residual lesions. Plast Reconstr Surg. study of infantile hemangiomas: clinical characteris- 2011;127(4):1643–8. doi: 10.1097/ tics predicting complications and treatment. Pediatrics. PRS.0b013e318208d2ac . 2006;118(3):882–7. Bonifazi E, Mazzotta F, Colonna V. Topical propranolol in Hoeger PH, Harper JI, Baselga E, Bonnet D, Boon LM, the superﬁ cial infantile hemangioma of the skin. Eur Atti MC, El Hachem M, Oranje AP, Rubin AT, Weibel J Pediatr Dermatol. 2010;20:247–51. L, Leaute-Labreze C. Treatment of infantile haeman- Breur JM, de Graaf M, Breugem CC, Pasmans giomas: recommendations of a European expert group. SG. Hypoglycemia as a result of propranolol during Eur J Pediatr. 2015;174(7):855–65. doi: 10.1007/ treatment of infantile hemangioma: a case report. s00431-015-2570-0 . Pediatr Dermatol. 2011;28(2):169–71. doi:PDE1224 Holland KE, Frieden IJ, Frommelt PC, Mancini AJ, Wyatt [pii]. D, Drolet BA. Hypoglycemia in children taking pro- Bruckner AL, Frieden IJ. Hemangiomas of infancy. J Am pranolol for the treatment of infantile hemangioma. Acad Dermatol. 2003;48(4):477–93; quiz 494-476. Arch Dermatol. 2010;146(7):775–8. doi: 10.1001/ Bruckner AL, Frieden IJ. Infantile hemangiomas. J Am archdermatol.2010.158 . Acad Dermatol. 2006;55(4):671–82. Jänig W. The integrative action of the autonomic nervous Chan H, McKay C, Adams S, Wargon O. RCT of timolol system : neurobiology of homeostasis. Cambridge: maleate gel for superﬁ cial infantile hemangiomas in Cambridge University Press; 2006. 5- to 24-week-olds. Pediatrics. 2013;131(6):e1739– Janmohamed SR, de Laat PC, Madern GC, Dorresteijn 47. doi:peds.2012-3828 [pii]. EM, Jan Danser AH, Oranje AP. Treating hemangi- Chantasart D, Hao J, Li SK. Evaluation of skin perme- oma of infancy with beta-blockers: is there really a ation of beta-blockers for topical drug delivery. Pharm risk of hypotension? J Am Acad Dermatol. Res. 2013;30(3):866–77. doi: 10.1007/ 2012a;67(2):315–6. doi: 10.1016/j.jaad.2012.01.046 ; s11095-012-0928-9 . author reply 316-318. Chiller KG, Passaro D, Frieden IJ. Hemangiomas of Janmohamed SR, de Laat PC, Madern GC, Oranje AP. Do infancy: clinical characteristics, morphologic sub- we have to check glucose in patients with haemangi- types, and their relationship to race, ethnicity, and sex. oma of infancy treated with beta-blockers? J Eur Acad Arch Dermatol. 2002;138(12):1567–76. Dermatol Venereol. 2011;25(12):1490. de Graaf M, Breur JM, Raphael MF, Vos M, Breugem CC, doi: 10.1111/j.1468-3083.2011.04191.x . Pasmans SG. Adverse effects of propranolol when Janmohamed SR, Madern GC, Nieuwenhuis K, de Laat used in the treatment of hemangiomas: a case series of PC, Oranje AP. Evaluation of intra-lesional corticoste- 28 infants. J Am Acad Dermatol. 2011;65(2):320–7. roids in the treatment of peri-ocular haemangioma of doi:S0190-9622(10)00763-2 [pii]. infancy: still an alternative besides propranolol. Drolet BA, Frommelt PC, Chamlin SL, Haggstrom A, Pediatr Surg Int. 2012b;28(4):393–8. doi: 10.1007/ Bauman NM, Chiu YE, Chun RH, Garzon MC, s00383-011-3037-7 . Holland KE, Liberman L, MacLellan-Tobert S, Kum JJ, Khan ZA. Propranolol inhibits growth of Mancini AJ, Metry D, Puttgen KB, Seefeldt M, hemangioma-initiating cells but does not induce apop- Sidbury R, Ward KM, Blei F, Baselga E, Cassidy L, tosis. Pediatr Res. 2014;75(3):381–8. doi: 10.1038/ Darrow DH, Joachim S, Kwon EK, Martin K, Perkins pr.2013.231 . J, Siegel DH, Boucek RJ, Frieden IJ. Initiation and use Lawley LP, Siegfried E, Todd JL. Propranolol treatment of propranolol for infantile hemangioma: report of a for hemangioma of infancy: risks and recommenda- consensus conference. Pediatrics. 2013;131(1):128– tions. Pediatr Dermatol. 2009;26(5):610–4. 40. doi:peds.2012-1691 [pii]. Leaute-Labreze C, Dumas de la Roque E, Hubiche T, Fonseca VA. Effects of beta-blockers on glucose and lipid Boralevi F, Thambo JB, Taieb A. Propranolol for metabolism. Curr Med Res Opin. 2010;26(3):615–29. severe hemangiomas of infancy. N Engl J Med. doi: 10.1185/03007990903533681 . 2008;358(24):2649–51. 78 S.R. Janmohamed et al.

Leaute-Labreze C, Hoeger P, Mazereeuw-Hautier J, Perez DM. The adrenergic receptors in the 21st century. Guibaud L, Baselga E, Posiunas G, Phillips RJ, Totowa: Humana Press; 2006. Caceres H, Lopez Gutierrez JC, Ballona R, Friedlander Pope E, Chakkittakandiyil A. Topical timolol gel for SF, Powell J, Perek D, Metz B, Barbarot S, Maruani A, infantile hemangiomas: a pilot study. Arch Dermatol. Szalai ZZ, Krol A, Boccara O, Foelster-Holst R, 2010;146(5):564–5. doi: 10.1001/ Febrer Bosch MI, Su J, Buckova H, Torrelo A, archdermatol.2010.67 . Cambazard F, Grantzow R, Wargon O, Wyrzykowski Puttgen KB, Summerer B, Schneider J, Cohen BA, Boss D, Roessler J, Bernabeu-Wittel J, Valencia AM, EF, Bauman NM. Cardiovascular and blood glucose Przewratil P, Glick S, Pope E, Birchall N, Benjamin L, parameters in infants during propranolol initiation for Mancini AJ, Vabres P, Souteyrand P, Frieden IJ, Berul treatment of symptomatic infantile hemangiomas. CI, Mehta CR, Prey S, Boralevi F, Morgan CC, Ann Otol Rhinol Laryngol. 2013;122(9):550–4. Heritier S, Delarue A, Voisard JJ. A randomized, con- Rang HP, Dale MM, Ritter JM, Flower R, Henderson trolled trial of oral propranolol in infantile hemangi- G. Rang & Dale’s pharmacology. 7th ed. New York: oma. N Engl J Med. 2015;372(8):735–46. Elsevier Health Sciences; 2011. doi: 10.1056/NEJMoa1404710 . Raphael MF, Breugem CC, Vlasveld FA, de Graaf M, Li P, Guo Z, Gao Y, Pan W. Propranolol represses infantile Slieker MG, Pasmans SG, Breur JM. Is cardiovascular hemangioma cell growth through the beta2-adrenergic evaluation necessary prior to and during beta-blocker receptor in a HIF-1alpha-dependent manner. Oncol therapy for infantile hemangiomas?: a cohort study. Rep. 2015;33(6):3099–107. doi: 10.3892/ J Am Acad Dermatol. 2015;72(3):465–72. or.2015.3911 . doi: 10.1016/j.jaad.2014.12.019 . Luu M, Frieden IJ. Haemangioma: clinical course, com- Raphael MF, de Graaf M, Breugem CC, Pasmans SG, plications and management. Br J Dermatol. Breur JM. Atenolol: a promising alternative to pro- 2013;169(1):20–30. doi: 10.1111/bjd.12436 . pranolol for the treatment of hemangiomas. J Am Manunza F, Syed S, Laguda B, Linward J, Kennedy H, Acad Dermatol. 2011;65(2):420–1. doi:S0190- Gholam K, Glover M, Giardini A, Harper 9622(10)02216-4 [pii]. JI. Propranolol for complicated infantile haemangio- Reiter MJ. Cardiovascular drug class specifi city: beta- mas: a case series of 30 infants. Br J Dermatol. blockers. Prog Cardiovasc Dis. 2004;47(1):11–33. 2010;162(2):466–8. doi:BJD9597 [pii]. doi:S0033062004000209 [pii]. Marqueling AL, Oza V, Frieden IJ, Puttgen Sans V, de la Roque ED, Berge J, Grenier N, Boralevi F, KB. Propranolol and infantile hemangiomas four Mazereeuw-Hautier J, Lipsker D, Dupuis E, Ezzedine years later: a systematic review. Pediatr Dermatol. K, Vergnes P, Taieb A, Leaute-Labreze C. Propranolol 2013;30(2):182–91. doi: 10.1111/pde.12089 . for severe infantile hemangiomas: follow-up report. Mouhari-Toure A, Azoumah KD, Tchamdja K, Saka B, Pediatrics. 2009;124(3):e423–31. doi:peds.2008-3458 Kombate K, Tchangai-Walla K, Pitche P. [Rapid [pii]. regression of infantile haemangioma with 2% pro- Schiestl C, Neuhaus K, Zoller S, Subotic U, Forster- pranolol ointment] Regression rapide d’un hemangi- Kuebler I, Michels R, Balmer C, Weibel L. Effi cacy ome infantile sous propranolol topique a 2 %. Ann and safety of propranolol as fi rst-line treatment for Dermatol Venereol. 2013;140(6–7):462–4. doi:S0151- infantile hemangiomas. Eur J Pediatr. 9638(13)00761-8 [pii]. 2011;170(4):493–501. doi: 10.1007/ Mulliken JB, Enjolras O. Congenital hemangiomas and s00431-010-1324-2 . infantile hemangioma: missing links. J Am Acad Sharma VK, Fraulin FO, Dumestre DO, Walker L, Harrop Dermatol. 2004;50(6):875–82. doi: 10.1016/j. AR. Beta-blockers for the treatment of problematic jaad.2003.10.670 . hemangiomas. Can J Plast Surg. 2013;21(1):23–8. Munroe WP, Rindone JP, Kershner RM. Systemic side Storch CH, Hoeger PH. Propranolol for infantile haeman- effects associated with the ophthalmic administration giomas: insights into the molecular mechanisms of of timolol. Drug Intell Clin Pharm. 1985;19(2):85–9. action. Br J Dermatol. 2010;163(2):269–74. Oranje AP, Janmohamed SR, Madern GC, de Laat doi:BJD9848 [pii]. PC. Treatment of small superfi cial haemangioma with Zhang Q, Chantasart D, Li SK. Evaluation of beta-blocker timolol 0.5% ophthalmic solution: a series of 20 cases. gel and effect of dosing volume for topical delivery. Dermatology. 2011;223(4):330–4. J Pharm Sci. 2015;104(5):1721–31. doi: 10.1002/ doi: 10.1159/000334778 . jps.24390 . Multiple Cutaneous Infantile Hemangioma and the Risk 9 of Internal Hemangioma

Astrid D. Vredenborg , Sherief R. Janmohamed , Peter C. J. de Laat , Gerard C. Madern , and Arnold P. Oranje

Abstract Infantile hemangioma (IH) is a frequently occurring tumor in infancy of which the pathogenesis is not completely understood. Although IHs are self-limiting, they can cause problems during their active growth and therapy may then be indicated. Generally, screening for internal hemangiomas is recommended when fi ve or more cutaneous IHs are present. This recommendation, however, is lacking solid scientifi c evidence. In this chapter, we discuss some controversies regarding the prevalence of IH, the nomenclature of “hemangiomas,” the nomenclature of multiple hemangiomas/hemangiomatosis, the therapy of IH, and the abovementioned screening recommendation. Since 1993, children with IHs have been evaluated in outpatient consultations by the working group on vascular anomalies Rotterdam (WEVAR), using an approach protocol. This protocol aimed at determining the relation between number of IHs and the occurrence of internal hemangiomas. We included all patients presenting with fi ve or more cutaneous IHs in the period of 1993–2011. These patients had all been referred for an ultrasound study for internal hemangiomas. We distinguished between children with ten or more IHs (hemangiomatosis group, group 1) and children with fi ve to nine IHs ( multiple IH group, group 2). Forty-three patients were included, 27 in group 1 and 16 in group 2. Nine infants in the hemangiomatosis group 1 showed

Astrid D Vredenborg and Sherief R Janmohamed are both ﬁ rst author

A. D. Vredenborg , MD, MSc G. C. Madern , MD, MSc Department of Dermatology , Catharina Hospital , Department of Pediatric Surgery , Erasmus MC , Eindhoven , The Netherlands Rotterdam , The Netherlands S. R. Janmohamed , MD, PhD, MHS, MSc A. P. Oranje , MD, PhD (*) Department of Dermatology , University Hospital Department of Dermatology , Brussels, Brussels , Belgium Dermicis Skin Hospital – Alkmaar , Kinderhuid.nl – Rotterdam, Rotterdam, P. C. J. de Laat , MD, PhD The Netherlands Department of Pediatrics , Erasmus MC , e-mail: [email protected] Rotterdam , The Netherlands

internal hemangiomas versus none in group 2. Further examination for internal hemangiomas in children with fewer than ten cutaneous IHs is controversial and does not seem to be necessary. However, we do recommend ultrasound examination for children with ten or more cutaneous IHs.

Keywords Controversy • Hemangioma • Hemangiomatosis • Hepatic hemangioma • Infantile hemangioma • Internal hemangioma • Miliary hemangioma • Hypoxia • Multiple hemangioma • Propranolol • Recommendation • Screening • Terminology • Therapy • Treatment • Ultrasound

Infantile hemangioma (IH) is the most frequent The pathogenesis of IH is still unknown benign tumor of infancy and is 1.5–5 times more (Collona et al. 2010 ). IH is characterized by the common in girls than in boys (Vredenborg et al. presence of the erythrocyte-type glucose trans- 2013 ; Bruckner and Frieden 2006 ). Its incidence porter GLUT-1 (Leon-Villapalos et al. 2005 ), is 10 % in the general population, with a higher which is not found in other vascular malforma- incidence (20–30 %) in prematurely born infants. tions. In a proliferative IH, rapidly growing endo- They are found on the face in 60 % of the cases thelial cells form blood vessels. Increased (Bruckner and Frieden 2006 ; Geh et al. 2007 ). apoptosis in the involution phase causes endothe- The diagnosis is usually only based on clinical lial cells to die, leading to regression of blood observation and history (Lee et al. 2009 ). IHs are vessels. In the end, the thick multilaminated rarely present at birth (Bruckner and Frieden basement membrane surrounding the endothelial 2006); they typically develop several days to layer is replaced by adipocytes in fi brous tissue weeks after birth and can grow very fast in a few (Boye et al. 2009). Furthermore, a signifi cant months (known as the proliferation phase). increase in the number of mast cells during the Eventually, after a short steady phase, they involution phase may alter the balance of angio- regress by approximately 10 % per year (known genic factors, thus promoting regression (Ritter as the involution phase) (Bramhall and Quaba et al. 2006 ). Many different causative mecha- 2008 ; Hohenleutner et al. 2001 ). nisms have been proposed (Bauland, et al. 2006 ; Boye et al. 2009; Lo et al. 2009; Ritter et al. 2006 ; Sidbury 2010 ). Genetic infl uences may Controversies contribute as several patients with IHs show signifi cant loss of heterozygosity for markers in a The prevalence of IH is controversial because a region of chromosome 5q (Walter et al. 1999 ). wide range has been reported in the literature, Placental embolization is thought to play a caus- varying from 5 % up to 20 % (the latter in prema- ative role, as many of the characteristic molecular ture infants). The nomenclature is controversial markers of endothelial cells in IHs are also because some professionals refer to several vas- expressed by normal placental endothelial cells. cular anomalies as “hemangioma.” This was Furthermore, hormonal infl uences may be common practice in the past. Nowadays, we pre- involved: stimulation with estrogen increases fer the term “infantile hemangioma” for better proliferation, migration, and survival of endothe- understanding and discrimination between IH lial cells. Also stem cell theories have been pro- and other vascular anomalies. posed because multipotential stem cells can be 9 Multiple Cutaneous Infantile Hemangioma and the Risk of Internal Hemangioma 81 derived from IHs that can produce neovascular- recently, however, with the introduction of pro- ization. Lastly, hypoxia may be involved in the pranolol, which halts the growth of hemangiomas pathogenesis of IH (Bauland, et al. 2006 ; Chang and even shrinks them. Systemic therapy with et al. 2007; Kleinman et al. 2007; Lo et al. 2009 ). oral glucocorticosteroids (GCS) or intralesional In 50 % of cases, an anemic macula (precursor therapy with GCS used to be the fi rst-line therapy lesion) occurs at a place where an IH will eventu- for alarming IHs (Bennett et al. 2001 ; Enjolras ally develop, supporting the idea that local isch- 2007; Greene et al. 2004; Hogeling et al. 2011 ; emia is important. Hypoxia triggers stabilization Lawley et al. 2009 ; Léauté-Labrèze et al. 2008 ; at the protein level of the transcription factor Price et al. 2011 ; Sidbury 2010 ; Storch and HIF1α. HIF1α in turn stimulates transcription of Hoeger 2010 ; Zvulunov et al. 2011 ), but it is now downstream target genes such as BNIP3, CA-IX, generally considered a second-line treatment for GLUT-1, pAKT, pS6, and vascular endothelial IHs. Propranolol (a nonselective beta-blocker), growth factor (VEGF) (Wang et al. 1995 ). These often used as therapy for high blood pressure in target genes might be regulated either directly by adults, has made corticosteroids and all the other HIF signaling or by hypoxia-induced downregu- treatments obsolete (Léauté-Labrèze et al. 2008 ). lation of mTORC1 signaling (Arsham et al. However, evidence on dosing, duration of ther- 2003). mTORC1 is a key player in the mTOR apy, and possible adverse events is inconclusive pathway, a protein complex with a central role in (Bayliss et al. 2010 ; Holland et al. 2010 ; Léauté- regulating cellular metabolism, driven by growth Labrèze et al. 2008; Mishra et al. 2010 ; Sans factors, nutrients, and hypoxia. Deregulation of et al. 2009 ). Until recently, small IHs were treated the mTOR pathway may lead to disorganized with topical steroids, imiquimod cream, or by growth (Wouters et al. 2008 ). As macrophages PDL laser for cosmetic reasons (Guo and Ni secrete proangiogenic molecules such as tumor 2010 ; Maguiness and Frieden 2010 ; McGuaig necrosis factor-α (TNF-α) and interleukin-1, they et al. 2009 ; Ni et al. 2011 ; Pandey et al. 2010 ; are also thought to be involved in the evolution of Pope and Chakkiiakandiyil 2010 ). Similar to pro- IH (Boye et al. 2009 ; Kleinman et al. 2007 ; Ritter pranolol, timolol is a nonselective beta-blocker et al. 2007 ). used in ophthalmic solution and eye gel as a drug Because IHs will eventually regress, the against increased ocular pressure. The available “watch-and-wait” principle is advocated. eye gel contains timolol 0.1 % gel and may be However, in approximately half of all cases, they used only after the age of 12 years. At present, we will leave scars, often necessitating surgery or treat superfi cial IHs with timolol ophthalmic plastic surgery. Although of a benign nature, IHs solution 0.5 % or propranolol cream 1 %. can cause problems during the proliferation Treatment in IH is controversial because it is phase, generally related to extensive growth or not evidence based. There are no generally location. Problems may be twofold. First, a accepted guidelines defi ning which patients need gigantic IH in the face is likely to carry a heavy which treatment and how. psychological burden. Parents have to explain it The use of the term hemangiomatosis is con- over and over again and older children can be troversial, as is the number of cutaneous IHs made fun of. Second, an IH can cause life- needed for this diagnosis. In most cases, the num- threatening or disabling complications such as ber of IHs is limited to one, but in 30 % of cases, visual impairment, compression of the airways, there are more than one (Atherton and Moss heart failure, and ulceration (Hohenleutner et al. 2004 ; Haggstrom et al. 2006). The presence of 2001; Ranchod et al. 2005 ; Sun et al. 2008 ). A fi ve or more IH is rare (3 % of all cases) (Metry multidisciplinary approach is recommended for et al. 2004 ). The term hemangiomatosis has been such alarming IHs (Schwartz et al. 2010 ). The used without a consensual defi nition (Fig. 9.1 ). It current empirically based therapy aims to induce is agreed that lesions must be small and multifo- or accelerate the natural involution process (Boye cal, but the minimal number of lesions is debated. et al. 2009). Therapy has radically changed Often the term hemangiomatosis is used to refer 82 A.D. Vredenborg et al.

Fig. 9.2 Ultrasound of a patient with multiple cutaneous miliary infantile hemangiomas (hemangiomatosis). In the liver, multiple lesions (internal hemangiomas) can be seen (From Vredenborg et al. ( 2013 ), with permission)

(Horii et al. 2011). At present, infants are screened for internal IHs when they have multiple cutaneous IHs (Dickie et al. 2009). In the literature and in most textbooks, this strategy is recommended if there are fi ve or more cutaneous IHs. Nevertheless, this cutoff point was evaluated in only a few studies (Haggstrom et al. 2006 ; Hughes et al. 2004; Some Nina et al. 2004 ). Thus, solid scientifi c evidence for this policy seems to be lacking. Fig. 9.1 Infant with multiple cutaneous infantile heman- It is controversial when to screen for internal giomas; > 15 in this photo alone (i.e., hemangiomatosis, hemangiomas. It is generally recommended to miliary infantile hemangioma) (From Vredenborg et al. (2013 ), with permission) screen in patients with fi ve or more cutaneous IHs, but this statement is lacking solid scientifi c evidence. Finally, it is controversial whether or to more than fi ve or even ten to hundreds of small not to screen only the liver (abdominal ultra- multifocal cutaneous IHs (Holden and Alexander sound) or both abdomen and brains. Scientifi c 1970 ). In a recent consensus meeting on IH evidence is lacking. (Entretien du Carla, France, 13–14 March 2014), The purpose of this study was to determine the experts agreed to distinguish between focal whether further examination for internal IHs IH, multiple IH, miliary IH (instead of the older should indeed be recommended and in which term “hemangiomatosis”), and segmental IH. patients. We distinguished between two catego- The most common extracutaneous site ries: multiple IHs (fi ve up to and including nine involved is the liver (Fig. 9.2 ). Other sites include IHs) and hemangiomatosis (≥10 IHs). The main brain, intestine, lungs, pancreas, and eyes controversy to be addressed is “is screening for (Holden and Alexander 1970 ). The mucosa is not internal hemangiomas necessary in infants with considered an internal organ. The severity of fi ve or more IHs?” Other controversies, discussed hepatic hemangioma varies from asymptomatic above, concern the prevalence of IH, the nomen- to life threatening, mostly due to congestive heart clature of “hemangiomas,” the nomenclature of failure. Identifi cation of infants with cutaneous multiple hemangiomas/hemangiomatosis, and IHs who are at risk for internal IHs seems crucial the therapy. 9 Multiple Cutaneous Infantile Hemangioma and the Risk of Internal Hemangioma 83

Materials and Methods Statistics 17.0.2 was used and differences were considered signifi cant when p - values were < 0.05. In 1993, a multidisciplinary outpatient clinic named WEVAR (workgroup on vascular anomalies Rotterdam) was started at the Erasmus Results Medical Centre – Sophia Children’s Hospital for children with alarming or disfi guring vascular Forty-three infants were included, 16 boys and 27 anomalies. The core medical team consists of a girls. Twenty-seven (62.8 %) were diagnosed with pediatric dermatologist, pediatric surgeon, and a hemangiomatosis (group 1, 10, or more IHs) and 16 pediatrician. Other medical specialists are con- (37.2 %) with multiple IH (group 2, fi ve to nine sulted when necessary. Treatment is standard- IHs). Ten of all (23.3 %) had been born prematurely. ized. All patients with fi ve or more IHs from the Demographic characteristics are given in Table 9.1 . WEVAR and the Pediatric Dermatology outpa- The two groups did not signifi cantly differ in tient clinics seen from 1993 until 2011 were sex, prematurity, or gestational age (p -value = 0.976, included in this study. They had all been referred 0.835, and 0.668, respectively). The median num- for further examination for internal hemangio- ber of IH in group 1 was 16 and in group 2 was 6.5 mas by ultrasound of the abdomen (and brain). ( p -value < 0.001). The majority of IH were in the This included Doppler measurements. This is a active phase. Phase did not signifi cantly differ retrospective study based on an approach proto- between the two groups ( p -value = 0.842). The IHs col and embedded in “Strawberry Marks” in group 1 were mainly round (55.6 %); those in (“Aardbeesie ”), the WEVAR project which the group 2 were mainly polycyclic (43.8 %) researches the pathogenesis and therapy of ( p -value = 0.07). The median size of IHs in group 1 IH. The study has been approved by the Medical was 1.50 cm; that in group 2 was 2.25 cm Ethics Review Board of the Erasmus Medical ( p-value = 0.069). Six patients in group 1 (22.2 %) Centre in Rotterdam, the Netherlands. were treated for the cutaneous IH, mostly with Two different patient groups were created: intralesional or systemic corticosteroids; four patients in group 2 (25.0 %) were treated, mostly Group 1 (hemangiomatosis) consists of children with intralesional corticosteroids (p -value = 0.835). diagnosed with ten or more cutaneous IHs. Further examination in group 1 took place at a Group 2 (multiple IH) consists of children diag- younger age than in group 2: 3.0 and 6.5 months, nosed with fi ve up to and including nine cuta- respectively (p -value = 0.003). Fourteen patients neous IHs. in group 1 (51.9 %) had an ultrasound of both the abdomen and brain versus four in group 2 (25.0 %, not signifi cant, p -value = 0.163). Nine Outcome Measures and Statistical patients in group 1 (33.3 %) were diagnosed with Methods internal IH versus none in group 2 ( p -value = 0.009). Five of those nine patients in Demographic and clinical characteristics col- group 1 had more than one internal IH. Most lected from the electronic and paper fi les (e.g., let- internal IH were located in the liver (eight out of ters and photos) were evaluated with the use of nine, one was located in the spleen). One patient descriptive statistics analyses. Outcome measures was treated for the internal IH (see Table 9.2 ). were abnormalities on ultrasound with or without symptoms. The Cramér’s V analysis served to test signifi cant differences in categorical demographic Discussion and clinical characteristics: the Wilcoxon rank sum (two-sample) analysis to test signifi cant dif- This study shows that only patients diagnosed ferences in numerical demographic and clinical with hemangiomatosis (ten or more IHs) are characteristics between the two groups. SPSS likely to be at risk for developing internal heman- 84 A.D. Vredenborg et al.

Table 9.1 Demographic and clinical characteristics of Table 9.2 Details of further examination of infants with patients with hemangiomatosis (ten or more infantile hemangiomatosis (ten or more infantile hemangiomas hemangiomas (IH), group 1) and multiple IHs (fi ve up to (IH), group 1) compared to infants with multiple IHs (fi ve and including nine IHs, group 2) up to and including nine IHs, group 2) Multiple Multiple IH Hemangiomatosis IH ( N =16) Descriptive Hemangiomatosis (N ( N =16) ( N =27) Number values =27) Number (%) Number (%) Descriptive values Number (%) (%) Age at screening (mth) Gender 10th 0.86 2.70 Male 10 (37.0) 6 (37.5) percentile Female 17 (63.0) 10 (62.5) Median 3.0* 6.5* Premature (< 37 wks) 90th 8.80 19.1 Yes 6 (22.2) 4 (25.0) percentile No 21 (77.8) 12 (75.0) Kind of screening (ultrasound) Gestational age (wks) Only 13 (48.1) 12 (75.0) abdomen Mean ± SD 37.5 ± 3.7 37.5 ± 4.5 Both 14 (51.9) 4 (25.0) Number of cutaneous IH abdomen 10th percentile 12.0 5.0 and brain Median 16.0* 6.5* Internal hemangioma 90th percentile 42.8 10.0 Yes 9* (33.3) 0* (0) Phase of IH (N missing = 1) No 18 (66.7) 16 (100) Active 17 (63.0) 10 (62.5) Localization of internal hemangioma Stable 5 (18.5) 4 (25.0) Liver 8 n/a Regression 4 (14.8) 2 (12.5) Spleen 1 n/a Aspect of IH (N missing = 1) Number of internal hemangioma Oval 7 (25.9) 3 (18.8) Solitary 4 n/a Round 15 (55.6) 4 (25.0) Multiple 5a n/a Drop shaped 1 (3.7) 2 (12.5) Symptoms of internal hemangioma Polycyclic 3 (11.1) 7 (43.8) Yes 0 (0) 0 Size of IH (cm diameter) No 9 (100) 16 10th percentile 0.32 0.50 Treatment for internal hemangioma Median 1.50 2.25 Yes 1 (11.1) n/a 90th percentile 4.40 8.0 No 8 (88.9) n/a Treatment of cutaneous IH Wks weeks, SD standard deviation, Mth month, n/a not Yes 6 (22.2) 4 (25.0) applicable No 21 (77.8) 12 (75.0) * p < 0.01 Kind of IH treatment a One patient had three internal hemangiomas in the liver. Intralesional 2 (33.3) 2 (50.0) The other four patients had more than one internal heman- corticosteroids gioma, but this number was unknown Topical 1 (16.7) 0 corticosteroids giomas, for one third of them had internal hem- Systemic 2 (33.3) 0 angiomas versus none of the infants with fi ve to corticosteroids nine IHs. We opted for ten IHs as a cutoff point Imiquimod 0 1 (25.0) because the cutoff point of fi ve IHs for further Laser 1 (16.7) 0 screening is controversial and because we have Pressure 0 1 (25.0) never seen internal hemangiomas in patients with Wks weeks, SD standard deviation, Mth month < 10 IHs. There was no consensus, too, about the * p < 0.001 9 Multiple Cutaneous Infantile Hemangioma and the Risk of Internal Hemangioma 85 defi nition of hemangiomatosis until the recent Unfortunately, this is also a retrospective study in expert meeting described in the introduction . only 19 patients. In that study, three patients Therefore, we described hemangiomatosis as the with > 10 hepatic hemangiomas were treated presence of ten or more IHs. (because of increased arterial blood fl ow). Their Prior studies have shown that infants with fi ve study distinguished between benign neonatal or more cutaneous IHs are generally at risk for hemangiomatosis and diffuse neonatal hemangi- internal hemangiomas (Berman and Lim 1978 ; omatosis. The authors hypothesize that the mech- Boon et al. 1996 ; Dickie et al. 2009 ; Golitz et al. anism may be different from that in IH: in their 1986 ; Horii et al. 2011 ; Lopriore and Markhorst cases, lesions were almost always present at 1999; Lyer et al. 1996 ). Horii et al. found that birth, and the increase was not in size but in num- 16 % of patients with fi ve or more IHs developed ber. Therefore, there was no ulceration. However, internal hemangiomas. Although they did not many complications occurred during pregnancy. distinguish between two groups, from their data Unfortunately, this study did also not distinguish it can be recalculated that nine of the 87 patients between “multiple cutaneous IHs” (fi ve to nine) with fi ve to nine IHs had hepatic hemangiomas and “hemangiomatosis” (ten or more IHs). Our (10 %) and that 15 of the 64 patients with ten or study is to our knowledge the fi rst to research more IHs had hepatic hemangiomas (23 %). The both groups separately. In doing so, we showed respective percentages in our study were 0 % and that patients with multiple IH are not at risk for 33 %. Therefore, Horii et al. recommend screen- developing internal hemangiomas, in contrast to ing when fi ve or more IHs are present, whereas patients with hemangiomatosis. from our study it can be concluded that screening In the present study, all but one internal hem- is recommended when ten or more IHs are pres- angioma was located in the liver. One was found ent. This seems the more because Horii et al. in the spleen. Only a few infants with internal found that none of their patients with fi ve to nine hemangioma required treatment for liver disease. IHs needed treatment for internal hemangioma. Previous studies also found low percentages of Therefore, this approach could also be more cost- infants requiring treatment (Horii et al. 2011 ) and effective. Conclusive evidence should come from concluded that IH of the liver can be asymptom- more and larger, preferably prospective studies. atic and not need treatment, even when multifo- Also, a meta-analysis can be performed within cal hepatic lesions are present (Horii et al. 2011 ). the existing literature. Statistically (but probably Other groups have identifi ed an association of less clinical signifi cance), the risk (odds ratio) between number of cutaneous IH and number of of internal hemangioma in the study of Horii hepatic hemangioma identifi ed on screening et al. is 2.7 times larger for patients with ten or ultrasound (Hughes et al. 2004 ). A more recent more IHs, compared to patients with fi ve to nine study did not fi nd such association (Haggstrom IHs (p -value 0.03, chi-square test). et al. 2006 ). In our study, we included more patients in the Ultrasound is a noninvasive and relatively group with ten or more IHs than did Horii et al., inexpensive technique to identify infants with probably because our study stems from a tertiary internal hemangiomas. However, this screening medical center which more often treats worse method is not conclusive. Hemangiomas of the cases than other hospitals. Furthermore, Horii liver are often diffi cult to distinguish from other et al. found a trend for greater risk of hepatic vascular malformations. Also, the technology for hemangioma in patients with greater numbers of diagnosing hemangiomas on ultrasound has been IH, which is in line with our fi ndings (Horii et al. improved over the years. It is evident that multi- 2011 ). Nonetheless, due to small sample size, we focal vascular lesions in the past may have been could neither confi rm nor disprove this. A recent diagnosed as internal hemangiomas, whereas a study from Maruani et al. also showed a trend different diagnosis (such as multifocal lymphan- toward greater hepatic involvement when there gioendothelioma, hemangioendothelioma, or are more cutaneous IHs (Maruani et al. 2011 ). pyogenic granuloma-like lesion) might have been 86 A.D. Vredenborg et al. more likely. This could explain why older studies nowadays, especially after the discovery in 2008 describe higher incidences of internal hemangi- (Léauté-Labrèze et al. 2008 ) that β-blockers, oma. Radiologists, preferably pediatric radiolo- both orally and topically, can also play a role in gists, have to be trained very well to recognize the treatment of superfi cial IHs. This study internal hemangiomas on ultrasound and to reports on patients selected from 1993 to 2011, distinguish these from other types of vascular and therefore most patients were treated by corti- malformations. costeroids rather than topical or systemic pro- Several limitations of this study should be pranolol. Systemic options used to be addressed. First, this is a retrospective study (but corticosteroids, with low success rates and based on a protocol) with relatively few patients. important complications, and vincristine IV, Second, the subjects were recruited from only a which also can give rise to side effects. Currently, specialized pediatric dermatology and multidis- propranolol is advocated in a dosage of 3 mg/kg ciplinary specialty practice in a university set- daily for 6 months (Léauté-Labrèze et al., NEJM , ting. This might have induced selection bias. submitted). Propranolol occasionally causes side Third, ages at screening differed signifi cantly effects like nightmares and cold acra, but also between the two groups, possibly because infants more serious side effects such as hypoglycemia with hemangiomatosis are referred to a specialist and hypotension have been reported. It is good to at a younger age than infants with multiple realize, however, that hypotension normally does IH. Furthermore, there are also limitations in the not occur in healthy infants because β-blockers examinations performed in the infants with inter- only work when the blood pressure is elevated nal hemangioma. The exact number of hepatic (Janmohamed et al. 2012 ). Regarding hypoglyce- lesions is often unknown. Retrospectively, we mia, this is never a direct effect of propranolol, could only fi nd out whether the lesions were soli- but rather the combined effect of propranolol and tary or multiple. Also, no heart echography had fasting, for example, because of vomiting or been performed. Most doctors would like to fever. This can also occur with combinations of know whether there are internal hemangiomas or particular medicines, such as propranolol and not and specifi cally hepatic hemangioma as these corticosteroids. As for topical treatment, the best carry a large risk of congestive heart failure. A current options are timolol 0.5 % ophthalmic classifi cation system for hepatic hemangioma solution and propranolol 1 % cream, applied was proposed by Christison-Lagay (Christison- three to four times daily (Bonifazi et al. 2010 ; Lagay et al. 2007 ). We did not use this classifi ca- Chan et al. 2013). We would like to stress that the tion system because our study was started before effect of topical treatment with these β-blockers this system was published. Apart from the limita- can only be seen after 2–4 months (with docu- tions, this study has a particular strength: it is the mented photographs) and that it is advised to fi rst to compare two separate groups, the heman- apply the medicine three to four times daily. giomatosis group (ten or more IHs) and the multiple IH group (fi ve to nine IHs), as we believe Conclusion that an infant with fi ve or more IHs is not compa- Generally, screening for internal hemangio- rable to one with 300 small drop-like IHs. mas is recommended when fi ve or more mul- Imiquimod was used as a local therapy option tiple cutaneous IHs are present, but this is for cutaneous IHs in patients in this study. One controversial. Based on the results of this infant with multiple IHs was treated with this study, we recommend referring patients with therapy. This therapy gives good results but can ten or more IHs for further examination for lead to a local (eczema-like) skin reaction. internal hemangiomas by ultrasound of abdo- Topical corticosteroids can be used to treat this men (and brain). However, the results of our reaction (Jiang et al. 2011 ). Therapy of IH has study suggest that further examination for changed considerably over the last years. The internal hemangioma in patients with fi ve to “watch-and-wait” principle is followed less often nine IHs is not necessary. 9 Multiple Cutaneous Infantile Hemangioma and the Risk of Internal Hemangioma 87

Bulleted List of Controversies editors. Rook’s textbook of dermatology. Malden: Blackwell Publishing; 2004. p. 104–5. 15.40–15.55; chapter 15. • The prevalence of IH is controversial because Bauland CG, van Steensel MA, Steijlen PM, Rieu PN, a wide range has been reported in the litera- Spauwen PH. The pathogenesis of hemangiomas: a ture, varying from 5 % up to 20 % (the latter in review. Plast Reconstr Surg. 2006;117:29e–35. premature infants). Bayliss SJ, Berk DR, Van Hare GF, Balzer D, Yamada K, Lueder G, Lanoel A, de la Fuente V, Cordisco MR. Re: • The nomenclature is controversial because propranolol treatment for hemangioma of infancy: some professionals refer to several vascular risks and recommendations. Pediatr Dermatol. anomalies as “hemangioma.” This was com- 2010;27:319–20. mon practice in the past. Nowadays, we prefer Bennett ML, Fleischer Jr AB, Chamlin SL, et al. Oral corticosteroid use is effective for cutaneous hemangio- the term “infantile hemangioma” for better mas: an evidence-based evaluation. Arch Dermatol. understanding and discrimination between IH 2001;137:1208–13. and other vascular anomalies. Berman B, Lim H. Concurrent cutaneous and hepatic • Use of the term hemangiomatosis is also con- hemangiomata in infancy: report of a case and a review of the literature. J Dermatol Surg Oncol. troversial, as is the number of cutaneous IHs 1978;4(11):869–73. needed for this diagnosis. In a recent Bonifazi E, Acquafredda A, Milano A, et al. Severe hypo- consensus-of-experts meeting on IH (Entretien glycemia during successful treatment of diffuse hem- du Carla, France, 13–14 March 2014), it was angiomatosis with propranolol. Pediatr Dermatol. 2010;27(2):195–6. agreed to distinguish between focal, multiple, Boon LM, Burrows PE, Paltiel HJ, et al. Hepatic vascular miliary, and segmental IH. anomalies in infancy: a twenty-seven-year experience. • Treatment in IH is controversial because it is J Pediatr. 1996;129(3):346–54. not evidence based. There are no generally Boye E, Jinnin M, Olsen BR. Infantile hemangioma: challenges, new insights, and therapeutic promise. accepted treatment protocols for defi ning J Craniofac Surg. 2009;20 Suppl 1:678–84. which patients need which treatment and how. Bramhall RJ, Quaba A. A review of 58 patients with peri- • It is controversial when to screen for internal orbital hemangiomas to determine appropriate cases hemangiomas. It is generally recommended to for intervention. J Plast Reconstr Aesthet Surg. 2008;61:138–49. screen in patients with fi ve or more cutaneous Bruckner AL, Frieden IJ. Infantile hemangiomas. J Am IHs, but this recommendation is lacking solid Acad Dermatol. 2006;55(4):671–82. scientifi c evidence. In our study, we did not Chan H, McKay C, Adams S, et al. RCT of timolol male- see internal hemangiomas in patients with up ate gel for superfi cial infantile hemangiomas in 5- to 24-week-olds. Pediatrics. 2013;131(6):e1739–47. to nine cutaneous IHs. Chang EI, Chang EI, Thangarajah H, Hamou C, • Finally, it is controversial whether only the Gurtner GC. Hypoxia, hormones, and endothelial liver (abdominal ultrasound) should be progenitor cells in hemangioma. Lymphat Res screened or both abdomen and brain. Scientifi c Biol. 2007;5:237–43. Christison-Lagay ER, Burrows PE, Alomari A, et al. evidence is lacking. Hepatic hemangiomas: subtype classifi cation and development of a clinical practice algorithm and registry. J Pediatr Surg. 2007;42(1):62–7. Acknowledgment We thank Ko Hagoort for the lan- Collona V, Resta L, Napoli A, Bonifazi E. Placental guage revision. hypoxia and neonatal hemangioma: clinical and histological observations. Br J Dermatol. 2010;162:208–9. Dickie B, Dasgupta R, Nair R, et al. Spectrum of hepatic hemangiomas: management and outcome. J Pediatr References Surg. 2009;44(1):125–33. Enjolras O. Color atlas of vascular tumors and vascular mal- Arsham AM, Howell JJ, Simon MC. A novel hypoxia- formations. Paris: Cambridge University Press; 2007. inducible factor-independent hypoxic response regu- Geh JL, Geh VS, Jemec B, et al. Surgical treatment of lating mammalian target of rapamycin and its targets. periocular hemangiomas: a single-center experience. J Biol Chem. 2003;278:29655–60. Plast Reconstr Surg. 2007;119:1533–62. Atherton DJ, Moss C. Naevi and other developmental Golitz LE, Rudikoff J, O’Meara OP. Diffuse neonatal defects. In: Burn T, Breathnach S, Cox N, Griffi ths C, hemangiomatosis. Pediatr Dermatol. 1986;3(2): 145–52. 88 A.D. Vredenborg et al.

Greene AK, Rogers GF, Mulliken JB. Management of Leon-Villapalos J, Wolfe K, Kangesu L. GLUT-1: an parotid hemangioma in 100 children. Plast Reconstr extra diagnostic tool to differentiate between heman- Surg. 2004;113:53–60. giomas and vascular malformations. Br J Plast Surg. Guo S, Ni N. Topical treatment for capillary hemangioma 2005;58(3):348–52. of the eyelid using beta-blocker solution. Arch Lo K, Mihm M, Fay A. Current theories on the pathogen- Ophthalmol. 2010;128:255–6. esis of infantile hemangioma. Semin Ophthalmol. Haggstrom AN, Drolet BA, Baselga E, et al. Prospective 2009;24:172–7. study of infantile hemangiomas: clinical characteris- Lopriore E, Markhorst DG. Diffuse neonatal hemangio- tics predicting complications and treatment. Pediatrics. matosis: new views on diagnostic criteria and progno- 2006;118(3):882–7. sis. Acta Paediatr. 1999;88(1):93–7. Hogeling M, Adams S, Wargon O. A randomized con- Lyer CP, Stanley P, Mahour GH. Hepatic hemangiomas in trolled trial of propranolol for infantile hemangiomas. infants and children: a review of 30 cases. Am Surg. Pediatrics. 2011;128(2):259–66. 1996;62(5):356–60. Hohenleutner S, Badur-Ganter E, Landthaler M, Maguiness SM, Frieden IJ. Current management of infan- Hohenleutner U. Long-term results in the treatment of tile hemangiomas. Semin Cutan Med Surg. childhood hemangioma with the fl ashlamp-pumped 2010;29:106–14. pulsed dye laser: an evaluation of 617 cases. Lasers Maruani A, Piram M, Sirinelli D, Herbreteau D, Saliba E, Surg Med. 2001;28:273–7. Machet MC, Lorette G. Visceral and mucosal involve- Holden KR, Alexander F. Diffuse neonatal hemangioma- ment in neonatal hemangiomatosis. J Eur Acad tosis. Pediatrics. 1970;46(3):411–21. Dermatol Venereol. 2011;2:1468–3083. Holland KE, Frieden IJ, Frommelt PC, et al. Hypoglycemia McCuaig CC, Dubois J, Powell J, et al. A phase II open- in children taking propranolol for the treatment of label study of the effi cacy and safety of imiquimod in infantile hemangioma. Arch Dermatol. the treatment of superfi cial and mixed infantile hem- 2010;146:775–8. angioma. Pediatr Dermatol. 2009;26:203–12. Horii KA, Drolet BA, Frieden IJ, et al. Prospective study Metry DW, Hawrot A, Altman C, et al. Association of of the frequency of hepatic hemangiomas in infants solitary, segmental hemangiomas of the skin with with multiple cutaneous infantile hemangiomas. visceral hemangiomatosis. Arch Dermatol. 2004; Pediatr Dermatol. 2011;28(3):245–53. 140(5):591–6. Hughes JA, Hill V, Patel K, et al. Cutaneous hemangioma: Mishra A, Holmes WJ, Grost C, Liew SH. Role of pro- prevalence and sonographic characteristics of associ- pranolol in the management of periocular hemangio- ated hepatic hemangioma. Clin Radiol. mas. Plast Reconstr Surg. 2010;126:671. 2004;59(3):273–80. Ni N, Wagner RS, Langer P, Guo S. New developments in Janmohamed SR, de Laat PC, Madern GC, et al. Treating the management of periocular capillary hemangioma hemangioma of infancy with beta-blockers: is there in children. J Pediatr Opthalmol Strabismus. really a risk of hypotension? J Am Acad Dermatol. 2011;48:269–76. 2012;67(2):315–6. Pandey A, Gangopadhyay AN, Shrama SP, Kumar V, Jiang C, Hu X, Ma G, Chen D, et al. A prospective self- Gupta DK, Gopal SC. Evaluation of topical steroids in controlled phase II study of imiquimod 5% cream in the treatment of superfi cial hemangioma. Skinmed. the treatment of infantile hemangioma. Pediatr 2010;8:9–11. Dermatol. 2011;28(3):259–66. Pope E, Chakkiiakandiyil A. Topical timolol gel or infan- Kleinman ME, Greives MR, Churgin SS, Blechman KM, tile hemangiomas; a pilot study. Arch Dermatol. Chang EI, Ceradini DJ, Tepper OM, Gurtner 2010;146:564–5. GC. Hypoxia-induced mediators of stem/progenitor Price CJ, Lattouf C, Baum B, McLeod M, Schachner LA, cell traffi cking are increased in children with heman- Duarte AM, Connelly EA. Propranolol vs corticoste- gioma. Arterioscler Thromb Vasc Biol. 2007;27: roids. Arch Dermatol. 2011;147(12):1371–6. 2664–70. Ranchod TN, Frieden IJ, Fredrick DR. Corticosteroid Lawley LP, Siegfried E, Todd JL. Propranolol treatment treatment of periorbital hemangioma of infancy: for hemangioma of infancy: risks and recommenda- review of the evidence. Br J Ophthalmol. tions. Pediatr Dermatol. 2009;26:610–4. 2005;89:1134–8. Léauté-Labrèze C1, Hoeger P, Mazereeuw-Hautier J, Ritter MR, Butschek RA, Friedlander M, Friedlander et al. A randomized, controlled trial of oral proprano- SF. Pathogenesis of infantile hemangioma: new lol in infantile hemangioma. N Engl J Med. molecular and cellular insights. Expert Rev Mol Med. 2015;372(8):735–46. doi: 10.1056/NEJMoa1404710 . 2007;9:1–19. Léauté-Labrèze C, Dumas de la Roque E, et al. Propranolol Ritter MR, Reinisch J, Friedlander SF, Friedlander for severe hemangiomas of infancy. N Engl J Med. M. Myeloid cells in infantile hemangioma. Am 2008;358:2649–51. J Pathol. 2006;168(2):621–8. Lee SJ, Shin DJ, Kim HY, et al. A fraction of deep vascu- Sans V, de la Roque ED, Berge J, et al. Propranolol for lar birthmarks are true deep hemangiomas of infancy. severe infantile hemangiomas: follow-up report. Int J Dermatol. 2009;48:817–21. Pediatrics. 2009;124:e423–31. 9 Multiple Cutaneous Infantile Hemangioma and the Risk of Internal Hemangioma 89

Schwartz RA, Sidor MI, Ml M, Lin RL, Micali G. Infantile giomas and the risk of internal hemangioma. Br hemangiomas: a challenge in pediatric dermatology. J Dermatol. 2013;169(1):188–91. J Eur Acad Dermatol Venereol. 2010;24:631–8. Walter JW, Blei F, Anderson JL, Orlow SJ, Speer MC, Sidbury R. Update on vascular tumors of infancy. Curr Marchuk DA. Genetic mapping of a novel familial Opin Pediatr. 2010;22:432–7. form of infantile hemangioma. Am J Med Genet. Some Nina K, Lorette G, Chantepie A, et al. Hypertrophic 1999;82:77–83. cardiomyopathy associated with oral corticosteroid Wang GL, Jiang BH, Rue EA, Semenza GL. Hypoxia- therapy for palpebral hemangioma. Ann Dermatol inducible factor 1 is a basic-helix-loop-helix-PAS het- Venereol. 2004;131(3):263–5. erodimer regulated by cellular O2 tension. Proc Natl Storch CH, Hoeger PH. Propranolol for infantile heman- Acad Sci U S A. 1995;92:5510–4. giomas: insights into the molecular mechanisms of Wouters BG, Koritzinsky M. Hypoxia signalling through action. Br J Dermatol. 2010;163:269–74. mTOR and the unfolded protein response in cancer. Sun ZY, Yi CG, Zhao H, Yin GQ, Gao M, Liu YB, Qin Nat Rev Cancer. 2008;8:851–64. JD, Wang SF, Guo SZ. Infantile hemangioma is origi- Zvulunov A, McCuaig C, Frieden IJ, et al. Oral proprano- nated from placental trophoblast, fact or ﬁ ction? Med lol therapy for infantile hemangiomas beyond the pro- Hypotheses. 2008;71(3):444–8. liferation phase: a multicenter retrospective study. Vredenborg AD, Janmohamed SR, de Laat PC, Madern Pediatr Dermatol. 2011;28:94–8. GC, Oranje AP. Multiple cutaneous infantile heman- Congenital Melanocytic Nevi: What to Do? 1 0

Linda De Raeve

Abstract Congenital melanocytic nevi are one of the most common skin lesions, occurring in 1 % of newborns. They are important lesions as they can give rise to melanoma. The larger cosmetically disﬁ guring nevi may also have a great impact on quality of life. Although the clinical diagnosis is mostly not challenging, the management remains a matter of controversy. Current understanding of the risks associated with congenital melanocytic nevi of different sizes and the strategies for management of these nevi are discussed in this chapter.

Keywords Congenital melanocytic nevus • Treatment • Melanoma risk • Benign nevomelanocytic proliferations • Early onset nevi • Congenital nevi

D e fi nition and Classifi cation migration along the dorsolateral pathway to the skin (Dessars 2009 ; Kinsler 2013 ). Congenital melanocytic nevi (CMN) are benign CMN are usually classifi ed into three major nevomelanocytic proliferations, present at birth groups according to fi nal size, namely, the great- or clinically evident within the fi rst year of life. est diameter they are predicted to attain in adult- These last ones are referred to as tardive CMN, or hood. Small CMN (SCMN) are defi ned as those early onset nevi. There is evidence that CMN less than 1.5 cm, medium-sized CMN (MCMN) arise as a result of an oncogenic mutation, most are those between 1.5 and 20 cm and large or commonly involving NRAS, occurring in a mela- giant CMN (GCMN) are those more than 20 cm noblast or neural crest precursor cell before its in projected adult size. It is important to consider that lesions that are regarded as small or medium in the newborn period may be designated medium or giant by late childhood or adulthood, given that CMN enlarge in proportion to the affected L. De Raeve , MD, PhD anatomic size. Roughly, the diameter of a CMN Department of Dermatology , UZ Brussel, on the head enlarges by a factor of 1.7, on the Vrije Universiteit Brussel , Brussels , Belgium e-mail: [email protected] lower extremities by a factor of 3.3 and on the

© Springer International Publishing Switzerland 2016 91 A.P. Oranje et al. (eds.), Practical Pediatric Dermatology, DOI 10.1007/978-3-319-32159-2_10 92 L. De Raeve upper extremities, trunk and feet by a factor of tan well-demarcated macules or papules or as tan 2.8 (Rhodes 1996 ). In order to facilitate the well-circumscribed lesions with mottled freck- development of an international clinical database ling. With time, they become elevated, and coarse for the study of large and giant CMN, Krengel dark hairs may or may not become prominent et al. (2013 ) recently published new recommen- (DeDavid 1997 ). Verrucous changes may be seen dations for the categorization of the cutaneous in older lesions. GCMN vary in size to cover features of congenital melanocytic nevi. In this large areas such as an arm or leg or extensive report, CMN size categories include small areas of the trunk. Such lesions are frequently (< 1.5 cm), medium (M1: 1.5–10 cm, M2: descriptively termed coat sleeve, stocking, cape- > 10–20 cm), large (L1: > 20–30 cm, L2: like, bathing trunk, giant hairy nevi and Tierfell > 30–40 cm) and giant (G1: > 40–60 cm, G2: nevus. These lesions have an irregular margin > 60 cm). In addition, the number of satellite nevi and are unevenly pigmented (Fig. 10.1 ). Their in the fi rst year of life is categorized into none, colour ranges from dark brown to black, and over 1–20, more than 20–50 and more than 50 satel- 95 % have a hairy component consisting of large lites. Additional descriptors of CMN include ana- coarse terminal hairs. Giant pigmented nevi may tomic localization, colour heterogeneity, surface have an uneven verrucous or papillomatous sur- rugousity, presence of hypertrichosis (described face. As the infant grows, the GCMN will grow as none, moderate, marked) and presence of der- proportionally with the anatomic site and become mal or subcutaneous nodules (none, scattered, thicker and frequently darker; the surface extensive). These clinical features are not classi- becomes irregular and frequently papules and fying features, but may be important for assess- nodules develop with time, most commonly in ing malignant potential. the fi rst 2 years of life. Almost invariably multi- SCMN occur in 1 % of newborns, MCMN in ple small satellite nevi are seen in these patients 0.6 % of newborns and GCMN in 1 in 20,000 to and often continue to develop over time (Egan 1 in 50,000 newborns (Castilla 1981 ). Females 1998 ). Satellite nevi are scattered congenital nevi appear to have a higher prevalence than males in which are distinct from the primary nevus and do most studies, with a female-to-male ratio of not necessarily occur in proximity to the GCMN around 3/2 (Bittencourt 2000a ). GCMN have in (Kinsler 2011 ). Besides the expansion in direct most cases a characteristic histology, with nevus proportion to growth of a given anatomic zone, cells extending in the lower two thirds of the der- surface pigmentation of a GCMN may also mis and in the subcutis, often associated with change: lightly pigmented GCMN may become skin appendages and neurovascular structures more darkly pigmented, and darkly pigmented and dispersed between collagen bundles in single GCMN eventually may lighten with age. Erosions fi le array (Mark 1973 ). Besides the fact that CMN may be cosmetically disfi guring, they also have an increased risk for malignant transformation. The melanoma risk is actually estimated between 0.05 and 10.7 % and strongly dependent on nevus size with a maximum risk during childhood (median age at diagnosis of 7 years).

Clinical Aspects

Congenital nevi have variable appearances. Compared to acquired nevi, they are mostly larger and more heterogeneous. SCMN and Fig. 10.1 Giant congenital melanocytic nevus, unevenly MCMN usually present as round or oval ﬂ at, pale pigmented 10 Congenital Melanocytic Nevi: What to Do? 93

(Borbujo 2000 ) may be present at birth or in early birth (six cases) or appeared in the fi rst 2 years of infancy and may represent benign superfi cial epi- life (nine cases). In a study from Massi ( 1999 ), dermal breakdown or be suggestive of melanoma. 131 cases with invasive melanomas were investi- Many associations with GCMN have been gated: 27/131 were associated with pre-existing described: cutaneous melanoma, leptomeningeal nevi. Of these, 12 (44.5 %) had features of melanoma, neurocutaneous melanocytosis SCMN. These studies suggest that SCMN might (NCM), brain malformations and possibly other predispose more to malignancy than actually malignant tumours such as rhabdomyosarcoma expected. At present, however, one particular and liposarcoma (Berg 2003; Christman 2014 ). problem with this supposition is the lack of speci- Other well-described associations are café au lait fi city of some of the histopathological criteria spots, mucosal nevi, benign nodules, plexiform considered to be characteristic of congenital overgrowths, fascicular schwannoma, lipoma, onset. In contrast to the age at which melanoma lymphangioma, capillary hemangioma and occurs in a GCMN, melanoma within a SCMN Mongolian spot. Limb hypertrophy or underlying tends to arise in a post-pubescent child. hypoplasia of the underlying fat may also be Accordingly, some authors recommend postpon- found (Caradona 2000 ). ing removal of SCMN until after puberty if there is no change in the nevus or until the child is old enough to co-operate suffi ciently to allow exci- Melanoma Risk and Management sion under local anaesthesia. This is around in CMN 8 years of age. By contrast, others recommend prophylactic excision in early childhood as life- Small CMN time follow-up of these patients is often not feasible and may entail more costs and anxiety than SCMN are found in about 1 % of newborns. prophylactic removal of the nevus. Recently, a There is as yet no consensus on whether these case of a melanoma in an SCMN in a 3-year-old lesions confer an increased risk of developing child has been reported (Zangari 2013 ), confi rm- malignant melanoma. As these nevi are much ing that melanoma can occur in SCMN, even at more common than GCMN, the epidemiological an early age. As most SCMN can easily be importance could be greater than that of excised, we are advocates of prophylactic exci- GCMN. To determine the risk of melanoma in sion of these lesions, especially if the nevus pres- SCMN, Rhodes et al. have examined melanomas ents atypical features, is in a location diffi cult to for histologic evidence of an existing congenital follow or on the free border of the eyelid nevus. They looked at 234 melanomas and (DeRaeve 1998 ). We manage these lesions on a found a three- to tenfold increased risk of mela- case-by-case basis and usually remove SCMN at noma in SCMN as compared with the general age of presentation of the child. If we observe the population and calculated a cumulative risk of nevus in infants during consultation, we advice 0.8–4.9 % for persons with SCMN who live to removal of the lesion at 1 year of age. Other the age of 60 years (Rhodes 1982 ). These authors experts in the fi eld however wait and see. estimated that the frequency of histologic association between SCMN and melanomas is 400– 13,000 times greater than the expected frequency Medium CMN based on surface area alone. Betti et al. (Betti 2000 ) collected a cohort of 190 cases of mela- The risk of developing melanoma in a medium- noma and found that 40/190 were associated with sized congenital melanocytic nevus (MCMN) is a pre-existing nevi. Of these, 15 with a diameter matter of controversy as there are only few fol- of less than 1.5 cm (SCMN) had congenital fea- low-up studies evaluating the risk of melanoma tures in their histology, and the parents of these limited to MCMN. In 1995, Swerdlow et al. pub- patients asserted that the nevi were present at lished the results of a cohort study assessing the 94 L. De Raeve risk of melanoma in patients with CMN, includ- risk estimates however do not distinguish ing MCMN. Of 239 patients, followed-up during between cutaneous and extra-cutaneous mela- 25 years, none developed a melanoma (Swerdlow noma, and the contribution of each to the overall 1995). A study reported by Sahin et al. ( 1998 ) risk estimate remains uncertain. Cutaneous mela- including 227 patients with MCMN followed up noma is often diffi cult to diagnose because of the for an average of 6.7 years similarly did not complex morphology of the GCMN. Therefore, reveal an increased risk for melanoma in benign- any visible pigmentary or nodular change, ulcer- appearing MCMN. However, in this study, the ation, bleeding or a cyst-like structure in a GCMN largest MCMN as well as those causing cosmetic prompts biopsy. Data from the NYU-LCMN reg- concern, those presenting unusual features and istry (Hale 2005 ) support that the risk for devel- those who could not be easily examined had been oping melanoma within a GCMN is probably selected and surgically treated and thereby fol- lower than that reported previously and that the lowed up for a shorter period of time or elimi- most important risk may lie in extra-cutaneous nated from the study. De Raeve et al. (1993 ) sites such as the CNS. In particular children with reported a case of melanoma occurring in a very large GCMN in association with numerous MCMN in a 10-year-old child and underscored satellite nevi are at greatest risk for NCM. NCM the need to register such cases in order to better is a melanocytic proliferation within the lepto- quantify the risk of malignancy in these lesions. meninges and the brain parenchyma. Malignant Only long-term follow-up in a prospective study, degeneration of those melanocytes results in starting from infancy, of a large group of patients development of primary CNS melanomas. with MCMN can establish the exact malignancy Benign proliferation of melanocytes of the lepto- risk of these nevi. The risk probably lies between meninges, however, can also result in serious that of GCMN and SCMN. We actually suggest complications or even death. Based on the pres- that any MCMN should be considered for exci- ence or absence of clinical manifestations, NCM sion and recommend early excision, especially has been divided in symptomatic and asymptom- for scalp lesions and body sites with increased atic forms. The most common initial symptoms mobility. If for some reason the nevus is not in symptomatic infants are related to increased excised, we recommend periodical follow-up intracranial pressure (lethargy, irritability, poor with photographic documentation. feeding, seizures), which may develop secondary to obstructed CSF fl ow, failure of cerebrospinal fl uid absorption due to subarachnoid infi ltration Giant CMN by pigmented cells or associated Dandy-Walker syndrome. Leptomeningeal melanoma develops Studies attempting to estimate malignancy risk in in approximately 40–62 % of symptomatic patients with GCMN reveal that the absolute patients, often within the fi rst years of life. The melanoma risk associated with GCMN is actu- prognosis of symptomatic NCM is poor, with ally reasonably well established to be in the death occurring within 3 years in more than half 1.25–10 % range (Bittencourt 2000b ) and the of patients and in 70 % within 10 years. The relative risk ranging from 52 to more than 1000 course and prognosis of patients with asymptom- (Zaal 2005 ). Important factors that seem to infl u- atic NCM is unknown and diffi cult to predict, but ence this risk include young age of the patient they appear to have few problems (Foster 2001 ). (half of melanomas associated with GCMN occur These children need magnetic resonance imaging in the fi rst 3 years of life, and 70 % of melanomas of the brain and periodic neurological examina- in GCMN develop in children under 10 years of tions (Slutsky 2010 ). age), location of the GCMN over the posterior Besides the risk of malignancy, another impor- axis (Fig. 10.1 ), the presence of multiple satellite tant concern is the stigma of this very visible nevi (Marghoob 2004 ) and GCMN larger than lesion and the psychological implications it will 40 cm (Krengel 2006). The published melanoma have. The psychosocial functioning of these 10 Congenital Melanocytic Nevi: What to Do? 95 patients can be affected by the deviant appear- Dermabrasion may cause transient reduction ance of the GCMN itself, by the anxiety for in pigmentation, but when too deep can result in malignancy, but also by the discomfort associ- scarring, and is often complicated by infection ated with the often multiple-staged surgical treat- (Bohn 2010 ). ments. Therefore, in the decision-making process The use of laser in GCMN treatment remains aesthetic and psychosocial issues, the potential controversial, as there is concern that the residual for malignant transformation, risk and technical nevus cells exposed to laser treatment have a diffi culty of surgery, fi nal cosmetic and func- higher probability of malignant transformation tional outcome must be considered. Considering (Kiang 2002 ). Moreover, repigmentation after the fact that the majority of cases of melanoma laser treatment is often reported. associated with GCMN occur early in childhood, Curettage of GCMN in the fi rst 2 weeks of life treatment should be rendered whenever and as is based on the observation that there is in the fi rst early as feasible. The rationale for early treat- few weeks of life a cleavage plane in these ment has different components: the presence of GCMN between the upper dermis, containing the highest risk for malignancy in the fi rst 3 years most of pigmented nevus cells and the lower der- of life, the elasticity and healing capacity of the mis. The advantages of curettage are numerous: skin early in life and the benefi t on the psycho- it is a relatively simple procedure with minimal logical development of the child. There are blood loss, a one-stage procedure well tolerated indeed studies revealing that three out of four by the infant and a technique by which lesions children and adolescents prefer a scar over the that are too large to be surgically resectable can original GCMN (Koot 2000 ). be treated. Healing is fast and results in good Many therapeutic modalities exist, but from immediate cosmetic results (DeRaeve 2006 ) an oncologic view treatment is aimed at complete (Fig. 10.2a, b ). Long-term follow-up shows that removal of the lesion. Full-thickness procedures the reduction in pigmentation is satisfactory, and remove more nevus cells than partial-thickness in most patients curettage results in soft pale procedures, but there is no solid evidence that scars (DeRaeve 2002 ). Cosmetic results decrease this reduces the risk of melanoma more effec- slightly with time: in some patients, repigmenta- tively. Moreover, there are several obstacles to tion and/or hypertrichosis is seen. No melanoma treating these enormous nevi. First, there are lim- developed in our series of 34 patients so treated. itations to how large an area can be resurfaced. Besides cosmetic outcome, research shows that Second, the morbidity of several surgical proce- the superfi cial component of the GCMN is more dures under general anaesthesia and the some- vascularized and more proliferative than its deep times less than desirable outcome with scarring component (De Raeve et al. 2006 ). These fi nd- and functional impairment may outweigh the ings support the idea that curettage of GCMN in risks of melanoma. Finally, the location of some the neonate may lower the risk for developing nevi, such as the eyelid and nose, makes com- cutaneous melanoma, not only by obtaining an plete excision impossible without mutilation. important numerical reduction of nevus cells but Malignancies can still develop, even after com- also by removing precisely the ‘active’ nevus plete surgical removal of the nevus, as melanoma cells with the highest proliferating activity. in these patients can occur at extra-cutaneous Considering these data together with the good sites. cosmetic and functional outcome, it is estimated In case complete removal surgery is impossi- that curettage is a valuable treatment for neonates ble or tends to lead to an unacceptable outcome, with GCMN (De Raeve 2006 ). Of course, this then partial removal of superfi cially located ‘superfi cial’ treatment does not eliminate the nevus resulting in a more acceptable cosmetic deeper nevus cells with the potential to develop outcome is another way of approaching these into melanoma or alters the overall disease pro- lesions and can be obtained by curettage, derm- cess in patients who will develop extra-cutaneous abrasion or laser therapy. melanoma. Recent publications do support the 96 L. De Raeve

a b

Fig. 10.2 Giant congenital melanocytic nevus before (a ) and 2 weeks after curettage (b )

a b

Fig. 10.3 Giant congenital melanocytic nevus on the back ( a ). First serial excision was performed at age 3 weeks. Postoperative result immediately after second serial excision at age 4 months (b ) place of curettage in the management of giant starting the fi rst intervention in the fi rst weeks of congenital nevi when complete nevus excision life, and obtained excellent results. When serial cannot be achieved (Arad 2014 ). excision however is not possible due to the exten- In recent years, great strides have also been sion of the lesion or the older age of the child, we made in excisional surgery. We could observe recommend tissue expansion. In this location, we that many large nevi can be excised completely do not recommend curettage, as the cleavage with very acceptable outcome if excision is per- plane in lesions on the scalp is more diffi cult to formed early in life. We therefore actually rec- fi nd and hence curettage may result in cicatricial ommend serial excisions for those lesions that alopecia. can be excised in two to three sessions (Fig. 10.3a, In conclusion, the management of GCMN b ). If this option is chosen, we strongly recom- needs to be tailored for each individual patient. mend starting intervention in the fi rst months of Malignancy risks, cosmetic and functional results life. Taking profi t of this unique period of laxity after surgery and psychological impact are of the skin results in better cosmetic outcome and important issues to take into consideration. reduction of the number of interventions. Treatment should be tailored to achieve optimal For scalp lesions, tissue expansion is well rec- aesthetic results whereby complete excision is ognized in the literature as the treatment modal- not always the goal. Surgery that is likely to ity of choice. Based on the good results of early result in signifi cant deformity or compromised excision in other locations, our plastic surgeons function should be avoided. The evidence sup- treated large scalp lesions by serial excision, porting a lower malignancy risk supports that 10 Congenital Melanocytic Nevi: What to Do? 97 partial removal should be integrated as part of Caradona SA, Gupta A, Bush CA, et al. Giant congenital any treatment algorithm. Based on our experi- melanocytic nevus with underlying hypoplasia of the subcutaneous fat. Pediatr Dermatol. ence with curettage, the good long-term clinical 2000;17(5):387–90. outcome after curettage and the results of our Castilla EE, Da Graca DM, Orioli Parreiras IM. research, this treatment is our preferred option Epidemiology of congenital pigmented nevi: inci- for most neonates with GCMN. Other valuable dence rates and relative frequencies. Br J Dermatol. 1981;104:307–15. treatment options in these children are early Christman MP, Kerner JK, Cheng C, et al. serial excision or tissue expansion. Of course Rhabdomyosarcoma arising in a giant congenital these patients must undergo lifelong regular melanocytic nevus. Pediatr Dermatol. 2014;31(5): examinations to detect any malignancy and be 584–7. De David M, Orlow SJ, Provost N, et al. A study of large educated on the importance of UV protection. congenital melanocytic nevi and associated malignant melanomas: review of cases in the NYU Registry and the world literature. J Am Acad Dermatol. Bulleted List of Controversies 1997;36:409–16. De Raeve L. Les nevus de l’enfant: que conseiller? J Pédiatr Puériculture. 1998;11:400–3. • The risk for the development of melanoma De Raeve LE. The giant congenital melanocytic nevus: a within CMN of various sizes is controversial. study evaluating the rationale for curettage in the neo- • Routine prophylactic removal of small- and nate. In: Doctoral Thesis in Medical Sciences. Brussels: Vrije Universiteit Brussel; 2006. medium-sized CMN is a matter of ongoing De Raeve LE, Roseeuw DI. Curettage of giant congenital debate. melanocytic nevi in neonates. A decade later. Arch • The aim of treatment of GCMN is complete Dermatol. 2002;138:943–8. resection or partial removal. De Raeve L, Danau W, De Backer A, et al. Prepubertal melanoma in a medium- sized congenital nevus. Eur • Laser therapy for GCMN is controversial J Pediatr. 1993;152:734–6. because of limited long-term data. De Raeve LE, Claes A, Ruiter D et al. Distinct phenotypic changes between the superfi cial and deep component of giant congenital melanocytic nevi: a rationale for curettage. Br J Dermatol. 2006;154:485–92. Dessars B, De Raeve LE, Morandini R, et al. Genotypic References and gene expression studies in congenital melanocytic nevi: insight into initial steps of melanotumorigenesis. Arad E, Zuker RM. The shifting paradigm in the manage- J Invest Dermatol. 2009;129(1):139–47. ment of giant congenital melanocytic nevi: review Egan CL, Oliveria SA, Elenitsas K, et al. Cutaneous mela- and clinical applications. Plast Reconstr Surg. noma risk and phenotypic changes in large congenital 2014;133(2):367–76. nevi: a follow-up study of 46 patients. J Am Acad Berg P, Lindelöf B. Congenital melanocytic nevi and Dermatol. 1998;39:923–32. cutaneous melanoma. Melanoma Res. 2003;13: Foster RD, Williams ML, Barkovich AJ, et al. Giant 441–5. congenital melanocytic nevi: the signifi cance of neu- Betti R, Inselvini E, Vergani R, et al. Small congenital rocutaneous melanosis in neurologically asymptom- nevi associated with melanoma: case reports and con- atic children. Plast Reconstr Surg. 2001;107: siderations. J Dermatol. 2000;27(9):583–90. 933–41. Bittencourt FV, Marghoob AA, Kopf AW, et al. Large Hale EK, Stein J, Ben-Porat L, et al. Association of mela- congenital melanocytic nevi and the risk for develop- noma and neurocutaneous melanocytosis with large ment of malignant melanoma and neurocutaneous congenital melanocytic nevi- results from the NYU- melanocytosis. Pediatrics. 2000a;106:736–41. LCMN registry. Br J Dermatol. 2005;152:512–7. Bittencourt MAW, Kopf KL, et al. Large congenital mela- Kiang L, Chan HH, Leung CK, et al. The effect of sub- nocytic nevi and the risk for the development of malig- lethal Q-switched 755nm lasers on the expression of nant melanoma and neurocutaneous melanocytosis. p16INK4A. Ann Dermatol Venereol. 2002;129:1S616. Pediatrics. 2000b;106:737–41. Kinsler V. Satellite lesions in congenital melanocytic Bohn J, Svensson H, Aberg M. Dermabrasion of large nevi- time for a change of name. Pediatr Dermatol. congenital melanocytic nevi in neonates. Scand J Plast 2011;28(2):212–3. Reconstr Surg Hand Surg. 2010;34:321–6. Kinsler VA, Thomas AC, Ishida M, et al. Multiple con- Borbujo J, Jara M, Cortes L, et al. A newborn with nodu- genital melanocytic nevi and neurocutaneous melano- lar ulcerated lesion on a giant congenital nevus. sis are caused by postzygotic mutations in codon 61 of Pediatr Dermatol. 2000;17(4):299–301. NRAS. J Invest Dermatol. 2013;133(9):2229–36. 98 L. De Raeve

Koot HM, de Waard-van der Spek F, Peer CD, et al. Rhodes AR, Melski JW. Small congenital nevocellular Psychosocial sequelae in 29 children with giant con- nevi and the risk of cutaneous melanoma. J Pediatr. genital melanocytic nevi. Clin Exp Dermatol. 1982;100:219–24. 2000;25(8):589–93. Sahin S, Levin L, Kopf AW, Rao BK, et al. Risk of mela- Krengel S, Hauschild A, Schafer T. Melanoma risk in noma in medium-sized congenital melanocytic nevi: congenital melanocytic nevi: a systematic review. Br a follow-up study. J Am Acad Dermatol. 1998;39: J Dermatol. 2006;155:1–8. 428–33. Krengel S, Scope A, Dusza SW, et al. New recommenda- Slutsky JB, Barr JM, Femia AN, et al. Large congenital tions for the categorization of cutaneous features of melanocytic nevi: associated risks and management congenital melanocytic nevi. J Am Acad Dermatol. considerations. Semin Cutan Med Surg. 2010;29: 2013;68(3):441–51. 79–84. Marghoob AA, Duzsa S, Oliveria S, et al. Number of sat- Swerdlow AJ, English JSC, Qiao Z. The risk of melanoma ellite nevi as a correlate for neurocutaneous melanocy- in patients with congenital nevi. A cohort study. J Am tosis in patients with large congenital melanocytic Acad Dermatol. 1995;32:595–9. nevi. Arch Dermatol. 2004;140:171–5. Zaal LH, Mooij WJ, Klip H, et al. Risk of malignant trans- Mark GJ, Mihm Jr MC, Liteplo MG, et al. Congenital formation of congenital melanocytic nevi: a retrospec- melanocytic nevi of the small and garment type. tive nationwide study from the Netherlands. Plast Human Pathol. 1973;4(3):395–418. Reconstr Surg. 2005;116:1902–9. Massi D, Carli P, Franchi A, et al. Nevus-associated melano- Zangari A, Ilari M, Nino F, et al. Report of a malignant mas: cause or chance? Melanoma Res. 1999;9(1):85–91. melanoma arising in a small congenital nevus in a Rhodes AR. Congenital nevomelanocytic nevi: propor- 3-year-old child. J Indian Assoc Pediatr Surg. tionate area expansion during infancy and early child- 2013;18(4):165–6. hood. J Am Acad Dermatol. 1996;34:51–62. Part IV Immune Disorders and Autoimmunity

Alopecia Areata 1 1 Abdullah Alkhalifah

Abstract Alopecia areata (AA) is a non-scarring hair loss condition that affects individuals of all ages and ethnic backgrounds. It is thought to be autoimmune in nature, but the exact cause is not yet known. This condition is usually asymptomatic and the patches are discovered incidentally in most patients. Scalp is the site most commonly affected by AA. AA patients have slightly higher chances of developing some other autoimmune conditions. There are no FDA-approved treatments for AA. Our treatment options aim to control the disease but none is curative. Despite the fact the treatment options for AA remained without major breakthroughs over the last few decades, recent understanding of the genetic structure of AA may carry newer management ideas. Addressing the psychological impact of the disease is of paramount importance in the management. This chapter will review the clinical picture and management of AA paying special attention to the pediatric age group.

Keywords Alopecia areata • Totalis • Universalis • Corticosteroids • Autoimmune • Immunotherapy • Topical • Intralesional • Phototherapy • GWAS (genome- wide association study)

Epidemiology

Alopecia areata (AA) is a fairly common condition that represents up to 3.8 % of dermatology visits (Alkhalifah 2010 ). The lifetime risk in an A. Alkhalifah , MD old US survey was estimated at 1.7 % (Safavi Department of Dermatology , 1995 ). There is no gender predilection Prince Sultan Military Medical City , Riyadh , Saudi Arabia (Wasserman 2007 ). AA affects children in about e-mail: [email protected] 20 % of the cases (Nanda 2002 ).

Clinical Features Table 11.1 summarizes the classifi cation of AA. Based on the extent of the disease, AA can be Most AA lesions are asymptomatic. However, classifi ed into patchy, total, or universal hair loss. few patients may report pruritus, burning, or pain Patchy AA is the most common affecting up to (Madani 2000 ). The scalp is the most commonly 75 % of patients (Lu 2006 ). Total scalp hair loss affected site (up to 90 % of patients) (Wasserman (Fig. 11.2 ) is seen in both alopecia totalis and uni- 2007). Lesions are typically well demarcated, versalis, but there is complete body hair loss in the round to oval, and skin-colored patches of non- latter. Patchy disease is also the most common scarring alopecia (Fig. 11.1 ) (Lu 2006 ). pattern. Other patterns include reticular, diffuse, Uncommonly, slight redness might be observed ophiasis (Fig. 11.3 ), and ophiasis inversus. Acute (Alkhalifah 2010). Exclamation mark hairs are diffuse alopecia areata is an acute and extensive characteristic (Wasserman 2007 ). These are hairs distinct variant that has been recently described that have a tapered proximal end and get wider as and can easily be misinterpreted as telogen effl u- you go distally. Active patches may have a posi- vium (Sato-Kawamura 2002 ; Lew 2009 ). tive hair pull test (Alkhalifah 2010 ). Gray hair is usually spared at the beginning, but it will be involved with disease progression (Alkhalifah 2010 ). Patients of all ages may have concerns about regrowing gray hair and should be reassured that this is a normal fi nding and the hair usually restores normal color with time.

Fig. 11.2 Alopecia totalis

Fig. 11.1 Multiple patchy alopecia areata

Table 11.1 Classifi cation of alopecia areata Classifi cation by extent Classifi cation by pattern Patchy AA Patchy AA Alopecia totalis (AT) Ophiasis Alopecia universalis (AU) Ophiasis inversus Reticular Diffuse Fig. 11.3 Alopecia areata, ophiasis pattern 11 Alopecia Areata 103

Several dermoscopic signs have been recog- Etiology nized as features of AA (Mane 2011 ; Ross 2006 ; Tosti 2008 ). These include yellow dots, black Stress (Elenkov 2002 ), genetics (McElwee dots, broken hairs, and short vellus hairs. The fre- 2001a ; Petukhova 2011 ), infections (Rodriguez quency of nail involvement in AA has been 2008), vaccinations (Ikeda 1967), and hormonal reported from 7 % up to 66 % (Ghandhi 2003 ). factors (McElwee 2001b ) have all been suggested Nail pitting is the most common associated as etiological triggering factors, but the exact eti- abnormality. Other abnormalities include trachy- ology is unknown. Autoimmunity is the major onychia, Beau’s lines, onychorrhexis, thinning or pathogenic factor in AA (Wang 2011 ). The pres- thickening, onychomadesis, koilonychia, punctu- ence of infl ammatory cells and hair follicle- ate or transverse leukonychia, and red spotted specifi c autoantibodies supports this hypothesis. lunulae (Alkhalifah 2010 ). The response to immunosuppressive medications and the association with other autoimmune diseases are two observations that also support the Associated Disorders autoimmune hypothesis. Few years ago, genome-wide association Autoimmune thyroid disease is the most com- study in AA discovered the association of this mon association with an incidence of 8–28 % disease to at least eight regions in the genome. (Seyrafi 2005 ). The presence of thyroid autoan- This discovery is shaping the future of AA treat- tibodies does not refl ect AA severity ment as we currently see several agents under (Kasumagic–Halilovic 2008 ). Vitiligo occurs in investigation, mainly for severe AA cases. 3–8 % of AA patients (Hordinsky 2004 ). Compared with the general population, atopy is twice as common in AA patients (Hordinsky Prognosis 2004). Down syndrome, Addison disease, autosomal recessive autoimmune polyglandular syn- Severe presentation (AT/AU) (Tosti 2006a ) and drome (APS-1), pernicious anemia, intermediate ophiasis pattern (Lew 2009 ) represent the most uveitis, Sjögren syndrome, psoriasis, lupus, important poor prognostic factors. Other poor rheumatoid arthritis, celiac disease, ulcerative prognostic factors include atopy, nail involve- colitis, myasthenia gravis, and multiple sclero- ment, a positive family history, the presence of sis were all reported to be associated with AA other autoimmune diseases, a long duration of (Ayuso 2011; Goh 2006; Rosenstein 2010 ). hair loss, and early age of onset (Madani 2000 ). Anxiety and mood disturbances occur fre- AA has an unpredictable course. Even without quently in AA patients (Ruiz- Doblado 2003 ). It treatment, recovery occurs in up to 50 % of is important to state that treating the associated patients within 1 year (Alkhalifah 2010 ). Eighty- disorders does not fi x AA. fi ve percent of patients will have another episode of hair loss at one stage of their lives (Finner 2011 ). The chance of AT in patients having their Differential Diagnosis disease before puberty reaches 50 % (Finner 2011 ). Unlike adult patients, pediatric AA should be differentiated from tinea capitis, trichotillomania, and temporal triangular alopecia (TTA). Scaling Histopathology and infl ammation can be seen in tinea capitis but unusual in AA. Trichotillomania is typically Histological features of AA depend on the stage bizarre shaped and may show roughness at the of the disease. In acute stage, peribulbar lympho- scalp surface. A single congenital patch at the cytic infi ltrate composed of CD4+ and CD8+ T temporal area should be differentiated from AA. cells (swarm of bees) is seen (Todes-Taylor 104 A. Alkhalifah

1984 ). Mast cells, plasma cells, eosinophils, and domized double-blind placebo-controlled trial Langerhans cells can be seen, as well (Dy 2011 ). (Tosti 2006b). On the other hand, desoximeta- Other features that can be seen around affected sone cream 0.25 % was not signifi cantly better hair follicles include edema, microvesiculation, than placebo in another randomized double-blind apoptosis, and necrosis (Whiting 2003 ); in the placebo-controlled trial (Charuwichitratana subacute stage, some infl ammation may still be 2000 ). Side effects of topical steroids are mild present. There is also marked increase in catagen and include folliculitis (more with ointment for- hairs. Chronic AA is characterized by signifi cant mulations) and rarely skin atrophy and miniaturization with little or no infl ammation telangiectasia. (Whiting 2003 ).

Intralesional Steroids Treatment For more than half a century, intralesional steroids There is no cure for AA. Many therapies are have been widely used for the treatment of adult available; however, no single agent is approved AA patients. Older children can tolerate this treat- for the treatment of AA by the FDA. High rate of ment modality with the help of anesthetic cream spontaneous remission, few number of random- or other pain-reducing options. The most com- ized trials, and lack of long-term data make AA monly used drug is triamcinolone acetonide. treatment evaluation diffi cult. Triamcinolone acetonide injections every Many of trials that we are going to discuss in 2 weeks showed hair regrowth in 71 % of patients this section – especially systemic agents – were with subtotal AA compared with 7 % of the con- done on adults. There is very little data published trol group (Abell 1973 ). on pediatric AA treatment. Choosing an agent Complete regrowth in 4 months was seen in should always be based on the benefi t versus risk 63 % of patients treated with monthly intrale- evaluation keeping in mind that we can control sional triamcinolone acetonide. Patients with but can’t cure pediatric AA. Individual topical and fewer, smaller patches, and shorter duration of systemic agents are going to be discussed below. the disease had the better response in this uncontrolled trial (Kubeyinje 1994 ). Treatment response is shown (Fig. 11.4a, b ). Topical Steroids Triamcinolone acetonide is injected monthly in the deep dermal/upper subcutaneous level using a Despite the wide use of midpotent and potent 30-gauge needle (Fig. 11.5 ). Various concentra- topical steroids in the treatment of AA, the evi- tions (2.5–10 mg/mL) can be used. 5 mg/mL for dence for their effi cacy is limited. Fluocinolone the scalp and 2.5 mg/mL for the face are the pre- acetonide cream was superior to vehicle in a ferred concentrations used by the author. Treatment double-blind half-head comparison (Pascher should be stopped if there is no improvement after 1970). In another randomized controlled trial, 6 months. This may happen because of the more than 75 % hair regrowth rate was seen in decreased expression of thioredoxin reductase 1 in 61 % of patients using 0.1 % betamethasone val- the outer root sheath (Sohn 2007 ). Transient skin erate foam in comparison with 27 % in the 0.05 % atrophy and telangiectasia may occur as a result of betamethasone dipropionate lotion group intralesional triamcinolone acetonide. (Mancuso 2003 ). 28.5 % of patients with AT/AU had a signifi cant improvement in a unilateral application of 0.05 % clobetasol propionate oint- Minoxidil ment under occlusion (Tosti 2003 ). 0.05 % clobetasol propionate foam showed positive effect Minoxidil is frequently prescribed for the treat- and did not modify cortisol levels in another ran- ment of AA in children. Its mechanism of action 11 Alopecia Areata 105

a b

Fig. 11.4 Patchy alopecia areata, (a ) before, (b ) after treatment

AA (Schmoeckel 1979 ; Fiedler- Weiss 1987 b). Anthralin 1 % cream is used as short contact therapy. The contact time can be increased by weekly increments from 15 min up to 1 h or until mild dermatitis develops. Anthralin should be used for at least 3 months before assessing its efﬁ cacy (Fig. 11.6a, b ). To be effective, anthralin should produce mild irritation. Side effects include lymphadenopathy, staining, and folliculitis.

Fig. 11.5 Intralesional steroid injections to the eyebrows Topical Immunotherapy using gauge 32 needle The ﬁ rst topical sensitizer to be used in AA was dinitrochlorobenzene (DNCB) back in 1976. It is is not fully understood. In extensive AA, the use not used anymore because of mutagenicity con- of 3 % minoxidil under occlusion with petrolatum cerns (Strobel 1980 ). Topical immunotherapy is was better than placebo (Price 1987 ). The use of used mainly for adults; however, there are reports 1 % and 5 % minoxidil in extensive AA resulted in of success in pediatric population (Orecchia a 38 % and 81 % response rate, respectively 1994 , 1995 ). Diphenylcyclopropenone (DPCP) (Fiedler- Weiss 1986 , 1987a ). Minoxidil is mostly and squaric acid dibutylester (SADBE) are the used as an adjuvant treatment to conventional AA compounds that are currently used. DPCP is therapies. The most common side effects are more commonly used because it is cheaper and hypertrichosis and contact dermatitis (Olsen more stable after compounding (Wilkerson 1984 , 2002; Lucky 2004). The use of minoxidil foam 1985 ). The mechanism of action of these com- can minimize contact dermatitis (Olsen 2007 ). pounds is not precisely determined. Perifollicular lymphocyte apoptosis (Herbst 2006), changes in the peribulbar CD4/CD8 ratio (Happle 1986 ; Anthralin Wasylyszyn 2007 ), interleukin-10 secretion (Hoffmann 1994 ), and antigenic competition The mechanism of action of anthralin in the treat- (Happle 1980 ) are examples of suggested ment of AA is unknown. Anthralin is a good option theories. for children with extensive AA. The response rate There is little difference between DPCP and is 25 % in severe AA and reaches 75 % in patchy SADBE. The average success rate of both com- 106 A. Alkhalifah

a b

Fig. 11.6 Alopecia totalis, (a ) before, (b ) 3 months after anthralin therapy

Fig. 11.7 DPCP solution is kept in amber bottles covered with aluminum foil to keep it from light

pounds is 50–60 % (Rokhsar 1998 ). In the largest esis with treatment seen by videocapillaroscopy series of DPCP patients, the success rate ranged (Ganzetti 2011 ). On the other hand, hyperpig- from 17.4 % (in AT/AU patients) to 100 % in mentation secondary to therapy was suggested to patients with 25–49 % scalp involvement be a poor prognostic factor (Ito 2012 ). (Wiseman 2001 ). Initial response was seen after DPCP is light sensitive and should be stored 3 months or more. Relapse rate was 62.6 % with away from ultraviolet light in protective bottles a median time of 2.5 years. Better response to (Fig. 11.7 ) (Wilkerson 1984 ). Using a cotton DPCP was seen in patients having neoangiogen- swab, DPCP 2 % is applied to a small area on the 11 Alopecia Areata 107 scalp. The patient is then reassessed after as side effects (Bearden 2004 ; Hart 2004 ; Tosti 2 weeks. If sensitization occurs, DPCP 0.001 % is 2004). Several case series showed failure of these applied to the same half of the scalp. The concen- agents to treat AA of the eyelashes (Faghihi 2009 ; tration is increased weekly until mild dermatitis Roseborough 2009; Ross 2005). Positive effect is obtained. When this is achieved, treatment is was reported by others (Coronel-Perez 2010 ; Vila carried on weekly for at least 6 months before 2010). Recently, bimatoprost 0.03 % twice daily assessing response. The solution should be left was comparable to mometasone furoate 0.1 % on the scalp for 48 h before washing it off. once daily for the treatment of adult patients with SADBE is an alternative option in patients who scalp AA (Zaher 2015 ). Prostaglandin analogs are are not sensitized after DPCP application usually well tolerated. Mild eye irritation may (Orrechia 1994 ; Dall’oglio 2005 ). occur (Ochoa 2009 ). Side effects of topical sensitizers include bullous reactions (Fig. 11.8 ), pigmentary abnormalities (Henderson 1995; Pan 2009 ), regional Systemic Therapies lymphadenopathy (Gordon 1996 ; Sotiriadis 2007 ), facial edema, contact urticaria (Alam,1999 ; In general, most of the available systemic thera- Francomano and Seidenari 2002 ; Tosti 1989 ), pies for alopecia areata are not attractive. Many ﬂ u-like symptoms, and erythema multiforme-like have unfavorable side-effect proﬁ le, and the reactions (Perret 1990 ). relapse rate is high after treatment discontinuation. In children, we should be more cautious as most of the studies were done on the adult population. Prostaglandin Analogs Systemic steroids are frequently used although there is only one randomized placebo-controlled Latanoprost and bimatoprost are used in the treat- trial published. Patients with extensive AA ment of open-angle glaucoma. Hypertrichosis of received prednisolone 200 mg weekly for the eyelashes and malar vellus hair were reported 3 months. Response rate was 35 % in the treatment group compared with none on the placebo group (Kar 2005 ). Other systemic steroid regimens are used with varying results (Ait-Ourhroui 2010 ; Friedli 1998 ; Kurosawa 2006 ; Olsen 1992 ; Price 1999 ; Sharma 1999 ). The reported relapse rate is 14–100 % (Alsantali 2011 ). Side effects include growth retardation, osteopenia, cataracts, obesity, immunosuppression, dysmenorrhea, acne, hyperglycemia, Cushing syndrome, and mood changes. Cyclosporine is a potent immunosuppressant that inhibits helper T-cell activation and suppresses interferon gamma production. It was used alone or in conjunction with systemic steroids with a success rate between 25 and 76.6 % (Gupta 1990 ; Kim 2008; Shapiro 1997 ). Hypertension, nephrotoxicity, and immune suppression are the most important side effects. In adult patients with severe AA, sulfasalazine resulted in a response rate of 23–27.3 % (Aghaei 2008 ; Ellis 2002 ; Rashidi 2008 ). The relapse rate was 45.5 %. Side effects include headache, gas- Fig. 11.8 Bullous reaction secondary to DPCP trointestinal distress, and skin rashes. 108 A. Alkhalifah

Methotrexate alone or in conjunction with able. Other useful modalities include excimer low-dose prednisolone resulted in complete hair laser and topical immune therapy. Promising regrowth in up to 63 % of adult AA patients for the future are topical prostaglandin analogs (Chartaux 2010 ) and relapse rate was 80 %. In and therapy with JAK inhibitor. children with severe AA, methotrexate had a response rate of 38 % (Royer 2011 ). Nausea, elevated liver enzymes, and lymphocytopenia are Bulleted List of Controversies possible side effects. • Screening for thyroid dysfunction is suggested, especially with a strong immediate Phototherapy family history of thyroid disease. • No approved FDA treatment for AA exists, but There are no randomized controlled trials for pho- treatment with JAK inhibitors is promising. totherapy with psoralen plus ultraviolet A • Treatment duration of six months or more is (PUVA). Available evidence suggests that it is as suggested to assess response for many treat- good as spontaneous remission rate (Healy 1993 ; ment options. Taylor 1995 ). Narrowband ultraviolet b (NB– • The treatment options should be as follows in UVB) was not effective in 25 AA patients children 12 years and older: (Bayramgurler 2011 ). Using 308-nm excimer – Intralesional corticosteroids laser in children aged 4–14 years, hair regrowth – Combined with minoxidil 5 % was noted in 60 % of AA patches (Al-Mutairi – Excimer laser treatment 2009 ). There is a single case report of a positive – Immunocontact therapy response to fractional Er:glass laser (Yoo 2010 ). – Methotrexate oral therapy – Treatment with JAK inhibitors if available (not FDA approved for AA) What Is in the Pipeline? • The treatment options should be as follows in children younger than 12 years: Tofacitinib is a Janus kinase (JAK) 1/3 inhibitor, – Topical corticosteroids of class 4 (EU) or and it is FDA approved for rheumatoid arthritis. class 2 (USA). There is a single case report of successful treat- – Combined with topical minoxidil 5 %. ment of AU within 5 months of therapy (Craiglow – Excimer laser treatment. 2014 ). Ruxolitinib is another JAK1/2 inhibitor – Immunocontact therapy in young children that showed success in three patients and further is controversial. DPCP has been used in data are underway (Xing 2014). Low-dose children younger than 12 years. recombinant interleukin-2 was partially successful in four out of ﬁ ve patients with severe AA (Castela 2014). These new modalities need fur- References ther evaluation before adding them to our therapeutic armamentarium. Until now, we don’t have Abell E, Munro DD. Intralesional treatment of alopecia any data on their use in pediatric AA. areata with triamcinolone acetonide by jet injector. Br J Dermatol. 1973;88(1):55–9. Aghaei S. An uncontrolled, open label study of sulfasala- Conclusions zine in severe alopecia areata. Indian J Dermatol The cause of AA is unknown, but it presum- Venereol Leprol. 2008;74(6):611–3. ably has autoimmune origin. Several triggers Ait Ourhroui M, Hassam B, Khoudri I. Treatment of alo- have been recognized. The most common pecia areata with prednisone in a once-monthly oral pulse. Ann Dermatol Venereol. 2010;137(8–9):514–8. associated abnormality is an autoimmune thy- Alam M, Gross EA, Savin RC. Severe urticarial reaction roid dysfunction. No effective treatment for to diphenylcyclopropenone therapy for alopecia AA exists. Intralesional steroids are most reli- areata. J Am Acad Dermatol. 1999;40(1):110–2. 11 Alopecia Areata 109

Alkhalifah A, et al. Alopecia areata update: part I. Clinical Fiedler-Weiss VC, et al. Topical minoxidil dose-response picture, histopathology, and pathogenesis. J Am Acad effect in alopecia areata. Arch Dermatol. Dermatol. 2010;62(2):177–88, quiz 189–90. 1986;122(2):180–2. Al-Mutairi N. 308-nm excimer laser for the treatment of Finner AM. Alopecia areata: clinical presentation, diag- alopecia areata in children. Pediatr Dermatol. 2009; nosis, and unusual cases. Dermatol Ther. 26(5):547–50. 2011;24(3):348–54. Alsantali A. Alopecia areata: a new treatment plan. Clin Francomano M, Seidenari S. Urticaria after topical immu- Cosmet Investig Dermatol. 2011;4:107–15. notherapy with diphenylcyclopropenone. Contact Ayuso VK, Pott JW, de Boer JH. Intermediate uveitis and Dermatitis. 2002;47(5):310–1. alopecia areata: is there a relationship? Report of 3 Friedli A, et al. Pulse methylprednisolone therapy for pediatric cases. Pediatrics. 2011;128(4):e1013–8. severe alopecia areata: an open prospective study of 45 Bayramgurler D, et al. Narrowband ultraviolet B photo- patients. J Am Acad Dermatol. 1998;39(4 Pt therapy for alopecia areata. Photodermatol 1):597–602. Photoimmunol Photomed. 2011;27(6):325–7. Gandhi V, Baruah MC, Bhattacharaya SN. Nail changes Bearden W, Anderson R. Trichiasis associated with pros- in alopecia areata: incidence and pattern. Indian taglandin analog use. Ophthal Plast Reconstr Surg. J Dermatol Venereol Leprol. 2003;69(2):114–5. 2004;20(4):320–2. Ganzetti G, et al. Videocapillaroscopic pattern of alopecia Castela E, et al. Effects of low-dose recombinant interleu- areata before and after diphenylciclopropenone treatment. kin 2 to promote T-regulatory cells in alopecia areata. Int J Immunopathol Pharmacol. 2011;24(4):1087–91. JAMA Dermatol. 2014;150(7):748–51. Goh C, et al. Profi le of 513 patients with alopecia areata: Chartaux E, Joly P. Long-term follow-up of the effi cacy of associations of disease subtypes with atopy, autoim- methotrexate alone or in combination with low doses mune disease and positive family history. J Eur Acad of oral corticosteroids in the treatment of alopecia Dermatol Venereol. 2006;20(9):1055–60. areata totalis or universalis. Ann Dermatol Venereol. Gordon PM, et al. Topical diphencyprone for alopecia 2010;137(8–9):507–13. areata: evaluation of 48 cases after 30 months’ follow- Charuwichitratana S, Wattanakrai P, Tanrattanakorn up. Br J Dermatol. 1996;134(5):869–71. S. Randomized double-blind placebo-controlled trial in Gupta AK, et al. Oral cyclosporine for the treatment of alo- the treatment of alopecia areata with 0.25% desoximeta- pecia areata. A clinical and immunohistochemical anal- sone cream. Arch Dermatol. 2000;136(10):1276–7. ysis. J Am Acad Dermatol. 1990;22(2 Pt 1):242–50. Coronel-Perez IM, Rodriguez-Rey EM, Camacho- Happle R. Antigenic competition as a therapeutic concept Martinez FM. Latanoprost in the treatment of eyelash for alopecia areata. Arch Dermatol Res. alopecia in alopecia areata universalis. J Eur Acad 1980;267(1):109–14. Dermatol Venereol. 2010;24(4):481–5. Happle R, Klein HM, Macher E. Topical immunotherapy Craiglow BG, King BA. Killing two birds with one stone: changes the composition of the peribulbar infi ltrate in oral tofacitinib reverses alopecia universalis in a alopecia areata. Arch Dermatol Res. 1986;278(3): patient with plaque psoriasis. J Invest Dermatol. 214–8. 2014;134(12):2988–90. Hart J, Shafranov G. Hypertrichosis of vellus hairs of the Dall’oglio F, et al. Topical immunomodulator therapy malar region after unilateral treatment with bimato- with squaric acid dibutylester (SADBE) is effective prost. Am J Ophthalmol. 2004;137(4):756–7. treatment for severe alopecia areata (AA): results of an Healy E, Rogers S. PUVA treatment for alopecia areata-- open-label, paired-comparison, clinical trial. does it work? A retrospective review of 102 cases. Br J Dermatolog Treat. 2005;16(1):10–4. J Dermatol. 1993;129(1):42–4. Dy LC, Whiting DA. Histopathology of alopecia areata, Henderson CA, Ilchyshyn A. Vitiligo complicating acute and chronic: why is it important to the clinician? diphencyprone sensitization therapy for alopecia uni- Dermatol Ther. 2011;24(3):369–74. versalis. Br J Dermatol. 1995;133(3):496–7. Elenkov IJ, Chrousos GP. Stress hormones, proinfl amma- Herbst V, et al. Diphenylcyclopropenone treatment of alo- tory and antiinfl ammatory cytokines, and autoimmu- pecia areata induces apoptosis of perifollicular lym- nity. Ann N Y Acad Sci. 2002;966:290–303. phocytes. Eur J Dermatol. 2006;16(5):537–42. Ellis CN, Brown MF, Voorhees JJ. Sulfasalazine for alope- Hoffmann R, et al. Cytokine mRNA levels in alopecia cia areata. J Am Acad Dermatol. 2002;46(4):541–4. areata before and after treatment with the contact aller- Faghihi G, Andalib F, Asilian A. The effi cacy of latano- gen diphenylcyclopropenone. J Invest Dermatol. prost in the treatment of alopecia areata of eyelashes 1994;103(4):530–3. and eyebrows. Eur J Dermatol. 2009;19(6):586–7. Hordinsky M, Ericson M. Autoimmunity: alopecia areata. Fiedler-Weiss VC. Topical minoxidil solution (1% and J Investig Dermatol Symp Proc. 2004;9(1):73–8. 5%) in the treatment of alopecia areata. J Am Acad Ikeda T. Produced alopecia areata based on the focal Dermatol. 1987;16(3 Pt 2):745–8. infection theory and mental motive theory. Fiedler-Weiss VC, Buys CM. Evaluation of anthralin in Dermatologica. 1967;134(1):1–11. the treatment of alopecia areata. Arch Dermatol. Ito T. Advances in the management of alopecia areata. 1987;123(11):1491–3. J Dermatol. 2012;39(1):11–7. 110 A. Alkhalifah

Kar BR, et al. Placebo-controlled oral pulse prednisolone Orecchia G, Malagoli P. Topical immunotherapy in chil- therapy in alopecia areata. J Am Acad Dermatol. dren with alopecia areata. J Invest Dermatol. 2005;52(2):287–90. 1995;104(5 Suppl):35S–6. Kasumagic-Halilovic E. Thyroid autoimmunity in patients Orecchia G, Malagoli P, Santagostino L. Treatment of with alopecia areata. Acta Dermatovenerol Croat. severe alopecia areata with squaric acid dibutylester in 2008;16(3):123–5. pediatric patients. Pediatr Dermatol. Kim BJ, et al. Combination therapy of cyclosporine and 1994;11(1):65–8. methylprednisolone on severe alopecia areata. Pan JY, et al. Vitiligo as an adverse reaction to topical J Dermatolog Treat. 2008;19(4):216–20. diphencyprone. Ann Acad Med Singapore. Kubeyinje EP. Intralesional triamcinolone acetonide in 2009;38(3):276–7. alopecia areata amongst 62 Saudi Arabs. East Afr Med Pascher F, Kurtin S, Andrade R. Assay of 0.2 percent fl uo- J. 1994;71(10):674–5. cinolone acetonide cream for alopecia areata and tota- Kurosawa M, et al. A comparison of the effi cacy, relapse lis. Effi cacy and side effects including histologic study rate and side effects among three modalities of sys- of the ensuing localized acneiform response. temic corticosteroid therapy for alopecia areata. Dermatologica. 1970;141(3):193–202. Dermatology. 2006;212(4):361–5. Perret CM, et al. Erythema multiforme-like eruptions: a Lew BL, Shin MK, Sim WY. Acute diffuse and total alo- rare side effect of topical immunotherapy with diphe- pecia: a new subtype of alopecia areata with a favor- nylcyclopropenone. Dermatologica. 1990;180(1):5–7. able prognosis. J Am Acad Dermatol. Petukhova L, et al. The genetics of alopecia areata: What’s 2009;60(1):85–93. new and how will it help our patients? Dermatol Ther. Lu W, et al. Alopecia areata: pathogenesis and potential 2011;24(3):326–36. for therapy. Expert Rev Mol Med. 2006;8(14):1–19. Price VH. Double-blind, placebo-controlled evaluation of Lucky AW, et al. A randomized, placebo-controlled trial topical minoxidil in extensive alopecia areata. J Am of 5% and 2% topical minoxidil solutions in the treat- Acad Dermatol. 1987;16(3 Pt 2):730–6. ment of female pattern hair loss. J Am Acad Dermatol. Price VH. Treatment of hair loss. N Engl J Med. 2004;50(4):541–53. 1999;341(13):964–73. Madani S, Shapiro J. Alopecia areata update. J Am Acad Rashidi T, Mahd AA. Treatment of persistent alopecia Dermatol. 2000;42(4):549–66; quiz 567–70. areata with sulfasalazine. Int J Dermatol. Mancuso G, et al. Effi cacy of betamethasone valerate 2008;47(8):850–2. foam formulation in comparison with betamethasone Rodriguez TA, Duvic M. Onset of alopecia areata after dipropionate lotion in the treatment of mild-to- Epstein-Barr virus infectious mononucleosis. J Am moderate alopecia areata: a multicenter, prospective, Acad Dermatol. 2008;59(1):137–9. randomized, controlled, investigator-blinded trial. Int Rokhsar CK, et al. Effi cacy of topical sensitizers in the J Dermatol. 2003;42(7):572–5. treatment of alopecia areata. J Am Acad Dermatol. Mane M, Nath AK, Thappa DM. Utility of dermoscopy in 1998;39(5 Pt 1):751–61. alopecia areata. Indian J Dermatol. Roseborough I, et al. Lack of effi cacy of topical latano- 2011;56(4):407–11. prost and bimatoprost ophthalmic solutions in promot- McElwee K, et al. Genetic susceptibility and severity of ing eyelash growth in patients with alopecia areata. alopecia areata in human and animal models. Eur J Am Acad Dermatol. 2009;60(4):705–6. J Dermatol. 2001a;11(1):11–6. Rosenstein ED, Warshauer BL. Alopecia areata and auto- McElwee KJ, et al. Melanocyte and gonad activity as immunity. J Am Acad Dermatol. 2010;62(6):1065. potential severity modifying factors in C3H/HeJ mouse Ross EK, et al. Lack of effi cacy of topical latanoprost in alopecia areata. Exp Dermatol. 2001b;10(6):420–9. the treatment of eyebrow alopecia areata. J Am Acad Nanda A, Al-Fouzan AS, Al-Hasawi F. Alopecia areata in Dermatol. 2005;53(6):1095–6. children: a clinical profi le. Pediatr Dermatol. Ross EK, Vincenzi C, Tosti A. Videodermoscopy in the 2002;19(6):482–5. evaluation of hair and scalp disorders. J Am Acad Ochoa BE, et al. Instilled bimatoprost ophthalmic solu- Dermatol. 2006;55(5):799–806. tion in patients with eyelash alopecia areata. J Am Royer M, et al. Effi cacy and tolerability of methotrexate Acad Dermatol. 2009;61(3):530–2. in severe childhood alopecia areata. Br J Dermatol. Olsen EA, Carson SC, Turney EA. Systemic steroids with 2011;165(2):407–10. or without 2% topical minoxidil in the treatment of alo- Ruiz-Doblado S, Carrizosa A, Garcia-Hernandez pecia areata. Arch Dermatol. 1992;128(11):1467–73. MJ. Alopecia areata: psychiatric comorbidity and Olsen EA, et al. A randomized clinical trial of 5% topical adjustment to illness. Int J Dermatol. 2003;42(6): minoxidil versus 2% topical minoxidil and placebo in 434–7. the treatment of androgenetic alopecia in men. J Am Safavi KH, et al. Incidence of alopecia areata in Olmsted Acad Dermatol. 2002;47(3):377–85. County, Minnesota, 1975 through 1989. Mayo Clin Olsen EA, et al. A multicenter, randomized, placebo- Proc. 1995;70(7):628–33. controlled, double-blind clinical trial of a novel for- Sato-Kawamura M, Aiba S, Tagami H. Acute diffuse and mulation of 5% minoxidil topical foam versus placebo total alopecia of the female scalp. A new subtype of in the treatment of androgenetic alopecia in men. J Am diffuse alopecia areata that has a favorable prognosis. Acad Dermatol. 2007;57(5):767–74. Dermatology. 2002;205(4):367–73. 11 Alopecia Areata 111

Schmoeckel C, et al. Treatment of alopecia areata by Tosti A, et al. Effi cacy and safety of a new clobetasol pro- anthralin-induced dermatitis. Arch Dermatol. pionate 0.05% foam in alopecia areata: a randomized, 1979;115(10):1254–5. double-blind placebo-controlled trial. J Eur Acad Seyrafi H, et al. Evaluation of the profi le of alopecia areata Dermatol Venereol. 2006b;20(10):1243–7. and the prevalence of thyroid function test abnormali- Tosti A, et al. The role of scalp dermoscopy in the diagno- ties and serum autoantibodies in Iranian patients. sis of alopecia areata incognita. J Am Acad Dermatol. BMC Dermatol. 2005;5:11. 2008;59(1):64–7. Shapiro J, et al. Systemic cyclosporine and low-dose pred- Vila TO, Camacho Martinez FM. Bimatoprost in the treat- nisone in the treatment of chronic severe alopecia ment of eyelash universalis alopecia areata. Int areata: a clinical and immunopathologic evaluation. J Trichology. 2010;2(2):86–8. J Am Acad Dermatol. 1997;36(1):114–7. Wang E, McElwee KJ. Etiopathogenesis of alopecia Sharma VK, Gupta S. Twice weekly 5 mg dexamethasone areata: Why do our patients get it? Dermatol Ther. oral pulse in the treatment of extensive alopecia areata. 2011;24(3):337–47. J Dermatol. 1999;26(9):562–5. Wasserman D, et al. Alopecia areata. Int J Dermatol. Sohn KC, et al. Effect of thioredoxin reductase 1 on glu- 2007;46(2):121–31. cocorticoid receptor activity in human outer root Wasylyszyn T, Kozlowski W, Zabielski SL. Changes in sheath cells. Biochem Biophys Res Commun. distribution pattern of CD8 lymphocytes in the scalp 2007;356(3):810–5. in alopecia areata during treatment with diphency- Sotiriadis D, et al. Topical immunotherapy with diphenyl- prone. Arch Dermatol Res. 2007;299(5–6):231–7. cyclopropenone in the treatment of chronic extensive Whiting DA. Histopathologic features of alopecia areata: alopecia areata. Clin Exp Dermatol. 2007;32(1):48–51. a new look. Arch Dermatol. 2003;139(12):1555–9. Strobel R, Rohrborn G. Mutagenic and cell transforming Wilkerson MG, Henkin J, Wilkin activities of 1-chlor-2,4-dinitrobenzene (DNCB) and JK. Diphenylcyclopropenone: examination for poten- squaric-acid-dibutylester (SADBE). Arch Toxicol. tial contaminants, mechanisms of sensitization, and 1980;45(4):307–14. photochemical stability. J Am Acad Dermatol. 1984; Taylor CR, Hawk JL. PUVA treatment of alopecia areata 11(5 Pt 1):802–7. partialis, totalis and universalis: audit of 10 years’ Wilkerson MG, et al. Squaric acid and esters: analysis for experience at St John’s Institute of Dermatology. Br contaminants and stability in solvents. J Am Acad J Dermatol. 1995;133(6):914–8. Dermatol. 1985;13(2 Pt 1):229–34. Todes-Taylor N, et al. T cell subpopulations in alopecia Wiseman MC, et al. Predictive model for immunotherapy areata. J Am Acad Dermatol. 1984;11(2 Pt 1):216–23. of alopecia areata with diphencyprone. Arch Dermatol. Tosti A, Guerra L, Bardazzi F. Contact urticaria during 2001;137(8):1063–8. topical immunotherapy. Contact Dermatitis. 1989; Xing L, et al. Alopecia areata is driven by cytotoxic T 21(3):196–7. lymphocytes and is reversed by JAK inhibition. Nat Tosti A, et al. Clobetasol propionate 0.05% under occlu- Med. 2014;20(9):1043–9. sion in the treatment of alopecia totalis/universalis. Yoo KH, et al. Treatment of alopecia areata with frac- J Am Acad Dermatol. 2003;49(1):96–8. tional photothermolysis laser. Int J Dermatol. Tosti A, et al. Hypertrichosis of the eyelashes caused by 2010;49(7):845–7. bimatoprost. J Am Acad Dermatol. 2004;51(5 Suppl): Zaher H, et al. Bimatoprost versus mometasone furoate in S149–50. the treatment of scalp alopecia areata: a pilot study. Tosti A, Bellavista S, Iorizzo M. Alopecia areata: a long Dermatology. 2015;230(4):308–13. term follow-up study of 191 patients. J Am Acad Dermatol. 2006a;55(3):438–41. Therapy of Juvenile Immune Bullous Disorders 1 2

Sultan Al-Khenaizan and Luluah Al Mubarak

Abstract Autoimmune blistering diseases are a heterogeneous group of diseases that result from autoantibodies generated against target antigens found in the skin and mucous membranes. Blistering diseases in children and adolescents pose difﬁ cult diagnostic and management challenges. Although rare, their morbidity and mortality necessitate understanding of their clinical presentation, natural history, sequelae, and management. Shared by blister formation, the number of entities is large and varies in presentation, clinical course, histopathology, and treatment. Here, we will brieﬂ y out- line the salient feature of each diseases and then focus on the most important therapeutic armamentarium in treating these diseases highlighting important therapeutic controversies.

Keywords Autoimmune bullous disorders • Pemphigus • Pemphigoid • Dermatitis herpetiformis • Vaccination • Childhood autoimmune blistering disease • Chronic bullous disease of childhood • Glucocorticoids

Autoimmune blistering diseases (ABDs) are a heterogeneous group of diseases that result from autoantibodies generated against target antigens found in the skin and mucous membranes. This S. Al-Khenaizan , MD (*) process disrupts keratinocyte adhesion and cel- King Abdulaziz Medical City-Ministry of National lular integrity, resulting in ﬂ uid accumulation and Guard, Riyadh , Saudi Arabia development of blisters at different levels consti- College of Medicine , King Saud Bin Abdulaziz tuting the clinical hallmark of these diseases. For University for Health Sciences , Riyadh , Saudi Arabia differential diagnoses of ABD and other causes e-mail: [email protected] of blisters (Table 12.1 ). ABDs are generally clas- L. Al Mubarak , MD siﬁ ed into two categories: intraepidermal blister- Department of Dermatology , Prince Sultan Military ing diseases and subepidermal blistering diseases Medical City-Riyadh Military Hospital, Riyadh , Saudi Arabia (Brenner and Mashiah 2000 ). Although clinical

Table 12.1 Differential diagnosis of ABD Hereditary: Porphyria Congenital blistering disorders (epidermolysis bullosa) Traumatic Infections: Bullous impetigo Herpetic infections Drug reactions: Bullous erythema multiforme Stevens–Johnson syndrome

Fig. 12.1 Photograph of a child with chronic bullous dis- diagnosis as bullous disease is not diffi cult, spe- ease of childhood showing annular tense bullae forming cifi c categorization requires histologic and “cluster of jewels” appearance immunopathological studies. The incidence and prevalence of childhood autoimmune blistering diseases (CABDs) are unknown as most of the side effect of severe hemolytic anemia, as well as existing literatures consist of cases and case regular subsequent monitoring of relevant blood series. The most common ABDs in childhood is work. Oral prednisolone at 1 mg/kg/day for 1–3 chronic bullous disease of childhood (CBDC), weeks, tapered over 3–6 weeks, can be started bullous pemphigoid, and dermatitis herpetifor- initially pending G6PD result. Topical steroids mis (DH) (Hofmann et al. 2009 ). Due to the rar- can be used concurrently with other therapies for ity of these diseases in pediatric age group, mild or localized disease. Other drugs that have controlled therapeutic studies with suffi ciently been used with success include erythromycin, large numbers of patients are diffi cult to achieve. colchicine, mycophenolate mofetil, and intrave- Therefore, off-label use of the applied therapeu- nous immunoglobulins (IVIGs) (Wolff et al. tic armamentarium is justifi ed (Hofmann et al. 2007 ). Most cases of CBDC resolve spontane- 2009 ). Also, many unsettled controversies and ously within 5 years (Sansaricq and Stein 2012 ). questions are not yet answered. Here, we will tackle some of salient controversies. Dermatitis Herpetiformis

Autoimmune Blistering Disease Dermatitis herpetiformis has an equal gender dis- in Children tribution and is seen more commonly in Europe than in North America for unknown reasons Chronic Bullous Disease of Childhood (Sansaricq and Stein 2012). The cornerstone of DH management is the strict gluten-free diet Despite its good prognosis, most children are leading to resolution of skin disease faster than treated to decrease disease severity and shorten bowel symptoms (Sansaricq and Stein 2012 ). its duration (Fig. 12.1). Large, randomized, The drug of choice of CBDC is dapsone with placebo-controlled, double-blind clinical studies typical prompt response within a few days. The have not been performed for the treatment of standard initial dose of dapsone in childhood is CBDC. The treatment of choice is dapsone, at a 0.5–2 mg/kg/day (Kenani et al. 2009 ). Other sul- dose of 0.5–1 mg/kg of body weight per day and fones such as sulfapyridine can also be used as increasing up to 2 mg/kg depending on the well as systemic steroid. Topical steroids can be response. A normal glucose-6-phosphate dehy- utilized for resistant areas. Relapses can occur drogenase (G6PD) level is required to avoid the frequently, due to diffi culties in maintaining a 12 Therapy of Juvenile Immune Bullous Disorders 115 strict gluten-free diet, which has to be lifelong with blisters (Sansaricq and Stein 2012 ). As the (Sansaricq and Stein 2012 ). antibody titers decrease, the clinical manifestations in the infant disappear typically within 2 weeks to 3 months (Sansaricq and Stein 2012 ). Pemphigus Topical steroids are occasionally needed to has- ten resolution. Pemphigus is extremely rare in children, with a mean age of 12 years at presentation, and it has better prognosis than in adults (Sansaricq and Epidermolysis Bullosa Acquisita Stein 2012 ). Systemic corticosteroid therapy is the mainstay of treatment with prednisolone used Epidermolysis bullosa acquisita (EBA) classi- as a fi rst-line agent in doses of 1–2 mg/kg/day. cally presents as a mechanobullous disease with Most patients require a steroid-sparing agent, skin fragility and trauma-induced blisters that such as dapsone, azathioprine, methotrexate, or heal with milia, dyspigmentation, and scarring cyclophosphamide (Sansaricq and Stein 2012 ). (Fig. 12.3 ). Mucous membranes, including eyes, Potent topical or intralesional steroid, if child age nose, and mouth, can also be affected (Sansaricq allows, can be used for isolated recalcitrant foci and Stein 2012 ). Prednisolone 1 mg/kg/day is of persistent blistering. effective in controlling the disease, and steroid- sparing agents are usually added upon diagnosis confi rmation (Kneisel and Hertl 2011 ). Transplacentally Transmitted Alternative therapies that have been reported Diseases include sulfapyridine, a combination of nicotinamide and erythromycin. Other options include Neonatal pemphigus and herpes (pemphigoid) azathioprine, dapsone, colchicine, mycopheno- gestationis can present in newborn due to the pas- late mofetil, gold, and IVIG. Long-term progno- sive transfer of immunoglobulins from the mother sis for EBA in children is much better than in to the fetus resulting in blistering in the newborn adults. Children with EBA generally undergo (Fig. 12.2 ). Approximately 2–10 % of neonates remission within 1–4 years, although some might born to mother with neonatal pemphigus and her- take longer to resolve. Localized lesions can be pes (pemphigoid) gestationis will be affected treated with super potent topical steroids.

Fig. 12.2 Photograph of a neonate born to a mother with Fig. 12.3 Photograph of a child with epidermolysis bul- pemphigus vulgaris with extensive erosion on the left losa acquisita showing linear tense bullae with milia, dys- chest pigmentation, and scarring 116 S. Al-Khenaizan and L. Al Mubarak

Bullous Pemphigoid pressive therapy, chronic infections like bacterial infections, HIV, hepatitis B and C, and tuberculo- Lesions of bullous pemphigoid)BP) are most sis should be ruled out to prevent possible reacti- commonly found on the face, neck, groin, inner vation of latent infections during thighs, and genitals. In infants palms and soles immunosuppression. are commonly affected and to a lesser extent the face (Sansaricq and Stein 2012 ). The bullae are large, tense, sometimes hemorrhagic, and arise Glucocorticoids on both inﬂ amed and normal-appearing skin. The treatment of choice for BP is systematic cortico- Despite numerous therapeutic advances, sys- steroids, starting with a dose of prednisolone of temic GCS remain the most rapid and powerful 1–2 mg/kg/day (Kneisel and Hertl 2011 ). Other option in the therapeutic armamentarium for the treatment modalities include dapsone or sulfa- treatment of ABD (Jackson et al. 2007 ). pyridine or a combination of erythromycin and Whenever long-term glucocorticoid therapy is nicotinamide (Kneisel and Hertl 2011 ). Prognosis deemed necessary, blood pressure should be for children with BP is good, with most patients monitored regularly as well as blood glucose, tri- remitting within 2 years or less (Kneisel and glycerides, and electrolytes. Tuberculin skin test- Hertl 2011 ). Topical corticosteroids can be used ing (TST) or interferon gamma release assay in mild or localized diseases. (IFNγRA) should be obtained before initiation of immune suppression. Calcium and vitamin D supplementation should be considered whenever Bullous Systemic Lupus long-term glucocorticoids are planned (Han Erythematosus 2009 ).

The treatment of choice for bullous systemic Dosage lupus erythematosus is dapsone, and the blister- Most indications in treating ABD in children ing tendency usually responds quickly. The prog- require 0.5–1 mg/kg in a single early morning nosis is good depending on the degree of systemic dose to minimize gastric irritation. Corticosteroid- involvement. sparing agents when deemed necessary are usually initiated with steroids or shortly after to allow quick tapering of steroid (Jackson et al. Therapeutic Armamentarium 2007 ). Intravenous pulse GCS are occasionally in the Treatment of Childhood needed in life-threatening ABD in a dose up to Autoimmune Blistering Diseases 30 mg/kg/day or more of methylprednisolone in slow intravenous infusion over 2 h to prevent car- Systemic medications are the mainstay of ther- diac arrhythmias. Pulse therapy is more powerful apy of ABD but topical agents can be rarely suf- in bringing rapid control of ABD because of ﬁ cient for localized disease. There are a wide more potent immune-modulating effects but has variety of drugs which can be used to treat ABD a higher risk of osteoporosis and osteonecrosis. with variable mechanisms of action (Table 12.2 ). Systemic antibiotics and intravenous immuno- How to Taper Oral Gucocorticosteroids globulin (IVIG) are used for their anti- Tapering of the GCS dose after control of ABD inﬂ ammatory and immunomodulator actions. may not be needed from the adrenal recovery Immunosuppressive agents such as glucocortico- standpoint in very short-term therapy but has steroids (GCS), azathioprine, cyclosporine, great importance when treatment lasts longer methotrexate, mycophenolate mofetil, and ritux- than a few weeks. Sudden tapering can result in imab are used for their abilities to suppress the symptoms of corticosteroid withdrawal syn- immune system. Before initiating immunosup- drome including arthralgias, myalgias, fatigue, 12 Therapy of Juvenile Immune Bullous Disorders 117

Table 12.2 Summary of medications used in the management of ABD Therapeutic Mechanism of action (MOA) Adverse effects Suggested monitoring Glucocorticoids Inhibition of pro- Increased risk of: Calcium and vitamin infl ammatory cytokines Infections D supplements Osteoporosis Blood pressure and HPA axis suppression glucose triglycerides Acid refl ux disease Electrolytes Hyperglycemia Tuberculin skin Hypertriglyceridemia testing or Proximal myopathy quantiferon Hyperactivity Glaucoma Cataracts Cushing disease Azathioprine Purine analogue Gastrointestinal toxicity CBC and liver Inhibits DNA replication Hepatotoxicity function test (LFT) Pancreatitis every 2 weeks Lymphoproliferative diseases baseline TPMT Infections levels (if available) Alopecia Mycophenolate Inhibits purine synthesis Gastrointestinal upset CBC mofetil Anemia LFT monthly Leukopenia Thrombocytopenia Increased risk of infections Inhibit DNA replication Methotrexate Inhibits dihydrofolate Hepatoxicity CBC reductase required for DNA Myelosuppression Electrolytes synthesis Ulcers Renal function Alopecia profi le (RFP) Interstitial pneumonitis and fi brosis LFT Nephrotoxicity Cyclosporine Suppresses T cells and Electrolyte abnormalities Renal function inhibits production of IL-2 Renal toxicity LFT Tremors CBC Hirsutism Electrolytes Hyperlipidemia Lipid profi le Hypertension Blood pressure Gingival hyperplasia Dapsone Inhibits neutrophil activity Hemolytic anemia CBC weekly during and chemotaxis Methemoglobinemia fi rst month Idiosyncratic peripheral motor Monthly during fi rst neuropathy 6 months Psychosis Quarterly thereafter Agranulocytosis LFT and RFP every Hypersensitivity syndrome 3 months Intravenous Purifi ed human IgG Renal failure Baseline IgA and immunoglobulin Fever LFT Headache CBC and CMP prior Myalgia to each cycle Nausea Tachycardia Hemolysis Aseptic meningitis Thrombotic event Anaphylaxis with IgA defi ciency (continued) 118 S. Al-Khenaizan and L. Al Mubarak

Table 12.2 (continued) Therapeutic Mechanism of action (MOA) Adverse effects Suggested monitoring Rituximab Chimeric murine/human Black box warnings due to fatalities monoclonal activity against resulting from infusion reactions CD20 antigen on B cells <24 h of ﬁ rst infusion Severe mucocutaneous reactions Progressive multifocal leukoencephalopathy Cyclophosphamide Alkylating agent Acute myelosuppression Renal function Binds DNA during cell cycle Mucosal ulcer CBC platelets Alopecia UA Nephrotoxicity Interstitial lung ﬁ brosis Azoospermia Hemorrhagic cystitis

headache, mood changes, and gastrointestinal Table 12.3 Possible benefi ts of alternate day steroids symptoms (Jackson et al. 2007 ). Tapering of therapy GCS can be rapid and aggressive in highly Less suppression and early recovery of hypothalamic– responsive dermatoses but should be very grad- pituitary–adrenal axis ual for resistant diseases such as pemphigus to Decreases risk of growth suppression avoid serious fl are of the disease. One method of Decreases risk of steroid myopathy tapering GCS is by gradually decreasing the daily Decreases risk of hypertension dose by 5–10 mg weekly. Another method to Decreases risk of opportunistic infections taper GCS dosage is to convert from the daily Decreases risk of neuropsychiatric side effects dose to alternate day therapy by reducing the daily dose on alternate days until it is completely eliminated (Jackson et al. 2007 ). Simultaneous prevent this complication by administration of tri- tapering and alternate day conversion can also be methoprim–sulfamethoxazole (TMP–SMX) done. Possible benefi ts of alternate day regimen 150 mg/m2 orally thrice weekly (Jackson et al. of glucocorticosteroids are listed in Table 12.3 . 2007). A meta-analysis of randomized trials of PCP prophylaxis in immunocompromised Risk of Infection patients without HIV infection concluded that this The immunosuppressive effects of GCS increase prophylaxis is warranted (Jackson et al. 2007 ). the susceptibility of patients to many viral, bacterial, fungal, and parasitic infections which might Advantages of Interferon Gamma be reduced by alternate day therapy (Jackson Release Assays (IFNγRA) et al. 2007 ). An increase in signifi cant complica- over Tuberculin Skin Testing (TST) tions associated with primary varicella has also A history of exposure to tuberculosis should be been reported (Jackson et al. 2007 ). taken before therapy with GCS in addition to a baseline tuberculin skin testing (TST). Pneumocystis Jiroveci Pneumonia Interpreting TST can be a problem in countries Prophylaxis in Patients Receiving Oral where bacillus Calmette–Guérin (BCG) vaccina- Glucocorticosteroids tion is used. Recently, interferon gamma release Pneumocystis jiroveci pneumonia, formerly assays (IFNγRA) have become available. These known as Pneumocystis carinii pneumonia (PCP), T-cell-based interferon gamma release assays is a potentially fatal infection in patients receiving (IGRA) offer several advantages over the TST, systemic GCS therapy for longer than 2 months including better specifi city especially in coun- (Jackson et al. 2007 ). Recently, many authors tries where BCG vaccination is used, elimination called for the use of prophylactic antibiotics to of the subjectivity of TST reading, and logistic 12 Therapy of Juvenile Immune Bullous Disorders 119 convenience (Chkhartishvili et al. 2013 ). Dapsone However, the data comparing IGRAs and the TST in immunocompromised persons is limited Dapsone is an antimicrobial agent, traditionally and shows no clear superiority of one test over proven very benefi cial and well tolerated in the another (Chkhartishvili et al. 2013 ). treatment of CBDC in children. Due to the risk of severe hemolysis, G6PD level should be obtained Risks of Vaccinating Children prior to treatment, and monitoring is indicated in During GCS Course G6PD-defi cient patients. In severely G6PD- During the use of immunosuppressive medica- defi cient patients, sulfapyridine is an alternative tions, vaccinations with live viral vaccines are (Guide and Marinkovich 2001). The usual dose contraindicated, as severe complications can of dapsone for children is 0.5–2 mg/kg/day result from reactivation of inoculated viruses. (Lara-Corrales and Pope 2010 ). Complete blood During GCS use, immunization with live vac- count with reticulocyte count should be moni- cines can be done if the duration is less than 2 tored weekly or fortnightly for an additional 4 weeks at any dose or if the dose of GCS is less weeks, and liver function tests should be moni- than 2 mg/kg of any duration. Immunization with tored monthly for the fi rst 3 months. Patients who live vaccines should not be done for at least 3 cannot tolerate dapsone may benefi t from treat- months after fi nishing GCS course (Klaus-Wolff ment with sulfapyridine which have structural et al. 2007 ). Vaccinations with killed or protein similarities with dapsone (Guide and Marinkovich vaccines can be performed but can be less suc- 2001). The side-effect profi le of sulfapyridine is cessful in eliciting immunization. similar to dapsone, but the toxicity is less, a feature that makes use of this agent possible in patients with dapsone intolerance (Guide and Other Medications Marinkovich 2001 ).

Azathioprine Cyclosporine Azathioprine is a purine analogue immunosuppressive used in organ transplantation. It is Cyclosporine is calcineurin inhibitor that has metabolized through thiopurine methyltransfer- been established as safe and effective second-line ase (TPMT) enzyme which is critical in deciding systemic treatments for a wide range of CABD. the dose and monitoring autoimmune diseases. For most dermatologic indication, doses rang- The activity of TPMT enzyme exhibits tri- ing from 3 to 5 mg/kg/day are used and are usually modal distribution within the population: 88.6 % well tolerated with minimal signifi cant adverse have normal activity, 11.1 % have intermediate effects. The dose can be later tapered as needed to activity, and 0.3 % have low or no detectable control the treated ABD. Combination of prednis- activity (Wise and Callen 2007 ). Pretreatment olone and cyclosporine therapy results in a reduc- knowledge of TPMT status, whether it is geno- tion in the time required for clinical remission and type or phenotype, is of great clinical benefi t shortening of hospital stay as compared with pred- allowing identifi cation of homozygous mutant nisolone monotherapy (Lapidoth et al. 1994 ). who are at risk for severe bone marrow suppression. Heterozygous have intermediate risk for myelosuppression with dose escalation, while Methotrexate patients with homozygous wild-type may require more aggressive dosing. Clinicians Methotrexate (MTX) is a folic acid analogue pio- should keep in mind continued hematologic neered for use in infl ammatory diseases by der- monitoring is needed as myelosuppression can matologists and used successfully for over 40 result through other mechanisms (Wise and years for a wide variety of cutaneous diseases Callen 2007 ). including ABD (Bangert and Costner 2007 ). 120 S. Al-Khenaizan and L. Al Mubarak

Methotrexate is administered once weekly, one quarter of the 1.2 g/m 2 per day maximum usually in a single dose making it of paramount dose recommended in pediatric renal transplanta- importance to understand this dosing schedule. tion patients (Farley-Li and Mancini 2003 ). The dose can be divided into three equal doses administered 12 h apart, but there is no clear benefi t in doing so over a single weekly dose (Bangert Intravenous Immunoglobulin (IVIG) and Costner 2007 ). The coadministration of folic acid has become a standard practice to decrease High-dose IVIG is a purifi ed immunoglobulin G the gastrointestinal and hematologic adverse collected from human pooled plasma. Preparation effects (see Table 12.2 ). of IVIG undergoes many independent processes As MTX interferes with the cellular utilization for the inactivation and removal of viral contami- of folic acid, folate depletion is considered to be nants, such as hepatitis and human immunodefi - the main cause of most of methotrexate side effects ciency virus. It is usually administrated as a slow especially gastrointestinal and hematologic IV infusion at variable doses ranging from 1 to adverse effects (see Table 12.2 ). Many studies 3 g/kg per cycle divided over 3–5 consecutive have supported the use of folate supplementation days. Treatment can be repeated every 4 weeks. to mitigate these adverse effects without reducing The mechanism of action is unknown but several the effi cacy of MTX. Folic acid at a dose of 1 mg/ are postulated. These include inhibition of Fc day should be given routinely to all patients taking receptors, inhibition of formation, and neutraliza- MTX on chronic basis. The dose may be increased tion of autoantibodies (Kazatchkine and Kaveri to 5 mg/day if needed. The benefi ts of folate sup- 2001; Prins et al. 2007 ). The combination of IVIG plementation is best illustrated by an updated sys- with immunosuppressive agents may bring about tematic review and meta-analysis of six rapid onset of action and offset any rebound fol- randomized trials involving 624 patients, which lowing antibody depletion by IVIG (Czernik and found a reduction in adverse effects without loss of Bystryn 2008 ). There are several potential compli- MTX effi cacy with the use of folic acid or of cations for IVIG treatment as shown in Table 12.2 . folinic acid supplementation compared with pla- Renal failure can result in patients with renal cebo (Bangert and Costner 2007 ). insuffi ciency although this is thought to occur only in old version of IVIG containing sucrose. If there is a previous history of infusion reactions, premed- Mycophenolate Mofetil ication with steroids and/or antihistamines is indicated. Other adverse effects are rare and include Mycophenolate mofetil (MMF) is a prodrug once fever, headache, myalgia, nausea, tachycardia, absorbed it is rapidly converted to mycophenolic hemolysis, aseptic meningitis, and thrombotic acid, which noncompetitively binds inosine event. Anaphylaxis in patients with IgA defi ciency monophosphate dehydrogenase blocking de novo due to trace amounts of IgA in the preparation is a purine synthesis making it highly selective for very rare but serious complication. IVIG is very lymphocytes (Zwerner and Fiorentino 2007 ). As expensive and generally should be reserved for an adjuvant to corticosteroids, MMF has had patients who do not respond or have serious excellent success in pemphigus vulgaris (PV) adverse events from standard immunosuppressive and pemphigus foliaceus (PF). Case reports have therapies (Prins et al. 2007 ). demonstrated MMF effi cacy in several other immunobullous disorders. It is available in 250- or 500-mg capsules and a 200-mg/mL suspen- Rituximab sion. The recommended dosage in treatment of CABD remains anecdotal. Treatment with myco- Rituximab is a genetically engineered, chime- phenolate mofetil is at a dose of 310 mg/m 2 per ric, murine/human monoclonal antibody day (100 mg twice daily), which is approximately directed against CD20 antigen on B cells. It is 12 Therapy of Juvenile Immune Bullous Disorders 121 given as an IV infusion, with premedication 1998), and erythromycin (Monia et al. 2011 ) may with acetaminophen and diphenhydramine to be of benefi t in CABD. The exact mechanism of avoid infusion reactions. Several theories exist action is unknown but is probably anti- on the drug’s ability to inhibit autoantibody- infl ammatory rather than antibacterial as blister producing B cells in the immune system fl uid obtained for culture is consistently sterile. (Cianchini et al. 2007). Rituximab targets the In a series of seven children with CBDC treated CD20 molecule, which is expressed on the sur- with fl ucloxacillin, disease clearance was face of B cells resulting in transient but almost achieved in all patients, but only four patients had complete depletion of B cells in the blood and long-lasting remission (Alajlan et al. 2006 ). They only partial depletion in the bone marrow are usually given at doses of 50 mg/kg/day, with (Cianchini et al. 2007 ). It has been used off- reported benefi t in affected children (Farrant label to treat and manage autoimmune and der- et al. 2008 ). Tetracycline plus nicotinamide have matologic diseases as an alternative or adjuvant also been used in combination for the treatment therapy to systemic treatments. Rituximab has of adults with bullous pemphigoid (Chaffi ns et al. several black box warnings due to serious 1993). Tetracyclines can be only utilized in chil- adverse events that had fatal outcomes. These dren above the age of 9 years due to the drug’s fatalities resulted from infusion reactions usu- adverse effects on developing teeth. ally occurring within the fi rst 24 h of the fi rst infusion, severe mucocutaneous reactions, and progressive multifocal leukoencephalopathy Oral and Mucous Membrane due to John Cunningham (JC) virus infection. Management

The incidence of mucous membrane involvement Systemic Antibiotics in ABD is variable as shown in Table 12.4. In the event of oral mucous membrane involvement, Case reports and small case series suggest that spicy and hot foods should be avoided and soft or systemic antibiotics including oxacillin (Kenani liquid meals should be encouraged. Good oral et al. 2009 ), dicloxacillin (Siegfried and Sirawan hygiene should be encouraged using gargles with

Table 12.4 Clinical features of mucosal involvement of ABD Diseases Clinical features Mucosal involvement 1. Pemphigus vulgaris Superfi cial fl accid blisters Very common Noninfl ammatory base 2. Pemphigus foliaceus Similar to pemphigus vulgaris Uncommon 3. Paraneoplastic pemphigus Common 4. Chronic bullous disease of Explosive onset Possible childhood Annular tense blister Clusters of jewels 5. Bullous pemphigoid Tense blisters Possible Red base Commonly involves palms and soles 6. Dermatitis herpetiformis Grouped (herpetiform) tense Uncommon blisters Very itchy 7. Pemphigoid gestationis Grouped herpetiform and annular Uncommon tense blisters 8. Epidermolysis bullosa Mechanobullous linear blisters Almost always acquisita 122 S. Al-Khenaizan and L. Al Mubarak saline or water. Sucking on ice cubes as well as Bulleted List of Controversies anesthetizing creams or solutions can be used before meals to reduce pain. Topical corticoste- • As glucocorticosteroids are the mainstay of roids can be suffi cient for mild or localized skin treatment of autoimmune bullous diseases in or mucosal disease (Ng and Venning 2011 ). High children, pediatricians and dermatologist must potency or superpotent topical corticosteroids in know the different methods of tapering gel, ointment, or mouthwashes can be applied to steroids. mucosal or skin lesions twice daily. Low- and • During treatment with glucocorticosteroids, medium-potency GCS are preferred for mucous Pneumocystis jiroveci pneumonia can arise. membrane. Treatment with topical calcineurin Prophylaxis treatment is still controversial but inhibitor such as tacrolimus ointment can also be should be considered. used. Cyclosporine suspension can be used as a • In countries practicing BCG vaccination, PPD mouthwash to treat refractory oral lesions of testing may not be accurate. A relatively new pemphigus (Lapidoth et al. 1994 ). In the event of test, the interferon gamma release assays, is conjunctival involvement and to prevent the being used instead of tuberculin skin testing. development of symblepharon, consultation with Its advantages will be discussed. pediatric ophthalmologist is warranted as well as • Vaccination schedule may arrive at the time of consistent eye hygiene and the use of topical eye glucocorticosteroids use for various indica- preparations of corticosteroids in the form of tions. The safety of different vaccines during ocular drops or ointment. glucocorticosteroids treatment will be discussed. Conclusions • Thiopurine methyltransferase is a serum test Autoimmune blistering diseases are chal- that can predict bone marrow toxicity of aza- lenging in both diagnosis and management thioprine. The use of this test will be for dermatologists and pediatric dermatolo- discussed. gists. We highlighted many controversies • Folate supplementation during methotrexate that can face the practitioner in managing treatment is practiced in many different ways. children affected with autoimmune blistering The benefi ts and methods of supplementation diseases. We hope that more future studies will be discussed. will be performed to delineate the rule of current applied medications in the management of childhood autoimmune blistering disease and need more study with many controver- References sies. Distinguishing between the different types of autoimmune blistering disease in Alajlan A, Al-Khawajah M, Al-Sheikh O, et al. Treatment of linear IgA bullous dermatosis of childhood with fl u- children is a diffi cult and challenging task. cloxacillin. J Am Acad Dermatol. 2006;54(4):652–6. Knowledge of the various clinical character- Bangert CA, Costner MI. Methotrexate in dermatology. istics of these disorders will aid in their diag- Dermatol Ther. 2007;20(4):216–28. nosis; however, histology and Brenner S, Mashiah J. Autoimmune blistering diseases in children: signposts in the process of evaluation. Clin immunofl uorescence studies are required to Dermatol. 2000;18(6):711–24. differentiate them. Although rare, long-term Chaffi ns ML, Collison D, Fivenson DP. Treatment of remission of autoimmune blistering disease pemphigus and linear IgA dermatosis with nicotin- of systemic immunosuppressive medications amide and tetracycline: a review of 13 cases. J Am Acad Dermatol. 1993;28(6):998–1000. can and does occur. This end point, complete Chkhartishvili N, Kempker RR, Dvali N, et al. Poor agree- remission of therapy, is the ultimate goal of ment between interferon-gamma release assays and any treatment regimen. The challenge for the tuberculin skin test among HIV-infected individu- future studies is to determine the most safe als in the country of Georgia. BMC Infect Dis. 2013;13:513. and effective way to achieve this end point. 12 Therapy of Juvenile Immune Bullous Disorders 123

Cianchini G, Corona R, Frezzolini A, et al. Treatment of Kenani N, Mebazaa A, Denguezli M, et al. Childhood lin- severe pemphigus with rituximab: report of 12 cases ear IgA bullous dermatosis in Tunisia. Pediatr and a review of the literature. Arch Dermatol. Dermatol. 2009;26(1):28–33. 2007;143(8):1033–8. Kneisel A, Hertl M. Autoimmune bullous skin diseases Czernik A, Bystryn JC. Improvement of intravenous part 2: diagnosis and therapy. J Dtsch Dermatol Ges. immunoglobulin therapy for bullous pemphigoid by 2011;9:927–47. adding immunosuppressive agents: marked improve- Lapidoth M, David M, Ben-Amitai D, et al. The efﬁ cacy ment in depletion of circulating antibodies. Arch of combined treatment with prednisone and cyclospo- Dermatol. 2008;144(5):658–61. rine in patients with pemphigus: preliminary study. Farley-Li J, Mancini AJ. Treatment of linear IgA bullous J Am Acad Dermatol. 1994;30:752–7. dermatosis of childhood with mycophenolate mofetil. Lara-Corrales I, Pope E. Autoimmune blistering diseases in Arch Dermatol. 2003;139(9):1121–4. children. Semin Cutan Med Surg. 2010;29(2):85–91. Farrant P, Darley C, Carmichael A. Is erythromycin an Monia K, Aida K, Amel K, et al. Linear IgA bullous der- effective treatment for chronic bullous disease of matosis in Tunisian children: 31 cases. Indian childhood? A national survey of members of the J Dermatol. 2011;56(2):153–9. British Society for Paediatric Dermatology. Pediatr Ng SY, Venning VV. Management of linear IgA disease. Dermatol. 2008;25(4):479–82. Dermatol Clin. 2011;29(4):629–30. Guide SV, Marinkovich MP. Linear IgA bullous dermato- Prins C, Gelfand EW, French LE. Intravenous immunoglob- sis. Clin Dermatol. 2001;19(6):719–27. ulin: properties, mode of action and practical use in der- Han A. A practical approach to treating autoimmune bul- matology. Acta Derm Venereol. 2007;87(3):206–18. lous disorders with systemic medications. J Clin Sansaricq F, Stein SL, Petronic-Rosic V. Autoimmune bullous Aesthet Dermatol. 2009;2(5):19–28. diseases in childhood. Clin Dermatol. 2012;30:114–27. Hofmann SC, Kautz O, Hertl M, et al. Results of a survey Siegfried EC, Sirawan S. Chronic bullous disease of of German dermatologists on the therapeutic childhood: successful treatment with dicloxacillin. approaches to pemphigus and bullous pemphigoid. J Am Acad Dermatol. 1998;39(5 Pt 1):797–800. J Dtsch Dermatol Ges. 2009;7(3):227–33. Wise M, Callen JP. Azathioprine: a guide for the manage- Jackson S, Gilchrist H, Nesbitt Jr LT. Update on the der- ment of dermatology patients. Dermatol Ther. matologic use of systemic glucocorticosteroids. 2007;20(4):206–15. Dermatol Ther. 2007;20(4):187–205. Wolff K, Goldsmith L, Gilchrest B, et al. Fitzpatrick’s Kazatchkine MD, Kaveri SV. Immunomodulation of auto- dermatology in general medicine. 7th ed. New York: immune and inﬂ ammatory diseases with intravenous McGraw-Hill; 2007. immune globulin. N Engl J Med. 2001;345(10): Zwerner J, Fiorentino D. Mycophenolate mofetil. 747–55. Dermatol Ther. 2007;20(4):229–38. Childhood Sweet Syndrome 1 3 Marla Jahnke , Devika Patel , and Tor Shwayder

Abstract Pediatric Sweet syndrome (acute neutrophilic dermatosis) is a rare dermatosis in children characterized by painful papules or nodules and a dense neutrophilic inﬁ ltrate in the dermis on histopathology. To date, there are less than 100 cases reported in the literature. Because of the rarity of this disease, controversies in its pathogenesis, classiﬁ cation, clinical presentations, and treatment exist. These controversies are discussed in this chapter.

Keywords Sweet syndrome • Childhood • Acute neutrophilic dermatosis • Pediatric • Controversies • Erythematous nodules • Neutrophilic inﬁ ltrate

Sweet syndrome, also known as acute febrile rare in children with less than one hundred cases neutrophilic dermatosis, was fi rst described in reported in the pediatric population to date. The 1964 by Robert Douglas Sweet. This disorder is disease in both children and adults is characterized by an abrupt appearance of tender, erythematous nodules and plaques, with histopathology M. Jahnke , MD showing a predominantly neutrophilic infi ltrate. Department of Pediatric Dermatology , Children’s Fever, leukocytosis, neutrophilia, and high Hospital of Michigan , Detroit , MI , USA infl ammatory markers usually accompany the Department of Dermatology , Henry Ford Hospital , eruption onset (Uihlein et al. 2012 ). Most pediat- Detroit , MI , USA ric cases follow a prodromal respiratory illness, D. Patel , MD but associations have been shown with a number Department of Dermatology , Henry Ford Hospital , of systemic conditions including malignancy. Detroit , MI , USA Oral corticosteroids are fi rst-line treatment, and * T. Shwayder , MD ( ) all symptoms related to the disorder tend to Department of Dermatology, Director Pediatric Dermatology , Henry Ford Hospital , Detroit , MI , USA respond rapidly; recurrence, however, in pediat- e-mail: [email protected] ric patients is common (Hospach et al. 2009 ).

Epidemiology Table 13.1 Criteria for diagnosis of Sweet syndrome. Two major and two minor fi ndings are needed for diagnosis Sweet syndrome in the pediatric population is rare and accounts for approximately 5 % of all cases Major criteria: (Fitzgerald et al. 1996 ). The fi rst reported case of Abrupt onset of tender or painful erythematous plaques or nodules, occasionally with vesicles, Sweet syndrome in the pediatric population was pustules, or bullae in 1976, describing a 10-year-old boy with new- Predominantly neutrophilic infi ltration in the dermis onset fever and painful plaques in the setting of without leukocytoclastic vasculitis promyelocytic leukemia (Klock and Oken 1976 ). Minor criteria: The mean age of pediatric patients with Sweet General malaise and fever syndrome is 5 years (Halpern and Salim 2009 ), Preceding nonspecifi c respiratory or gastrointestinal and the youngest reported patient was 10 days old tract infection or vaccination or associated with infl ammatory disease, hemoproliferative disorders, (Parsapour et al. 2003 ). Women are more com- solid malignant tumors, or pregnancy monly affected among adults (von den Driesch Excellent response to treatment with systemic 1994 ); in patients under the age of 3, however, corticosteroids or potassium iodide there is a male predominance. An equal sex distri- Abnormal laboratory values at disease onset (3 of 4 of bution is seen in affected pediatric patients over the following abnormal): ESR >20 mm, positive μ the age of 3 years (von den Driesch 1994 ; Hospach C-reactive protein, >8000/ L leukocytes, >70 % segmented nuclear neutrophils et al. 2009 ; Halpern and Salim 2009 ).

controversy, nonetheless, about how Sweet Pathogenesis syndrome should be subdivided. Some have proposed subclassifying cases into four groups The pathogenesis of Sweet syndrome is not fully based on etiology (Table 13.2 ): (1) classic/ understood. A hypersensitivity reaction in response idiopathic, (2) parainfl ammatory, (3) paraneo- to systemic factors including infection, hematologic plastic, and (4) pregnancy associated (Hospach disease, medication, malignancy, pregnancy, et al. 2009 ). Many also include a “drug-related” infl ammatory disease, autoimmune disease, and subtype as a fi fth category (von den Driesch vaccination have all been proposed. Some studies 1994 ; Hospach et al. 2009 ). Others only use a suggest that Sweet syndrome is caused by an inap- three-subset classifi cation: (1) classic, which propriate activation of T helper cells and an includes pregnancy and infl ammatory etiolo- increased production of several cytokines, includ- gies, (2) paraneoplastic, and (3) drug related ing interleukin-1, interleukin-2, interferon-gamma, (Cohen 2007 ). and granulocyte colony- stimulating factor The idiopathic/classic group includes (Giasuddin et al. 1998 ; Kawakami et al. 2004 ). patients without associated diseases or with Another theory is that a defect in neutrophil func- transient disease (most commonly respiratory tion, caused primarily by an increase in granulocyte infections or otitis media). Patients with infl am- colony-stimulating factor, causes this disorder matory disease, either resulting from autoim- (Alvaro et al. 1991; Park et al. 1992; Going 1987). munity (e.g., from vasculitis, arthritis, lupus Additionally, a genetic association with HLA-B54 erythematosus), cardiac disease (especially and Sweet syndrome in primarily the Japanese pop- aortitis), recurrent infections (infl ammation due ulation has been postulated (Mizoguchi et al. 1988). to immunodefi ciency), or chronic infections, are categorized into the parainfl ammatory class. Paraneoplastic Sweet syndrome consists of Controversies in Classifi cation patients with malignant or premalignant diseases. It is controversial whether drug-associ- The diagnostic criteria are well established as ated cases should be categorized according to discussed further in the “Clinical Features” the underlying disease being treated or as a new section and outlined in Table 13.1 . There is category. 13 Childhood Sweet Syndrome 127

Table 13.2 Subclassifi cation of Sweet syndrome and (three of four of the following: erythrocyte sed- examples of associated illness imentation rate (ESR) >20 mm/h, positive Subtype Examples C-reactive protein, >8000 leukocytes, and Classic/idiopathic Transient illnesses: otitis media, >70 % neutrophils) (von den Driesch 1994 ). upper respiratory infection (viral Sweet syndrome usually presents abruptly with or streptococcal), gastroenteritis multiple, tender, edematous, and erythematous Parainfl ammatory Chronic infl ammatory conditions: autoimmune, cardiac nodules and plaques (Fig. 13.1 ). Pustules and/or (aortitis), recurrent infections vesicles may occur. Lesions appear most com- (due to immunodefi ciency), monly on the limbs (90 %) and/or head (70 %), and infl ammatory bowel disease less commonly on the trunk (25 %) (Fig. 13.2 ). Paraneoplastic Malignant or premalignant Pathergy is common. In the majority of cases, fever diseases: acute promyelogenous leukemia (AML), osteosarcoma, precedes the eruption (Halpern and Salim 2009 ). myelodysplastic syndrome Mucosal involvement has only been described Pregnancy Pregnancy in approximately 5 % of pediatric patients associated (Halpern and Salim 2009; Parsapour et al. 2003 ; Drug related Granulocyte colony- stimulating Herron et al. 2005 ; Cohen et al. 1993 ; Makis factor, trimethoprim– sulfamethoxazole, all-trans et al. 2010 ). While in adult Sweet syndrome, retinoic acid, carbamazepine, mucosal involvement has been associated with azathioprine, celecoxib, underlying malignancy, this association has not diazepam, diclofenac, been observed in pediatric patients (Herron et al. hydralazine, levonorgestrel/ ethinyl estradiol, minocycline, 2005 ). The cutaneous manifestations of Sweet nitrofurantoin, propylthiouracil syndrome can present concurrently with arthralgias, general malaise, and/or conjunctivitis (Halpern and Salim 2009 ). Associated laboratory Clinical Features fi ndings include leukocytosis, neutrophilia, anemia, elevated ESR, and thrombocytosis (Halpern In 1968, Su and Liu (1986 ) proposed criteria and Salim 2009 ). for the diagnosis of Sweet syndrome. These cri- Skin lesions generally heal without scarring; teria were modifi ed in 1989 (Von den Driesch post-infl ammatory dyspigmentation and acquired et al. 1989 ) and further revised in 1994 by von cutis laxa, however, have been described in approx- den Driesch (von den Driesch 1994 ). Current imately one-third of pediatric cases (Bi et al. 2008 ; criteria are based on the fulfi llment of both of Hazen et al. 1983 ; Timmer-DE Mik et al. 2009 ; the two major criteria and two or more of the Christensen and Gonzalez-Crussi 1983 ; Muster four minor criteria as described by von den et al. 1983 ; Hwang et al. 1995; Guia et al. 1999 ). Driesch with some modifi cations (Table 13.1 ). Patients demonstrating pathergy are more likely to The two major criteria include (1) abrupt onset present with vesicles or pustules and have a greater of tender or painful erythematous or violaceous chance of post-infl ammatory skin changes and/or plaques or nodules, occasionally with vesicles, acquired cutis laxa (von den Driesch 1994 ; Halpern pustules, or bullae, and (2) histopathologic evi- and Salim 2009 ; Bi et al. 2008 ). dence of a dense neutrophilic infi ltrate in the dermis without leukocytoclastic vasculitis. Minor criteria include (1) pyrexia; (2) associa- Associated Features tion with underlying hematologic or visceral malignancy, infl ammatory disease or preg- Of the reported pediatric cases, 42 % have been nancy, or preceded by upper respiratory infec- classifi ed as classic/idiopathic type. Of these, tion, gastrointestinal infection, or vaccination; about one-quarter were reported to have transient (3) excellent response to treatment with sys- diseases, mostly respiratory tract infections and temic glucocorticoids or potassium iodide; and otitis media (Hospach et al. 2009 ). Gastroenteritis (4) abnormal laboratory values at presentation and other infectious illnesses are also known 128 M. Jahnke et al.

a b

Fig. 13.1 ( a) Three-week-old white male with juicy nodules of Sweet syndrome head to toe. Originally presented at 10 days of age. (b ) Same child at 8 weeks of age associations. While the parainfl ammatory type 1986). The most common association seen with accounts for approximately one-third of pediatric Pediatric Sweet syndrome is osteoarticular dis- cases, approximately 25 % of reported cases are ease, including arthritis, arthralgias, and chronic categorized as paraneoplastic and comprise both recurrent multifocal osteomyelitis (Garty et al. malignant and premalignant diseases (Hospach 1996; Majeed et al. 1989; Arndt 1987 ; Edwards et al. 2009; Halpern and Salim 2009 ). Younger et al. 1986). Primary and secondary immunodefi - cases appear more likely secondary to infection, ciency has been described in approximately 10 % whereas in children over the age of 3, disease is of reported pediatric cases. In all such patients, more likely to be associated with malignancy the diagnosis of Sweet syndrome preceded that (Kourtis 2002 ; Sedel et al. 1994 ). of immunodefi ciency (Garty et al. 1996 ; Brady Sweet syndrome has been reported to involve et al. 1999 ; Elliott and Mallory 1999 ; Sedel et al. almost every organ system and has been described 1994 ; Lipp et al. 1999; Haliasos et al. 2005 ; in association with hepatitis (von den Driesch Hospach et al. 2009 ). Other reported associations 1994 ), acute renal failure (Unis and Hill 1987 ), include medications, hematologic disease, and pulmonary infi ltrates (Lazarus et al. 1986 ), peri- autoimmune diseases (Halpern and Salim 2009 ). carditis, aortitis (Guia et al. 1999 ; Rodriguez de Children are at increased risk for cardiovas- la Serna et al. 1985 ), encephalitis (Sobol et al. cular complications, especially if the patient 2009 ; Nobeyama and Kamid 2003 ), ileitis develops acquired cutis laxa (Muster et al. (McDermott et al. 2001 ), conjunctivitis and 1983 ). Of the reported Pediatric Sweet syn- episcleritis, lymphadenitis (Fortna et al. 2010 ), drome cases, approximately 15 % developed sterile abscesses (Klinger et al. 2009 ), myositis cardiovascular complications including aortitis, (Christ et al. 1996), and sterile osteomyelitis pericarditis, aortic aneurysms, valvular disease, (Majeed et al. 1989; Arndt 1987 ; Edwards et al. obliteration and stenosis of coronary vessels, 13 Childhood Sweet Syndrome 129

Histopathology

Histopathology for Sweet syndrome is characteristic. Marked edema and a dense neutrophilic infi ltrate appear in the upper and mid dermis extending into the subcutaneous tissue. The marked papillary edema may resemble a subepidermal bulla. The infi ltrate may be prominently perivascular with leukocytoclasis and formation of nuclear dust, but there must be no true leukocytoclastic vasculitis. While endothelial swelling may be seen, there is no actual vessel destruction or fi brinoid changes in the vessel wall. In the later stages of disease, a band-like infi ltrate of histio- cytes, eosinophils, and mononuclear cells can be seen, along with vasodilation of vascular endothelium with moderate erythrocyte extravasation (Garty et al. 1996 ; Dunn et al. 1992; Takada et al. 1999 ; Lear et al. 1997 ).

Controversies in Monitoring

Appropriate screening guidelines in Pediatric Sweet syndrome are preliminary and controversial due to the limited number of reported cases. As most cases of Sweet syndrome are associated Fig. 13.2 Young adult male with juicy pustule-studded with other diseases, Hospach et al. suggested plaques on upper arms careful screening and monitoring of these patients, especially concerning malignant/prema- and even myocardial infarction (Klock and lignant diseases, immunodefi ciency, cardiovas- Oken 1976 ; Majeed et al. 1989; Campos et al. cular involvement, autoimmune diseases, and 2005 ; Christensen and Gonzalez-Crussi 1983 ). drug associations. It is important to note that Sweet syndrome can precede, occur concurrently with, or follow the diagnosis of an associated dis- Differential Diagnosis ease, thus necessitating an initial investigation of underlying causes with possible longer-term fol- The cutaneous fi ndings in Sweet syndrome in low- up. At the time of initial diagnosis, blood children can be atypical. Although classic pressure, ESR, complete blood count, blood lesions may appear, the clinical differential smear, ANA, lactate dehydrogenase, uric acid, may become broad and includes erysipelas, quantitative immunoglobulins, granulocyte and cellulitis, erythema nodosum, urticaria, leuke- lymphocyte function tests, tetanus and diphtheria mia cutis, vasculitis, genetic autoinfl ammatory titers, HIV and other appropriate infectious test- syndromes, pyoderma gangrenosum, and ery- ings, and echocardiography should be consid- thema multiforme. Confi rmation of clinical ered. If bone pain is present, x-ray should be suspicion with a biopsy showing characteristic ordered, and if negative or inconclusive, an MRI fi ndings is one of the mandatory diagnostic is recommended. If anemia is present, a test for criteria. Fanconi anemia by diepoxybutane cytogenetic 130 M. Jahnke et al. studies should be considered. Follow-up exami- include classic/idiopathic, parainfl ammatory, nation is recommended for all patients on a paraneoplastic, and pregnancy associated. A weekly basis with ESR and differential blood drug-related subtype is often a fi fth category count as long as the disease is active. Due to the with lack of clarity regarding Sweet syndrome high mortality in patients with cutis laxa, echo- caused by the drug itself or the underlying dis- cardiography and follow-up at 3-month intervals ease the drug is treating. extending into adulthood should be considered • Appropriate screening guidelines are contro- (Hospach et al. 2009 ). versial and preliminary due to the limited number of cases. Careful screening and monitoring for patients concerning malignant/premalig- Controversies in Treatment nant diseases, immunodefi ciencies, cardiovascular involvement, autoimmune diseases, The cutaneous lesions typically resolve within infections, and drug associations should be months if no treatment is instituted, although a considered. much more rapid response usually occurs with • The use of long-term corticosteroid treatment systemic corticosteroids. Systemic corticosteroid in recurrent disease is controversial as they are is typically initiated at doses of 1–2 mg/kg of usually effective but are associated with prednisone per day for 10 days, followed by a numerous side effects. slow taper. The prognosis overall is good, especially in patients with classic-type disease. Recurrences, however, are common in pediatric References patients, especially in association with malignant or premalignant conditions or in patients who Alvaro T, Garcia del Moral R, Gomez-Morales M, develop cutis laxa-like lesions at previously Aneiros J, O’Valle F. Immunopathological studies of Sweet’s syndrome. Br J Dermatol. 1991;124:111–2. affected sites. Not only are morbidity and mortal- Arndt JH. Sweet’s syndrome and chronic recurrent multi- ity increased in these patients but also the recur- focal osteomyelitis. Am J Dis Child. 1987;141:721. rences present a particular challenge in treatment. Bi XL, Gu J, Yan M, Gao CF. A case of Sweet’s syndrome Alternative therapies are often sought to prevent with slack skin and pathergy phenomenon. Int J Dermatol. 2008;47:842–4. the long-term side effects associated with cortico- Brady RC, Morris J, Connelly BL, Boiko S. Sweet’s syn- steroids with steroid-sparing treatments including drome as an initial manifestation of pediatric human colchicine, dapsone, cyclosporine, potassium immunodefi ciency virus infection. Ann Allergy. iodide, doxycycline, indomethacin, methotrexate, 1999;72:125–8. Campos LM, Castellanos AL, Afi une JY, Kiss MH, Silva clofazimine, and intravenous immunoglobulin VA. Takayasu’s arteritis with aortic aneurysm associ- (IVIG). None of these therapies, however, have ated with Sweet’s syndrome in childhood. Ann Rheum proven to be as benefi cial as corticosteroids. Dis. 2005;64:168–9. Christ E, Linka A, Jacky E, Speich R, Marincek B, Schaffner A. Sweet’s syndrome involving the musculoskeletal system during treatment of promyelocytic leukemia with Bulleted List of Controversies all-trans retinoic acid. Leukemia. 1996;10:731–4. Christensen CC, Gonzalez-Crussi F. Postinfl ammatory • The pathogenesis of Sweet syndrome is con- elastolysis and cutis laxa: report of a case with aortitis. Pediatr Pathol. 1983;1:199–210. troversial with postulated etiologies including Cohen PR, Holder WR, Tucker SB, Kono S, Kurzrock a hypersensitivity reaction, inappropriate pro- R. Sweet syndrome in patients with solid tumors. duction of cytokines and helper T cells, and a Cancer. 1993;72:2723–31. defect in granulocyte function. Cohen PR. Sweet’s syndrome – a comprehensive review of an acute febrile neutrophilic dermatosis. Orphanet • The criteria for Sweet syndrome are generally J Rare Dis. 2007;26:34. clearly established and accepted. There is con- Dunn TR, Saperstein HW, Biederman A, Kaplan troversy, however, surrounding the subclassi- RP. Sweet syndrome in a neonate with aseptic menin- fi cation in pediatric patients. The major types gitis. Pediatr Dermatol. 1992;9:288–92. 13 Childhood Sweet Syndrome 131

Edwards TC, Stapleton FB, Bond MJ, Barrett FF. Sweet’s Klinger S, Mathis N, Jackson S. Bullous Sweet syndrome syndrome with multifocal sterile osteomyelitis. Am associated with an aseptic splenic abscess. Cutis. J Dis Child. 1986;140:817–8. 2009;84:255–8. Elliott SP, Mallory SB. Sweet syndrome: an unusual pre- Klock JC, Oken RL. Febrile neutrophilic dermatosis in sentation of chronic granulomatous disease in a child. acute myelogenous leukemia. Cancer. 1976;37:922–7. Pediatr Infect Dis J. 1999;18:568–70. Kourtis AP. Sweet syndrome in infants. Clin Pediatr. Fitzgerald RL, McBurney EI, Nesbitt Jr LT. Sweet’s syn- 2002;41:175–7. drome. Int J Dermatol. 1996;35:9–15. Lazarus AA, McMillan M, Miramadi A. Pulmonary Fortna RR, Toporcer M, Elder DE, Junkins-Hopkins involvement in Sweet’s syndrome (acute febrile neu- JM. A case of sweet syndrome with spleen and lymph trophilic dermatosis). Preleukemic and leukemic node involvement preceded by parvovirus B19 infec- phases of acute myelogenous leukemia. Chest. tion, and a review of the literature on extracutaneous 1986;90:922–4. sweet syndrome. Am J Dermatolpathol. 2010; Lear JT, Atherton MT, Byrne JP. Neutrophilic dermatoses: 32:621–7. pyoderma gangrenosum and Sweet’s syndrome. Garty BZ, Levy I, Nitzan M, Barak Y. Sweet syndrome Postgrad Med J. 1997;73:65–8. associated with G-CSF treatment in a child with gly- Lipp KE, Shenefelt PD, Nelson RP, Messina JL, Fenske cogen storage disease type Ib. Pediatrics. 1996;97: NA. Persistent Sweet’s syndrome occurring in a child 401–3. with a primary immunodefi ciency. J Am Acad Giasuddin A, El-Orfi AH, Ziu MM, El-Barnawi Dermatol. 1999;40:838–41. NY. Sweet’s syndrome: is the pathogenesis mediated Majeed HA, Kalaawi M, Mohanty D, Teebi A, Tunjekar by helper T cell type 1 cytokines? J Am Acad MF, al-Gharbawy F, Majeed SA, al-Gazzar Dermatol. 1998;39:940–3. AH. Congenital dyserythropoietic anemia and chronic Going JJ. Is the pathogenesis of Sweet’s syndrome recurrent multifocal osteomyelitis in three related chil- mediated by interleukin-1? Br J Dermatol. dren and the association with Sweet syndrome in two 1987;116:282–3. siblings. J Pediatr. 1989;115:730–4. Guia JM, Frias J, Castro FJ, Gracian M. Cardiovascular Makis A, Stavrou S, Chaliasos N, Zioga A, Vlahos AP, involvement in a boy with Sweet’s syndrome. Pediatr Gaitanis G, Siamopoulou A, Bassukas ID. Acute Cardiol. 1999;20:295–7. febrile neutrophilic dermatosis (Sweet syndrome) in a Haliasos E, Soder B, Rubenstein DS, Henderson W, child associated with a rotavirus infection: a case Morrell DS. Pediatric Sweet syndrome and immu- report. J Med Case Reports. 2010;4:281. nodefi ciency successfully treated with intravenous McDermott MB, Corbally MT, O’Marcaigh immunoglobulin. Pediatr Dermatol. 2005;22: AS. Extracutaneous Sweet syndrome involving the 530–5. gastrointestinal tract in a patient with Fanconi anemia. Halpern J, Salim A. Pediatric sweet syndrome: case report J Pediatr Hematol Oncol. 2001;23:59–62. and literature review. Pediatr Dermatol. Mizoguchi M, Matsuki K, Mochizuki M, et al. Human 2009;26:452–7. leucocyte antigen in Sweet’s syndrome and its Hazen PG, Kark EC, Davis BR, Carney JF, Kurczynski relationship to Behcet’s disease. Arch Dermatol. E. Acute febrile neutrophilic dermatosis in children. 1988;124:1069–73. Report of two cases in male infants. Arch Dermatol. Muster AJ, Bharati S, Herman JJ, Esterly NB, Gonzalez- 1983;119:998–1002. Crussi F, Holbrook KA. Fatal cardiovascular disease Herron MD, Coffi n CM, Vanderhooft SL. Sweet syn- and cutis laxa following acute febrile neutrophilic der- drome in two children. Pediatr Dermatol. matosis. J Pediatr. 1983;102:243–8. 2005;22:525–9. Nobeyama Y, Kamid R. Sweet’s syndrome with neuro- Hospach T, von den Driesch P, Dannecker GE. Acute logic manifestation: case report and literature review. febrile neutrophilic dermatosis (Sweet’s syndrome) in Int J Dermatol. 2003;42:438–43. childhood and adolescence: two new patients and Park JW, Mehrotra B, Barnett BO, Baron AD, Venook review of the literature on associated diseases. Eur AP. The Sweet syndrome during therapy with granulo- J Pediatr. 2009;168:1–9. cyte colony-stimulating factor. Ann Intern Med. Hwang ST, Williams ML, McCalmont TH, Frieden 1992;116:996–8. IJ. Sweet’s syndrome leading to acquired cutis laxa Parsapour K, Reep MD, Gohar K, Shah V, Church A, (Marshall’s syndrome) in an infant with alpha Shwayder TA. Familial sweet’s syndrome in 2 broth- 1- antitrypsin defi ciency. Arch Dermatol. ers, both seen in the fi rst 2 weeks of life. J Am Acad 1995;131:1175–7. Dermatol. 2003;49:132–8. Kawakami T, Ohashi S, Kawa Y, Takahama M, Ito M, Rodriguez de la Serna A, Domingo-Pedrol P, Blanch- Soma Y, et al. Elevated serum granulocyte colony- Torra L, Perez-Perez A, Obrador-Mayol D. Acute stimulating factor levels in patients with active phase febrile neutrophilic dermatosis (Sweet’s syndrome) of sweet syndrome and patients with active Behcet associated with post-myocardial infarction syndrome disease: implication in neutrophil apoptosis dysfunc- (Dressler’s syndrome). Arch Intern Med. 1985; tion. Arch Dermatol. 2004;140:570–4. 145:1522–4. 132 M. Jahnke et al.

Sedel D, Huguet P, Lebbe C, Donadieu J, Odievre M, Timmer-DE Mik L, Broekhuijsen-VAN Henten DM, Labrune P. Sweet syndrome as the presenting manifes- Oldhoff JM, DE Geer DB, Sigurdsson V, Pasmans tation of chronic granulomatous disease in an infant. SG. Acquired cutis laxa in childhood Sweet’s syn- Pediatr Dermatol. 1994;11:237–40. drome. Pediatr Dermatol. 2009;26:358–60. Sobol UA, Sherman KL, Smith J, Nagda SN, Micetich K, Uihlein LC, Brandling-Bennett HA, Lio PA, Liang Nickoloff BJ, Shoup MC. Sweet’s syndrome with neu- MG. Sweet syndrome in children. Pediatr Dermatol. rologic manifestations in a patient with esophageal 2012;29:38–44. adenocarcinoma: case report and review of the litera- Unis ME, Hill GS. Sweet’s syndrome associated with ture. Int J Dermatol. 2009;48:1062–5. acute renal failure. Cutis. 1987;40:139–42. Su WP, Liu HN. Diagnostic criteria for Sweet’s syndrome. Von den Driesch P, Gomez RS, Kiesewetter F, Hornstein Cutis. 1986;37:167–74. OP. Sweet’s syndrome: clinical spectrum and associ- Takada S, Matumoto K, Sakura T, Shiozaki H, Miyamwaki ated conditions. Cutis. 1989;44:193–200. S. Sweet’s syndrome followed by retinoic acid syn- Von den Driesch P. Sweet’s syndrome (acute febrile neu- drome during the treatment of acute promyelocytic trophilic dermatosis). J Am Acad Dermatol. leukemia with all-trans retinoic acid. Int J Hematol. 1994;31:535–56. 1999;70:26–9. Childhood Vitiligo 1 4 Rashmi Sarkar and Shuchi Bansal

Abstract Vitiligo is an acquired cutaneous achromia characterized by depigmented macules of various shapes and sizes occurring irrespective of age, sex, and race. Vitiligo in children differs from that in adults by showing a higher incidence in females, segmental vitiligo being more common and less frequently associated with other systemic autoimmune and endocrine disorders. Childhood vitiligo deserves special attention not only because of its frequent occurrence but also being a tough challenge as regards to treatment is concerned.

Keywords Childhood vitiligo • Depigmented macules • Achromia • Loss of melanocytes • Pigmentary disorder

Vitiligo is an acquired cutaneous achromia char- 2012). Childhood vitiligo deserves special atten- acterized by depigmented macules of various tion not only because of its frequent occurrence shapes and sizes occurring irrespective of age, but also being a tough challenge as regards to sex, and race (Koranne and Sachdeva 1988 ; treatment is concerned. Kanwar and Kumaran 2012 ). Vitiligo in children Despite being a common disease seen in the differs from that in adults by showing a higher population, controversies continue to exist both incidence in females, segmental vitiligo being regarding the pathogenesis, as well as the treat- more common and less frequently associated ment of this challenging pigmentary disorder with other systemic autoimmune and endocrine (Tamesis and Morelli 2010 ). disorders (Pajvani et al. 2006 ; Antoniou et al.

Controversies in Pathogenesis R. Sarkar , MD, MNAMS (*) • S. Bansal , MD Department of Dermatology and Venereology , The pathogenesis of vitiligo has been an enigma; Maulana Azad Medical College and Lok Nayak research is continuing to generate a clear under- Hospital, New Delhi , India standing of this complex multifactorial disorder e-mail: [email protected]; rashmisarkar@ gmail.com (Nordlund et al. 2006 ). Although the underlying

© Springer International Publishing Switzerland 2016 133 A.P. Oranje et al. (eds.), Practical Pediatric Dermatology, DOI 10.1007/978-3-319-32159-2_14 134 R. Sarkar and S. Bansal biological phenomenon is loss of melanocytes 2005 ; Marshal 2004 ). Though there have been from the involved areas, the exact mechanism many propositions, the practical implications of which leads to the fi nal loss of pigment is not it are few, and a defi nite evidence on the role of completely elucidated. There is a clear consensus diet in occurrence or healing of vitiligo lesions is that genetic factors do play an important role in still lacking. the pathogenesis of vitiligo; however, how many The role of UV light has also been suggested genes and in what combination are actually either by causing direct cytotoxicity or affecting involved has not been identifi ed with reasonable the redox⁄free radical state of the melanocyte, certainty. Three genes that have been strongly resulting in oxidative stress and cell damage from associated include HLA, PTPN22 , NALP1 , and reactive oxygen species; however the evidentiary perhaps CTLA4 (Spritz 2008 ). support for this is negligible (Sturm 1998 ; In addition to the genetic factors, there has Meyskens et al. 2001 ). been compelling evidence to support the role of Amidst controversies regarding pathogenesis, autoimmunity in the pathogenesis of vitiligo the treatment of vitiligo remains to be a chal- (Ongenae et al. 2003 ; Le Poole and Luiten 2008 ). lenge, especially in children where the safety The association of vitiligo with other autoim- profi le of various treatment modalities is yet to be mune diseases like thyroid disease, alopecia established. Moreover, there is still a paucity of areata, and lupus erythematosus strongly sup- randomized controlled studies on various thera- ports an autoimmune diathesis for the occurrence peutic modalities (Table 14.1 ) in childhood vitil- of the disorder. igo, and hence a uniform treatment protocol for Apart from the genetic and autoimmune fac- management of patients which can be followed tors, various environmental triggers have been universally is far-fetched. proposed to play a role in causation. Puberty, pregnancy, and infections all have been suggested; however, there is no compelling evidence Controversies in Management to support them as being specifi c causative fac- of Localized Vitiligo tors that can be targeted for treatment purposes. The occurrence of lesions at sites of mechanical Many topical therapies are in use for localized trauma also suggests that the melanocytes of vitiligo; however, there are no FDA-approved genetically susceptible individuals might be rela- therapies for the condition. Topical steroids low, tively loosely anchored to the normal dermal sub- mid, or high potency are often the fi rst-line stratum, subject to dislodgement and consequent cell death (Dell’anna and Picardo 2006 ). Table 14.1 A comprehensive list of various treatment There has been a recent interest in the role of modalities for childhood vitiligo diet in vitiligo. Food contaminants, additives, and Localized Topical corticosteroids preservatives have been proposed to aggravate Calcineurin inhibitors (tacrolimus, vitiligo lesions by increasing the oxidative stress pimecrolimus) (Bickers and Athar 2006 ; Namazi and Chee Leok Vitamin D analogs 2009). Increased consumption of omega-6 fatty Topical PUVA acids and polyphenolic compounds (tannins) Combination of above occurring in mango, cashews, pistachio, oaks, Excimer laser (308 nm) raspberries, and blackberries have also been Surgical treatment associated with increased incidence of vitiligo Cosmetic camoufl age (Birol et al. 2006 ). On the other hand, food prod- Generalized Systemic steroids (daily or minipulse ucts rich in omega-3 fatty acids, quercetin, crem- therapy) ini mushrooms, and whey could have a benefi cial Systemic PUVA effect owing to their free radical-scavenging Narrowband UVB properties (Jeong et al. 2005 ; Obayashi et al. Immunosuppresives 14 Childhood Vitiligo 135

Table 14.2 Studies on topical corticosteroids in childhood vitiligo No. of Authors patients Treatment Duration (months) Response Kose et al. 40 Mometasone cream (0.1 %) 3 Mometasone was effective on all ( 2010 ) once daily or pimecrolimus body parts; pimecrolimus was not cream (1 %) twice daily (20 effective except for the face each) Lepe et al. 20 Clobetasol (0.05 %) cream 2 Tacrolimus was as effective as (2003 ) vs tacrolimus 0.1 % clobetasol cream and caused no ointment side effects treatment because they are easy and convenient pimecrolimus 1 % cream, pimecrolimus was mode of treatment used for many decades. found to be effective only on the facial lesions. The repigmentation of vitiliginous skin is not However, there has been a recent concern uniform, and a variable response rate ranging regarding the use of TCI in children due to a bio- from 45 to 60 % has been reported in various logically plausible risk of lymphomas. The studies of childhood vitiligo (Table 14.2 ) (Halder Pediatric Advisory Committee of US FDA has 1997; Cho et al. 2000 ; Lepe et al. 2003 ; Kose recently implemented a black box warning for et al. 2010 ). Nevertheless, a meta-analysis of tacrolimus and pimecrolimus due to the lack of various controlled studies for localized childhood long-term safety data and the potential risk of the vitiligo indicates that potent topical steroids development of malignancies. This warning is have the highest odds for success compared with based on information from animal studies, case placebo (Morelli 2001 ). However, long-term reports in a small number of patients, and how use of potent topical steroids in children is asso- these drugs work. It may take human studies of ciated with complications like epidermal atrophy, 10 years or longer to determine if use of pimecro- striae, telangiectasia, systemic absorption, and limus or tacrolimus is actually linked to cancer. Hypothalamic pituitary axis (HPA axis) suppres- Meanwhile, short-term judicious use of these sion, and hence the prescription of steroid creams drugs specifi cally on sites like eyelids where in childhood vitiligo has been a matter of contro- atrophy from long-term corticosteroid use is a versy. Whereas some practitioners continue to major concern is probably the best alternative. use it as a fi rst-line treatment, others prefer to use Synthetic vitamin D analogs like calcipotriol newer topical agents like vitamin D analogs and are also being used for their effi cacy in repig- calcineurin inhibitors. mentation of vitiliginous skin; however, the Topical calcineurin inhibitors (TCIs), tacroli- improvement achieved with the use of these mus ointment and pimecrolimus cream, have agents is variable and less than that with topical emerged as an important therapeutic modality in steroids and TCIs (Table 14.4 ) (Parsad et al. treatment of childhood vitiligo, having lesser side 1999 ; Gargoom et al. 2004 ; Sarma and Singh effects when compared to long-term topical ste- 2004 ). In a prospective uncontrolled study with roids usage (Table 14.3) (Silverberg et al. 2004 ; topical calcipotriol, 75–100 % pigmentation was Kanwar et al. 2004 ; Grimes et al. 2002 ). A pro- achieved in 55 % patients, whereas almost no spective study by Lepe et al. in children with vit- pigmentation was seen in 22 % patients. iligo, in which he compared tacrolimus with Combination treatment with calcipotriol and clobetasol propionate, found that tacrolimus was topical corticosteroids has also been done; the as effective as clobetasol propionate and caused repigmentation achieved with the combination minimum side effects. In another study by treatment was found to be faster, stable, and with Silverberg et al., best response was seen with very less adverse effects in comparison to either tacrolimus on facial lesions of segmental type. In of the treatments used singly (Travis and a comparative study of mometasone cream with Silverberg 2004 ; Kumaran et al. 2006 ). 136 R. Sarkar and S. Bansal

Table 14.3 Studies on topical tacrolimus in childhood vitiligo Authors No. of patients Treatment Duration (months) Response Silverberg et al. 57 Tacrolimus 0.1 % 3 Best response was (2004 ) ointment seen on facial vitiligo of segmental type Kanwar et al. (2004 ) 25 Tacrolimus 0.03 % 3 Topical tacrolimus ointment twice daily was found to be effective with minimal side effects

Table 14.4 Studies on topical calcipotriol in childhood vitiligo Authors No. of patients Treatment Duration (months) Response Parsad et al. (1999 ) 18 Topical calcipotriol 3–16 Most of the lesions 50 ug/g and sunlight for repigmented by 6–12 10–15 min once daily weeks Gargoom et al. 4 Topical calcipotriol 3 Ointments found better (2004 ) than cream Sarma and Singh 8 Topical calcipotriol and 6 Percentage pigmentation ( 2004 ) sunlight for 15–20 min seen = 41.50 % once daily

Controversies in Management However, 48 (34.8 %) of the patients relapsed of Generalized Vitiligo during a follow-up period of 1 year. Other immunosuppressive drugs like cyclo- Stabilization of the disease followed by repig- phosphamide, cyclosporine, and TNF-alpha antag- mentation is the primary aim of treatment in gen- onists have also been tried for progressive vitiligo eralized vitiligo. This is often a diffi cult task, and in adults; however, the potential side effects of the disease often follows a rapidly progressive these drugs do not justify their use in children. course for years together involving large surface Phototherapy in the form of narrowband UVB areas before it fi nally stabilizes. and PUVA is well known for treatment of vitiligo. Systemic steroids are often prescribed in While narrowband UVB is safe, systemic PUVA unstable generalized disease where they do arrest is contraindicated in children less than 12 years of disease progression and also lead to repigmenta- age. Although much data of narrowband UVB tion in a signifi cant proportion of patients; how- exists in adults, there is a paucity of its reports in ever, due to their unacceptable side effects, the children. Since most of the trials conducted on use of oral steroids in children is a matter of con- narrowband UVB are uncontrolled open studies, troversy. Apart from the usual daily therapy, the conclusions derived by these studies are debat- pulse therapy with long-acting agents like dexa- able by several experts (Table 14.5 ) (Kanwar and methasone and betamethasone has also been tried Dogra 2005 ; Njoo et al. 2000 ; Brazzelli et al. and has shown promising results (Pasricha and 2005 ). About 75 % pigmentation has been Khaitan 1993 ). However, one major problem achieved in 50–75 % patients over a period of 6 with the use of oral steroids is the relapse of dis- months to 1 year. However, presently there is ease once the treatment is stopped. In a study of insuffi cient data to provide recommendation for 180 patients of childhood vitiligo by Majid and the safe maximum dose and duration of therapy of Imran (2013 ), oral minipulse therapy was insti- narrowband UVB in children. tuted with methylprednisolone for a period of 6 Targeted phototherapy with excimer laser has months, and all of them achieved complete remis- also been tried for treatment of childhood vitil- sion of disease during the treatment period. igo, with the advantage being that the treatment is 14 Childhood Vitiligo 137

Table 14.5 Studies on narrowband UVB in childhood vitiligo Authors No. of patients Treatment Duration Response Kanwar and Dogra 51 Nb UVB twice 1 year 75 % pigmentation in (2005 ) weekly 75 % patients Njoo et al. (2000 ) 15 Nb UVB thrice 1 year 75 % pigmentation in weekly 53 % patients Brazzelli et al. 10 Nb UVB twice to 5.6 months 75 % pigmentation in ( 2005 ) thrice weekly 50 % patients localized to the lesional site, thus sparing the nor- Although many therapeutic options are available mal skin from unwanted side effects like photo- for the treatment of childhood vitiligo, the result aging (Al-Otaibi et al. 2009 ; Cho et al. 2011 ; with most of the agents is far from satisfactory. Hui-Lan et al. 2009 ). In a study conducted by Moreover, the occurrence of unacceptable side Cho et al., 56.7 % patients attained 50 % pigmen- effects and lack of safety data calls for a cautious use tation, and 12.5 % patients achieved >75 % pig- of agents in children. There have been only few mentation. The excimer laser emits a wavelength properly designed double-blinded placebo- adjacent to that of narrowband UVB 311 nm pho- controlled studies in childhood vitiligo, and hence totherapy and has similar biological and clinical no consensus guidelines exist regarding the treat- effects. Although narrowband UVB is effective, ment protocol till date. Controversies continue to lesions in hard to reach areas such as skinfolds do exist as to which topical agents be preferred, for how not receive adequate exposure, and excimer laser long a particular agent be continued, when to switch can be a useful therapeutic option in such patients. to systemic therapy, and when to stop the treatment. Various surgical modalities used in adults Based on the published literature, a few con- have also been tried for treatment of childhood clusions may be drawn. Firstly, since the response vitiligo, like miniature punch grafting, suction with any treatment is far from satisfactory and blister epidermal grafts, thin Thiersch grafts, and long-term therapy is often required, it is impor- cultured and noncultured melanocyte transplan- tant to decide as to who should be treated. Lesions tation (Gupta and Kumar 2002 ; Gupta and Kumar on lips, palms, and soles usually show poor or no 2003 ; Mulekar et al. 2010 ; Sahni et al. 2011 ). response, and it is probably worthwhile to leave However, surgical therapy is not the primary these areas untreated. modality in treatment of childhood vitiligo. This If the area of involvement is less than 20 % is because even the stable vitiligo lesions increase and the disease is not spreading, topical treatment proportionately in size as the body size increases is the preferred choice. Among the topical agents, with age. Nevertheless, different surgical tech- the fi rst-line treatment could be either potent top- niques have been employed on highly motivated ical steroids or topical calcineurin inhibitors. adolescents and adults with localized or segmen- Calcineurin inhibitors may be a valid choice tal vitiligo that is immunologically stable and especially in areas like eyelids where atrophy unresponsive to conventional therapy. Among all with long-term use of corticosteroids is a major of these, suction blister epidermal grafts have concern. In other areas, the two agents may be been the most extensively used and most accept- used in combination to prevent side effects occur- able among vitiligo patients and treating ring with any individual agent. physicians. If the area of involvement is greater than Permanent depigmentation with monobenzyl 20 %, phototherapy with narrowband UVB ether of hydroquinone is usually not considered should probably be the preferred choice owing to as a treatment option even in patients with exten- its two-pronged effects in arresting disease pro- sive unresponsive vitiligo unlike adults, owing to gression and also causing repigmentation. It is consequences of permanent depigmentation and also the safest systemic therapy which can be requirement of strict photoprotective measures. used in patients with large areas of involvement 138 R. Sarkar and S. Bansal as compared with systemic steroids and immu- References nosuppressive agents. In case of failure to medical therapy, surgical Al-Otaibi SR, Zadeh VB, Al-Abdulrazzaq AH, et al. treatment may be attempted. Punch grafting and Using a 308-nm excimer laser to treat vitiligo in Asians. Acta Dermatovenerol Alp Panonica Adriat. suction blister grafts can be done once the stabil- 2009;18:13–9. ity of the lesion is confi rmed. Antoniou C, Miniati A, Lagogianni E, et al. Childhood- In spite of the huge therapeutic armamentarium and later-onset vitiligo have diverse epidemiologic available, the treatment of childhood vitiligo con- and clinical characteristics. J Am Acad Dermatol. 2012;66:954–8. tinues to be a challenge teeming with controver- Bickers RD, Athar M. Oxidative stress in the pathogenesis sies, and hence extensive research is still warranted of skin disease. J Invest Dermatol. to provide a universally acceptable consensus pro- 2006;126:2565–75. tocol for the diagnosis and management of this Birol A, Kisa U, Kurtipek GS, et al. Increased tumor necrosis factor alpha (TNF-alpha) and interleukin 1 highly stigmatized cutaneous disorder. alpha (IL1-alpha) levels in the lesional skin of patients with nonsegmental vitiligo. Int J Dermatol. 2006;45:992–3. Bulleted List of Controversies Brazzelli V, Prestinari F, Castello M, et al. Useful treatment of vitiligo in 10 children with UVB narrowband (311 nm). Pediatr Dermatol. 2005;22:257–61. • Although the underlying biological phenome- Cho S, Kang HC, Hahm JH. Characteristics of vitiligo in non is loss of melanocytes from the involved Korean children. Pediatr Dermatol. 2000;17:189–93. areas, the exact mechanism which leads to the Cho S, Zheng Z, Park YK, Roh MR. The 308 nm excimer laser: a promising device for the treatment of child- fi nal loss of pigment is not completely hood vitiligo. Photodermatol Photoimmunol elucidated. Photomed. 2011;27:24–9. • Many topical therapies are in use for localized Dell’anna ML, Picardo M. A review and a new hypothesis vitiligo; however, there are no FDA-approved for non-immuno-logical pathogenetic mechanisms in vitiligo. Pigment Cell Res. 2006;19:406–11. therapies for the condition. Gargoom AM, Duweb GA, Elzorghany AH, et al. • The repigmentation of vitiliginous skin is not Calcipotriol in the treatment of childhood vitiligo. Int uniform, and a variable response rate ranging J Clin Pharmacol Res. 2004;24:11–4. from 45 to 60 % has been reported in various Grimes PE, Soriano T, Dytoc MT. Topical tacrolimus for repigmentation of vitiligo. J Am Acad Dermatol. studies of childhood vitiligo. 2002;47:789–91. • Synthetic vitamin D analogs like calcipotriol Gupta S, Kumar B. Epidermal grafting for vitiligo in ado- are also being used for their effi cacy in repig- lescents. Pediatr Dermatol. 2002;19:159–62. mentation of vitiliginous skin; however, the Gupta S, Kumar B. Epidermal grafting in vitiligo: infl u- ence of age, site of lesions, and type of disease on out- improvement achieved with the use of these come. J Am Acad Dermatol. 2003;49:99–104. agents is variable and less than that with topi- Halder RM. Childhood vitiligo. Clin Dermatol. cal steroids and TCIs. 1997;15:899–906. • Systemic steroids are often prescribed in Hui-Lan Y, Xiao-Yan H, Jian-Yong F, Zong- Rong L. Combination of 308 nm excimer laser with topical unstable generalized disease where they do pimecrolimus for the treatment of childhood vitiligo. arrest disease progression and also lead to Paediatr Dermatol. 2009;26:354–6. repigmentation in a signifi cant proportion of Jeong YM, Choi YG, Kim DS, et al. Cytoprotective effect patients; however, due to their unacceptable of green tea extract and quercetin against hydrogen peroxide-induced oxidative stress. Arch Pharm Res. side effects, the use of oral steroids in children 2005;28:1251–6. is a matter of controversy. Kanwar AJ, Kumaran MS. Childhood vitiligo: treatment • Although many therapeutic options are avail- paradigms. Indian J Dermatol. 2012;57:466–74. able for the treatment of childhood vitiligo, the Kanwar AJ, Dogra S, Parsad D. Topical tacrolimus for treatment of childhood vitiligo in Asians. Clin Exp result with most of the agents is far from satis- Dermatol. 2004;29:589–92. factory. Moreover, the occurrence of unaccept- Kanwar AJ, Dogra S. Narrow-band UVB for the treatment able side effects and lack of safety data calls of generalized vitiligo in children. Clin Exp Dermatol. for a cautious use of agents in children. 2005;30:332–6. 14 Childhood Vitiligo 139

Koranne RV, Sachdeva KG. Vitiligo. Int J Dermatol. Obayashi K, Kurihara K, Okano Y, et al. L-Ergothioneine 1988;27:676–80. scavenges superoxide and singlet oxygen and sup- Kose O, Arca E, Kurumlu Z. Mometasone cream versus presses TNF-alpha and MMP-1 expression in pimecrolimus cream for the treatment of childhood UV-irradiated human dermal ﬁ broblasts. J Cosmet Sci. localized vitiligo. J Dermatolog Treat. 2010;21:133–9. 2005;56:17–27. Kumaran MS, Kaur I, Kumar B. Effect of topical calcipot- Ongenae K, Van Geel N, Naeyeert JM. Evidence for an riol, betamethasone dipropionate and their combina- autoimmune pathogenesis of vitiligo. Pigment Cell tion in the treatment of localized vitiligo. J Eur Acad Res. 2003;16:90–100. Dermatol Venereol. 2006;20:269–73. Pajvani U, Ahmad N, Wiley A, et al. The relationship Lepe V, Moncada B, Castanedo-Cazares JP, et al. A between family medical history and childhood vitil- double-blind randomized trial of 0.1% tacrolimus vs igo. J Am Acad Dermatol. 2006;55:238–44. 0.05% clobetasol for treatment of childhood vitiligo. Parsad D, Saini R, Nagpal R. Calcipotriol in vitiligo: Arch Dermatol. 2003;139:582–5. preliminary study. Pediatr Dermatol. 1999;16: Le Poole IC, Luiten RM. Autoimmune etiology of general- 317–20. ized vitiligo. Curr Dir Autoimmun. 2008;10:227–43. Pasricha JS, Khaitan BK. Oral mini-pulse therapy with Majid I, Imran S. Relapse after methylprednisolone oral betamethasone in vitiligo patients having extensive or minipulse therapy in childhood vitiligo: a 12-month fast spreading disease. Int J Dermatol. 1993;32: follow-up study. Indian J Dermatol. 2013;58:113–6. 753–7. Marshal K. Therapeutic applications of whey protein. Sahni K, Parsad D, Kanwar AJ. Noncultured epidermal Altern Med Rev. 2004;2:136–56. suspension transplantation for the treatment of stable Meyskens Jr FL, Farmer P, Fruehauf JP. Redox regulation vitiligo in children and adolescents. Clin Exp in human melanocytes and melanoma. Pigment Cell Dermatol. 2011;36:607–12. Res. 2001;14:148–54. Sarma N, Singh AK. Topical calcipotriol in childhood vit- Morelli J. Vitiligo: is there a treatment that works? Pediatr iligo: an Indian experience. Int J Dermatol. 2004;43: Dermatol. 2001;17:81. 856–9. Mulekar SV, Al Aisa A, Delvi MB, et al. Childhood vitil- Silverberg NB, Lin P, Travis L, et al. Tacrolimus ointment igo: a long term study of localized vitiligo treated by promotes repigmentation of vitiligo in children: a non cultured cellular grafting. Paedtr Dermatol. review of 57 cases. J Am Acad Dermatol. 2004;51: 2010;27:132–6. 760–6. Namazi MR, Chee Leok G. Vitiligo and diet: a theoretical Spritz RA. The genetics of generalized vitiligo. Curr Opin molecular approach with practical implications. Indian Autoimmun. 2008;10:244–57. J Dermatol Venereol Leprol. 2009;75:116–8. Sturm RA. Human pigmentation genes and their response Njoo MD, Bos JD, Westerhof W. Treatment of general- to solar UV radiation. Mutat Res. 1998;422:69–76. ized vitiligo in children with narrow-band (TL-01) Tamesis MEB, Morelli MD. Vitiligo treatment in child- UVB radiation therapy. J Am Acad Dermatol. hood: a state of the art review. Pediatr Dermatol. 2000;42:245–53. 2010;27:437–45. Nordlund JJ, Boissy RE, Hearing VJ, King RA, Oetting Travis LB, Silverberg NB. Calcipotriene and corticoste- WS, Ortonne J-P, editors. The pigmentary system. roid combination therapy for vitiligo. Pediatr Malden: Blackwell; 2006. p. 551–98. Dermatol. 2004;21:495–8. Part V Psychology

Childhood Trichotillomania: Diagnostic Algorithm 1 5 and Systematic Problem-Solving Management Using the 5W1H (Kipling’s Principle)

Nisha Suyien Chandran , Jeroen Novak , Matilde Iorizzo , Ramon Grimalt , and Arnold P. Oranje

Abstract Trichotillomania is an often underdiagnosed condition. Despite the fact that the amount of literature has been gradually increasing, still little is known about childhood trichotillomania. The Kipling method or 5W1H (“Who,” “What,” “When,” “Where,” “Why,” and “How”) facilitates thorough documentation of each aspect of the child’s hair loss in a standardized way. This method can better equip clinicians to approach unexplained hair loss in a child. Increased knowledge of characteristics of childhood trichotillomania will aid to structure the history and diagnose the disorder correctly. The Kipling method may provide a better start in diagnosing and treating trichotillomania properly by trying to understand the hair condition in relation to the patient and his/her family/context. We proposed to apply a systematic information-gathering approach using the Kipling method (“5W1H”) to facilitate the diagnosis and management of childhood trichotillomania. Many dermatologists neither give much attention to the diagnosis nor treatment of trichotillomania, and this can be easily corrected.

N. S. Chandran , MRCP (UK) Division of Dermatology , University Medicine R. Grimalt , MD, PhD Cluster, National University Hospital , Department of Dermatology , Universitat Singapore , Singapore Internacional de Catalunya , Barcelona , Spain J. Novak , MD e-mail: [email protected] PsyQ, Parnassiagroep , Breda/Rotterdam , A. P. Oranje , MD, PhD (*) The Netherlands Department of Dermatology , M. Iorizzo Dermicis Skin Hospital – Alkmaar , Private Dermatology Practice , Kinderhuid.nl – Rotterdam, Rotterdam , Bellinzona , Switzerland The Netherlands e-mail: [email protected] e-mail: [email protected]

Keywords Hair disease in children • Alopecia • Trichotillomania • Kipling’s principle • Hair pulling

Trichotillomania (hair pulling) is a disorder in in information gathering. It challenges existing which an individual repeatedly pulls his or her perceptions and opens new perspectives on the own hair, often to the point of noticeable alope- problem. The application of this method has cia. Although it was fi rst described as long ago as been advocated for approaching conditions in 1889 by Hallopeau, it remains a frequently mis- which clinical information may similarly be understood, underdiagnosed, and often ineffec- masked, such as physical abuse in children (Bilo tively treated disorder (Oranje et al. 1986 ). et al. 2013). It has never been applied in tricho- Over the past decade, there has been increas- tillomania or in other habit disorders or ing focus on trichotillomania, mainly in psychiat- self-mutilation. ric and psychological circles. Several trichotillomania-specifi c instruments have been developed and implemented to better understand General Aspects the psychopathology, treatments, and outcomes of this condition. However, the striking physical Trichotillomania is a psychiatric disorder with a manifestations of trichotillomania mean that dermatological expression. In the fi fth edition of patients are often initially presented to physicians the Diagnostic and Statistical Manual of Mental who are not trained in the fi eld of mental health. Disorders (DSM-5 ), trichotillomania or hair- In this fi eld, the medical and dermatological lit- pulling disorder is included under obsessive- erature on trichotillomania remains scarce. Even compulsive and related disorders (Arlington et al. less is known about the disorder in children who 2013 ). See the DSM-5 for specifi c criteria. are perhaps the most vulnerable population of Two distinct types of hair pulling have been trichotillomania sufferers. described for trichotillomania: automatic and If children or parents admit to hair pulling and focused pulling (Flessner et al. 2007 ; Christenson the clinical presentation is concordant, then the et al. 1991a ). Automatic pulling occurs outside of diagnosis is clear. However, childhood trichotil- one’s own awareness, while focused pulling, in lomania is often diffi cult to diagnose due to the contrast, occurs in awareness and in response to secretive nature of hair pulling, patients not being negative emotional states (stress, sadness, anger, forthcoming with information, and underdiagno- or anxiety), in intense thoughts or urges, or in an sis by medical professionals. In children, the attempt to establish asymmetry (Diefenbach additional dimension of parental denial of the et al. 2002 ). Children more often fall in the auto- child’s self-induced problem further masks the matic category, and therefore, they do not recall diagnosis. Thus when faced with a child with the actual pulling, but may admit to “playing with non-scarring alopecia of uncertain etiology, the hair,” or they have been noted to pull their hair in differential diagnosis must be explored for other a trance-like, disengaged state (Walther et al. underlying causes of hair loss. There is a need for 2014 ; Sah et al. 2008 ). a simple and easily applicable diagnostic and Panza et al. demonstrated a developmental management approach that can be utilized in the progress of symptoms, with focused hair pulling clinic when faced with such a scenario. increasing signifi cantly as the child grew older, The Kipling’s principle, also known as the while automatic pulling remained constant. Older “5W1H” method, is a systematic problem- children became more aware of their hair-pulling solving procedure which utilizes a set of ques- urges and were less able to refrain from pulling tions whose answers are considered to be basic (Panza et al. 2013 ). 15 Childhood trichotillomania 145

It is well recognized parents seldom notice the 1994 ; Golomb et al. 2000 ). Perhaps the variation hair-pulling behavior in childhood trichotilloma- in form and texture of hair, compared to nails, for nia. Even if they do, many do not believe that example, makes it a more likely target. For some, their child’s own actions are the cause of the hair there is a sensation that draws the fi ngers to the loss. Children tend to pull their hair when alone site of pulling [ http://www.trich.org/treatment/ and in relaxed surroundings which serves to options.html ]. make their actions less obvious to people around them (Tay et al. 2004; Sah et al. 2008). Our fi nding that many children who pulled their hair Numbers while at rest are in accordance with this observation. Interestingly, although only two patients The prevalence of childhood trichotillomania is had parents who noticed actual hair pulling dur- probably underestimated as hair-pulling behavior ing sleep, other parents noticed clues such as hair is shrouded in secrecy, and the condition is under- on or under the bed which suggested that these recognized by medical professionals. Also mild children also pulled hair in their sleep. Physicians trichotillomania is not recognized as a serious must consider the possibility of “sleep-isolated event by the patients or parents themselves. Prior trichotillomania” as children and parents alike studies have shown an estimated prevalence of may not be aware of this phenomenon that occurs 0.6 % among adults, but more recent studies in diminished consciousness (Murphy et al. report an estimated prevalence of 1.2 % of clini- 2006 ). It is interesting to note that a survey of cally signifi cant hair pulling (excluding the dermatologists showed that only 24 % would ask requirement of building tension or release) children who denied hair pulling while awake if (Christenson et al. 1991b ; Duke et al. 2009 ). they pulled their hair during sleep (Murphy et al. To date, the majority of studies on trichotillo- 2007). Direct questioning by physicians such as mania have focused primarily on adults and ado- “do you ever notice hair on or around your child’s lescents and indicate that the most common age bed?” may lead parents to reveal this observation of onset is in pre- or early adolescence (9–13 and thus to diagnosis. Similar questioning about years) (Panza et al. 2013 ; Tay et al. 2004 ; Cohen visible hair on clothes, on the fl oor, etc., could et al. 1995 ; Snorrason et al. 2012 ; Malhotra et al. allude to when hair pulling occurs. 2008 ). However, it is known that trichotillomania Nail-biting has been associated with trichotil- frequently (even more frequently) occurs in early lomania in 15–20 % of children in several pediat- childhood, and it has been reported from as early ric series (Oranje et al. 1986; Tay et al. 2004 ; as 12 months of age (Oranje et al. 1986 ; Swedo Walther et al. 2014). Comorbid repetitive stereo- and Leonard 1992 ; Byrd et al. 2002 ; Wright and typical movements, also referred to as body- Holmes 2003 ). The peak age at onset of hair loss focused repetitive behaviors (BFRBs), have been in our cohort was 1–2 years (36 %) with an aver- noted in up to 42 % of cases of childhood tricho- age age of 5.5 years suggesting that the onset of tillomania. In a child who displays BFRBs, it is hair-pulling behavior is also common in this fascinating why he/she should focus on hair and younger preschool age-group. not on other easily accessible body parts such as Trichotillomania is seven times more common the nails. Perhaps as hair is much more abundant, in children as compared to adults. There are two a subsequent decrease of hair is therefore less peak ages: between 2 and 5 years of age and obvious. This could be true of older children who between 12 and 15 years of age. The disease is feel ashamed of their habit and want to conceal it. considered as a habit disorder in the very young Furthermore, infants and younger children with children, while the pathologic mechanism is childhood trichotillomania have been described often more serious in older children. as natural fi ddlers who have a need for tactile Many authors have speculated that distinct stimulation via their fi ngertips to soothe them- subsets of hair-pulling behavior exist in chil- selves (Sperling 1968 ; Golomb and Mansueto dren of different ages. Tay et al. and Swedo 146 N.S. Chandran et al. et al. distinguished habitual hair pulling in chil- hair pulling was triggered by physical appear- dren <5 years of age from trichotillomania in ance tended to be older. With increased pressure older children, arguing that the former has a to look good and conform in preadolescent and more benign episodic course which resolves adolescent children, it is no surprise that insecu- without intervention (Swedo and Leonard rity about physical appearance can trigger hair- 1992 ; Tay et al. 2004 ). Walther et al. found that pulling behavior. Starting a new school, poor compared to preschool children (0–5 years old), performance, bullying, and strained teacher- school-aged children (6–10 years old) with student relationships have been described as hair-pulling behavior had higher levels of causes of hair pulling (Chandran et al. 2015 ). impairment or distress and had more comorbid For these reasons, trichotillomania may be diagnoses (Walther et al. 2014 ). interpreted as a symptom rather than a separate A younger age of onset is a good prognostic disease. Trichotillomania can be viewed as a factor, and the condition in this age-group tends form of self-harm. The function of self-harm is to be self-limiting and is considered as a habit almost always to decrease distress; this can be disorder such as thumb-sucking. This lends sup- categorized into decreasing distress directly or port to the concept that different pediatric age- indirectly by affecting the person or his/her local groups represent different subsets of environment (in a manner that decreases the per- trichotillomania. son’s short-term distress) (Hopwood et al. 2014 ). In the adult population, trichotillomania has a The main risk of approaching trichotillomania as female gender bias. Explanations for this gender a separate disease is neglecting the surrounding distribution include male hair pullers avoiding factors (environmental conditions) that can main- treatment or ascribing their condition to male- tain or reinforce the triggers for pulling hair. It is pattern hair loss, their ability to shave their heads perhaps more elegant to approach it as a to minimize the effects of hair pulling, and ele- comorbidity. vated anxiety in women which infers a greater Gershuny et al. reported a higher prevalence need to self-regulate resulting in more severe hair of post-traumatic stress disorder (PTSD) and his- pulling (Duke et al. 2009; Christenson et al. tory of traumatic events in adult trichotillomania 1994 ; Penzel 2003 ). Our pediatric cohort showed sufferers (Gershuny et al. 2006 ). Trichotillomania a marked predominance of girls. Even if older may serve as a form of coping vis-à-vis self- preadolescent children (>9 years) were excluded, soothing in these traumatized individuals. The there was still a female predominance. This is in high prevalence of associated stressful triggers in contrast with the literature where previous pedi- our cohort and other pediatric series highlights atric reports demonstrate an equal gender distri- that stress similarly plays a role in hair pulling in bution (Tay et al. 2004 ; Whiting 1999 ; Cohen childhood (Swedo and Leonard 1992 ; Wright et al. 1995 ). We postulate that girls may be more and Holmes 2003 ). It has been postulated that prone to pull their hair as they tend to internalize pulling could produce “counterirritation” to emo- behavior to cope in a stressful situation, unlike tional distress (Christenson et al. 1991a ). Yet, boys who tend to externalize behavior and act out many children pull their hair in times of apparent (Bornstein et al. 2010 ; Kaiseler et al. 2012 ). relaxation when alone and in relaxed surroundings (Sah et al. 2008 ; Stein et al. 2006 ), i.e., situations where they are not directly exposed to a Patho-etiology stressor. This may suggest that stress may act as a triggering factor for hair pulling, but the child can The etiology of trichotillomania is complex. subsequently be conditioned to carry out the Triggers were associated with the onset of tricho- behavior in particular recurrent nonstressful situ- tillomania in half of the children. Family-related ations such as while watching television or when issues accounted for the majority of the children’s in bed. It is most probably the need to reduce problems (Oranje et al. 1986 ). Children whose stress after being exposed to a stressor. At the 15 Childhood trichotillomania 147 time of the exposure, more primary defense their eyelashes or eyebrows tended to be older mechanisms such as fi ght, fl ight, or freeze are (ages 9.6–13.4 years). This is in concordance used. with the literature that children with trichotillo- In comparison with adult trichotillomania, mania tend to pull from multiple sites at a much childhood trichotillomania is thought to be a lower rate than adults, suggesting a developmen- habit phenomenon and not usually a sign of seri- tal progression in the number of pulling sites ous emotional disturbance. Associated psychiat- (Panza et al. 2013 ; Franklin et al. 2008 ). ric, behavioral, or developmental problems have Usually one or more areas are affected, but been described in children with trichotillomania. changing with time. Smaller or larger areas can However, Wright and Holmes examined ten tod- also be detected as well as possible total scalp dlers (average age 26 months) who showed hair- involvement. In classical presentations, the areas pulling behavior and found that 50 % had a are not well demarcated. The diagnosis becomes comorbid psychiatric diagnosis of anxiety, 20 % even more diffi cult when the eyebrows or eye- had developmental problems (e.g., language lashes are involved. A peculiar variant presents delay), and family stress/problems were found in with just a “tonsure” or rim of unpulled hairs like all cases (Wright and Holmes 2003 ). Walther Friar Tuck in the Robin Hood stories. In fact the et al. reported 23.6 % prevalence of comorbid term “Friar Tuck” exists in the literature as Friar psychiatric diagnoses in children aged 0–10 years Tuck sign and Friar Tuck alopecia. (Walther et al. 2014). Other studies with mixed Complications of trichotillomania include samples of young children and adolescents trichophagia with an extreme manifestation of a showed relatively high rates (40–70 %) of comor- trichobezoar (hair ball in the stomach) and bid psychiatric disorders (Malhotra et al. 2008 ; repeated traction with permanent damage to the Reeve et al. 1992 ; Santhanam et al. 2008 ). It is hairs. Trichophagia has been reported in up to possible that younger children present with 10 % of children (Oranje et al. 1986 ). However reduced comorbidity because older children may we have not observed any cases in Rotterdam. simply have had more time to develop comorbid conditions than younger ones, irrespective of the duration of hair pulling. Lastly, children with Diagnosis trichotillomania tend to have perfectionistic per- sonalities. When considering the effect of gender The presence of patchy, non-scarring hair loss on associated comorbidity, higher levels of anxi- without concurrent scalp pathology should alert ety, depression, and distress were found in girls physicians to the possibility of trichotillomania. than in boys with childhood trichotillomania There are several methods of assessment of (Panza et al. 2013 ). In particular, all children with trichotillomania (Franklin et al. 2012 ) including anxiety-related problems were female (ages 7–10 the trichotillomania diagnostic interview, the years). trichotillomania severity scale, the trichotillomania impairment scale, the hair-pulling symptom severity scale, and the Milwaukee test. The Clinical Features majority of these tests will not be used in practice. The most common area for hair pulling is found Besides the clinical aspects of trichotilloma- to be the scalp as has been noted in multiple pedi- nia that help the clinician in making the diagnosis atric series (Tay et al. 2004; Cohen et al. 1995 ; of this disorder (short broken hairs of various Walther et al. 2014 ; Wright and Holmes 2003 ). lengths within the alopecic areas, scalp erosions, Often the areas of hair loss were not well demar- and negative hair-pull test), the hair and scalp cated or had bizarre irregular confi gurations and evaluation via the dermatoscope is an easy and occurred contralateral to or on the side of to the rapid method to gather information. Dermoscopic handedness of the patient. Children who pulled features of trichotillomania include coiled hairs 148 N.S. Chandran et al. with frayed ends, short hairs with trichoptilosis should be assessed to see if the areas of highest (split ends), and fl ame hairs (Miteva and Tosti traction are concordant with those of hair loss. 2012 ). Diffuse hair loss, slow growth, or alteration in It is noninvasive and painless and well texture is typical of LAHS, whereas trichotillo- accepted by the patients and parents. Alopecia mania more frequently presents as bizarre, areata is the main differential diagnosis of tricho- sharply demarcated areas of hair loss. LAHS also tillomania. Dermoscopy of both alopecia areata presents with a positive hair-pull test and typical and trichotillomania can show yellow dots, black light microscopy fi ndings. One last controversy, dots, broken hairs, coiled hairs, and exclamation- the authors have seen combinations of alopecia mark hairs. Trichotillomania shows the breakage areata and trichotillomania occur together. of hairs at different lengths and signifi cant tricho- An approach to a child with localized non- ptilosis, which is even more easily seen if the der- scarring hair loss is highlighted in Fig. 15.1 . The matoscope is used in the polarizing light mode. hair-pull test is a simple, easily performed bed- In trichotillomania invasive investigations side test that is acceptable to children and par- such as scalp biopsy are usually unnecessary, but ents. Gentle traction is exerted on a group of hairs can be helpful if the clinical picture is unclear or (about 20) on three different areas of the scalp. if the child or parent is unwilling to accept the The test is considered positive if more than fi ve diagnosis. Of note there are cases in which the hairs are extracted. All patients in our cohort had trichotillomania got worse after biopsy. a negative hair-pull test. The hair-pull test is Differential diagnoses of trichotillomania especially useful to differentiate trichotillomania include alopecia areata, tinea capitis, secondary from alopecia areata, which can be established by syphilis, traction alopecia, and loose anagen hair a positive test in the active disease phase. If alo- syndrome (LAHS) (Tay et al. 2004; Sah et al. pecia areata is not in the active phase, the hair- 2008 ; Hautmann et al. 2002 ). In alopecia areata, pull test is negative, but regrowing hair should be there are smooth areas of hair loss with visible sooner or later. If the test remains persis- “exclamation- mark” hairs and “cadaverized” tently negative or if regrowth is not present at hairs; regrowing hairs may be present at the bor- serial follow-up, the primary diagnosis of alope- der of the lesion, and fi ne, sometimes unpig- cia areata should be revised, and trichotillomania mented, hairs may be present within the lesion; should be suspected instead. regular pitting and red lunula might be present in the nails, especially in the hands. Alopecia areata of the eyelashes usually involves both upper and Treatment lower lashes. In contrast, the upper lid lashes and not the shorter, more diffi cult to grasp, lower lid A treatment plan can be formulated once the lashes are usually affected in trichotillomania patient has been comprehensively evaluated. In (Radmanesh et al. 2006 ; Shelleh et al. 2006 ). 2008, the Child and Adolescent Trichotillomania Tinea capitis presents with easily extractable Impact Project (CA-TIP) indicated that less than hairs from a scaly erythematous scalp. Potassium half of children treated for trichotillomania hydroxide 10 % solution examination of the hair improved in terms of their hair-pulling symp- shafts for fungal elements and fungal culture of toms. Since then, more evidence has surfaced to the hair will confi rm the diagnosis. Secondary lend support to specifi c treatment approaches syphilis presents with moth-eaten non-scarring (Franklin et al. 2008 ). alopecia concurrent with papulosquamous skin Behavioral therapy (BT) in particular is very lesions of the trunk, palms, and/or soles; serology promising and could comprise the backbone of should be performed in these patients. Traction therapy in pediatric trichotillomania. Therapy is alopecia results from long-standing traction on aimed at exploring stressful situations which lead the hair such as from tight ponytails or hair to discharge of tension via the symptomatic behav- weaves or hair extensions; history of hairstyling ior (in this case hair pulling). Mapping the behav- 15 Childhood trichotillomania 149

Common causes of non-scarring hairloss in children

Hairpull test (HPT) positive (pos.) Hairpull test (HPT) negative (neg.) at border of alopecia at border of alopecia

Dermoscopic appearance

Specific changes Aspecific Aspecific Aspecific Specific

Alopecia Areata Tinea capitis [AA] Traction (diagnosis by Trichotillomania AA (When stabilized alopecia KOH scrapings) negative HPT)

Fig. 15.1 Approach to a child with non-scarring hair loss ior is signifi cant; when does a child do it, for how young children, case reports suggest that these long, and in what way? The problem is then rede- patients do respond favorably. For example, fi ned as a developmental problem: the child has an response prevention is a treatment shown to be inadequate solution for releasing tension (Verhulst effective for benign habits such as thumb-sucking. et al. 2007). A randomized controlled trial showed Severe hair pulling was eliminated in a 2-year-old that BT produced signifi cant reduction in hair-pull- child by the implementation of response preven- ing symptoms in children with trichotillomania and tion using a sock over the child’s hand and brief that treatment gains were sustained posttreatment time-out when the unwanted behavior was per- (Franklin et al. 2010 , 2011a , b , 2012 ). This lack of formed (Byrd et al. 2002 ). Response prevention in relapse in children stands in contrast to adult trials this case consisted of simple placement of socks for BT which showed that relapse is common after on the child’s hands. Our experience with the use discontinuation of treatment, suggesting that treat- of a woolly toy is encouraging. Parents are advised ment of TTM in childhood or adolescence may be to acquire a woolly toy with physical characteris- associated with more durable outcomes than treat- tics similar to the child’s hair, with the aim of ment during adulthood (Diefenbach et al. 2006 ; allowing the child to pluck the toy’s hair while Keijsers et al. 2006 ). leaving his/her own hair alone. This approach It is unclear whether developmental issues pre- allows children to have an outlet to release their clude the effective use of child-focused BT, as urge to pull hair without doing it on themselves younger children with trichotillomania may not (Heaton 2009 ). It also validates the diagnosis to have developed the expressive skills and emo- the parents as they are able to witness the behav- tional awareness required for BT. Accompaniment ior in question. In older children, the use of plas- by parents is indicated especially if the child is ters (Band-Aids) on the distal index fi ngers may very young and if the symptoms are persistent. increase awareness of hair pulling. Such simple Despite the lack of robust research on BT in very behavioral interventions are easily administered 150 N.S. Chandran et al. in the outpatient dermatologic or pediatric clinical used to consider the means to go about further setting. management once a diagnosis has been made. Pharmacotherapy for childhood trichotillomania has shown mixed results. Selective serotonin Who reuptake inhibitors (SSRIs) are ineffective for Who is it about (patient and its caregivers/envi- reduction of hair-pulling symptoms per se, while ronment)? Who sees these patients? Who the opioid antagonist naltrexone and the atypical expresses the most concern about the hair or psy- neuroleptic olanzapine show some effi cacy chological condition? Who has referred the (Franklin et al. 2011b ). However, the side effects patient? of these drugs prompt caution for their use in children. In contrast to the effi cacy in the majority of What adults, a recent randomized controlled trial of What other problems are there? What else is N-acetylcysteine (NAC) limited benefi t in the associated? Under what circumstances does the treatment of trichotillomania in children (Bloch TTM take place? What are current and past et al. 2013 ). NAC treatment was used unsuccess- stressors in the patient’s life? fully in one of our patients; this was a 7-year-old girl in whom both behavioral therapy (woolly toy) When and pharmacotherapy (melatonin and NAC) failed. When did the TTM start? At which age was the She was subsequently referred to a psychiatrist. onset? Were there previous episodes of hair loss? For the reasons mentioned above, pharmacotherapy is rarely a fi rst-line option in childhood tricho- Where tillomania. A combined treatment approach of BT Where on the head/body is the hair loss? On and pharmacotherapy is encouraging, but awaits which location was it noticed or takes its place? validation in further trials (Dougherty et al. 2006 ). Why Why did the hair loss occur (triggers, psychiatric/ The Kipling Method psychological problems)? Try to make up a hypothesis why this patient is pulling their hair Utilizing the “5Ws and 1H” of the Kipling by using the information provided by the fi rst method enables the physician to thoroughly cover 4W’s. all aspects of a patient’s clinical presentation, workup, and treatment (Table 15.1 ). There are How many benefi ts to this fact-fi nding approach, the How will the hair loss be investigated and treated? critical guiding principles of which have been applied in journalism and politics. Firstly, it Pro’s of the 5W1H enables a typical profi le of children with tricho- • Easy to assess and low threshold tillomania to be obtained. Secondly, this method • Can provide us a wealth of information for can be used to assess any child with unexplained understanding the diagnosis, its severity, its non-scarring hair loss, whereby the diagnosis is impact on patient, and its caregivers and not readily obvious or where hair pulling is sus- environment pected but not yet confi rmed. Thirdly, it helps to • Can make the patient and its caregivers feel convince the parents who do not believe that their more taken seriously/understood and with that child is pulling his/her hair. Considering each of can increase compliance the 5Ws and 1H systematically with the patient could reveal information that may otherwise be Con’s of the 5W1H masked. The 5Ws can be used to delve deeper • It is not yet scientifi cally proven that it works, into the circumstances surrounding the patient although it is very well accepted in journalism and clinical problem at hand, while the H can be for achieving relevant information. 15 Childhood trichotillomania 151 psychologist/psychiatrist psychological treatment (caregivers refuse to accept the diagnosis of trichotillomania): hair other literature about how pulling can be diminished (e.g., medication)) circumstances (home/family/school) or Münchausen syndrome by proxy Treatment Treatment options accept psychological Caregivers treatment; refer to psychologist/ psychiatrist for coaching and psychotherapy toward are ambivalent Caregivers psychological treatment: dermatologist and Dual policy: No possibility to refer for brochures or give Bibliotherapy: (Dermatological interventions Be alert to hostile environmental 5W1H interview Understanding the problem Built trust/connecting with patient and caregivers treatment options Evaluate patient’s/caregiver’s (evaluate psychological attitude toward treatment) Differential Differential diagnosis Nontrichotillomania (algorithm stops, continue with dermatological research or treatment) Trichotillomania Research Anamnesis/medical history Inspection/physical examination Hair-pluck test Proposed algorithm (or guideline) for diagnosing and treating trichotillomania using the 5W1H Proposed algorithm (or guideline) for diagnosing and treating trichotillomania using the 5W1H Patient and caregivers and caregivers Patient are being referred to the dermatologist because of hair loss Table 15.1 152 N.S. Chandran et al.

Everyday practice and collecting data for (ret- information on characteristics of children suf- rospective) studies show us large number of fering from TTM. Although the 5W1H has its patients who were lost to follow up, and this limitations in providing us with all the answers demonstrates a signifi cant diffi culty in treating to every question, we have about trichotilloma- trichotillomania. nia in retrospective research, and utilizing this Unwillingness to accept the diagnosis with a systematic questioning and approach may subsequent lack of confi dence in treatment is a seem tedious, with perseverance and practice it major factor in failure to attend follow-up. can be a very helpful tool in everyday clinical Therefore one of the foremost priorities in use. By utilizing the 5W1H to approach hair managing a child with trichotillomania is to con- loss which cannot be explained by a somatic vince parents of the diagnosis and to win their cause, information gathering about this condi- trust in a sound and clear management plan. tion is thorough and complete. This is crucial Investing time in establishing a strong patient- to better understand this disease and to equip physician and parent-physician relationship clinicians to fi nd a suitable treatment and guide would boost chances of continued follow-up. the child and his or her parents toward it. Our Using the Kipling method as the guiding approach hypothesis is that the implementation of the is a good means of establishing this. In order to Kipling method combined with adequate provide patients with support and encouragement explanation of the condition will result in to keep up with follow-up and treatment, the fewer relapses of trichotillomania. assistance of a nurse practitioner trained in psychodermatology would be benefi cial. The clinician itself also seems to play an Bulleted List of Controversies important factor in the loss to follow up the patient in diagnosing and treating trichotilloma- • Childhood trichotillomania is a poorly under- nia. In a recent survey, only 18 % of American stood and an underdiagnosed condition. dermatologists reported a clear understanding of • Clinicians are apprehensive about making the psychodermatology (Jafferany et al. 2010 ). This diagnosis of childhood trichotillomania. probably represents the iceberg phenomenon as • Clinicians who often send patients with child- poor emphasis on training in psychocutaneous hood trichotillomania away are convinced that it disorders is pervasive. With increased knowledge will clear up spontaneously and do not spend and competence in trichotillomania and its treat- enough time with them to explore and help to ment, dermatologists and pediatricians will be clear the main background cause of the disorder. better equipped to provide basic psychological • Clinicians lack a strong tool to assist them in care and follow-up for young trichotillomania making an accurate diagnosis. sufferers. Consultations with colleagues in child • The Kipling method is a novel tool for evalua- psychiatry/child psychiatrists may provide inspi- tion of a child with unexplained non-scarring ration and confi dence in caring for these patients. hair loss, although it is well known in journal- The development of dermatology-psychiatry liai- ism and politics. son services, dedicated psychodermatology clinics, and training-specialized nurse practitioners would do much to improve quality of trichotillomania management. References

Conclusion Arlington V, editor. American psychiatric association: diagnostic and statistical manual of mental disorders, In conclusion, when faced with a child with 5th edn. American Psychiatric Association; 2013. seemingly puzzling non-scarring hair loss Bilo R, Oranje A, Shwayder T, Hobbs C. Cutaneous mani- many physicians may feel very discouraged. festations of child abuse and their differential diagno- Using the 5W1H can provide us a wealth of sis. Berlin/Heidelberg: Springer; 2013. 15 Childhood trichotillomania 153

Bloch MH, Panza KE, Grant JE, et al. N-Acetylcysteine in Franklin ME, Edson AL, Ledley DA, Cahill SP. Behavior the treatment of pediatric trichotillomania: a randomized, therapy for pediatric trichotillomania: a randomized double-blind, placebo-controlled add-on trial. J Am controlled trial. J Am Acad Child Adolesc Psychiatry. Acad Child Adolesc Psychiatry. 2013;52(3):231–40. 2011b;50(8):763–71. Bornstein MH, Hahn CS, Haynes OM. Social compe- Franklin ME, Zagrabbe K, Benavides KL. Trichotillomania tence, externalizing, and internalizing behavioral and its treatment: a review and recommendations. adjustment from early childhood through early Expert Rev Neurother. 2012. adolescence: developmental cascades. Dev Gershuny BS, Keuthen NJ, Gentes EL, Russo AR, Psychopathol. 2010;22(4):717–35. Emmott EC, Jameson M, et al. Current posttraumatic Byrd MR, Richards DF, Hove G, Friman PC. Treatment of stress disorder and history of trauma in trichotilloma- early onset hair pulling as a simple habit. Behav nia. J Clin Psychol. 2006;62(12):1521–9. Modif. 2002;26(3):400–11. Golomb R, Mansueto C. Trichotillomania in children. In Chandran NS, Novak J, Iorizzo M, Grimalt R, Oranje Touch (newsletter of the Trichotillomania Learning AP. Trichotillomania in children. Skin Appendage Center). 1994;2:6–7. Disord. 2015;1:18–24. Golomb R, Vavrichek S. The hair pulling “Habit” and Christenson GA, Mackenzie TB, Mitchell you: how to solve the trichotillomania puzzle. Silver JE. Characteristics of 60 adult chronic hair pullers. Spring M, editor: Writers’ Cooperative of Greater Am J Psychiatry. 1991a;148(3):365–70. Washington; 2000. Christenson GA, Pyle RL, Mitchell JE. Estimated lifetime Hautmann G, Hercogova J, Lotti T. Trichotillomania. prevalence of trichotillomania in college students. J Am Acad Dermatol. 2002;46(6):807. J Clin Psychiatry. 1991b;52(10):415–7. Heaton P. Habitual hair-pulling responsive to doll therapy. Christenson GA, MacKenzie TB, Mitchell JE. Adult men J Paediatr Child Health. 2009;45(5):318–9. and women with trichotillomania. A comparison of Hopwood CJ, Swenson C, Bateman A, Yeomans FE, male and female characteristics. Psychosomatics. Gunderson JG. Approaches to psychotherapy for bor- 1994;35(2):142–9. derline personality: demonstrations by four master cli- Cohen LJ, Stein DJ, Simeon D, Spadaccini E, Rosen J, nicians. Personal Disord. 2014;5(1):108–16. [Internet] Aronowitz B, et al. Clinical proﬁ le, comorbidity, and Http://www.trich.org/treatment/options.html . treatment history in 123 hair pullers: a survey study. Jafferany M, Vander Stoep A, Dumitrescu A, Hornung J Clin Psychiatry. 1995;56(7):319–26. R. The knowledge, awareness, and practice patterns of Diefenbach GJ, Mouton-Odum S, Stanley MA. Affective dermatologists toward psychocutaneous disorders: correlates of trichotillomania. Behav Res Ther. results of a survey study. Int J Dermatol. 2002;40(11):1305–15. 2010;49(7):784–9. Diefenbach GJ, Tolin DF, Hannan S, Maltby N, Crocetto Kaiseler M, Polman R, Nicholls A. Gender differences in J. Group treatment for trichotillomania: behavior ther- appraisal and coping: an examination of the situational apy versus supportive therapy. Behav Ther. and dispositional hypothesis. Int J Sport Psychol. 2006;37(4):353–63. 2012;43:1–14. Dougherty DD, Loh R, Jenike MA, Keuthen NJ. Single Keijsers GP, van Minnen A, Hoogduin CA, Klaassen BN, modality versus dual modality treatment for trichotil- Hendriks MJ, Tanis-Jacobs J. Behavioural treatment lomania: sertraline, behavioral therapy, or both? J Clin of trichotillomania: two-year follow-up results. Behav Psychiatry. 2006;67(7):1086–92. Res Ther. 2006;44(3):359–70. Duke DC, Bodzin DK, Tavares P, Geffken GR, Storch Malhotra S, Grover S, Baweja R, Bhateja G. Trichotillomania EA. The phenomenology of hairpulling in a commu- in children. Indian Pediatr. 2008;45(5):403–5. nity sample. J Anxiety Disord. 2009;23(8):1118–25. Miteva M, Tosti A. Hair and scalp dermoscopy. J Am Flessner CA, Woods DW, Franklin ME, Keuthen NJ, Acad Dermatol. 2012;67(5):1040–8. Piacentini J, Cashin SE, et al. The Milwaukee inven- Murphy C, Valerio T, Zallek SN. Trichotillomania: an tory for styles of trichotillomania-child version NREM sleep parasomnia? Neurology. 2006;66(8):1276. (MIST-C): initial development and psychometric Murphy C, Redenius R, O’Neill E, Zallek S. Sleep- properties. Behav Modif. 2007;31(6):896–918. isolated trichotillomania: a survey of dermatologists. Franklin ME, Flessner CA, Woods DW, Keuthen NJ, J Clin Sleep Med. 2007;3(7):719–21. Piacentini JC, Moore P, et al. The child and adolescent Oranje AP, Peereboom-Wynia JD, De Raeymaecker trichotillomania impact project: descriptive psychopathol- DM. Trichotillomania in childhood. J Am Acad ogy, comorbidity, functional impairment, and treatment Dermatol. 1986;15(4 Pt 1):614–9. utilization. J Dev Behav Pediatr. 2008;29(6):493–500. Panza KE, Pittenger C, Bloch MH. Age and gender cor- Franklin ME, Edson AL, Freeman JB. Behavior therapy relates of pulling in pediatric trichotillomania. J Am for pediatric trichotillomania: exploring the effects of Acad Child Adolesc Psychiatry. 2013;52(3):241–9. age on treatment outcome. Child Adolesc Psychiatry Penzel F. The hair pulling problem. Oxford: University Ment Health. 2010;4:18. Press; 2003. Franklin ME, Zagrabbe K, Benavides KL. Trichotillomania Radmanesh M, Shaﬁ ei S, Naderi AH. Isolated eyebrow and its treatment: a review and recommendations. and eyelash trichotillomania mimicking alopecia Expert Rev Neurother. 2011a;11(8):1165–74. areata. Int J Dermatol. 2006;45(5):557–60. 154 N.S. Chandran et al.

Reeve EA, Bernstein GA, Christenson GA. Clinical char- Tay YK, Levy ML, Metry DW. Trichotillomania in child- acteristics and psychiatric comorbidity in children hood: case series and review. Pediatrics. with trichotillomania. J Am Acad Child Adolesc 2004;113(5):e494–8. Psychiatry. 1992;31(1):132–8. Verhulst F, Verheij F, Ferdinand R. Child and youth psy- Sah DE, Koo J, Price VH. Trichotillomania. Dermatol chiatry, psychopathology. Assen: Van Gorcum; 2007. Ther. 2008;21(1):13–21. p. 51–5. Santhanam R, Fairley M, Rogers M. Is it trichotillomania? Walther MR, Snorrason I, Flessner CA, Franklin ME, hair pulling in childhood: a developmental perspective. Burkel R, Woods DW. The trichotillomania impact Clin Child Psychol Psychiatry. 2008;13(3):409–18. project in young children (TIP-YC): clinical charac- Shelleh HH, Khan SA, Al-Hatiti HS. Trichotillomania or teristics, comorbidity, functional impairment and alopecia areata? Int J Dermatol. 2006;45(10):1196–8. treatment utilization. Child Psychiatry Hum Dev. Snorrason I, Belleau EL, Woods DW. How related are hair 2014;45(1):24–31. pulling disorder (trichotillomania) and skin picking Whiting DA. Traumatic alopecia. Int J Dermatol. disorder? A review of evidence for comorbidity, simi- 1999;38(1):34–44. larities and shared etiology. Clin Psychol Rev. Wright HH, Holmes GR. Trichotillomania (hair pulling) 2012;32(7):618–29. in toddlers. Psychol Rep. 2003;92(1):228–30. Sperling M. Trichotillomania, trichophagy, and cyclic vomiting. A contribution to the psychopathology of female sexuality. Int J Psychoanal. 1968;49(4):682–90. Stein DJ, Chamberlain SR, Fineberg N. An A-B-C model of Suggested Reading habit disorders: hair-pulling, skin-picking, and other ste- reotypic conditions. CNS Spectr. 2006;11(11):824–7. Chandran NS, Novak J, Iorizzo M, Grimalt R, Oranje Swedo SE, Leonard HL. Trichotillomania. An obsessive AP. Trichotillomania in children. Skin Appendage compulsive spectrum disorder? Psychiatr Clin North Disord. 2015;1:18–24. Am. 1992;15(4):777–90. Child Abuse: More Than Skin Deep 1 6 Robert A.C. Bilo

Abstract The skin is the most accessible organ of the human being. It is also the most frequently injured organ in accidents and in child abuse. Skin abnormalities are visible to everyone. The diagnosis of these abnormalities in suspected child abuse, however, is the work of specialists. Diagnostic errors can be prevented through close cooperation between forensic pediatrics and pediatric dermatology.

Keywords Child abuse and neglect • Physical ﬁ ndings • Differential diagnosis • Forensic pediatrics • (Pediatric) dermatology

The skin is the most accessible organ of the human sports, play, or traffi c, but may also be infl icted, body. For that reason, the skin is easy to observe by due to child abuse, in which the skin is the pri- anyone: well-trained physicians as well as untrained mary target organ. bystanders. The interpretation of skin fi ndings is The World Health Organization (2006 ) defi nes primarily the task of physicians: (pediatric) derma- child abuse as follows: “child abuse or maltreat- tologists in case of suspected dermatovenereologi- ment constitutes all forms of physical and/or cal disorders and forensic doctors (consultants in emotional ill-treatment, sexual abuse, neglect or forensic pediatrics, child abuse pediatricians) in negligent treatment or commercial or other case of suspected infl icted injuries. exploitation, resulting in actual or potential harm The skin is the most frequently injured organ to the child’s health, survival, development or in children. Injuries happen accidentally due to dignity in the context of a relationship of respon- sibility, trust or power.” In Table 16.1, an overview is given of types of child abuse and neglect Ce qu’il y a de plus profond de l’homme, c’est la peau. (CAN) which can be recognized in clinical (Paul Valery, French poet, 1871–1945) practice. R.A.C. Bilo , MD CAN-related skin fi ndings can be seen in all Department of Forensic Medicine, Section of types of child abuse and neglect. These fi ndings Forensic Pediatrics , Netherlands Forensic Institute , may play a central role in establishing the diag- Postbus 24044 , The Hague 2490AA , The Netherlands e-mail: r.bilo@nfi .minvenj.nl nosis when CAN is suspected in:

Table 16.1 Types of child abuse and neglect (CAN) in articles, and chapters in textbooks have been pub- clinical practice lished regarding the misinterpretation of, e.g., Physical abuse normal variants or pediatric dermatovenereologi- Neglect, including physical neglect and other types of cal disorders as cutaneous manifestations of negligent behavior CAN (Kirschner and Stein 1985 ; Wheeler and Sexual abuse Hobbs 1988 ; Bays 2001 ; Oranje and Bilo 2011 ; Psychological/emotional abuse Bilo et al. 2013 ). Of all the dilemmas concerning Pediatric condition falsifi cation/fi ctitious disorder by dermatological disorders and skin fi ndings which proxy/medical child abuse (US terminology)/ fabricated or induced illness (UK terminology) are described in the medical literature in CAN, (formerly known as Munchausen syndrome by proxy) this dilemma is most often described in medical From Bilo et al. (2013 ), with permission literature. Wheeler and Hobbs (1988 ) showed that misinterpretation of dermatological disorders as • Physical abuse: e.g., bruising, burning, or even CAN may happen with a variety of different skin lacerating of the skin fi ndings. Wheeler evaluated the data of 2,578 • Neglect: e.g., skin or hair abnormalities caused children who were reported because of suspected by defi ciencies or to unexpected delay in heal- CAN. In 50 cases (less than 2 %), the initial sus- ing of skin disorders or wounds picion was incorrect. In 42 of these cases, skin • Sexual abuse: e.g., sexually transmitted fi ndings were the reason for the suspicion of diseases CAN: • Psychological/emotional abuse: e.g., self- mutilation of the skin • ”Bruising” ( n = 23): Mongolian spots, capil- • Pediatric condition falsifi cation: e.g., skin lary hemangioma, prominent facial veins, fi ndings mimicking dermatovenereological immune thrombocytopenia (ITP), hemophilia, disorders hemorrhagic disease of the newborn, eczema, erythema nodosum, allergic periorbital swell- Differentiating between dermatovenereologi- ing, subconjunctival hemorrhage secondary to cal disorders and cutaneous manifestations of pertussis, ink (or dye or paint) on the face, CAN is not always simple. Misinterpretation of coin rubbing, bruised face after dental physical fi ndings can have serious consequences treatment for children and parents, but also for the doctors • “Scalds” or “burns” ( n = 18): impetigo, diaper who misinterpreted the fi ndings. dermatitis, chilblain, fi xed drug eruption, In this chapter, the interface between dermato- mechanical abrasion, and concentrated vine- logical disorders and CAN and some of the gar burn resulting dilemmas are discussed. • Other: alopecia areata (n = 1)

Schwartz et al. ( 2014) found physical abuse Dilemma 1: Dermatovenereologic mimickers in almost 5 % of children evaluated Disorders Mimicking Child Abuse for physical abuse (n = 2890 children). Half of and Neglect these mimickers were cutaneous mimickers. In most of the cases (93 %), the mimicker was dif- Conditions That Mimic Findings ferentiated from physical abuse-related injuries of Physical Abuse and Neglect through a combination of the medical history and physical examination with basic screening for The correct interpretation of suspicious skin ﬁ nd- physical abuse. The basic screening was deﬁ ned ings is not always simple. Since the publication by Schwartz as nondirected, thorough history, of Kempe’s classical article “The Battered Child” complete physical examination, laboratory (Kempe et al. 1962 ), many case histories, review screening (CBC with platelets, PT, and activated 16 Child Abuse: More Than Skin Deep 157

PTT), a skeletal survey (in children under the age preferably in all cases in which the skin fi nding is of 24 months), and cranial imaging (in children used to support the suspicion of child abuse. under the age of 6 months). Most prevalent mimicker was Mongolian spots. Also less commonly described mimickers Conditions That Mimic Findings as contact dermatitis, clothing dye, and tinea of Sexual Abuse were seen in multiple children. One of the most striking fi ndings in this study was that no child Physical fi ndings can be helpful in confi rming a with a congenital coagulation factor defi ciency suspicion of child sexual abuse. If conclusive presented as a cutaneous mimicker. Schwartz they can be used as proof in legal procedures. stated that one should always consider a mim- Most sexually abused children however will have icker because of the signifi cant number and per- normal or non-specifi c physical fi ndings and centage of children with an identifi ed mimicker. therefore will not have any physical evidence of Schwartz did not identify frequently mentioned the abuse, and only a minority of these children mimickers for abuse, such as traditional medi- will have conclusive physical fi ndings (Kotik cine, Ehlers–Danlos syndrome, lymphangiomas, et al. 2011 ; Fortin and Jenny 2012 ; Hobbs 2012 ). factor VIII or IX defi ciency, and alopecia areata. Because of this low prevalence of specifi c Many of the misinterpreted cutaneous fi nd- physical fi ndings in child sexual abuse, one ings are relatively common normal variants (e.g., should be reticent in interpreting anogenital fi nd- Mongolian spots, striae) or disorders (e.g., hem- ings as being the result of sexual abuse. angioma, ITP, eczema, phytophotodermatitis). In Table 16.2 an overview is given of some The clinical manifestations of these fi ndings are dermatovenereological disorders that were mis- not atypical in most cases. This suggests that sus- taken for sexual abuse-related skin fi ndings in picion may have been caused not by the physical children and adolescents, e.g., by simulating fi nding itself but by more or less subjective fac- healing trauma or suggesting sexual tors, e.g., background risk factors in the family. transmission. Sometimes the diagnosis is considerably more diffi cult where the fi nding follows an atypical clinical course or has an atypical location. Dilemma 2: Child Abuse Disorders, which are relatively rare, are often and Neglect Mimicking described only once or twice in the medical lit- Dermatovenereological Disorders erature as a single case report, for example, hepatoerythropoietic porphyria (Cantatore-Francis Although many physical fi ndings in CAN may et al. 2010) or Kasabach–Merritt syndrome mimic dermatovenereological disorders (e.g., (Bouvet et al. 2014 ; Cyrulnik et al. 2014 ). Most infl icted scalds in the diaper area mistaken for of these rare abuse mimickers are not found in impetigo bullosa), the chance of misinterpretation larger series (Wheeler and Hobbs 1988 ; Schwartz is the largest in pediatric condition falsifi cation et al. 2014 ). (fabricated or induced illness, formerly known as Confusion can be avoided by a careful medi- Munchausen syndrome by proxy). cal history and detailed registration of the physi- Pediatric condition falsifi cation is a form of cal examination and repeated examination physical and psychological child abuse, in which (Hobbs et al. 1999 ; Schwartz et al. 2014 ). If in an illness is feigned (fabricated) or induced in a doubt, it is advised to photograph the fi ndings child by a parent (mostly the mother) or someone systematically. In addition, it is important to who is responsible for the child’s welfare. The review the physical fi ndings periodically after a behavior of the perpetrator leads to recurrent pre- suitable length of time. Consultation with or a sentation of the child within the healthcare sys- second opinion of a specialized pediatrician, der- tem, resulting in repeated medical examinations matologist, or pediatric dermatologist is advised, and possible interventions. 158 R.A.C. Bilo

Table 16.2 Overview of some dermatovenereological disorders, mistaken for sexual abuse-related skin fi ndings Dermatovenereological disorders Diaper dermatitis Perianal lymphangioma circumscriptum mistaken for genital warts Aphthous ulceration in the genital area in association with acute illness Allergic or toxic contact dermatitis, e.g., nickel allergy from a bed-wetting alarm, laxative-induced skin lesions in the anogenital area Atopic dermatitis Vasculitis, e.g., Henoch–Schonlein purpura Lichen sclerosus et atrophicus Lichen simplex chronicus Lichen planus Phytophotodermatitis Bullous disease, vulvar pemphigoid Behcet disease Psoriasis Vulvitis circumscripta plasmacellularis Infections Nonspecifi c vulvovaginitis Nonsexually transmitted STDs, e.g., intrauterine or perinatal transmission Nonsexually transmitted infections: Viral, e.g., genital herpes zoster, anogenital warts Bacterial, e.g., perianal streptococcal cellulitis, streptococcal vulvovaginitis Fungal, e.g., candidiasis Parasitic, e.g., scabies Neoplasm Papilloma Sarcoma Congenital anomalies Anogenital hemangiomas Other venous abnormalities Nevi on the labia Klippel–Trenaunay syndrome Failure of midline fusion Systemic diseases Perianal and vulvar fi ndings Crohn’s disease Megacolon Other Vaginal foreign bodies with a short or long history of genital symptoms Use of steroid cream Urethral polyp Data from Harth and Linse (2000 ), Elder (2007 ), Swerdlin et al. (2007 ), AlJasser and Al-Khenaizan (2008 ), Hornor (2009 )

Pediatric condition falsifi cation should be dif- The skin fi ndings in active induction may ferentiated from the fi ndings in factitious disor- range from easily identifi able artifi cial abnormal- ders in children and adolescents (Bilo and Oranje ities to very complicated infectious diseases of 2006). Both are characterized by the intentional the skin (Bilo and Oranje 2006 ). According to feigning (fabrication) or induction of signs and/ Harth et al. (2010 ), skin fi ndings can be induced or symptoms in order to assume the sick role by mechanical trauma (e.g., pressure, friction, (Stanziale et al. 1997 ). Factitious disorders in occlusion, biting, cutting, stabbing), thermal children and adolescents (also referred to as child trauma (heat, cold), chemical trauma (e.g., appli- and adolescent illness falsifi cation) may go unde- cation of toxic substances), or self-infl icted infec- tected for a long time (Libow 2000 ). tions (e.g., with wound healing impairment or Factitious disorders of the skin can present abscesses). In Table 16.3 an overview is given of themselves in different ways, ranging from a skin fi ndings in pediatric condition falsifi cation medical history suggestive for a skin condition that were either observed and interpreted by a (passive induction = fi ctitious = fabrication) to physician or reported by the perpetrator. Pediatric clearly visible and fairly persistent skin abnor- condition falsifi cation, but also other infl icted malities (active induction = factitious = artifi cial). injuries, should also be differentiated from the 16 Child Abuse: More Than Skin Deep 159

Table 16.3 Overview of some skin fi ndings in pediatric injury of fractures) in 4 % of 2890 children, condition falsifi cation evaluated for physical abuse. Coagulopathies/ hemorrhagic tendency/easy bruising Cutaneous abnormalities in food allergy and other allergic reactions Dilemma 4: Neither Cutaneous abscesses (sterile or infected) Dermatovenereological Disorders Cyanosis nor Child Abuse and Neglect Dermatitis artefacta/(cutaneous) rashes of unknown cause Diaphoresis Doctors working in forensic pediatrics or in Eczema (pediatric) dermatology can get involved in situa- Erythema tions in which a child has skin abnormalities Excoriations and erosions which cannot be classifi ed easily, although the Foamy discharge from the scalp physical fi ndings may suggest the presence of a Granuloma annulare dermatovenereological disorder or an injury Nail plate shedding with severe pain and bleeding (accidental or infl icted). This can happen in chil- Edema dren with physiological habits or self-mutilation, Otitis externa in children treated with traditional medicine, or Painting of the skin (may mimic cellulitis or purpura) in children who were (often unobserved) exposed Soft tissue infection with intestinal fl ora (sometimes to ink, dye, crayon, or paint. after vaccination) Physiological habits are defi ned as age- Vaginal discharge and other abnormalities, such as dependent behavior that can be seen as a normal vaginal or anal bleeding and/or abnormalities in the developmental stage at a certain age period, e.g., anogenital area thumb- and fi ngersucking, which is very com- Vesicular eruptions (clustered, chronic) mon in young children (Bilo and Oranje 2006 ). Data from Stankler (1977 ), Rosenberg (1994 ), Schreier and Libow ( 1994 ), Johnson (1995 ), Weston and Morelli These habits can be seen as self-soothing and ( 1997), Bilo ( 2003), Vennemann et al. ( 2006 ), Sugandhan self-comforting behavior. It can be seen at all et al. ( 2010 ), Patnaik et al. (2013 ), Boyd et al. (2014 ) times of day. This type of habits disappears when it loses its function. Physiological habits can fi ndings in self-mutilation in children and adoles- result in skin lesions, caused by the habit itself or cents (see later). by complicating factors, e.g., the development of paronychia and warts in nail-biting (Bilo and Oranje 2006 ). Dilemma 3: Dermatovenereological Self-mutilation is defi ned as the deliberate Disorders as Well as Child Abuse alteration or destruction of one’s own body tissue and Neglect without any conscious suicidal intent. The injury is self-infl icted, without the assistance of another One should always realize that fi nding a der- person, and the injury is severe enough to result matovenereological disorder does not exclude in tissue damage. Self-mutilation can be observed child abuse, and fi nding physical evidence for in children as young as 3 years of age (Bilo and child abuse does not exclude the existence of a Oranje 2006 ). Most prevalent behavior in self- dermatovenereological disorder. In other mutilation is cutting, burning, and bruising. words, each child with a dermatovenereologi- The difference between physical fi ndings in cal disorder can be a victim of child abuse, and this dilemma and the fi ndings described under each victim of child abuse can suffer from a the heading of dilemma 2 is that the intention of dermatovenereological disorder. Schwartz the behavior is not to deceive doctors or to assume et al. (2014 ) identifi ed the coexistence of a the sick role, but to self-comfort or to self-sooth cutaneous mimicker and physical abuse (sig- in physiological habits and blunting of emotional nifi cant injuries as infl icted traumatic brain pain in self-mutilation. 160 R.A.C. Bilo

The skin fi ndings in traditional medicine and In other words, a suspicion of child abuse cultural practices, e.g., coining, spooning, because of physical fi ndings must be cupping, tui na (a form of chinese manipulative approached like any other medical problem in therapy), moxibustion, salting (ice salt cube chal- a child, namely, based on expertise and multi- lenge), may be misinterpreted as injuries caused disciplinary cooperation. by CAN, especially if the fi ndings are patterned, And as was stated by Carlsen and Weismann which is usual in the skin manifestations of cul- (2007 ) in an article about phytophotodermati- tural practices (Ravanfar and Dinulos 2010 ). tis and CAN in its differential diagnosis: “The Application of ink, crayon, paint, or dyes has doctors' perception is based on the doctors’ been described as fi ndings that have been con- education.” fused with cutaneous manifestations of CAN. Colored spots caused by dyes can be found on the face (Wheeler and Hobbs 1988 ). Also Bulleted List of Controversies clothing dyes, especially the dyes in often new and unwashed jeans (blue, gray, or black), may • Dermatovenereological disorders can be mis- lead to a bluish-blue-gray discoloration/rash of taken for physical signs and suspicions of the skin, which may be confused with abuse- child abuse. related bruising, especially when the discolor- • Physical fi ndings in an abused child can be mis- ation is found on the hands, the thighs and taken for dermatovenereological disorders. abdomen, and the legs and hips (Bilo et al. 2013 ). • Child abuse-related injuries and dermatovenereological disorders do coexist in children. Conclusions • Not all skin fi ndings in children are the result Children and their parents are entitled to the of dermatovenereological conditions or child best medical diagnostic care in all situations, abuse. in which the well-being of a child is at risk. • Skin fi ndings should always be evaluated by This includes situations in which child abuse expert doctors who are trained in reading the is suspected. skin. Skin fi ndings may play a critical role in the • A second opinion should be part of the routine recognition of child abuse. Physicians who are clinical and forensic examination of children working in forensic pediatrics need to have an suspected for child abuse, because of the sig- extensive knowledge of normal skin variants nifi cant number and percentage of children and of (pediatric) dermatology to prevent pain- with an identifi ed mimicker. ful mistakes, either by wrongly diagnosing child abuse in normal variants or pediatric dermatological disorders or wrongly assuming a References normal variant or a pediatric dermatological disorder in case of child abuse. It is therefore AlJasser M, Al-Khenaizan S. Cutaneous mimickers of not surprising that forensic pediatrics and child abuse: a primer for pediatricians. Eur J Pediatr. 2008;167(11):1221–30. (pediatric) dermatology do regularly intersect Bays J. Conditions mistaken for child physical abuse. In: in order to establish an adequate differential Reece RM, Ludwig S, editors. Child abuse, medical diagnosis in suspected cases of child abuse. diagnosis and management. 2nd ed. Philadelphia: Mistakes have been made in the past and Lippincott Williams & Wilkins; 2001. p. 177–206. Bilo RAC. Forensic pediatric dermatology: my skin is only will still be made in the future. The risk of mak- the toplayer of the problem. In: Oranje AP, de Waard – ing mistakes can be reduced largely by a multi- van der Spek FB, Bilo RAC. Dermatology from young disciplinary approach and cooperation between to old. Zwolle: Isala series nr 43; 2003. p. 45–52. professionals in forensic pediatrics, pediatrics, Bilo RAC, Oranje AP. Physiological habits, self- mutilation and factitious disorders. In: Harper J, and (pediatric) dermatology. Children, their Oranje A, Prose N, editors. Textbook of pediatric der- parents, and their families will benefi t from this matology. 2nd ed. Oxford: Blackwell Publishing; cooperation. 2006. p. 2096–109. 16 Child Abuse: More Than Skin Deep 161

Bilo RAC, Oranje AP, Shwayder T, Hobbs CJ. Cutaneous Kotik A, Zaitsev K, Shperber A, Hiss J. [The prevalence manifestations of child abuse and their differential of physical evidence in the anogenital area in sexual diagnosis – blunt force trauma. New York: Springer; assault cases of children in Israel] [Article in Hebrew]. 2013. Harefuah. 2011;150(12):895–8, 936. Bouvet R, Pierre M, Toutain F, et al. Tufted angioma with Libow JA. Child and adolescent illness falsifi cation. Kasabach-Merritt syndrome mistaken for child abuse. Pediatrics. 2000;105(2):336–42. Forensic Sci Int. 2014;245C:e15–7. Oranje A, Bilo RA. Skin signs in child abuse and differen- Boyd AS, Ritchie C, Likhari S. Munchausen syndrome tial diagnosis. Minerva Pediatr. 2011;63(4):319–25. and Munchausen syndrome by proxy in dermatology. Patnaik S, Mishra BR, Mohanty I, Nayak S. Foamy dis- J Am Acad Dermatol. 2014;71(2):376–81. charge on the scalp of the infant: Munchausen syn- Cantatore-Francis JL, Cohen-Pfeffer J, Balwani M, et al. drome by proxy. Indian J Dermatol. 2013;58(5): Hepatoerythropoietic porphyria misdiagnosed as child 410–1. abuse: cutaneous, arthritic, and hematologic manifes- Ravanfar P, Dinulos JG. Cultural practices affecting the tations in siblings with a novel UROD mutation. Arch skin of children. Curr Opin Pediatr. 2010;22(4): Dermatol. 2010;146(5):529–33. 423–31. Carlsen K, Weismann K. Phytophotodermatitis in 19 chil- Rosenberg DA. Munchausen syndrome by proxy. In: dren admitted to hospital and their differential diagno- Reece RM, editor. Child abuse – medical diagnosis ses: child abuse and herpes simplex virus infection. and management. Philadelphia: Lea Febiger; 1994. J Am Acad Dermatol. 2007;57(5 suppl):S88–91. p. 266–78. Cyrulnik AA, Dawkins MC, Smalberger GJ, et al. Schreier HA, Libow JA. Munchausen by proxy syndrome: Kaposiform hemangioendothelioma with Kasabach- a modern pediatric challenge. J Pediatr. Merritt syndrome mistaken for child abuse in a new- 1994;125:S110–5. born. Cutis. 2014;93(3):E17–20. Schwartz KA, Metz J, Feldman K, Sidbury R, Lindberg Elder DE. Interpretation of anogenital fi ndings in the liv- DM, the ExSTRA Investigators. Cutaneous fi ndings ing child: implications for the paediatric forensic mistaken for physical abuse: present but not pervasive. autopsy. J Forensic Leg Med. 2007;14(8):482–8. Pediatr Dermatol. 2014;31(2):146–55. Fortin K, Jenny C. Sexual abuse. Pediatr Rev. Stankler L. Factitious skin lesions in a mother and two 2012;33(1):19–32. sons. Br Med J. 1977;97:217. Harth W, Taube KM, Gieler U. Factitious disorders in der- Stanziale SF, Christopher JC, Fisher RB. Brodifacoum matology [Article in English, German]. J Dtsch rodenticide ingestion in a patient with shigellosis. Dermatol Ges. 2010;8(5):361–72. South Med J. 1997;90(8):833–5. Harth W, Linse R. Dermatological symptoms and sexual Sugandhan S, Gupta S, Khandpur S, et al. ‘Munchausen abuse: a review and case reports. J Eur Acad Dermatol syndrome by proxy’ presenting as battered child syn- Venereol. 2000;14(6):489–94. drome: a report of two cases. Int J Dermatol. Hobbs CJ, Hanks HGI, Wynne JM. Physical abuse. In: 2010;49(6):679–83. Hobbs CJ, Hanks HGI, Wynne JM, editors. Child Swerdlin A, Berkowitz C, Craft N. Cutaneous signs of abuse and neglect – a clinician’s handbook. 2nd ed. child abuse. J Am Acad Dermatol. London/New York: Churchill Livingstone; 1999. 2007;57(3):371–92. p. 63–104. Vennemann B, Perdekamp MG, Weinmann W, et al. A Hobbs CJ. Physical evidence of child sexual abuse. Eur case of Munchausen syndrome by proxy with subse- J Pediatr. 2012;171(5):751–5. quent suicide of the mother. Forensic Sci Int. Hornor G. Common conditions that mimic fi ndings of 2006;158(2–3):195–9. sexual abuse. J Pediatr Health Care. Weston WL, Morelli JG. “Painful and disabling granu- 2009;23(5):283–8. loma annulare”: a case of Munchausen by proxy. Johnson CF. Dermatological manifestations. In: Levin Pediatr Dermatol. 1997;14(5):363–4. AV, Sheridan MS, editors. Munchausen syndrome by Wheeler DM, Hobbs CJ. Mistakes in diagnosing non- proxy – issues in diagnosis and treatment. New York: accidental injury, 10 years’ experience. Br Med Lexington Books; 1995. p. 189–200. J. 1988;296:1233–6. Kempe CH, Silverman FN, Steele BF, et al. The battered- WHO (World Health Organization). Preventing child mal- child syndrome. JAMA. 1962;181:17–24. treatment: a guide to taking action and generating evi- Kirschner RH, Stein RJ. The mistaken diagnosis of child dence. Geneva: World Health Organization and abuse. A form of medical abuse? Am J Dis Child. International Society for Prevention of Child Abuse 1985;139(9):873–5. and Neglect; 2006. Part VI Miscellaneous

Solar Protection Policy in School Children: Proposals for Progress 1 7

Yi Chun Lai , Edmund J. Janniger , and Robert A. Schwartz

Abstract Children are especially susceptible to the deleterious effects of UV radiation, making childhood a critical period for a solar protection policy and its implementation. Sun-protective behaviors established early in life are likely to persist into adulthood. Limiting exposure to both artiﬁ cial and natural UV radiation during childhood and adolescence lowers the risk for the development of skin cancer. A comprehensive approach to solar protection, including skill-based health education, supportive school environ- ments, extensive family and community involvement, mass-media coverage, and sun-safety legislation, is essential. This chapter provides recommendations for sun protection in school children, discusses current controversies regarding sunscreen use and vitamin D deﬁ ciency, and summarizes current knowledge on pathophysiology, risk factors, as well as prevention of skin cancer.

Keywords Sun protection policy • Skin cancer • Melanoma • Sunscreen • Vitamin D deﬁ ciency • Indoor tanning devices/sunbeds • Ultraviolet light

Y. C. Lai , MD, MPH Department of Dermatology , Rutgers New Jersey Medical School, 185 South Orange Avenue , Skin cancer is the most prevalent type of cancer, Newark , NJ 07103 , USA representing essentially 50 % of all cancers in the e-mail: [email protected] USA (Skin Cancer Facts 2013 ). The incidence of E. J. Janniger squamous and basal cell carcinoma is more than Rutgers University School of Public Affairs and 3.5 million cases each year, with melanoma Administration, 185 South Orange Avenue , Newark , NJ 07103 , USA accounting for more than 76,600 cases in 2013 (Skin Cancer Facts 2013 ). Exposure to both solar R. A. Schwartz , MD, MPH, DSc (Hon), FRCP Edin (*) Departments of Dermatology, Pediatrics, and and artiﬁ cial ultraviolet radiation from indoor Pathology , Rutgers New Jersey Medical School and tanning devices is the most signiﬁ cant prevent- Rutgers University School of Public Affairs and able risk factor for any kind of skin cancer Administration, 185 South Orange Avenue , Newark , (Greinert and Boniol 2011 ). Childhood is a NJ 07103 , USA e-mail: [email protected] susceptible life stage for both short-term and

Fig. 17.1 Child wearing hat and sunglasses in Crete in the intense summer sun at the Palace of Knossos (Courtesy of the author)

long-term effects of UV radiation for several rea- ideal primary prevention, such as modifying sons. First, it is estimated that approximately half natural and artifi cial exposure conditions and of the cumulative UV exposure to age 60 occurs encouraging sun protection, should be initiated before age 20, even though childhood and teen in school children in order to establish healthy years make up only one third of the time (McBride and consistent patterns throughout life (Fig 17.1 ) 2009 ). Second, compared to adults, children and (Glanz et al. 2002 ). adolescents have more opportunities to be exposed to sunlight, since they often spend more time outside (Buller and Borland 1999 ). Third, it Pathophysiology of Sun Exposure has been postulated that sunlight exposure during and Skin Cancer childhood and teenage years imposes more risk of developing melanoma than exposure during Ultraviolet radiation from sunlight is divided into adulthood. This is based on a theory that nevo- UVC (100–280 nm), UVB (280–315 nm), and genesis and peak melanocytic activity are present UVA (315–400 nm) (Quatrano and Dinulos 2013 ). early in life, increasing young melanocytes’ sus- Almost all of the UV radiation that reaches the ceptibility to UV carcinogenesis (Balk 2011 ). In Earth’s surface is UVA, with UVB wavelength addition, vellus hair follicles lie nearer to the sur- longer than 295 nm making up the remainder face of the skin than adult hair follicles, suggest- (Quatrano and Dinulos 2013 ). Although both UVA ing that equivalent amount of UV radiation may and UVB contribute to photocarcinogenesis and result in more DNA damage in juvenile skin photoaging, different mechanisms are involved (Garcia et al. 2011). Fourth, melanoma, the (Berneburg and Surber 2009 ). UVB radiation deadliest skin cancer, is the second most com- directly causes pre-mutagenic DNA lesions via the mon cancer among adolescent and young formation of cyclobutyl pyrimidine dimers (CPDs) adults from age 15 to 29, partly due to increased and 6–4 photoproducts (6–4 PP), whereas UVA usage of indoor tanning facilities (Herzog et al. induces highly reactive oxygen species (ROS), 2006 ). Studies have demonstrated that approxi- which indirectly leads to DNA damage in the form mately two to three million indoor tanners are of 8-oxoguanosine (8-oxoG) (Berneburg and adolescents, representing 24 % of all tanning Surber 2009 ). Recent research, however, shows device users (Zeller et al. 2006 ). Therefore, that UVA is also capable of inducing CPDs, sug- 17 Solar Protection Policy in School Children: Proposals for Progress 167 gesting that UVA-induced CPDs are the main Photoaging, mediating by the induction of player for pre-mutagenic DNA damages (Greinert matrix metalloproteinases (MMP) and degrada- and Boniol 2011 ). Repeated UV exposure can tion of collagen fi bers, is one of the long-term overwhelm the innate DNA repair mechanism, deleterious effects of primarily UVA radiation resulting in inactivation of the p53 gene, one of the (Berneburg and Surber 2009). Another long-term key tumor suppressor genes, or activation of the harm of sunlight exposure, possibly caused by oncogenes (Bukhari et al. 2009 ). UVA radiation, is the suppression of the immune system, which increases one’s susceptibility to developing skin cancer (Glanz et al. 2002 ). Short- and Long-Term Effects of UV Radiation on the Skin Risk Factors for Skin Cancer Besides its photocarcinogenicity, UV radiation has various short- and long-term effects on the Excessive UV Exposure in Childhood skin. Tanning is one of the short-term effects and Adolescence from sunlight exposure, mediating by formation UV radiation early in life is responsible for future of ROS and photooxidation of preexisting mela- development of both basal cell carcinoma and nin (Quatrano and Dinulos 2013 ). In response to melanoma (Glanz et al. 2002 ). Based on a model UVB, new melanin will form adaptively 3 days proposed by Stern et al., approximately 50 % of after exposure to provide mild UVB protection one’s cumulative sunlight exposure was received (Quatrano and Dinulos 2013 ). Sunburn is another by age 18–20 (Stern et al. 1986 ). Furthermore, immediate effect appearing 4–6 h after excessive although less than 0.5 % of melanomas take place UV exposure, mainly from the UVB component before age 10, the incidence of melanoma dra- (Quatrano and Dinulos 2013 ). It is characterized matically rises after puberty, such that 85 % of by intense erythema, burning sensation, and the cases diagnosed in patients under age 20 occasionally pain (Quatrano and Dinulos 2013 ). occur in those between age 15 and 19 (Baade Severe blistering sunburn from intermittent et al. 2011 ). Childhood is implicated as an impor- intensive UV exposure during childhood and tant time period for the development of melano- adolescence is a well-recognized risk factor for cytic nevi, a signifi cant risk factor for melanoma both basal cell carcinoma and malignant mela- (Glanz et al. 2002 ). Having numerous and noma (Dennis et al. 2008 ). Epidemiological data unusual types of nevi are also considered as sig- demonstrate a threefold increase in melanoma nifi cant measurable predictors for melanoma risk with a history of fi ve episodes of sunburn (Glanz et al. 2002 ). In addition, nevus prevalence within a decade (Dennis et al. 2008 ). It is impor- in children is directly correlated with the amount tant, however, to realize that skin cells already of ambient UV radiation they are exposed to sustained DNA damage if there is tanning, even early in life (English et al. 2006 ). One prospec- in the absence of sunburns (Schulman and Fisher tive study indicates that a history of sunburns and 2009 ). Cui et al. indicate that p53 plays a pivotal spending 5–6 h weekly outdoors between 10 a.m. role in tanning process by recognizing DNA and 4 p.m. are associated with increased total damage and stimulating the production of pro- nevus count (Oliveria et al. 2009 ). Limiting the opiomelanocortin, which subsequently results in amount of sunlight exposure in youngsters, the release of melanocyte-stimulating hormone undoubtedly, can dramatically reduce their and the production of melanin (Cui et al. 2007 ). chances of developing skin cancer in the future. This suggests that DNA damage and p53 are central to the process of tanning and photocar- Host Determinants of Skin Cancer cinogenesis. Tanning and sunburns, thus, are Skin color and ethnicity are two variables that immediate manifestations of skin cells to pre- determine one’s predisposition to develop skin can- mutagenic DNA lesions. cer. People with certain characteristics are more at 168 Y.C. Lai et al. risk, including those with blue eyes, red/blond hair, sunlight and subject a user to 1.2 times the aver- and fair skins that readily sunburn yet tan poorly age amount of yearly sunlight exposure after only (Glanz et al. 2002 ). In the National Cancer Database 20 sessions (Gerber et al. 2002 ). These fi ndings of the USA, 90–95 % of all melanoma cases from pose a particular concern for children and adoles- age 15–19 are represented by non-Hispanic white cents, since between two and three million users children (Lange et al. 2007 ). However, it should be of tanning beds are adolescents, and 24 % of all emphasized that although dark-skinned individuals users are between age 13 and 19 (Zeller et al. are less prone to develop skin cancer, the risk 2006). Given the association of indoor tanning increases nonetheless if they are exposed to UV with skin cancer as well as the marketing of tan- radiation excessively (Pennello et al. 2000 ). ning beds to teenagers, laws protecting those minors may be of value (Grewal et al. 2013 ). Indoor Tanning Devices as a Source of Artifi cial UV Radiation UV tanning devices have been categorized as car- Current Guidelines on Sun- cinogenic to human beings by the World Health Protective Behaviors Organization in 2009 (El Ghissassi et al. 2009 ). The International Agency for Research on Cancer The Centers for Disease Control and Prevention has shown that UV exposure from sunbeds (CDC) has recommended several primary preven- increased the risk of melanoma by 75 % if usage tative measures for skin cancer, including “mini- occurred before age 35 (Green 2007 ). Young mizing exposure to the sun between 10 a.m. and women, in particular, are signifi cantly more likely 4 p.m.; seeking shade from the midday sun, espe- than men of the same age to use tanning beds, cially during the 1-h period before and after noon subjecting them at a higher risk for the develop- hour; wearing sun-protective clothing; using ment of melanoma (Demko et al. 2003 ). For broad-spectrum sunscreen with a sun protection example, a study conducted in England discov- factor (SPF) of ≥15; and prohibiting the use of ered that tanning bed use is responsible for 25 % indoor tanning devices” (Glanz et al. 2002 ). of melanoma in young women (Diffey 2007 ). In Certain characteristics of clothing provide greater addition to melanoma, indoor tanning devices shielding effects, such as tighter weave, natural also play a central role in the development of non- cotton, darker colors, and less stretched and dry melanoma skin cancer. A study suggests that the fabric; children who plan to participate in outdoor risk of developing squamous and basal cell carci- activities should be encouraged to wear these noma are 2.5 and 1.5 times more likely, respec- types of clothing (Glanz et al. 2002 ). Legionnaire tively, in tanning bed users than nonusers (Karagas hats, wide-brimmed hats, or sunglasses should et al. 2002 ). Furthermore, both an increase in also be worn by children to protect the head, eyes, melanocytic count and a change in existing nevi ears, nose, and face (Fig. 17.2 ) (Diffey 1992 ). are associated with tanning bed use, providing more evidence that using sunbeds early in life leads to an increased risk of melanoma in the Sunscreens future (Aalborg et al. 2009 ). To further compound the risk, indoor tanning devices are equipped with Current Recommendations UV radiation levels that exceed those found in Regarding Sunscreen Use nature (Miller et al. 1998 ). Artifi cial UV radia- The CDC guidelines recommend practicing sun- tion, compared to its environmental counterpart, protective behaviors as the fi rst-line measure to also comprises a different UVA to UVB ratio, reduce exposure to the full spectrum of UV radia- with 95–99 % of the tanning light as UVA and tion while using sunscreens as an adjunct (Glanz 1–5 % as UVB (Miller et al. 1998 ). A study sug- et al. 2002 ). American Academy of Dermatology gests that UVA rays from tanning beds may be up (AAD) has provided recommendations for proper to 15 times more intense than those from noon use of sunscreens. 17 Solar Protection Policy in School Children: Proposals for Progress 169

Fig. 17.2 Young child with wide-brimmed hat in sunny Venice, Italy (Courtesy of the author)

Everyone, including people of all skin colors, Sunscreen and Infants should use broad-spectrum, water-resistant sun- Since infants and toddlers are at even greater screen with a minimum SPF of 30, by applying gen- risks for UV damage, American Academy of erously and uniformly on all exposed areas of the Pediatrics (AAP) has developed guidelines for body not covered by clothing. One should use at sunscreen use as well as means to reduce UV least 1 ounce of sunscreen and pay particular atten- exposure in infants (Quatrano and Dinulos 2013 ). tion to vulnerable sites, such as the nose, shoulders, Infants <6 months old should be kept out of direct and dorsal feet. One should apply sunscreen every sunlight whenever possible; infants ≥6 months old day at least 15 min before going outdoors and reap- should protect skin with clothing or shade whenever ply every 2 h, especially after swimming or heavy possible and use a broad- spectrum, water-resistant perspiration (Sunscreen FAQs 2013 ). sunscreen with a minimum SPF of 30 to cover Despite these explicit recommendations, exposed skin (Quatrano and Dinulos 2013 ). most individuals fail to apply sunscreens on a Reasons for increased susceptibility among regular basis, but use sunscreen only during infants include thinner an skin with less concen- outdoor activities or even to extend the period trated melanin and immature immune system of sunlight exposure to acquire tanning (Paller et al. 2011 ). (Quatrano and Dinulos 2013). A study demonstrates that sunscreen use, in fact, prolongs the duration of UV exposure by 13–39 %, increas- Controversies Surrounding ing the risk of skin cancer and photoaging Sunscreen (Autier et al. 2007 ). Sunscreens, therefore, offer inadequate UV protection alone and Sunscreen and Melanoma should be considered only as a complementary measure alongside wearing sun- protective Although sunscreen use is well established as an clothing and seeking shade. effective means to reduce both actinic keratoses 170 Y.C. Lai et al.

(precursors to SCC) and SCC itself, its role in tice in children should include providing lowering the incidence of basal cell carcinoma sunglasses, shade, wearing protective clothing or and melanoma is less defi nitive (Glanz et al. wide-brimmed hat, and, only on the uncovered 2002). Paradoxically, several observational stud- areas, the use of broad-spectrum sunscreen. The ies suggest that sunscreen use is associated with increasingly widespread use of sunscreens among increased risk of cutaneous melanoma the pediatric population has generated concern, (Huncharek and Kupelnick 2002). Since there is as children have a higher body surface area–vol- no observable dose relationship between devel- ume ratio and unique immature skin that may opment of cutaneous melanoma and sunscreen absorb a greater fraction of topically applied sub- use, it is hypothesized that inadequate or incon- stances. Because of the controversy on systemic sistent use of sunscreen by the general population absorption of UV fi lters, especially benzophe- is partly responsible for this risk (Azfar et al. nones, one should recommend the use of sun- 2004 ). On the other hand, a more recent publica- screens with only inorganic UV fi lters in children tion from Australia indicates that proper sun- <2 years old (Jansen et al. 2013 ). screen application on chronically exposed areas during non- intentional sun exposure can decrease the risk of melanoma (Green et al. 2011 ). Sunscreen Use and Vitamin D Defi ciency

Toxicity and Potential Systemic In addition to its role in the skeletal system and Effects in Children calcium homeostasis, vitamin D is benefi cial in reducing cancer severity, enhancing cardiovascu- Skin irritation, sensitization, phototoxicity, and lar function, and downregulating autoimmune carcinogenicity have been proposed as possible activities (Kannan and Lim 2014 ). Since the adverse reactions associated with sunscreen prod- endogenous source of vitamin D mainly derives ucts (Nohynek et al. 2010 ). Through vigorous risk from cutaneous synthesis upon exposure to UVB assessment, sunscreen products have been veri- radiation specifi cally at a wavelength of fi ed to produce little to no systemic effects, since 300 ± 5 nm, controversies have centered on the inorganic fi lters, such as titanium dioxide, do not possibility of sunscreen use resulting in vitamin penetrate the skin, and organic fi lters only pene- D defi ciency (Kannan and Lim 2014 ). trate the skin in minimal amounts (Sadrieh et al. Various studies from controlled settings dem- 2010 ; Gonzalez 2010 ). Newborn and infants are onstrate the ability of sunscreen to block vitamin special populations that are more prone to experi- D production. One of the common components in ence percutaneous drug toxicity, perhaps due to a sunscreen products, para-aminobenzoic acid higher surface area-to-weight ratio, an immature (PABA), interferes with vitamin D synthesis, metabolic system, as well as an underdeveloped both in vivo and in vitro (Matsuoka et al. 1987 ). epidermal barrier in the case of premature infants In fact, whole-body application of sunscreen pre- (Berneburg and Surber 2009 ). Currently, no study vents cutaneous synthesis of vitamin D entirely has been conducted on absorption of organic/inor- (Matsuoka et al. 1990 ). A randomized controlled ganic fi lters in children. However, the systemic trial indicates that the production of vitamin D is effects of sunscreen on newborns or infants can be inversely correlated with the thickness of sun- regarded as negligible because continual large- screen layer applied (Faurschou et al. 2012 ). area application of sunscreen is rather unlikely When thinner-than-recommended (<2 mg/cm2 ) (Berneburg and Surber 2009 ). sunscreen layers are used, vitamin D synthesis UVR exposure in children should be reduced increases exponentially with decreasing thick- or prevented as a fi rst-line strategy against solar ness (Faurschou et al. 2012 ). In contrast, larger- UVR damage, with sunscreen used as a comple- scale studies that better refl ect sunscreen use in mentary measure. Suitable photoprotective prac- real life fail to demonstrate a similar relationship 17 Solar Protection Policy in School Children: Proposals for Progress 171

(Burnett and Wang 2011 ). Moreover, a positive suffi cient evidence to support its effectiveness in correlation between serum level of 25(OH) D and improving covering-up behavior (e.g., wearing sunscreen use has been documented, possibly hats, long-sleeved clothing, or pants), increasing secondary to intentionally prolonged UV expo- sunscreen use, as well as enhancing knowledge sure after sunscreen application (Burnett and and attitudes regarding skin cancer prevention Wang 2011 ). (Saraiya et al. 2004 ). A recent study evaluating Theoretically, when an adequate amount of at the effectiveness of three Comprehensive Cancer least 2 mg/cm2 is applied on all sun-exposed Control (CCC) programs that implement sun pro- areas, sunscreen is capable of causing vitamin D tection policy in children from kindergarten to defi ciency (Kannan and Lim 2014 ). In real life, eighth grade reveals that innovative approaches however, average users often fail to apply sun- are needed to overcome various barriers, such as screen frequently and correctly such that its long- changes in staff workloads or troubles in reach- term use exert little to no effect on vitamin D ing school principals (Townsend et al. 2011 ). level (Burnett and Wang 2011 ). Despite the rela- These innovative strategies include using mini tionship between vitamin D defi ciency and regu- grants or school assemblies to improve recruit- lar sunscreen use, dietary supplementation with ment, having community partners to facilitate vitamin D can often help to achieve the daily policy implementation, and reaching out to edu- requirement (Burnett and Wang 2011 ). cators in various settings (Townsend et al. 2011 ). Arizona’s SunWise program, one of the CCC programs in the study, is most successful in terms Solar Protection Policy of its ability to reach nearly all school children, in the Primary and Secondary primarily due to a legislation that mandates sun- Schools of the USA safety education in Arizona (Townsend et al. 2011). Ideally, school-based sun protection pol- CDC has published the following guidelines for icy should be an integral component of a more skin cancer prevention in schools in 2002 (Glanz comprehensive approach to promote skin cancer et al. 2002 ): prevention. This includes, but not limited to, passing legislation that mandates nationwide sun 1. Establish policies that reduce exposure to protection education, banning sunbed use in chil- ultraviolet radiation dren, encouraging healthcare providers to assume 2. Develop an environment that supports sun- a more active role in primary/secondary preven- safety practices tion, and educating caregivers to foster sun- 3. Provide health education to teach students the protective behaviors in children (Townsend et al. knowledge, attitudes, and behavioral skills 2011). This approach is best exemplifi ed by they need to prevent skin cancers Australia, which has launched a nationwide cam- 4. Involve family members in skin cancer pre- paign to combat skin cancer. The Australian vention efforts SunSmart program advertises wearing skin- 5. Include skin cancer prevention with profes- protective clothing, hats/caps, and shoes, as well sional development of staff as applying sunscreen regularly both inside and 6. Complement and support skin cancer preven- outside schools (Berneburg and Surber 2009 ). tion with school health services Furthermore, the SunSmart program improves 7. Periodically evaluate whether schools are awareness and sun-protective behaviors by con- implementing the guidelines on policies, envi- veying important messages via leafl ets for teach- ronmental change, education, families, pro- ers, posters, radio, and television (Berneburg and fessional development, and health services Surber 2009 ). While primary school is the main target for Systemic review on the effectiveness of sun implementation of sun protection policy, few sec- protection policy in primary school has provided ondary schools have these policies in place. In a 172 Y.C. Lai et al. survey published in 2006, only 10 % of the schools based activities to raise skin cancer awareness. reported having sun protection policies, such as Schools can establish partnerships with com- not scheduling outdoor activities during hours of munity members to promulgate sun-protective peak sunlight exposure, requiring children to wear interventions. long-sleeved shirt, wide-brimmed hats, and sun- 4. Mass-media campaigns (Hufford and glasses, or requiring them to use sunscreens Rehfuess 2003 ). (Buller et al. 2006). Although many secondary Mass media, such as television, radio, or schools are receptive toward developing a sun pro- newspaper, should be utilized widely to publi- tection policy, various barriers must be addressed cize sun protection policy beyond school. before this is plausible. One such barrier is the Internet and social networking websites can existing policies that prohibit the use of hats and also serve as a cost-effective means to spread sunglasses. Another is the diffi culty for most skin cancer prevention message among ado- schools to adjust schedules in order to avoid peak lescents and young adults. sunlight exposure (Buller et al. 2006 ). Furthermore, 5. Legislation and regulation. sun-safety behaviors in preadolescents and adoles- Lawmakers should be encouraged to enact cents might be the most diffi cult to modify, since legislation regarding sun protection educa- many believe that a tan is desirable (Marks 1988 ; tion, primary prevention and screening for Banks et al. 1992 ). Teenagers’ faux perception that skin cancer, as well as tanning bed use. tanned skin is favorable needs to be reversed fi rst 6. Recognition that sunscreens should be aes- in order to implement successful sun protection thetically pleasing and provide uniform pro- campaigns, since teens’ attitude to solar protection tection against both ultraviolet A and is signifi cantly affected by the group behavior ultraviolet B light (Jansen et al. 2013 ). (Berneburg and Surber 2009 ). 7. Comprehension that broad-spectrum sunscreens are adjunctive to other photoprotective measures. Essential Components of Sun 8. For children under 2 years of age, sunscreens Protection Policy containing inorganic UV fi lters may be used on exposed areas (Jansen et al. 2013 ) . 1. Skill-based health-promoting education (Hufford and Rehfuess 2003 ). Table 17.1 provides a list of successful school- Curriculum should aim at developing not based sun-protective activities, adopted from a only sun protection knowledge, but also pre- compilation prepared by California Department ventive health habits or skills. Sun protection of Public Health (Manthe 2008 ). education should be incorporated into various types of curriculum, such as science, history, Conclusion art, or physical education, to reinforce sun- Childhood represents a susceptible time period protective behaviors. for detrimental effects of ultraviolet radiation, 2. School environment supportive of sun protec- making this a critical period for initiating sun tion (Hufford and Rehfuess 2003 ). protection policy. Moreover, adolescents often Schools should provide either built or natu- perceive a tan as desirable, receive large pro- ral shade structures and implement sensible portion of total lifetime exposure, are less mal- sun protection policy. School staff should leable than children to adopt health-promoting adopt sun-protective measures themselves and behaviors, and are least likely of all age groups act as role models for school children. to practice skin protection. Thus, sun protec- 3. Family and community involvement (Hufford tion should start as early as feasible (Heckman and Rehfuess 2003 ). and Coups 2011 ). Parents should be encouraged to adopt sun- A recent study on sun protection training protective behaviors and participate in school- suggests that cognitive–behavioral intervention, 17 Solar Protection Policy in School Children: Proposals for Progress 173

Table 17.1 Skin cancer prevention activities in school Identify skin cancer survivors in the community to share stories with students and school staffs Invite healthcare professionals, such as dermatologist or pediatrician, to “adopt a school” and provide didactic presentation on skin cancer prevention Integrate skin cancer prevention educational materials into lesson plans of various curriculums: discuss stratospheric ozone loss and its link to skin cancer in science class, explore changing attitudes and societal values regarding tanning in history or social science class, etc. Include sun-safety information in school handbook as well as local/school newspaper and distribute it to students/ teachers/parents Survey students/parents on their sun-protective behaviors Recruit students to distribute skin cancer prevention posters, brochures, and ﬂ yers in school/community Student-run ecology club can locate trees/plants in the surroundings and place them strategically on campus to provide natural shade Parent–Teacher Association can purchase wide- brimmed hats, sunscreens, and sunglasses for all students Conduct sun protection relay races, “silly hat” contests, and skin cancer prevention poster contests to encourage participation in sun-safety behaviors Help students design a sun-safety mascot, song, video, website, or public service announcements at local radio stations to convey sun protection messages beyond school Prepare a sun-safety resolution and present it for adoption by the PTA or board of education Organize fund-raising events to support sun-protective measures: apply a grant from a local dermatology chapter, partnership with local business to provide discount on group purchase of sun-safety supplies, run a sun protection walkathon or jump-rope-a-thon or hold a bake sale Adapted from Manthe (2008 ); with permission

such as using theater play and role modeling, well as developing a nationally coordinated sun is more effective for enhancing sun-protective protection program for all school children, behaviors in school children than didactic will be invaluable in future prevention of skin method alone (Seidel et al. 2013 ). Complementing cancer. the established educational program with inter- active theater plays seems to be a promising way for primary prevention of skin cancer (Seidel et al. 2013 ). Bulleted List of Controversies

Unlike Australia, there is no offi cial nation- • Sunscreen use is paradoxically associated ally coordinated solar protection policy in the with an increased incidence of melanoma, primary and secondary schools of the USA partly due to inconsistent or inadequate use. currently, making multifaceted skin cancer • Sunscreen products have been proposed to cause education campaign less practical. In addition various adverse reactions, especially in newborn to school-based intervention, Australia’s and infants. Sun protection in this population, SunSmart utilizes a multicomponent public thus, should include providing protective cloth- health approach by distributing sun protection ing, wide-brimmed hat, and sunglasses and resources via multimedia coverage and insti- using sunscreen only on the uncovered body tuting environmental changes at recreational parts. In children under 2 years of age, sunscreen settings, workplaces, and local government with only inorganic UV fi lter should be used. (Eagle et al. 2010 ). Creative approaches, such • Sunscreen use is thought to be associated as incorporating cognitive–behavioral interven- with vitamin D defi ciency due to its ability to tion into current policy, offering mini grants block UVB radiation. Though sunscreen has and school assemblies, encouraging partner- been shown to interfere with vitamin D syn- ship with healthcare professionals, appointing thesis in controlled settings, its regular use in dedicated program advocates within schools, as real life does not correlate with lower vitamin 174 Y.C. Lai et al.

D levels. This can be a result of inadequate Demko CA, Borawski EA, Debanne SM, Cooper KD, and inappropriate sunscreen application by Stange KC. Use of indoor tanning facilities by white adolescents in the United States. Arch Pediatr Adolesc average users. One should not stop using sun- Med. 2003;157:854–60. screen to avoid vitamin D defi ciency. Instead, Dennis LK, Vanbeek MJ, Beane Freeman LE, Smith BJ, one should be encouraged to apply sunscreen Dawson DV, Coughlin JA. Sunburns and risk of cuta- regularly and achieve adequate vitamin D lev- neous melanoma: does age matter? A comprehensive meta-analysis. Ann Epidemiol. 2008;18(8):614–27. els via dietary supplementation. doi: 10.1016/j.annepidem.2008.04.006 . Diffey B. Sunbeds, beauty and melanoma. Br J Dermatol. 2007;157(2):215–6. doi: 10.1111/j.1365-2133.2007. 07960.x . References Diffey BL, Cheeseman J. Sun protection with hats. Br J Dermatol. 1992;127(1):10–2. Aalborg J, Morelli JG, Mokrohisky ST, Asdigian NL, Byers Eagle UL, Jones SJ, Hiom S, Kemp G, Naumann L, Cerny TE, Dellavalle RP, Box NF, Crane LA. Tanning and C. National skin cancer campaigns. 2010. Available increased nevus development in very-light- skinned chil- via: http://www.nice.org.uk/nicemedia/live/13310/ dren without red hair. Arch Dermatol. 2009;145(9):989– 52652/52652.pdf . Accessed 30 Dec 2013. 96. doi: 10.1001/archdermatol.2009.193 . El Ghissassi F, Baan R, Straif K, Grosse Y, Secretan B, Autier P, Boniol M, Dore JF. Sunscreen use and increased Bouvard V, et al. A review of human carcinogens part duration of intentional sun exposure: still a burning D: radiation. Lancet Oncol. 2009;10:751–2. issue. Int J Cancer. 2007;121(1):1–5. doi: 10.1002/ English DR, Milne E, Simpson JA. Ultraviolet radiation at ijc.22745 . places of residence and the development of melanocytic Azfar RS, Schwartz RA, Berwick M. Primary melanoma nevi in children (Australia). Cancer Cause Control. prevention in children. G Ital Dermatol Venereol. 2006;17(1):103–7. doi: 10.1007/s10552-005-0425-0 . 2004;39:1–6. Faurschou A, Beyer DM, Schmedes A, Bogh MK, Baade PD, Green AC, Smithers BM, Aitken JF. Trends in Philipsen PA, Wulf HC. The relation between sun- melanoma incidence among children: possible infl u- screen layer thickness and vitamin D production after ence of sun-protection programs. Expert Rev Anticancer ultraviolet B exposure: a randomized clinical trial. Br Ther. 2011;11(5):661–4. doi: 10.1586/era.11.28 . J Dermatol. 2012;167:391–5. Balk SJ, Council on Environmental Health; Section on Garcia AM, McLaren CE, Meyskens FL, Melanoma J. Is Dermatology. Ultraviolet radiation: a hazard to chil- hair the root of the problem? Pigment Cell Melanoma dren and adolescents. Pediatrics. 2011;127(3):e791– Res. 2011;24(1):110–8. doi: 10.1111/j.1755- 817. doi: 10.1542/peds.2010-3502 . 148X.2010.00782.x . Banks BA, Silverman RA, Schwartz RH, Tunnessen Jr Gerber B, Mathys P, Moser M, Bressoud D, Braun- WW. Attitudes of teenagers toward sun exposure and Fahrlander C. Ultraviolet emission spectra of sunbeds. sunscreen use. Pediatrics. 1992;89(1):40–2. Photochem Photobiol. 2002;76(6):664–8. Berneburg M, Surber C. Children and sun protection. Br Glanz K, Saraiya M, Wechsler H, Centers for Disease J Dermatol. 2009;161 Suppl 3:33–9. C. Prevention guidelines for school programs to pre- doi: 10.1111/j.1365-2133.2009.09447.x . vent skin cancer. MMWR Recomm Rep. Bukhari MH, Niazi S, Khaleel ME, Sharif MA, Ghani R, 2002;51(RR-4):1–18. Mehmood MT, Tahseen M, Chaudhry NA, Hasan Green AC. The association of use of sunbeds with cutane- M. Elevated frequency of p53 genetic mutations and ous malignant melanoma and other skin cancers: a AgNOR values in squamous cell carcinoma. J Cutan systematic review. Int J Cancer. 2007;120:1116–22. Pathol. 2009;36(2):220–8. doi: 10.1111/ Green AC, Williams GM, Logan V, Strutton GM. Reduced j.1600-0560.2008.01006.x . melanoma after regular sunscreen use: randomized Buller DB, Borland R. Skin cancer prevention for children: trial follow-up. J Clin Oncol. 2011;29(3):257–63. a critical review. Health Educ Behav. 1999;26:317–43. doi: 10.1200/JCO.2010.28.7078 . Buller DB, Buller MK, Reynolds KD. A survey of sun Greinert R, Boniol M. Skin cancer – primary and second- protection policy and education in secondary schools. ary prevention (information campaigns and screen- J Am Acad Dermatol. 2006;54(3):427–32. ing) – with a focus on children & sunbeds. Prog doi: 10.1016/j.jaad.2005.11.1030 . Biophys Mol Biol. 2011;107(3):473–6. doi: 10.1016/j. Burnett ME, Wang SQ. Current sunscreen controversies: a pbiomolbio.2011.08.008 . critical review. Photodermatol Photoimmunol Photomed. Grewal SK, et al. Compliance by California tanning facili- 2011;27:58–67. doi:10.1111/j.1600-0781.2011.00557.x . ties with the nation’s fi rst statewide ban on use before Cui R, Widlund HR, Feige E, Lin JY, Wilensky DL, Igras the age of 18 years. J Am Acad Dermatol. VE, D’Orazio J, Fung CY, Schanbacher CF, Granter 2013;69(6):883–9. SR, Fisher DE. Central role of p53 in the suntan Gonzalez H. Percutaneous absorption with emphasis on response and pathologic hyperpigmentation. Cell. sunscreens. Photochem Photobiol Sci. 2010;9(4):482– 2007;128(5):853–64. doi: 10.1016/j.cell.2006.12.045 . 8. doi: 10.1039/b9pp00149b . 17 Solar Protection Policy in School Children: Proposals for Progress 175

Heckman CJ, Coups EJ. Correlates of sunscreen use baseline fi ndings and predictors of nevus count. Am among high school students: a cross-sectional survey. J Epidemiol. 2009;169(1):41–53. doi: 10.1093/aje/ BMC Public Health. 2011;11:679. doi: 10.1186/ kwn289 . 1471-2458-11-679 . Paller AS, Hawk JL, Honig P, Giam YC, Hoath S, Mack Herzog C, Pappo A, Bondy M, Bleyer A, Kirkwood MC, Stamatas GN. New insights about infant and tod- J. Malignant melanoma. In: Bleyer A, O’Leary M, dler skin: implications for sun protection. Pediatrics. Barr R, Ries LAG (editors). Cancer epidemiology in 2011;128(1):92–102. doi: 10.1542/peds.2010-1079 . older adolescents and young adults 15–29 years of Pennello G, Devesa S, Gail M. Association of surface age, including SEER incidence and survival 1975– ultraviolet B radiation levels with melanoma and non- 2000. National Cancer Institute, NIH publication No. melanoma skin cancer in United States blacks. Cancer 06–5767. Bethesda; 2006. p. 53–63. Epidemiol Biomarkers Prev. 2000;9(3):291–7. Hufford D, Rehfuess E. Sun protection and schools: how Quatrano NA, Dinulos JG. Current principles of sunscreen to make a difference. Geneva: World Health use in children. Curr Opin Pediatr. 2013;25(1):122–9. Organization; 2003. doi: 10.1097/MOP.0b013e32835c2b57 . Huncharek M, Kupelnick B. Use of topical sunscreens Sadrieh N, Wokovich AM, Gopee NV, Zheng J, Haines D, and the risk of malignant melanoma: a meta-analysis Parmiter D, Siitonen PH, Cozart CR, Patri AK, of 9067 patients from 11 case–control studies. Am McNeil SE, Howard PC, Doub WH, Buhse LF. Lack J Public Health. 2002;92(7):1173–7. of signifi cant dermal penetration of titanium dioxide Jansen R, et al. Photoprotection: part II. Sunscreen: devel- from sunscreen formulations containing nano- and opment, effi cacy, and controversies. J Am Acad submicron-size TiO2 particles. Toxicol Sci. Dermatol. 2013;69(6):867–e1. 2010;115(1):156–66. doi: 10.1093/toxsci/kfq041 . Kannan S, Lim HW. Photoprotection and vitamin D: a Saraiya M, Glanz K, Briss PA, Nichols P, White C, Das D, review. Photodermatol Photoimmunol Photomed. Smith SJ, Tannor B, Hutchinson AB, Wilson KM, 2014;30:137–45. doi: 10.1111/phpp.12096 . Gandhi N, Lee NC, Rimer B, Coates RC, Kerner JF, Karagas MR, Stannard VA, Mott LA, Slattery MJ, Hiatt RA, Buffl er P, Rochester P. Interventions to pre- Spencer SK, Weinstock MA. Use of tanning devices vent skin cancer by reducing exposure to ultraviolet and risk of basal cell and squamous cell skin cancers. radiation: a systematic review. Am J Prev Med. J Natl Cancer Inst. 2002;94(3):224–6. 2004;27(5):422–66. doi: 10.1016/j.amepre.2004.08.009 . Lange JR, Palis BE, Chang DC, Soong SJ, Balch Schulman JM, Fisher DE. Indoor ultraviolet tanning and CM. Melanoma in children and teenagers: an analysis of skin cancer: health risks and opportunities. Curr Opin patients from the National Cancer Data Base. J Clin Oncol. Oncol. 2009;21(2):144–9. doi: 10.1097/ 2007;25(11):1363–8. doi: 10.1200/JCO.2006.08.8310 . CCO.0b013e3283252fc5 . Manthe A. Successful school-based skin cancer prevention Seidel N, Stoelzel F, Garzarolli M, Herrmann S, Breitbart activities. ASHA successful school sun safety imple- EW, Berth H, Baumann M, Ehninger G. Sun protec- mentation. California Department of Public Health. tion training based on a theater play for preschoolers: 2008. Available via: http://www.cdph.ca.gov/programs/ an effective method for imparting knowledge on sun SkinCancer/Documents/SKIN-ASHASuccessfulSchoo protection? J Cancer Educ. 2013;28(3):435–8. lSunSafetyImpl.pdf . Accessed10 Jan 2014. doi: 10.1007/s13187-013-0483-z . Marks R. Role of childhood in the development of skin Skin Cancer Facts American Cancer Society. http://www. cancer. Aust Paediatr J. 1988;24(6):337–8. cancer.org/Cancer/CancerCauses/ Matsuoka LY, Ide L, Wortsman J, Maclaughlin JA, Holick SunandUVExposure/skin-cancer-facts?sitearear_ MF. Sunscreens suppress cutaneous vitamin D3 syn- PED2008 . Accessed 28 Dec 2013. thesis. J Clin Endocrinol Metab. 1987;64:1165–8. Stern RS, Weinstein MC, Baker SG. Risk reduction for Matsuoka LY, Wortsman J, Hollis BW. Use of topical sun- nonmelanoma skin cancer with childhood sunscreen screen for the evaluation of regional synthesis of vita- use. Arch Dermatol. 1986;122(5):537–45. min D3. J Am Acad Dermatol. 1990;22:772–5. Sunscreen FAQs. American Academy of Dermatology. McBride P. Cutaneous squamous cell carcinoma and its http://www.aad.org/media-resources/stats-and-facts/ determinants. Dissertation, University of Queensland; prevention-and-care/sunscreens. Accessed 30 Dec 2009. 2013. Miller SA, Hamilton SL, Wester UG, Cyr WH. An analy- Townsend JS, Pinkerton B, McKenna SA, Higgins SM, sis of UVA emissions from sunlamps and the potential Tai E, Steele CB, Derrick SR, Brown C. Targeting importance for melanoma. Photochem Photobiol. children through school-based education and policy 1998;68(1):63–70. strategies: comprehensive cancer control activities in Nohynek GJ, Antignac E, Re T, Toutain H. Safety assess- melanoma prevention. J Am Acad Dermatol. ment of personal care products/cosmetics and their 2011;65(5 Suppl 1):S104–13. doi: 10.1016/j. ingredients. Toxicol Appl Pharmacol. jaad.2011.05.036 . 2010;243(2):239–59. doi: 10.1016/j.taap.2009.12.001 . Zeller S, Lazovich D, Forster J, Widome R. Do adolescent Oliveria SA, Satagopan JM, Geller AC, Dusza SW, indoor tanners exhibit dependency? J Am Acad Weinstock MA, Berwick M, Bishop M, Heneghan Dermatol. 2006;54(4):589–96. doi: 10.1016/j. MK, Halpern AC. Study of Nevi in Children (SONIC): jaad.2005.12.038 . Adolescent Tanning Practices: Understanding the Popularity 1 8 of Excessive Ultraviolet Light Exposure

Thomas J. Jasterzbski , Edmund J. Janniger , and Robert A. Schwartz

Abstract The sun and other sources of ultraviolet (UV) radiation, such as tanning beds, are major contributors to the development of premature cutaneous aging and skin cancer. The popularity of tanning salons and the limited use of sun protection have caused a dramatic increase in skin cancer, especially among adolescents. Basal cell carcinoma (BCC), squamous cell carcinoma (SCC), and melanoma have all been linked to UV exposure. SCC is correlated with total lifetime UV damage and prolonged occupational exposure, whereas BCC and melanoma are associated with intermittent and recreational exposure. Although the carcinogenic properties of UVA and UVB are not proportional, both forms of UV radiation have proven to be carcinogenic. The indoor tanning industry has become a multibillion- dollar- a-year business and is widely popular among adolescents, especially teenage females. Because the effects of UV exposure are cumulative and adolescents are particularly vulnerable to UV damage, the widespread use of indoor tanning facilities by adolescents is a major public health problem. This trend is complex and inﬂ uenced by multiple variables; however, the majority of teens tan to gain an “attractive” appearance. Although many policies have been enacted to regulate indoor tanning, stricter legislation and policy enforcement are needed. Natural tanning has also had a signiﬁ cant impact on the rising prevalence of skin cancer. Research has

T. J. Jasterzbski , MD R. A. Schwartz , MD, MPH, DSc (Hon), FRCP Edin (*) Department of Dermatology , Departments of Dermatology , Pediatrics and Rutgers New Jersey Medical School , Pathology, and Rutgers New Jersey Medical School , Newark , NJ , USA Newark , NJ , USA e-mail: [email protected] Department of Dermatology , Rutgers University E. J. Janniger School of Public Affairs and Administration , Rutgers University School of Public Affairs and Newark , NJ , USA Administration, Newark , NJ , USA e-mail: [email protected]

shown that suntanning without appropriate protection, such as sunscreen, is also common among adolescents. Some studies even indicate that the actual process of tanning can be addictive. Because tanning practices are strongly associated with the rising incidence of skin cancer, limiting adolescent tanning behavior should be a major public health focus. A comprehensive approach, including stricter tanning salon legislation, parental guidance, patient education, and educational campaigns at the primary and secondary school level might be effective.

Keywords Tanning practices in adolescents • Skin cancer • Tanning bed use in youth • Ultraviolet radiation • Indoor tanning legislation

Every year, herds of people fl ock to beaches, increasing, with melanoma being the second and lakes, and pools to enjoy the fresh air and to soak third most common cancer in women and men in up the warm rays of the sun (Fig 18.1 ). The pro- their twenties, respectively (Balk et al. 2013 ; cess is simple, relaxing, and natural; wear mini- Lostritto et al. 2012 ; Prior et al. 2014 ). Studies mal clothing, lie out on a towel, and let the sun demonstrate that there is a correlation between bronze your skin. This recreational activity, these rates and the popularity of tanning bed use known as tanning, has been a part of human cul- among minors (Balk et al. 2013 ; Lostritto et al. ture for decades. Although this practice may 2012 ; Karagas et al. 2014 ). A recent survey of appear to be harmless, the damage it infl icts can indoor tanning practices among US high school be severe and irreversible. It is well known that students indicated a prevalence of 30.7 and 6.1 % the sun and other sources of ultraviolet radiation, for non-Hispanic white females and males, such as tanning beds, are major contributors to respectively (Guy et al. 2015 ). Such behavior the development of unsightly premature cutane- may be a result of social pressures and the cul- ous aging and skin cancer. Not surprisingly, with tural belief that tan skin is healthy/attractive skin the popularity of tanning salons and the limited (Yoo and Hur 2014; Sahn et al. 2012 ). Because use of sun protection, incidence of melanoma and skin cancer rates continue to rise, it is essential nonmelanoma skin cancer has been increasing that efforts be made on the public health and clin- dramatically (O’Leary et al. 2014 ; Abdulla et al. ical levels to help stifl e this major health 2005 ; Balk et al. 2013 ; Lostritto et al. 2012 ; Prior concern. et al. 2014; Leiter et al. 2014). According to the CDC, the incidence of melanoma in the United States has increased signifi cantly by 1.6 % per Types of Skin Cancer year in white men and women from 2001 to 2010 (CDC, 2014 ). On an international level, mela- The three main types of skin cancer are basal cell noma is the most rapidly increasing cancer carcinoma (BCC), squamous cell carcinoma among light-complexioned populations, with (SCC), and malignant melanoma; each has been incidence rates rising fi vefold in the last three linked to UV exposure. Basal cell carcinoma, decades (Prior et al. 2014 ; Leiter et al. 2014 ). which is the most common form of skin cancer in According to Leiter et al., incidence rates of mel- light-complexioned individuals, is responsible anoma in Europe will likely rise to 40–50/100,000 for approximately 80 % of the nonmelanoma inhabitants/year in the following decades (Leiter (BCC and SCC) skin cancer cases (Abdulla et al. et al. 2014 ). Most alarming is that skin cancer 2005). Basal cell carcinoma is characterized by rates for young adults have also been steadily mutagenesis of basal cells in the epidermis and 18 Adolescent Tanning Practices: Understanding the Popularity of Excessive Ultraviolet Light Exposure 179

Fig. 18.1 Mother and child enjoying a sunny day in rooftop swimming pool of elegant hotel in Heraklion, Crete (Courtesy of the author) can have a variety of different appearances on the noma is seen less frequently in the general popu- skin surface. Although BCC is not generally met- lation than nonmelanoma skin cancers, it astatic, its growth can often disturb surrounding represents the majority of skin cancers and skin tissues. Squamous cell carcinoma is classiﬁ ed by cancer deaths in the pediatric population the mutagenesis of the ﬂ at, outermost squamous (O’Leary et al. 2014 ; Fisher and James 2010 ). cells of the epidermis and accounts for 20 % of the nonmelanoma skin cancer cases (Abdulla et al. 2005 ). Although it is less common than UV Radiation and Skin Cancer BCC, SCC is responsible for most of the nonmelanoma skin cancer deaths that occur in the Although all three categories of skin cancer are United States each year and is the most common caused by UV radiation, the carcinogenic proper- skin cancer in dark-complexioned people ties of the different forms of UV radiation are not (Hussein 2005 ). Malignant melanoma, which proportional. Furthermore, the amount of time constitutes mutagenesis of the epidermal melano- that an individual is exposed to UV radiation can cytes (pigment cells), is the deadliest form of skin also determine the likelihood of carcinogenesis. cancer. Occurring in only about 4 % of skin can- Therefore, if a person is determined to go tanning cer cases, malignant melanoma is responsible for or has to work in a UV-intense environment, it is approximately 79 % of skin cancer deaths important that they know what behaviors put (Abdulla et al. 2005 ). Although malignant mela- them at a greater risk for developing skin cancer. 180 T.J. Jasterzbski et al.

For example, there is a correlation between SCC more carcinogenic form of UV radiation, it might and total lifetime UV damage, such as prolonged be assumed that artifi cial tanning is safer than occupational sun exposure, whereas BCC and natural tanning. However, tanning beds may be melanoma are associated with intermittent or rec- just as dangerous as natural sunlight for the fol- reational exposure (Abdulla et al. 2005 ). The UV lowing reasons: a greater surface of the individu- radiation produced by the sun arrives at the sur- al’s skin is exposed to UV radiation during face of the Earth in a continuous spectrum. For tanning bed use, UVA has carcinogenic proper- research purposes, this spectrum is arbitrarily ties, and UVB remains a potent carcinogen even divided into UVC (200–290 nm), UVB (290– at small concentrations. When tanning on the 320 nm), and UVA (320–400 nm). Of these forms beach or at a swimming pool, the UVB creates of ultraviolet radiation, UVC is the highest in the burning sensation, which signals an individ- energy and has the greatest potential for causing ual to go inside and stop UV exposure. In an arti- mutagenesis. However, it is entirely absorbed by fi cial UVA tanning booth, the lack of UVB results the Earth’s atmosphere (Hussein 2005 ). in no trigger for this signal. Of the two forms of UV radiation that reach the Earth’s surface, UVB is the highest energy form and the most effective at causing skin can- Indoor Tanning cer (Hussein 2005 ). In fact, it has been reported that UVB radiation is 1000–10,000 times more As defi ned by Young, tanning is the “induction of carcinogenic than UVA (Woo and Eide 2010 ). facultative pigmentation by UV radiation” However, despite this difference in carcinogenic- (2004 ). Internationally, tanning is a popular rec- ity, recent studies have demonstrated that the reational activity, and both natural and artifi cial UVA region of the spectrum is also effective at tanning are commonly practiced. However, fol- causing skin cell mutagenesis (O’Leary et al. lowing their debut in 1979, the use of tanning bed 2014). Longer periods of exposure to UVA, such facilities has increased dramatically. According as frequent indoor tanning, may enhance the car- to Levine et al., the annual revenue of the artifi - cinogenic properties of UVA. For example, a cial tanning industry has increased substantially study indicated that psoriasis patients that were from $1 billion in 1992 to approximately $5 bil- treated with high-exposure doses of psoralen and lion (Levine et al. 2005 ). What is even more UVA radiation (PUVA) had an incidence of squa- alarming about the rise of the artifi cial tanning mous cell carcinoma that was 14 times greater industry is its popularity among adolescents, than those treated with low-exposure doses (Stern especially adolescent females (O’Leary et al. et al. 1997 ). 2014 ; Abdulla et al. 2005 ; Balk et al. 2013 ; Guy et al. 2015 ; Yoo and Hur 2014; Sahn et al. 2012 ). It has been estimated that approximately 2.3 mil- Sources of UV Radiation lion teens visit a tanning facility each year (Levine et al. 2005). Because the effects of UV The two main ways to acquire UV radiation exposure are cumulative and adolescents are par- include natural exposure via the sun and artifi cial ticularly vulnerable to UV damage, the wide- exposure via tanning beds or sunlamps. Although spread use of indoor tanning facilities by both types of exposure include different ratios of adolescents is a major public health problem. In UVA to UVB, each can be carcinogenic. It is esti- fact, tanning bed exposure before age 30 mated that the sunlight that passes through the increases the risk of melanoma by 75 % (Woo Earth’s atmosphere is composed of 90–95 % and Eide 2010 ). Although this statistic is fright- UVA and 5–10 % UVB and that the light that is ening enough, studies have also shown that the emitted in newer tanning beds is composed of probability of acquiring SCC and BCC also 0.5–5 % UVB and 95–95.5 % UVA (Abdulla increases with an earlier age of exposure to tan- et al. 2005 ). With the knowledge that UVB is the ning beds (Karagas et al. 2002 ). Despite the 18 Adolescent Tanning Practices: Understanding the Popularity of Excessive Ultraviolet Light Exposure 181 numerous studies that demonstrate the carcino- cheerleading even encourage a tanned appear- genic properties of artifi cial tanning, a large per- ance as part of the “uniform” (Rawe 2006 ). centage of adolescents continue to visit indoor According to Rawe, the main challenge in reduc- tanning facilities each year (Guy et al. 2015 ). ing tanning facility use includes “combating the This trend in widespread adolescent use is adolescent culture that currently encourages complex and is infl uenced by multiple variables compulsive tanning” (Rawe 2006 ). including: inadequate information about the dan- While Hollywood and the media have been gers of artifi cial tanning, concern with gaining a infl uential in perpetuating the belief that tan skin more “attractive” appearance, tanning facility is attractive skin, the tanning industry has been advertisement, and emulation of parents that incredibly successful at exploiting this belief practice artifi cial tanning. For the subset of indi- that is engrained in teen culture. The tanning viduals who lack awareness about the dangers of industry uses teen-related advertisements and artifi cial tanning, public health campaigns, offers student discounts/packages in order to tar- school programs, and physician guidance could get adolescents (Balk and Geller 2008 ). be instrumental in reducing its use. For example, Furthermore, the increasing availability of tan- some individuals are misinformed and believe ning facilities has also contributed to the rise in that indoor tanning is a safer way to tan. This idea indoor tanning use among adolescents (Woo and comes from two main misconceptions: the belief Eide 2010; Pagoto et al. 2014). In a study of 116 that artifi cial tanning provides a protective “base US cities, an average of 41.8 tanning salons per tan” and the belief that UV radiation from artifi - city was documented as well as higher tanning cial tanning devices is safer than natural UV radi- facility densities in cities that had higher propor- ation. In regard to the “base tan” theory, base tions of teenagers and females of ages 15–29 tanning can be just as harmful as a sunburn (Woo and Eide 2010 ). because tanning, no matter what type, does not occur without preceding DNA damage (Woo and Eide 2010 ). Furthermore, individuals who get a Regulation of Indoor Tanning “base tan” typically spend more time in the sun, Facilities thus accumulating more UV radiation, because they have a lower chance of getting a sunburn. As As a result of the numerous studies that have for the “safer UV radiation theory,” no form of linked tanning devices to skin cancer, the World UV radiation is safe. Although modern tanning Health Organization and International Agency devices emit lower concentrations of UVB than for Research on Cancer in 2009 listed tanning natural sunlight, low levels of UVB can still be beds as a group I carcinogen alongside asbestos, highly carcinogenic. cigarettes, and arsenic. With this declaration and Although basic educational campaigns might similar reports making their way into the media, prevent this “misinformed” group of individuals state legislators have been increasingly con- from tanning, there still remains a large group cerned with regulating tanning bed use, espe- who use artifi cial tanning devices despite know- cially among adolescents. Although the FDA ing the health risks. In this case of “informed” currently monitors the tanning devices used by use, there are three main contributing factors tanning salons and requires tanning salons to pro- including: looking good, feeling good, and suc- vide eye protection, warning statements, and cumbing to the marketing strategies of the tan- exposure schedules to customers, states have ning industry. Many adolescents visit tanning recently started to impose their own regulations salons in an effort to improve their appearance. on tanning facilities (Woo and Eide 2010 ). For example, some teenagers, especially teenage Currently, eleven countries, ten US states, and six girls, get pre-prom and pre-beach tans with the Australian territories completely ban indoor tan- impression that a tanned body looks healthier and ning for minors (Pagoto et al. 2014 ; Gottlieb more attractive. Some scholastic sports such as et al. 2015 ). Other localities have implemented 182 T.J. Jasterzbski et al. parental consent policies and age restrictions on of skin cancer. Similar to indoor tanning, sun- indoor tanning; however, further legislation is bathing is practiced for a variety of reasons: some still needed to combat this high-risk behavior sunbathe because they want to get an “attractive” (Pagoto et al. 2014 ; Gottlieb et al. 2015 ). tan, some fi nd it relaxing, and others believe that In addition to state policies aimed at reducing it is healthy. Because the sun is a source of vita- indoor tanning among adolescents, the US gov- min D and can let us feel warm and soothing, ernment incorporated a 10 % tax on indoor tan- individuals often make the assumption that sun- ning services involving UV light as a provision of tanning is healthy. However, the act of sunbath- the Patient Protection and Affordable Care Act ing, which involves prolonged sun exposure, is (PPACA). This “tanning tax,” which took effect not healthy. In fact, UV radiation from the sun is on July 1, 2010, was designed to generate funds highly carcinogenic, as it contains a large con- to help support expanding medical coverage and centration of UVB. Furthermore, for most indi- to make indoor tanning less affordable for teens viduals, there are no vitamin D benefi ts to (Brod 2013 ). However, due to several loopholes sunbathing because the body gets enough vita- in the provision, the tax only generated $36.6 min D from day-to-day exposure to UV radia- million, falling well short of the $200 million tion. Studies have demonstrated that natural UV return that was projected (Brod 2013 ). radiation is linked to both melanoma and non- Furthermore, a survey of 308 tanning facilities in melanoma skin cancers and that UV radiation the state of Illinois indicated only a mild decrease from the sun may be responsible for at least 65 % in tanning facility use since the tax was instated of the melanoma cases worldwide (Geller et al. (Jain et al. 2012). Although the tanning tax may 2002 ). have a modest impact in decreasing the use Even more frightening is that natural tanning, among adolescents, an all-out ban on tanning unlike indoor tanning, cannot be regulated. With salons for individuals under 18 would likely be no fees involved and the sun everywhere around most effective at reducing indoor tanning us, people of all ages can suntan as long as the behavior among this patient population. It is also weather permits this behavior. As was the case important that legislators consider prohibiting with indoor tanning, research has also indicated advertisements that target adolescents including that suntanning without appropriate protection student discounts/packages. Because there are so such as sunscreen is a common practice among many tanning facilities across the country, strict adolescents (Robinson et al. 1997 ). A study by enforcement of tanning laws could present a chal- Robinson et al. regarding teen sun exposure lenge. For example, in North Carolina, only 13 % reported that most teenagers who used sunscreen of tanning facilities followed the guardian consent had it supplied by parents (Robinson et al. 1997 ). laws, and only 19 % of facilities followed the If teenagers are not showing initiative to engage FDA requirement of providing risk statements in sun-protective behaviors on their own, it is (Woo and Eide 2010 ). Therefore, in addition to possible that they could carry these practices into enacting more stringent indoor tanning laws, leg- adulthood. Furthermore, since tanning culture is islators should also develop effi cient strategies to associated with wearing minimal clothing, sun- monitor compliance with these regulations. screen is usually the only form of protection used by sunbathers. Because sunscreen can be expensive, uncomfortable to some, and prevent indi- Natural Tanning viduals from achieving a desired tan, it is sometimes not used at all. Also for those who do Although indoor tanning has received much of use sunscreen while sunbathing, protection is not the criticism regarding the dramatic increase of always 100 %; sunscreen can dissipate as a result skin cancer cases, it is not the only contributing of sweating or contact with water and may be factor. Natural tanning or “sunbathing” has also inadequately applied to some regions of the body, had a signifi cant impact on the rising prevalence such as the back. Therefore, the most effective 18 Adolescent Tanning Practices: Understanding the Popularity of Excessive Ultraviolet Light Exposure 183 ways to stay protected from the sun’s harmful chance that they will continue such behaviors UV radiation include refraining from sunbathing into adulthood. Studies have shown that teen- altogether and using sun-protective clothing/ agers who use sunscreen on their own had par- accessories when in the outdoors. ents that insisted on sunscreen use when they were children (Robinson et al. 1997 ). In addition to promoting the use of protec- Addictive Properties of Tanning tive clothing and sunscreen, efforts must be made to reduce the popularity of indoor tan- Although individuals may become obsessed with ning among adolescents, especially adoles- tanning for reasons pertaining to appearance, cent females. Adolescents are not only highly studies have also shown that the actual tanning vulnerable to the harmful effects of UV radia- process may be addictive (O’Leary et al. 2014 ; tion but are also susceptible to the social pres- Banerjee et al. 2014 ). The release of beta- sures of tanning for a perceived attractive endorphin, with the cleavage of pro- appearance. Even adolescents who are aware opiomelanocortin to alpha-MSH, along with of the health risks associated with indoor tan- feelings of warmth and relaxation, may all con- ning continue to visit tanning salons just to fi t tribute to the addictive properties of tanning in. Therefore, educational campaigns that (O’Leary et al. 2014 ). Research has also shown speak just on the dangers of indoor tanning that individuals who have engaged in tanning might be insuffi cient. In this case, a more behavior for a longer period of time show greater comprehensive approach including stricter diffi culty in quitting such tanning behaviors tanning salon legislation, parental guidance, (Woo and Eide 2010 ). One study even revealed physician education, and educational cam- that four of eight frequent tanners had withdrawal paigns that delve deeper into the adolescent symptoms consisting of nausea and jitteriness psyche might be more effective. For example, when given an opioid antagonist before UV educational campaigns that show how UV exposure, an effect not observed in infrequent radiation can decrease attractiveness could be tanners (Kaur et al. 2006 ). Although more more benefi cial than campaigns that speak of research needs to be done before UV radiation the general risks of tanning. Two recent stud- can be classifi ed as an addictive substance, these ies indicate success with incorporating stu- studies could provide insight as to why frequent dent-personalized UV photo-aged images into tanning has become such a popular behavior. sun-safety education (Lo Presti et al. 2014 ; Morris et al. 2014 ). It has also been demon- Conclusion strated that if teens have parents that practice Similar to smoking and reckless driving, tan- indoor tanning and/or permit indoor tanning, ning is a high-risk behavior that has been they are much more likely to engage in indoor unfortunately glamorized. Because tanning tanning behavior (Woo and Eide 2010 ). practices, both indoor and natural, are strongly Therefore, in order for popularity of indoor associated with the signifi cant rise in skin can- tanning to decrease, it is imperative that par- cer, limiting tanning behavior should be a ents guide their children away from tanning major public health focus. Most importantly, behavior. Lastly, more widespread legislation public health efforts should be directed at chil- limiting tanning facility use and stricter dren and adolescents. Since UV damage is enforcement of such policies could also help cumulative, the earlier an individual is exposed reduce the popularity of indoor tanning. With to UV radiation, the greater the chance the cases of malignant melanoma, basal cell carci- individual will develop skin cancer in adult- noma, and squamous cell carcinoma on the hood (Karagas et al. 2014 ; Cust et al. 2011). rise, it is essential that efforts be made to Furthermore, if health-protective behaviors are reduce obsessive tanning behavior among instilled in children early on, there is a greater adolescents. 184 T.J. Jasterzbski et al.

Bulleted List of Controversies Drug Administration’s black box warning. Ann Surg Oncol. 2015;22(3):701–3. Guy Jr GP, Berkowitz Z, Everett Jones S, Holman DM, • Despite the well-known health risks associ- Garnett E, Watson M. Trends in indoor tanning among ated with UV radiation, tanning continues to US high school students, 2009-2013. JAMA Dermatol. be glamorized in popular culture. 2015;151(4):448–50. • Although public policy in some jurisdictions Hussein MR. Ultraviolet radiation and skin cancer: molecular mechanisms. J Cutan Pathol. has been enacted to stifl e indoor tanning 2005;32:191–205. among adolescents, stricter and more uniform Jain N, Rademaker A, Robinson JK. Implementation of legislation may be desirable. the federal excise tax on indoor tanning services in • Preventing adolescents from enjoying time in Illinois. Arch Dermatol. 2012;148:122–4. Karagas MR, Stannard VA, Mott LA, Slattery MJ, Spencer the sun may be an unrealistic goal; therefore, SK, Weinstock MA. Use of tanning devices and risk of it is important for the clinician to promote basal cell and squamous cell skin cancers. J Natl sun-protective behaviors and discourage prac- Cancer Inst. 2002;94:224–6. tices like indoor tanning that lead to unneces- Karagas MR, Zens MS, Li Z, Stukel TA, Perry AE, Gilbert-Diamond D, Sayarath V, Stephenson RS, sary UV exposure. Barton D, Nelson HH, Spencer SK. Early-onset basal • Focusing on cosmetically undesirable effects cell carcinoma and indoor tanning: a population-based of UV radiation through personalized UV study. Pediatrics. 2014;134:e4–12. photo-aged images may be desirable for chil- Kaur M, Liguori A, Lang W, Rapp SR, Fleischer Jr AB, Feldman SR. Induction of withdrawal-like symptoms dren and adolescent, although some parents in a small randomized, controlled trial of opioid block- may feel such health education does not ade in frequent tanners. J Am Acad Dermatol. belong in schools. 2006;54:709–11. Leiter U, Eigentler T, Garbe C. Epidemiology of skin cancer. Adv Exp Med Biol. 2014;810:120–40. Levine JA, Sorace M, Spencer J, Siegel DM. The indoor References UV tanning industry: a review of skin cancer risk, health benefi t claims, and regulation. J Am Acad Abdulla FR, Feldman SR, Williford PM, Krowchuk D, Dermatol. 2005;53:1038–44. Kaur M. Tanning and skin cancer. Pediatr Dermatol. Lo Presti L, Chang P, Taylor MF. Young Australian adults’ 2005;22:501–12. reactions to viewing personalised UV photoaged pho- Balk SJ, Fisher DE, Geller AC. Teens and indoor tanning: tographs. Australas Med J. 2014;7:454–61. a cancer prevention opportunity for pediatricians. Lostritto K, Ferrucci LM, Cartmel B, Leffell DJ, Molinaro Pediatrics. 2013;131:772–85. AM, Bale AE, Mayne ST. Lifetime history of indoor Balk SJ, Geller AC. Teenagers and artifi cial tanning. tanning in young people: a retrospective assessment of Pediatrics. 2008;121:1040–2. initiation, persistence, and correlates. BMC Public Banerjee SC, Hay JL, Geller AC, Gagne JJ, Frazier Health. 2012;12:118. AL. Quitting the “cancer tube”: a qualitative examina- Morris KL, Cooper DP, Goldenberg JL, Arndt J, Gibbons tion of the process of indoor tanning cessation. Transl FX. Improving the effi cacy of appearance-based sun Beh v Med. 2014;4:209–19. exposure interventions with the terror management Brod BA. Health care reform produces both heat and light health model. Psychol Health. 2014;29:1245–64. with the indoor tanning tax. Cutis. 2013;91:221–3. O’Leary RE, Diehl J, Levins PC. Update on tanning: more Cust AE, Armstrong BK, Goumas C, Jenkins MA, Schmid risks, fewer benefi ts. J Am Acad Dermatol. H, Hopper JL, Kefford RF, Giles GG, Aitken JF, Mann 2014;70:562–8. GJ. Sunbed use during adolescence and early adulthood Pagoto S, Hillhouse J, Heckman CJ, Coups EJ, Stapleton is associated with increased risk of early-onset mela- J, Buller D, Turrisi R, Robinson J, Geller AC. Society noma. Int J Cancer. 2011;128:2425–35. of behavioral medicine (SBM) position statement: ban Fisher DE, James WD. Indoor tanning – science, behav- indoor tanning for minors. Transl Behav Med. ior, policy. N Engl J Med. 2010;363:901–3. 2014;4:124–6. Geller AC, Colditz G, Oliveria S, Emmons K, Jorgensen Prior SM, Fenwick KD, Peterson JC. Adolescents’ rea- C, Aweh GN, Frazier AL. Use of sunscreen, sunburn- sons for tanning and appearance motives: a prelimi- ing rates, and tanning bed use among more than nary study. Body Image. 2014;11:93–6. 10,000 US children and adolescents. Pediatrics. Rawe J. Why teens are obsessed with tanning. Time. 2002;109:1009–14. 2006;168:54–6. Gottlieb M, Balk SJ, Geller AC, Gershenwald JE. Teens Robinson JK, Rademaker AW, Sylvester JA, Cook and indoor tanning: time to act on the US Food and B. Summer sun exposure: knowledge, attitudes, and 18 Adolescent Tanning Practices: Understanding the Popularity of Excessive Ultraviolet Light Exposure 185

behaviors of Midwest adolescents. Prev Med. ralen) and ultraviolet A radiation (PUVA). The PUVA 1997;26:364–72. follow-up study. N Engl J Med. 1997;336:1041–5. Sahn RE, Mcllwain MJ, Magee KH, Veledar E, Chen Woo DK, Eide MJ. Tanning beds, skin cancer, and vita- SC. A cross-sectional study examining the correlation min D: an examination of the scientiﬁ c evidence and between sunless tanning product use and tanning public health implications. Dermatol Ther. beliefs and behaviors. Arch Dermatol. 2010;23:61–71. 2012;148:448–54. Yoo JJ, Hur WM. Body-tanning attitudes among female Skin Cancer Trends (2014) Centers for disease control college students. Psychol Rep. 2014;114:585–96. and prevention. http://www.cdc.gov/cancer/skin/sta- Young AR. Tanning devices – fast track to skin cancer? tistics/trends.htm . Pigment Cell Res. 2004;17:2–9. Stern RS, Nichols KT, Vakeva LH. Malignant melanoma in patients treated for psoriasis with methoxsalen (pso- Androgenetic Alopecia in Adolescents 1 9

Rubina Alves and Ramon Grimalt

Abstract Androgenetic alopecia (AGA) is a nonscarring progressive miniaturization of the hair follicle with a usually characteristic pattern distribution in genetically predisposed men and women. Although AGA is the most common form of hair loss in adults, little is known about its prevalence and response to treatments in the pediatric population. As in adults, the diagnosis of this type of alopecia in adolescents is made by recognizing the pattern and progression of hair loss in the context of the family history. A negative family history does not exclude the diagnosis. Early-onset AGA can be the presenting sign of an underlying endocrine disorder. Adolescents are invariably sensitive about their external features and , thus , may easily withdraw psychologically and avoid social activities due to AGA development. They can feel anxious and unattractive with a negative body image about themselves. Accurately recognizing AGA in adolescents will help patients and their families understand the diagnosis and its natural progression, allowing timely medical intervention for hair loss and any associated endocrine or psychosocial morbidity. Treatment of adolescent AGA has not been well studied, and currently there are no FDA-approved treatments for this condition. This article provides an overview of the embryology and normal hair development, pathogenesis, diagnosis, and management of adolescent androgenetic alopecia.

R. Alves , MD (*) Department of Dermatology , Universitat Internacional de Catalunya , Barcelona , Spain e-mail: [email protected] R. Grimalt , MD, PhD Department of Dermatology , Universitat Internacional de Catalunya , Barcelona , Spain e-mail: [email protected]

Keywords Androgenetic alopecia • Adolescent • Telogen efﬂ uvium • Diffuse alopecia areata • Topical minoxidil • Finasteride

Androgenetic alopecia (AGA) is a common the adolescents who present with hair thinning chronic dermatologic disease, affecting both men can feel unattractive with a negative body image and women. It is characterized by progressive (Budd et al. 2000 ). This source of distress can hair loss usually occurring in a pattern distribu- lead to anxiety, depression, and social isolation tion. The onset of AGA is usually gradual and the (Cash 1992 ; Cash et al. 1993 ). condition slowly develops over the years. AGA is undoubtedly the most common form of hair loss (Tosti and Piraccini 1999 ), affecting Embryology and Normal Hair around 80% of Caucasian men aged over 70 Development years (Blume-Peytavi et al. 2011 ; Rathnayake and Sinclair 2010 ). As in men, the frequency and Hair follicles are derived from an interaction severity of AGA increase with age in women between embryological ectoderm and mesoderm (Gan and Sinclair 2005 ). that begins around 9 weeks of gestation (Moreno- Although it’s more frequent in adults, it can Romero and Grimalt 2014 ). Then, the develop- also appear in adolescents. There are different ment of the hair progresses in a cephalocaudal studies (Gonzalez et al. 2010 ; Kim et al. 2006 ; direction, becoming fi rst visible in the eyebrow, Trancik et al. 2001a , b) that have documented the upper lip, and chin regions. Around 16 weeks ges- prevalence and early age at onset of AGA. tation, hair production begins in the follicles, with In children and adolescents with a genetic pre- lanugo hair formation. At 18–20 weeks gestation, disposition, the fi rst signs of AGA can appear the entire initial population of follicles is com- with rising androgens at puberty (Gonzalez et al. pleted, including those on the scalp (Cutrone and 2010 ; Kim et al. 2006 ) and have been observed as Grimalt 2005 ). At birth, about 5 million hair fol- early as 6 years of age (Tosti et al. 2005 ). On an licles cover the human body, and approximately average, adolescent AGA onset presents between 100,000 are scalp hairs (Sinclair et al. 1999 ). 13.5 and 15 years of age (McDonough and Each follicle can produce three different types Schwartz 2011 ). of hair: lanugo, vellus, and terminal. In our society, strong and dense hair is associ- The lanugo hair is a nonmedullated, fi ne, soft, ated with youth, beauty, health, attractiveness, usually nonpigmented hair that can be found on and success. Independent of age and gender, the body of a newborn. Around the third or fourth patients diagnosed with AGA undergo signifi cant month after birth, the initial fi ne lanugo scalp impairment in their quality of life. hairs are shed in a synchronized wave pattern. During the adolescence, self-esteem plays a The vellus hair is a short, fi ne, light-colored, crucial role when teenagers start to notice and barely noticeable hair that covers almost the changes about their body, own environment, and whole body. At puberty, the androgen hormone the outside world. A positive or healthy body causes much of the vellus hair to turn into termi- image means feeling happy and satisfi ed about nal hair and stimulates the growth of new hair in our own body. Perceived or real physical defects the face, axillary, and the pubic area (Moreno- may be important for an adolescent trying to Romero and Grimalt 2014 ). establish self-image and adjust socially (Strauch Terminal hairs are larger, thicker, and strongly and Greenstein 1997 ). pigmented hairs found on the scalp, eyebrows, Concerning the infl uence of many factors in axillary and pubic areas, chest, and face. Both vel- body image, such as media and fashion industry, lus and terminal hairs coexist in the same areas, 19 Androgenetic Alopecia in Adolescents 189 and absolute distinction is not always possible 1996 ). Inheritance is almost certainly poly- (Harrison and Sinclair 2003 ). The normal ratio of genic, with genetic input from both parents. terminal to vellus hairs in a normal scalp is 7–8:1. Studies performed on monozygotic twins The hair follicle is anatomically divided into showed strong concordance rates between 80 three parts: upper (infundibulum), middle (isth- and 90 %, reinforcing the implication of a mus), and lower (inferior segment). The infun- genetic basis (Chumlea et al. 2004 ). Family his- dibulum and isthmus comprise the permanent tory predisposes to early development and rapid portions of the hair follicle, while the inferior progression of the alopecia (Tosti and Piraccini segment is transient and undergoes cyclical 1999 ). Its etiology is multifactorial and poly- regeneration (Shapiro et al. 2004 ). genetic (Blume- Peytavi et al. 2011 ; Blumeyer Human hair grows in a continuous cyclic pat- et al. 2011 ). tern known as hair cycle. The hair cycle is classi- The androgen hormones testosterone and cally composed of four distinct phases: anagen dihydrotestosterone (DHT) each have selective (growth phase – 85–90 % of hairs), catagen roles at puberty. Testosterone is converted to (regression or involution phase – <1 % of hairs), DHT by the enzyme 5-alpha-reductase that has telogen (resting phase – 4–15% of hairs), and two isoenzymes: 5-alpha-reductase type I (pres- fi nally the shedding exogen phase. The duration of ent in the liver and sebaceous glands) and anagen growth phase of scalp hairs typically varies 5-alpha-reductase type II (present in the scalp, between 2 and 6 years, catagen phase lasts 2 or 3 beard, chest, liver, and prostate gland). weeks, and telogen phase approximately 3 months Testosterone is associated with increased (Moreno-Romero and Grimalt 2014 ; Harrison and muscle mass, growth of the scrotum, voice Sinclair 2003 ). The normal hair cycle results in the change, and the presence of terminal pubic and replacement of every hair on the scalp every 3–5 axillary hair fi bers. An increased activity of years (Harrison and Sinclair 2003 ). 5-alpha-reductase type II plays an important role At birth, within anatomical regions, all hairs are in the development of AGA (Blume-Peytavi et al. initially synchronous in anagen phase, and during 2011). Levels of this isoenzyme are higher in childhood there is a gradual transition of scalp hair men than in women and in the areas affected by from vellus to terminal hairs (Olsen 1994a , b ). The AGA (Tosti and Piraccini 1999 ). type of hair produced by an individual follicle can DHT is associated with temporal scalp hair change with age or under the infl uence of hor- recession, acne, growth of the prostate gland, and mones (Harrison and Sinclair 2003 ). the development of terminal hairs in the beard Around puberty, there is an increase of the cir- region, external ears, and limbs. culating adrenal androgens, which leads to a site- The hormone DHT activates the genes respon- specifi c response from the hair follicles. With the sible for the shortening of hair growth cycle as presence of androgens, the hairs of the scalp min- well as the transformation of large hair follicles iaturize, while the hair of the body enlarges. At into smaller follicles that progressively become this time, the hairs of axillary, pubic, chest, and miniaturized (Price 2003 ). beard (boys) change from vellus to terminal hair, AGA is characterized by the miniaturization contributing to the development of the secondary of the hair that only occurs in certain areas: the sex characteristics (Moreno-Romero and Grimalt frontotemporal and vertex area in men and the 2014 ; Harrison and Sinclair 2003 ). crown region in women. These scalp regions are susceptible to the effects of androgens. During the gradual transformation of the miniaturized Etiology and Pathogenesis follicles (from terminal to vellus-like follicles), the anagen phase shortens, and for this reason For the development of AGA, the presence of more hairs are in telogen phase (Kaufman 1996 ). androgens, in combination with genetically There is no loss of hair follicles in AGA, just susceptible hair follicles, is necessary (Kaufman miniaturized. 190 R. Alves and R. Grimalt

Clinical Features of AGA in Adolescents

The physician should record age, sex, and age at the fi rst manifestation of hair loss and course of the disorder (chronic or intermittent) in the patient as well as in the family history. In adolescents it’s important to differentiate if the hair loss is congenital or acquired. Look for physical and mental development, particularly in case of early onset of puberty (Blume-Peytavi et al. 2011 ). If there’s any systemic or newly diagnosed Fig. 19.1 Androgenetic alopecia developed in a 16-year- disease within 1 year prior to the fi rst signs of old boy hair loss, one should suspect that could be secondary to other causes or aggravating factors. It is known that AGA may be aggravated by The most frequently used scales in practice chronic disease, metabolic disease, endocrino- are Hamilton–Norwood scale (Norwood 1975 ) logical disease, stress, emotional change, and for male-pattern distribution and Ludwig scale medication (Tosti and Piraccini 1999 ; Kim (Ludwig 1977 ) or Olsen scale (Olsen 2003 ) et al. 2006 ). (frontal accentuation ⁄ Christmas tree pattern) for The clinical expression of AGA in adolescents a female-pattern AGA. Women who develop is milder than in adults (Price 2003 ). A family balding in a pattern similar to men can be classi- history for AGA is frequently positive (father, fi ed using the Hamilton–Norwood scale. mother, both), but a negative family history does In adolescent girls with AGA, a careful evalu- not exclude the diagnosis. ation of the gynecological history should include Clinically, a male AGA is relatively easy to menarche, menstrual cycle, and amenorrhea. The diagnose. It is symmetric and progressive, and hair loss usually occurs in the absence of any the pattern of hair loss can vary among individu- underlying endocrinopathy. Occasionally, it may als. In boys, AGA is recognized by changes in appear as part of a hyperandrogenemic state such three scalp regions: frontal scalp, vertex region, as the one that occurs in polycystic ovary syn- and bitemporal region. It commonly manifests as drome, hyperprolactinemia, or adrenal or ovarian bitemporal recession and thinning in the frontal tumors (Gonzalez et al. 2010 ). and vertex regions. The frontal and vertex regions If indicated, laboratory evaluation may include may show mild, decreased hair density, and min- free androgen index test [FAI = total testoster- iaturized, shorter, fi ner hair (Fig. 19.1 ) (Price one × 100⁄sex hormone-binding globulin 2003 ). The occipital density is relatively spared (SHBG)], luteinizing hormone/follicle- in AGA. stimulating hormone, and prolactin as screening In girls, AGA is more diffi cult to identify and parameters (Blume-Peytavi et al. 2011 ). diagnose than in boys (Fig. 19.2 ). Early diffuse Depending on the results, further endocrinologi- hair thinning is usually the most evident over the cal investigations may be required. frontal scalp, with an increased spacing between Because of the clinical features associated hairs and a widened appearance of the central with hyperandrogenism, male adolescents typi- part. The size of the ponytail is decreased (Price cally do not present with signs or symptoms of 2003 ). The most common patterns of hair loss in androgen excess (Witchel 2002 ). women are centrifugal loss at the crown and the The diagnosis of AGA is usually clinical. frontal accentuation or “Christmas tree” pattern Some specifi c techniques may be used to improve (Olsen et al. 2005 ; Olsen 2003 ). the diagnostic accuracy. 19 Androgenetic Alopecia in Adolescents 191

discoloration, wavy hair, and honeycomb pigmentation (Rakowska et al. 2009 , 2012 ). In high-magnifi cation (70×) dermoscopy, three major diagnostic criteria and three minor diagnostic criteria were proposed (Rakowska et al. 2009). The major criteria were the following: more than four yellow dots in four fi elds in the frontal area, decreased average shaft thickness in the frontal area compared to the occipital scalp, and more than 10 % of thin hairs in the frontal area. Minor criteria included the following: perifollicular discoloration, increased single- hair pilosebaceous units in the frontal area compared to the occipital area, and increased vellus hairs in the frontal area compared to the occiput. Two major criteria and/or one major and one minor criterion have a specifi city of 98 % (Werner and Mulinari-Brenner 2012 ). Biopsy is usually not necessary for the diagnosis of AGA. It can be performed if there’s some diffi culties in establishing the diagnosis, for example, in men who present a female pattern of Fig. 19.2 Androgenetic alopecia developed in a 12-year- hair loss or in females in order to exclude other old girl causes of diffuse hair loss, such as telogen effl u- vium (Kaliyadan et al. 2013 ). The hair-pull test is an examination easy to do The better site to perform a biopsy is the cen- in order to analyze active hair shedding. To per- tral scalp in an area representative of hair loss. form the test, one should grasp around 50–60 The punch biopsy should have at least 4 mm in hairs between index and thumb and then lift with diameter and follow the direction of the hair shafts gentle traction (Blume-Peytavi et al. 2011 ). The until subcutaneous fat, where anagen hair bulbs hair-pull test is considered positive if more than are usually located (Olsen et al. 2005 ; Kaliyadan 10 % of the hairs are released. et al. 2013 ; Whiting 1993 ; Whiting et al. 1999 ). In patients with AGA, the hair-pull test is pos- Biopsies smaller than 4-mm punch reduce the itive only in the active phase with increased telo- total number of follicles available for examina- gen hairs in the affected area. Otherwise, hair-pull tion, and since follicles are not uniformly affected test is typically normal in AGA. False positives by disease and some are lost in a given process, a can occur if the test is performed on the day of smaller biopsy diminishes the probability of mak- hair washing. ing a defi nitive diagnosis (Olsen 1994a ). Trichoscopy, a noninvasive technique, has Some histologic features of AGA include emerged as a valuable tool in the differential diag- perifollicular infi ltrate (predominantly lympho- nosis of most hair and scalp diseases. Trichoscopy histiocytic around the upper or lower follicle), is useful in the diagnosis of AGA and to evaluate normal total number of follicles, and miniaturiza- the therapeutic response of hair loss (Rudnicka tion of terminal hairs. The biopsy also allows et al. 2008 ; Kowalska-Oledzka et al. 2012 ). (when sectioned horizontally) calculating the Male and female AGA share similar tricho- hair ratio of terminal/vellus (T:V) hairs. scopic features, including hair thickness hetero- The T:V ratio is reduced in AGA, typically geneity, thin hairs, vellus hairs, single-hair less than 4:1 (Werner and Mulinari-Brenner pilosebaceous units, yellow dots, perifollicular 2012 ). 192 R. Alves and R. Grimalt

Differential Diagnosis Dietary restrictions, especially protein and iron restrictions, should be excluded, and vege- The diagnosis of AGA is usually made clinically tarians are a risk group for TE. Emotional stress by examination of hair and scalp. A diffuse alo- is commonly attributed as a cause of acute TE, pecia may present a diagnostic challenge, and it’s but the evidence for this is weak (Harrison and important to rule out the more commonly differ- Sinclair 2002 ). As is of our knowledge, there is ential diagnosis of AGA such as telogen effl u- no data that suggests the stresses of everyday life vium (TE) and diffuse alopecia areata (Werner are suffi cient to induce diffuse hair loss (Cash and Mulinari-Brenner 2012 ). 2001 ; Grover and Khurana 2013 ). Telogen effl uvium is an abnormality of hair In TE, the hair-pull test is strongly positive, cycling that can occur at any age. It is character- with a high percentage of telogen hairs (>20 %) ized by a nonscarring, global diffuse pattern of (Rakowska et al. 2009 ; Sinclair and Jolliffe alopecia with an increased shedding of otherwise 2013 ). The most widely accepted histological normal telogen hairs. It may begin with a sudden parameter for differentiating the TE from AGA is increase of hair loss and maintenance of the fron- the number of terminal hairs compared to the tal hair density (Werner and Mulinari-Brenner number of vellus hairs. In TE, the terminal/vellus 2012 ). This shedding occurs in response to a ratio is >7:1, while in AGA is <4:1 (Werner and pathologic or physiologic alteration in health Mulinari-Brenner 2012 ). condition. Management of this condition is by treatment Seasonal changes in hairs are obvious in many of the underlying disorder with appropriate mammals. In humans, there are also seasonal replacement drugs or medical therapy (Harrison changes in hair growth, although it’s less clear and Sinclair 2003 ). The prognosis for TE is very and not synchronized. The condition tends to run good if the precipitating event is eliminated. a fl uctuating course, and the number of shed hairs Alopecia areata (AA) is a nonscarring pat- reached a peak around August/September, when terned alopecia that can occur in children, adoles- least follicles were in anagen (Randall and Ebling cents, and adults, affecting different ethnicities 1991 ; Courtois et al. 1996 ). with equal sex incidence. The classic presenta- The main causes that can precipitate a TE are tions such as patchy AA (most common pattern), nutritional disorders (protein–calorie malnutri- alopecia totalis, and alopecia universalis are easy tion, zinc defi ciency, starvation), high fever, sur- to differentiate from AGA. A diffuse alopecia gery, drugs (allopurinol, colchicine, B-blockers, areata is the principal pattern to rule out. antihypertensives), systemic illness, endocrine Diffuse alopecia areata is described as a disorders, and pregnancy (Patel et al. 2013 ). unique AA that lacks the characteristic patches Although rare, TE has been reported to be sec- and, instead, demonstrates widespread scalp hair ondary to immunization (Tuccori et al. 2012 ; thinning (Zhao et al. 2012 ). Wise et al. 1997 ). Tuccori et al. ( 2012 ) described Trichoscopy examination is of great value in two cases of TE occurring in two 11-year-old the diagnosis of diffuse AA and has the same children following bivalent human papillomavi- characteristics features of AA. The dermoscopy rus (HPV) vaccine administration. The two chil- features that can be found in diffuse AA are short dren started to lose their hair following the second “exclamation-mark” hairs, specially at the mar- HPV vaccine dose, and the alopecia worsened gins of the lesion, “yellow dots” in a follicular following the third vaccine dose. After a few distribution, broken hairs, and black dots months, the hair regrew spontaneously. All other (Rudnicka et al. 2008 ; Werner and Mulinari- causes of hair loss were excluded. According to Brenner 2012 ; Randall and Ebling 1991 ). the authors, it is not recommended to discontinue The hair-pull test is positive (Alkhalifah the immunization as it provides health benefi ts et al. 2010 ). AA is associated with nail involve- that overcome the possible adverse effect of tran- ment, particularly nail pitting; trachyonychia, sitory TE. brittle nails, onycholysis, and koilonychia 19 Androgenetic Alopecia in Adolescents 193 have also been reported (Madani and Shapiro had an earlier response to treatment than those 2000; Tosti et al. 1991 ). who used 2 % topical minoxidil. Both 2 and 5 % topical minoxidil solutions were well tolerated by the men without evidence of systemic effects. Treatment Concerning the treatment of female-pattern hair loss, either 2 or 5 % (used off-label) topical Patients should be informed about the pathogen- minoxidil solution appears safe to use in women esis of AGA and the course of the disease. After with AGA. The only additional risk of the 5 % the diagnosis is confi rmed and considering that topical minoxidil solution over the 2 % topical severity of AGA increases with age, the treat- minoxidil solution is a higher incidence of facial ment should begin as soon as possible (Herskovitz hypertrichosis (Olsen et al. 2005 ). and Tosti 2013 ). Patients must avoid hair care Minoxidil has not been thoroughly studied in products likely to damage scalp/hair and main- adolescents, and data are limited to information tain an adequate diet (Olsen et al. 2005 ). from scientifi c meetings and case series. In adults, there are two drugs approved by the Regarding the use of topical minoxidil in ado- US Food and Drug Administration (FDA) for the lescents with AGA, a retrospective study Trancik et treatment of AGA: topical minoxidil and oral fi n- al. 2001b was performed in 448 boys and girls with asteride. There is no approved therapy for AGA a mean age of 15.6 years. After 5 % topical minoxi- in the adolescent population. dil had been applied for approximately 18 months, Minoxidil, a pyrimidine derivate, is converted to 95 % of patients responded to treatment; more than minoxidil sulfate, which opens ATP-sensitive 50 % had improvement in scalp coverage, and more potassium channels in cell membranes, leading to a than 40 % had slowing of further hair thinning. vasodilatory effect. Topical minoxidil increases the Based on these fi ndings, minoxidil appears to be an duration of the anagen phase and leads to produc- effective and well-tolerated treatment for adoles- tion of hairs that are gradually thicker and longer cents with AGA (Gonzalez et al. 2010 ; Price 2003 ; (Olsen et al. 2005 ). This results in partial reversion Trancik et al. 2001c ). of miniaturization (Tosti and Piraccini 1999 ). Topical minoxidil requires proper use of the for- The 2 % solution was fi rst approved by the US mulation and it is only effective in the area applied. Food and Drug Administration (FDA) in 1988 for Approximately 1 ml of solution should be applied the treatment of AGA in men (18–50 years) and in directly to dry hair and scalp, twice a day in affected 1991 in women (18 and 45 years). The 5 % solution area. Hands should be washed with warm water was approved in 1997 for the treatment of AGA in after application. If hair is to be washed after apply- men followed by approval of the 5 % foam in 2006 ing minoxidil, the patient must wait at least 1 h also for the treatment of AGA in men (Blumeyer before shampooing (Blumeyer et al. 2011 ). et al. 2011). The 5 % lotion and 5 % foam are not Side effects of minoxidil treatment include licensed by the FDA for use in women, but it is allergic contact dermatitis, which precludes fur- commonly used off-label for this purpose. ther use of the drug and reversible hypertrichosis. Several studies (Alanis et al. 1991 ; van Zuuren Minoxidil is contraindicated during pregnancy et al. 2012b ; Olsen et al. 2002 ; Krupa Shankar and lactation (Blumeyer et al. 2011 ). et al. 2009 ; Lucky et al. 2004 ; Price et al. 1999 ) Some patients may experience increased hair have demonstrated that minoxidil applied twice a shedding during the fi rst months of the treatment. day is an effective treatment for AGA in both men This is transitory and only indicates that the drug and women. is stimulating telogen follicles to reenter anagen. Olsen et al. 2002 performed a randomized Treatment should be continued for a minimum clinical trial comparing the use of 5 % topical period of 12 months before deciding about the minoxidil versus 2 % topical minoxidil and pla- effi cacy, although the fi rst signs of hair regrowth cebo in the treatment of AGA in men. The authors can appear after 4–6 months of therapy. If the refer that the men who used 5 % topical minoxidil treatment prescribed is effective, it should be 194 R. Alves and R. Grimalt maintained, since AGA will relapse after with- fi nasteride use. According to authors, fi nasteride drawal of treatment (Tosti and Piraccini 1999 ). halted hair loss in six adolescent boys. More pro- Olsen et al. (1990 ) performed a 5-year follow- spective data evaluating the safety and effi cacy of up of men with AGA treated with topical minoxi- fi nasteride in adolescent hair loss are needed. dil and referred that hair regrowth with topical minoxidil tended to peak at 1 year with a slow Conclusion decline in regrowth over subsequent years. There The psychological and cosmetic importance are several explanations as to why topical min- of hair is immense in our society. Disruption oxidil could be less effective at 5 years than at 1 in the normal appearance of hair can predis- year. Perhaps this is secondary to tachyphylaxis pose to low self-esteem and negative body or an obligatory cycling in hair growth. Topical image (Moreno- Romero and Grimalt 2014 ). minoxidil stimulates the growth of epidermal AGA is the most common cause of adoles- cells in culture and presumably stimulates hair cent hair loss. The teenagers who present with growth by initiating and promoting the anagen hair thinning can feel unattractive with a nega- phase of these epidermally derived structures tive body image. This source of distress can (Olsen et al. 1987 ; Katz et al. 1987). However, at lead to anxiety, depression, and social 4–5 years, maintenance of nonvellus hairs beyond isolation. that seen at baseline was still evident. The typical history of AGA is a chronic Finasteride is a synthetic drug approved by hair loss with thinning mainly over the frontal, FDA in 1993 for therapy of mild to moderate parietal, or vertex areas. Family history is usu- AGA in men with 18 years and older. It is not ally positive for AGA. In female patients, indicated in women and is contraindicated in careful attention must be given to assess any pregnant women, because of the risk of feminiza- associated hormonal dysfunction. If appropri- tion of a male fetus (Blumeyer et al. 2011 ). ated, further endocrinological investigations Finasteride is a type II 5-alpha-reductase may be required. inhibitor which decreases DHT in the serum, There is no approved therapy for AGA in prostate, and scalp. A single oral administration the adolescent population. of fi nasteride 1 mg decreases serum DHT as well According to several studies and case as scalp DHT up to 70 % compared to baseline. series, topical minoxidil appears to be an There is no known interaction with other effective and well-tolerated treatment for ado- drugs, such as warfarin, theophylline, digoxin, lescents (girls and boys) with AGA (Gonzalez and propranolol (Blumeyer et al. 2011 ). Minimal et al. 2010 ; Price 2003 ; Trancik et al. 2001a , b , period of use prior to assessing the effi cacy is 6 c ). Finasteride 1 mg has been used in boy ado- months for reducing hair loss and 12 months for lescents with increased hair density and no regrowth of hair. progression in hair loss. Although it is not approved for AGA in men Treatment options for AGA should be fur- under 18 years of age, some physicians commonly ther evaluated in the adolescent population to used fi nasteride 1 mg off-label for this purpose. ensure safety and effi cacy. Individualized con- Gonzalez et al. (2010 ) performed a study in sideration of attitudes, concerns, self-treating which seven boys, aged 14–17 years, were treated efforts, and expectations is crucial for effec- with both 5 % minoxidil and fi nasteride solutions tive management of AGA. (1 mg daily), and two were treated with fi nasteride alone (18 and 19 years old). Follow-up was available for the six of nine patients treated with Bulleted List of Controversies fi nasteride; all six boys (four also using minoxidil 5 %) reported increased hair density with no pro- • Currently, there is no FDA-approved treat- gression in hair loss. One experienced decreased ment for androgenic alopecia in adolescents. sexual function that resolved despite continued Although an off-label indication, physicians 19 Androgenetic Alopecia in Adolescents 195

commonly use topical minoxidil and oral fi n- Cutrone M, Grimalt R. Transient neonatal hair loss. Eur asteride with this purpose. J Pediatr. 2005;164(10):630–2. Gan DC, Sinclair RD. Prevalence of male and female pat- • Continued use of topical minoxidil seems to tern hair loss in Maryborough. J Investig Dermatol prevent further hair loss. Although success Symp Proc. 2005;10:184–9. rates of minoxidil during long-term follow-up Gonzalez ME, Cantatore-Francis J, Orlow SJ. tend to be lower, maintenance of nonvellus Androgenetic alopecia in the paediatric population: a retrospective review of 57 patients. Br J Dermatol. hairs beyond that seen at baseline was still 2010;163(2):378–85. evident. Grover C, Khurana A. Telogen effl uvium. Indian • Emotional stress is widely thought to be a J Dermatol Venereol Leprol. 2013;79(5):591–603. common cause of telogen effl uvium. However, Harrison S, Sinclair R. Optimal management of hair loss (alopecia) in children. Am J Clin Dermatol. how much the role of stress is actually respon- 2003;4(11):757–70. Review. sible for increased telogen hair loss is not sci- Harrison S, Sinclair R. Telogen effl uvium. Clin Exp entifi cally proven, and, until now, the research Dermatol. 2002;27(5):389–5. Review. literature does not offer a completely consis- Herskovitz I, Tosti A. Female pattern hair loss. Int J Endocrinol Metab. 2013;11(4), e9860. tent answer about this question. Kaliyadan F, Nambiar A, Vijayaraghavan S. Androgenetic alopecia: an update. Indian J Dermatol Venereol Leprol. 2013;79:613–25. References Katz HI, Hien NT, Prawer SE, Goldman SJ. Long-term effi cacy of topical minoxidil in male pattern baldness. J Am Acad Dermatol. 1987;16(3 Pt 2):711–8. Alanis A, Barbara F, Meurehg C, De Oca FL, Ramirez Kaufman KD. Androgen metabolism as it affects hair L. Double-blind comparison of 2 % topical minoxidil growth in androgenetic alopecia. Dennatol Clin. and placebo in early male pattern baldness. Curr Ther 1996;14:697–711. Res Clin Exp. 1991;49(5):723–30. Kim BJ, Kim JY, Eun HC, Kwon OS, Kim MN, Ro Alkhalifah A, Alsantali A, Wang E, McElwee KJ, Shapiro BI. Androgenetic alopecia in adolescents: a report of J. Alopecia areata update: part I. Clinical picture, his- 43 cases. J Dermatol. 2006;33(10):696–9. topathology, and pathogenesis. J Am Acad Dermatol. Kowalska-Oledzka E, Slowinska M, Rakowska 2010;62(2):177–88, quiz 189–90. A. Sensitivity and specifi city of the trichoscopy. Blume-Peytavi U, Blumeyer A, Tosti A, Finner A, Marmol Indian J Dermatol Venereol Leprol. 2012;78: V, Trakatelli M, Reygagne P, Messenger A, European 636–7. Consensus Group. S1 guideline for diagnostic evalua- Krupa Shankar D, Chakravarthi M, Shilpakar R. Male tion in androgenetic alopecia in men, women and ado- androgenetic alopecia: population-based study in lescents. Br J Dermatol. 2011;164(1):5–15. 1,005 subjects. Int J Trichology. 2009;1(2):131–3. Blumeyer A, Tosti A, Messenger A, Reygagne P, Del Lucky AW, Piacquadio DJ, Ditre CM, Dunlap F, Marmol V, Spuls PI, Trakatelli M, Finner A, Kantor I, Pandya AG, Savin RC, Tharp MD. A ran- Kiesewetter F, Trüeb R, Rzany B, Blume-Peytavi U, domized, placebo-controlled trial of 5% and 2% European Dermatology Forum (EDF). Evidence- topical minoxidil solutions in the treatment of based (S3) guideline for the treatment of androgenetic female pattern hair loss. J Am Acad Dermatol. alopecia in women and in men. J Dtsch Dermatol Ges. 2004;50(4):541–53. 2011;9 Suppl 6:S1–57. Ludwig E. Classifi cation of the types of androgenetic alo- Budd D, Himmelberger D, Rhodes T, Cash TE, Girman pecia (common baldness) occurring in the female sex. CJ. The effects of hair loss in European men: a survey Br J Dermatol. 1977;97:247–54. in four countries. Eur J Dermatol. 2000;10(2):122–7. Madani S, Shapiro J. Alopecia areata update. J Am Acad Cash TF. The psychological effects of androgenetic alope- Dermatol. 2000;42(4):549–66; quiz 567–70. cia in men. J Am Acad Dermatol. 1992;26:926–31. McDonough PH, Schwartz RA. Adolescent androgenic Cash TF, Price VH, Savin RC. Psychological effects of alopecia. Cutis. 2011;88(4):165–8. androgenetic alopecia on women; comparisons with Moreno-Romero JA, Grimalt R. Hair loss in infancy. G balding men and with female control subjects. J Am Ital Dermatol Venereol. 2014;149(1):55–78. Acad Dermatol. 1993;29:568–75. Norwood OT. Male pattern baldness: classifi cation and Cash TF. The psychology of hair loss and its implications incidence. South Med J. 1975;68:1359–65. for patient care. Clin Dermatol. 2001;19(2):161–6. Olsen EA, DeLong ER, Weiner MS. Long-term follow-up Chumlea WC, Rhodes T, Girman CJ. Family history and of men with male pattern baldness treated with topical risk of hair loss. Dermatology. 2004;209:33–9. minoxidil. J Am Acad Dermatol. 1987;16(3 Pt 2): Courtois M, Loussouarn G, Hourseau S, Grollier 688–95. JF. Periodicity in the growth and shedding of hair. Br Olsen EA, Dunlap FE, Funicella T, Koperski JA, Swinehart J Dermatol. 1996;134(1):47–54. JM, Tschen EH, Trancik RJ. A randomized clinical trial 196 R. Alves and R. Grimalt

of 5% topical minoxidil versus 2% topical minoxidil Tosti A, Iorizzo M, Piraccini BM. Androgenetic alopecia and placebo in the treatment of androgenetic alopecia in in children: report of 20 cases. Br J Dermatol. men. J Am Acad Dermatol. 2002;47(3):377–85. 2005;152:556–9. Olsen EA, Messenger AG, Shapiro J. Evaluation and Tosti A, Piraccini BM. Androgenetic alopecia. Int treatment of male and female pattern hair loss. J Am J Dermatol. 1999;38 Suppl 1:1–7. Review. Acad Dermatol. 2005;52:301–11. Trancik RJ, Spindler JR, Rose S. Incidence of androge- Olsen EA, Weiner MS, Amara IA, DeLong ER. Five-year netic alopecia in males 15 to 17 years of age. Poster follow-up of men with androgenetic alopecia treated presented at: 3rd Intercontinental Meeting of the with topical minoxidil. J Am Acad Dermatol. Hair Research Societies; 13–15 June 2001a; Tokyo. 1990;22(4):643–6. p. 127. Olsen EA. Current and novel methods for assessing effi - Trancik RJ, Spindler JR, Cuddihy RV. Clinician survey cacy of hair growth promoters in pattern hair loss. evaluating minoxidil topical solution in the treatment J Am Acad Dermatol. 2003;48(2):253–62. of androgenetic alopecia in patients under 18 years of Olsen EA. Hair loss in childhood. In: Olsen EA, editor. age. Poster presented at: 3rd Intercontinental Meeting Disorders of hair growth. Diagnosis and treatment. of the Hair Research Societies; June 13–15, 2001b; 2nd ed. New York: McGraw Hill; 1994a. p. 177–238. Tokyo. p. 129. Olsen EA. Clinical tools for assessing hair loss. In: Olsen Trancik RJ, Spindler JR, Ferry JJ, et at. Investigation of EA, editor. Disorders of hair growth. Diagnosis and the systemic bioavailability of 5% minoxidil topical treatment. 2nd ed. New York: McGraw Hill; 1994b. solution in young males with early androgenetic alo- p. 59–69. pecia. Poster presented at: 3rd Intercontinental Patel M, Harrison S, Sinclair R. Drugs and hair loss. Meeting of the Hair Research Societies; 13–15 June Dermatol Clin. 2013;31(1):67–73. 2001c; Tokyo. p. 126. Price VH, Menefee E, Strauss PC. Changes in hair weight Tuccori M, Pisani C, Bachini L, Pardini M, Mantarro S, and hair count in men with androgenetic alopecia, Antonioli L, Fornai M, Rubinelli M, Cirinei C, after application of 5% and 296 topical minoxidil, pla- Blandizzi C. Telogen effl uvium following bivalent cebo, or no treatment. J Am Acad Dermatol. 1999;41(5 human papillomavirus vaccine administration: a report Pt 1):717–21. of two cases. Dermatology. 2012;224(3):212–4. Price VH. Androgenetic alopecia in adolescents. Cutis. van Zuuren EJ, Fedorowicz Z, Carter B, Andriolo RB, 2003;71(2):115–21. Review. Schoones J. Interventions for female pattern hair loss. Rakowska A, Slowinska M, Kowalska-Oledzka E, Cochrane Database Syst Rev. 2012a;16:5. Olszewska M, Rudnicka L. Dermoscopy in female van Zuuren EJ, Fedorowicz Z, Carter B. Evidence-based androgenic alopecia: method standardization and treatments for female pattern hair loss: a summary diagnostic criteria. Int J Trichology. 2009;1:123–30. of a Cochrane systematic review. Br J Dermatol. Rakowska A, et al. Androgenetic alopecia. In: Rudnika L, 2012b;167(5):995–1010. Olszewska M, Rakowska A, editors. Atlas of trichos- Werner B, Mulinari-Brenner F. Clinical and histological copy. London: Springer; 2012. p. 221–35. challenge in the differential diagnosis of diffuse alope- Randall VA, Ebling FJ. Seasonal changes in human hair cia: female androgenetic alopecia, telogen effl uvium growth. Br J Dermatol. 1991;124(2):146–51. and alopecia areata - part I. An Bras Dermatol. Rathnayake D, Sinclair R. Male androgenetic alopecia. 2012;87(5):742–7. Expert Opin Pharmacother. 2010;11(8):1295–304. Whiting DA, Waldstreicher J, Sanchez M, Kaufman Rudnicka L, Olszewska M, Rakowska A, Kowalska-Oledzka KD. Measuring reversal of hair miniaturization in E, Slowinska M. Trichoscopy: a new method for diag- androgenetic alopecia by follicular counts in horizontal nosing hair loss. J Drugs Dermatol. 2008;7:651–4. sections of serial scalp biopsies: results of fi nasteride Shapiro R, et al. Hair anatomy and histology. In: Unger WP, 1 mg treatment of men and postmenopausal women. Shapiro R. Hair transplantation. 4th ed. Revised and J Investig Dermatol Symp Proc. 1999;4(3):282–4. expanded; Marcel Dekker, New York: 2004. p. 25–33. Whiting DA. Diagnostic and predictive value of horizon- Sinclair R, Jolliffe V. Diffuse hair loss-telogen effl uvium. tal sections of scalp biopsy specimens in male pattern In: Fast facts: disorders of the hair and scalp. 2nd ed. androgenetic alopecia. J Am Acad Dermatol. Oxford: Health Press; 2013. p. 51–7. 1993;28:755–63. Sinclair RD, Banfi eld CC, Dawber RP. Hair structure and Wise RP, Kiminyo KP, Salive ME. Hair loss after routine function. In: Sinclair RD, Banfi eld CC, Dawber RP, immunizations. JAMA. 1997;278(14):1176–8. editors. Handbook of diseases of the hair and scalp. Witchel SF. Hyperandrogenism in adolescents. Adolesc Oxford: Blackwell Science; 1999. p. 3–23. Med. 2002;13(1):89–99, vi–vii. Strauch B, Greenstein B. Cosmetic plastic surgery in ado- Zhao Y, Zhang B, Caulloo S, Chen X, Li Y, Zhang lescents. Adolesc Med. 1997;8(3):537–45. X. Diffuse alopecia areata is associated with intense Tosti A, Fanti PA, Morelli R, Bardazzi F. Trachyonychia infl ammatory infi ltration and CD8+ T cells in hair loss associated with alopecia areata: a clinical and patho- regions and an increase in serum IgE level. Indian logical study. J Am Acad Dermatol. 1991;25:266–70. J Dermatol Venereol Leprol. 2012;78(6):709–14. Classifi cation of Mastocytosis 2 0 Dirk Van Gysel

Abstract The term “mastocytosis” denotes a heterogeneous group of disorders, characterized by local or diffuse increased growth and accumulation of mast cells in the skin and/or in internal organs. Most classiﬁ cations consider cutaneous mastocytosis and systemic mastocytosis as mutually exclusive conditions. However, as bone marrow studies to demonstrate a systemic involvement are not routinely performed nor recommended in children, a classiﬁ cation of pediatric mastocytosis according to the morphological appearance of the lesions can be followed.

Keywords Mastocytosis • Classiﬁ cation of mastocytosis • Cutaneous mastocytosis • Systemic mastocytosis

The term mastocytosis denotes a heterogeneous Mastocytosis was ﬁ rst described in 1869 by group of disorders, characterized by local or dif- Nettleship and Tay as a “chronic urticaria, leav- fuse increased growth and accumulation of mast ing brown stains; nearly 2 year’s duration” in the cells (MCs) in the skin and/or in internal organs British Medical Journal (Nettleship and Tay (Stein 1986 ; Kettelhut and Metcalfe 1991 ; Horan 1869). It was not until 1877, however, that mast et al. 1992 ; Marney 1992 ; Longley et al. 1995 ). cells were actually described by Ehrlich (Ehrlich The clinical signs and symptoms are produced by 1877 ). He considered them to be the result of the functional effects of MC-derived mediators overfeeding (in German Mästung) and accord- and the anatomical distribution of the MC that ingly named them Mastzellen. Subsequently, in produced and released them. The skin is the most 1878, Sangster described a patient with a pruritic, frequently involved organ, but all organs may be pigmented urticarial rash, and he labeled this involved (Metcalfe 1991a ; Soter 1991 , 2000 ). cutaneous eruption urticaria pigmentosa (Sangster 1878 ). The importance of mast cells in this disorder was not discovered until 1887, when D. Van Gysel , MD, PhD Unna showed the presence of large numbers of Department of Pediatrics , O. L. Vrouw Hospital , dermal mast cells in the skin lesions of affected Moorselbaan , Aalst , Belgium e-mail: [email protected] patients (Unna 1887 ). Almost 50 years later,

Sézary fi rst used the terms mastocytoma and – Localized extracutaneous MC prolifera- mastocytosis in the current sense (Sézary et al. tions, either presenting as a malignancy 1936). It was not until 1949 that Ellis discovered (mast cell sarcoma (MCS)) or as a benign involvement of internal organs in mastocytosis in tumor (extracutaneous mastocytoma) an autopsy case of a 1-year-old infant (Ellis 1949 ). Mast cell leukemia (MCL) was reported In that concept, the diagnosis of CM is based for the fi rst time in 1957 (Efrati et al. 1957 ). on clinical and histological fi ndings in the skin The classifi cation of mastocytosis has evolved together with the absence of criteria that would over the years (Travis et al. 1988 ; Metcalfe allow the diagnosis SM. 1991b ; Lennert and Parwaresch 1979 ). A fi rst The clinical expressions of CM include soli- attempt to classify several variants of mastocyto- tary mastocytoma, maculopapular CM, and dif- sis was made by Degos in 1955 (Degos 1955 ). In fuse cutaneous mastocytosis (DCM). 1979 a new classifi cation was proposed by Telangiectasia macularis eruptiva perstans Lennert and Pawaresch (Lennert and Parwaresch (TMEP) is an entity that has not been recog- 1979 ). This classifi cation has in the meantime nized by the WHO (Soter 2000 ; Leonardi et al. been abandoned but served as basis of the updated 2012 ). classifi cation of mastocytosis developed by Metcalfe in 1991 (Metcalfe 1991a ). The fi rst WHO classifi cation was published in 2001 by Mastocytoma Valent et al. (2001a , b ) and updated in 2008 (Table 20.1 ) in light of new developments, con- Of children with mastocytosis, 10–30 % pres- sidering MC disease as a myeloproliferative neo- ent with solitary mastocytoma(s). Arbitrarily, plasm and systemic mastocytosis (SM) as a in patients with mastocytoma(s), a maximum subcategory of MC disease with bone marrow of fi ve localized skin lesions are present. They involvement (Valent et al. 2007; Horny et al. present as round to oval, slightly elevated mac- 2008 ; Tefferi and Vardiman 2008 ). ules, plaques, or nodules, and their color varies This classifi cation defi nes three major from that of the surrounding skin to yellowish categories: or brownish (Fig. 20.1 ). The skin surface may resemble the pitted skin of an orange (“peau • Cutaneous mastocytosis (CM), with the skin d’orange”) and bullae may be present (Soter being the only organ involved 1991 ; Munro and Farr 1992 ). The diameter • SM, further subdivided into four major varies from 1 to 5 cm, but lesions up to 15 cm subtypes: in diameter may occur. Systemic involvement – Indolent systemic mastocytosis (ISM), is rare, but may occur (Birt and Nickerson including isolated bone marrow mastocyto- 1959). sis and smoldering systemic mastocytosis (SSM) – Systemic mastocytosis with an a ssociated Maculopapular CM c lonal h ematologic n on- m ast cell lineage d isease (SM-AHNMD) Maculopapular CM (formerly known as urticaria – Aggressive systemic mastocytosis (ASM), pigmentosa) is by far the most common variant characterized by organ impairment due to (70–90 %) of childhood mastocytosis. The erup- MC infi ltrates tion consists of slightly elevated, skin-colored, – Mast cell leukemia (MCL), which may brown-red or yellow macules, plaques, or nod- (fi rst) present as an aleukemic subvariant ules (Fig. 20.2). The lesions occur in a general- (<10 % MC in blood smears) or show a leu- ized distribution but tend to be of highest density kemic pattern at diagnosis (MC ≥ 10 % in on the trunk. Acral areas are often spared (Soter blood smears) 1991 ). 20 Classifi cation of Mastocytosis 199

Table 20.1 Classifi cation and characteristics of the different variants of mastocytosis Disease entities Investigation(s) a Typical fi nding(s) Cutaneous mastocytosisa (CM) SM criteriaa Not fulfi lled including Skin lesions Present, MC infi ltrates, c-kit Mastocytoma mutation in Lesional skin Maculopapular CM Bone marrow histologya Negative, no MC infi ltrates Diffuse CM Peripheral blood counts Normala Serum tryptase <20 ng/mla Indolent systemic mastocytosis SM criteria Fulfi lled (ISM) including: Skin lesions Present (vast majority) Smoldering SM Bone marrow histology Multifocal MC infi ltrates Isolated BM mastocytosis Bone marrow cytology (smears) Bone marrow MC <20 %, low grade CD2/CD25 on bone marrow MC Found Peripheral blood counts Normal or slightly abnormal Serum tryptase >20 ng/ml Liver/spleen/lymph nodes Organomegaly may be found Systemic mastocytosis with an SM criteria Fulfi lled AHNMD (SM-AHNMD)b WHO/FAB criteriab AHNMD including: SM-acute myeloid leukemia SM-myelodysplastic syndromes SM-chronic myelomonocytic leukemia SM-non-Hodgkin’s Lymphoma SM-Myeloproliferative disease SM-Hypereosinophilic syndrome Aggressive systemic mastocytosis SM criteria Fulfi lled (ASM) Skin lesions Often absent Bone marrow histology Multifocal MC infi ltrates Bone marrow cytology MC <20 %, low- or high-grade Bone marrow may be dys/ hyperplastic, but no AHNMD (FAB/WHO)b Peripheral blood counts Abnormal Liver/spleen/lymph nodes Organomegaly Organ function impaired Mast cell leukemia (MCL) SM criteria Fulfi lled including an aleukemic subvariant Skin lesions Absent (in peripheral blood: MC <10 %) Bone marrow histology 'Positive' (diffuse and dense) Bone marrow cytology ≥20 % MC, often high grade Peripheral blood counts <1 0 % or ≥10 % MC Organ function Impaired (liver, bone marrow, others) Mast cell sarcoma SM criteria Not fulfi lled Macroscopic Unifocal, destructive growth Histology High-grade focal MC tumor Extracutaneous mastocytoma SM criteria Not fulfi lled Macroscopic Unifocal, benign tumor Histology Low-grade focal MC tumor Modifi ed from Valent et al. (2001b ), with permission a Most pediatric cases are diagnosed as CM by skin biopsy and blood examination only; they do not need to have further examinations or tests b AHNMD: a ssociated c lonal h ematologic n on- m ast cell lineage d isease. To diagnose an AHNMD, the French- American-British Cooperative Leukaemia Group (Bennett et al. 1994)/World Health Organization (Harris et al. 1999 ) (FAB/WHO) criteria have to be fulfi lled 200 D. Van Gysel

DCM MC-derived mediators may dominate the clinical picture (Kettelhut and Metcalfe 1991 ). DCM is a rare variant that generally presents in the Systemic mastocytosis can occur with or with- neonatal period. Large areas of the skin are infi l- out skin lesions. For the diagnosis of SM, at least trated by MCs. The skin may have a smooth or 1 major + 1 minor or at least 3 minor criteria leathery appearance or may appear normal. The should be fulfi lled (Table 20.2 ). skin may be covered with papules with a yellowish Theoretically involvement of other (internal) hue and resemble pseudoxanthoma elasticum organs should be excluded before the diagnosis of (Selye 1965 ). The skin surface may have a uniform CM can be made, and systemic mastocytosis can be red color, giving the patient an erythrodermic excluded. However bone marrow studies to demon- appearance (Requena 1992 ). Blister formation may strate a systemic involvement are not routinely per- occur in the neonatal period and mimic “staphylo- formed and are in fact not recommended in children. coccal scalded skin” syndrome (Oranje et al. 1991 ). Serum tryptase levels are a good tool to distinguish Recently, our group described two major variants, a patients with mastocytosis at an extracutaneous red large blistering (Fig. 20.3 ) and an orange-yellow location. Serum tryptase levels in mastocytosis are small blistering (Fig. 20.4 ) one (Heide et al. 2009 ). normal in most cases of uncomplicated CM but are In CM the visible cutaneous abnormalities are >20 ng/L in SM. In adults with SM, a positive cor- most often of major concern to the patient and its relation between density of the skin lesions, dura- family. However, in some patients the signs and tion of the disease and constitutional symptoms, symptoms produced by the functional effects of organomegaly, and raised serum tryptase levels has been shown, whereas in children such a relationship has not been observed (Brockow et al. 2003 ). For this reason, a classifi cation of pediatric mastocytosis according to the morphological appearance of the lesions can be followed. In 2002 Hartmann and Henz (Hartmann and Henz 2002 ) published such a proposal, distinguishing fi ve variants of CM:

• Maculopapular CM • Plaque-type CM • Nodular CM/mastocytoma • DCM • Telangiectatic CM (formerly known as Fig. 20.1 Mastocytoma TMEP)

a b

Fig. 20.2 ( a ) Maculopapular mastocytosis overview. (b ) Maculopapular cutaneous mastocytosis detail 20 Classiﬁ cation of Mastocytosis 201

Fig. 20.3 DCM: the red large blistering variant

Table 20.2 Proposed criteria for systemic mastocytosis gorized as ISM. In contrast, plaque-type CM has Major: Multifocal dense infi ltrates of MC (>15 lesions of several centimeters in diameter, and MC aggregating) detected in sections of the the solitary mastocytomas do not evolve but tend bone marrow and/or of other to disappear. extracutaneous organs by tryptase A similar classifi cation was presented by our immunohistochemistry or other stains group (Heide et al. 2008 ; Van Gysel et al. 2011 ), Minor: (a) >25 % of MC in MC infi ltrates detected in sections of the bone marrow or other distinguishing three more common subtypes of extracutaneous organs are spindle shaped CM: or presence of >25 % atypical MC in bone marrow aspirates • Maculopapular mastocytosis (more than two (b) Detection of a c-kit point mutation at localized skin lesions) codon 816 in the bone marrow or blood or other extracutaneous organs • Mastocytoma (number of localized skin (c) Kit + mast cells in the bone marrow or lesions limited to a maximum of two) blood or other extracutaneous organs • DCM (diffuse skin involvement) co-express CD2 or/and CD25 (d) Serum total tryptase concentration Serum tryptase levels are a good tool to distin- persistently >20 ng/ml (in case of an associated clonal hematologic non-mast guish patients with mastocytosis at an extracuta- cell lineage disease (AHNMD), (d) is not neous location. Serum tryptase levels in valid) mastocytosis are normal in most cases of uncom- If One major and one minor or three minor plicated CM but are >20 ng/L in SM. In adults criteria are fulfi lled; then the diagnosis is with SM, a positive correlation between density systemic mastocytosis (SM) of the skin lesions, duration of the disease and Valent et al. (2001a ), with permission constitutional symptoms, organomegaly, and raised serum tryptase levels has been shown, These authors suggested, based on the course whereas in children such a relationship has not and prognosis, that maculopapular mastocytosis been observed (Brockow et al. 2003 ). in fact consists of different variations of In 2010 a working conference was organized CM. Maculopapular CM has small lesions, with the aim to propose a global unifying occurs in children and in adults, rarely resolves classifi cation of all MC disorders and pathologic spontaneously, and will often eventually be cate- MC reactions. The members argued that both 202 D. Van Gysel

Fig. 20.4 DCM: the orange-yellow small blistering variant (Courtesy of Prof. Z. Szalae)

mastocytosis and MC activation syndromes Bulleted List of Controversies (MCAS) should be integrated into a global classifi cation of MC-related disorders, including • The WHO classifi cation considers MC dis- neoplastic and nonneoplastic conditions, “a ease as a myeloproliferative neoplasm and needed extension beyond previous (WHO) clas- systemic mastocytosis as a subcategory of MC sifi cations of MC disorders” (Valent et al. 2012 ). disease with bone marrow involvement. This classifi cation includes four major • As bone marrow studies to demonstrate a sys- categories: temic involvement are not routinely performed nor recommended in children, a classifi cation • MC hyperplasia of pediatric mastocytosis according to the • MCAS morphological appearance of the lesions can • Mastocytosis be followed (cfr Hartmann and Henz 2002 and • Myelomastocytic-overlap conditions Oranje et al. 1991 ). • In adults with SM, a positive correlation In this classifi cation mastocytosis is divided between density of the skin lesions, duration into CM, SM, and local MC tumors (mastocy- of the disease and constitutional symptoms, toma and MCS). CM and SM are mutually organomegaly, and raised serum tryptase lev- exclusive conditions. CM is defi ned by “masto- els has been shown, whereas in children such cytosis in the skin” (MIS) criteria (see Chap. 21 ) a relationship has not been observed (Brockow and the absence of SM (criteria for SM not ful- et al. 2003 ). fi lled). SM is defi ned by the presence of SM cri- • In 2010 a global unifying classifi cation of all teria. Both CM and SM may be further divided MC disorders and pathologic MC reactions into subvariants. MCA can occur in any variant was proposed (cfr Valent et al. 2012 ). of mastocytosis. Ideally, the classifi cation of • Ideally the classifi cation of childhood mas- childhood mastocytosis should defi ne very dis- tocytosis should defi ne very distinct types tinct types with a prognostic correlation. Such with a prognostic correlation, but such clas- classifi cation, however, is still not attained sifi cation is still not attained (cfr Torrelo (Torrelo et al. 2012 ). et al. 2012 ) . 20 Classifi cation of Mastocytosis 203

References Lennert K, Parwaresch MR. Mast cells and mast cell neo- plasia: a review. Histopathology. 1979;3(5):349–65. Leonardi S, Vitaliti G, Pratico AD, La Rosa Bennett JM, Catovsky D, Daniel MT, Flandrin G, Galton M. Telangiectasia macularis eruptiva perstans (TMEP) DA, Gralnick H, Sultan C, Cox C. The chronic in childhood: a case report and literature review. myeloid leukaemias: guidelines for distinguishing Allergol Immunopathol (Madr). 2012;40(5):321–3. chronic granulocytic, atypical chronic myeloid, and doi: 10.1016/j.aller.2011.05.006 . chronic myelomonocytic leukaemia. Proposals by the Longley J, Duffy TP, Kohn S. The mast cell and mast cell French-American-British Cooperative Leukaemia disease. J Am Acad Dermatol. 1995;32(4):545–61; Group. Br J Haematol. 1994;87(4):746–54. quiz 562–544. Birt AR, Nickerson M. Generalized fl ushing of the skin Marney Jr SR. Mast cell disease. Allergy Proc. with urticaria pigmentosa. Arch Dermatol. 1992;13(6):303–10. 1959;80:311–7. Metcalfe DD. Classifi cation and diagnosis of mastocyto- Brockow K, Akin C, Huber M, Metcalfe DD. Assessment sis: current status. J Invest Dermatol. 1991a;96(3):2S–4. of the extent of cutaneous involvement in children and Metcalfe DD. Conclusions. Clinical advances in mastocy- adults with mastocytosis: relationship to symptom- tosis: an interdisciplinary round table discussion. atology, tryptase levels, and bone marrow pathology. J Invest Dermatol. 1991b;96(3):S64–5. J Am Acad Dermatol. 2003;48(4):508–16. Munro CS, Farr PM. Solitary mastocytoma causing recur- doi: 10.1067/mjd.2003.98 . rent blistering in infancy. Arch Dis Child. Degos R. Urticaria pigmentosa and other types of masto- 1992;67(8):1038–9. cytosis; attempted classifi cation of cutaneous masto- Nettleship J, Tay W. Rare forms of urticaria. Br Med cytoses. Actas Dermosifi liogr. 1955;46(9):759–85. J. 1869;2:323–4. Efrati P, Klajman A, Spitz H. Mast cell leukemia? Oranje AP, Soekanto W, Sukardi A, Vuzevski VD, van der Malignant mastocytosis with leukemia-like manifesta- Willigen A, Afi ani HM. Diffuse cutaneous mastocyto- tions. Blood. 1957;12(10):869–82. sis mimicking staphylococcal scalded-skin syndrome: Ehrlich P. Berträge zur Kenntnis der anilifarbungen und report of three cases. Pediatr Dermatol. ihrer Verwendung in der microscopischem Technik. 1991;8(2):147–51. Arch Mikros Anat. 1877;13:163–77. Requena L. Erythrodermic mastocytosis. Cutis. Ellis JM. Urticaria pigmentosa; a report of a case with 1992;49(3):189–92. autopsy. Arch Pathol. 1949;48(5):426–35. Sangster A. An anomalous mottled rash, accompanied by Harris NL, Jaffe ES, Diebold J, Flandrin G, Muller- pruritus, factitious urticaria and pigmentation, ‘urti- Hermelink HK, Vardiman J, Lister TA, Bloomfi eld caria pigmentosa (?)’. Trans Clin Soc London. CD. The World Health Organization classifi cation of 1878;11:161–3. neoplastic diseases of the hematopoietic and lymphoid Selye H. Diseases. In: Selye H, editor. The mast cells. tissues. Report of the Clinical Advisory Committee London: Butterworth; 1965. p. 262–75. meeting, Airlie House, Virginia, November, 1997. Ann Sézary A, Levy-Coblentz G, Chauvillon Oncol. 1999;10(12):1419–32. P. Dermographisme et mastocytose. Bull Soc Fr Hartmann K, Henz BM. Classifi cation of cutaneous mas- Dermatol Syphiligr. 1936;43:359–61. tocytosis: a modifi ed consensus proposal. Leuk Res. Soter NA. The skin in mastocytosis. J Invest Dermatol. 2002;26(5):483–4; discussion 485–486. 1991;96(3):32S–8; discussion 38S–39S. Heide R, Beishuizen A, De Groot H, Den Hollander JC, Soter NA. Mastocytosis and the skin. Hematol Oncol Clin Van Doormaal JJ, De Monchy JG, Pasmans SG, Van North Am. 2000;14(3):537–55, vi. Gysel D, Oranje AP. Mastocytosis in children: a proto- Stein DH. Mastocytosis: a review. Pediatr Dermatol. col for management. Pediatr Dermatol. 1986;3(5):365–75. 2008;25(4):493–500. doi:PDE738 [pii] Tefferi A, Vardiman JW. Classifi cation and diagnosis of 10.1111/j.1525-1470.2008.00738.x . myeloproliferative neoplasms: the 2008 World Health Heide R, Zuidema E, Beishuizen A, Den Hollander JC, Organization criteria and point-of-care diagnostic Van Gysel D, Seyger MM, Pasmans SG, Kakourou T, algorithms. Leukemia. 2008;22(1):14–22. Oranje AP. Clinical aspects of diffuse cutaneous mas- doi: 10.1038/sj.leu.2404955 . tocytosis in children: two variants. Dermatology. Torrelo A, Alvarez-Twose I, Escribano L. Childhood mas- 2009;219(4):309–15. doi: 10.1159/000243808 . tocytosis. Curr Opin Pediatr. 2012;24(4):480–6. Horan RF, Schneider LC, Sheffer AL. Allergic skin disor- doi: 10.1097/MOP.0b013e328355b248 . ders and mastocytosis. JAMA. 1992;268(20):2858–68. Travis WD, Li CY, Bergstralh EJ, Yam LT, Swee Horny HP, Akin C, Metcalfe D. Mastocytosis. In: RG. Systemic mast cell disease. Analysis of 58 cases Swerdlow SH, Campo E, Harris NL, et al., editors. and literature review. Medicine (Baltimore). World Health Organization (WHO) classifi cation of 1988;67(6):345–68. tumours of haematopoietic and lymphoid origin, vol. Unna PG. Beitrage zur Anatomie und Pathogenese der 2. 4th ed. Lyon: IARC Press; 2008. p. 54–63. Urticaria simplex und pigmentosa. Mschr Prakt Kettelhut BV, Metcalfe DD. Pediatric mastocytosis. Dermatol. 1887;6:1. J Invest Dermatol. 1991;96(3):15S–8. 204 D. Van Gysel

Valent P, Akin C, Arock M, Brockow K, Butterfi eld JH, Valent P, Horny HP, Escribano L, Longley BJ, Li CY, Carter MC, Castells M, Escribano L, Hartmann K, Schwartz LB, Marone G, Nunez R, Akin C, Sotlar K, Lieberman P, Nedoszytko B, Orfao A, Schwartz LB, Sperr WR, Wolff K, Brunning RD, Parwaresch RM, Sotlar K, Sperr WR, Triggiani M, Valenta R, Horny Austen KF, Lennert K, Metcalfe DD, Vardiman JW, HP, Metcalfe DD. Defi nitions, criteria and global clas- Bennett JM. Diagnostic criteria and classifi cation of sifi cation of mast cell disorders with special reference mastocytosis: a consensus proposal. Leuk Res. to mast cell activation syndromes: a consensus pro- 2001a;25(7):603–25. posal. Int Arch Allergy Immunol. 2012;157(3):215– Valent P, Horny HP, Li CY, Longley BJ, Metcalfe D, 25. doi: 10.1159/000328760 . Parwaresch MR, Bennett JM. Mastocytosis (mast cell Valent P, Akin C, Escribano L, Fodinger M, Hartmann K, disease). In: Jaffe ES, Harris NL, Stein H, Vardiman J, Brockow K, Castells M, Sperr WR, Kluin-Nelemans editors. World Health Organization (WHO) classifi ca- HC, Hamdy NA, Lortholary O, Robyn J, van Doormaal tion of tumours: pathology and genetics, Tumours of J, Sotlar K, Hauswirth AW, Arock M, Hermine O, haematopoietic and lymphoid tissues, vol. 1. Lyon: Hellmann A, Triggiani M, Niedoszytko M, Schwartz IARC Press; 2001b. p. 291–302. LB, Orfao A, Horny HP, Metcalfe DD. Standards and Van Gysel D, van Schaik RH, Oranje AP. Mastocytosis. standardization in mastocytosis: consensus statements In: Irvine AD, Hoeger PH, Yan AC, editors. Harper’s on diagnostics, treatment recommendations and textbook of paediatric dermatology, vol. 1. 3rd ed. response criteria. Eur J Clin Invest. 2007;37(6):435– West Sussex: Wiley-Blackwell; 2011. p. 75.71–15. 53. doi: 10.1111/j.1365-2362.2007.01807.x . Mastocytosis in Children: What to Do? 2 1

Dirk Van Gysel

Abstract The diagnosis of mastocytosis in children can often readily be made on history and clinical examination. Histology with immunohistochemistry and, if available, c-KIT mutation analysis are necessary in the presence of atypical skin lesions. Measurement of serum tryptase and rarely bone marrow biopsy on strict indication are necessary for diagnosing childhood mastocytosis in the absence of skin lesions and for distinguishing cutaneous mastocytosis (CM) from systemic mastocytosis (SM). Therapy is directed at control of the mediator-related symptoms in patients with indolent disease.

Keywords Mastocytosis • Diagnostic algorithm for mastocytosis • Anti-mediator therapy for mastocytosis • KIT-targeting therapy for mastocytosis • Serum tryptase in the diagnosis of mastocytosis • Anesthesia and mastocytosis

Mastocytosis is a heterogeneous disease, charac- Bibi et al. 2014; Ma et al. 2014). The skin is the terized by an accumulation of pathological mast organ most frequently involved, but all organs cells (MCs) in different tissues and most com- may be affected. In cutaneous mastocytosis (CM) monly associated with activating c-KIT muta- the mast cell accumulations are limited to the tions, in keeping with a clonal process. In adults, skin. In systemic mastocytosis (SM) at least two neoplastic mast cells (MCs) show the c-KIT organs are involved. SM can occur with and with- D816V mutation, whereas in children, MCs out skin involvement. invading the skin are often positive for non-c- KIT D816V mutations (Bodemer et al. 2010 ; Diagnosis

The ﬁ rst step in all children who are suspected to D. Van Gysel , MD, PhD have mastocytosis is a skin examination to detect Department of Pediatrics , O. L. Vrouw Hospital , typical skin lesions (Fig. 21.1 ). In the presence of Moorselbaan 164 , Aalst 9300 , Belgium e-mail: [email protected] typical skin lesions (see Chap. 20 , “Classiﬁ cation

© Springer International Publishing Switzerland 2016 205 A.P. Oranje et al. (eds.), Practical Pediatric Dermatology, DOI 10.1007/978-3-319-32159-2_21 206 D. Van Gysel of Mastocytosis”), the diagnosis of “mastocytosis • In children with MIS and tryptase levels lower in the skin” (MIS) can readily be made. Rubbing than < 20 ng/ml and no other signs of SM, the or trauma of the affected skin results into a wheal diagnosis of CM can be made without any fur- with ﬂ are (Darier’s sign) in more than 90 % of the ther examinations (no bone marrow examina- patients. In these circumstances a biopsy for his- tion (BME) necessary). topathological examination is not indicated. • In children with MIS and a tryptase level of In the presence of atypical skin lesions, histol- 20–100 ng/ml and no other signs of SM, the ogy with immunohistochemistry (IHC) (using provisional diagnosis of MIS should be kept; antibodies against tryptase, CD117 (KIT), and these patients should be monitored until CD 25) and, if available, c-KIT mutation analysis puberty. If the skin lesions persist after puberty is necessary to establish the diagnosis. In normal or the tryptase levels remain higher than and reactive states, all mast cells co-express 20 ng/ml, a complete staging with BME tryptase and CD117, but tryptase expression may should be performed. be strongly decreased or even lost in rare cases of • A complete staging with BME and the appli- mastocytosis, thus leading to an incomplete cation of all SM criteria should also be per- “CD117-only” immunophenotype. Cells not formed in all adult patients and in all children expressing CD117 are not mast cells. CD25 is not in whom the serum tryptase is higher than expressed by normal or reactive but by trans- 100 ng/ml or in whom other signs of systemic formed mast cells and has been found to be the disease are found. most reliable immunohistochemical marker for diagnosis of mastocytosis (Sotlar et al. 2004 ; Signs of systemic disease include hemateme- Horny et al. 2014 ; Valent et al. 2010 ). sis, melena, severe bone pain and bone involve- The next step is classifying children with MIS ment, and abnormal hematological values. as having CM or SM (Fig. 21.2 ). Measurement of Screening for systemic involvement should serum tryptase and a thorough history and clini- include a complete blood cell count. Anemia, cal examination for other signs and symptoms of leukopenia, leukocytosis, and/or thrombocytope- systemic disease can help to identify possible nia, not explained by something else, and obser- systemic cases (Van Gysel et al. 1996 ). vation of mast cells in peripheral blood indicate

Typical skin Atypical Darier’s sign Other skin diseases + + lesions skin rash positive excluded

Histology, tryptase IHC

Mast cell aggregates (15 MC/cluster) or Histology monomorphic infiltrate with > 20 MC per HPF questionable

C-kit mutation analysis in lesional skin

Mastocytosis in the skin (MIS)

CM ? SM

Fig. 21.1 Diagnostic algorithm for “mastocytosis in the skin” (MIS) (Adapted from Valent et al. (2007 ) ) 21 Mastocytosis in Children: What to Do? 207

MIS

Childhood Adult

Tryptase Tryptase Tryptase < 20 ng/ml 20-100 ng/ml < 100 ng/ml

Other signs of systemic disease – + – +

CM MIS

Complete staging, apply Monitoring until adolescence SM-criteria

Skin lesions regress and Skin lesions persist and /or tryptase<20 ng/ml tryptase ≥ 20 ng/ml

CM SM Monitoring?

Fig. 21.2 Search for SM in patients with MIS (Adapted from Valent et al. (2007 ) ) bone marrow involvement and make a bone without MIS result from MC mediator release marrow examination necessary. Also early osteo- and include unexplained anaphylaxis (Brockow porosis should be evaluated. Other complaints et al. 2008), unexplained osteopathy, unexplained such as abdominal pain should require other neurological or constitutional symptoms, unex- investigations such as ultrasound or magnetic plained chronic diarrhea or ulcerative intestinal resonance examinations. disease, and unexplained “endocrinological syn- Although serum tryptase has become the drome.” In these patients the diagnosis can be golden standard in the diagnosis of mastocytosis established by measurement of serum tryptase (Akin and Metcalfe 2002 ; Valent 2006 ; Sperr (van Doormaal et al. 2012 ) and bone marrow et al. 2002 ; Brockow et al. 2003 ; Schwartz 2006 ), biopsy (performed if tryptase levels are tryptase levels should not be used as the sole cri- elevated). terion. As serum tryptase level correlates with In the near future KIT mutation analysis of total body mast cell burden, a basal tryptase level peripheral blood (PB) might become a useful less than 20 ng/mL does not rule out mastocyto- tool, as already demonstrated in adult patients sis, whereas slight tryptase increases greater than with anaphylaxis in whom a positive KIT D816V 20 ng/mL can be seen in individuals other than mutation in PB subsequently led to a diagnosis of those with mastocytosis (including those with SM in spite of normal or low basal serum tryptase renal disease, myeloid neoplasms, and idio- level and absent or inconspicuous skin lesions pathic) and even in apparently healthy controls (Broesby-Olsen et al. 2015 ; Kristensen et al. (Akin and Valent 2014 ). 2014 ). However, the use of KIT D816V mutation In the absence of skin lesions, the diagnosis of analysis of PB as a screening tool for SM in chil- mastocytosis can be very diffi cult and is often dren carries a higher risk of false-negative results postponed. Clinical conditions suggesting SM than in adults because a larger fraction carries 208 D. Van Gysel another mutation (Bodemer et al. 2010 ; Bibi Table 21.1 Factors known to stimulate mast cell et al. 2014 ; Ma et al. 2014 ). degranulation Follow-up of children with mastocytoma and Drugs (acetylsalicylic acid, narcotics (e.g., codeine, noncomplicated maculopapular mastocytosis morphine), procaine, polymyxin B, amphotericin B, atropine, thiamine, d-tubocurarine, quinine, with normal values of serum tryptase and no radiographic contrast media containing iodine, complaints is not necessary. For the follow-up of scopolamine, gallamine, decamethonium, reserpine) the other children with mastocytosis, a clinical Foods (alcohol, cola, nuts, spinach, eggplant scoring system (e.g., the SCORMA Index (aubergine), egg white, onion, strawberry, avocado, (SCORing MAstocytosis) (Heide et al. 2009 )) fermented food, paprika, tomato, banana, grains, pork, tuna, beans (boiled), herring, pineapple, cheese, fruit and regular serum tryptase measurements (Akin juices, salami, citrus fruit, mackerel, salmon, cocoa, and Metcalfe 2002 ; Sperr et al. 2002 ) can be maize, shellfi sh, coconut, millet, soybean) used. Increased serum tryptase levels, a high Bacterial toxins , snake and hymenoptera venoms extent of skin involvement, and extensive blister- Biological polypeptides (released by Ascaris , jellyfi sh, ing were shown to be predictors for the severity crayfi sh, and lobster) of mast cell activation episodes in children with Physical (cold, heat, sunlight, friction) and immunological stimuli mastocytosis (Alvarez-Twose et al. 2012 ; (IgE,C3A, C5A) Stress Brockow et al. 2012 , 2014; Chatzipetrou et al. 2014 ; Barnes et al. 2014 ). In adults with SM the KIT D816V burden diarrhea may benefi t from treatment with an H2 appears to be a valuable follow-up parameter receptor antagonist, with or without disodium (Hoermann et al. 2014 ). cromoglycate (a stabilizer of mast cell membranes) (Czarnetzki and Behrendt 1981 ; Businco et al. 1984). A double-blind placebo-controlled Treatment clinical trial, however, failed to show any benefi - cial effect of this agent in systemic mastocytosis Treatment recommendations are mostly based on (Frieri et al. 1985 ). expert opinion rather than evidence obtained Patients with signifi cant malabsorption may from controlled clinical trials. Therapy is directed need oral prednisone treatment (Metcalfe 1991 ). at alleviation of symptoms, since a curative ther- However, it includes a real danger of accentuat- apy doesn’t exist. ing concomitant bone disease that is caused by As most variants of the disease usually run a the mast cells in the marrow. benign course, therapy can often be limited to Isolated mastocytomas with resultant severe reassurance and avoidance of factors known to symptoms can be treated by topical corticoste- stimulate mast cell degranulation (Table 21.1 ). roids (Heide et al. 2007; Barton et al. 1985 ; Further treatment must be tailored to the Guzzo et al. 1991) with or without occlusion or symptom complex of the individual patient with topical pimecrolimus (Correia et al. 2010 ; (Heide et al. 2008 ). Ma et al. 2010). If this fails, excision in toto can H1 receptor antagonists (e.g., desloratadine, be considered (Hartmann and Metcalfe 2000 ). levocetirizine, rupatadine) can control symptoms Treatment of bullae is supportive and consists such as pruritus, urtication, and fl ushing of local care and prevention of infection (Golitz (Kettelhut and Metcalfe 1991 ; Metcalfe 1991 ; et al. 1984 ). Siebenhaar et al. 2013 ). If necessary a dose up to Children with mastocytosis and a history of fourfold the usual daily dose can be considered. anaphylaxis should be equipped with an autoin- The addition of an H2 receptor antagonist jector of epinephrine (Simons et al. 2002 ) and be (e.g., cimetidine, ranitidine) may be warranted in prepared to self-medicate. children who exhibit gastrointestinal symptoms Ultraviolet A (UVA) or UVA combined with of hyperacidity or ulceration (Metcalfe 1991 ; oral psoralen (PUVA) can be used in adolescents Hirschowitz and Groarke 1979). Patients with and adults for skin manifestations that are 21 Mastocytosis in Children: What to Do? 209

resistant to more standard therapy (Granerus human clinical trials in adults have not been as et al. 1981 ). impressive (Gotlib et al. 2007; Rondoni et al. Recently omalizumab, a humanized anti-IgE 2007; Verstovsek et al. 2007 ; Aichberger et al. antibody, has been shown to be effective in symp- 2008 ). In addition, non-TK KIT signaling tom control (Matito et al. 2013 ; Douglass et al. inhibitors (e.g., geldanamycin, rapamycin) tar- 2010 ; Siebenhaar et al. 2007 ). geting signaling downstream KIT may evolve Controversy exists about the risk of anesthesia as future therapeutic options (Chan et al. 2013 ; in children with mastocytosis. Quite recently, Sotlar 2007). several literature reviews (Carter et al. 2008 ; Ahmad et al. 2009 ; Klein and Misseldine 2013 ) concluded that deviations from routine anesthe- Bulleted List of Controversies sia techniques were not necessarily warranted, as long as drugs which cause minimal histamine • Although serum tryptase has become the release were used and meticulous preparation to golden standard in the diagnosis of mastocyto- treat possible adverse events was made. However, sis, tryptase levels should not be used as the as all patients with mastocytosis are at risk for sole criterion. unprovoked anaphylaxis (Silva et al. 2008 ; • In the presence of typical skin lesions and Desborough et al. 1990; Vaughan and Jones tryptase levels < 20 ng/ml and no other signs 1998 ), we still recommend preventive measures of SM, the diagnosis of CM can be made with- (Heide et al. 2008 ) at narcosis in children with out any further examinations. large or unknown disease burden, being the chil- • Follow-up of children with mastocytoma and dren with a history of anaphylaxis, with bullous noncomplicated maculopapular mastocytosis skin lesions or diffuse CM, with SM, or with high with normal values of serum tryptase and no serum tryptase levels. For these children, we complaints is not necessary. For the follow-up advise to give a “single shot” of an H1 antagonist of the other children with mastocytosis, a clin- and prednisolone preoperatively. Cytoreductive ical scoring system and regular serum tryptase agents should be avoided if possible in patients measurements can be used. with indolent SM, where the disease cause is • The use of KIT D816V mutation analysis of nonprogressive (Kors et al. 1996 ). peripheral blood as a screening tool for SM in The expression of mutated KIT in neoplas- children carries a higher risk of false-negative tic MC has led to the development of KIT- results than in adults because a larger fraction targeting agents using tyrosine kinase inhibitors carries another mutation. (TKIs). The prototype is imatinib, which is • We recommend preventive measures before already successfully used in clinical practice anesthesia in children with large or unknown for severe recalcitrant cases of (systemic) mas- disease burden. Such children would include a tocytosis in children and adults (Akin et al. history of anaphylaxis, bullous skin lesions, 2004 ; Akin and Metcalfe 2004; Hoffmann diffuse CM, SM, or high serum tryptase levels. et al. 2008 ; Droogendijk et al. 2006; Fuller 2012 ; Chan et al. 2013 ). Unfortunately, the most frequent c-KIT D816V mutation is asso- References ciated with relative resistance against imatinib. However, TKIs with activity against c-KIT Ahmad N, Evans P, Lloyd-Thomas AR. Anesthesia in D816V-positive cells have recently been devel- children with mastocytosis--a case based review. Paediatr Anaesth. 2009;19(2):97–107. doi:PAN2904 oped, and some of them (dasatinib, nilotinib/ [pii] 10.1111/j.1460-9592.2008.02904.x . AMN107, PKC412) are already tested in phase Aichberger KJ, Sperr WR, Gleixner KV, Kretschmer A, I/II trials. Although both dasatinib and PKC412 Valent P. Treatment responses to cladribine and dasat- display remarkable in vitro activity against inib in rapidly progressing aggressive mastocytosis. Eur J Clin Invest. 2008;38(11):869–73. c-KIT D816V, the preliminary results from doi: 10.1111/j.1365-2362.2008.02036.x . 210 D. Van Gysel

Akin C, Fumo G, Yavuz AS, Lipsky PE, Neckers L, Brockow K, Ring J, Alvarez-Twose I, Orfao A, Escribano Metcalfe DD. A novel form of mastocytosis associ- L. Extensive blistering is a predictor for severe com- ated with a transmembrane c-kit mutation and response plications in children with mastocytosis. Allergy. to imatinib. Blood. 2004;103(8):3222–5. doi: 10.1182/ 2012;67(10):1323–4. doi: 10.1111/all.12013 . blood-2003-11-3816 . Broesby-Olsen S, Oropeza AR, Bindslev-Jensen C, Akin C, Metcalfe DD. Surrogate markers of disease in Vestergaard H, Moller MB, Siebenhaar F, Kristensen mastocytosis. Int Arch Allergy Immunol. T, Mortz CG. Recognizing mastocytosis in patients 2002;127(2):133–6. with anaphylaxis: value of KIT D816V mutation Akin C, Metcalfe DD. The biology of Kit in disease and analysis of peripheral blood. J Allergy Clin the application of pharmacogenetics. J Allergy Clin Immunol. 2015;135(1):262–4. doi: 10.1016/j. Immunol. 2004;114(1):13–9; quiz 20. doi: 10.1016/j. jaci.2014.06.031 . jaci.2004.04.046 S0091674904014174 [pii]. Businco L, Cantani A, Businco E, Pepys J. Systemic mas- Akin C, Valent P. Diagnostic criteria and classifi cation of tocytosis in a 5-year-old child: successful treatment mastocytosis in 2014. Immunol Allergy Clin North with disodium cromoglycate. Clin Allergy. Am. 2014;34(2):207–18. doi: 10.1016/j.iac.2014.02. 1984;14(2):147–52. 003 . Carter MC, Uzzaman A, Scott LM, Metcalfe DD, Alvarez-Twose I, Vano-Galvan S, Sanchez-Munoz L, Quezado Z. Pediatric mastocytosis: routine anesthetic Morgado JM, Matito A, Torrelo A, Jaen P, Schwartz management for a complex disease. Anesth Analg. LB, Orfao A, Escribano L. Increased serum baseline 2008;107(2):422–7. doi:107/2/422 [pii] 10.1213/ tryptase levels and extensive skin involvement are pre- ane.0b013e31817e6d7c . dictors for the severity of mast cell activation episodes Chan IJ, Kasprowicz S, Tharp MD. Distinct signalling in children with mastocytosis. Allergy. pathways for mutated KIT(V560G) and KIT(D816V) 2012;67(6):813–21. doi: 10.1111/j.1398-9995. in mastocytosis. Clin Exp Dermatol. 2013;38(5):538– 2012.02812.x . 44. doi: 10.1111/ced.12000 . Barnes M, Van L, DeLong L, Lawley LP. Severity of cuta- Chatzipetrou A, Koulias C, Zeliou CG, Potika M, Chliva neous fi ndings predict the presence of systemic symp- K, Makris M. PD34 - Childhood mastocytosis: serum toms in pediatric maculopapular cutaneous baseline total tryptase levels and extent of cutaneous mastocytosis. Pediatr Dermatol. 2014;31(3):271–5. disease as predictors of mast cell mediator release doi: 10.1111/pde.12291 . symptoms. Clin Transl Allergy. 2014;4 Suppl 1:P34. Barton J, Lavker RM, Schechter NM, Lazarus doi: 10.1186/2045-7022-4-S1-P34 . GS. Treatment of urticaria pigmentosa with corticoste- Correia O, Duarte AF, Quirino P, Azevedo R, Delgado roids. Arch Dermatol. 1985;121(12):1516–23. L. Cutaneous mastocytosis: two pediatric cases treated Bibi S, Langenfeld F, Jeanningros S, Brenet F, Soucie E, with topical pimecrolimus. Dermatol Online Hermine O, Damaj G, Dubreuil P, Arock M. Molecular J. 2010;16(5):8. defects in mastocytosis: KIT and beyond KIT. Immunol Czarnetzki BM, Behrendt H. Urticaria pigmentosa: clini- Allergy Clin North Am. 2014;34(2):239–62. cal picture and response to oral disodium cromogly- doi: 10.1016/j.iac.2014.01.009 . cate. Br J Dermatol. 1981;105(5):563–7. Bodemer C, Hermine O, Palmerini F, Yang Y, Grandpeix- Desborough JP, Taylor I, Hattersley A, Garden A, Wolff Guyodo C, Leventhal PS, Hadj-Rabia S, Nasca L, A, Bloom SR, Morgan M. Massive histamine release Georgin-Lavialle S, Cohen-Akenine A, Launay JM, in a patient with systemic mastocytosis. Br J Anaesth. Barete S, Feger F, Arock M, Catteau B, Sans B, Stalder 1990;65(6):833–6. JF, Skowron F, Thomas L, Lorette G, Plantin P, Douglass JA, Carroll K, Voskamp A, Bourke P, Wei A, Bordigoni P, Lortholary O, de Prost Y, Moussy A, O’Hehir RE. Omalizumab is effective in treating sys- Sobol H, Dubreuil P. Pediatric mastocytosis is a clonal temic mastocytosis in a nonatopic patient. Allergy. disease associated with D816V and other activating 2010;65(7):926–7. doi: 10.1111/j.1398-9995.2009. c-KIT mutations. J Invest Dermatol. 2010;130(3):804– 02259.x . 15. doi: 10.1038/jid.2009.281 . Droogendijk HJ, Kluin-Nelemans HJ, van Doormaal JJ, Brockow K. Epidemiology, prognosis, and risk factors in Oranje AP, van de Loosdrecht AA, van Daele mastocytosis. Immunol Allergy Clin North Am. PL. Imatinib mesylate in the treatment of systemic 2014;34(2):283–95. doi: 10.1016/j.iac.2014.01.003 . mastocytosis: a phase II trial. Cancer. 2006;107(2):345– Brockow K, Akin C, Huber M, Metcalfe DD. Assessment of 51. doi: 10.1002/cncr.21996 . the extent of cutaneous involvement in children and adults Frieri M, Alling DW, Metcalfe DD. Comparison of the with mastocytosis: relationship to symptomatology, trypt- therapeutic effi cacy of cromolyn sodium with that of ase levels, and bone marrow pathology. J Am Acad combined chlorpheniramine and cimetidine in Dermatol. 2003;48(4):508–16. doi: 10.1067/mjd.2003.98 . systemic mastocytosis. Results of a double-blind clini- Brockow K, Jofer C, Behrendt H, Ring J. Anaphylaxis in cal trial. Am J Med. 1985;78(1):9–14. patients with mastocytosis: a study on history, clinical Fuller SJ. New insights into the pathogenesis, diagnosis, features and risk factors in 120 patients. Allergy. and management of mastocytosis. Hematol Oncol 2008;63(2):226–32. doi:ALL1569 [pii] Clin North Am. 2012;26(6):1143–68. doi: 10.1016/j. 10.1111/j.1398-9995.2007.01569.x . hoc.2012.08.008 . 21 Mastocytosis in Children: What to Do? 211

Golitz LE, Weston WL, Lane AT. Bullous mastocytosis: Kettelhut BV, Metcalfe DD. Pediatric mastocytosis. diffuse cutaneous mastocytosis with extensive blisters J Invest Dermatol. 1991;96(3):15S–8. mimicking scalded skin syndrome or erythema multi- Klein NJ, Misseldine S. Anesthetic considerations in forme. Pediatr Dermatol. 1984;1(4):288–94. pediatric mastocytosis: a review. J Anesth. Gotlib J, George TI, Corless C, Linder A, Ruddell A, Akin 2013;27(4):588–98. doi: 10.1007/s00540-013-1563-2 . C, DeAngelo DJ, Kepten I, Lanza C, Heinemann H, Kors JW, Van Doormaal JJ, Breukelman H, Van Voorst Yin O, Gallagher N, Graubert T. The KIT Tyrosine Vader PC, De Monchy JG. Long-term follow-up of Kinase Inhibitor Midostaurine (PKC412) Exhibits a indolent mastocytosis in adults. J Intern Med. High Response Rate in Aggressive Systemic 1996;239(2):157–64. Mastocytosis (ASM): interim results of a Phase II Kristensen T, Vestergaard H, Bindslev-Jensen C, Moller Trial. Blood (ASH Annu Meet Abstr). 2007;110:3536. MB, Broesby-Olsen S. Sensitive KIT D816V muta- Granerus G, Roupe G, Swanbeck G. Decreased urinary tion analysis of blood as a diagnostic test in mastocy- histamine metabolite after successful PUVA treatment tosis. Am J Hematol. 2014;89(5):493–8. doi: 10.1002/ of urticaria pigmentosa. J Invest Dermatol. ajh.23672 . 1981;76(1):1–3. Ma D, Stence AA, Bossler AB, Hackman JR, Bellizzi Guzzo C, Lavker R, Roberts 2nd LJ, Fox K, Schechter N, AM. Identifi cation of KIT activating mutations in pae- Lazarus G. Urticaria pigmentosa. Systemic evaluation diatric solitary mastocytoma. Histopathology. and successful treatment with topical steroids. Arch 2014;64(2):218–25. doi: 10.1111/his.12212 . Dermatol. 1991;127(2):191–6. Ma Z, Tovar JP, Kwong KY, Paek D. Pimecrolimus Hartmann K, Metcalfe DD. Pediatric mastocytosis. induces apoptosis of mast cells in a murine model of Hematol Oncol Clin North Am. 2000;14(3):625–40. cutaneous mastocytosis. Int Arch Allergy Immunol. Heide R, Beishuizen A, De Groot H, Den Hollander JC, 2010;153(4):413–8. doi: 10.1159/000316353 . Van Doormaal JJ, De Monchy JG, Pasmans SG, Van Matito A, Blazquez-Goni C, Morgado JM, Alvarez- Gysel D, Oranje AP. Mastocytosis in children: a proto- Twose I, Mollejo M, Sanchez-Munoz L, Escribano col for management. Pediatr Dermatol. L. Short- term omalizumab treatment in an adolescent 2008;25(4):493–500. doi:PDE738 [pii] with cutaneous mastocytosis. Ann Allergy Asthma 10.1111/j.1525-1470.2008.00738.x . Immunol. 2013;111(5):425–6. doi: 10.1016/j.anai.2013. Heide R, de Waard-van der Spek FB, den Hollander JC, 08.014 . Tank B, Oranje AP. Effi cacy of 25 % diluted fl utica- Metcalfe DD. The treatment of mastocytosis: an over- sone propionate 0.05 % cream as wet-wrap treatment view. J Invest Dermatol. 1991;96(3):55S–6; discus- in cutaneous mastocytosis. Dermatology. sion 56S–59S. 2007;214(4):333–5. doi: 10.1159/000100885 . Rondoni M, Paolini S, Colarossi S, Piccaluga PP, Heide R, van Doorn K, Mulder PG, van Toorenenbergen Papayannidis C, Palandri F, Laterza C, De Rosa F, AW, Beishuizen A, de Groot H, Tank B, Oranje Pregno P, Gatto S, Ottaviani E, Saglio G, Cilloni D, AP. Serum tryptase and SCORMA (SCORing Pane F, Triggiani M, Soverini S, Zaccaria A, Baccarani MAstocytosis) Index as disease severity parameters in M, Martinelli G. Response to dasatinib in patients childhood and adult cutaneous mastocytosis. Clin Exp with aggressive systemic mastocytosis with D816V Dermatol. 2009;34(4):462–8. doi:10.1111/j.1365-2230. Kit mutation. Blood (ASH Annu Meet Abstr). 2008.03005.x . 2007;110:3562. Hirschowitz BI, Groarke JF. Effect of cimetidine on gas- Schwartz LB. Diagnostic value of tryptase in anaphylaxis tric hypersecretion and diarrhea in systemic mastocy- and mastocytosis. Immunol Allergy Clin North Am. tosis. Ann Intern Med. 1979;90(5):769–71. 2006;26(3):451–63. doi: 10.1016/j.iac.2006.05.010 . Hoermann G, Gleixner KV, Dinu GE, Kundi M, Greiner Siebenhaar F, Fortsch A, Krause K, Weller K, Metz M, G, Wimazal F, Hadzijusufovic E, Mitterbauer G, Magerl M, Martus P, Church MK, Maurer Mannhalter C, Valent P, Sperr WR. The KIT D816V M. Rupatadine improves quality of life in mastocyto- allele burden predicts survival in patients with mas- sis: a randomized, double-blind, placebo-controlled tocytosis and correlates with the WHO type of the trial. Allergy. 2013;68(7):949–52. doi: 10.1111/ disease. Allergy. 2014;69(6):810–3. doi:10.1111/ all.12159 . all.12409 . Siebenhaar F, Kuhn W, Zuberbier T, Maurer M. Successful Hoffmann KM, Moser A, Lohse P, Winkler A, Binder B, treatment of cutaneous mastocytosis and Meniere Sovinz P, Lackner H, Schwinger W, Benesch M, Urban disease with anti-IgE therapy. J Allergy Clin Immunol. C. Successful treatment of progressive cutaneous mas- 2007;120(1):213–5. doi: 10.1016/j.jaci.2007.05.011 . tocytosis with imatinib in a 2-year-old boy carrying a Silva I, Carvalho S, Pinto PL, Machado S, Rosado Pinto somatic KIT mutation. Blood. 2008;112(5):1655–7. J. Mastocytosis: a rare case of anaphylaxis in paediat- doi:10.1182/blood-2008-03-147785 . ric age and literature review. Allergol Immunopathol Horny HP, Sotlar K, Valent P. Mastocytosis: immunophe- (Madr). 2008;36(3):154–63. doi:13124722 [pii]. notypical features of the transformed mast cells are Simons FE, Gu X, Silver NA, Simons KJ. EpiPen Jr ver- unique among hematopoietic cells. Immunol Allergy sus EpiPen in young children weighing 15 to 30 kg at Clin North Am. 2014;34(2):315–21. doi: 10.1016/j. risk for anaphylaxis. J Allergy Clin Immunol. iac.2014.01.005 . 2002;109(1):171–5. doi:S009167490272109X [pii]. 212 D. Van Gysel

Sotlar K. Therapeutically relevant mutations in the recep- Valent P, Cerny-Reiterer S, Herrmann H, Mirkina I, tor tyrosine kinase KIT in mastocytosis. Verh Dtsch George TI, Sotlar K, Sperr WR, Horny Ges Pathol. 2007;91:169–76. HP. Phenotypic heterogeneity, novel diagnostic Sotlar K, Horny HP, Simonitsch I, Krokowski M, markers, and target expression profi les in normal Aichberger KJ, Mayerhofer M, Printz D, Fritsch G, and neoplastic human mast cells. Best Pract Res Valent P. CD25 indicates the neoplastic phenotype of Clin Haematol. 2010;23(3):369–78. doi: 10.1016/j. mast cells: a novel immunohistochemical marker for beha.2010.07.003 . the diagnosis of systemic mastocytosis (SM) in rou- van Doormaal JJ, van der Veer E, van Voorst Vader PC, tinely processed bone marrow biopsy specimens. Am Kluin PM, Mulder AB, van der Heide S, Arends S, J Surg Pathol. 2004;28(10):1319–25. Kluin-Nelemans JC, Oude Elberink JN, de Monchy Sperr WR, Jordan JH, Fiegl M, Escribano L, Bellas C, JG. Tryptase and histamine metabolites as diagnostic Dirnhofer S, Semper H, Simonitsch-Klupp I, Horny HP, indicators of indolent systemic mastocytosis without Valent P. Serum tryptase levels in patients with masto- skin lesions. Allergy. 2012;67(5):683–90. cytosis: correlation with mast cell burden and implica- doi: 10.1111/j.1398-9995.2012.02809.x . tion for defi ning the category of disease. Int Arch Van Gysel D, Oranje AP, Vermeiden I, de Lijster de Raadt Allergy Immunol. 2002;128(2):136–41. doi:59404. J, Mulder PG, van Toorenenbergen AW. Value of uri- Valent P. Diagnostic evaluation and classifi cation of mas- nary N-methylhistamine measurements in childhood tocytosis. Immunol Allergy Clin North Am. mastocytosis. J Am Acad Dermatol. 1996;35(4): 2006;26(3):515–34. doi: 10.1016/j.iac.2006.05.002 . 556–8. Valent P, Akin C, Escribano L, Fodinger M, Hartmann K, Vaughan ST, Jones GN. Systemic mastocytosis presenting Brockow K, Castells M, Sperr WR, Kluin-Nelemans as profound cardiovascular collapse during anaesthe- HC, Hamdy NA, Lortholary O, Robyn J, van Doormaal sia. Anaesthesia. 1998;53(8):804–7. J, Sotlar K, Hauswirth AW, Arock M, Hermine O, Verstovsek S, Tefferi A, Cortes J, O’Brien S, Garcia- Hellmann A, Triggiani M, Niedoszytko M, Schwartz Manero G, Pardanani A, Akin C, Faderl S, Thomas D, LB, Orfao A, Horny HP, Metcalfe DD. Standards and Kantarjian H. Phase II study of dasatinib standardization in mastocytosis: consensus statements (SPRYCELTM) in Philadelphia chromosome- negative on diagnostics, treatment recommendations and acute and chronic myeloid diseases, including sys- response criteria. Eur J Clin Invest. 2007;37(6):435– temic mastocytosis. Blood (ASH Annu Meet Abstr). 53. doi: 10.1111/j.1365-2362.2007.01807.x . 2007;110:3551. Erythema Multiforme, Stevens- Johnson Syndrome and Toxic 2 2 Epidermal Necrolysis

Lea Solman and John Harper

Abstract EM is an acute, immune-mediated mucocutaneous condition, fi rst described by von Hebra in 1866. It is characterised by the abrupt onset of red macules and papules, which evolve into characteristic target lesions. It is controversial as to whether EM is a well-defi ned disease or a spectrum of manifestations. EM can be divided into two forms – EM minor and EM major. Both of them are characterised by typical target lesions; however, EM minor is used to describe classic, mild disease without mucosal lesions, while EM major is characterised by systemic symptoms and mucosal involvement. The term EM major should not be used to refer to SJS. Although EM is usually self- limiting, frequent episodes over the course of years can lead to recurrent disease in some patients. The exact incidence of EM is unknown, and it occurs predominantly in young adults and has no racial predilection. Most common aetiological factors include infection, medication use, malignancy, autoimmune disease, sarcoidosis, radiation and immunisation. Of these factors, infection accounts for 90 % of cases, with herpes simplex virus as the most common identifi ed agent. Mycoplasma pneumoniae infection is another important cause of EM, particularly in children. Genetic predisposition may play a role in some of the patients with EM; a link between EM and HLA DQB1*0301 allele has been reported. An even stronger HLA DQB1*0301 association was found in the patient group with herpes-associated EM.

Keywords Erythema multiforme • Stevens-Johnson syndrome • Toxic epidermal necrolysis • Intravenous immunoglobulins in paediatric dermatology • Genetic predisposition in erythema multiforme

L. Solman , MD, FRCPCH (*) J. Harper , MBBS, MD, FRCP, FRCPCH Department of Paediatric Dermatology , Great Ormond Street Hospital for Children, London , UK e-mail: [email protected]; [email protected]

Erythema multiforme (EM), Stevens-Johnson Clinical Manifestations (SJS) and toxic epidermal necrolysis (TEN) are a group of mucocutaneous diseases, characterised Due to certain similarities and overlap in clinical by varying degrees of skin and mucosal involve- presentation, EM minor, EM major and SJS were ment, with the latter two conditions associated until recently considered to be part of a single with high morbidity and mortality. The similari- disease spectrum. There is now strong evidence ties and overlaps between EM, SJS and TEN to support the concept that EM is distinct from have led to confusion and controversy over the SJS (Assier et al. 1995 ). Distinction can be made precise classifi cation, aetiology and treatment of based on clinical criteria: type of elementary skin these conditions. lesions, distribution, mucosal involvement and presence or absence of systemic symptoms. The term multiforme denotes a spectrum of Erythema Multiforme symptoms and signs that may be observed. The characteristic lesion of EM is a target lesion. It EM is an acute, immune-mediated mucocutaneous measures <3 cm and has a round shape and well- condition, fi rst described by von Hebra in 1866 . It defi ned border. It has three concentric colour is characterised by the abrupt onset of red macules zones – a dusky or dark red centre which may and papules, which evolve into characteristic tar- evolve into a blister/bulla, a middle pink ring and get lesions. It is controversial as to whether EM is a bright red outermost ring. Early lesions or atyp- a well-defi ned disease or a spectrum of manifesta- ical lesions may show just two zones – dusky red tions. EM can be divided into two forms – EM centre and bright red outer zone. The lesions are minor and EM major. Both of them are character- distributed predominantly on the extremities, but ised by typical target lesions; however, EM minor may involve also the trunk and face. The eruption is used to describe classic, mild disease without is polymorphous as the lesions can be at various mucosal lesions, while EM major is characterised stages of development. Cutaneous lesions are by systemic symptoms and mucosal involvement. distributed preferentially on the extensor surfaces The term EM major should not be used to refer to of distal extremities and spread in a centripetal SJS. Although EM is usually self-limiting, fre- manner (Huff et al. 1983 ). The palms, soles, fl ex- quent episodes over the course of years can lead to ural surfaces of the extremities, neck, face and recurrent disease in some patients (Assier et al. trunk may also be affected (Huff et al. 1983 ). 1995 ). The exact incidence of EM is unknown, Mucosal lesions consist of mucosal erythema, and it occurs predominantly in young adults and oedema, vesicles and painful erosions. They can has no racial predilection (Huff et al. 1983 ). Most involve oral, ocular and/or genital mucosa. common aetiological factors include infection, Prodromal symptoms such as fever, malaise, medication use, malignancy, autoimmune disease, headache, sore throat, rhinorrhoea and cough are sarcoidosis, radiation and immunisation (Huff usually mild. It is not always clear whether these et al. 1983 ). Of these factors, infection accounts symptoms are prodromal symptoms of EM or for 90 % of cases (Weston 2005 ), with herpes sim- represent symptoms of preceding infectious ill- plex virus as the most common identifi ed agent. ness. Systemic symptoms such as fever, arthral- Mycoplasma pneumoniae infection is another gia, myalgia and pain are usually present in EM important cause of EM, particularly in children major and absent or limited in EM minor. (Schalock et al. 2006 ). Genetic predisposition may Most EM lesions appear within 3–5 days and play a role in some of the patients with EM; a link resolve over the course of approximately 2 between EM and HLA DQB1*0301 allele has weeks. The skin lesions usually heal without been reported (Khalil et al. 1991 ). An even stron- sequelae; however, occasional postinfl ammatory ger HLA DQB1*0301 association was found in hypo- or hyperpigmentation may remain for the patient group with herpes-associated EM months after resolution. For recurrent EM due to (Khalil et al. 1991 ). proven or presumed HSV, prophylactic acyclovir 22 Erythema Multiforme, Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis 215 can be prescribed and frequency of attacks moni- Toxic Epidermal Necrolysis tored (Tatnall et al. 1995 ). In 1956, Scottish dermatologist Alan Lyell used the term TEN to describe a life-threatening muco- Stevens-Johnson Syndrome cutaneous disorder characterised by extensive and rapidly evolving epidermal detachment, erythema In 1922 Stevens and Johnson described two boys and necrosis (Lyell 1956 ). The incidence of TEN with acute mucocutaneous disease characterised is 0.4–1.2 cases per million per year (Rzany et al. by extensive mucosal necrosis and purpuric mac- 1999 ), and the mortality is between 20 and 30 % ules on the skin, associated with fever, stomatitis (Roujeau and Stern 1994). More than 200 medi- and ophthalmia (Stevens 1922 ). Thomas later cations have been implicated, but only a few of designated SJS as EM major in 1950 (Thomas them are most commonly involved – antibiotics 1950 ). Current opinion is that EM major should (sulphonamides, tetracyclines and quinolones), not be used for SJS, as they are two distinctive anticonvulsants (phenytoin, phenobarbital, cloba- syndromes. The mortality rate for SJS varies zam and carbamazepine), nevirapine, abacavir, between 1 and 5 % (Roujeau and Stern 1994 ). NSAID and allopurinol (Mockenhaupt et al. Most cases of SJS are linked to medications; 2008 ; Schwartz et al. 2013b ). however some cases may be caused by Infection agents ( Mycoplasma pneumonia , Mycoplasma pneumoniae , especially in paediat- herpes virus), systemic lupus erythematosus, ric patients (Kunimi et al. 2011 ). Most common immunisation and tissue transplantation with medications associated with SJS are antibiotics acute GVHD have also been associated with (sulphonamides, tetracyclines, cephalosporins, TEN (Torchia et al. 2012 ; Dobrosavljevic et al. macrolides and penicillin), anticonvulsants (phe- 1999 ; Ball et al. 2001 ; Fournier et al. 1995 ). nytoin, carbamazepine, phenobarbital, valproate In TEN there is widespread erythematous or and lamotrigine), non-steroidal anti-infl ammatory purpuric macules with blistering, which rapidly drugs, allopurinol and paracetamol (Levi et al. spreads and becomes confl uent with detachment 2009; Ferrandiz-Pulido and Garcia-Patos 2013 , of the epidermis. This initial phase is sometimes 2011 ; Forman et al. 2002 ). referred to as SJS-TEN overlap. In full-blown A prodrome of non-specifi c symptoms such TEN, the loss of epidermis is about 30 % of the as fever, cough, malaise and rhinorrhoea can pre- body surface area, if not signifi cantly more. cede mucocutaneous manifestations. Skin A prodrome of cough, rhinorrhoea, fever, lesions of SJS are variable in extent. They usu- anorexia, and malaise precedes mucocutaneous ally appear as dusky, erythematous or purpuric manifestations. Mucosal involvement is present macules with a tendency to coalesce. In some in all patients with TEN. Common symptoms patients, fl at, irregular, atypical target lesions of include purulent conjunctivitis and infl amma- two zones are present. The skin lesions are ten- tion; erosions; ulcers and crusts of other muco- der and together with mucosal involvement at sal surfaces like the mouth, nose, pharynx, this stage should raise a strong suspicion of respiratory and digestive tracts; and anogenital evolving SJS. The initial skin lesions become mucosa, which may result in potentially life- confl uent and develop into fl accid blisters, which threatening complications, such as bleeding then coalesce to result in epidermal detachment and infection (Goyal et al. 2009 ). Involvement of up to 10 % in SJS. There is signifi cant involve- of the larynx and tracheobronchial tree is com- ment of mucous membranes; erythema and ero- monly associated with airway compromise and sions of mucosal surfaces are present in more progressive respiratory failure (Del Pozzo- than 90 % of patients (Rzany et al. 1993 ). The Magana et al. 2011 ). The gastrointestinal tract mucosal lesions can involve oral, ocular and can be involved with rectal bleeding and genital mucosa and are usually very tender and sloughing of intestinal mucosa; also liver dys- haemorrhagic. function can occur. 216 L. Solman and J. Harper

Acute complications are similar to those in Ocular damage in TEN can be prevented by extensive burn patients: fl uid loss, infection, renal continual lubrication of the eye, topical antibiotic failure, pneumonia and pneumonitis. Septicaemia use and lysis of adhesions. Daily antibiotic and and multisystem organ failure are primary causes corticosteroid eye drops along with lubricants are of death. recommended in order to minimise infection and Ocular complications are most common chronic infl ammation. complications of SJS/TEN, described in 20 % Careful monitoring of respiratory function (Wilkins et al. 1992 )–77 % (Haber et al. 2005 ) of with the prompt implementation of supplemental patients and include xerosis, symblepharon, con- oxygen, intubation and mechanical ventilation junctivitis and corneal scarring. Skin sequelae are should be initiated as required. usually related to pigmentary changes, scarring, The fl uids and nutritional requirements of onycholysis, onychodystrophy, alopecia and pruri- children with SJS/TEN need to be calculated tus. Genitourinary problems are also observed after carefully, ensuring adequate replacement with TEN, including dyspareunia, adhesions and introi- the help of a dietician. tal stenosis (Schwartz et al. 2013a , b ). Genetic susceptibility also plays a crucial role in the development of SJS/TEN. HLA-B1502 has Systemic Treatment been associated with carbamazepine-induced SJS/TEN (He et al. 2013 ; Aggarwal et al. 2014 ) There is no established standard or specifi c medi- and HLA-B5801 with allopurinol-induced SJS/ cal treatment for EM, SJS and TEN. Literature of TEN (Kaniwa et al. 2008 ; Tassaneeyakul et al. specifi c treatment in children is scant and contro- 2009 ), both in Asian patients. HLA-B allele versial, with a lack of randomised clinical trials. screening may be benefi cial to Asian patients The most commonly studied therapy by far is the before starting carbamazepine and allopurinol. use of intravenous immunoglobulins (IVIG), followed by corticosteroid treatment.

Management of SJS and TEN Systemic Corticosteroids There has been ongoing controversy regarding The most important actions to be taken when a child the effi cacy of systemic steroids in EM, SJS and is affected from SJS or TEN are the removal of the TEN. Corticosteroids have anti-infl ammatory offending agent and a prompt admission to a burns and immunoregulatory properties and are unit or paediatric intensive care unit, as this has been believed to decrease the disease severity when shown to directly decrease morbidity and mortality given early in the course of illness. No ran- rates (Prendiville et al. 1989 ; Sheridan et al. 1999 ). domised trials have been published to assess the For the most severely affected patients, seda- effi cacy of systemic steroids in SJS and TEN. tion and ventilation are necessary. General care There are four observational studies published measures include maintenance and reconstruc- between 1976 and 2000; they have compared the tion of the skin barrier, fl uid balance, prevention outcomes of paediatric patients with SJS and of the ocular damage, mouth care, septic moni- TEN treated with or without systemic steroids. A toring, pain management and nutritional and prospective study was performed of 16 paediatric respiratory support. patients with SJS (Kakourou et al. 1997 ). Ten The local wound treatment is important to patients received bolus infusion of methylpred- avoid complications derived from the loss of bar- nisolone (4 mg/kg/day) for two more days after rier function and includes gentle debridement of the fever subsided, while remaining six children broken blisters, removal of necrotic epithelium, received only supportive measures. The only topical treatment with antimicrobials and wound objective outcome difference between both coverage with either biological or biosynthetic groups was duration of fever (4.0 ± 1.9 days vs wound dressings (Fernando 2012 ). 9.5 ± 4.2 days). 22 Erythema Multiforme, Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis 217

Leaute-Labreze retrospectively reported 42 Antitumour Necrosis Factor Alpha paediatric patients with EM or SJS (17 patients The tumour necrosis factor alpha (TNF-α) is a with SJS). Ten patients received steroids (predni- cytokine with potent pro-infl ammatory effects sone or prednisolone 1 mg/kg/day for 1 week in protecting immune responses against a vari- with progressive decrease). Mean disease dura- ety of infectious agents. On a cellular level, tion showed no signifi cant difference, with 16 TNF-α might result in cell death caused by days in the steroid group versus 15 days in non- direct cytotoxicity and induction of apoptosis steroid group (Leaute-Labreze et al. 2000 ). (Hunger et al. 2005 ). In patients with TEN, Two older retrospective observational studies TNF-α is strongly expressed in keratinocytes found increased complication rate in paediatric and macrophages of lesional skin, and high con- patients treated with steroids. Rasmussen com- centrations are found in cutaneous blister fl uid pared 32 paediatric patients with SJS; 17 were (Paquet et al. 1994 ; Nassif et al. 2004 ). TNF-α treated with steroids (prednisolone 40–80 mg/ blockade with infl iximab or etanercept has been m2, duration not mentioned) (Rasmussen 1976 ). proven effi cacious in controlling TEN in six Nine patients, all from the steroid-treated group, patients (Hunger et al. 2005 ; Fischer et al. 2002 ; suffered a complication, infection being the most Al-Shouli et al. 2005 ; Kreft et al. 2010 ; Gubinelli common complication, occurring in four patients. et al. 2009 ; Famularo et al. 2007 ). Two paediat- Ginsburg described 51 cases of SJS; 19 patients ric patients were successfully treated with inf- were treated with steroid medication (dose and liximab, which lead to dramatic improvement duration not mentioned). 74 % of patients from (Wojtkiewicz et al. 2008 ; Scott-Lang et al. steroid-treated group experienced complication, 2014 ). Anti-TNF-α treatment may be a logical compared with 28 % of patients from nonsteroid- therapeutic option for SJS/TEN, but well-con- treated group. The most common complication ducted studies of the effi cacy and safety of such was infection, including sepsis and urinary tract treatment are needed. infection (Ginsburg 1982 ).

Intravenous Immunoglobulin Summary The use of intravenous immunoglobulins (IVIG) in children has been controversial. IVIG inhibits Controversial issues relating to this spectrum of Fas-mediated keratinocyte apoptosis in vitro – conditions are summarised below. There is a rec- the key mechanism in the pathogenesis of SJS ognised overlap between EM major and SJS and (Viard et al. 1998 ). There are no published ran- between SJS and TEN: Are these separate enti- domised controlled trials to assess the efﬁ cacy of ties? There is evidence now to suggest a genetic the IVIG in children with SJS/TEN. predisposition. For children with recurrent EM/ Systematic review of paediatric patients with SJS, is this due to one trigger factor or is this a SJS/TEN consisted of 57 patients with ages rang- genetic susceptibility, which can be precipitated ing between 0.4 and 15 years (Wootton et al. by different trigger factors at different times in 2011 ). Some patients received one or two doses the same patient? More studies are needed to of steroids prior to their hospital admission and address these questions. IVIG. The doses of IVIG ranged from 0.25 to 1.5 g/kg/d for 1–5 days. Duration of fever after the treatment onset ranged from 1 to 3 days, and Bulleted List of Controversies in EM, mean disease duration ranged from 4 to 18 days. SJS and TEN Two patients did not respond to the treatment. Four patients developed a complication – sepsis, Are these all the same condition ? rhabdomyolysis, severe GI bleeding and severe • EM is a separate entity. neutropenia. No deaths were reported (Del • SJS and TEN represent a spectrum of Pozzo-Magana et al. 2011 ). severity. 218 L. Solman and J. Harper

Aetiology Ferrandiz-Pulido C, Garcia-Fernandez D, Dominguez- • EM: most common cause is infection. Sampedro P, Garcia-Patos V. Stevens-Johnson syndrome and toxic epidermal necrolysis in children: a • SJS/TEN: most common cause is an review of the experience with paediatric patients in a adverse drug reaction. university hospital. J Eur Acad Dermatol Venereol Are corticosteroids benefi cial ? JEADV. 2011;25(10):1153–9. • For severe EM and SJS/TEN, intravenous Fischer M, Fiedler E, Marsch WC, Wohlrab J. Antitumour necrosis factor-alpha antibodies (infl iximab) in the methylprednisolone given at the onset of treatment of a patient with toxic epidermal necrolysis. symptoms can be useful. Br J Dermatol. 2002;146(4):707–9. IVIG ? Forman R, Koren G, Shear NH. Erythema multiforme, Yes. Stevens-Johnson syndrome and toxic epidermal necrolysis in children: a review of 10 years' experi- Anti-TNF ? ence. Drug Saf. 2002;25(13):965–72. Theoretically a good treatment, but use may be Fournier S, Bastuji-Garin S, Mentec H, Revuz J, Roujeau limited in the presence of infection. JC. Toxic epidermal necrolysis associated with mycoplasma pneumoniae infection. Eur J Clin Microbiol Infect Dis Off Publ Eur Soc Clin Microbiol. 1995;14(6):558–9. References Ginsburg CM. Stevens-Johnson syndrome in children. Pediatr Infect Dis. 1982;1(3):155–8. Aggarwal R, Sharma M, Modi M, Garg VK, Salaria Goyal S, Gupta P, Ryan CM, Kazlas M, Noviski N, M. HLA-B * 1502 is associated with carbamazepine Sheridan RL. Toxic epidermal necrolysis in children: induced Stevens-Johnson syndrome in North Indian medical, surgical, and ophthalmologic considerations. population. Hum Immunol. 2014;75(11):1120–2. J Burn Care Res Off publ Am Burn Assoc. Al-Shouli S, Abouchala N, Bogusz MJ, Al Tufail M, 2009;30(3):437–49. Thestrup-Pedersen K. Toxic epidermal necrolysis asso- Gubinelli E, Canzona F, Tonanzi T, Raskovic D, Didona ciated with high intake of sildenafi l and its response to B. Toxic epidermal necrolysis successfully treated infl iximab. Acta Derm Venereol. 2005;85(6):534–5. with etanercept. J Dermatol. 2009;36(3):150–3. Assier H, Bastuji-Garin S, Revuz J, Roujeau JC. Erythema Haber J, Hopman W, Gomez M, Cartotto R. Late out- multiforme with mucous membrane involvement and comes in adult survivors of toxic epidermal necrolysis Stevens-Johnson syndrome are clinically different dis- after treatment in a burn center. J Burn Care Rehabil. orders with distinct causes. Arch Dermatol. 2005;26(1):33–41. 1995;131(5):539–43. He XJ, Jian LY, He XL, Wu Y, Xu YY, Sun XJ, et al. Ball R, Ball LK, Wise RP, Braun MM, Beeler JA, Salive Association between the HLA-B*15:02 allele and car- ME. Stevens-Johnson syndrome and toxic epidermal bamazepine-induced Stevens-Johnson syndrome/toxic necrolysis after vaccination: reports to the vaccine epidermal necrolysis in Han individuals of northeast- adverse event reporting system. Pediatr Infect Dis ern China. Pharmacol Rep PR. 2013;65(5):1256–62. J. 2001;20(2):219–23. Huff JC, Weston WL, Tonnesen MG. Erythema multi- Del Pozzo-Magana BR, Lazo-Langner A, Carleton B, forme: a critical review of characteristics, diagnostic Castro-Pastrana LI, Rieder MJ. A systematic review of criteria, and causes. J Am Acad Dermatol. treatment of drug-induced Stevens-Johnson syndrome 1983;8(6):763–75. and toxic epidermal necrolysis in children. J Popul Hunger RE, Hunziker T, Buettiker U, Braathen LR, Ther Clin Pharmacol J de la therapeutique des popula- Yawalkar N. Rapid resolution of toxic epidermal tions et de la pharamcologie clinique. necrolysis with anti-TNF-alpha treatment. J Allergy 2011;18:e121–33. Clin Immunol. 2005;116(4):923–4. Dobrosavljevic D, Milinkovic MV, Nikolic MM. Toxic Kakourou T, Klontza D, Soteropoulou F, Kattamis epidermal necrolysis following morbilli-parotitis- C. Corticosteroid treatment of erythema multiforme rubella vaccination. J Eur Acad Dermatol Venereol major (Stevens-Johnson syndrome) in children. Eur JEADV. 1999;13(1):59–61. J Pediatr. 1997;156(2):90–3. Famularo G, Di Dona B, Canzona F, Girardelli CR, Kaniwa N, Saito Y, Aihara M, Matsunaga K, Tohkin M, Cruciani G. Etanercept for toxic epidermal necrolysis. Kurose K, et al. HLA-B locus in Japanese patients Ann Pharmacother. 2007;41(6):1083–4. with anti-epileptics and allopurinol-related Stevens- Fernando SL. The management of toxic epidermal necrol- Johnson syndrome and toxic epidermal necrolysis. ysis. Australas J Dermatol. 2012;53(3):165–71. Pharmacogenomics. 2008;9(11):1617–22. Ferrandiz-Pulido C, Garcia-Patos V. A review of causes of Khalil I, Lepage V, Douay C, Morin L, al-Daccak R, Stevens-Johnson syndrome and toxic epidermal Wallach D, et al. HLA DQB1*0301 allele is involved necrolysis in children. Arch Dis Child. in the susceptibility to erythema multiforme. J Invest 2013;98(12):998–1003. Dermatol. 1991;97(4):697–700. 22 Erythema Multiforme, Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis 219

Kreft B, Wohlrab J, Bramsiepe I, Eismann R, Winkler M, pneumoniae infection in two children. Pediatr Marsch WC. Etoricoxib-induced toxic epidermal Dermatol. 2006;23(6):546–55. necrolysis: successful treatment with infl iximab. Schwartz RA, McDonough PH, Lee BW. Toxic epidermal J Dermatol. 2010;37(10):904–6. necrolysis: part II. Prognosis, sequelae, diagnosis, dif- Kunimi Y, Hirata Y, Aihara M, Yamane Y, Ikezawa ferential diagnosis, prevention, and treatment. J Am Z. Statistical analysis of Stevens-Johnson syndrome Acad Dermatol. 2013a;69(2):187.e1–16; quiz 203–4. caused by mycoplasma pneumonia infection in Japan. Schwartz RA, McDonough PH, Lee BW. Toxic epidermal Allergol Int Off J Jpn Soc Allergol. 2011;60(4): necrolysis: part I. Introduction, history, classifi cation, 525–32. clinical features, systemic manifestations, etiology, Leaute-Labreze C, Lamireau T, Chawki D, Maleville J, and immunopathogenesis. J Am Acad Dermatol. Taieb A. Diagnosis, classifi cation, and management of 2013b;69(2):173.e1–13; quiz 85–6. erythema multiforme and Stevens-Johnson syndrome. Scott-Lang V, Tidman M, McKay D. Toxic epidermal Arch Dis Child. 2000;83(4):347–52. necrolysis in a child successfully treated with infl ix- Levi N, Bastuji-Garin S, Mockenhaupt M, Roujeau JC, imab. Pediatr Dermatol. 2014;31(4):532–4. Flahault A, Kelly JP, et al. Medications as risk factors Sheridan RL, Weber JM, Schulz JT, Ryan CM, Low HM, of Stevens-Johnson syndrome and toxic epidermal Tompkins RG. Management of severe toxic epidermal necrolysis in children: a pooled analysis. Pediatrics. necrolysis in children. J Burn Care Rehabil. 2009;123(2):e297–304. 1999;20(6):497–500. Lyell A. Toxic epidermal necrolysis: an eruption resem- Stevens AMJF. A new eruptive fever associates with sto- bling scalding of the skin. Br J Dermatol. matitis and ophthalmia; report of two cases in chil- 1956;68(11):355–61. dren. Am J Dis Child. 1922;24:526–33. Mockenhaupt M, Viboud C, Dunant A, Naldi L, Halevy S, Tassaneeyakul W, Jantararoungtong T, Chen P, Lin PY, Bouwes Bavinck JN, et al. Stevens-Johnson syndrome Tiamkao S, Khunarkornsiri U, et al. Strong associa- and toxic epidermal necrolysis: assessment of medication between HLA-B*5801 and allopurinol-induced tion risks with emphasis on recently marketed drugs. Stevens-Johnson syndrome and toxic epidermal The EuroSCAR-study. J Invest Dermatol. necrolysis in a Thai population. Pharmacogenet 2008;128(1):35–44. Genomics. 2009;19(9):704–9. Nassif A, Moslehi H, Le Gouvello S, Bagot M, Lyonnet Tatnall FM, Schofi eld JK, Leigh IM. A double-blind, L, Michel L, et al. Evaluation of the potential role of placebo-controlled trial of continuous acyclovir ther- cytokines in toxic epidermal necrolysis. J Invest apy in recurrent erythema multiforme. Br J Dermatol. Dermatol. 2004;123(5):850–5. 1995;132(2):267–70. Paquet P, Nikkels A, Arrese JE, Vanderkelen A, Pierard Thomas BA. The so-called Stevens-Johnson syndrome. GE. Macrophages and tumor necrosis factor alpha in Br Med J. 1950;1(4667):1393–7. toxic epidermal necrolysis. Arch Dermatol. Torchia D, Romanelli P, Kerdel FA. Erythema multiforme 1994;130(5):605–8. and Stevens-Johnson syndrome/toxic epidermal Prendiville JS, Hebert AA, Greenwald MJ, Esterly necrolysis associated with lupus erythematosus. J Am NB. Management of Stevens-Johnson syndrome and Acad Dermatol. 2012;67(3):417–21. toxic epidermal necrolysis in children. J Pediatr. Viard I, Wehrli P, Bullani R, Schneider P, Holler N, 1989;115(6):881–7. Salomon D, et al. Inhibition of toxic epidermal necrol- Rasmussen JE. Erythema multiforme in children. ysis by blockade of CD95 with human intravenous Response to treatment with systemic corticosteroids. immunoglobulin. Science. 1998;282(5388):490–3. Br J Dermatol. 1976;95(2):181–6. Von Hebra F. Atlas der hautkrankheiten. Vienna: Roujeau JC, Stern RS. Severe adverse cutaneous reactions Kaiserliche Akademie der; 1866. to drugs. N Engl J Med. 1994;331(19):1272–85. Weston WL. Herpes-associated erythema multiforme. Rzany B, Mockenhaupt M, Stocker U, Hamouda O, J Invest Dermatol. 2005;124(6):xv–xvi. Schopf E. Incidence of Stevens-Johnson syndrome Wilkins J, Morrison L, White Jr CR. Oculocutaneous and toxic epidermal necrolysis in patients with the manifestations of the erythema multiforme/Stevens- acquired immunodefi ciency syndrome in Germany. Johnson syndrome/toxic epidermal necrolysis spec- Arch Dermatol. 1993;129(8):1059. trum. Dermatol Clin. 1992;10(3):571–82. Rzany B, Correia O, Kelly JP, Naldi L, Auquier A, Stern Wojtkiewicz A, Wysocki M, Fortuna J, Chrupek M, R. Risk of Stevens-Johnson syndrome and toxic epi- Matczuk M, Koltan A. Benefi cial and rapid effect of dermal necrolysis during fi rst weeks of antiepileptic infl iximab on the course of toxic epidermal necrolysis. therapy: a case–control study. Study group of the Acta Derm Venereol. 2008;88(4):420–1. international case control study on severe cutaneous Wootton CI, Patel AN, Williams HC. In a patient with adverse reactions. Lancet. 1999;353(9171):2190–4. toxic epidermal necrolysis, does intravenous immuno- Schalock PC, Dinulos JG, Pace N, Schwarzenberger K, globulin improve survival compared with supportive Wenger JK. Erythema multiforme due to mycoplasma care? Arch Dermatol. 2011;147(12):1437–40. Kawasaki Disease 2 3 Katherine Johnson and Tor Shwayder

Abstract Kawasaki disease (KD) is a disorder that affects many organs including the skin, the mucous membranes, the lymph nodes, and the heart. It was originally described by Tomisaku Kawasaki in 1967. Even with vast amounts of research, KD remains an enigma in the medical fi eld. It remains a controversial topic as its etiology, pathogenesis, diagnosis, and management are complicated by many uncertainties. KD can be a devastating disease if not recognized early and treated appropriately, resulting in childhood death and increased morbidity during adulthood. Research has explored the etiology of KD, ranging from genetic and environmental susceptibility to suggestion of a new virus that has yet to be identifi ed. Complicating matters, KD does not always fulfi ll diagnostic criteria, as patients can have an incomplete presentation that mimics benign childhood illnesses. As initial treatment is not always successful, grading systems have been developed in an attempt to predict nonresponders and those at higher risk of serious disease. Finally, there is little longitudinal evidence suggesting proper long-term management of KD patients throughout adulthood.

Keywords Kawasaki disease in pediatrics • Coronary artery aneurysms and Kawasaki disease • Intravenous immunoglobulin in Kawasaki disease • Vasculitis • Incomplete Kawasaki disease • Pediatric patients with Kawasaki disease

K. Johnson , DO • T. Shwayder , MD (*) Department of Pediatric Dermatology , Henry Ford Hospital , Detroit , MI , USA e-mail: [email protected]

Kawasaki disease (KD) has been surrounded by Table 23.1 Clinical and laboratory features of Kawasaki controversy since its emergence in the literature in disease 1967. It was fi rst reported by Tomisaku Kawasaki in Fever ≥ 5 days plus the following: the Japanese Journal of Allergy in a paper titled ≥4 principal criteria <4 principal criteria “Acute febrile mucocutaneous lymph node syn- (diagnosis can be made Coronary artery on day 4 of the illness drome: clinical observation of 50 cases” (Kawasaki abnormalities seen on with these criteria two-dimensional ECHO or and Naoe 2014 ; Nakamura et al. 2012 ). Within 10 fulfi lled) angiography years, the association between sudden cardiac death Principal criteria: and KD was made, and by 1976, two-dimensional Changes in extremities echocardiography was introduced into the diagno- Acute: erythema/edema of hands and feet sis and management of the disease. In 1994, almost Subacute: periungual peeling of fi ngers and toes in 30 years after its introduction, the Chapel Hill weeks 2–3 Consensus Conference on the Nomenclature of Polymorphous exanthem usually within 5 days of start Systemic Vasculitides classifi ed KD as a medium- of illness sized vasculitis that affects the skin, mucous mem- Painless, bilateral conjunctival injection without exudate branes, and lymph nodes (Jennette et al. 1994 ). Changes in lips and oral cavity KD is an acute, systemic, medium-sized vas- Strawberry tongue culitis that affects previously healthy children Oropharyngeal erythema who are typically under 5 years of age. Within Erythema, peeling, fi ssuring, cracking of lips the fi rst 10 days, the disease manifests with a Cervical lymphadenopathy characteristic high fever and, in the classic form, ≥ 1 lymph node that is > 15 mm in diameter four of fi ve additional features (Table 23.1 ; Other observed fi ndings: Fig. 23.1a, b ). It is a self-limited disease and Laboratory abnormalities: elevated ESR, CRP, serum often resolves within 1–3 weeks. However, it has transaminases, gamma-glutamyl transpeptidase; a predilection for the coronary arteries and can dyslipidemia; leukocytosis in the blood and synovial cause coronary artery abnormalities (CAA), spe- fl uid; pleocytosis of CSF; hypoalbuminemia; hyponatremia; anemia cifi cally aneurysms, in 25–30 % of untreated Cardiovascular fi ndings cases. It is now the leading cause of acquired Electrocardiogram changes, auscultation pediatric cardiac disease in the developed world. abnormalities Despite over 40 years of research, the etiology Respiratory fi ndings of KD remains a mystery. Consequently, there is Cough, rhinorrhea no single confi rmative test and diagnosis relies Arthritis and arthralgias on clinical criteria. The treatment of KD is also a Diarrhea, vomiting, and abdominal pain point of controversy, as the etiologic target CNS fi ndings: agitation, aseptic meningitis, transient remains elusive and standard treatments are not sensorineural hearing loss always effective. As this disease can have signifi - CNS central nervous system, CRP C-reactive protein, CSF cant morbidity and mortality in the pediatric pop- cerebrospinal fl uid, ECHO echocardiography, ESR erythrocyte sedimentation rate ulation, future identifi cation of the causative agent will revolutionize the diagnosis and treatment for this mystifying disease. review by Burgner et al. (2005 ) summarized a list of proposed, although unproven, causes of KD. Many of the reports found in the literature Controversies in Etiology stem from the early years of KD research, prob- and Pathogenesis ing for causative agents such as common childhood viruses, living near a body of water, house Environmental Causes of KD dust mites, and exposure to carpet shampoo. Clinical similarities between mercury hypersen- Efforts have been made to associate KD with a sitivity (acrodynia) and KD have been appreci- variety of environmental insults and exposures. A ated, although no causation has been proven. 23 Kawasaki Disease 223

a b

Fig. 23.1 ( a , b ) Exanthem on the arms and legs in children with Kawasaki disease

Infectious Causes of KD Others hypothesize that KD is due to multiple etiologic agents, as numerous viruses and bacte- Clinical, epidemiological, and pathological evi- ria have been isolated from affected patients. dence support the hypothesis that a ubiquitous However, because children experience many infectious agent is responsible for KD. Despite asymptomatic infections throughout their fi rst consistent clinical observations, science has years of life, it is more likely that the isolated failed to either identify a causative pathogen or microorganisms are coexisting with KD rather successfully develop an experimental animal than a true causal relationship. This can be model. observed in recent history, as polio, roseola, and Clinical fi ndings that are consistent with an fi fth disease were all believed to be due to multi- infectious agent include its characteristic fever, ple infectious agents, and eventually a sole abrupt onset, self-limited nature, and observance of microorganism was found to be responsible. seasonal patterns. Many notable childhood dis- Finally, there is suggestion of a new virus as eases show increased activity during particular the causative agent of KD. In the ciliated bron- times of the year. For instance, infl uenza and respi- chial epithelium of KD patients, intracytoplasmic ratory syncytial virus are more prevalent in the inclusion bodies containing viruslike particles winter months and enteroviruses are seen in the have been identifi ed (Rowley et al. 2008 ). These summer months. Similarly, KD cases in Japan have particles are homologous to several different shown a bimodal seasonal pattern, affecting chil- RNA families, but more studies are required for dren in January, which is the coldest month, and in further genetic assessment. June/July, which are the months with the highest precipitation. Not only does KD show seasonal variation, but it also has caused nationwide epi- Superantigens or Conventional demics in 1979, 1982, and 1986 (Burns et al. 2005 ). Antigens Causing KD The affected ages of KD suggest an infection that is preventable by passive or developed The excessive degree of immunomodulatory immunity. It rarely affects infants under 3 months abnormalities seen in KD is similar to that of age, which could be due to protection from observed in superantigen-mediated disorders. passive transfer of maternal antibodies. Also, KD Superantigens are proteins specifi c to a bacteria is infrequently seen in the adult population, sug- or virus that interact nonspecifi cally with the gesting that adults were likely exposed as chil- major histocompatibility complex class II mole- dren and experienced a subclinical, cules and with the variable β (V β) portion of the inconsequential infection with development of T-cell receptor (TCR) (Reichardt et al. 2002 ; Abe protective immunity. et al. 1993 ). Staphylococcal toxic shock syn- 224 K. Johnson and T. Shwayder drome toxin one is an example of a superantigen shown prominent IgA plasma cells, which is that leads to an expansion of T cells with a spe- intriguing because infants and children have cifi c V β portion and little TCR variability. Some immature and low levels of systemic investigators favor the idea that a bacterial toxin IgA. However, the mucosal IgA response in this is responsible for KD, as some of the features age group is mature, so it is likely that the microbe resemble a staphylococcal or streptococcal enters through the respiratory or gastrointestinal toxin- mediated illness. However, no bacterial tract and stimulates B-cell switching to IgA. These toxin has been isolated from patients with KD to IgA plasma cells are oligoclonal rather than poly- support this theory (Meissner and Leung 2000 ; clonal, supporting the hypothesis that KD is due Nagata et al. 2009 ; Leung et al. 2002 ). to a conventional antigen-driven response. There are many confl icting reports regarding the expanded T-cell population in KD and its implications. Studies have analyzed different Genetic Predisposition to KD subsets of V β T cells, including the 2+, 6+, and 8.1+ subtypes. The V β T cell 2+ type shows age- Although KD has been reported worldwide, it is related differences, as younger children have disproportionately overrepresented in people of naturally occurring higher levels. Supporting the Asian descent with an increased incidence of idea of a V β T cell-driven process, one study 10–20-fold. Some KD cases show a familial sus- compared age-matched controls, children with ceptibility, as the incidence of second-case rates febrile illnesses, and children with KD. The KD in siblings is about tenfold that of the general subset showed strikingly elevated levels of the V population, and 10 % of twins in the general pop- β 2+ T-cell population. Coincidentally, there ulation developed KD on the same date (Fujita were two females with toxic shock syndrome et al. 1989 ). There is an increased probability of showing similarly elevated levels, suggesting that a parent with a history of KD having a child with a comparable superantigen-driven process causes KD when compared to an unaffected parent. KD. None of the age-matched controls or febrile Additionally, children with a parent who had KD patients showed increases in V β 2+ T cells. are more likely to develop recurrent disease and The mucosal surfaces have been a focus of be at an increased risk of coronary artery involve- research, as many believe that the etiologic agent ment, indicating that parental involvement may enters through the respiratory or gastrointestinal indicate increased severity of disease. mucosal surfaces. Some hypothesize that a In a retrospective study performed in the superantigen-type organism becomes colonized United States, there were many reports of KD in on the gastrointestinal mucosal membranes, siblings, other family members, and family mem- causing a local infl ammatory response and bers that spanned generations (Dergun et al. absorption of the toxin into the circulation result- 2005 ). No clear pattern of inheritance could be ing in the clinical fi ndings of KD. Studies of gas- deducted from studying the pedigrees of the trointestinal bacteria in patients with KD have affected families, but the authors concluded that shown that there may be a complex interplay physicians should counsel affected families with between gram-negative gut fl ora and superanti- KD that other relatives, especially young chil- genic gram-positive microbes. dren, can have an increased risk of developing the The hypothesis of superantigens is compelling disease (Uehara et al. 2004 , 2011 ). but not without confl icting data. Overall isolation rates of superantigen-producing bacteria have been shown to not be statistically signifi cant Pathogenesis of CAA between KD patients and febrile controls, suggesting a different pathogenesis of disease. More The development of CAA is a multistep process, recent studies suggest that KD is due to a conven- beginning with endothelial cell swelling and tional antigen-driven process that enters via the edema in the vessel wall. Histologic observations mucosal epithelium. Children with KD have indicate that this swelling allows for infi ltration 23 Kawasaki Disease 225 of large mononuclear cells, plasma cells, and Furthermore, at high magnifi cation the infi ltrate lymphocytes, all of which are called to the area is composed of IgA within the cells, confi rming by interleukins and other cell traffi cking signals. that the vasculopathy in KD is not due to immune The internal elastic lamina can be destroyed with complex deposition. resultant aneurysmal formation. As the infl ammation subsides, remodeling takes place with increased fi broblastic activity and scarring Controversies in Diagnosis (Suzuki et al. 2000 ). Interleukin-1 is secreted in high levels during Incomplete KD the acute phase of KD and is associated with the expression of endothelial cell antigens, endothe- Over the past two decades, it has been recognized lial leukocyte adhesion molecule-1, and intercel- that some patients do not develop the complete lular adhesion molecule-1 (Leung et al. 1989 ). characteristic profi le of KD and instead fall into By increasing the expression of intercellular an “incomplete” category. This becomes a diag- adhesion molecule-1 and endothelial leukocyte nostic dilemma, as many of these features are adhesion molecule-1, infl ammatory cells are tar- nonspecifi c and similar to common childhood geted to the arterial walls, leading to a cascade of diseases (Witt et al. 1999 ). infl ammatory events causing severe pathological The American Heart Association’s sequelae. Transforming growth factor β, platelet- “Committee on Rheumatic Fever, Endocarditis, derived growth factor A, basic fi broblast growth and Kawasaki Disease” made a statement in 2004 factor, and vascular endothelial growth factor are regarding the evaluation of suspected incomplete four factors that promote angiogenesis, vascular KD (Newburger et al. 2004 ). They recommend repair, and migration of smooth muscle cells after that if a child has a fever greater than or equal to the initial infl ammatory infl ux. 5 days and 2–3 clinical criteria with patient char- The decrease in interleukin-1 levels during the acteristics consistent with KD, laboratory stud- convalescent phase correlates with a decrease in ies, including a C-reactive protein, erythrocyte multisystem infl ammation, especially in the cor- sedimentation rate, complete metabolic profi le, onary arteries. However, in cases that are nonre- complete blood count, and urinalysis, should be sponders to intravenous immunoglobulin (IVIG), performed. the interleukin-1 levels do not improve and infl ammation of the coronary arteries persists. Aneurysms slowly form as the vessel wall is Infants with KD compromised, and eventually the aneurysms can develop occlusions. There are three different Infants less than 1 year of age are more likely to types of occlusions that have been identifi ed: pro- have an incomplete presentation of KD, which gressive stenosis of the artery, thrombosis caus- often results in delayed administration of IVIG ing occlusion, and a less common occlusion from (Chang et al. 2006 ). Infants are also more likely to an extracellular matrix-like jelly. Transforming have CAA than older children, although this could growth factor β, platelet-derived growth factor A, be due to the delay in diagnosis and proper treat- basic fi broblast growth factor, and vascular endo- ment. Infants less than or equal to 6 months old thelial growth factor become active again as the with an unexplained fever of greater than or equal occlusions cause the vessels to recanalize. to 7 days duration should undergo laboratory test- Infi ltration of IgA plasma cells has been dis- ing and an echocardiogram (ECHO) if there is covered in aortic, renal artery, and coronary evidence of systemic infl ammation, regardless of artery walls in KD patients, which is unlike any clinical characteristics. Redness of a bacillus other vasculitic disease (Mantis et al. 2011 ; Calmette-Guérin inoculation site, abnormal labo- Rowley et al. 1997 , 2001 ). In the coronary arter- ratory studies, and cardiac complications other ies, the plasma cells are found in the intima, than coronary artery pathology should be consid- media, and adventitia of the vessel wall. ered as possible manifestations of KD. 226 K. Johnson and T. Shwayder

Use of ECHO, Computed Tomography Japan, the Harada score is used to assess the need Angiography, and Magnetic for IVIG, although this scoring system is becom- Resonance Angiography ing less utilized as almost 90 % of children with in Evaluating CAA KD receive IVIG (Harada 1991 ). In the Harada classifi cation, additional measurements such as When suspecting KD, transthoracic ECHO age, gender, and laboratory values are taken to should be performed to evaluate cardiac function determine the risk of development of CAA in and the coronary arteries (Yim et al. 2013 ). A patients with a clinical diagnosis of KD. In a normal ECHO, however, does not rule out KD, study assessing Harada’s guidelines, only two and repeat studies should be performed if KD patients that did not fulfi ll criteria for IVIG remains a possibility. ECHO is also useful in administration went on to develop coronary evaluating infants and patients who show features artery pathology. of incomplete KD, as evidence of coronary A Cochrane review in 2003 concluded that involvement can solidify the diagnosis. children meeting the diagnostic criteria of KD, ECHO is operator dependent and can result in rather than the laboratory measurements in subjective diagnostic errors. Intravascular ultra- Harada’s classifi cation, should be treated with a sound and cardiac catheterization are better apt to single dose of 2 g/kg of IVIG within 10 days of investigate arterial lumen abnormalities, but they symptom onset to reduce the chance of CAA are both invasive and not without risks. Newer (Oates-Whitehead et al. 2003 ; Sleeper et al. technologies such as computed tomography angi- 2011). By treating acute KD, the risk of develop- ography (CTA) and magnetic resonance angiogra- ment of CAA drops from 25 to 5 %. phy are less invasive techniques and can provide There is an increasing tendency for physicians high-resolution imaging of the coronary vascula- to diagnose and treat patients who do not fulfi ll ture (Goo et al. 2006 ). However, CTA requires a the diagnostic criteria for KD, as studies show breath-holding technique for quality images, a that the risk of developing CAA does not corre- task that is not easy in young children. Another late with the development of the established fea- drawback of CTA is the exposure of children to tures of the disease (Ayusawa et al. 2005 ). IVIG ionizing radiation when there are other less haz- treatment within 10 days of symptom onset is ardous imaging options. Currently, ECHO remains most benefi cial in reducing the chance of CAA, the imaging of choice and magnetic resonance so treatment seems justifi ed in children that have angiography and CTA may be considered when an incomplete KD to avoid long-term cardiac trying to avoid more invasive techniques. Despite risks from an otherwise treatable disease. the potential for magnetic resonance angiography and CTA in the future, more studies are needed to assess their utility and diagnostic values. How to Approach IVIG Nonresponders

Controversies in Treatment There is a subset of patients who are considered nonresponders to the standard IVIG treatment Use of IVIG and may require adjuvant therapy (Davies et al. 2015 ). Patients are categorized as nonresponders IVIG is a cornerstone in the treatment of acute when they have a persistent or recrudescent fever KD (Burns et al. 1998 ; Burns and Glodé 2004 ; despite proper IVIG dosing and administration. Jolliff et al. 1982 ). In Japan, 89.5 % of patients In the Japanese nationwide epidemiological sur- with KD were administered with IVIG, and it vey, 16.6 % of patients did not respond to the ﬁ rst was most commonly given by the ﬁ fth day of dis- dose of IVIG and required additional therapies ease. However, the criterion for IVIG initiation (Kobayashi et al. 2006 ), a rate that is similar to varies among countries. In some health centers in those found in studies in North America. 23 Kawasaki Disease 227

The proper approach to the nonresponding tive and specifi c when assessing patients at risk patient has not been determined. Most patients for IVIG resistance, and addition of intravenous receive subsequent IVIG doses until the fever methylprednisolone is benefi cial as adjunctive abates. This may be accompanied by other anti- treatment in KD. infl ammatory therapies such as intravenous ste- Despite its use in Japan, the United States and roids, anti-tumor necrosis factor alpha agents, or United Kingdom have shown that the Kobayashi, other immunomodulators such as cyclosporine. Egami, and Sano scoring systems are poor predic- An association between IVIG resistance and tors of IVIG resistance and that further studies are severity of coronary artery lesions has not been needed to develop relevant prognostic biomarkers proven. However, patients initially treated with (Davies et al. 2015 and Sleeper et al. 2011 ). IVIG who developed persistent or recurrent fever had an increased prevalence of CAA when compared to afebrile patients. Studies have shown Use of Corticosteroids that the majority of CAA seen on ultrasound regress during the subacute phase of disease. Systemic steroids are a mainstay of treatment of Therefore, long-term prognosis and severity of acute vasculitides, although their administration residual disease are best assessed at 1 month after has been a topic of debate in the treatment of the onset of KD. KD. A randomized double-blind placebo- controlled study assessed effi cacy of the addition of 30 mg/kg intravenous methylprednisolone to Risk Scoring Systems to Predict IVIG the standard treatments of IVIG and aspirin Nonresponders (ASA). The study concluded that the addition of steroid did not improve coronary artery outcomes Three Japanese scoring systems, Kobayashi, at weeks 1 and 5. However, it did appear to be Egami, and Sano, have attempted to determine benefi cial in children who required retreatment which individuals are at risk for treatment failure. of IVIG due to persistent fever. Other fi ndings Patients with higher scores are more likely to show that IVIG plus prednisolone had signifi cant have severe disease and to not respond to the fi rst advantage over IVIG alone for prevention of round of IVIG. A study by Kobayashi et al. CAA in severe KD (Ogata et al. 2012 ; Newburger (2006 ) showed that hyponatremia and high aspar- et al. 2007 ; Kobayashi et al. 2012 ). tate transaminase levels had a strong predictive value for IVIG resistance, so they are used as measurements in the scoring system. All three Use of Anti-tumor Necrosis Factor systems use liver enzymes and C-reactive protein Agents levels in determining risk, alongside other laboratory and demographic variables. Infl iximab has been used worldwide for the Ogata et al. (2012 ) used the Egami scoring treatment of KD that is unresponsive to IVIG, system to predict IVIG nonresponders before ini- and many anecdotal case reports have been pub- tiation of treatment. Patients that were deter- lished on its use in KD. To better study the safety mined to be at risk for treatment failure were and effi cacy of infl iximab in treatment-resistant divided into two groups to either receive IVIG KD, a phase III randomized, double-blind alone or in combination with intravenous methyl- placebo- controlled study was performed in the prednisolone. Those patients who received IVIG United States (Tremoulet et al. 2014). Infl iximab and intravenous methylprednisolone had signifi - 5 mg/kg for one dose followed by IVIG 2 g/kg cant improvement of disease, less need for a sec- for one dose and ASA 80–100 mg/kg/daily was ond treatment, and faster regression of fever administered to the treatment patients. The con- when compared to those given only IVIG. This trol arm received IVIG and ASA at the same study concluded that scoring systems are sensi- doses. Addition of infl iximab did not reduce the 228 K. Johnson and T. Shwayder treatment resistance of IVIG, although it did lesions in KD differs from that in atherosclerosis. show a reduction in fever duration and infl am- In KD, there are no accumulation of lipid, no matory markers. fatty streaks, and only a few macrophages in the vasculature, which are all characteristics of atherosclerosis. The intimal wall thickening in KD Use of ASA is due to the excessive amount of angiogenesis, as shown by increased transforming growth fac- Despite its lack of solid evidence, ASA remains a tor β, platelet-derived growth factor A, basic mainstay of treatment alongside IVIG, as the fi broblast growth factor, and vascular endothelial combination shows a signifi cantly lower inci- growth factor, leading to proliferation of smooth dence of CAA than in treatment with ASA alone muscle cells and extracellular matrix (Rowley (Durongpisitkul et al. 1995 ). Generally, ASA is et al. 1997 , 2001 ). administered as 80–100 mg/kg/daily in four Although it is unlikely that KD causes athero- doses. However, there are confl icting opinions on sclerosis, adults with a history of KD and cardiac the recommended dose of ASA administered involvement should be counseled on proper diet during the acute phase. In a meta-analysis evalu- and to avoid risk factors for atherosclerotic heart ating IVIG and ASA, there was no statistically disease, which can become superimposed on the signifi cant difference of CAA development KD vasculopathy. between low-dose ASA (<80 mg/kg/day) and high-dose ASA (≥80 mg/kg/day) given with IVIG during the acute phase of the disease. Long-Term Monitoring of KD Patients Furthermore, a 2006 Cochrane review concluded that there is insuffi cient evidence that ASA is KD can result in permanent damage to the car- benefi cial in the treatment of KD, and well- diovascular system, such as coronary artery dila- designed randomized controlled trials are needed tion, aneurysms, giant aneurysms, valvular for further evaluation (Baumer et al. 2006 ). lesions, coronary stenosis, and myocardial infarc- The length of ASA treatment varies; some tion. However, there is little data to counsel authors continue the dose until the child has been patients on the long-term prognosis and proper afebrile for 48–72 h, while others continue the dose management of the disease. Immunohistochemical until the 14th day of illness. Once the high- dose studies have shown increased activity of angio- aspirin is discontinued, the child remains on ASA genesis factors in coronary lesions years after the 3–5 mg/kg/day for 6–8 weeks after illness. This is acute disease, suggesting persistent remodeling due to increased platelet counts and aggregation and recanalization, which can lead to gradual car- activity during the convalescent phase of KD, diac disease (Lin et al. 2015 ). which can lead to thrombosis in damaged vessels. As more KD patients reach adulthood, cardiol- If there is residual coronary artery involvement, the ogists are presented with a unique subset of child should remain on ASA indefi nitely. In chil- patients with abnormal coronary fi ndings. Studies dren with giant coronary artery aneurysms, warfa- show that approximately 5 % of young adults that rin in addition to ASA reduces the incidence of present with cardiac symptoms who undergo coro- occlusion, infarction, and death (Su et al. 2014 ). nary angiography have pathology suggestive of KD, although they may be unaware that they ever had the disease. Once the diagnosis of KD is made, KD and Atherosclerosis cardiologists must be aware of the unique fi ndings and management between KD and typical athero- There is no evidence-based data addressing the sclerotic heart disease (Daniels et al. 2012a , b ). association of KD and development of premature Patients with large aneurysms should be on atherosclerosis. Immunohistochemistry demon- long-term therapy with systemic anticoagulation strates that the remodeling of coronary artery in addition to antiplatelet agents. In adults, coro- 23 Kawasaki Disease 229

Table 23.2 Long-term management of adults with history of KD Study CT ECHO Other tests Pharmacologic therapy San Diego Adult For patients with no coronary artery changes in childhood Small aneurysms or KD Collaborative One time calcium Assess for wall motion, N/A remodeling of larger Study (Daniels CT score aortic root diameter, and aneurysms: et al. 2012b ) valvular function Aspirin 81 mg or clopidogrel If these tests are normal: no pharmacologic therapy. Reevaluate Large aneurysms every 10 years (>8 mm) If abnormal, follow the below recommendations: Aspirin 81 mg daily For patients with CA changes in childhood or abnormal tests from Warfarin to INR of above screening: 2–3 or other Coronary artery CT Stress ECHO annually; if Cardiac MRA if anticoagulants angiogram abnormal then invasive no coronary angiography artery CT Japanese Patients with no CA changes in childhood No pharmacologic Circulation Not indicated Follow up as desired N/A treatment; aspirin not Society (2014 ) necessary Asymptomatic patients with CA aneurysms from childhood Aspirin 81 mg or Coronary 2–3 times a year N/A clopidogrel arteriogram once every several years CT computed tomography, ECHO echocardiography, INR international normalized ratio, KD Kawasaki disease, MRA magnetic resonance angiography, N/A not applicable

nary CTA may be useful in identifying the size and Bulleted List of Controversies location of aneurysms and the presence of throm- bus, stenosis of arteries, or aneurysmal calcifi ca- • A ubiquitous infectious agent is likely respon- tion. Recommendations for KD management vary sible for Kawasaki disease (KD), causing clin- and are summarized in Table 23.2 . ical disease in those that are genetically susceptible. However, this infectious agent Conclusion has yet to be identifi ed. Some believe that it is KD remains a conundrum in the fi eld of medi- a superantigen-driven bacterium, while others cine and is a bane for researchers worldwide. believe it is a new, unidentifi ed virus (Rowley Due to its potentially devastating effects on et al. 2011 ). children, studies aim to identify the etiologic • A genetic predisposition to KD is suggested, agent. In the meantime, patients with incom- which has been observed in epidemiological plete KD should be recognized early and studies in Japan. appropriately treated. Better scoring systems • It is unclear why KD has such an affi nity to need to be developed to predict IVIG nonre- the coronary arteries. Studies have shown sponders. Diagnostic imaging, such as ECHO, increased amounts of interleukin-1 and cell should be used without hesitation as identifi - traffi cking signals directed to the vascular cation of cardiac involvement can quickly endothelium. IgA plasma cell infi ltration has change the approach to treatment. Finally, also been discovered in the vessel walls, which patients with a childhood history of KD should is unlike anything ever seen in vasculitic be managed by a cardiologist who is familiar diseases. with the disease. Our current understanding of • Incomplete KD is a true Kawasaki diagnosis KD will undoubtedly change, as technological and should be treated as such. Additionally, and scientifi c advances will eventually unwrap infants more commonly present with an its mysterious nature. incomplete clinical picture. Diagnosis can 230 K. Johnson and T. Shwayder

often be delayed due to a confusing clinical Daniels LB, Gordon JB, Burns JC. Kawasaki disease: late presentation and echocardiography should be cardiovascular sequelae. Curr Opin Cardiol. 2012a;27:572–7. employed if KD is suspected. Daniels LB, Tjajadi MS, Walford HH, Jimenez-Fernandez • Approximately 15 % of patients are nonre- S, Trofi menko V, Fick Jr DB, et al. Prevalence of sponsive to the fi rst round of intravenous Kawasaki disease in young adults with suspected immunoglobulin. Scoring systems have been myocardial ischemia. Circulation. 2012b;125: 2447–53. used in Japan to predict nonresponders; how- Davies S, Sutton N, Blackstock S, Gormley S, Hoggart ever, their use has not been successful in the CJ, Levin M, et al. Predicting IVIG resistance in UK United States and United Kingdom. Kawasaki disease. Arch Dis Child. 2015;100:366–8. • Systemic steroids have shown effi cacy in Dergun M, Kao A, Hauger SB, Newburger JW, Burns JC. Familial occurrence of Kawasaki syndrome in treating patients who have severe KD and in North America. Arch Pediatr Adolesc Med. patients who require a second round of intra- 2005;159:876–81. venous immunoglobulin. Durongpisitkul K, Gururaj VJ, Park JM, Martin CF. The • Aspirin should be used in KD although there prevention of coronary artery aneurysm in Kawasaki disease: a meta-analysis on the effi cacy of aspirin and is poor evidence-based data suggesting the immunoglobulin treatment. Pediatrics. proper dose and duration. 1995;96:1057–61. • There are vague guidelines for the manage- Fujita Y, Nakamura Y, Sakata K, Hara N, Kobayashi M, ment of adults with a history of KD in child- Nagai M, et al. Kawasaki disease in families. Pediatrics. 1989;84:666–9. hood. As the population ages and KD cases Goo HW, Park IS, Ko JK, Kim YH. Coronary CT angiog- are longitudinally studied, more data should raphy and MR angiography of Kawasaki disease. be available regarding proper screening and Pediatr Radiol. 2006;36:697–705. management of these patients. Harada K. Intravenous gamma-globulin treatment in Kawasaki disease. Acta Paediatr Jpn. 1991;33:805–10. Japanese Circulation Society Joint Working Group. Guidelines for diagnosis and management of cardio- References vascular sequelae in Kawasaki disease (JCS 2013). Digest version. Circ J. 2014;78:2521–62. Jennette JC, Falk RJ, Andrassy K, Bacon PA, Churg J, Abe J, Kotzin BL, Meissner C, Melish ME, Takahashi M, Gross WL, et al. Nomenclature of systemic Fulton D, et al. Characterization of T cell repertoire vasculitides. Proposal of an international consensus changes in acute Kawasaki disease. J Exp Med. conference. Arthritis Rheum. 1994;37:187–92. 1993;177:791–6. Jolliff CR, Cost KM, Stivrins PC, Grossman PP, Nolte Ayusawa M, Sonobe T, Uemura S, Ogawa S, Nakamura Y, CR, Franco SM, et al. Reference intervals for serum Kiyosawa N, et al. Revision of diagnostic guidelines IgG, IgA, IgM, C3, and C4 as determined by rate for Kawasaki disease (the 5th revised edition). Pediatr nephelometry. Clin Chem. 1982;28:126–8. Int. 2005;47:232–4. Kawasaki T, Naoe S. History of Kawasaki disease. Clin Baumer JH, Love SJ, Gupta A, Haines LC, Maconochie I, Exp Nephrol. 2014;18:301–4. Dua JS. Salicylate for the treatment of Kawasaki dis- Kobayashi T, Inoue Y, Takeuchi K, Okada Y, Tamura K, ease in children. Cochrane Database Syst Rev. Tomomasa T, et al. Prediction of intravenous immuno- 2006;(4):CD004175. globulin unresponsiveness in patients with Kawasaki Burgner D, Harnden A. Kawasaki disease: what is the epi- disease. Circulation. 2006;113:2606–12. demiology telling us about the etiology? Int J Infect Kobayashi T, Saji T, Otani T, Takeuchi K, Nakamura T, Dis. 2005;9:185–94. Arakawa H, et al. Effi cacy of immunoglobulin plus Burns JC, Capparelli EV, Brown JA, Newburger JW, prednisolone for prevention of coronary artery abnor- Glode MP. Intravenous gamma-globulin treatment and malities in severe Kawasaki disease (RAISE study): a retreatment in Kawasaki disease. Pediatr Infect Dis randomised, open-label, blinded-endpoints trial. J. 1998;17:1144–8. Lancet. 2012;379:1613–20. Burns JC, Cayan DR, Tong G, Bainto EV, Turner CL, Leung DY, Cotran RS, Kurt-Jones E, Burns JC, Newburger Shike H, et al. Seasonality and temporal clustering of JW, Pober JS. Endothelial cell activation and high Kawasaki syndrome. Epidemiology. 2005;16:220–5. interleukin-1 secretion in the pathogenesis of acute Burns JC, Glodé MP. Kawasaki syndrome. Lancet. Kawasaki disease. Lancet. 1989;2:1298–302. 2004;364:533–44. Leung DY, Meissner HC, Shulman ST, Mason WH, Chang FY, Hwang B, Chen SJ, Lee PC, Meng CC, Lu Gerber MA, Glode MP, et al. Prevalence of JH. Characteristics of Kawasaki disease in infants superantigen-secreting bacteria in patients with younger than six months of age. Pediatr Infect Dis Kawasaki disease. J Pediatr. 2002;140:742–6. J. 2006;25:241–4. 23 Kawasaki Disease 231

Lin MT, Sun LC, Wu ET, Wang JK, Lue HC, Wu cytoplasmic inclusion bodies provide new insight. MH. Acute and late coronary outcomes in 1073 Nat Rev Microbiol. 2008;6:394–401. patients with Kawasaki disease with and without intra- Rowley AH, Baker SC, Shulman ST, Rand KH, Tretiakova venous gamma-immunoglobulin therapy. Arch Dis MS, Perlman EJ, et al. Ultrastructural, immunofl uo- Child. 2015;100:542. rescence, and RNA evidence support the hypothesis of Mantis NJ, Rol N, Corthesy B. Secretory IgA’s complex a “new” virus associated with Kawasaki disease. roles in immunity and mucosal homeostasis in the gut. J Infect Dis. 2011;203:1021–30. Mucosal Immunol. 2011;4:603–11. Rowley AH, Eckerley CA, Jack HM, Shulman ST, Baker Meissner HC, Leung DY. Superantigens, conventional SC. IgA plasma cells in vascular tissue of patients with antigens and the etiology of Kawasaki syndrome. Kawasaki syndrome. J Immunol. 1997;159:5946–55. Pediatr Infect Dis J. 2000;19:91–4. Rowley AH, Shulman ST, Spike BT, Mask CA, Baker Nagata S, Yamashiro Y, Ohtsuka Y, Shimizu T, Sakurai Y, SC. Oligoclonal IgA response in the vascular wall in Misawa S, et al. Heat shock proteins and superanti- acute Kawasaki disease. J Immunol. genic properties of bacteria from the gastrointestinal 2001;166:1334–43. tract of patients with Kawasaki disease. Immunology. Sleeper LA, Minich LL, McCrindle BM, Li JS, Mason W, 2009;128:511–20. Colan SD, et al. Evaluation of Kawasaki disease risk- Nakamura Y, Yashiro M, Uehara R, Sadakane A, Tsuboi scoring systems for intravenous immunoglobulin S, Aoyama Y, et al. Epidemiologic features of resistance. J Pediatr. 2011;158:831–835.e3. Kawasaki disease in Japan: results of the 2009–2010 Su D, Wang K, Qin S, Pang Y. Safety and effi cacy of war- nationwide survey. J Epidemiol. 2012;22:216–21. farin plus aspirin combination therapy for giant coro- Newburger JW, Sleeper LA, McCrindle BW, Minich LL, nary artery aneurysm secondary to Kawasaki disease: Gersony W, Vetter VL, et al. Randomized trial of a meta-analysis. Cardiology. 2014;129:55–64. pulsed corticosteroid therapy for primary treatment of Suzuki A, Miyagawa-Tomita S, Nakazawa M, Yutani Kawasaki disease. N Engl J Med. 2007;356:663–75. C. Remodeling of coronary artery lesions due to Newburger JW, Takahashi M, Gerber MA, Gewitz MH, Kawasaki disease: comparison of arteriographic and Tani LY, Burns JC, et al. Diagnosis, treatment, and immunohistochemical fi ndings. Jpn Heart long-term management of Kawasaki disease: a state- J. 2000;41:245–56. ment for health professionals from the committee on Tremoulet AH, Jain S, Jaggi P, Jimenez-Fernandez S, rheumatic fever, endocarditis, and Kawasaki disease, Pancheri JM, Sun X, et al. Infl iximab for intensifi ca- council on cardiovascular disease in the young, tion of primary therapy for Kawasaki disease: a phase American Heart Association. Pediatrics. 3 randomised, double-blind, placebo-controlled trial. 2004;114:1708–33. Lancet. 2014;383:1731–8. Oates-Whitehead RM, Baumer JH, Haines L, Love S, Uehara R, Yashiro M, Nakamura Y, Yanagawa H. Clinical Maconochie IK, Gupta A, et al. Intravenous immuno- features of patients with Kawasaki disease whose par- globulin for the treatment of Kawasaki disease in chil- ents had the same disease. Arch Pediatr Adolesc Med. dren. Cochrane Database Syst Rev. 2004;158:1166–9. 2003;(4):CD004000. Uehara R, Yashiro M, Nakamura Y, Yanagawa H. Parents Ogata S, Ogihara Y, Honda T, Kon S, Akiyama K, Ishii with a history of Kawasaki disease whose child also M. Corticosteroid pulse combination therapy for had the same disease. Pediatr Int. 2011;53:511–4. refractory Kawasaki disease: a randomized trial. Witt MT, Minich LL, Bohnsack JF, Young PC. Kawasaki Pediatrics. 2012;129:e17–23. disease: more patients are being diagnosed who do not Reichardt P, Lehmann I, Sierig G, Borte M. Analysis of meet American Heart Association criteria. Pediatrics. T-cell receptor V-beta 2 in peripheral blood lympho- 1999;104, e10. cytes as a diagnostic marker for Kawasaki disease. Yim D, Curtis N, Cheung M, Burgner D. An update on Infection. 2002;30:360–4. Kawasaki disease II: clinical features, diagnosis, treat- Rowley AH, Baker SC, Orenstein JM, Shulman ment and outcomes. J Paediatr Child Health. ST. Searching for the cause of Kawasaki disease– 2013;49:614–23. Retinoids 2 4 Dirk Van Gysel

Abstract Retinoids regulate a wide range of biological processes – including development, barrier integrity, and immunity – by their impact on cellular proliferation, differentiation, and apoptosis. They can be considered a breakthrough treatment in pediatric dermatology for disorders characterized by pathologic changes in keratinization such as acne, ichthyoses, Darier’s disease, and pityriasis rubra pilaris. The major problems however are the adverse effects for both topical and systemic retinoids.

Keywords Adverse effects of retinoids • Keratinization • Retinoids • Pediatric use of retinoids • Vitamin A in pediatric dermatology • Isotretinoin use in pediatrics

Retinoids are a class of natural and synthetic ulate a wide range of biological processes compounds that possess vitamin A activity. including (embryonic) development, barrier While the molecular structure of some synthetic integrity, and immunity (Li et al. 2014 ; Gudas retinoids do not resemble vitamin A, they all 2012 ). have in common that they bind to and activate, Retinol, retinal, and retinoic acid are collec- directly or after metabolic conversion, intranu- tively known as vitamin A. The major source of clear RARs (retinoic acid receptors) and RXRs natural vitamin A in industrialized nations is reti- (retinoic X receptors), which themselves are nyl esters in the diet derived from animal food DNA-binding transcriptional regulators (Das sources including dairy, ﬁ sh, and meat. After et al. 2014 ). By their effect on cellular prolifera- hydrolysis of the retinyl esters by pancreatic tion, differentiation, and apoptosis, retinoids reg- enzymes, retinol is taken up by the enterocytes and transported in serum to target cells. In the target cells, retinol is oxidized to retinal and retinoic acid or converted back to retinyl esters for cellu- D. Van Gysel , MD, PhD lar storage. In developing nations, individuals get Department of Pediatrics , O. L. Vrouw Hospital , their retinoids mainly from provitamin A carot- Aalst , Belgium e-mail: [email protected] enoids from plants, which are converted within

© Springer International Publishing Switzerland 2016 233 A.P. Oranje et al. (eds.), Practical Pediatric Dermatology, DOI 10.1007/978-3-319-32159-2_24 234 D. Van Gysel the body into retinal and further processed into Tretinoin was the fi rst retinoid to be studied. retinoic acid (Penniston and Tanumihardjo 2006 ; When exposed to light, 50 % degradation of treti- Li et al. 2014 ). noin was observed after 2 h and 95 % after 24 h The synthetic retinoids were developed as (Martin et al. 1998 ). Therefore, tretinoin should therapeutic doses of natural vitamin A and were be applied once daily at bedtime. accompanied by unacceptable side effects. There Adapalene is nowadays the fi rst-choice topical are now three generations of synthetic retinoids: retinoid in the treatment of mild-to-moderate acne because improvement occurs faster and tolerabil- • First-generation retinoids: which include reti- ity is higher compared to tretinoin, while their nol, retinal, tretinoin (retinoic acid), isotreti- effi cacy is equal (Cunliffe et al. 1998 ). Adapalene noin (13 -cis retinoic acid), and alitretinoin also demonstrates chemical stability to oxygen • Second-generation retinoids: which include and light, even in the presence of benzoyl perox- etretinate and its metabolite acitretin ide, which allows that this combination can be • Third-generation retinoids: which include taz- used simultaneously without loss of effi cacy arotene, bexarotene, and adapalene (Bershad et al. 1999 ; Thiboutot et al. 2007 ). Tazarotene is pharmacologically inactive until First- and second-generation retinoids are able metabolic conversion to the active metabolite taz- to bind with several retinoid receptors due to the arotenic acid. It has been reported that tazarotene fl exibility imparted by their alternating single has greater comedolytic activity compared to and double bonds. Third-generation retinoids are other available topical retinoids (Guenther 2002 ), less fl exible and therefore interact with fewer but it causes more skin irritation (Webster et al. retinoid receptors, which contribute to an 2002 ; Leyden et al. 2002 ; Gregoriou et al. 2014 ). improved tolerance. Retinoids can be applied Tazarotene is not approved for acne treatment in topically or administered systemically. Europe. The initial effect of a topical retinoid is often noticeable after 2–3 weeks, but it may take 4–6 Topical Retinoids weeks or longer before substantial clinical improvement occurs. Maximum improvement Topical retinoids are available as creams, lotions, occurs after 3–4 months. foams, and (microsphere) gels. Topical retinoids Other less conventional indications for off- can be considered as fi rst-line therapy for mild- label use of topical retinoids in children are acan- to-moderate acne. With their antihyperprolifera- thosis nigricans (Kapoor 2010 ; Weisshaar et al. tive, normalizing-of-differentiation, and 2001 ), alopecia areata (Talpur et al. 2009 ), anti-infl ammatory effects (Thielitz and Gollnick Darier’s disease (English et al. 1999 ), follicular 2008 ; Thielitz et al. 2008 ), the topical retinoids mucinosis (Alikhan et al. 2013 ), granular para- effectively control microcomedo development, keratosis (Compton and Jackson 2007 ), lichen reduce existing comedones (whiteheads and sclerosus et atrophicus (Guerriero et al. 2008 ), blackheads) and infl ammatory lesions (Gollnick lichen planus (Petruzzi et al. 2013 ), nevus come- and Krautheim 2003 ), and minimize the forma- donicus (Kaliyadan et al. 2014 ), (nail) psoriasis tion of new acne lesions. When infl ammatory (Dogra and Kaur 2010; Diluvio et al. 2007 ), lesions are present, topical retinoids are often scars, keloids, striae (Berman et al. 2007 ), and used in combination with an (oral or topical) antiviral warts (Boull and Groth 2011 ). microbial therapy, with an improved effi cacy of Topical retinoids have fewer and milder side either component as a result (Gollnick et al. effects than systemic retinoids. The major 2003 ). adverse effect is irritation of the skin, including The topical retinoids classically used in the erythema, dryness, peeling, itching, and burning. treatment of acne are tretinoin, adapalene, and One commonly used approach is to start with the tazarotene gel or cream. lowest concentration and increase as tolerated. 24 Retinoids 235

Although studies regarding the use of topical 2012 ). It should be used “sooner rather than later” retinoids in pediatric patients are extremely rare (Cunliffe et al. 1997 ), as a quick reduction of in the literature, experts are convinced that topi- infl ammation in acne may prevent the occurrence cal retinoids (tretinoin, adapalene, tazarotene) are of clinical and psychological scarring and also safe and effective and may be used for all types signifi cantly improves quality of life and reduces and severities of acne in children and adolescents the risk of depression (Layton 2001; Rubinow of all ages (Eichenfi eld et al. 2013 ). Although et al. 1987 ). This is different from the current several studies have proven that – due to their European Directive for prescribing oral isotreti- very low percutaneous absorption – the use of noin stating “oral isotretinoin should only be used topical tretinoin or adapalene is not associated in severe acne, nodular and conglobate acne, that with an increased risk of malformations consis- has or is not responding to appropriate antibiotics tent with retinoic acid embryopathy (Jick et al. and topical therapy”(Layton et al. 2006 ). 1993 ; Loureiro et al. 2005; Birth defects due to The evidence on the best dosage, including topical adapalene and tretinoin 1998 ; Topical cumulative dosage, is rare and partly confl icting. retinoids during pregnancy (continued) 2005 ), In most trials, higher dosages have lead to better administration during pregnancy and breastfeed- response rates while having less favorable safety/ ing is diffi cult to justify because alternatives are tolerability profi les. Most recent guidelines (“The available and acne is not a life-threatening American Academy of Dermatology Consensus disease. Conference on The Safe and Optimal Use of Isotretinoin,” “The European Evidence-Based (S3) Guidelines for the Treatment of Acne,” and Systemic Retinoids the “Evidence-Based Recommendations for the Diagnosis and Treatment of Pediatric Acne” Systemic retinoids are indicated for patients included) recommend a starting dose of 0.3– severely affected by disorders characterized by 0.5 mg/kg per day for the fi rst 4 weeks to avoid pathologic changes in keratinization such as initial fl ares, increasing to the full dosage of acne, psoriasis, ichthyoses, Darier’s disease, and 1 mg/kg per day until a cumulative dose of pityriasis rubra pilaris. Isotretinoin, a fi rst- 120 mg/kg is attained. Total doses lower than generation retinoid, is the most effective systemic 120 mg/kg are associated with higher rates of retinoid against acne. It affects all four patho- acne relapse (Layton et al. 1993 ; Goldsmith et al. genic factors by reducing the size and secretions 2004; Thielitz and Gollnick 2013; Nast et al. of sebaceous glands, secondarily inhibiting the 2012 ; Stainforth et al. 1993 ; Del Rosso 2012 ). growth of Propionibacterium acnes and the Isotretinoin therapy induces a more rapid resulting infl ammation, and preventing comedo- improvement of infl ammatory lesions as com- genesis through normalization of the differentia- pared with comedones. Usually, after 2–4 weeks tion of follicular keratinocytes (Gollnick 2003 ; of treatment, a 50 % regression of the pustules Ganceviciene and Zouboulis 2010). In addition, can be expected. Improvement continues during it is the only acne treatment that leads to remis- the posttreatment period (Orfanos and Zouboulis sion that may be permanent (Layton et al. 1993 ). 1998 ). If a second course is needed, an interval of The new evidence-based European S3 guide- at least 8 weeks should be respected as patients line recommends that systemic isotretinoin should may continue to improve while off isotretinoin. be considered as the fi rst-line treatment for severe In contrast with the European Directive (Layton papulopustular, moderate nodular, and severe et al. 2006 ), the abovementioned recent guide- nodular/conglobate acne, especially when prog- lines suggest that being less than 12 years old nostically unfavorable factors are present: family does not necessarily contraindicate the use of history of acne, early onset, marked seborrhea, isotretinoin. localization on the trunk, scarring, psychosocial Isotretinoin has been used in chronic recalci- disability, or persistent/late-type acne (Nast et al. trant disabling cases of other disorders such as 236 D. Van Gysel pityriasis rubra pilaris, psoriasis, Darier’s dis- reactions, such as erythema multiforme, Stevens– ease, palmo-plantar keratoderma, and ichthyosi- Johnson syndrome, and toxic epidermal necroly- form disorders. For a complete list of unapproved sis, has been reported (Health Canada 2010 ). indications/uses and cutaneous disorders, we Additionally, ophthalmologic, neuromuscular, refer to “Isotretinoin – unapproved indications/ and gastrointestinal side effects have been docu- uses and dosage: a physician’s reference” by mented (Brecher and Orlow 2003 ). Some patients Virendra N. Sehgal (Sehgal et al. 2006 ). None of may experience increases in serum triglycerides the other oral retinoids is approved for use in and changes in liver enzymes. The side effects children, although there are case reports of their are dose- and disease-dependent and are gener- off-label use in the pediatric population and some ally treatable and reversible. of them are approved for specifi c indications in Patients must be warned about depression, adults. suicidal thoughts, and psychosis, although a Alitretinoin, another fi rst-generation retinoid, causal relationship with oral retinoids remains has been shown effective in the treatment of controversial (Marqueling and Zane 2007 ; Saitta severe chronic hand eczema (Schmitt-Hoffmann et al. 2011a , b; Prevost and English 2013 ; Strahan et al. 2011 ; Tejera-Vaquerizo et al. 2012 ; Ruzicka and Raimer 2006 ). Isotretinoin has been sus- et al. 2008 ) and is used by some for the treatment pected to increase the risk of IBD. However, of Morbus Darier (also known as Darier–White) recent data demonstrate that isotretinoin expo- (Letule et al. 2013 ) and pityriasis rubra pilaris sure is not associated with an increased risk for (Amann et al. 2014 ). ulcerative colitis or Crohn’s disease (Etminan Acitretin, a metabolite of etretinate, is a et al. 2013 ; Racine et al. 2014 ; Alhusayen et al. second- generation retinoid that is used for the 2013 ). treatment of (pustular and erythrodermic) psoria- The absolute contraindications for systemic sis and disorders of keratinization (Shelnitz et al. isotretinoin are pregnancy and breastfeeding. 1987 ; Rosinska et al. 1988 ; de Oliveira et al. Relative contraindications are leukopenia, 2010 ; Tamayo and Ruiz-Maldonado 1981 ; moderate-to- severe hypercholesterolemia or Blanchet-Bardon et al. 1991; Lacour et al. 1996 ; hypertriglyceridemia; signifi cant hepatic or renal Singh et al. 2001; Digiovanna et al. 2013 ; dysfunction; hypothyroidism, depressive symp- Ormerod et al. 2010 ). toms, or suicidal ideation; pseudotumor cerebri; Teratogenicity is the major concern in treating diabetes mellitus; and severe osteoporosis. fertile women with oral retinoids. Defects seen in Furthermore, patients should be advised not to retinoid embryopathy include abnormalities of drink alcohol and not to take vitamin A supple- the CNS, external ear, cardiovascular system, ments in excess. Tetracyclines (risk of raising eye, and axial and acral skeleton, as well as cra- intracranial pressure) and high doses of aspirin niofacial and thymus gland anomalies (Stern (potentiation of mucosal damage) should be et al. 1984 ; Lammer et al. 1985 ). These abnor- avoided (Ganceviciene and Zouboulis 2010 ). malities can lead to premature birth, spontaneous Clinical monitoring requires physical exami- abortion, or fetal death. For this reason, contra- nation every 4 weeks to manage mucocutaneous ception is essential in women of childbearing age adverse effects and to ensure compliance. Both during and for 1 month after isotretinoin (Perlman fasting serum lipids and liver function tests et al. 2001 ) or 3 years after acitretin (Lambert should be obtained at baseline and monitored at et al. 1992 ) treatment. monthly intervals thereafter. If elevations appear, Almost all patients suffer from mucocutane- isotretinoin dose should be reduced to 50 % or the ous side effects. These include cheilitis; dry skin treatment should be interrupted (Johnson and and mucosae (mouth, eyes, nose, and epistaxis); Nunley 2000 ). Since the major cause of elevated skin, hair, and nail fragility; photosensitivity; serum fats is the diet, requestioning the patient granulation tissue; and pyogenic granulomas-like regarding dietary fat intake should be done. lesions. An association with more severe skin Monitoring skeletal toxicity during a single 24 Retinoids 237 course of isotretinoin therapy is generally not Berman B, Perez OA, Konda S, Kohut BE, Viera MH, indicated. Repeated short courses or long-term Delgado S, Zell D, Li Q. A review of the biologic effects, clinical effi cacy, and safety of silicone elasto- use of isotretinoin (beyond the usual 20-week mer sheeting for hypertrophic and keloid scar treat- course for acne) may require monitoring for skel- ment and management. Dermatol Surg Off Publ Am etal toxicity. Soc Dermatol Surg [et al]. 2007;33(11):1291–302. doi: 10.1111/j.1524-4725.2007.33280.x ; discussion 1302–1293. Bershad S, Poulin YP, Berson DS, Sabean J, Brodell RT, Bulleted List of Controversies Shalita AR, Kakita L, Tanghetti E, Leyden J, Webster GF, Miller BH. Topical retinoids in the treatment of acne • Most experts are convinced that topical reti- vulgaris. Cutis. 1999;64(2 Suppl):8–20; quiz 21–23. Birth defects due to topical adapalene and tretinoin. noids are safe and effective and may be used Prescrire Int. 1998;7(37):148–9. in children and adolescents of all ages. Blanchet-Bardon C, Nazzaro V, Rognin C, Geiger JM, However, administration during pregnancy Puissant A. Acitretin in the treatment of severe disor- and breastfeeding is diffi cult to justify. ders of keratinization. Results of an open study. J Am Acad Dermatol. 1991;24(6 Pt 1):982–6. • In contrast with the European Directive, sys- Boull C, Groth D. Update: treatment of cutaneous viral temic isotretinoin is recommended by most warts in children. Pediatr Dermatol. 2011;28(3):217– experts as fi rst-line therapy for severe and/or 29. doi: 10.1111/j.1525-1470.2010.01378.x . refractory acne in adolescents and may be Brecher AR, Orlow SJ. Oral retinoid therapy for dermatologic conditions in children and adolescents. J Am used in patients younger than 12 years old. Acad Dermatol. 2003;49(2):171–82; quiz 183–176. • For the treatment of severe to very severe Compton AK, Jackson JM. Isotretinoin as a treatment for acne, most experts recommend a starting dose axillary granular parakeratosis. Cutis. 2007;80(1):55–6. of systemic isotretinoin of 0.3–0.5 mg/kg per Cunliffe WJ, Poncet M, Loesche C, Verschoore M. A comparison of the effi cacy and tolerability of ada- day for the fi rst 4 weeks, increasing to the full palene 0.1% gel versus tretinoin 0.025% gel in patients dosage of 1 mg/kg per day until a cumulative with acne vulgaris: a meta-analysis of fi ve randomized dose of 120 mg/kg is attained. trials. Br J Dermatol. 1998;139 Suppl 52:48–56. • In milder cases, one may consider 7–10 days Cunliffe WJ, van de Kerkhof PC, Caputo R, Cavicchini S, Cooper A, Fyrand OL, Gollnick H, Layton AM, per month treatment of systemic isotretinoin Leyden JJ, Mascaro JM, Ortonne JP, Shalita of 0.5 mg/kg. A. Roaccutane treatment guidelines: results of an inter- • Systemic isotretinoin has been used in chronic national survey. Dermatology. 1997;194(4):351–7. recalcitrant disabling cases of other disorders Das BC, Thapa P, Karki R, Das S, Mahapatra S, Liu TC, Torregroza I, Wallace DP, Kambhampati S, Van with varying degrees of success. Veldhuizen P, Verma A, Ray SK, Evans T. Retinoic acid signaling pathways in development and diseases. Bioorg Med Chem. 2014;22(2):673–83. doi: 10.1016/j. References bmc.2013.11.025 . de Oliveira ST, Maragno L, Arnone M, Fonseca Takahashi MD, Romiti R. Generalized pustular psoriasis in Alhusayen RO, Juurlink DN, Mamdani MM, Morrow RL, childhood. Pediatr Dermatol. 2010;27(4):349–54. Shear NH, Dormuth CR. Isotretinoin use and the risk doi: 10.1111/j.1525-1470.2010.01084.x . of infl ammatory bowel disease: a population-based Del Rosso JQ. Face to face with oral isotretinoin: a closer cohort study. J Invest Dermatol. 2013;133(4):907–12. look at the spectrum of therapeutic outcomes and why doi: 10.1038/jid.2012.387 . some patients need repeated courses. J clin aesthet Alikhan A, Griffi n J, Nguyen N, Davis DM, Gibson derm. 2012;5(11):17–24. LE. Pediatric follicular mucinosis: presentation, histo- Digiovanna JJ, Mauro T, Milstone LM, Schmuth M, Toro pathology, molecular genetics, treatment, and out- JR. Systemic retinoids in the management of ichthyo- comes over an 11-year period at the Mayo Clinic. ses and related skin types. Dermatol Ther. Pediatr Dermatol. 2013;30(2):192–8. doi: 10.1111/ 2013;26(1):26–38. doi: 10.1111/j.1529-8019.2012. pde.12019 . 01527.x . Amann PM, Susic M, Gluder F, Berger H, Krapf W, Diluvio L, Campione E, Paterno EJ, Mordenti C, El Loffl er H. Alitretinoin (9-cis retinoic acid) is effective Hachem M, Chimenti S. Childhood nail psoriasis: a against pityriasis rubra pilaris: a retrospective clinical useful treatment with tazarotene 0.05%. Pediatr study. Acta Derm Venereol. 2014;95:329–31. Dermatol. 2007;24(3):332–3. doi: 10.1111/j. doi: 10.2340/00015555-1928 . 1525-1470.2007.00421.x . 238 D. Van Gysel

Dogra S, Kaur I. Childhood psoriasis. Indian J Dermatol Jick SS, Terris BZ, Jick H. First trimester topical tretinoin Venereol Leprol. 2010;76(4):357–65. and congenital disorders. Lancet. 1993;341(8854): doi: 10.4103/0378-6323.66580 . 1181–2. Eichenﬁ eld LF, Krakowski AC, Piggott C, Del Rosso J, Johnson BA, Nunley JR. Use of systemic agents in the Baldwin H, Friedlander SF, Levy M, Lucky A, treatment of acne vulgaris. Am Fam Physician. Mancini AJ, Orlow SJ, Yan AC, Vaux KK, Webster G, 2000;62(8):1823–30; 1835–1826. Zaenglein AL, Thiboutot DM. Evidence-based recom- Kaliyadan F, Nambiar A, Al Ameer A, Amri M. Nevus mendations for the diagnosis and treatment of pediat- comedonicus of the scalp. Skinmed. 2014;12(1):59–60. ric acne. Pediatrics. 2013;131 Suppl 3:S163–86. Kapoor S. Diagnosis and treatment of Acanthosis nigri- doi: 10.1542/peds.2013-0490B . cans. Skinmed. 2010;8(3):161–4; quiz 165. English 3rd JC, Browne J, Halbach DP. Effective treat- Lacour M, Mehta-Nikhar B, Atherton DJ, Harper JI. An ment of localized Darier’s disease with adapalene appraisal of acitretin therapy in children with inherited 0.1% gel. Cutis. 1999;63(4):227–30. disorders of keratinization. Br J Dermatol. Etminan M, Bird ST, Delaney JA, Bressler B, Brophy 1996;134(6):1023–9. JM. Isotretinoin and risk for inﬂ ammatory bowel dis- Lambert WE, Meyer E, De Leenheer AP, De Bersaques J, ease: a nested case-control study and meta-analysis of Kint AH. Pharmacokinetics and drug interactions of published and unpublished data. JAMA derm. etretinate and acitretin. J Am Acad Dermatol. 2013;149(2):216–20. doi: 10.1001/ 1992;27(6 Pt 2):S19–22. jamadermatol.2013.1344 . Lammer EJ, Chen DT, Hoar RM, Agnish ND, Benke Ganceviciene R, Zouboulis CC. Isotretinoin: state of the PJ, Braun JT, Curry CJ, Fernhoff PM, Grix Jr AW, art treatment for acne vulgaris. Journal der Deutschen Lott IT, et al. Retinoic acid embryopathy. N Engl Dermatologischen Gesellschaft = J Ger Soc Derm J Med. 1985;313(14):837–41. doi:10.1056/ JDDG. 2010;8 Suppl 1:S47–59. NEJM198510033131401 . doi: 10.1111/j.1610-0387.2009.07238.x . Layton AM. Optimal management of acne to prevent Goldsmith LA, Bolognia JL, Callen JP, Chen SC, Feldman scarring and psychological sequelae. Am J Clin SR, Lim HW, Lucky AW, Reed BR, Siegfried EC, Dermatol. 2001;2(3):135–41. Thiboutot DM, Wheeland RG. American Academy of Layton AM, Dreno B, Gollnick HP, Zouboulis CC. A Dermatology Consensus Conference on the safe and review of the european directive for prescribing sys- optimal use of isotretinoin: summary and recommen- temic isotretinoin for acne vulgaris. J Eur Acad dations. J Am Acad Dermatol. 2004;50(6):900–6. Dermatol Venereol JEADV. 2006;20(7):773–6. doi: 10.1016/j.jaad.2004.02.012 . doi: 10.1111/j.1468-3083.2006.01671.x . Gollnick H. Current concepts of the pathogenesis Layton AM, Knaggs H, Taylor J, Cunliffe WJ. Isotretinoin of acne: implications for drug treatment. Drugs. for acne vulgaris – 10 years later: a safe and successful 2003;63(15):1579–96. treatment. Br J Dermatol. 1993;129(3):292–6. Gollnick H, Cunliffe W, Berson D, Dreno B, Finlay A, Letule V, Herzinger T, Ruzicka T, Molin S. Treatment of Leyden JJ, Shalita AR, Thiboutot D. Management of Darier disease with oral alitretinoin. Clin Exp acne: a report from a global alliance to improve out- Dermatol. 2013;38(5):523–5. doi: 10.1111/ced.12078 . comes in acne. J Am Acad Dermatol. 2003;49(1 Leyden JJ, Tanghetti EA, Miller B, Ung M, Berson D, Lee Suppl):S1–37. doi: 10.1067/mjd.2003.618 . J. Once-daily tazarotene 0.1 % gel versus once-daily Gollnick HP, Krautheim A. Topical treatment in acne: tretinoin 0.1 % microsponge gel for the treatment of current status and future aspects. Dermatology. facial acne vulgaris: a double-blind randomized trial. 2003;206(1):29–36. doi:67820. Cutis. 2002;69(2 Suppl):12–9. Gregoriou S, Kritsotaki E, Katoulis A, Rigopoulos D. Use Li Y, Wongsiriroj N, Blaner WS. The multifaceted nature of tazarotene foam for the treatment of acne vulgaris. of retinoid transport and metabolism. Hepatobiliary Clin cosmet investig dermatol. 2014;7:165–70. surg nutr. 2014;3(3):126–39. doi: 10.3978/j. doi: 10.2147/CCID.S37327 . issn.2304-3881.2014.05.04 . Gudas LJ. Emerging roles for retinoids in regeneration Loureiro KD, Kao KK, Jones KL, Alvarado S, Chavez C, and differentiation in normal and disease states. Dick L, Felix R, Johnson D, Chambers CD. Minor Biochim Biophys Acta. 2012;1821(1):213–21. malformations characteristic of the retinoic acid doi: 10.1016/j.bbalip.2011.08.002 . embryopathy and other birth outcomes in children of Guenther LC. Topical tazarotene therapy for psoriasis, women exposed to topical tretinoin during early preg- acne vulgaris, and photoaging. Skin Therapy Lett. nancy. Am J Med Genet A. 2005;136(2):117–21. 2002;7(3):1–4. doi: 10.1002/ajmg.a.30744 . Guerriero C, Manco S, Paradisi A, Capizzi R, Fossati B, Marqueling AL, Zane LT. Depression and suicidal behav- Fabrizi G. Extragenital lichen sclerosus and atrophicus ior in acne patients treated with isotretinoin: a system- treated with topical steroids and retinoids in a child atic review. Semin Cutan Med Surg. with vitiligo. Int J Immunopathol Pharmacol. 2007;26(4):210–20. doi: 10.1016/j.sder.2008.03.005 . 2008;21(3):757–9. Martin B, Meunier C, Montels D, Watts O. Chemical sta- Health Canada. Accutane (isotretinoin) - Association with bility of adapalene and tretinoin when combined with Cases of Severe Skin Reactions. 2010. http://www. benzoyl peroxide in presence and in absence of visible healthycanadians.gc.ca/recall-alert-rappel-avis/hc- light and ultraviolet radiation. Br J Dermatol. 1998;139 sc/2010/14584a-eng.php . Suppl 52:8–11. 24 Retinoids 239

Nast A, Dreno B, Bettoli V, Degitz K, Erdmann Schmitt-Hoffmann AH, Roos B, Sauer J, Spickermann J, R, Finlay AY, Ganceviciene R, Haedersdal M, Stoeckel K, Edwards D, van de Wetering J, Coenraads Layton A, Lopez- Estebaranz JL, Ochsendorf F, PJ, Maares J. Pharmacokinetics, effi cacy and safety of Oprica C, Rosumeck S, Rzany B, Sammain A, alitretinoin in moderate or severe chronic hand Simonart T, Veien NK, Zivkovic MV, Zouboulis eczema. Clin Exp Dermatol. 2011;36 Suppl 2:29–34. CC, Gollnick H. European evidence-based (S3) doi: 10.1111/j.1365-2230.2011.04035.x . guidelines for the treatment of acne. J Eur Acad Sehgal VN, Srivastava G, Sardana K. Isotretinoin-- Dermatol Venereol JEADV. 2012;26 Suppl 1:1–29. unapproved indications/uses and dosage: a physician’s doi: 10.1111/j.1468-3083.2011.04374.x . reference. Int J Dermatol. 2006;45(6):772–7. Orfanos CE, Zouboulis CC. Oral retinoids in the treat- doi: 10.1111/j.1365-4632.2006.02830.x . ment of seborrhoea and acne. Dermatology. Shelnitz LS, Esterly NB, Honig PJ. Etretinate therapy for 1998;196(1):140–7. generalized pustular psoriasis in children. Arch Ormerod AD, Campalani E, Goodfi eld MJ. British Dermatol. 1987;123(2):230–3. Association of Dermatologists guidelines on the effi - Singh S, Bhura M, Maheshwari A, Kumar A, Singh CP, cacy and use of acitretin in dermatology. Br J Dermatol. Pandey SS. Successful treatment of harlequin ichthy- 2010;162(5):952–63. doi: 10.1111/j.1365-2133.2010. osis with acitretin. Int J Dermatol. 2001; 09755.x . 40(7):472–3. Penniston KL, Tanumihardjo SA. The acute and chronic Stainforth JM, Layton AM, Taylor JP, Cunliffe toxic effects of vitamin A. Am J Clin Nutr. WJ. Isotretinoin for the treatment of acne vulgaris: 2006;83(2):191–201. which factors may predict the need for more than one Perlman SE, Leach EE, Dominguez L, Ruszkowski AM, course? Br J Dermatol. 1993;129(3):297–301. Rudy SJ. “Be smart, be safe, be sure”. the revised Stern RS, Rosa F, Baum C. Isotretinoin and pregnancy. pregnancy prevention program for women on isotreti- J Am Acad Dermatol. 1984;10(5 Pt 1):851–4. noin. J Reprod Med. 2001;46(2 Suppl):179–85. Strahan JE, Raimer S. Isotretinoin and the controversy of psy- Petruzzi M, Lucchese A, Lajolo C, Campus G, Lauritano chiatric adverse effects. Int J Dermatol. 2006;45(7):789– D, Serpico R. Topical retinoids in oral lichen planus 99. doi: 10.1111/j.1365-4632.2006.02660.x . treatment: an overview. Dermatology. 2013;226(1):61– Talpur R, Vu J, Bassett R, Stevens V, Duvic M. Phase I/II 7. doi: 10.1159/000346750 . randomized bilateral half-head comparison of topical Prevost N, English JC. Isotretinoin: update on controver- bexarotene 1% gel for alopecia areata. J Am Acad sial issues. J Pediatr Adolesc Gynecol. Dermatol. 2009;61(4):592 e591–99. doi: 10.1016/j. 2013;26(5):290–3. jaad.2009.02.037 . Racine A, Cuerq A, Bijon A, Ricordeau P, Weill A, Tamayo L, Ruiz-Maldonado R. Long-term follow-up of Allemand H, Chosidow O, Boutron-Ruault MC, 30 children under oral retinoid Ro 10-9359. In: Carbonnel F. Isotretinoin and risk of infl ammatory Orfanos CE, Braun-Falco EM, Farber EM, et al., edi- bowel disease: a french nationwide study. Am tors. Retinoids: advances in basic research and ther- J Gastroenterol. 2014;109(4):563–9. doi: 10.1038/ apy. Berlin: Springer; 1981. p. 287–94. ajg.2014.8 . Tejera-Vaquerizo A, Sanchez-Vizcaino JS, Haro- Rosinska D, Wolska H, Jablonska S, Konca I. Etretinate in Gabaldon V. Successful treatment of recalcitrant severe psoriasis of children. Pediatr Dermatol. chronic foot eczema with alitretinoin. Actas 1988;5(4):266–72. Dermosifi liogr. 2012;103(10):931–2. doi: 10.1016/j. Rubinow DR, Peck GL, Squillace KM, Gantt GG. Reduced ad.2011.12.023 . anxiety and depression in cystic acne patients after Thiboutot DM, Weiss J, Bucko A, Eichenfi eld L, Jones T, successful treatment with oral isotretinoin. J Am Acad Clark S, Liu Y, Graeber M, Kang S. Adapalene- Dermatol. 1987;17(1):25–32. benzoyl peroxide, a fi xed-dose combination for the Ruzicka T, Lynde CW, Jemec GB, Diepgen T, Berth- treatment of acne vulgaris: results of a multicenter, Jones J, Coenraads PJ, Kaszuba A, Bissonnette R, randomized double-blind, controlled study. J Am Varjonen E, Hollo P, Cambazard F, Lahfa M, Elsner P, Acad Dermatol. 2007;57(5):791–9. doi: 10.1016/j. Nyberg F, Svensson A, Brown TC, Harsch M, Maares jaad.2007.06.006 . J. Effi cacy and safety of oral alitretinoin (9-cis retinoic Thielitz A, Abdel-Naser MB, Fluhr JW, Zouboulis CC, acid) in patients with severe chronic hand eczema Gollnick H. Topical retinoids in acne--an evidence- refractory to topical corticosteroids: results of a ran- based overview. Journal der Deutschen domized, double-blind, placebo-controlled, multicen- Dermatologischen Gesellschaft = J Ger Soc Derm tre trial. Br J Dermatol. 2008;158(4):808–17. JDDG. 2008;6(12):1023–31. doi: 10.1111/j.1610-0387. doi: 10.1111/j.1365-2133.2008.08487.x . 2008.06741.x . Saitta P, Keehan P, Yousif J, Way BV, Grekin S, Brancaccio Thielitz A, Gollnick H. Topical retinoids in acne vulgaris: R. An update on the presence of psychiatric comor- update on effi cacy and safety. Am J Clin Dermatol. bidities in acne patients, part 1: overview of preva- 2008;9(6):369–81. doi: 10.2165/0128071-200809060- lence. Cutis. 2011a;88(1):33–40. 00003 . Saitta P, Keehan P, Yousif J, Way BV, Grekin S, Brancaccio Thielitz A, Gollnick H. Isotretinoin. How should it be R. An update on the presence of psychiatric comor- used? Der Hautarzt; Zeitschrift fur Dermatologie, bidities in acne patients, part 2: depression, anxiety, Venerologie, und verwandte Gebiete. 2013;64(4):263– and suicide. Cutis. 2011b;88(2):92–7. 8. doi: 10.1007/s00105-012-2467-z . 240 D. Van Gysel

Topical retinoids during pregnancy (continued). Prescrire Weisshaar E, Bonnekoh B, Franke I, Gollnick Int. 2005;14(77):100–1. H. Successful symptomatic tazarotene treatment of Webster GF, Guenther L, Poulin YP, Solomon BA, Loven juvenile acanthosis nigricans of the familial obesity- K, Lee J. A multicenter, double-blind, randomized associated type in insulin resistance. Der Hautarzt; comparison study of the efﬁ cacy and tolerability of Zeitschrift fur Dermatologie, Venerologie, und ver- once-daily tazarotene 0.1% gel and adapalene 0.1% wandte Gebiete. 2001;52(6):499–503. gel for the treatment of facial acne vulgaris. Cutis. 2002;69(2 Suppl):4–11. Cyclosporine in Pediatric Dermatology 2 5

Nawaf Al-Mutairi

Abstract Cyclosporine is a highly effective and rapidly acting systemic treatment effective in many dermatological conditions. Concern over the adverse effects of cyclosporine has largely limited its substantial use in children. Emerging from the controversies in the past, cyclosporine has been found to be better tolerated in children than adults. Various controversies surrounding its use in children, dosage, indications, precautions, monitoring, administration regimens, and adverse effects have been discussed in this chapter.

Keywords Cyclosporine • Pediatric dermatology • Controversies in pediatric dermatology • Cyclosporine and psoriasis • Cyclosporine and atopic dermatitis • Cyclosporine contraindications

Cyclosporine is a highly effective and rapidly in Europe it has been approved for the treatment acting systemic treatment effective in many der- for atopic dermatitis also (Amor et al. 2010 ; matological conditions. It was fi rst discovered in Mrowietz et al. 2002 ; Ryan et al. 2010 ). Apart 1970 as an antifungal agent isolated from soil from severe psoriasis and atopic dermatitis, it has fungus Tolypocladium infl atum. In 1976, it was been used “off-label” in many other skin diseases developed as a potent immunosuppressant for use with high effi cacy. Cyclosporine is a lipophilic in organ transplant and was subsequently cyclic polypeptide, consisting of 11 amino acids observed to improve psoriasis in 1979. The fi rst (Fig. 25.1 ). It is commercially produced from controlled trail of cyclosporine in psoriasis was fungus Beauveria nivea . published in 1986. In 1997, FDA approved it for use in psoriasis and rheumatoid arthritis, although Mechanism of Action

Cyclosporine was the ﬁ rst immunosuppressant to N. Al-Mutairi , MD, FRCPC act selectively on T-cells, which play a key role in Dermatology Unit, Department of Medicine , pathogenesis of several dermatoses. It forms a Faculty of Medicine, Kuwait University , Kuwait e-mail: [email protected] complex with cyclophilin which inhibits calci-

H3C ents and children with autoimmune disorders CH treated with cyclosporine contribute considerably to evaluation of its safety in children. Amidst con- HC troversies, cyclosporine has been documented CH2 successful and safe in treating children suffering H with off-label indications in several anecdotal HO CH CH3 C pediatric case reports.

MeVal N CH C Abu MeGly Psoriasis MeLeu CH3 O MeLeu Childhood psoriasis usually follows a benign MeLeu D-Ala Ala MeLeu Val course and can be successfully managed with

C62H111N11O12 Mol. Wt. 1202.63 topical therapy. Cyclosporine can be considered as an effective therapeutic option apart from Fig. 25.1 The chemical structure of cyclosporine, a lipo- other well-known therapies like retinoids, photo- philic cyclic polypeptide consisting of 11 amino acids therapy, methotrexate, and biologics. Treating young children with psoriasis with systemic ther- neurin phosphatase, preventing phosphorylation apies has been controversial. Most of the suc- of nuclear factor of activated T-cells (NFAT), cessful, effective, and well-tolerated use of which is required for transcription of genes encod- cyclosporine in children and adolescents has ing interleukin-2 (IL-2). IL-2 is necessary for full been with pustular and generalized plaque psori- activation of the T-cell pathway, interferon asis. It induced rapid remission and can be used gamma, and granulocyte-macrophage colony- as rescue therapy to bridge to other treatments. stimulating factor. Hence, cyclosporine inhibits Childhood cases of psoriasis may require higher the activation of T-cells, natural killer cells, and dosages or thrice per day administration due to antigen-presenting cells, depleting lymphocytes differences in pharmacokinetics between chil- and macrophages from the skin. Its inhibitory dren and adults. None of the children studied effect on the infl ammatory cascade leads to inhi- required dose higher than 4 mg/kg/day with good bition of keratinocyte hyperproliferation, inhibi- initial response and three of six children achieved tion of histamine release from mast cells, and complete remission during subsequent 12–24 downregulation of cellular adhesion molecules on months, in a study by Pereira et al. (2006 ). dermal capillaries. Tapering cyclosporine and shifting to maintenance therapies has been often debated. Combination treatment with topical steroid, anthralin, and calci- Indications potriol can be of potential benefi t in improving its effi cacy and hence reducing the dosage or treatment Cyclosporine is approved for treatment of severe duration of cyclosporine. Acitretin has been used atopic dermatitis and severe psoriasis in adults, for short periods for controlling relapse while taper- with widespread cutaneous involvement, rapid ing cyclosporine without increasing the dose of recurrences, and resistance to therapies, leading cyclosporine. This combination leads to signifi cant to severe reduction in quality of life. Cyclosporine improvement without increasing its toxicity and is highly effective because of its rapid onset of may also protect against its carcinogenic risks, in action and is primarily used for induction or res- carefully selected and well-monitored children with cue therapy. It has been successfully used in severe refractory psoriasis. Cyclosporine has been treatment of children especially for those with found to be signifi cantly more effi cacious than other severe resistant atopic dermatitis. Not only chil- current therapies and has less side effects than reti- dren with skin diseases but also transplant recipi- noids which are poorly tolerated because of their 25 Cyclosporine in Pediatric Dermatology 243 mucocutaneous side effects and potential to cause similar safety profi les and almost equally effi ca- skeletal abnormalities and growth alterations. cies 59.8 % and 51.7 %, respectively. Patients In childhood psoriasis, cyclosporine may be treated with higher initial dose had more rapid employed as rescue therapy or as short-course improvement at 2 weeks than those treated with intermittent therapy for 12–16 weeks to induce lower initial dose, but those receiving a higher remission which might then be repeated in case dose reported a greater number of cyclosporine- of relapse. Rarely, patients with more active related side effects, leading to higher chances of disease might require maintenance therapy and treatment withdrawal. However, at 6–8 weeks, the long-term continuous cyclosporine therapy. In decrease in severity of the disease was almost such cases, least effective dose should be used for 55 % at continuous cyclosporine treatment at any duration below 2 years. Continuous therapy has of the doses, in the systemic review and meta- been found to be more effective than intermittent analysis by Schmitt et al. (2007 ). Maximal benefi - therapy, which has less side effects and cumula- cial effect is usually seen at 10 weeks of therapy. tive toxicity. For maintenance, weekend cyclo- Harper et al. (2000 ) found cyclosporine effective sporine therapy at dose of 5 mg/kg/day for 2 and well tolerated in children with severe atopic consecutive days per week was found to have dermatitis over 1-year period, improving the qual- lesser adverse effects, lesser mean daily dose, ity of the life for both children and their families. more convenient and equally effective to continu- More consistent control was achieved with con- ous cyclosporine at 3 mg/kg/day, in a study by tinuous therapy, with no signifi cant increase in Fernandes (2013 ) for 20 weeks. Liposolubility of serum creatinine or blood pressure over intermit- cyclosporine allows its storage in adipose tissue tent 12-week courses of cyclosporine. However, and can be discontinued for 3–5 days taking short course was adequate to produce prolonged advantage of the slow infl ammatory recovery remission in some cases and even reduced cumu- time in psoriasis. Cyclosporine is also effective in lative drug toxicity. Hence, treatment should be nail psoriasis especially in nail bed disease, alone tailored to the individual patient’s need. or in combination with topical calcipotriol or Cyclosporine is better tolerated in children, dithranol. and despite pharmacokinetic differences, it has similar effi cacy at 2.5–5.0 mg/kg/day dose in both adults and children with atopic dermatitis. Atopic Dermatitis The response of itch is most sensitive of all the other signs and symptoms of eczema. It is usually Cyclosporine is highly effective and well toler- fi rst to improve after cyclosporine treatment and ated in the short-term treatment of severe child- fi rst to arise after the drug is stopped. After with- hood atopic dermatitis that could not be adequately drawal of the drug, 50 % of the patients relapse controlled with conventional topical therapies within 2 weeks and about 80 % within 6 weeks, (Berth-Jones et al. 1996 ; Bunikowski et al. 2001 ). but extent of disease and symptoms remain better It has been approved in Europe and the United than at baseline scores. Oral cyclosporine is also Kingdom and recommended by the AAD guide- effective in controlling severe fl ares of atopic lines for the care committee in the United States dermatitis caused by infections, once infection for these patients. Starting at a dose 5 mg/kg/day has been treated with appropriate antibiotics. If for 2 weeks for induction and then according to there are no adverse effects, reintroduction of the clinical response, gradually tapering to a dose cyclosporine to treat relapse, as intermittent of 1.5 mg/kg/day over 3 months has been sug- short-term treatment, might have good benefi t to gested. Zonneveld et al. (1996 ) found both the risk ratio. When recurrences are rapid, continu- step-down regimen starting at 5 mg/kg/day, ous long-term therapy at lowest effective dose decreased to 3 mg/kg/day as tolerated, and step- can be opted. After 1 year, discontinuation should up regimen starting at 3 mg/kg/day, increased to be attempted, though treatment seems safe up to 5 mg/kg/day as needed, are well tolerated with 2 years of use, with close monitoring of patients. 244 N. Al-Mutairi

Other Off-Label Indications 4 mg/kg/day dose. Cyclosporine was continued for 2 months at this dose and then tapered every 2 Very Good Response months to 0.3 mg/kg/day. She maintained remis- Cyclosporine has been reported to show very sion on low-dose continuous cyclosporine therapy good response in pyoderma gangrenosum, dyshi- given till 14 months and continued further. Thus, drotic eczema, and palmoplantar pustulosis. cyclosporine can be an effective, well-tolerated, Patients of pyoderma gangrenosum, who do not steroid-sparing tool in childhood chronic urticaria achieve remission with treatment of the underly- with monitoring for short-term and long-term side ing disease or in idiopathic cases, systemic treat- effects. A regimen by Galindo Bonilla et al. ( 2002 ) ment with cyclosporine at a dose of 5 mg/kg/day started at 3 mg/kg/day cyclosporine in 2 divided or less, alone or in combination with systemic doses for 6 weeks, followed by 3 weeks of 2 mg/ steroids is recommended. Rapid and dramatic kg/day and then 3 weeks of 1 mg/kg/day dose, response is observed within 1–3 weeks, with high could achieve full remission or signifi cant improve- rate relapse on discontinuation. It has been used in ment in more than two thirds of his patients. infants as young as 8 months old with pyoderma Oral cyclosporine can be the treatment of gangrenosum of thigh, which failed to respond to choice in extensive disseminated lichen planus, oral prednisolone and topical betamethasone val- erosive lichen planus, lichen planus resistant to erate. McAleer et al. (2008 ) reported that it started systemic corticosteroids or retinoids, and initial to heal within fi rst 3 days of combination treat- phases of lichen planopilaris before severe follic- ment of cyclosporine at 5 mg/kg/day with oral ular damage occurs. Short-term therapy starting prednisolone and topical silver sulfadiazine. with 2.5–3.0 mg/kg/day for 3 months can be use- Cyclosporine was continued for 12 weeks at the ful, but mucosal forms tend to be more resistant, same dose and then tapered over 9 months. requiring higher doses (maximum of 5 mg/kg/ Severe recalcitrant dyshidrotic eczema or day). Laeijendecker et al. (2005 ) reported refrac- chronic vesicular hand dermatitis also shows tory erosive oral lichen planus in a male child dramatic response within 2 weeks of high-dose responded to cyclosporine 4 mg/kg/day combined cyclosporine at 5 mg/kg/day. Reitamo and with systemic steroids (30 mg/kg/day for 6 weeks) Granlund ( 1994) found six of their seven patients with remissions and exacerbations. Cyclosporine with chronic hand dermatitis improving on leads to signifi cant but temporary remission of cyclosporine, with fi ve of them at a dose of erosive lichen planus. Hence, it may be used as 2.5 mg/kg/day. They remained disease free at a rescue in acute phase, so that adjuvant therapies maintenance dose of 1.25–2 mg/kg/day and such as skin grafting may be performed. There are three patients remained in remission even after anecdotal reports of successful use of cyclospo- cyclosporine was discontinued. rine in palmoplantar and actinic lichen planus. Cyclosporin has been found superior to col- Good Response chicine and an effective steroid-sparing mono- Good response has been reported in chronic urti- therapy in Behcet’s disease. It is especially useful caria, lichen planus, Behcet’s disease, pityriasis in refractory eye disease, mucocutaneous dis- rubra pilaris (PRP), and photodermatoses like ease, and arthritis, but may be required in high polymorphic light eruption, chronic actinic der- doses to execute control. It can lead to resolution matitis, and solar urticaria. of recurrent polyarteritis nodosa-like skin lesions, In severe chronic idiopathic urticaria unrespon- associated with Behcet’s disease, but is less effec- sive to antihistamines, cyclosporine may be used as tive in preventing neurological involvement. an alternative to corticosteroids, either as steroid- Wetzig et al. (2003 ) has reported signifi cant sparing agent or to treat chronic urticaria that is improvement of erythrodermic juvenile pityriasis refractory to corticosteroids. A 12-year- old girl rubra pilaris in a 4-year-old boy, within 5 weeks with chronic urticaria unresponsive to antihista- of cyclosporine therapy at 3 mg/kg/day dose, mines and corticosteroids was successfully treated without recurrence till 8 months post therapy. by Giuliodori et al. (2009 ) with cyclosporine at Hence, cyclosporine can be an effective option 25 Cyclosporine in Pediatric Dermatology 245 for erythrodermic form of PRP in children not • Malignancies or a previous history of malig- responding to conventional treatment. nancies (except basal cell carcinoma) • Simultaneous phototherapy Good Optional Therapy Cyclosporine has been reported as a good option tool in the therapeutic armamentarium of connec- Relative Contraindications tive tissue diseases like dermatomyositis and scleroderma. It has been proposed as a second- line • Severe hepatic dysfunction agent for both juvenile and adult dermatomyositis • Primary or secondary immunodefi ciency unresponsive to other immunosuppressants. In disorders combination with systemic corticosteroids, it is • Premalignant conditions especially effective for esophageal and lung • Pregnancy and lactation involvement in dermatomyositis. It allows tapering of steroids and can act as steroid-sparing drug. Cyclosporine has resulted in resolution of digital Use with Caution infarcts and signifi cant skin softening in scleroderma, but its potential to worsen hypertension or • Diabetes Mellitus renal disease associated with systemic sclerosis • Obesity lands it in gray zone. Cyclosporine has been con- • Hyperlipidemia sidered as second-line therapy in prurigo nodularis. • Drug/alcohol abuse It leads to signifi cant reduction in pruritis within 2 • Inability to attend for regular monitoring weeks, allowing nodules to heal. Pemphigus vulgaris, bullous pemphigoid, epidermolysis bullosa Patients previously treated with PUVA and to acquisita, and benign familial pemphigus are the a lesser extent with methotrexate or other immu- group of vesiculobullous disorders in which cyclo- nosuppressive agents, UVB, coal tar, or radiation sporine has been reported to be of some benefi t. It therapy can be at an increased risk of developing can act as a double-edged sword in severe alopecia skin malignancies with cyclosporine. Adequate areata, allowing hair regrowth in alopecia patches sun protection should be advised considering the in a child with Down syndrome and developing long latencies of their carcinogenic potential. alopecia areata in children on cyclosporine for Pediatric patients, treated with cyclosporine for atopic dermatitis or renal transplant. Cyclosporine dermatological disorders, who have not been sig- has also found its way in the management of eosin- nifi cantly exposed to other immunosuppressants ophilic pustular folliculitis (Ofuji disease) and or phototherapies, are not likely to be at increased hidradenitis suppurativa, in patients who failed risk of malignancies. fi rst- and second-line therapies.

Pharmacokinetics Contraindications Cyclosporine is a lipophilic drug with wide varia- The physician should be cautious and aware of tion in bioavailability on oral administration. the following contraindication of cyclosporine: Newer hydrophilic microemulsion (Neoral, Novartis) has allowed greater bioavailability, more rapid response, higher remission rates, 10 % Absolute Contraindications lower dose, and less interindividual ﬂ uctuation as compared to the original (Sandimmune, Novartis). • Uncontrolled hypertension Hence, these preparations as well as newer generic • Signiﬁ cant renal disease (except nephrotic forms are not bioequivalent. Different brands syndrome) should not be used interchangeably without close • Serious infections monitoring. For pediatric use, oral solution 246 N. Al-Mutairi

(100 mg/5 ml) can be drawn up with the syringe inhibit CYP450 system can lead to higher levels of provided and mixed with orange or apple juice or cyclosporine. Anticonvulsants like phenytoin, phe- milk. Cyclosporine has a fi rst-pass effect of 27 % nobarbital, carbamazepine, or other drugs such as in the liver. The dose of cyclosporine should be octreotide, rifampicin, etc. can stimulate CYP450 divided into twice daily administration, taken at and hence lower cyclosporine levels. Cyclosporine the same time each day. Parents or the child can delay the metabolism of drugs like predniso- should be advised to consistently stick to the lone, digoxin, diclofenac, methotrexate, etc. administration timing, before or after meals, as Nephrotoxic drugs like aminoglycosides, clotrima- higher serum concentrations are achieved before zole, ciprofl oxacin, fi brates, and nonsteroidal anti- rather than after meals. Although highly lipo- infl ammatory drugs used for psoriatic arthritis that philic, it is primarily distributed to lean body can further impair renal function during cyclospo- mass. It can lead to toxicity, if dose is calculated rine treatment should be avoided. according to actual body weight, especially in obese children at higher doses. For dermatological diseases like psoriasis and atopic dermatitis, Adverse Effects bodyweight-independent regimens have been safe and effective, because of the lower doses involved, Concern over the adverse effects of cyclosporine as compared to children on transplant treatments. has largely limited its substantial use, highly effec- There are pharmacokinetic differences tive in many dermatoses. Most of these adverse between children and adults, with children hav- effects are dose and duration dependent and are ing lower oral absorption, more rapid clearance, reversible on discontinuation, except the structural and greater volume of distribution at steady state. renal abnormalities. Cyclosporine-induced mito- Hence, pediatric psoriasis cases might require chondrial dysfunction has been mainly responsi- higher doses due to dose-dependent effi cacy of ble for these adverse outcomes. The predominant the drug. Despite these differences, pediatric cause of dermatologist’s concern is renal dysfunc- atopic dermatitis cases show similar effi cacy at tion observed with cyclosporine use. Acute renal 2.5–5.0 mg/kg/day of cyclosporine, as in adults. deterioration leading to increased serum creatinine Decreased bioavailability has also been related to due to renal vascular or tubular changes is typi- shorter bowel length in children apart from other cally reversible on withdrawal of cyclosporine. differences. African Americans have lower bio- Intermittent short-term therapy allows normaliza- availability of the drug as compared to whites tion of renal function between courses; hence, because of polymorphisms of genes coding for renal dysfunction remains transient and revers- cytochrome P450 isoenzymes (CYP3A) respon- ible, provided dose of 5 mg/kg/day is not sible for systemic clearance of cyclosporine. exceeded. Prolonged treatment exceeding 1 year of continued use leads to vasculopathy and tubu- lopathy with structural changes that are irrevers- Drug Interactions ible and chronic. Coexisting renal conditions, hypertension, nephrotoxic medication, obesity, Cyclosporine is almost entirely metabolized in the and older age as compared to younger patient can liver by cytochrome P450 IIIA system and hence increase the risk further. Children are less suscep- interacts with drugs inhibiting or stimulating this tible to cyclosporine- induced nephropathy than system. Concomitant use of erythromycin to treat adults. Cyclosporine-induced hypertension is a infected atopic eczema or grapefruit juice can rare phenomenon in children on cyclosporine for increase cyclosporine toxicity, especially in pediat- dermatological indications. It is less often dose- ric population. Other macrolide antibiotics and dependent and should be managed by antihyper- drugs such as calcium channel blockers, azole anti- tensives, rather by dose reduction. Calcium fungals, metoclopramide, ranitidine, etc. which channel blockers such as amlodipine or isradipine 25 Cyclosporine in Pediatric Dermatology 247 are antihypertensives of choice to treat cyclosporine- after 4 weeks, cyclosporine must be discontinued. mediated hypertension. Older obese psoriatic It needs to be permanently withdrawn if similar rise patients have inherent risk of hypertension due to occurs after reintroduction on achieving normal metabolic syndrome as compared to younger blood values. After successful response to therapy, atopic eczema patients treated with cyclosporine. cyclosporine needs to be reduced in steps of 0.5– In general, cyclosporine is tolerated better in chil- 1.0 mg/kg/day every 2 weeks to achieve lowest effi - dren than adults. cacious maintenance dose. In case of inadequate Risk of cutaneous tumors and lymphomas is response, cyclosporine is increased to a maximum more with cyclosporine therapy being used along of 5 mg/kg/day. In the United States, a ceiling of 1 with other immunosuppressants in transplant year of treatment has been recommended, whereas patients. But it has been observed in psoriatics in the United Kingdom and Europe, it is permitted treated with psoralens and ultraviolet radiation or to be used till 2 years. other immunosuppressants. No such increase has been found in dermatological use of cyclosporine in children. Hyperbilirubinemia due to competi- Short-Term Intermittent Therapy tive inhibition of bilirubin transport, rather than direct hepatotoxicity, can occur. Cyclosporine- Short-term intermittent therapy is the most fre- associated hyperlipidemia normalizes on drug quently used strategy. Short courses of 12–16 discontinuation but may require active manage- weeks of cyclosporine are recommended until ment in psoriasis, as it involves metabolic syn- signifi cant clinical improvement is achieved, fol- drome. Cyclosporine can lower epilepsy lowing which treatment is discontinued. In case threshold especially in those taking high doses of of relapse, cyclosporine is reintroduced at the systemic steroids. Tetracyclines should not be previously effective dose. used concomitantly even to treat cyclosporine- induced acne because of the risk of pseudotumor cerebri. Gingival hyperplasia associated with Rescue or Bridging Therapy cyclosporine has often been related to poor oral hygiene in children. Hypertrichosis, keratosis Rescue therapy is used to control severe fl ares of pilaris, folliculitis, and sebaceous hyperplasia are disease, taking advantage of the rapid onset of few other cutaneous side effects of cyclosporine, action of cyclosporine. It is started usually at especially at doses used in transplant therapy. 5 mg/kg/day and then reduced gradually according to clinical response. It is a bridging therapy to achieve rapid control, until an alternative Dosage maintenance treatment is introduced. In general, cyclosporine is overlapped with alternative treat- Cyclosporine up to 5 mg/kg/day has been safe and ments and then withdrawn with minimally effi cacious in children as both intermittent and increased risk of side effects for a short period of continuous therapy for up to a year. Depending on overlap. disease severity, the starting dose is usually between 2.5 and 5 mg/kg/day, divided into morning and evening dose. A dose reduction of 2.5 % Long-Term Therapy may be required in case of elevation of serum creatinine by at least 30 % over baseline value, in at Cyclosporine needs to be continued for long least 2 successive blood samples at an interval of period of time in case of frequent and rapid recur- 2 weeks or in case of new-developed hyperten- rence of severe forms of psoriasis or atopic der- sion. If blood pressure or serum creatinine matitis or other chronic skin diseases, at a lowest remained elevated under the reduced dosage even possible dose that maintains control of disease. 248 N. Al-Mutairi

Such a regimen is found to be more effective in Pretreatment Screening achieving continuous long-term remission and in turn improving the quality of life of the child and Prior to initiating cyclosporine, the patient has to the family, but it leads to increased cumulative be screened thoroughly with a careful history, annual dose and hence associated side effects. physical examination, and baseline laboratory Hence, a ceiling of 1 year and 2 years has been set investigations. by the United States and Europe, respectively. • History, particularly of malignancy, organ dysfunction, hypertension, current infections, Combination Therapy and current or past medications especially history of PUVA therapy, NSAID, or other over- Cyclosporine can be synergistically combined the- counter medications. with topical corticosteroids, anthralin, and calci- • Physical examination including skin assess- potriol. Combination of cyclosporine with sys- ment in view of malignancy or actinic damage. temic agents like methotrexate, fumaric acid Blood pressure should be measured at two dif- esters, or mycophenolate mofetil can be associ- ferent times and mean taken as baseline value. ated with more side effects. It can be used in rota- • Any active infection like warts and molluscum tional therapy with the above drugs to minimize contagiosum should be eliminated and active duration and hence toxicity of cyclosporine. herpes simplex lesions resolved before starting of therapy. • Children should maintain good oral hygiene Therapeutic Ending and visit dentist at regular intervals to monitor for gingival hypertrophy. Cyclosporine requires discontinuation in case of • Patients should be advised for long-term sun persistence of side effects despite dose reduction, protection in view of reports of skin cancers development of malignancies, or severe infection associated with high-dose cyclosporine in or after achieving adequate response in intermit- transplant patients. tent 12–16 weeks regimen. Special situations in • Vaccinations: children like planned vaccination or exposure to potentially infectious children might necessitate Live vaccines are contraindicated due to func- interruption of cyclosporine therapy. It can be dis- tional immunosuppression associated with cyclo- continued abruptly without a risk of rebound or sporine. Effi cacy of pneumococcal vaccination reduced in a stepwise manner, which can possibly and standard diphtheria and tetanus booster vac- delay a rapid recurrence. Tapering is done by cination is comparable to healthy children. stepwise reduction at a rate of 0.5–1 mg/kg/day Immune response to hepatitis B and infl uenza every 2 weeks. After discontinuation of cyclospo- vaccine is reduced. Vaccination should be com- rine, patient can be started on other maintenance pleted before the initiation of cyclosporine treat- therapies without temporal delay. This transition ment. Even though response to annual infl uenza might require an overlap of both treatments for a and pneumococcal vaccine may be suboptimal, few weeks to avoid a rapid recurrence. they are advocated. Tuberculin skin testing is recommended before starting the therapy.

Therapeutic Monitoring Baseline Laboratory Investigations Close monitoring of cyclosporine therapy makes it safe for children and increases the confi dence Serum creatinine, complete blood count, blood of the dermatologist, to comfortably use it in a urea nitrogen (BUN), serum potassium, bilirubin, multitude of dermatoses. liver enzymes, uric acid, magnesium, fasting lipids, 25 Cyclosporine in Pediatric Dermatology 249 and urine analysis for proteinuria should be done at cause of concern for dermatologists treating the beginning to record baseline values. An average children. Intermittent short-term therapy allows of fasting serum creatinine done at two separate normalization of renal dysfunction between occasions is taken as baseline value to be compared courses; hence, renal dysfunction remains tran- later on. sient and reversible, provided dose of 5 mg/kg/ day is not exceeded. • Children are less susceptible to cyclosporine- Follow-Up Investigations induced nephropathy than adults. Cyclosporine- induced hypertension is a rare phenomenon in Serum creatinine, BUN, and blood pressure children on cyclosporine for dermatological should be monitored regularly at weeks 2, 4, 6, indications. Hence, cyclosporine is better toler- and 8 and then monthly, or at 2-monthly interval ated in children than adults in general and has in long-term treatment of cyclosporine. For der- similar effi cacy at 2.5–5.0 mg/kg/day dose as in matological diseases, serum cyclosporine con- adults. centrations are not necessary, but can be done to • Reintroduction of cyclosporine to treat assess patient compliance or effects of possible relapse, as intermittent short-term treatment, drug interactions. Annual GFR monitoring is might have good benefi t to risk ratio, if there essential for patients treated with cyclosporine are no adverse effects. When recurrences are continuously for more than 1 year. Close long- rapid, continuous long-term therapy at lowest term monitoring is advised particularly of chil- effective dose can be opted for a more effec- dren treated with cyclosporine due to uncertainty tive outcome with lesser side effects and regarding the long latencies of its rare adverse cumulative toxicity, especially in children at effects. risk of poor self-esteem and depression due to Children are especially at risk of poor self- dermatological conditions. esteem and depression due to the signifi cant psychosocial and emotional stress caused by dermatological conditions especially atopic der- References matitis and psoriasis. Relapse of disease after remission achieved by cyclosporine therapy may Amor KT, et al. The use of cyclosporine in dermatology: be highly distressing and can cause signifi cant part I. J Am Acad Dermatol. 2010;63(6):925–46. Berth-Jones J, et al. Cyclosporine in severe childhood limitation of quality of life. Hence, in pediatric atopic dermatitis: a multicenter study. J Am Acad and adolescent patients, continuous therapy for Dermatol. 1996;34(6):1016–21. up to 1 year can be preferred over intermittent Bunikowski R, et al. Low-dose cyclosporin A microemul- therapy. Cyclosporine is better tolerated by chil- sion in children with severe atopic dermatitis: clinical and immunological effects. Pediatr Allergy Immunol. dren as compared to adults and hence safe as 2001;12(4):216–23. maintenance therapy at low dose for longer dura- Fernandes IC. Weekend cyclosporine A therapy compa- tion or as rescue therapy started at higher doses rable to daily treatment for psoriasis. J Am Acad (maximum 5 mg/kg/day) for severe fl ares in Dermatol. 2013;68:341–2. Galindo Bonilla PA, et al. Urticaria and cyclosporine. pediatric population. Allergy. 2002;57:650–1. Giuliodori K, et al. A non-responsive chronic autoimmune urticaria in a 12-year-old autistic girl treated Bulleted List of Controversies with cyclosporin. J Eur Acad Dermatol Venereol. 2009;23:619–20. Harper JI, et al. Cyclosporin for severe childhood atopic • Concern over the adverse effects of cyclospo- dermatitis: short course versus continuous therapy. Br rine has largely limited its substantial use in J Dermatol. 2000;142(1):52–8. many dermatoses, highly responsive to it. Laeijendecker R, et al. Oral lichen planus in childhood. Pediatr Dermatol. 2005;22:299–304. Irreversible structural renal abnormalities McAleer MA, et al. Infantile pyoderma gangrenosum. appearing after its prolonged use is the main J Am Acad Dermatol. 2008;58(2):S23–8. 250 N. Al-Mutairi

Mrowietz U, et al. Cyclosporine therapy in dermatology. Schmitt J, et al. Cyclosporin in the treatment of patients JDDG Journal der Deutschen Dermatologischen with atopic eczema – a systematic review and meta- Gesellschaft. 2002;7:474–8. analysis. J Eur Acad Dermatol Venereol. 2007;21(5): Pereira TM, et al. Cyclosporine A treatment in severe 606–19. childhood psoriasis. J Eur Acad Dermatol Venereol. Wetzig T, et al. Juvenile pityriasis rubra pilaris: successful 2006;20(6):651–6. treatment with ciclosporin. Br J Dermatol. 2003;149: Reitamo S, Granlund H. Cyclosporin A in the treatment of 202–3. chronic dermatitis of the hands. Br J Dermatol. Zonneveld IM, et al. The long-term safety and efﬁ cacy of 1994;130:75–8. cyclosporin in severe refractory atopic dermatitis: a Ryan C, et al. The use of cyclosporine in dermatology: comparison of two dosage regimens. Br J Dermatol. part II. J Am Acad Dermatol. 2010;63(6):949–72. 1996;135(48):15–20. Laser Therapy: When, Where, and Why 2 6

Jasem Alshaiji

Abstract Pediatric dermatology is a unique and promising subspecialty in dermatology. It deals with various genetic and acquired skin disorders that affect children and adolescents. Since they are young and vulnerable patients, the treatment of these diseases should be safe and effective, and it should not cause any harm to them. Laser therapy is one treatment modality that can be used to treat various genetic and acquired dermatologic conditions. But, in certain situations, there are still challenges and controversies of using it in kids, which I will discuss.

Keywords Laser therapy in dermatology • Vascular lesions • Pigmented lesions • Pediatric population and laser therapy • Lasers in pediatric dermatology • Pediatric dermatology and lasers

Laser therapy is one of the physical therapeutic be specifi cally deposited within a target tissue modalities that can be utilized by laser surgeons (chromophore) resulting in controlled destruc- to treat many dermatologic conditions both in tion with minimal damage to surrounding struc- children and adults. Dr. Leon Goldman fi rst used tures (Cole et al. 2007 ). The pulse dye laser was it to treat various skin disorders such as port-wine the fi rst laser developed based on this theory stain (PWS) in 1963 by using ruby laser (694 nm). (Hanke et al. 2013 ; Stier et al. 2008 ). But since the earlier lasers were nonselective and The use of laser to treat skin disorders in pedi- have a high risk of complications, Anderson and atric population poses a unique challenge for the Parrish proposed the theory of “selective photo- clinician on a variety of levels. Physically, the thermolysis” in 1983, in which laser energy can composition of many vascular and pigmented lesions changes as children age making them more resistant to laser therapy; thus, treating J. Alshaiji , MD lesions at an early age in many conditions has Department of Dermatology , Amiri Hospital, resulted in clearing in fewer sessions and with Ministry of Health, PO Box 161 , fewer complications. Mechanically, lasers and Al-surra 45702 , Kuwait e-mail: [email protected] laser settings used for the treatment of adult

© Springer International Publishing Switzerland 2016 251 A.P. Oranje et al. (eds.), Practical Pediatric Dermatology, DOI 10.1007/978-3-319-32159-2_26 252 J. Alshaiji lesions may have to be adjusted for the smaller target, and suffi cient fl uence to damage the tar- vessels and the unpredictable nature of scarring get. TRT of tissue is defi ned as the time neces- with children’s skin. Other issues specifi c to the sary for the targeted tissue to cool down to half pediatric population include the determination of the temperature to which it was heated suitable anesthesia, the provision of size- (Cordisco 2009 ). The characteristics of laser appropriate safety equipment, and the assessment parameters are wavelength (200–500 nanome- and management of patient and parent anxiety ters (nm)), pulse duration (nanoseconds to mil- (Cantatore and Kriegel 2004 ). liseconds), energy fl uence (J/cm2 ), spot size (1–15 mm), and repetition rate (1–10 Hz) (Cordisco 2009 ). Laser Physics

The word laser is an acronym that stands for l ight Laser Modalities a mplifi cation by s timulated e mission of r adia- tion. Lasers are sources of high-intensity, mono- There are wide ranges of lasers that can be used chromatic or single-wavelength, coherent, and to treat different dermatological conditions in collimated light (Cantatore and Kriegel 2004 ). the pediatric population. They are basically All laser systems are composed of the laser divided according to their indications into vas- medium, the optical cavity, and a power source. cular lasers, pigment lasers, resurfacing lasers, The laser medium, which can be a solid (e.g., and disease-state lasers (Cantatore and Kriegel ruby, Nd:YAG, and alexandrite), a liquid (e.g., 2004 ). dye), or a gas (e.g., argon, krypton, and CO2 ), Vascular lasers include fl ash lamp-pumped determines the wavelength of the emitted light. pulsed dye laser (PDL) (577–600 nm/yellow) The optical cavity, which contains the laser and quasi-continuous-mode lasers (such as argon medium, serves as a resonator in which the laser (577–585 nm/yellow), KTP (532 nm/green), cop- process occurs. Despite the relatively large num- per bromide (578 nm/yellow), copper vapor ber of laser systems currently available for medi- (578 nm/yellow), and krypton (568 nm/yellow)). cal use, they span only a narrow portion of the Pigment lasers include Q-switched ruby laser electromagnetic spectrum. The different applica- (694 nm/red), Q-switched alexandrite laser tions of the laser systems are generally deter- (755 nm/red), Q-switched Nd:YAG laser mined as functions of their wavelengths, the (532 nm/green, 1,064 nm/infrared), pigment- amount of energy delivered to the tissue (fl u- specifi c pulsed dye laser (510 nm/green), and ence), the length of time the light has contact copper vapor laser (510 nm/green). with the skin (pulse duration), and the optical Resurfacing lasers include carbon-dioxide characteristics of the tissue (the chromophores: laser (CO2 ) (10,600 nm/infrared) and Er:YAG oxyhemoglobin, melanin, and water) which laser (2,940 nm/infrared). absorb light at certain wavelengths (Cantatore Disease-state lasers include diode (1,450 nm/ and Kriegel 2004 ). infrared, 800 nm/red), narrowband blue light The oxyhemoglobin has absorption peaks at (407–420 nm/blue) and excimer (308 nm/ultra- 418, 542 and 577 nm, which all lie within the violet blue) (Cantatore and Kriegel 2004 ). visible spectrum, whereas melanin has a broad range of peaks absorbing both infrared and visible wavelengths (Cordisco 2009 ). The selec- Laser Indications in Pediatric tive photothermolysis theory is achieved by Dermatology three basic parameters: a wavelength of light that reaches and is selectively absorbed by tar- There are many pediatric skin disorders, either get tissues, a pulse duration equal to or less congenital or acquired, which can be treated by than the thermal relaxation time (TRT) of the laser. These disorders are divided into vascular 26 Laser Therapy: When, Where, and Why 253

Table 26.1 Indications for laser use in pediatric dermatology Reasonable indications Controversial indications Doubtful indications Complicated IHs IHs (small in the proliferative phase, Tattoo removal (yellow, green, and early vs. late treatment) orange pigments, professional tattoos) Many pigmented lesions (e.g., nevi PWS (early vs. late treatment) AA on the extremities and alopecia of Ota and Ito, lentigines, freckles, totalis tattoos, black, blue and red, nevus spilus, and Mongolian spot) Warts (ﬂ at) Suspicious nevus spilus Vitiligo in “UV-resistant areas” such as the upper and lower extremities Psoriasis Congenital melanocytic nevus (giant) Porokeratosis cafe au last macule and Becker nevus Epidermal nevi Hypertrichosis in prepubertal children Hypertrophic scars and keloids Warts (common, plantar) Striae Nevus sebaceous ILVEN

lesions, pigmented lesions, and other conditions and red: Q-switched Nd:YAG 532 nm/pulsed (Table 26.1). The vascular lesions are further dye 510 nm green), hypertrichosis (long-pulsed subdivided into PWS (PDL), hemangiomas ruby/long- pulsed alexandrite/diode/IPL/long- (PDL), telangiectasias (PDL), pyogenic granu- pulsed Nd:YAG), keloids/hypertrophic scars loma (PDL/CO2 ), angiofi bromas (PDL/CO2 / (PDL), striae (PDL/Nd:YAG 1,320 nm), and warts copper vapor/KTP), angiokeratomas (PDL), (CO2 /PDL/KTP) (Cantatore and Kriegel 2004 ; venous malformations (PDL/Nd:YAG), mixed Cordisco 2009 ; Chapas and Geronemus 2005 ). lymphatic- hematological malformations (PDL/ Er:YAG), and mixed arterial-venous malformations (usually ineffective). Controversies of Using Laser The pigmented lesions are further subdivided in Pediatric Dermatology into lentigines (any pigment-specifi c lasers), nevus of Ota (Q-switched ruby/Q-switched There are several pediatric dermatological disor- alexandrite/Q-switched Nd:YAG 1,064 nm), con- ders in which the use of laser in treating them is genital melanocytic nevi (normal ruby/Q-switched still controversial, and they include: ruby/Q-switched Nd:YAG 532 nm), nevus spilus (normal ruby/normal alexandrite/Q-switched ruby/Q-switched Nd:YAG 532 nm), and Infantile Hemangiomas Mongolian spot (Q-switched ruby/Q-switched alexandrite/Q-switched Nd:YAG 532 nm). Infantile hemangiomas are well known to prolif- Other conditions in which laser can be used erate and then involute on their own. Because of include acne (NB blue light 410–420 nm/infra- this there are controversies whether to treat red laser 1,450 nm) and acne scarring (abla- aggressively with a laser (usually a pulsed dye). tive, CO2 /Er:YAG; nonablative, 585–1,540-nm If small and not threatening to life or organs, then fl ash lamp multiwavelength), psoriasis watchful waiting is acceptable. If large, bleeding, (NB-UVB 308 nm/PDL), vitiligo (NB-UVB ulcerating, getting infected, causing pain, or 308 nm), epidermal nevi (CO2/Er:YAG), tat- obstructing vital organs, then treatment has been toos (black: Q-switched ruby/Q-switched suggested. There are further controversies alexandrite/Q-switched Nd:YAG; blue green: whether early treatment is preferred (versus treat- Q-switched ruby/Q-switched alexandrite/ ing in the late involuting stage) and whether the Q-switched Nd:YAG blue only; yellow, orange, risk of general anesthesia is warranted versus 254 J. Alshaiji local anesthesia (Cantatore and Kriegel 2004 ; Al pulsed (600 nm), Nd:YAG (1064 nm), and alex- Buainian et al. 2003 ; Azizkhan 2003 ; Stier et al. andrite (755 nm) lasers can be utilized, but there 2008 ). is a risk of complications (e.g., purpura, pig- These controversies came from the natural mentary alterations) (Cole et al. 2007 ; Hanke characteristics of IHs and to the potential side et al. 2013 ; Yang et al. 2005 ). effects of the PDL on the lesions such as atrophic scarring, ulceration, rarely life-threatening hem- orrhages, pain, and residual scarring (Kono et al. Pigmented Lesions 2006 ; Witman et al. 2006 ). Also, some authors recommend using laser therapy (PDL) for early Many pigmented lesions (such as nevi of Ota and initially fl at IHs to prevent further progression and Ito, lentigines, freckles, tattoos, nevus spilus, con- complications, while others advocate the use of genital melanocytic nevus (CMN), and Mongolian laser (PDL) to treat superfi cial involuting and spot) can be treated with pigment lasers especially ulcerating IHs. Other authors advocate the treat- Q-switched lasers and by IPL and PDL especially ment of superfi cial IHs during the proliferative for epidermal pigmented lesions (Hanke et al. phase utilizing frequent treatments at 2–3-week 2013). Regarding nevus spilus, it should be noted intervals at higher energies (11–12 J/cm2 , 7-mm that only lesions not suspected of malignant mela- spot size) (Chapas and Geronemus 2005). The noma degeneration and without raised papular treatment of early superfi cial IHs by laser does elements should be admitted to laser therapy (Van not prevent development of deeper component Leeuwen and Bastiaens 1997 ). The treatment of (Ashinoff and Geronemus 1991 ; Spicer and giant congenital melanocytic nevi by laser is still Goldberg 1996 ); instead some authors recom- controversial since 1–5 % of these lesions may mend the use of KTP or CW/ long-pulsed Nd:YAG develop into melanoma over a lifetime and laser to treat deep IHs although there is a risk whether or not laser surgery impacts this small of scarring, blistering, crusting, dyschromias, risk has not been determined (Chapas and and textural abnormalities (Stier et al. 2008 ). Geronemus 2005 ; Downs et al. 2004 ). The treat- Currently, there are no optimal laser systems for ment of cafe au lait macules and Becker nevus by hemangioma treatment (Drolet et al. 1999 ). pigment lasers are still diffi cult and controversial since they can get worsen and frequently recur. Although tattooing is still a common practice Vascular Malformations especially among teenagers, many of them “change their mind” for various reasons and The PDL is still the gold standard therapy for decided to remove it. Optimal tattoo removal is PWS, and it is highly effective and safe espe- best achieved by pigment-specifi c cutaneous cially for small facial PWS in infants <6 months lasers and its type depends on the absorption of age under local anesthesia with clearance rate spectra of the various ink colors present within the of 88.6 % (Ashinoff and Geronemus 1991 ; tattoo. Black, blue, and red pigments are easily Chapas and Geronemus 2005; Cordoro and removed by pigment lasers, but yellow and orange Frieden 2010 ). However, the PDL is less effec- pigments are often the most diffi cult to remove tive for PWS on centrofacial skin, especially V2 because they absorb minimally at any of the com- distribution and extremity lesions (Renfro and mercially available wavelengths. Green pigment, Geronemus 1993 ). Also, controversies exist although it absorbs Q-switched ruby laser energy about early and late treatment of PWS, in par- well, is speculated to be resistant to laser lighten- ticular because general anesthesia may be ing owing to an inherent quality of the ink mix- needed in young children (Mann 2014 ). For ture. Professional tattoos are generally more those PWSs that are resistant to PDL (due to resistant to treatment than amateur tattoos due to their sizes, anatomic locations, age of the deep, densely packed ink and the presence of patients, vessel depth and diameter), long- multiple colors (Cantatore and Kriegel 2004 ). 26 Laser Therapy: When, Where, and Why 255

Alopecia Areata (AA) limits its usefulness (Vashi et al. 2001 ). Most US insurances do not cover it, and the costs can be A study by Al-Mutairi in 2007 demonstrates that high. An obvious controversy is when and even the 308-nm excimer laser (twice a week for 3 “if” a child’s hypertrichosis should be treated. months) is an effective and safe therapeutic modal- Taunting, bullying, and school avoidance issues ity for treatment of limited patchy AA on the scalp are three obvious reasons to begin treatments. both in children and adult with 76.5 % showing a complete regrowth, but not effective for AA on the Warts extremities and for alopecia totalis. Another study Various laser types (such as CO2 , PDL, KTP) can by Al-Mutairi in 2009 demonstrates almost same be utilized to treat warts, but they have many side fi ndings as his previous study with 63.6 % of the effects. CO2 laser is associated with severe and scalp AA patients showed a complete response prolonged postoperative pain, delayed wound (Al-Mutairi 2007 , 2009). Atopic diathesis emerged healing, and scarring (Torrelo 2002 ). Although as a poor prognostic factor in these studies, and the PDL therapy is known to be safe and effective problem of recurrence after stopping the therapy modality, the reported cure rates have varied, and remains a major concern. until 2007 no studies have reported treatment of pediatric patients alone (Park et al. 2007 ). In this study by Park et al., the authors demonstrated Vitiligo that the clearance rates of periungual (51.4 %) and fl at warts (69.2 %) appeared to be better than Although many studies regarding the effective- those of common (41.6 %) and plantar warts ness of 308-nm excimer laser in vitiligo treat- (38.7 %). Because of the expense, discomfort, ment have been conducted, the usefulness of this and prolong healing, laser treatment of warts in modality in childhood vitiligo still remains insuf- children may be reserved mostly for lesions resis- fi cient. Vitiligo lesions on “UV-sensitive areas” tant to other, less aggressive treatment modalities such as the face, neck, and trunk responded better (Cantatore and Kriegel 2004 ). to the excimer laser than lesions on “UV-resistant areas” such as the upper and lower extremities. Psoriasis Although vitiligo on the face yielded the best Although the 308-nm excimer laser has been repigmentation scores with a lower cumulative shown to be safe and effective in the treatment of dose, they also exhibited the highest rate of burns. localized mild-to-moderate plaque-type psoriasis More studies are required to establish the optimal in adults, its effi cacy and safety in children have cessation time for excimer laser treatment (Cho not yet been demonstrated until 2005 in a study et al. 2011 ). by Pahlajani et al. (2005 ).

Hypertrichosis Porokeratosis Permanent hair removal methods such as laser A report of McCullough and Lesher ( 1994 )) therapy (e.g., ruby, alexandrite, diode, IPL, and revealed an unusual case of rapid recurrence of a Nd:YAG) for primary hypertrichosis have not large lesion (4.1 × 2.0 cm) of porokeratosis of been studied in prepubertal children, their use has Mibelli in a 9-year-old girl 2 months after CO 2 been limited in older children and adolescents, and laser vaporization with curettage (Pahlajani et al. it has many side effects such as perifollicular ery- 2005 ). Due to its aggressive nature, deep excision thema, edema, pigmentary alterations, and even up to subcutaneous fat with 4-mm lateral margins scarring if excessive treatment ﬂ uences are used was performed to avoid further problems. (Cantatore and Kriegel 2004 ). Laser electrolysis is uncomfortable for children, and is only possible Nevus Sebaceous when the hairs are dark, and is best when the hairs The treatment of nevus sebaceous is controver- are dark and the underlying skin is light, which sial. Many investigators still treat it by surgical 256 J. Alshaiji

excision. The CO2 laser can be used to remove laser is associated with ash-gray tissue, crust, and only the portion of the nevus sebaceous that lies transient purpura. Copper vapor is associ- at the epidermis or papillary dermis, not the ated with hypertrophic scar and hypo-/ entire lesion (Ashinoff 1993 ). Of note, the malig- hyperpigmentation. nancy risk in nevus sebaceous has been shown to CO2 laser is associated with erythema, wound be very low (0.8 %) in two different studies infection, hypertrophic scar, and hypo-/hyper- (Cribier et al. 2000 ; Rosen et al. 2009 ). Since the pigmentation. Er:YAG laser is associated with risk of malignancy is so low, some physicians do same side effects as CO2 laser in addition to not remove this lesion and all simply wait and incomplete hemostasis. Diode laser is associ- see. ated with transient erythema and edema. Excimer laser is associated with transient pain- Hypertrophic Scars and Keloids ful blister. The CO2 laser, Er:YAG laser, and recently PDL have been used to treat hypertrophic scars and Conclusion keloids. The data are far from conclusive, and Laser therapy remains a good therapeutic future studies are necessary to determine the true modality of choice for many expanding pedi- effectiveness of the PDL on scarring, especially atric skin disorders especially vascular birth- in children (Cantatore and Kriegel 2004 ). marks since its introduction by Goldman in the 1960s. Nowadays, the PDL is the gold Striae standard for the treatment of PWSs since its There are no universally effective treatments for fi rst clinical application and the proposal of striae (Cantatore and Kriegel 2004 ). the “selective photothermolysis” theory by Anderson and Parrish in 1983. The laser treat- Epidermal Nevi ment of hemangiomas remains controversial, Both CO2 laser and Er:YAG laser can be used to but many authors show benefi t of treating treat epidermal nevi; however relative to the superfi cial involuting and ulcerating heman- Er:YAG, there is more residual hypopigmenta- giomas, while others advocate the use of early tion with CO2 laser. It should be noted that laser laser therapy to treat initially fl at cutaneous treatments are usually ineffective at improving hemangiomas to prevent several complica- infl ammatory linear verrucous epidermal nevi tions and to provide psychological relief for (Chapas and Geronemus 2005 ). both the patients and their parents (Bruscino et al. 2012). We look forward to the future when many of these controversies will be clar- Side Effects of Laser ifi ed and proper laser use will benefi t all the diseases in our table. There are several side effects associated with laser therapy. Quasi-continuous-mode lasers (argon, KTP, copper bromide, copper vapor, and Bulleted List of Controversies krypton) are associated with hypertrophic scarring and textural changes. PDL is associated with • PWS and Lasers: Children of age less than 1 purpura that lasts 10–14 days after treatment. year seem to have the most effective lighten- Q-switched ruby laser is associated with ash- ing and require fewer treatments than older white tissue and edema after treatment in addi- individuals, and so physicians advise treating tion to hypo-/hyperpigmentation. Q-switched the patient as early as physically possible to alexandrite laser is associated with decreased decrease the psychologic effect of the birth- hypopigmentation. Q-switched Nd:YAG is asso- mark and avoid hypertrophy with age. ciated with purpura. Pigment-specifi c pulsed dye However, contrary to this some researchers 26 Laser Therapy: When, Where, and Why 257

have found no signifi cant difference in lesion References clearing between age groups. • PWS lesions located on the periorbital area, Al Buainian H, Verhaeghe E, Dierckxsens L, Naeyaert lateral facial cheeks, chest, and proximal JM. Early treatment of hemangiomas with lasers. Dermatology. 2003;206:370–3. aspect of the arms respond best to treatment, Al-Mutairi N. 308-nm excimer laser for the treatment of whereas the malar areas of the face and distal alopecia areata. Dermatol Surg. 2007;33:1483–7. limbs do not respond well, even with many Al-Mutairi N. 308-nm excimer laser for the treatment of treatment sessions. alopecia areata in children. Pediatr Dermatol. 2009;26:547–50. • Treatment of infantile hemangioma remains Ashinoff R, Geronemus RG. Flashlamp-pumped pulsed extremely controversial, because there are a dye laser for port-wine stains in infancy: earlier versus wide range of outcomes for infantile heman- later treatment. J Am Acad Dermatol. 1991;24: gioma, from fully resolved to disfi guring scars 467–72. Ashinoff R. Linear nevus sebaceous of Jadassohn treated to life-threatening obstructions. One argument with the carbon dioxide laser. Pediatr Dermatol. dictates an aggressive approach, using early 1993;10:189–91. intervention to lessen the impact of a poten- Azizkhan RG. Laser surgery: new applications for pediat- tially threatening lesion, whereas the contrast- ric skin and airway lesions. Curr Opin Pediatr. 2003;15:243–7. ing argument advises a wait-and-see approach, Bruscino N, Bonan P, Cannarozzo G, et al. Laser use in in the belief that most infantile hemangiomas infantile hemangiomas, when and how. Dermatol resolve with a more cosmetically adequate Ther. 2012;25:314–21. outcome without treatment. Cantatore JL, Kriegel DA. Laser surgery: an approach to the pediatric patient. J Am Acad Dermatol. • Laser therapy for pigmented melanocytic 2004;50:165–84. nevi : Some argue that ablation of the pig- Chapas AM, Geronemus RG. Our approach to pediatric mented portion of a nevus might mask the dermatologic laser surgery. Lasers Surg Med. occurrence of tumors within the treated area. 2005;37:255–63. Cho S, Zheng Z, Park YK, Roh MR. The 308-nm excimer Others argue the opposite, and data are lack- laser: a promising device for the treatment of child- ing to support either contention. hood vitiligo. Photodermatol Photoimmunol • Laboratory studies examining malignant Photomed. 2011;27:24–9. changes after laser irradiation have been per- Cole PD, Sonabend ML, Levy ML. Laser treatment of pediatric vascular lesions. Semin Plast Surg. formed. Results have varied, with some giving 2007;21:159–66. cause for concern and others not. Cordisco MR. An update on lasers in children. Curr Opin • There is considerable variability in the Pediatr. 2009;21:499–504. response of café-au-lait macules to laser treat- Cordoro KM, Frieden IJ. Pulsed dye laser for port wine stains. J Am Acad Dermatol. 2010;62:1065–6. ment, not only between the various types of Cribier B, Scrivener Y, Grosshans E. Tumors arising in lasers but also between different café au-lait nevus sebaceous: a study of 596 cases. J Am Acad macules treated with the same laser. In fact, Dermatol. 2000;42:263–8. café-au-lait macules may darken, lighten, or Downs AM, Rickard A, Palmer J. Laser treatment of benign pigmented lesions in children: effective long- recur after laser treatment. term benefi ts of the Q-switched frequency-doubled • Hair removal: Laser treatments may have Nd:YAG and long-pulsed alexandrite lasers. Pediatr advantages over other semipermanent meth- Dermatol. 2004;21:88–90. ods of hair removal, because they are rapid, Drolet BA, Esterly NB, Frieden IJ. Hemangiomas in children. N Engl J Med. 1999;341:173–81. less painful, relatively simple to operate, and Hanke CW, Moy RL, Roenigk RK, et al. Current status of effective. However, laser hair removal has surgery in dermatology. J Am Acad Dermatol. expected side effects, such as perifollicular 2013;69:972–1001. erythema and edema, and has the potential for Kono T, Sakurai H, Groff WF, Chan HH, Takeuchi M, Yamaki T, et al. Comparison study of a traditional more serious complications, such as pigmen- pulsed dye laser versus a long-pulsed dye laser in the tary alterations or even scarring if excessive treatment of early childhood hemangiomas. Lasers treatment fl uences are used. Surg Med. 2006;38:112–5. 258 J. Alshaiji

Mann JA. Update on pediatric dermatologic surgery from Stier MF, Glick SA, Hirsch RJ. Laser treatment of pediat- tots to teens. Curr Opin Pediatr. 2014;26:452–9. ric vascular lesions: port wine stains and hemangio- McCullough TL, Lesher JL. Porokeratosis of Mibelli: mas. J Am Acad Dermatol. 2008;58:261–85. rapid recurrence of a large lesion after carbon dioxide Torrelo A. What’s new in the treatment of viral warts in laser treatment. Pediatr Dermatol. 1994;11:267–70. children. Pediatr Dermatol. 2002;19:191–9. Pahlajani N, Katz BJ, Lozano AM, et al. Comparison of the Van Leeuwen RL, Bastiaens MT. Management of nevus efﬁ cacy and safety of the 308 nm excimer laser for the spilus with laser. Pediatr Dermatol. 1997;14:155–6. treatment of localized psoriasis in adults and in chil- Vashi RA, Mancini AJ, Paller AS. Primary generalized dren: a pilot study. Pediatr Dermatol. 2005;22:161–5. and localized hypertrichosis in children. Arch Park HS, Kim JW, Jang SJ, Choi JC. Pulsed dye laser Dermatol. 2001;137:877–84. therapy for pediatric warts. Pediatr Dermatol. Witman PM, Wagner AM, Scherer K, Waner M, Frieden 2007;24:177–81. IJ. Complications following pulsed dye laser treatment Renfro L, Geronemus RG. Anatomical differences of of superﬁ cial hemangiomas. Lasers Surg Med. port-wine stains in response to treatment with the 2006;38:116–23. pulsed dye laser. Arch Dermatol. 1993;129:182–8. Yang MU, Yaroslavsky AN, Farinelli WA, Flotte TJ, Rius- Rosen H, Schmidt B, Lam H, et al. Management of nevus Diaz F, Tsao SS, Anderson RR. Long-pulsed sebaceous and the risk of basal cell carcinoma; an neodymium:yttrium-aluminum-garnet laser treatment 18-year review. Pediatr Dermatol. 2009;26:676–81. for port-wine stains. J Am Acad Dermatol. Spicer MS, Goldberg DJ. Lasers in dermatology. J Am 2005;52:480–90. Acad Dermatol. 1996;34:1–25. Photography in Pediatric Dermatology: More Important 2 7 than Many Physicians Think

Frans Bel and Arnold P. Oranje

Abstract Taking clinical photographs is an essential component of patient care in dermatology. Photographs of physical and dermatological ﬁ ndings should be an essential routine procedure in (pediatric) dermatology. It should always be conducted before taking a biopsy. It is primarily meant to be a diagnostic tool in order to document the presence or absence of visible physical dermatological ﬁ ndings.

Keywords Photography in pediatric dermatology • Pediatric dermatologic photography • Clinical photography in dermatology • Dermatologic photography • Photographic equipment for clinical photography

Why Do You Take Photographs? procedure in (pediatric) dermatology. It should always be conducted before taking a biopsy. It is Taking clinical photographs is an essential com- primarily meant to be a diagnostic tool in order to ponent of patient care in dermatology (Lakdawala document the presence or absence of visible et al. 2012 ). Photographs of physical and derma- physical dermatological ﬁ ndings: tological ﬁ ndings should be an essential routine • Normal variants, congenital dermatological abnormalities, and acquired dermatological disorders. • Aspects of growth and development. F. Bel , RMF Department of Medical Photography , Erasmus MC , • Photographic documentation also provides Postbus 2060 , Rotterdam 300 CB , The Netherlands objective information to discuss the e-mail: [email protected] development of skin abnormalities in time A. P. Oranje , MD, PhD (*) with those who are responsible for the child, Department of Dermatology , especially the parents or the guardians of the Dermicis Skin Hospital – Alkmaar , child. Kinderhuid.nl – Rotterdam, Rotterdam, The Netherlands • Finally, photographic documentation provides e-mail: [email protected] essential material for teaching and research.

Written informed consent from both the par- The Circumstances ents and the child (if older than 11 years) should and the Photographic Conditions preferably be asked. The parents and the child (if appropriate) should be informed why the photo- Photographs should be taken in a well-lit and graphs are taken (patient care, lesion documenta- quiet room or in the lightest corner of the consul- tion, teaching, and research or combinations of tation room without messy or busy background. these items). They should be reassured that pho- A (preferably green or blue and otherwise creamy tographic documentation is highly confi dential or white) wall or a piece of paper (e.g., from a and will be carefully looked after, especially fl ip-over) may be used as a neutral and light when it is used for educational purposes. improving background. A light blue or gray cloth Moreover, all will be done to conceal the identity held behind the patient also works very well to of the child. provide a neutral background without distracting clutter. An assisting person (doctor, student, or nurse) When and by Whom? may be very useful in handling the child in case the child is nervous or subconscious or by posing Photographs should be taken according to the the required body positions of the child during standardized procedures (as outlined below), to the photography. document the skin abnormality. The patient (12 years and over) and/or parents will give a written consent for use of the photographs. The Photographic Equipment Photographs are preferably taken by an experienced medical photographer, although in rou- It is most important that the camera is correctly tine practice often by one of the nurses. adjusted. Photographs should only be taken with a However, with modern digital technology, a mobile telephone camera only when there is no properly trained physician will be able to take other possibility. Professional digital mirror refl ex photographs by himself or organize photo- cameras (with a minimum of 10 Mb) with change- graphic documentation by medical staff accord- able objectives are preferred above compact cameras ing to the minimal standards (and the required as these cameras have better optical characteristics quality). The white balance is especially impor- and use a larger chip than compact cameras. tant in order to obtain photographs that are com- For experienced photographers using profes- parable in time. sional digital mirror refl ex cameras, the follow- The examining doctor is responsible for ing preset conditions should be applied (assuming clear and detailed instructions to the medical suffi cient light conditions): photographer of what should be photographed and the manner in which the dermatological 1. Macro lens and light-sensitive lens (60 mm fi ndings should be documented. The medical f/2.8 and 105 mm f/2.8, respectively). photographer is responsible for the photo- 2. ISO 400–1000, ISO 2000 in case of full-frame graphic quality of the photographs based on the cameras. instructions of the doctor for determining their 3. RAW fi le format (RAW/JPG-fi ne combina- medical value. tion or RAW compressed). Written guidelines on taking photographs 4. Camera on “M” (manual). should be available at the institution as they may 5. Measure light on gray scale. be referred to in case the origin, the contents, and 6. Adjust white balance using a gray or white the quality of the photographs are questioned scale (using the cameras’ preset white afterward. balance). 27 Photography in Pediatric Dermatology: More Important than Many Physicians Think 261

7. Do not take a photograph of a color scale (e.g., Step 1 may seem superfl uous; however, in X-Rite ColorChecker) because it is not using this order, one can be confi dent that all the reliable. photographs between steps 1 and 4 are from the same child. For less experienced photographers using When using mirror refl ex cameras, it is advised compact cameras and in medical settings like an to focus manually: preferably, do not autofocus emergency room, the following minimal require- (the autofocus uses areas with large contrast, which ments should be met: may be a different area than the body site of interest). It is advised not to use fl ash equipment. Direct 1. Zoom function with macro mode (“rose” or fl ash (at 90° to the surface) may ruin the visibility “tulip” permanently, allows focusing from 0 of the dermatologic abnormalities/signs, the birth- to 1.5 m). mark, or the relevant lesion. With a direct fl ash, the 2. ISO max 400–800. center of the photo is bleached or displays the light 3. JPG-fi ne fi le format. “blossom” of any refl ective surface. 4. Disable auto-fl ash function. By using the above guidelines, the series of 5. Use “P” (program). photographs as a whole has the optimal constel- 6. Manually set white balance is the best. lation to be recognized as that belonging to the However, automatic white balance in most same child, while the affected body parts, the cameras may be useful. birthmarks, the lesions, and the injuries (or 7. Enable movement reduction (anti-shake, absence of injuries) can be identifi ed correctly in “hand”). the overviews and the close-ups. We are not sup- 8. Do not use a measure tape, but measure the porting the use of a measuring scale (such as a abnormality if necessary and document it in ruler) because it adds no further information for the fi le. the consultation.

Standardized Order of Taking Bulleted List of Controversies Photographs • One should take the time to take the photo- As mentioned before, a standardized order should graphs in an optimal environment or condi- be used for correctly establishing the identity of tion. However, this is extremely diffi cult in a the child. An experience-based and literature- busy outpatient consultation situation. based order is given below: • It is easy to photograph with a mobile telephone; however, the quality will be subopti- 1. Take a photograph of an ID or an insurance mal. Still many doctors do it in this way. “card.” • Physicians think that they can photograph 2. Take a portrait photograph if it is not available with their camera in automatic setting. in the fi les. However, this is not always optimal. 3. Take several overview photographs from • With the continuous evolution of the digital top to bottom (to enable recognition of the and smartphone technology, physicians must body part in question) (or take an overview maintain ethical and medicolegal standards of the entire body side in case of a small (Kunde et al. 2013 ). child). • Choosing a camera for use in dermatological 4. Take an overview photograph of a specifi c practice is diffi cult, particularly in the case of region of interest (try to incorporate several a digital camera because the market is con- anatomical sites for reference purposes). stantly evolving (Barco et al. 2012 ). 262 F. Bel and A.P. Oranje

• Clinical photography of hair disorders is an References addition in dermatology practice. Dermatoscopy/trichoscopy can also be incor- Ashique K, Kaliyadan F. Clinical photography for trichol- porated in clinical practice for image docu- ogy practice: tips and tricks. Int J Trichol. 2011;3:7–13. Barco L, Ribera M, Casanova JM. Guide to buying a cam- mentation (Ashique and Kaliyadan 2011 ) . era for dermatological photography [original in Spanish]. Actas Dermosiﬁ liogr. 2012;103:502–10. Acknowledgments None of the authors has a ﬁ nancial Kunde L, McMeniman E, Parker M. Clinical photography interest in any of the products, devices, or drugs mentioned in in dermatology: ethical and medico-legal consider- this manuscript. We are indebted to Andre van den Bosch ations in the age of digital and smartphone technology. and Hubert G. T. Nijs, who together with Frans Bel wrote the Australas J Dermatol. 2013;54:192–7. chapters “Forensic Photography in Suspected Child Abuse” Lakdawala N, Fontanella D, Grant-Kels JM. Ethical con- and “Cutaneous Manifestations of Child Abuse and Their siderations in dermatologic photography. Clin Differential Diagnosis,” Springer, 2013. Dermatol. 2012;30:486–91. Index

A differential diagnosis , 103 AAD . See American Academy of Dermatology (AAD) epidemiology , 101 α -Adrenergic receptors , 70 etiology , 103 β-Adrenergic receptors, 70 histopathology , 103–104 ABDs . See Autoimmune blistering diseases (ABDs) prognosis , 103 A C D . See Allergic contact dermatitis (ACD) systemic therapies , 107–108 Acitretin , 47, 236 treatment Acquired cutis laxa , 128 anthralin , 105 Acute febrile mucocutaneous lymph node intralesional steroids , 104 syndrome , 222 minoxidil , 104–105 Acute febrile neutrophilic dermatosis . See Sweet prostaglandin analogs , 107 syndrome topical immunotherapy , 105–107 Adapalene , 234 topical steroids , 104 A G A . See Androgenetic alopecia (AGA) Alopecia totalis , 102, 106 Aggressive systemic mastocytosis (ASM) , 198 American Academy of Dermatology Alitretinoin , 236 (AAD), 3–4, 168 Allergic contact dermatitis (ACD) American Academy of Pediatrics (AAP) , 169 advice for , 25–26 American Board of Dermatology (ABD) , 4 children American Heart Association (AHA) , 225 atopic dermatitis , 21 Androgenetic alopecia (AGA) diapers , 24–25 clinical features, adolescents , 190–191 emollients and skin care products , 21–22 differential diagnosis , 192–193 juvenile plantar dermatosis and foot distress , 188 eruptions , 22–23 embryology and normal hair development , 188–189 natural remedies , 22 etiology and pathogenesis , 189 prognosis , 25 treatment , 193–194 shin guards , 23 ‘Angry back syndrome’ , 20 tattoos , 23–24 Anthralin (dithranol) , 45 toys , 25 Arizona’s SunWise program , 171 treatment , 25 Atopic dermatitis (AD) controversies , 26 allergy tests diagnosis , 18 aeroallergen allergy , 34 patient’s clinical history and physical examination contact allergy , 34–35 reading patch tests , 19–20 food , 32–34 skin testing , 18 controversies , 14–15, 35 test technique , 19 diagnosis of , 32 use test/ROAT , 20 exacerbations and remissions , 11 recalcitrant eczema , 18, 25 general aspects topical corticosteroids , 26 bathing , 12–13 Allergology , 5 emollients , 13 Allergy tests . See Atopic dermatitis (AD) proactive therapy , 13 Alopecia areata (AA) step-down (step-up) therapy, maintenance associated disorders , 103 phase, 13 clinical features , 102–103 itching dermatitis , 11 controversies , 108 management of , 32

Atopic dermatitis (AD) (cont .) Child abuse and neglect (CAN) parents education , 13 dermatovenereologic disorders systemic therapy , 12 cutaneous mimicker and physical abuse , 159 Australian SunSmart program , 171 forensic pediatrics , 159 Autoimmune blistering diseases (ABDs) mimic dermatovenereological azathioprine , 119 disorders , 157–159 children physical abuse and neglect , 156–157 bullous pemphigoid , 116 physiological habits/self-mutilation , 159 bullous systemic lupus erythematosus , 116 sexual abuse , 157 chronic bullous disease , 114 physical fi ndings , 156 dermatitis herpetiformis , 114–115 types , 156 differential diagnosis of , 114 Child and Adolescent Trichotillomania Impact EBA , 115 Project (CA-TIP), 148 pemphigus , 115 Childhood transplacentally transmitted diseases , 115 ABD , 114 cyclosporine , 119 PRP (see Pityriasis rubra pilaris (PRP) ) dapsone , 119 trichotillomania (see Trichotillomania ) IVIG , 120 vitiligo (see Vitiligo ) methotrexate , 119 Children MMF , 120 contact allergy (see Allergic contact dermatitis mucosal involvement of , 121 (ACD) ) oral and mucous membrane management , 121–122 school (see Sun protection policy ) rituximab , 120–121 Chlorhexidine , 21 systemic antibiotics , 121 CMN . See Congenital melanocytic nevus (CMN) therapeutic armamentarium, CABD Coal tar , 45 dosage , 116 Committee for Medicinal Products for Human Use glucocorticoids , 116 (CHMP) , 21 oral glucocorticosteroids , 116, 118 Compound allergy , 20 risk of infection , 118–119 Comprehensive Cancer Control (CCC) programs , 171 systemic medications , 116–118 Computed tomography angiography (CTA) , 226 vaccinations , 119 Confederation of European Specialists in Paediatrics (CESP) , 4 Congenital melanocytic nevus (CMN) , 254 B clinical aspects , 92–93 Basal cell carcinoma (BCC) , 178 defi nition and classifi cation , 91–92 “Base tan” theory , 181 melanoma risk and management Beauveria nivea , 241 giant CMN , 94–97 Behavioral therapy (BT) , 148 medium CMN , 93–94 Behcet’s disease , 244 small CMN , 93 Beta-blockers Contact urticaria syndrome , 19 mechanism of , 70 Cornifi cation disorder , 51 oral β-blockers, 72, 74 Coronary artery abnormalities (CAA) , 222 safety and side effects , 71–73 Corticosteroid withdrawal syndrome , 116 systemic therapy of , 73 “Counterirritation,” 146 topical therapy of , 73, 75, 76 Cramér’s V analysis , 83 ‘Black henna’ tattoos , 23, 24 Crohn’s disease , 236 Body-focused repetitive behaviors (BFRBs) , 145 Curettage , 95 Bone marrow examination (BME) , 206 Cutaneous lesions , 214 Bufexamac , 21 Cutaneous mastocytosis (CM) , 198, 205 Bullous pemphigoid (BP) , 116 Cutaneous melanoma , 93, 95, 170 Cyclobutyl pyrimidine dimers (CPDs) , 166 Cyclosporine , 47–48, 107 C adverse effects , 246–247 CAA . See Coronary artery abnormalities (CAA) atopic dermatitis , 243 “Cadaverized” hairs , 148 contraindications , 245 Calcipotriol , 135 dosage CAN . See Child abuse and neglect (CAN) combination therapy , 248 Candida albicans , 24 long-term therapy , 247–248 Centers for Disease Control and Prevention (CDC) , 168 rescue/bridging therapy , 247 Cephalic pustulosis , 63 short-term intermittent therapy , 247 Index 265

drug interactions , 246 F indications , 242 Facial and fl exural psoriasis , 42 mechanism of action , 241–242 Factitious disorders , 158 off-label indications , 244–245 Filaggrin (FLG) , 18 pharmacokinetics , 245–246 Finasteride , 194 psoriasis , 242–243 “5W1H” method . See Kipling method therapeutic ending of , 248 therapeutic monitoring of baseline laboratory investigations , 248–249 G follow-up investigations , 249 Genetic diseases , 5 pretreatment screening , 248 Giant congenital melanocytic naevus (GCMN) , 94–97 Cytochrome P450 isoenzymes (CYP3A) , 246 Gingival hyperplasia , 247 Glucocorticosteroids (GCS) , 81, 116 Glucose-6-phosphate dehydrogenase (G6PD) , 114 D Griffi ths classifi cation, juvenile PRP , 53 Dandy-Walker syndrome , 94 Guttate psoriasis , 39 Darier’s disease , 234 Dehydroepiandrosterone (DHEA) , 61 Delayed type allergy , 34 H Dermabrasion , 95 Hair-pulling behavior , 145 Diagnostic and Statistical Manual of Mental Hair-pull test , 147, 148, 191, 192 Disorders (DSM-5), 144 Hamilton–Norwood scale , 190 Diffuse cutaneous mastocytosis (DCM) , 198, 200–202 Harada’s classifi cation , 226 Dihydrotestosterone (DHT) , 189 Hemangiol , 71, 73 Dinitrochlorobenzene (DNCB) , 105 Hemangiomatosis , 81 Diphenylcyclopropenone (DPCP) , 105, 106 demographic and clinical characteristics of , 84 Disease-state lasers , 252 infants with , 84 Down syndrome , 103, 245 HIV-follicular syndrome , 52, 55 Human Genome Project , 5 Human papillomavirus (HPV) , 192 E Hyperbilirubinemia , 247 Early onset naevi , 91 Hypoglycaemia , 72 Echocardiogram (ECHO) , 225, 226 Hypothalamic-pituitary-adrenal axis (HPA axis) , 135 EECDRG . See European Environmental Contact Hypoxia , 81 Dermatitis Research Group (EECDRG) Ehlers–Danlos syndrome , 157 Emollients , 12–14, 21–22, 25, 44 I “Endocrinological syndrome,” 207 IH . See Infantile hemangioma (IH) Epidermal hyperactivity , 52 Imiquimod , 86 Epidermolysis bullosa acquisita (EBA) , 115 Immediate type food allergy , 33–34 Erythema multiforme (EM) Immunohistochemistry (IHC) , 206 clinical manifestations , 214–215 Indolent systemic mastocytosis (ISM) , 198 EM major , 214 Infantile hemangioma (IH) EM minor , 214 alarming vs. non-alarming IHS , 70 Erythrocyte sedimentation rate (ESR) , 127 beta-blockers Etretinate , 58 mechanism of , 70 European Academy of Allergy and Clinical oral β-blockers, 72, 74 Immunology (EAACI) , 18 safety and side effects , 71–73 European Academy of Dermatology systemic therapy of , 73 and Venereology (EADV) , 4 topical therapy of , 73, 75, 76 European Board of Pediatrics , 4 controversies , 80–82 European Environmental Contact Dermatitis Research hemangiomatosis , 84 Group (EECDRG), 18 hepatic hemangioma , 85 European Society for Pediatric Dermatology internal haemangioma (see (ESPD), 4, 5 Internal haemangioma) European Society for Pediatric Endocrinology , 4 internal hemangiomas , 85, 86 European Union of Medical Specialists (UEMS) , 5 materials and methods , 83 Excimer laser , 256 outcome measures and statistical methods , 83 ‘Excited skin syndrome’ , 20 results , 83 “Exclamation-mark” hairs , 148, 192 ultrasound , 85 266 Index

Interferon gamma release assay laser modalities , 252 (IFNγRA) , 116, 118–119 laser physics , 252 Interleukin (IL), 38, 47. 105 , 225 pediatric dermatology Internal haemangioma (IH) alopecia areata , 255 hemangiomatosis , 83 epidermal nevi , 256 liver , 85 hypertrichosis , 255 multifocal vascular lesions , 85 hypertrophic scars and keloids , 256 ultrasound , 83, 85 indications , 252–253 International Agency for Research on Cancer , 168, 181 infantile hemangiomas , 253–254 International Contact Dermatitis Research Group nevus sebaceous , 255–256 (ICDRG), 19, 20 pigmented lesions , 254 Intravenous immunoglobulins (IVIGs) , 114, 116, porokeratosis , 255 120, 130, 217 psoriasis , 255 Irritant contact dermatitis (ICD) , 23 striae , 256 Isotretinoin therapy , 235 vascular malformations , 254 IVIGs . See Intravenous immunoglobulins (IVIGs) vitiligo , 255 warts , 255 side effects of , 256 J Leptomeningeal melanoma , 93, 94 Janus kinase (JAK) , 108 Liquor carbonis detergens (LCD) , 45 John Cunningham (JC) virus infection , 121 Loose anagen hair syndrome (LAHS) , 148 Juvenile rheumatoid arthritis (JRA) , 41, 48 ‘Lucky Luke’ dermatitis , 24 Ludwig scale , 190

K Kasabach–Merritt syndrome , 157 M Kawasaki disease (KD) Magnetic resonance angiography , 226 CAA pathogenesis , 224–225 Malassezia clinical and laboratory features of , 222 M. furfur , 62 diagnosis controversies M. globosa , 63 CTA , 226 M. sympodialis , 62, 63 ECHO , 226 Malassezia folliculitis , 63 incomplete KD , 225 Marigold (Calendula ofﬁ cinalis) , 22 infants with , 225 Mast cell leukemia (MCL) , 198 magnetic resonance angiography , 226 Mast cell sarcoma (MCS) , 198 environmental causes , 222 Mastocytosis etiology and pathogenesis controversies , 222 children genetic predisposition , 224 diagnosis , 205–208 infectious causes of , 223 treatment , 208–209 superantigens/conventional antigens , 223–224 classiﬁ cation treatment controversies and characteristics , 199 anti-tumor necrosis factor agents , 227–228 chronic urticaria , 197 ASA , 228 DCM , 200–202 and atherosclerosis , 228 maculopapular CM , 198 corticosteroids , 227 mastocytoma , 198 IVIG, use of , 226 Mastocytosis in the skin (MIS) , 206 long-term monitoring of patients , 228–229 Matrix metalloproteinases (MMP) , 167 nonresponders, IVIG , 226–227 MC activation syndromes (MCAS) , 202 risk scoring systems , 227 Medium-sized congenital melanocytic naevus Keratinization , 235 (MCMN), 93–94 Keratolytics , 44 Methotrexate (MTX) , 47, 58, 108, 115–117, 119, 248 Kipling method , 150–152 Milwaukee test , 147 KIT-targeteting therapy , 209 Minoxidil , 104–105, 193 Koebner phenomenon , 38, 39, 56 “Minute” therapy , 45 MTX . See Methotrexate (MTX) Mucosal lesions , 214, 215 L Mycophenolate mofetil (MMF) , 120 LAHS . See Loose anagen hair syndrome (LAHS) Mycoplasma pneumoniae infection , 214, 215 Lanugo hair , 188 Myeloproliferative neoplasm , 198 Laser therapy Myroxylon pereirae , 22 Index 267

N circumstances and photographic conditions , 260 N-acetylcysteine (NAC) , 150 clinical photographs , 259 Nail pitting , 39, 41, 43, 56, 103 equipment , 260–261 Nail psoriasis , 41 skin abnormality , 260 Napkin psoriasis , 38 standardized order , 261 Narrowband ultraviolet b (NB–UVB) , 108 written informed consent , 260 Neonatal acne controversies vs. pityrosporum Photopatch tests , 18, 26 folliculitis Phototherapy , 46, 108, 136 clinical presentation , 62–63 Phototoxic dermatitis , 17 differential diagnosis , 64 Pigmented lesions , 253 etiology , 61–62 Pigment lasers , 252 NCP , 63–64 Pityriasis rubra pilaris (PRP) treatment , 64 classiﬁ cation controversies , 52 Neonatal diseases , 5 clinical features Neurocutaneous melanocytosis (NCM) , 93 juvenile atypical (type V) , 55 Nickel , 21 juvenile circumscribed (type IV) , 53, 56 Nicotinamide , 121 juvenile classical (type III) , 53–55 Non-scarring hair loss , 149 type VI PRP , 55 Nuclear factor of activated T-cells (NFAT) , 242 differential diagnosis , 56 epidemiology , 52 histopathology , 56–58 O pathogenesis , 52 Ofuji disease , 245 treatment controversies , 58 Oligoarticular asymmetrical arthritis , 41 Pityrosporum folliculitis , 63–64 Olsen scale , 190 Placental embolization , 80 Omalizumab , 209 Plaque psoriasis , 39 Ophthalmology , 5 Pneumocystis carinii pneumonia (PCP) , 118 Oral antibiotics , 47 Pneumocystis jiroveci pneumonia , 118 Oral β-blockers , 72, 74 Port-wine stain (PWS) , 251 Oral minipulse therapy , 136 Post-traumatic stress disorder (PTSD) , 146 Oxyhemoglobin , 252 PPACA . See Patient Protection and Affordable Care Act (PPACA) Proactive therapy, AD P controversies , 14–15 Palmoplantar keratoderma , 55, 57 exacerbations and remissions , 11 Para-aminobenzoic acid (PABA) , 170 general aspects Paraneoplastic Sweet syndrome , 126, 127 bathing , 12–13 Patch testing , 18, 19, 24, 26 emollients , 13 Patchy disease , 102 intensive topical anti-inﬂ ammatory therapy , 13 Pathergy , 127 step-down (step-up) therapy, maintenance Patient Protection and Affordable Care Act phase, 13 (PPACA) , 182 itching dermatitis , 11 Pediatric dermatology parents education , 13 controversies , 6 systemic therapy , 12 cyclosporine (see Cyclosporine ) Propionibacterium acnes , 235 pediatricians and dermatologists , 6–7 Propranolol , 70–73, 81 photography (see Photography ) P R P . See Pityriasis rubra pilaris (PRP) subspecialty , 3 Psoralen plus ultraviolet A (PUVA) , 46, 108, 208 tertiary pediatric dermatology Psoriasis and requirements, 4 clinical features of , 38–39 training epidemiology , 38 full training center , 5 etiology and pathogenesis , 37–38 training program, delivery of , 5–6 management controversies , 42–44 training units , 5 presentation patterns, children Pemphigus foliaceus (PF) , 120 guttate psoriasis , 39 Pemphigus vulgaris (PV) , 120 mucosal involvement , 41 Perianal streptococcal dermatitis (PSD) , 38 nail psoriasis , 41 p -Phenylenediamine (PPD) , 23 napkin psoriasis , 39 Photoaging , 167 plaque psoriasis , 39 Photography psoriatic arthropathy , 41–42 268 Index

Psoriasis (cont .) Skin testing , 18 psoriatic erythroderma , 41 “Sleep-isolated trichotillomania,” 145 pustular psoriasis , 41 Small congenital melanocytic naevus (SCMN) , 93 systemic therapy Smoldering systemic mastocytosis (SSM) , 198 acitretin , 47 Sorbitan sesquioleate , 24 biologics , 48 Squamous cell carcinoma (SCC) , 178, 179 cyclosporine , 47–48 Squaric acid dibutylester (SADBE) , 105 diet and supportive care , 48 “Staphylococcal scalded skin” syndrome , 200 methotrexate , 47 Staphylococcus aureus , 14 oral antibiotics , 47 “Step-down” therapy , 12 topical therapy Steroids therapy , 118 anthralin , 45 Stevens-Johnson syndrome coal tar , 45 management of corticosteroids , 44–45 antitumour necrosis factor alpha , 217 emollients and keratolytics , 44 IVIG , 217 phototherapy , 46 systemic corticosteroids , 216–217 tazarotene , 45 skin lesions , 215 topical calcineurin inhibitors , 46 “Strawberry Marks” (“Aardbeesie ”) , 83 vitamin D analogues , 45–46 Streptococcal pharyngitis , 38 Psoriasis Area severity Index (PASI) , 42 Suction blister grafts , 138 Psoriatic arthritis (PsA) , 38, 41 Sulfapyridin , 119 Psoriatic diaper rash . See Napkin psoriasis Sun protection factor (SPF) , 168 Psoriatic erythroderma , 41 Sun protection policy Pulse dye laser (PDL) , 251, 252 controversies , 173–174 Punch biopsy , 191 solar protection policy Punch grafting , 138 essential components of , 172 Pustular psoriasis , 41 primary and secondary schools, USA , 171–172 sun exposure and skin cancer, pathophysiology of risk factors , 167–168 R UV radiation, short-and long-term effects , 167 Reactive oxygen species (ROS) , 166 sun-protective behaviors Repeated open application tests (ROATs) , 18, 20, 26 infants, sunscreen and , 169 Resurfacing lasers , 252 sunscreen recommendations , 168–169 Retinoic acid receptors (RAR) , 233 sunscreen controversies , 169–171 Retinoic X receptors (RXRs) , 233 Sunscreens Retinoids and infants , 169 synthetic retinoids , 234 and melanoma , 169–170 systemic retinoids , 235–237 toxicity and potential systemic effects, topical retinoids , 234–235 children , 170 R O A T s . See Repeated open application tests (ROATs) usage, current recommendations , 168–169 Ruby laser , 251 vitamin D defi ciency , 170–171 Ruxolitinib , 108 Sweet syndrome classifi cation controversies , 126–127 clinical features , 127 S controversies Satellite naevi , 92 in monitoring , 129 Scalp psoriasis , 41, 46 in treatment , 130 SCMN . See Small congenital melanocytic naevus diagnosis , 126, 129 (SCMN) epidemiology , 126 Scoring atopic dermatitis (SCORAD) , 12 histopathology , 129 Selective photothermolysis theory , 251 pathogenesis , 126 Selective serotonin reuptake inhibitors (SSRIs) , 150 Systemic mastocytosis (SM) , 198, 201, 205 Sex hormone-binding globulin (SHBG) , 190 “Short contact” therapy , 45 Skin cancer T excessive UV exposure , 167 Tanning beds , 180 host determinants of , 167–168 Tanning practices in adolescents indoor tanning devices, artifi cial UV addictive properties of , 183 radiation, 168 CDC , 178 prevention activities, school , 173 indoor tanning Index 269

artifi cial tanning , 181 clinical features , 147 facilities , 181–182 controversies , 152 SCC and BCC , 180 diagnosis , 147–148 natural tanning/sunbathing , 182–183 general aspects , 144–145 skin cancer numbers , 145–146 types , 178 patho-etiology , 146–147 UV radiation , 179–180 treatment , 148–152 skin cancer types , 178–179 Trimethoprim–sulfamethoxazole (TMP–SMX) , 118 UV radiation , 180 Tuberculin skin testing (TST) , 116, 118–119 “Tanning tax,” 182 Tumor necrosis factor-α (TNF-α) , 38, 58, 81, 217 Tardive congenital melanocytic naevus , 91 Tyrosine kinase inhibitors (TKIs) , 209 Tazarotene , 45, 234 T-cell receptor (TCR) , 223 Telangiectasia macularis eruptiva perstans U (TMEP), 198 Ulcerative colitis , 236 Telogen effl uvium (TE) , 192 Ultraviolet A (UVA) , 208 Temporal triangular alopecia (TTA) , 103 Urticaria pigmentosa , 198 TEN . See Toxic epidermal necrolysis (TEN) US Food and Drug Administration (FDA) , 193 Teratogenicity , 236 Terminal hairs , 188 Tetracyclines , 64, 121 V Thermal relaxation time (TRT) , 252 Vascular endothelial growth factor (VEGF) , 81 Thiopurine methyltransferase (TPMT) enzyme , 119 Vascular lasers , 252 Three-Item Severity (TIS) , 12 Vellus hair , 188 Timolol , 75, 76, 81 Vitamin D defi ciency , 170–171, 173, 174 Tofacitinib , 108 Vitiligo Tolypocladium infl atum , 241 acquired cutaneous achromia , 133 Tonsillectomy , 47 localized vitiligo, management Topical calcineurin inhibitors (TCIs) , 46, 135 controversies , 134–136 Topical coal tar (TCT) , 25 management controversies Topical corticosteroids , 21, 25 generalized vitiligo , 136–138 Topical immunomodulators (TIM) , 12 localized vitiligo , 134–136 Topical immunotherapy , 105–107 narrowband UVB , 137 Topical minoxidil , 192–194 pathogenesis controversies , 133–134 Topical psoralens , 46 topical corticosteroids , 135 Toxic epidermal necrolysis (TEN) topical tacrolimus , 136 acute GVHD , 215 treatment modalities , 134 management of antitumour necrosis factor alpha , 217 IVIG , 217 W systemic corticosteroids , 216–217 “Watch-and-wait” principle , 81 Tretinoin , 234 Wet wrap treatment (WWT) , 12 Triamcinolone acetonide injections , 104 Workgroup on vascular anomalies Rotterdam Trichophagia , 147 (WEVAR), 83 Trichoscopy , 191 World Health Organization (WHO) , 155, 168, Trichotillomania , 103 181, 198