sign in sign up
<<
Home , Anodontia, Bloom syndrome, Focal dermal hypoplasia, Lymphedema, Microstomia, Oral pigmentation

Journal of Medicine, Radiology, Pathology & (2017), 4, 22–27

NARRATIVE REVIEW

Oral manifestation of genodermatoses L. Kavya, S. Vandana, Swetha Paulose, Vishwanath Rangdhol, W. John Baliah, T. Dhanraj

Department of and Radiology, Indira Gandhi Institute of Dental Sciences, Pudhucherry, India

Keywords Abstract Genodermatoses, , oral Genodermatoses are inherited dermatological disorders associated with the structure manifestation and functions of skin and its appendages. Several genodermatoses presenting with

Correspondence multisystem involvement lead to increased morbidity and mortality. Dermatological Dr. L. Kavya, Department of Oral Medicine and diseases, besides including the skin and its supplements may also involve the oral cavity, Radiology, Indira Gandhi Institute of Dental which deserves special considering that they may be the only presenting sign Sciences, Pudhucherry, India. of these disorders. The important aspect to be noted about these disorders is the rarity Phone: +91-9442902745. of the conditions and lack of awareness among the population which are the major E-mail: [email protected] drawbacks in the early diagnosis and prompt management of these diseases. This review intends to outline various genodermatoses with their characteristic oral manifestations. Received: 11 April 2017; Accepted: 15 May 2017 doi: 10.15713/ins.jmrps.97

Introduction hence, it is simplified under three classifications based on its distinct features. Genodermatoses or genetic diseases are a group of inherited According to William et al. 2005:[3] skin disorders with a collection of cutaneous and systemic signs 1. Chromosomal and symptoms. In the oral cavity, a wide spectrum of diseases 2. Single occurs due to genetic modifications ranging from developmental 3. Polygenetic. disturbances of hard and soft tissues to precancerous and According to Irvine and Mellerio in 2010:[4] cancerous lesions. Dermatological diseases, besides including 1. Inherited immunobullous disorders the skin and its supplements may also involve the oral cavity, • (EB) of different groups. which deserves special attention considering that they may be 2. Disorders of keratinization the early presenting clinical feature or the only sign of these • disorders. The oral mucosal lesions in dermatological disorder • Palmoplantar can be life-threatening and also affect the quality of life in terms • Erythrokeratoderma [1] of pain, discomfort, social, and functional limitations. • Follicular . The rarity of the conditions and lack of awareness are the 3. Hereditary disorders of pigmentation major complications in the management of these diseases. Several • genodermatoses presenting with multisystem involvement may • Chediak-Higashi syndrome (CHS) [2] lead to increased morbidity and mortality. • Griscelli syndrome. 4. Familial multiple tumor syndrome Classification • Type 1 and 2 • Tuberous sclerosis complex (TSC) Genodermatoses are a vast group of disorders including • Gardner syndrome common, uncommon, and very rare diseases. Categorizing • these diseases into different groups are arduous because of the • Peutz-Jeghers syndrome. overlapping clinical features of many conditions. It is difficult 5. Ectodermal dysplasias (EDAs) and disorders of to comprise all genodermatoses under one broad classification; ectodermal appendages

22 Journal of Medicine, Radiology, Pathology & Surgery ● Vol. 4:3 ● May-Jun 2017 Oral genodermatoses Kavya, et al.

6. Disorders with defects in DNA repair and chromosomal • syndrome instability • Multiple syndrome (Cowden syndrome) • • Pachonychia congenita • Xerodermapigmentosum • EB • . • Multiple endocrine neoplasia syndrome 7. Poikilodermatous disorders • White sponge . • Rothmund-Thomson syndrome 4. Genodermatoses affecting bones and facies • Dyskeratosis congenital (DKC) • Mccune-Albright syndrome • Acrokeratoticpoikiloderma of Weary • EDS • . • 8. disorders • Focal dermal hypoplasia syndrome • Ehlers-Danlos syndrome (EDS) • Gardner syndrome • • Basal cell nevus syndrome • Marfan syndrome • Orofacial digital syndrome Type 1. • 5. Genodermatoses causing pigmentation of • • Carney complex • Williams syndrome • Neurofibromatosis Type 1 and 2 • Menkes kinky hair syndrome. • Mccune-Albright syndrome 9. Vascular and lymphatic disorders • Lipoid proteinosis • Osler-Rendu-Weber syndrome Type 1 and 2 • Pseudoxanthoma elasticum • distichiasis syndrome. • Peutz-Jeghers syndrome 10. Porphyrias • Congenital erythropoietic porphyria 11. Disorders associated with • Hypomelanosis of ito • Wiskott-Aldrich syndrome • Sturge-Weber syndrome • Omenn syndrome. • Hereditary hemorrhagic telengiectasia syndrome. 12. Miscellaneous disorder 6. Genodermatoses with malignant potential • Bazex syndrome • (XP) • Goltz syndrome • DKC. • Pachydermoperiostosis In this review, the various genodermatoses along with • -patella syndrome their oral manifestations are discussed. [Table 1] shows Oral • Apert syndrome. genodermatoses with their corresponding mutated . Arora and Mane proposed a classification in 2016:[5] 1. Genodermatoses affecting teeth and dentition EB • Ichthyosis • Sjogren-Larrson syndrome EB is a chronic blistering disease of the skin and mucosa. • Incontinentia pigment The three major types of EB are EB simplex, junctional EB, • EDS and dystrophic EB. Oral involvement has been reported in • Focal dermal hypoplasia syndrome the junctional and dystrophic forms of the disease, which is characterized by bulla and vesicle formation following mild • Gardner syndrome [6] • EDA physical trauma. Oral manifestations include blistering • Hyperimmunoglobulin E syndrome (Job syndrome). and ulceration of the oral mucosa, abnormal eruption, 2. Genodermatoses affecting periodontium and gingiva depapillation of tongue, , ablated palatal rugae, • Ichthyosis and . • Sjogren-Larrson syndrome Ichthyoses • Papillon Lefevre syndrome • Tuberous sclerosis Ichthyoses form a large, clinically and etiologically heterogeneous • CHS group of cornification disorders that typically affect all or most of • EDS the skin surface.[7] It is caused by abnormality in keratinization • Focal dermal hypoplasia syndrome. and exfoliation of the horny cell layer. Oral and dental findings 3. Genodermatoses affecting oral mucosa reported in ichthyosis include , periodontitis, • Darier’s disease , high caries incidence, delayed primary • Neurofibromatosis Type 1 and 2 and eruption, , bifid teeth, irregular • CHS morphology of teeth, and hyperkeratotic plaques on the tongue. • EDS Angular and facial dermatitis may occur as side effects of • Lipoid proteinosis oral retinoid therapy.

Journal of Medicine, Radiology, Pathology & Surgery ● Vol. 4:3 ● May-Jun 2017 23 Kavya, et al. Oral genodermatoses

Palmoplantar keratoderma (PPK) Table 1: Oral genodermatoses with their corresponding mutated genes PPK is a common hereditary cutaneous disorder characterized Oral genodermatoses Mutated gene by marked on the surface of palms and soles.[8] EB KRT5/KRT14/COL7A1 Periodontitis can affect both the deciduous and permanent teeth. Initially, there tends to be gingival inflammation, which can be Ichthyoses ABCA12/FLJ39501/FLG/STS followed by destruction of periodontium leads to premature loss PPK KRT1/KRT16/TRPV3 of primary teeth. CHS CHS1 gene in 1q42‑43 band NF NF1 and NF2 CHS TSC TSC1 (9q34), TSC2 (16p13.3) CHS is an autosomal recessive disease that affects the production of organelles in many cells including melanocytes, platelets, and Gardner syndrome APC (5q21q22) leukocytes. Neutrophils are characterized by abnormal giant Peutz‑Jeghers syndrome STK11 containing enzymes and with impaired ability to DKC NOP10/NHP2 [9] release them. It is associated with severe gingivitis, periodontal EDS COL5A1 disease and premature loss of dentition. Marfen syndrome FBN1 Neurofibromatosis Cowden’s syndrome PTEN (10q22‑23) Neurofibromatosis comprises several distinct genetic disorders Apert syndrome C934G/C937G that lead to the formation of tumors surrounding nerves and many EB: Epidermolysis bullosa, PPK: , other pathological features. Oral lesions are present in 5-10% of CHS: Chédiak‑Higashi syndrome, TSC: Tuberous sclerosis complex, NF: Neurofibromatosis, EDS: Ehlers‑Danlos syndrome, DKS: Dyskeratosis cases, as papillomatous tumors of , buccal mucosa, tongue congenital and , or as , which is usually asymmetrical.[10] Common sites of the oral solitary include tongue, buccal mucosa, alveolar ridge, labial mucosa, palate, gingiva, lesions are usually flat, painless, brown pigmented patches of nasopharynx, paranasal sinuses, , floor of the , and the buccal mucosa, tongue or labial mucosa. Microscopically, salivary gland. Tumors may also arise within the bone. these lesions show mild acanthosis with elongation of rete pegs and increased production of pigment in the basal layer [14] TSC without increase in the melanocyte number.

TSC is an autosomal dominant, systemic disorder characterized EDA by the formation of in multiple organ systems, most commonly the brain, skin, , and eye. Oral lesions EDA is the term used to describe a group of rare, inherited have been reported in about 11% of patients. These lesions disorders characterized by dysplasia of tissues of ectodermal mainly consist of fibrous growths affecting the oral mucosa origin which primarily involves nails, teeth, skin, and of the anterior gingiva, lips, tongue, and palate. Pitted enamel occasionally dysplasia of mesodermally derived tissues.[15] hypoplasia is another characteristic oral manifestation of the Craniofacial structures[16] affected in this disease are depressed disease found in 58% of patients.[11] and hypoplastic midface region, high and broad cheek bone. The chin may be pointed and the lips are everted and protuberant. In nontreated patients, craniofacial deviations increase with Gardner syndrome advancing age with a tendency toward a Class III pattern Gardner syndrome is characterized by multiple epidermoid with anterior growth rotation. The other characteristic facial , premalignant intestinal polyps, and fibrous features are frontal bossing, depressed nasal bridge, prominent tumors of skin and other organs. Oral manifestations are large supra orbital ridges, prominent and obliquely set ears and the osteomas of the mandibular ramus region or condyle limiting lower third of the appears small due to lack of alveolar the mandibular opening, increased prevalence of , bone development. In the oral cavity, the most striking feature supernumerary teeth, and impacted teeth.[12] is oligodontia.[17] Teeth in the anterior region of and are conical in shape. There is a wide midline diastema Peutz-Jeghers syndrome and hypoplastic labial frenum. Consistent variations in the Peutz-Jeghers syndrome is a rare disorder characterized by number and morphology of teeth occurs which appear to be a intestinal polyposis and pigmentation of the skin and mucous characteristic dental phenotype for EDAs with different modes membrane.[13] The significant oral changes are perioral of inheritance. , if present is frequently seen on and/or , which develops in childhood. Non the second deciduous molars. A few patients have congenital sun-dependent freckling of the skin around the lips and the . There are generally more teeth in the maxilla than vermilion zone of the lips is a common feature. Intraorally, the in the mandible, sometimes complete edentulous arches may be

24 Journal of Medicine, Radiology, Pathology & Surgery ● Vol. 4:3 ● May-Jun 2017 Oral genodermatoses Kavya, et al. seen. Most often the lower and premolars are missing, feature of this rare syndrome. Oral findings are present in 80% followed by the upper premolars and incisors. The edentulous of patients and may serve as an important clinical marker in early EDA patients do not have any alveolar processes either. In those diagnosis. Oral hamartomas occur mainly on gingiva, buccal and patients with some natural teeth, there is a striking difference in palatal mucosa.[21] The oropharynx, larynx, and nasal mucosa the intraoral height and breadth of the bone. In areas where no may also be involved. The typical appearance of multiple, teeth have developed, the alveolar bone is missing and the bone coalescent, and flat topped mucosal has been described ridge is very thin in contrast to the normal alveolus surrounding as cobblestone-like and is seen in 40% of patients.[22] an occasional tooth. Many patients complain of dryness of oral mucosa due to reduced salivary secretion. Analysis of the saliva Apert syndrome has revealed a reduced buffer capacity and an increased number Apert syndrome is a rare congenital Type 1 acrocephalosyndactyly of bacterial cultures. Most affected EDA patients are susceptible syndrome, characterized by craniosynostosis (premature fusion to dental caries. of cranial sutures), severe syndactyly of the hands and feet, and dysmorphic facial features.[23] Oral manifestations include XP impaction, severe crowding, delayed eruption of dentition, thick gingiva, supernumerary teeth or genetically missing teeth, XP is a rare recessive disease characterized by photosensitivity, Class III , anterior open bite, bilateral posterior pigmentation disorders, premature skin ageing, neoplasia, cross bite, or unilateral posterior cross bite.[24] The configuration and abnormal DNA repair. Some patients with XP also have of the palatal arch is characterized by bilateral swellings of the neurological complications. Oral findings[18] are , palatine processes, resulting in a pseudocleft in the midline. , and (SCC) of the tip of Other frequent oral findings include hypotonic lips, bifid uvula, the tongue, , and SCC of the lips. In the general delayed or ectopic eruption, and malocclusion. population, SCC most frequently affects the posterolateral and ventral surfaces of the tongue and floor of the mouth of elderly Marfan’s syndrome users of tobacco and alcohol and runs an aggressive course. By contrast, XP associated SCC affects the tip of the tongue Marfan’s syndrome is a heritable of the of persons younger than 20 years of age and runs a slowly connective tissue. People with Marfan’s syndrome tend to be progressive course. Actinic cheilitis is a potentially malignant unusually tall, thin built with long limbs and scoliosis. The most lesion that affects the lower of white patients who were serious complications are defects of the valves and aorta frequently exposed to sun. Pain is a consequence of fibrous area, which includes aortic aneurysms and mitral valve prolapse and resulting from successive labial surgery, that stretches when the left ventricular dysfunction. Syndrome also affects the , patients opens the mouth for feeding, speaking, breathing, and eyes, dural sac surrounding the spinal cord, skeleton, and hard for oral hygiene performance. Therefore, the patient has poor palate.[25] Oral features are retrognathic maxilla and mandible, hygiene and consequently, a high rate of dental plaque, caries, deep narrow palate leading to crowding of teeth, Angle’s and . Class II relationship, and lack of space which is caused by palatal position of upper laterals in relation to the centrals.[26] DKC Root deformity, abnormal pulp shape, and pulpal inclusions DKC is a group of rare inherited disorders characterized by are a frequent finding in patients with Marfans’ syndrome. pigmentation and atrophy of the skin, nail dystrophy, leukoplakia, Early diagnoses of both craniofacial and dental defects aid in bone marrow failure, and a predisposition to malignancy.[19] As satisfactory prognosis. per Walne et al.[19] in DC both the hard and the soft tissues in the oral cavity are affected. Oral mucosal changes manifest in the form EDS of a white keratotic patch. Earlier cases reported of vesicles and EDS are a heterogeneous group of disorders characterized ulcerations preceding the development of leukoplakia. Dental by abnormal formation of collagen or molecules related to caries, periodontitis and oral ulcerations, bleeding and atrophic collagen synthesis, abnormalities in the matrix glycoprotein , lichenoid lesions, and pigmentations are noted. Enamel tenascin, and probably fibronectin.[27] Oral mucosal fragility with ground section shows thin enamel, indistinct incremental lines delayed healing but without scar formation, early periodontal of Retzius, scanty enamel spindles, short enamel tufts, absence of disease, because of easily traumatized gingiva, subluxation of gnarled enamel, abundance of enamel lamellae and flat interface the , and 50% of patients will be able between enamel and dentine. , delayed eruption, to touch their nose with the tongue.[28] Dental abnormalities [20] and short blunted roots are observed clinically. include hypoplastic enamel and , high cusps with deep occlusal fissures, deformed roots with pulp stones, and multiple Cowden’s syndrome odontogenic .[29] Cowden’s syndrome multiple hamartomas of ectodermal, This review is a compilation of literature evidence from endodermal, and mesodermal origin are the characteristic standard articles obtained from PubMed, MEDLINE and other

Journal of Medicine, Radiology, Pathology & Surgery ● Vol. 4:3 ● May-Jun 2017 25 Kavya, et al. Oral genodermatoses databases on various aspects such as historic nomenclature, genetic disorders has become easier. At present, successful gene definitions, etiology, clinical features and focusing on genetic therapy is available for only a few disorders. The technology basis of these diseases. Apart from, the routine online data bases required to correct the defective gene formation is yet to be a specific web link - OMIM http://omim.org/was used to access developed fully. Further active research in this field will bring data on genetic disorders. This web link has been providing new hopes for effective management of these incurable disorders. immediate access to current information on human genes and genetic diseases for more than 25 years. References Observations made from this review are that: i. There exists no standard classification system to group all the 1. Gonçalves LM, Bezerra Júnior JR, Cruz MC. Clinical evaluation disorders under the title “Genodermatoses.” However, many of oral lesions associated with dermatologic diseases. An Bras authors have mentioned a few disorders suitable for the same Dermatol 2010;85:150-6. header 2. Gupta M, Jyoti B, Srivastava R, Pachauri A. in oral medicine. A review. J Indian Acad Oral Med Radiol ii. There exists fewer data on Indian epidemiology of 2014;26:62-8. genodermatoses. Data pertaining to malignant transformation 3. William J, Timothy B, Dirk E. Andrews’ Diseases of the Skin: occurring in some of the genodermatoses has to be updated Clinical Dermatology. 10th ed. Philadelphia, PA: Saunders iii. Abundant data are available in the literature on various Elsevier; 2005. aspects of genodermatoses such as prenatal diagnosis, 4. Irvine AD, Mellerio JE. Genetics and genodermatoses. In: molecular basis, and etiopathology which general population Burns T, Breathnach S, Cox N, Griffiths C, editors. Rook’s is not aware of Textbook of Dermatology. 8th ed. Oxford: Blackwell Science; iv. The primary reason for patients to seek medical help is due to 2010. p. 15.1-15.97. associated esthetic problems or functional compromise, but 5. Arora M, Mane D. A proposed classification to identify the oral not being aware of adverse effects, oral or systemic effects or manifestations of genodermatoses. J Coll Physicians Surg Pak 2016;26:636-7. on the familial/genetic pattern of disease. 6. Rajendran R, Shivapathasundaram B. Shafer’s Text Book of Oral The formation of standard registries for noting on various Pathology. 5th ed. Philadelphia, PA: Saunders; 1983. aspects of these genetic disorders is needed for formation and 7. Akiyama M, Shimizu H. An update on molecular aspects of the implementation of common guidelines/consensus for diagnosis non-syndromic ichthyoses. Exp Dermatol 2008;17:373-82. and management of these disorders is needed at the moment. 8. Hennies HC, Küster W, Mischke D, Reis A. Localization of a Genodermatoses are usually associated with high morbidity locus for the striated form of palmoplantar keratoderma to and poor quality of life because of the incurable nature of the 18q near the desmosomal gene cluster. disease. Some are associated with increased mortality. Lesions Hum Mol Genet 1995;4:1015-20. are noted primarily on the skin and secondarily involve the oral 9. Lozano ML, Rivera J, Sánchez-Guiu I, Vicente V. Towards the targeted management of Chediak-Higashi syndrome. Orphanet cavity. Dental management mainly aims at improving the overall J Rare Dis 2014;9:132. oral health. In general, dental treatments include topical steroids 10. Shekar V, Rangdhol V, Baliah WJ, Thirunavukarasu S. An for oral ulcers and , oral prophylaxis and oral hygiene unusual oral manifestation of Type 1 neurofibromatosis: A case instructions to maintain good oral hygiene, prophylactic pit report and review of literature. J Nat Sci Biol Med 2015;6:261-3. and fissure sealant application for those with high caries index, 11. Sparling JD, Hong CH, Brahim JS, Moss J, Darling TN. Oral antifungal therapy for , prosthetic rehabilitation, findings in 58 adults with tuberous sclerosis complex. J Am and orthodontic management for correction of malocclusion. Acad Dermatol 2007;56:786-90. 12. Madani M, Madani F. Gardner’s syndrome presenting with dental complaints. Arch Iran Med 2007;10:535-9. Conclusion 13. Heymann WR. Peutz-Jeghers syndrome. J Am Acad Dermatol 2007;57:513-4. The available research in genetics related to genodermatoses 14. Daley TD, Armstrong JE. Oral manifestations of gastrointestinal has been narrowed to the western population; very few reports diseases. Can J Gastroenterol 2007;21:241-4. have been published from Indian studies. There is now better 15. Weech AA. Hereditarty (congenital understanding of the genetic basis of genodermatoses with ectodermal defect). Am J Dis Child 1929;37:766-90. tremendous progress in their molecular diagnosis. Definitive 16. Visinoni AF, Lisboa-Costa T, Pagnan NA, Chautard-Freire- diagnosis of most of the genodermatoses is difficult in resource- Maia EA. Ectodermal dysplasias: Clinical and molecular review. poor countries such as India; hence, clinical acumen of the Am J Med Genet A 2009;149A:1980-2002. 17. Ghergie M, Cocîrla E, Lupan I, Kelemen BS, Popescu O. Genes physician with appropriate diagnostic algorithm for each group and dental disorders. Clujul Med 2013;86:196-9. of disorder is helpful means to reach a provisional diagnosis; 18. DiGiovanna JJ, Kraemer KH. Shining a light on xeroderma however, management is symptomatic in most of the cases. pigmentosum. J Invest Dermatol 2012;132:785-96. and prenatal diagnostic facilities bring a 19. Walne AJ, Vulliamy T, Marrone A, Beswick R, Kirwan M, ray of hope to affected families. With advancement in the fetal Masunari Y, et al. Genetic heterogeneity in autosomal recessive diagnostic technique, definitive prenatal diagnosis of several with one subtype due to in

26 Journal of Medicine, Radiology, Pathology & Surgery ● Vol. 4:3 ● May-Jun 2017 Oral genodermatoses Kavya, et al.

the -associated NOP10. Hum Mol Genet Genet C Semin Med Genet 2005;139C:4-9. 2007;16:1619-29. 26. De Coster PJ, Martens LC, De Paepe A. Oral manifestations of 20. Mochizuki Y, He J, Kulkarni S, Bessler M, Mason PJ. Mouse patients with Marfan syndrome: A case-control study. Oral Surg mutations affect accumulation of telomerase RNA and Oral Med Oral Pathol Oral Radiol Endod 2002;93:564-72. small nucleolar RNA, telomerase activity, and ribosomal RNA 27. Badauy CM, Gomes SS, Sant’Ana Filho M, Chies JA. Ehlers- processing. Proc Natl Acad Sci U S A 2004;101:10756-61. Danlos syndrome (EDS) Type IV: Review of the literature. Clin 21. Chaudhry SI, Shirlaw PJ, Morgan PR, Challacombe SJ. Cowden’s Oral Investig 2007;11:183-7. syndrome (multiple hamartoma and neoplasia syndrome): 28. Hagberg C, Berglund B, Korpe L, Andersson-Norinder J. Diagnostic dilemmas in three cases. Oral Dis 2000;6:248-52. Ehlers-danlos syndrome (EDS) focusing on oral symptoms: A 22. Hildenbrand C, Burgdorf WH, Lautenschlager S. Cowden questionnaire study. Orthod Craniofac Res 2004;7:178-85. syndrome-diagnostic skin signs. Dermatology 2001;202:362-6. 29. Klingberg G, Hagberg C, Norén JG, Nietzsche S. Aspects on 23. Canpolat M, Buyukayhan D, Gunes T, Akcakus M, Ozturk A, dental hard tissues in primary teeth from patients with Ehlers- Kurtoglu S. Apert syndrome: A case report. Erciyes Med J Danlos syndrome. Int J Paediatr Dent 2009;19:282-90. 2009;31:53-61. 24. Batra P, Duggal R, Parkash H. Dentofacial characteristics in Apert syndrome: A case report. J Indian Soc Pedod Prev Dent How to cite this article: Kavya L, Vandana S, Paulose S, 2002;20:118-23. Rangdhol V, Baliah WJ, Dhanraj T. Oral manifestation of 25. Dietz HC, Loeys B, Carta L, Ramirez F. Recent progress towards a molecular understanding of Marfan syndrome. Am J Med genodermatoses. J Med Radiol Pathol Surg 2017;4:22-27.

Journal of Medicine, Radiology, Pathology & Surgery ● Vol. 4:3 ● May-Jun 2017 27