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A CLINICAL STUDY ON GENODERMATOSES AND THEIR EFFECT ON

QUALITY OF LIFE – PROSPECTIVE OBSERVATIONAL STUDY IN A TERTIARY

CARE HOSPITAL

Dissertation Submitted to

THE TAMILNADU DR.M.G.R. MEDICAL UNIVERSITY

IN PARTIAL FULFILMENT FOR THE AWARD OF THE DEGREE OF

DOCTOR OF

IN

DERMATOLOGY, VENEREOLOGY &

Register No.: 201730253

BRANCH XX

MAY 2020

DEPARTMENT OF VENEREOLOGY & LEPROSY

TIRUNELVELI MEDICAL COLLEGE

TIRUNELVELI -11

BONAFIDE CERTIFICATE

This is to certify that the dissertation titled as “A CLINICAL STUDY ON

GENODERMATOSES AND THEIR EFFECT ON QUALITY OF LIFE –

PROSPECTIVE OBSERVATIONAL STUDY IN A TERTIARY CARE HOSPITAL”

submitted by Dr.P.KARTHIKRAJA to the Tamil Nadu Dr.M.G.R. Medical University,

Chennai,in partial fulfilment of the requirement for the award of the Degree of DOCTOR

OF MEDICINE in DERMATOLOGY, VENEREOLOGY AND LEPROSY during the academic period 2017 – 2020 is a bonafide research work carried out by him under direct supervision & guidance.

Dr.P.Nirmaladevi MD., Dr.S.M.Kannan MS , MCh.,

Professor and HOD The Dean

Department of Dermatology,Venereology &Leprosy Tirunelveli Medical College

Tirunelveli Medical College Tirunelveli

Tirunelveli

CERTIFICATE

This is to certify that the dissertation titled as “A CLINICAL STUDY ON

GENODERMATOSES AND THEIR EFFECT ON QUALITY OF LIFE –

PROSPECTIVE OBSERVATIONAL STUDY IN A TERTIARY CARE HOSPITAL”

submitted by Dr.P.KARTHIKRAJA is a original work done by him in the Department of

Dermatology,Venereology & Leprosy,Tirunelveli Medical College,Tirunelveli for the award of the Degree of DOCTOR OF MEDICINE in DERMATOLOGY, VENEREOLOGY

AND LEPROSY during the academic period 2017 – 2020.

Place: Tirunelveli GUIDE

Date: Professor and HOD

Department of Dermatology,Venereology &Leprosy

Tirunelveli Medical College

Tirunelveli

DECLARATION

I solemnly hereby declare that the dissertation entitled “A CLINICAL STUDY ON

GENODERMATOSES AND THEIR EFFECT ON QUALITY OF LIFE –

PROSPECTIVE OBSERVATIONAL STUDY IN A TERTIARY CARE HOSPITAL was done by me at the Department of Dermatology, Venereology & Leprosy, Tirunelveli

Medical College under the guidance and supervision of my Professor and HOD Dr.P.

Nirmaladevi MD.,. The dissertation is submitted to the Tamil Nadu Dr.M.G.R. Medical

University, Chennai,in partial fulfilment for the award of the Degree of DOCTOR OF

MEDICINE in DERMATOLOGY, VENEREOLOGY AND LEPROSY

This is my original work and the dissertation has not formed the basis for the award of any degree, diploma, associate ship, fellowship or similar other titles. It had not been submitted to any other university or Institution for the award of any degree or diploma.

Place: Tirunelveli Dr.P.KARTHIKRAJA Register No.: 201730253 Date: Post graduate in M.D DVL, Department of DVL, Tirunelveli Medical College, Tirunelveli-627011

ACKNOWLEDGEMENT Language with all elaborations seems to be having limitation especially when it

comes to expression of feelings. It is not possible to convey it in words all the emotions and

feelings one wants to say. It would take pages to acknowledge everyone who, in one way or

another has provided me with assistance, but certain individuals deserve citation for their

invaluable help.

I am grateful to the Dean, Dr.S.M.Kannan MS MCh., Tirunelveli Medical College

Hospital and Medical Superintendent of the Tirunelveli Medical College Hospital for

allowing me to do this dissertation and utilize the institutional facilities.

I fall short of words to express my deep sense of gratitude for my esteemed and reverend teacher and guide Dr.P.Nirmaladevi MD, Professor & Head of the Department of

Dermatology, Venereology and Leprosy , Tirunelveli Medical College, for her ever-inspiring guidance and personal supervision. The finest privilege in my professional career has been the opportunity to work under her inspirational guidance.

I would like to express my sincere and heartfelt thanks to Dr.M. Selvakumar M.D.,

Associate Professor,Dept of DVL, who has been a guiding light with his constant encouragement throughout my post-graduation course.

I sincerely thank Dr.P.Sivayadevi MD., and Dr.K,Punithavathi MD., Associate

Professors for their valuable suggestions and support throughout the period of this study.

I immensely thank (Late) Dr.R.Karthikeyan MD., Dr.A.N.M.Maalik Babu MD,

Dr.S.Judith Joy MD, Dr.P.Kalyanakumar DDVL,Dr.S.Seeniammal MD.,

Dr.M.Kalaiarasi DDVL, Dr.A.Kamala Nehru DDVL, my assistant Professors for their constant support and encouragement. I heartfully thank my seniors Dr.K.Amuthavalli and Dr.P.Sulochana, all my

colleagues Dr.M.Aravind Baskar, Dr.B.Arunkumar,Dr.M.G.Vijaikumar,

Dr.S.Soundharyaa Moorthi and Dr.R.Monisha and my juniors for their encouragement

and support during this study.

I heartfully thank my family, friends, seniors and junior colleagues for their

involvement for completing this study.

Last but definitely not the least, I would like to thank my patients who cooperated

with me throughout my work. Finally, it is endowment of spiritualism and remembrance of almighty for all that I achieved. I owe my sincere thanks to all those patients who participated in the study for their co-operation which made this study possible. Finally, I thank the

Almighty for without him nothing would have been possible.

I express my apologies and gratitude to those wittingly or unwittingly remained unsung during my research work.

Date :

Place :Tirunelveli Medical College Hospital Dr.P.Karthikraja

CERTIFICATE-II

This is to certify that this dissertation titled ““A CLINICAL STUDY ON

GENODERMATOSES AND THEIR EFFECT ON QUALITY OF LIFE –

PROSPECTIVE OBSERVATIONAL STUDY IN A TERTIARY CARE HOSPITAL” of the candidate Dr.P.KARTHIKRAJA with registration number 201730253 for the award of degree of M.D. in the branch of Dermatology, Venereology and Leprosy. I personally verified the urkund.com website for the purpose of plagiarism check. I found that the uploaded file contents from introduction to conclusion page shows 2 percentage of plagiarism in the dissertation.

Guide & Supervisor sign with seal

CONTENTS

SL.NO. TITLE PAGE NO.

1. INTRODUCTION 1

2. REVIEW OF LITERATURE 2

3. AIMS AND OBJECTIVES 53

4. MATERIALS AND METHODOLOGY 54

5. OBSERVATION AND RESULTS 56

6. DISCUSSION 83

7. SUMMARY 93

8. CONCLUSION 95

9. LIMITATIONS OF THE STUDY 97

10. BIBLIOGRAPHY

ANNEXURES

 PROFORMA  CLINICAL PHOTOGRAPHS  MASTER CHART  CONSENT FORM

LIST OF ABBREVIATIONS USED IV – VULGARIS

RXLI – RECESSIVE X LINKED ICHTHYOSIS

HI – HARLEQUIN ICHTHYOSIS

LI-

BIE – BULLOUS ICHTHYOSIFORM ERYTHRODERMA

EKV-ERYTHROKERATODERMA VARIABILIS

NS –

DPR- DERMATOPATHIA PIGMENTOSA RETICULARIS

DSH – DYSCHROMATOSIS SYMMETRICA HEREDITARIA

IP –

NF –

TSC – TUBEROUS SCLEROSIS COMPLEX

PCT –

PXE –

EDV- EPIDERMODYSPLASIA VERRUCIFROMIS

JEB – JUNCTIONAL

ACC –

CALM – CAFÉ – AU -LAIT MACULES

ESCN – EXTRANEURAL SPORADIC CUTANEOUS RAK – RETICULATE ACROPIGMENTATION OF KITAMURA

DUH- DYSCHROMATOSIS UNIVERSALIS HEREDITERIA

HED – HYPOHIDROTIC

CEP – CONGENITAL ERYTHROPOIETIC PORPHYRIA

EB – EPIDERMOLYSIS BULLOSA

DLQI -DERMATOLOGY LIFE QUALITY INDEX

MR – MITRAL REGURGITATION

ASD – ATRIAL SEPTAL DEFECT

CdLS – CORNELIA de LANGE SYNDROME

AD – AUTOSOMAL DOMINANT

AR – AUTOSOMAL RECESSIVE

XLR- X LINKED RECESSIVE

XLD – X LINKED DOMINANT

FASI – FOCAL AREAS OF SIGNAL HYPERINTENSITIES

PPK – PALMOPLANTAR

IQ – INTELLIGENCE QUOTIENT

INTRODUCTION

The genodermatoses consign to a large group of inherited disorders with a

conglomeration of cutaneous . Most of these disorders are rare.

However, the identification of their findings is important not only for starting

appropriate therapy but also for the identification of other associated abnormalities, including

malignancy, in these frequently multisystem disorders. The commonest group was ichthyosis,

followed by epidermolysis bullosa, neurocutaneous syndromes,ectodermal dysplasia, cutis

laxa, precancerous conditions, , Rothmund Thomson syndrome,

congenita. Prenatal diagnosis can be done for ichthyosis, infantile hyalinosis,

and progeria. 1

The rarity of the conditions and lack of awareness are the major obstacles in the

treatment and the planning of research in this group.The first step is therefore setting up a

disease specific national registries with phenotypic inputs for confirmation of accurate

diagnosis.The major strength of the study is that it is an example for multidisciplinary

approach to management for with involvement of dermatologist, neurologist,

general physician and physician.2

Many patients carry the risk of malignancy and premature death due to

,respiratory failure,.Management of these disorders are not limited to

the diagnosis of the patients,but also probing into the family tree to know the inheritance

pattern,providing options for prenatal diagnosis to the parents,and to

prevent further such occurrence are also necessary.

Studies on genodermatoses are mainly concentrated on individual diseases and there is lack of literature on study of genodermatoses as a whole including systemic assesment and only few studies have been done in India.Many disease diagnosis are missed due to lack of facilities and diagnostic accuracy

1

REVIEW OF LITERATURE

Genodermatoses are genetically determined inherited disorders showing both cutaneous and systemic involvement which either follow the established Mendelian modes of inheritance , or they occur due to lethal surviving by mosaicism, or they belong to the group of chromosomal disorders.The genodermatoses are studied based on the basic structural involvement like keratinocyte,,ectodermal derivatives like ,,teeth,sweat glands,collagen and . Classification of genodermatoses are as follows:3

I. INHERITED DISORDERS OF CORNIFICATION

1.Ichthyoses

2. Palmoplantar

II. INHERITED ACANTHOLYTIC AND BLISTERING DISORDERS

1.Hailey Hailey disease

2. Darier’s disease

3. Epidermolysis bullosa simplex

4. Junctional Epidermolysis bullosa

5. Dystrophic Epidermolysis bullosa

6. Kindler’s syndrome

III.ECTODERMAL DYSPLASIAS

1.Hypohidrotic ectoderma dysplasia

2.X linked Hypohidrotic ectodermal dysplasia with Immunodeficiency

3.Hidrotic ectodermal dysplasia(Clouston Syndrome)

4.Ankyloblepharon- ectodermal defect- Cleft / syndrome(AEC)

5.Ectrodactyly- ectodermal defect- Cleft lip/palate syndrome(EEC)

6.Tricho-dento-osseous syndrome

2

7.Trichorhinophalangeal syndrome

8.Hidrotic ectodermal dysplasia

9.(Goltz Syndrome)

10.MIDAS syndrome

11.Focal facial dermal dysplasia

IV.GENETIC DISORDERS OF PIGMENTATION

(i) HYPOPIGEMENTATION DISORDERS

1.

2.Oculocutaneous

3.

4.Hermansky–Pudlak syndrome

5.Chediak–Higashi syndrome

6.Griscelli–Prunieras syndrome types I and II

7.Oculocerebral syndrome with ()

8.Albinism–deafness syndrome (Ziprkowski–Margolis syndrome/Woolf

syndrome)

9.Hypomelanosis of Ito

(ii) HYPERPIGMENTION DISORDERS

1.Familial progressive / progressive hyperpigmentation and generalized without associated systemic symptoms/familial progressive hyper and hypopigmentation

2.Incontinentia pigmenti

3.Linear and whorled naevoid hypermelanosis

4.

3

5.Naegeli–Franceschetti–Jadassohn syndrome and Dermatopathia pigmentosa reticularis

6.Dowling–Degos disease

7.Reticulate acropigmentation of Kitamura

8.Peutz–Jeghers–Touraine syndrome

(iii)DYSCHROMATOSES

1.Dyschromatosis symmetrica hereditaria

2.Dyschromatosis universalis hereditaria

V.INHERITED HAIR DISORDERS

1.Generalised and Localized disorders

2.Atrichias

3.Non syndromic and syndromic hypotrichosis disorders

4. Hair shaft abnormalities - , , Wolly hair, , , ,Pili triangulati et canaliculi,

Pili annulati and pseudoannulati, , Kinky hair, Spiky hair.

VI.GENETIC DEFECTS OF NAILS AND NAIL GROWTH

1.

2. Dyskeratosis Congenita

3.Nail patella

4. Hereditary

VII.GENETIC DISORDERS OF COLLAGEN ,ELASTIN, DERMAL

MATRIX

(i)INHERITED DISORDERS OF COLLAGEN

1.Ehlers–Danlos syndrome

2.Prolidase deficiency

4

3.Osteogenesis imperfecta

(ii)INHERITED DISORDERS OF ELASTIC FIBRES

I.Elastinopathies

1.Inherited generalized

2.Williams–Beuren syndrome

3.Michelin tyre baby

II.Fibrillinopathy

1.

(iii)INFANTILE STIFF SKIN SYNDROMES

1.Hyaline fibromatosis syndrome

2.Stiff skin syndrome

3.Winchester syndrome

4.

(iv)PREMATURE AGEING SYNDROMES

1.Progeria

2.

3.Acrogeria

4.Familial

5.Mulvihill–Smith syndrome

6.Neonatal progeroid syndrome

(v)DISORDERS OF ECTOPIC CALCIFICATION AND ABNORMAL

MINERALIZATION

1.Pseudoxanthoma elasticum

2.Fibrodysplasia ossificans progressiva

3.Primary hypertrophic osteoarthropathy

5

(vi)MISCELLANEOUS DERMAL DISORDERS

1.Adermatoglyphia

2.Lipoid proteinosis

3.Pterygium syndromes

VIII. INHERITED METABOLIC DISORDERS

(i)LYSOSOMAL STORAGE DISORDERS

1. Mucopolysaccharidoses

2. Glycoprotein degradation disorders

3. Individual glycoprotein degradation disorders

4. Mucolipidoses types II and III

5. Sphingolipidoses

6. Fabry disease

(ii)MITOCHONDRIAL RESPIRATORY CHAIN DISORDERS

1. Dermatological features of mitochondrial disorders

2. Multiple symmetrical lipomatosis

3. Acrocyanosis

4.

(iii)CONGENITAL DISORDERS OF GLYCOSYLATION

1. Phosphomannomutase 2 deficiency

(iv)DISORDERS OF AMINO ACID METABOLISM AND TRANSPORT

1. Phenylketonuria

2. Tyrosinaemia type 2

3. Alkaptonuria

4. Prolidase deficiency

5. Argininosuccinic aciduria

6

6. Hartnup disease

(v)DISORDERS OF CHOLESTEROL SYNTHESIS

1. SmithLemliOpitz syndrome

2. Mevalonate deficiency

(vi)OTHER METABOLIC DISORDERS

1. Lesch–Nyhan syndrome

2. Disorders of biotin metabolism

3. Acrodermatitis enteropathica

4. and

5. Wilson disease

6. Familial tumoral calcinosis

IX. PORPHYRIAS

(i)PORPHYRIAS WITH CUTANEOUS DISEASE AND NO ACUTE ATTACKS

1. Congenital erythropoietic porphyria

2. Porphyria cutanea tarda

3. Erythropoietic protoporphyria

(ii)PORPHYRIAS WITH CUTANEOUS DISEASE AND ACUTE ATTACKS

1. Hereditary coproporphyria

2. Variegate porphyria

(iii)MISCELLANEOUS

1. Pseudoporphyria

X. CONGENITAL NAEVI AND OTHER DEVELOPMENTAL

ABNORMALITIES

(i)CONGENITAL NAEVI

1. Congenital epidermal naevi

7

2. Congenital pigment cell naevi

3. Congenital melanocytic naevi

4. Congenital Spitz naevus,congenital blue naevus and congenital naevus spilus

5. Congenital naevi and naevi

6. ‘Naevoid’ entities and currently unclassifiable naevi like Gorlin syndrome

(ii)OTHER DEVELOPMENTAL ABNORMALITIES AFFECTING THESKIN

1.Aplasia cutis congenita

2.Congenital muscle

3.Heterotrimeric G mosaic disorders

(a)McCune–Albright syndrome

(b)Sturge–Weber syndrome

(c) pigmentovascularis

XI. HAMARTONEOPLASTIC SYNDROMES

1. Neurofibromatosis

2. Tuberous sclerosis complex

3. Gardner syndrome

4.

XII. SYNDROMES WITH PREMATURE AGEING

1. Werner syndrome

2.

3. Progeroid and related conditions

4. Hutchinson–Gilford progeria syndrome

5. Mandibuloacral dysplasia with type A and type B lipodystrophy

6. Cutis laxa: autosomal dominant and autosomal recessive

8

XIII.DNA REPAIR DISORDERS WITH CUTANEOUS FEATURES

1. Xeroderma pigmentosum

2.

3. Trichothiodystrophy

4. Ataxia (Louis Bar syndrome

5. Fanconi anaemia

6. Muir–Torre syndrome

XIV. SYNDROMES

1. Dyskeratosis congenita

2. Rothmund–Thomson syndrome

3. Poikiloderma with neutropenia, Clericuzio type

4. Hereditary fibrosing poikiloderma with contractures, myopathy and

pulmonary fibrosis

5. Acrokeratotic poikiloderma of Weary

XV.DISORDERS AFFECTING CUTANEOUS VASCULATURE

(i)CAPILLARY DISORDERS

1. Capillary malformation

2. Sturge–Weber syndrome

3. Capillary malformation–arteriovenousmalformation

4. serpiginosum

5. Cerebral cavernous malformation

6. Capillary malformation in localized overgrowth syndromes

7. Microcephaly–capillary malformation syndrome

(ii)ARTERIOVENOUS DISORDERS

1. Arteriovenous malformation

9

2. Hereditary haemorrhagic telangiectasia

3. PTEN hamartoma tumour syndrome

(iii)VENOUS DISORDERS

1. Venous malformation

2. Mucocutaneous venous malformation

3. Blue rubber bleb naevus syndrome

4. Glomuvenous malformation

5. Maffucci syndrome

(iv)LYMPHATIC DISORDERS

1. Schimmelpenning–Feuerstein–Mims syndrome

2. Hereditary lymphoedema type IA

3. Lymphoedema–distichiasis syndrome

4. Hypotrichosis–lymphoedema–telangiectasia syndrome

5. Hennekam lymphangiectasia–lymphoedema syndrome

6. Microcephaly with or without chorioretinopathy, lymphoedema or mental

retardation

7. Choanal atresia and lymphoedema

8. Primary lymphoedema with myelodysplasia

XVI.GENETIC DISORDERS OF ADIPOSE TISSUE

1.Congenital (familial) lipodystrophies

(i)Congenital generalized lipodystrophies

(ii)Familial partial lipodystrophies

2.Hereditary obesity

3.CLOVES syndrome

4.Hereditary panniculitis

10

5.Familial lipoedema

XVII. CHROMOSOMAL DISORDERS

(i)AUTOSOMAL CHROMOSOME DEFECTS

1. Down syndrome (trisomy 21)

2. Trisomy 18 (Edwards syndrome)

3. Trisomy 13

(ii)SEX CHROMOSOME DEFECTS

1.Turner syndrome

2.Klinefelter syndrome

XVIII. INHERITED IMMUNODEFICIENCIES

1. Combined immunodefi ciencies

2. Combined immunodefi ciencies with associated or syndromic features

3. defi ciencies

4. Diseases with immune dysregulation

5. Congenital defects of phagocyte function,differentiation and adhesion

6. Defects in innate immunity

7. Complement diseases

11

I.INHERITED DISORDERS OF CORNIFICATION

CONGENITAL ICHTHYOSIS

SYNONYMS

Fish skin disease, Alligator skin disease, Sauriasis, Congenital

HISTORY

The term ichthyosis (4) derives from the Greek root ‘ichthys’ for fish.

CLASSIFICATION

Revised nomenclature and classification of inherited ichthyoses: Results of the First Ichthyosis Consensus Conference in Sorèze 2009.

NON SYNDROMIC FORMS :

Common ichthyoses

Ichthyosis vulgaris (IV)

Nonsyndromic recessive Xlinked ichthyosis (RXLI)

Autosomal recessive congenital ichthyosis (ARCI)

Harlequin ichthyosis (HI)

Lamellar ichthyosis (LI)

Congenital ichthyosiform erythroderma (CIE)

Selfhealing collodion baby(SHCB)

Acral selfhealing collodion baby

Bathing suit ichthyosis (BSI)

Keratinopathic ichthyosis (KPI)

Epidermolytic ichthyosis (EI)

Superficial epidermolytic ichthyosis (SEI)

Congenital reticular ichthyosiform erythroderma (CRIE)

Annular epidermolytic ichthyosis (AEI)

12

Ichthyosis Curth–Macklin (ICM)

Autosomal recessive epidermolytic ichthyosis (AREI)

Epidermolytic naevi

Other nonsyndromic forms

Loricrin keratoderma (LK)

Erythrokeratodermia variabilis(EKV)

Inflammatory peeling skin disease (PSS type B)

Exfoliative ichthyosis

Keratosis linearis–ichthyosis congenita–keratoderma (KLICK)

SYNDROMIC FORMS:

Xlinked ichthyosis syndromes

Recessive Xlinked ichthyosis (RXLI)

Ichthyosis follicularis alopecia photophobia (IFAP)

Conradi–Hünermann–Happle syndrome (CDPX2)

Autosomal ichthyosis syndromes with prominent hair abnormalities

Netherton syndrome (NS

Severe –multiple –metabolic wasting (SAM)

Ichthyosis with hypotrichosis

Neonatal ichthyosis–sclerosing cholangitis (NISCH)

Autosomal ichthyosis syndromes with prominent neurological signs

Refsum syndrome (HMSN4)

Multiple sulphatase deficiency (MSD)

Gaucher syndrome type 2

Sjögren–Larsson syndrome (SLS)

Neutral lipid storage disease (NLSD) with ichthyosis

13

Trichothiodystrophy (TTD)

Cerebral dysgenesis–neuropathy–ichthyosis–palmoplantar keratoderma

(CEDNIK)

Arthrogryposis–renal dysfunction–cholestasis (ARC)

Autosomal ichthyosis syndromes with deafness

Keratitis–ichthyosis–deafness (KID)

ELOVL4 deficiency

Mental retardation–enteropathy–deafness–neuropathy–ichthyosis

keratodermia (MEDNIK)

Autosomal ichthyosis syndromes with transient neonatal respiratory distress

Ichthyosis–prematurity syndrome (IPS)

PATHOGENESIS:

The primary function of the corneocyte layer is to provide a barrier to water loss, without which normal life is not possible. Defective barrier activity leads to increased transepidermal water loss, a characteristic feature of ichthyosis.

The is a double compartment system similar to a brick wall, in which the corneocytes (“bricks”) provide the structural building blocks, around which a lipid enriched (the “mortar”) is deposited, to provide the permeability barrier

to systemic water loss. These lipids, mostly the neutral lipids, cholesterol sulphate, free fatty acids , polar lipids and ceramides, form repeating units of electron lucent and electron-dense membranes, termed lamellar unit structures, when seen with ruthenium tetroxide . Lamellar bodies contain glycosyl ceramides, phospholipids , cholesterol sulphate and certain hydrolytic enzymes4. Upon secretion, some of these enzymes process glycosylceramides and

phospholipids to ceramides and free fatty acids respectively. Conversion of cholesterol

14

sulphate to cholesterol by cholesterol sulphatase present on the surface, leads

to breakdown of the intercellular lipid lamellae and resultant .

Disordered keratinization also results from alterations in structural like

cornified cell envelope and enclosed aggregated filaments, which are the major

components of the stratum corneum. Envelope precursors such as involucrin, loricrin, small

proline- rich proteins and envoplakin, are synthesized late in stratification and cross- linked by the action of transglutaminase enzymes, which are synthesized in the stratum granulosum.

They are aggregated by interaction with (filament aggregating protein), a basic histidine rich protein, stored as profilaggrin in keratohyaline granules.

In the hyperproliferative ichthyoses, epidermal homeostasis is disturbed, the process of desquamation is abnormal as well.

NON SYNDROMIC FORMS

ICHTHYOSIS VULGARIS

Most common inherited ichthyoses, with a reported incidence of 1 in 100 5. It is an autosomal semidominant disorder with variable phenotypic expression and , so severity can vary between generations and affected siblings.

Pathogenesis

Absence or decrease of filaggrin and its precursor, profilaggrin is seen in the from patients with ichthyosis vulgaris in biomedical studies6 . Expression of

mRNA is reduced7.There may be selectively impaired post transcriptional control of

profilaggrin synthesis or the profilaggrin may be influenced by other mutated genes8.

Scale formation is resulting from loss of water retaining aminoacids derived from filaggrin

catabolism. The hyperkeratosis is regarded as a retention resulting from increased adhesiveness of stratum corneum.

15

Pathology

In the epidermis, there is moderate degree of orthohyperkeratosis with a thin or

absent granular layer. Ultrastructure reveals scarce and crumbly keratohyaline granules.

Hyperkeratosis often extends in to the hair follicles, resulting in large keratotic follicular plugs.

Clinical features

Scaling is obvious from first months of age or may be further delayed. Clinical

symptoms and severity depend on season and climate, improving during the summer with

increasing humidity and worsening in a dry, cold environment.

Wells and Kerr found demonstrable scaling in 40% of their patients at the age of 3 months9. Scaling is most pronounced on the extensor surfaces of the arms and lower legs.

The groin and flexural areas are spared because of increased humidity in those regions. Face

is usually spared, if involved localizes to forehead ,cheeks and perioral region .Scales are

light grey, small, flaky or branny and semi adherent with turned up edges giving a “pasted- on” appearance. Palms and soles show accentuated skin markings – hyper linearity, due to mild hyperkeratosis.

Associations10

Keratosis follicularis,Atopic triad of , hay fever and , Allergic

rhinitis, Ocular manifestations and testicular cancer have been reported.

AUTOSOMAL RECESSIVE CONGENITAL ICHTHYOSIS

Synonyms

Ichthyosis congenita

It is an umbrella term that includes all nonsyndromic autosomal recessive congenital

forms of ichthyosis without a tendency towards blistering [1]. Thus the spectrum includes

harlequin ichthyosis (HI), bathing suit ichthyosis (BSI), lamellar ichthyosis (LI), congenital

16

ichthyosiform erythroderma (CIE), selfimproving congenital ichthyosis (SICI) as well as transient manifestations, such as collodion baby.

HARLEQUIN ICHTHYOSIS

Synonym

Ichthyosis congenita gravior

The term is derived from the variegated textile pattern used to clothe medieval jesters.

Very , inherited in a autosomal recessive manner11 but sporadic cases were

reported due to new dominant mutation12.It is lethal in around 44% cases.13

Pathogenesis

It is due to peculiar nonsense and /or frameshift mutations in the ABCA12 gene 14

which usually results in mRNA decay and loss of expression of the protein .

ABCA12 transfer lipids such as glucosylceramides, which are needed for epidermal

barrier formation into lamellar bodies. It plays a vital role in the formation of lamellar bodies

that also transport proteases such as kallikrein 5, 7 and 14 and secrete these proteins into the

intercellular spaces in the stratum corneum .These play an important role in desquamation by

degrading corneodesmosomes , thus leading to retention hyperkeratosis.

Clinical features

Babies are usually born prematurely, sometimes as stillborn with armour like skin.

Body is encased in a rigid , taut, hard, armour like, yellow brown adherent membrane.

Shortly after birth broad, deep and intensively red fissures form in a geometric pattern. Head

appears microcephalic, with severe , conjunctival oedema, , rudimentary

ear andnose, giving a grotesque appearance. Hands and feet are edematous,swollen and

covered by mitten like casing with well developed digits. Around 10% of children develop

autoamputation of digits. RespiratVitamin Ddeficiency causing rickets and osteomalacia can

occur.13

17

Pathology

Extraordinary thickened stratum corneum with parakeratosis and and

non polar lipids are reduced ,while expression of proteases like kallikrein 5 and cathepsin D

are dramatically reduced14.Electron microscopy show abnormal lamellar bodies in the

granular layer, absent extracellular lipid lamellae and presence of lipid inclusion or remnant

organelles in the stratum corneum.15

LAMELLAR ICHTHYOSIS AND CONGENITAL ICHTHYOSIFORM

ERYTHRODERMA(CIE)

Classical lamellar ichthyosis is inherited as an autosomal recessive disorder. The term

‘lamellar ichthyosis’ was coined by the American dermatologist Frost.16It is characterized by

large platelike dark brown hyperkeratosis covering the entire body with mild palmoplantar

involvement.

Prevelance

Deficiency of TG1 as the most frequent cause of ARCI is responsible for 32% - 55

% of ARCI cases.17

Pathogenesis

It is due to deleterious of the transglutaminase gene on chromosome 14q11,

leading to transglutaminase-1 deficiency18, which catalyzes the calcium dependent cross

linking of proteins of cornified envelope, through γ glutamyl – lysine isopeptide bonds. It also

occurs due to malfunction of the following proteins.Lipoxygenases E3 and 12B,19

NIPAL4 gene encodes ichthyin (41),CYP4F2 encodes polypeptide 20

CERS3 gene encodes ceramide synthase 3,LIPN encodes an acid lipase and PNPLA1 belongs to the patatin like phospholipase family

18

Pathology

Lamellar ichthyosis is a retention type ichthyosis .There is massive orthokeratotic

hyperkeratosis , acanthosis and mild . Granular layer is normal or increased.

Electron microscopy shows elongated cholesterol clefts ,translucent lipid droplets in stratum corneum with a thin or absent cornified cell envelope.

Clinical features

At birth the disease presents as collodion baby, followed by scaling within the first

month of life. Erythroderma is usually less intense .Severe ectropion leads to exposure

keratitis. Deep fissures in flexures cause limitation of joint movement, flexion contracture

and sclerodactyly. Other features are palmoplantar keratoderma, secondary nail dystrophy,

severe heat intolerance due to epidermal constriction of sweat ducts and recurrent ear

due to accumulation of scale in the external ear canal. 21

KERATINOPATHIC ICHTHYOSIS (KPI)

Keratinopathic ichthyoses (KPI) are a group of very severe rare cornification

disorders which often present at birth with erythroderma, scales and erosions having a

prevelance of 1:350000.22 The term ‘keratinopathic’ was coined at the Soreze Consensus

Conference as an umbrella term for all types of ichthyoses which are caused by mutations in

one of the keratin .

Pathophysiology

Mutations in keratin genes like KRT1, KRT10 or KRT2 are usually associated with

epidermolytic hyperkeratosis (EHK) on histology and with the occurrence of cytoplasmic

keratin aggregates (keratin clumps) or perinuclear shell formation.23

It is induced by trauma or environmental conditions, e.g. high temperature, fever or

skin infections. Keratin aggregates have been shown to interact with activated MAP ,

molecular chaperones such as Hsp70 and components of the ubiquitin proteasome system and

may contribute to inflammatory changes seen in the disease.24

19

KPI have been considered as autosomal dominant disorders, recessive and semidominant inheritance of KRT10 and KRT1 mutations have been reported, respectively25.

Epidermolytic epidermal naevus results from somatic mutations in KRT1 or KRT10.

Epidermolytic Superficial Ichthyosis Congenital reticular Ichthyosis(EI) Epidermolytic Curth-Macklin Ichthyosiform Ichthyosis(SEI) (ICM) erythroderma(CRIE) Mode of AD AD AD AD inheritance (Rarely AR in KRT 10) Gene KRT 1 or 10 KRT 2 KRT 1 KRT 10 Onset At birth At birth Early At birth childhood Initial Large erosions, Erythroderma Striate or Exfoliative CIE presentation Erythroderma Diffuse PPK Disease Erosions Hyperkeratosis Hyperkeratotic Patchy pattern Course Hyperkeratosis Extensor sides plaques on Annular of joints trunk and polycyclic extremities erythematous scales Distribution Generalized Friction areas Palms and Generalized of scaling Friction areas soles Reticular Joints Large joints Ichthyosiform pattern Scaling type Adherent Adherent Thick spiky Fine Moderate Moderate hyperkeratosis Palmoplantar KRT 10 No Massive PPK, Yes Involvement Palams and Deep bleeding, soles spared painful fissures Extacutaneous Growth failure - Gangrene and Growth failure with involvement with some loss of digits some severe severe phenotypes phenotypes Skin EHK, Superficial Binuclear cells, of ultrastructure aggregations EHK, cytolysis particular superficial granular and clumping in concentric cells and of keratin granular cells perinuclear filamentous material filaments in of affected ‘shells’ of in suprabasal body areas; no aberrant – vacuolated cells cells; partly keratin putatively – cytolysis, clumping keratin lamellar body material accumulation

20

ERYTHROKERATODERMA

ERYTHROKERATODERMA VARIABILIS

It is a rare disease characterized by migrating polycyclic erythematous lesions with

hyperkeratosis.

Pathophysiology

Inheritance of EKV is usually autosomal dominant. But some dominant negative

mutations in GJB3 encoding 31 or GJB4 encoding connexin 30.3 have been found

(47). form gap junctions, which are aqueous intercellular channels that are found

in all tissues of the human body, including the skin, nervous tissue, and muscle .26

Clinical features

Onset is usually in infancy. The manifestations vary within a family and within the

individual. There are two types of lesions: relatively fixed well demarcated keratotic and

bizarrely shaped erythematous plaques involving extensor surfaces, lateral trunk and buttocks

and transient erythematous, polycyclic or comma shaped macular lesions occurring at any site.

SYNDROMIC ICHTHYOSIS

COMÈL–NETHERTON SYNDROME(CNS)

A rare autosomal recessive disorder that is characterized by the concurrence of

ichthyosis with polycyclic migrating plaques known as ichthyosis linearis circumflexa (ILC),

characteristic hair shaft abnormality and atopy27. CNS may account for up to 18% of all cases

of infantile erythroderma with a prevalence of 1/50 000 –200 000.28

Pathogenesis

It is due to mutation in the SPINK5 gene ( inhibitor Kazal type 5)

which encodes LEKT1 (lympho epithelial Kazal type related inhibitor)29 expressed in

epidermis ,thymus ,oral and vaginal mucosa which is important in the down regulation of

21

inflammatory pathways. Loss of LEKT1 leads to premature and uncontrolled proteolytic

activity of serine proteases which results in abnormalities of structure of lamellar lipid membrane.30

In the hair, failure to convert sulphydryl groups to disulphide bonds leads to weak

coherence of cortical cells. Such focal softening of hair shaft may allow invagination of distal

shaft in to the dilated proximal cup.

Pathology

Erythroderma –shows hyperkeratosis, parakeratosis, , acanthosis,

intraepidermal microabscesses andsubcorneal split .

Microscopy of Hair – taken from scalp / eyebrow31 shows trichorrhexis Invaginata

(bamboo hair) in 20 – 50% cases. It consists of a bulbous distal hair end invaginating a

concave dilated proximal hair terminal giving a ball and socket appearance . Nodular

thickening of the distal end of broken hair shafts (‘golf tee’)32, pilitorti, trichorrhexis nodosa

and helical hair may also be seen.

Clinical features

At birth generalized erythroderma is present and scaling quickly develops along with neonatal failure to thrive and early development of with high levels of IgE and hypereosinophilia.During child hood, 50% develop ichthyosis linearis circumflexa (ILC). It is an erythematous, scaly, annular or polycyclic, flat patch with an incomplete advancing double edge of peeling scale.

Atopy – Atopic diathesis is seen in 50% of patients and manifests as atopic dermatitis or asthma. Eosinophilia and allergic reactions to various foods are common. Serum IgE levels are markedly elevated ranging from 100 to 10,000 Iu/ml33.

22

Hair – scalp, eyebrow, eyelash, body hair remain sparse, lustreless and brittle. Hair is

unruly, short and spiky. Broken hair shafts at follicular orifice produces a peppered

appearance.

TREATMENT

Inherited ichthyoses require lifelong management based on the establishment of the correct molecular diagnosis. Collodion babies should be placed in a high humidity incubator

with close monitoring of body temperature. To start with humidity in the range of 60–80%,

and to decrease every 3–4 days in order to reach normal humidity.

Regular, paraffin based emollient application is of benefit to all patients.Other agents

are Urea 5–10%,Lactic acid 5%,Sodium chloride 3–10 %,Dexpanthenol 5–10 %,

Macrogol 400 20–30% ,Propylene glycol 15–20% ,Glycerol 10–15%,Vitamin E acetate 5%

Tretinoin 0.025–0.05 % and Calcipotriol 0.05 × 10-3%.

Systemic retinoids are effective in most of the patients with severe congenital

ichthyosis except in Netherton’s syndrome, where deterioration with systemic retinoid is

noted.

OTHER ASPECTS OF TREATMENT:

Surgical correction of severe ectropion , Cleaning of horny material from external

auditory canal, physiotherapy to treat flexural contractions, Vitamin D supplementation and treatment of superinfections with antibiotics.

II.HAMARTONEOPLASTIC SYNDROMES

These conditions have diverse clinical and genetic features and need detailed

condition specific knowledge along with specific treatment guidelines . They are united by

the common features of extensive and diverse skin manifestations along with somatic

and have a significant risk of cutaneous and noncutaneous tumours.

1. Neurofibromatosis

23

2. Tuberous sclerosis complex

3. Gardner syndrome

4. Cowden syndrome

NEUROFIBROMATOSIS

The neurofibromatosis comprise multiple distinct genetic disorders that lead to the

formation of tumours surrounding nerves and many pathological features. The main two

forms are:

1. Type -1 neurofibromatosis ( 85%)

2. Type-2 neurofibromatosis ( 10%)

NEUROFIBROMATOSIS - 1

Definition

NF -1 is an inherited neuroectodermal disorder, characterised by the presence of

multiple cafe-au-lait macules, axillary and palmar , multiple neurofibromas and

Lisch nodules.NF -2 is characterised by acoustic neuromas ,mostly bilateral, menigiomas

and other tumors of CNS.

Etiology

The mode of inheritance is autosomal dominant with 100% penetrance by the age of 5

years. Sporadic cases result from a high gene mutation rate. The prevalance is 1:2500 – 3500.

The gene for NF1 is located on chromosome 17. NF-1 encodes a protein named

neurofibromin, which is expressed predominantly in neurons, schwann cells,

oligodendrocytes, keratinocytes, and leucocytes. Neurofibromin shows

significant similarity to the GTP ase – activating protein - and is capable of downregulating

Ras activity. Most of the NF-1 germline mutations alter the reading frame or insert a premature stop codon.

24

CLINICAL FEATURES

According to the National Institute of Health Consensus Development Conference

Statement developed in 1988,Diagnosis of Neurofibromatosis need to fulfil 2 or more of

the following criteria.34

1. Six or more cafe-au-lait macules > 5mm in greatest diameter in prepubertal and > 15mm in

post pubertal age group.

2. Two or more neurofibromas of any type or one plexiform NF.

3. Freckling in the axillary or inguinal regions.

4. Optic

5. Two or more Lisch nodules

6. A distinctive osseous lesion such as sphenoid dysplasia or thinning of long bone cortex

with or without pseudoarthrosis

7. A first degree relative(parent ,sibling, offspring) with NF-1 by the above criteria

CUTANEOUS FEATURES

Café-au-lait Macules (CALM)

It is the earliest lesion to appear in all children usually found all over the body except scalp, eyebrows, palms and soles characterized by sharply defined light brown macules and patches with smooth borders vary in size from 0.5 to 50 cm.

Cutaneous Neurofibromas

1. Cutaneous or mollusca fibrosa: are soft, lilac - pink, sessile or pedunculated tumours ,dome shaped, mostly on the trunk and limbs, on gentle digital pressure, the lesions herniate into the called ‘button hole ’sign. Blue red macules and pseudo atrophic macules can appear.

25

2. Plexiform neurofibromatosis : for NF-1 . Diffuse elongated

along the course of a nerve, frequently involving the trigeminal or upper cervical

nerves, usually seen within first 2 years of life and have a feel like a “bag of worms.”

3. Elephantiasis neurofibromatosa is associated with over growth of the

subcutaneous tissue and of the skin producing gross disfigurement. Dark pigmented patches

over plexiform neurofibroma may be seen. If the tumour extends to the midline, it indicate

that the tumour may involves the spinal cord. Plexiform neurofibromas may be a precursor lesion for malignant peripheral nerve sheath tumour .

3. Freckling

Freckles are small, tan brown macules that are 1–3mm in diameter. Crowe’s sign35

indicates axillary freckling which is virtually pathognomonic and it is also seen in groin and

palms(79) .

Other Diagnostic Cutaneous Features

Three types of hypopigmentation can occur . They are ash leaf macules, small

punctate macules and local areas of hypoplasia that can appear blue red ( Pseudo atrophic

macules ). The typical order in which clinical features appear are 1) Cafe-au-lait macules 2)

Axillary freckling, 3) Lisch nodules, 4) Neurofibromas ( according to NIH, National Institute

of Health Criteria).

NON CUTANEOUS FEATURES

I. Ocular

Lisch nodules - Pigmented melanocytic iris hamartomas are dome shaped, translucent

brown spots, bilateral ,asymptomatic and most common manifestation of NF-136, occurs in

more than 90% of patients and does not occur in bilateral acoustic or segmental type of NF.

26

II. Neurological Manifestations

Occurs in 40% of cases. Most common is optic glioma . Optic glioma - is an

astrocytic tumour of the optic nerve occurs in 15% of patients with NF1, 80% are

asymptomatic. The common features are , cerebrovascular accident, headache,

intellectual, behavioural and emotional disturbances. The other common intracranial tumours

reported are and schwannomas.

III. Skeletal Manifestations

Sphenoid wing dysplasia often results in pulsating exophthalmos,Kyphoscoliosis

(2%)37,Congenital pseudo arthrosis (common in tibia or radius ) (1%),Vertebral scalloping

Macrocephaly ,Short stature and Thinning of cortex resulting in pathological fractures.

IV. Oral Lesions

Occurs in 5 – 10% of cases as unilateral , papillomatous tumours of buccal mucous membranes, palate, tongue and .

V. Endocrine abnormalities38

They are precocious puberty, acromegaly, hyperparathyroidism, Addison’s disease,

gynaecomastia and phaeochromocytoma.

VI. Renal39

The common renal manifestation are renovascular hypertension 40due to renal

stenosis , coarctation of aorta and phaeochromocytoma,. Renal tubular defect may results in

osteomalacia .

VII. Pulmonary Changes ( 10-20%)

1. Fibrosing alveolitis, 2. Interstitial fibrosis 3.Pulmonary hypertension

27

VIII. Gastro Intestinal ( 25%)41

Constipation may be due to dysfunction of colonic musculature or colonic

NF,Intussuception ( occurs in and jejunum) , Recurrent obstruction and

Haemorrhage.

IX. Malignancies Associated with NF-1(3-5%)42

They are neurofibrosarcoma (1.5-15%), retinoblastoma, malignant , rhabdomyosarcoma, Wilms tumour, several types of leukemia, malignant schwannoma with melanocytic differentiation.

RICCARDI’S Classification System of Neurofibromatosis43

NF Inheritance Main Clinical – Features NF1 Autosomal Cafe-au-lait spots (CLS), axillary or inguinal freckles, NF, dominant Gene Lischnodules, opticglioma, bony changes. 17q 11.2 (AD) NF2 AD, Gene Bilateral vestibular (acoustic) schwannoma,multiple CNS 22q12.2 Tumours – meningiomas,ependymomas, spinal astrocytomas, cataracts,retinal hamatoma. NF3 AD (or) Sporadic Features of NF1 and NF2 including some CLS,freckling, NF, CNS or paraspinal tumours, no vestibular shawannoma or lisch nodules NF4 Sporadic Atypical NF. Mostly occur as a variant of type II NF5 Sporadic or Segmental NF44- NF-1 that is localized to one A.D somatic quadrant /one side of the body – arises from mutation of post zygotic somatic mutation and is not NF1 with or heritable. It can occur as bilateral segmental NF without germ with or without CLS cell mutation NF6 AD Multiple CLS, without neuro fibroma. It must occur in two generation to be diagnosed. NF7 Sporadic Adult onset cutaneous NF with onset at end of 3rd decade or later. Lisch nodules are absent. NF also appears after immunosuppresion.45 NF8 Case which are definitely NF but do not fit into any of the other categories.

28

Histopathology

Histological Types

1. Extra neural sporadic cutaneous neurofibromas ( ESCN )

They are eosinophilic, circumscribed, non encapsulated showing thin spindle cells

with elongated, wavy nuclei which are regularly spaced among wavy collagenous strands. It can be homogenous ( closely packed ) or loosely spaced in a clear matrix. There are large number of nerve fibres and mast cells .

2. Extraneural deep diffuse variant

The matrix is ibrous and faintly acidophilic . Nerves within the lesion usually are small, internally symmetrical , hypercellular and the perineuria are hyperplastic.

3. Deep circumscribed (intra neural) variant and plexiform variant

The axial bundles of symmetrically arranged nerve fibres, are remnants of the axial bundle of the nerve of origin. The schwann cells are hyperplastic and tightly placed. Special stains used are Bodian stain and Silver stain. Immuno histochemical (IHC) markers that are used are S-100 protein (+) and CD57 antigen (leu-7), basic protein (MBP)

TUBEROUS SCLEROSIS COMPLEX (TSC)

Synonyms : EPILOIA, BOURNEVILLE’S DISEASE

Definition

Tuberous sclerosis complex (TSC) is an autosomal dominant(AD) disease complex

characterized by systemic hamartomas involving mostly the skin, brain, heart, eyes and

kidneys.

Epidemiology

Occurs in 1 / 10000. All races, both sexes are affected and has world wide

distribution.

29

Etiology

Inheritance is by:

1. Single autosomal dominant gene with variable expression of 40%,

2. Sporadic cases may occur due to new mutations in 60% cases.

Two specific genes are involved, namely :

I. TSC 1 - It is due to Chromosome 9q34 which encodes for a protein called

hamartin46 . It accounts for 30-50% of all familial cases.

II. TSC 2 – It is due to Chromosome 16p13 which encodes for a protein called tuberin 46which shows an area of homology to the GTP activating protein Rap1 which is involved in regulation of cell proliferation & differentiation (similar to Ras oncogene in neurofibroma). When tumour suppressor role is lost, tumour formation occurs. The most commonly observed manifestations are of skin, CNS followed by ocular, cardiac and renal system.

In 1998, the diagnostic criteria from the consensus report of the National Tuberous

Sclerosis Association was modified and divided into 2 groups: major and minor criteria as followed.

Revised Diagnostic Criteria for Tuberous Sclerosis Complex:47

Major features:

 Facial or forehead plaque

 Nontraumatic ungual or periungual fibroma

 Hypomelanotic macules ( 3 or more )

 Shagreen patch (connective tissue )

 Multiple retinal nodular hamartomas

 Cortical tuber

 Subependymal

30

 Subependymal giant cell

 Cardiac , single or multiple

 Lymphangiomyomatosis

 Renal

Minor features:

 Multiple randomly distributed pits in dental enamel

 Hamartomatous rectal polyps

 Bone

 Cerebral white matter radial migration lines

 Gingival

 Nonrenal hamartoma

 Retinal achromic patch

 “Confetti” skin lesions

 Multiple renal cysts.

Definite TSC : Either 2 major features or 1 major feature plus 2 minor features.

Probable TSC: 1 major feature and 1 minor feature

Possible TSC: Either 1 major feature or 2 or more minor features.

CLINICAL FEATURES :

Cutaneous – Seen in 60% to 70%

1. Facial (80 to 90%) usually starts at around 3-10 years of age and may rarely be present at birth. Lesions are firm, discrete, reddish brown, telangiectatic , 1 to 10 mm in diameter,extending from nasolabial furrows to the cheeks and chin.

Unusual types - Cauliflower like, segmental forms with unilateral distribution48. Multiple

facial angiofibroma like lesions have been observed in multiple endocrine . (MEN

Type1)

31

2. White ovoid or Ash leaf macules: They are ovoid or lance ovate shaped

macules of about 1-3 cm in length present at birth (earliest marker)49,50 .They can also seen

in a confetti like or segmental distribution and easily detectable by wood’s lamp. They are

commonly seen in trunk and limbs.

3. Shagreen patch is commonly located in lumbosacral region as irregularly

thickened soft, slightly elevated, skin coloured plaque with a “pig skin’,‘elephant hide’, or

‘orange peel appearance.

4. Periungual fibromas ( Koenen’s tumours ): They are smooth, firm, flesh colored excrescences emerging from the nail folds usually 5 to 10mm in size.

Other cutaneous lesions

Gingival, palatal & lip fibromas, firm fibromatous plaques over the fore head / scalp, soft fibromas in neck & axilla ( 5.7%), port wine stain, cafe-au-lait macules, . Small enamel pits ( common in adults) which are conical and cylindrical shaped, 80-500 microns in

size is a constant and pathognomic sign.

Systemic Manifestation : CNS

Seizures51– It is the earliest and most frequent complaint in TSC which is seen in all

cases with mental retardation. They may be temporal lobe epilepsy, persistent infantile spasm

like (21.2%), intractable seizures and tonic clonic seizures (37.1%).

Tumours : Sub ependymal giant cellastrocytoma, cortical tubers, sub ependymal

nodules. Forehead plaque may be acutaneous marker of CNS involvement in TSC.52

II. Renal manifestations

The common renal manifestations reported are renal angiomyolipoma53, aneurysmal

dilatation of renal , renal artery stenosis and polycystic kidneys (12%). Hypertension

in children with TSC can be due to renal parenchymal lesions (cysts and )..

32

III. Pulmonary Manifestation54

Pulmonary lymphangio leiomyomatosis are due to proliferation of

cells is common in women. Micronodular multifocal pneumocyte hyperplasia, cysts and recurrent intra pleural cysts are common.

IV. Ocular Manifestation

Ocular manifestations are seen in 50% patients. Retinal phacomas, pigmentary and other retinal abnormalities can occur. Symptoms are rare. Hypopigmented spots in the iris also occur and these may be analogous to the ash leaf macule in the skin.

V. Cardiac Manifestation

Benign of the heart are common and may be associated with

conduction defects. Fetal cardiac rhabdomyomatosis is a prenatal marker for the detection of

latent TSC. 80% of all children presenting with Rhabdomyoma have TSC.55

VI. Other disorders associated with TSC

Pituitary –adrenal dysfunction, premature puberty and thyroid disorders, primary localized gigantism and diffuse cutaneous reticulohistiocytosis have been reported.

HISTOPATHOLOGY

 Angiofibroma : hyperplastic blood vessels with increased dermal collagen

atrophic sebaceous glands and immature hair follicles.

 Shagreen patch: 2 types ( histopathologically ). Sclerotic mass of very broad

collagen bundles in an interwoven pattern (common), Uniform mass of collagen

with .

RADIOLOGICAL FINDINGS:

• SKULL : Calcification is seen on plain skull Xray in about 50% of patients.

Investigation should now include CT and MRI56 . The characteristic CT findings include

33

parenchymal hamartomas (cortical tubers), periventricular (subependymal) nodules,

ventriculomegaly and rarely, subependymal giant cell astrocytomas.

• HANDS AND FEET57 . Cystlike lesions of the phalanges and irregular thickening of

the cortex of the metatarsals and metacarpals have been reported, and similar lesions

localized in the vertebrae, pelvis or long bones have been reported.

• . Irregular reticulation of the lung fields

• KIDNEYS. Investigation includes and CT . Angiography

is helpful in differentiating renal hamartomas from other lesions58 .

III.GENETIC DISORDERS OF HYPERPIGMENTATION

INCONTINENTIA PIGMENTI(IP)

DEFINITION

Incontinentia pigmenti (IP) is a Xlinked dominant ectodermal dysplasia that is lethal

in males and classically presents in females with skin lesions, teeth abnormalities, alopecia,

nail dystrophy, and ocular and neurological findings .59 Birth prevalence is

0.6–0.7/1000000. Female to Male ratio is 20 : 1.

PATHOPHYSIOLOGY AND

It is caused by mutations of the IKBKG gene encoding nuclear factor (NF)-κB

essential modulator (NEMO), and also known as the inhibitor of the NFκB kinase subunit

gamma (IKKγ)60 .

CLINICAL FEATURES

IP clinical findings typically presents in the perinatal period with an erythematous vesicular following lines of Blaschko’s . Stage I evolves within a few months to a verrucous stage II, which occurs mainly on the limbs . Stage III is hyperpigmented streaks and whorls along lines of Blaschko’s which begin within months and fade in adolescence .

34

Stage IV patients have pale, hairless ,atrophic linear streaks or patches common on the lower

extremities at adolescence. Most of the patients (>60%) are neurologically normal.61

DIFFERENTIAL DIAGNOSIS

Stage I - Bullous , epidermolysis bullosa, herpes or varicella.

Stage II - or epidermal naevus syndrome.

Stage III - Conditions with ‘linear and swirled’ pigmentation.

Stage IV - Ito’s hypomelanosis or Hypopigmentary disorders with localized

alopecia.

COMPLICATIONS AND COMORBIDITIES

Life expectancy is normal. Patients without CNS abnormalities have normal physical

and cognitive development.

MANAGEMENT

No specific treatment is available . Symptomatic treatment includes management of

blisters. Ophthalmological followup is required for retinal neovascularization monitoring and

treatment (cryotherapy and laser photocoagulation) and treatment of retinal detachment if it

occurs. Patients should be referred to a paediatric neurologist for evaluation if microcephaly,

seizures are present. MRI is indicated in child with functional neurological abnormalities or

retinal neovascularization.

NAEGELI–FRANCESCHETTI–JADASSOHN SYNDROME AND

DERMATOPATHIA PIGMENTOSA RETICULARIS

These two diseases are interrelated autosomal dominant ectodermal dysplasia

syndromes that are caused by nonsense or frameshift mutations at the start of the KRT14

gene sequence.62 These mutations result in haploinsufficiency for and are associated with increased susceptibility of keratinocytes to pro apoptotic stimuli .63

35

Genetic analysis has showed a close association with NFJ syndrome and EBS with mottled

pigmentation.

CLINICAL FEATURES:

The clinical features of Naegeli–Franceschetti–Jadassohn syndrome are reticular

cutaneous pigmentation in early life without an inflammatory stage, diminished sweat gland

function, poor teeth and hyperkeratosis of the palms and soles 64. Males and females are

equally affected.

In dermatopathia pigmentosa reticularis cutaneous findings include reticulate

hyperpigmentation, noncicatricial alopecia of scalp,axilla,eyebrows, pubic hair and

onychodystrophy.

These two diseases clinically share complete absence of dermatoglyphics ,reticulate

pattern of skin hyperpigmentation mainly involving the proximal extremities, trunk and face.

The presence of small “confetti” like macules gives rise to a characteristic reticulate pattern.

palmoplantar keratoderma, abnormal sweat gland function and non scarring acral bullae in

early childhood, dental anomalies and nail dystrophy.65 Fine punctate spots on the cornea and brown pigmentation of the bulbar conjunctiva have also been reported .

HISTOPATHOLOGY:

Histopathology shows clumps of -laden melanophages in the papillary dermis in a patchy distribution without overlying epidermal hyperpigmentation.

TREATMENT AND PROGNOSIS:

There is no known treatment for the pigmentary disorder.The associated keratoderma can be treated with etretinate66

36

DYSCHROMATOSIS SYMMETRICA HEREDITARIA(DSH)

Dyschromatosis symmetrica hereditaria (DSH) – also known as symmetrical

dyschromatosis of the extremities and symmetrical or reticulate acropigmentation of Dohi67 –

is an autosomal dominant disorder commonly described in Asians has an onset during

childhood. The prevalence of DSH in the Japanese population is estimated to be 1.5 per 100

00068 .It is due to mutation of the double-stranded RNA specific adenosine deaminase gene

(ADAR1 or DSRAD) located at the 1q21.1-q21.2.It mediates a posttranscriptional

modification of the messenger RNA known as RNA editing. Impaired RNA editing affects the differentiation of melanoblasts during melanogenesis into hyper and hypoactive melanocytes. The affected melanoblasts are those that emigrate the farthest, thus explains the

distribution of the disorder.

CLINICAL FEATURES

The lesions begin in the first to second decade and are classically non progressive which is characterized by frecklelike pigmented macules on the face associated with small hyper and hypopigmented macules affecting the back of the hands and feet which may extend to the proximal portions of the limbs (knees and elbows).

HISTOPATHOLOGY :

The histology shows increased or decreased basilar pigmentation in the hyperpigmented or hypopigmented lesions respectively.

TREATMENT AND PROGNOSIS :

Surgical therapy with transplantation of thin split thickness skin autografts ,Q- switched ruby, Q-switched alexandrite, Q-switched Nd:YAG, 510 mm pulsed dye lasers have been used to treat pigmented macules especially on face.65

37

IV.PALMOPLANTAR KERATODERMA:

PALMOPLANTAR KERATODERMA WITH CARDIOMYOPATHY

NAXOS DISEASE

It is characterized by arrythmogeneic right ventricular cardiomyopathy, Non epidermolytic palmoplantar Keratoderma(NEPPK), and woolly hair.69It is due to 2bp deletion within the JUP gene encoding plakoglobin70 , which is a cell junction protein found in the in the epidermis and .

CLINICAL FEATURES:

Onset is during the first year of life in which striate or diffuse, nontransgredient hyperkeratosis with erythematous borders are seen. Woolly hair is present at birth. Cardiac manifestations start late after puberty in the form of , cardiac failure and sudden death and show 100% penetrance.71 Cardiac histology shows loss of myocardium replaced by fibrous tissue. Whenever woolly hair is associated with PPK, search for cardiac abnormalities should be done.72

V.DEVELOPMENTAL ABNORMALITIES OF SKIN

APLASIA CUTIS CONGENITA(ACC)

Aplasia cutis congenital(ACC) is defined as the congenital absence of a part of the skin including epidermis, dermis with or without subcutaneous tissue 73. It is a rare benign disorder. Incidence is 1-3 out of every 10,000 live births .The most common site is a solitary lesion in scalp especially affecting the parietal region74 and it can occur in any site. It can be associated with underlying defects in muscle, bone and dura. At birth it may present either as a healed lesion with scarring with a thin parchmentlike membrane, or may present with ulcers which extend through the full thickness of the dermis. A ring of hair around the defect

38

is called as ‘haircollar’ sign, which is associated with an increased risk of underlying defects.

Frieden’s classification system of Aplasia Cutis Congenita

Type 1 - Non syndromic Scalp aplasia cutis congenita

Type 2 - Scalp aplasia cutis congenita with associated limb abnormalities

Type 3 - Scalp aplasia cutis congenita with associated epidermal nevi

Type 4 - Aplasia cutis congenita overlying embryologic malformation

Type 5 - Aplasia cutis congenita associated with fetus papyraceus

Type 6 - Aplasia cutis congenita associated with epidermolysis bullosa

Type 7 - Aplasia cutis congenita localized to extremities without blistering

Type 8a - Aplasia cutis congenita caused by specific teratogens

Type 8b - Aplasia cutis congenita caused by intrauterine infections.

Type 9 - Aplasia cutis congenita associated with malformation syndromes.

. Truncal aplasia cutis is usually associated with fetus papyraceus (mummified dead

fetus) that is twin or triplet that died in utero during the second trimester. It presents with

symmetrical stellate or linear areas of congenital absence of skin over trunk and limbs with

fibrous constriction bands. The skin defect is due to release of thromboplastin from placenta

after an intrauterine death that causes a cutaneous infarct 75..

Though it is a benign condition, careful examination should be done to rule out other

congenital abnormalities and other syndromic association.H & E section usually shows atrophic epidermis, fibrosis in dermis and complete absence of adnexal structures 76

39

VI.DISORDERS OF DERMAL CONNECTIVE TISSUE

PSEUDOXANTHOMA ELASTICUM :

Pseudoxanthoma elasticum is an autosomal recessive disorder characterized by generalized fragmentation and progressive calcification and abnormal mineralization of elastic tissue predominantly in the dermis, blood vessels and Bruch’s membrane of the eye.

Prevelance is about 1/50 00077.

PATHOPHYSIOLOGY:

Pseudoxanthoma elasticum is caused by mutations in the ABCC6 gene located on

chromosome 16p13.1 78.

Pathology

The elastic fibres in the mid dermis are clumped, fragmented, degenerate and swollen, which stain positively for calcium.

CLINICAL FEATURES

Skin changes

The skin lesions consist of tiny (1–3 mm), yellowish papules in a linear or reticular pattern, which coalesce into confluent plaques. The skin is soft, lax, wrinkled, and may hang in folds..Most common sites are the sides of the neck, below the clavicles, the axillae , abdomen, groin perineum and thighs..

Cardiovascular changes

Calcification of the internal elastic lamina of the arteries leads to vascular occlusion which causes intermittent claudication with diminished peripheral pulses, and accelerated with hypertension79.

40

Ocular changes

A ‘peau d’orange’ fundus, which corresponds to yellowish lesions of the retinal

pigment epithelium is the earliest ophthalmic sign. of the are seen as

slate grey, illdefined streaks radiating from an incomplete greyish ring surrounding

the optic nerve head 80.

Gastrointestinal changes

The most common problem is upper gastrointestinal bleeding involving the stomach.

Obstetric risk

Increased risk of miscarriage due to failure of placental development may occur.

Plomp et al - Diagnostic criteria for pseudoxanthoma elasticum (PXE)81

Major diagnostic criteria

1 Skin

a Yellowish papules / plaques on the lateral part of the neck and/or

flexural parts of the body; or

b Increase of morphologically altered elastin with fragmentation, clumping and

calcification of elastic fibres in skin biopsy taken from clinically affected skin

2 Eye

a Peau d’orange of the retina; or

b One or more angioid streaks, each as long as one disk diameter.

3 Genetics

a A pathogenic mutation of both alleles of the ABCC6 gene; or

b A first degree relative (parent, child, sibling) who meets the diagnostic criteria for definitive PXE

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Minor diagnostic criteria

1 Eye

One angioid streak

2 Genetics

A pathogenic mutation of one allele of the ABCC6 gene

Requirements for the diagnosis of PXE

1 Definitive diagnosis

The presence of two (or more) major criteria not belonging to the same (skin, genetic ,

eye,) category

2 Probable diagnosis

The presence of two major eye or two major skin criteria or one major criterion and

one or more minor criteria not belonging to the same category as the major criterion

3 Possible diagnosis

The presence of a single major criterion or one or more minor criteria

DIFFERENTIAL DIAGNOSIS82

Disseminated form of dermatofibrosis lenticularis (Buschke– Ollendorff),Juvenile

elastoma and Papular elastorrhexis

INVESTIGATIONS

Calcium and phosphate levels should be checked. Histological examination of PXE

are often characteristic which shows elastic fibres in the middermis are clumped, degenerate,

swollen ,fragmented and the abnormal fibres stain positively for calcium). The definitive

diagnosis is made by molecular analysis of the ABCC6 gene.

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MANAGEMENT

Annual and cardiovascular assessments are advised. Patients and their families should also receive genetic counselling.

First line

Restriction of dietary calcium has been tried. Ophthalmologists recommend an

Amsler grid in the early detection of visual loss. Cardiovascular risks can be minimized with avoidance of smoking , control of blood pressure, weight and serum lipids and advice about regular exercise. and nonsteroidal antiinflammatory medications should be avoided to reduce the risk of gastrointestinal bleeding.The cosmetic appearance of the skin lesions can be improved by plastic surgery .

Second line

Laser photocoagulation may be helpful in preventing retinal haemorrhage83

Intravitreal antivascular endothelial growth factor (antiVEGF) therapy is useful .

VII.VIRAL INFECTIONS

EPIDERMODYSPLASIA VERRUCIFORMIS

Epidermodysplasia verruciformis is an inherited disorder 84 in which there is

persistent and widespread infection with Human Papilloma Virus(HPV) characterized by

combination of plane warts, pityriasis versicolorlike lesions and reddish plaques. It occurs

mainly in sunexposed sites presenting in childhood. Those affected individuals have reduced

Th cell numbers and function. The increased NK cell activity is interpreted as an appropriate

response.There is no impairment of DNA repair. There is no association with HLAA or B

antigens. Malignant change in the form of is very common in adult

life but rarely metastasise.

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PATHOPHYSIOLOGY

PATHOLOGY 85

As in plane warts, there is hyperkeratosis and acanthosis with ballooning in the

perinuclear area of keratinocytes which is more extensive in the upper part of the spinous layer. Viral particles are identified ultrastructurally in the malpighian cells and in basal cells.

CAUSATIVE ORGANISMS

The types most commonly found in the skin of these patients are types 5, 8, 9, 12,

14, 15, 17 and 19–25 rarely types like 28, 36, 37, 38, 47, 49, 50, 75, 76, 77, 93 and 9686 .

HPV5 and 8 are the main types associated with malignancy

GENETICS

It is usually autosomal recessive, though autosomal dominant and X – linked

dominant patterns have been reported. Two loci on chromosome 17 are associated with the

disease. Mutations in two genes EVER1 and EVER2 (160) are linked with the disease The

EVER1 and EVER2 genes code for zinccontaining transmembrane proteins TMC6 and

TMC8 respectively.

CLINICAL FEATURES87

Lesions seen on the face and neck are generally indistinguishable from

plane warts, but on the trunk and limbs they are larger and are of two main types. Scaly

macules resembling pityriasis versicolor with , or brown

pigmentation and are dull pink, brown or violet in coloured plaques resembling seborrhoeic

keratosis or pigmented warts are seen .

DIFFERENTIAL DIAGNOSIS

Acrokeratosis verruciformis and

COMPLICATIONS

44

Dysplastic and malignant changes such as actinic keratoses and Bowen disease are seen on sun exposed skin due to UV exposure.

MANAGEMENT88

First line: Imiquimod, Photodynamic therapy and Cryotherapy

Second line :Acitretin ,

VIII.TUMOURS OF SKIN APPENDAGES

TRICHOEPITHELIOMA

It is a hamartoma of the hair germ cells composed of immature islands of

basaloid cells with focal areas of primitive follicular differentiation and cellular stroma

induction. It is a part of spectrum of trichoblastoma. Most affected patients are young adult

females.

PATHOLOGY

It contains lobules of small dark basaloid cells with a peripheral palisading

pattern surrounding a central area of eosinophilic amorphous material89 .Sometimes hair

shaftlike structures can be seen in these central part.

GENETICS

The gene for has been identified in a locus on chromosome

9p21 90. The Brooke–Spiegler syndrome is an autosomal dominant condition which consists

of multiple , cylindromas and spiradenomas.The gene is mapped to

chromosome 16q12–13 .

CLINICAL FEATURES

It is a smooth nodule, usually on the face, which clinically mimics a nonulcerated basal cell carcinoma. Larger lesions are yellow, pink or sometimes bluish from pigmentation, and there may be dilated blood vessels over the surface.

45

DISEASE COURSE AND PROGNOSIS

The lesion is benign and malignant transformation is very rare.

MANAGEMENT

If any malignant change is suspected adequate excision and histological examination has to be done. The only other reason for treatment is cosmetic. 91

IX.ECTODERMAL DYSPLASIAS

HYPOHIDROTIC ECTODERMAL DYSPLASIA(HED)

X linked hypohidrotic ectodermal dysplasia is the commonest of the ectodermal

dysplasias, but autosomal dominant and autosomal recessive forms have been described.

Decreased sweating leads to heat intolerance and leads to dryness of the skin. It’s prevalence was 21.9 per 100 000 92.

ASSOCIATED DISEASES

Immunodeficiency, , lymphoedema, breast hypoplasia or aplasia (134)

PATHOPHYSIOLOGY

Xlinked hypohidrotic ectodermal dysplasia 1 (ECTD1, HED/EDA) is caused by a

mutation in the EDA gene, which encodes ectodysplasin/ NFkB pathway. 93

PREDISPOSING FACTORS

A positive family history is a predisposing factor.

PATHOLOGY

Histology shows decreased sweat glands and sebaceous glands. The epidermis is

thinned out with flattened rete ridges. Hair follicles and their sebaceous glands are reduced in

number. Apocrine glands and mucous glands of the upper respiratory tract may be sparse or

absent.

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CLINICAL FEATURES

• Hair. The hair is sparse, dry and lusterless with a light colour. The bar code appearance that mirrors a microscopic artefact is seen in patients with HED. Scanning electron microscopy show follicular distortion, follicular ridging and distorted bulbs.

Eyebrows are scanty or absent.The eyelashes may be normal, sparse or completely absent.

Hair shaft defects are twisting, pili canaliculi and trichorrhexis nodosa.

• Teeth. Dental abnormalities include complete absence of teeth () to

sparse, abnormally shaped teeth which may be conical or peg shaped. Both deciduous and permanent teeth are affected.

• Sweat glands. Sweating is often severely diminished or absent due to absence of

eccrine glands.

• Skin. At birth, affected males show marked scaling or peeling of their skin which

may be mistaken for a collodion membrane. Periorbital hyperpigmentation and fine wrinkling

around the eyes are characteristic features of the disorder.. Small milialike papules may be

found on the face. Dermatoglyphics are often reduced or even absent. Lower lips are often

prominent and ears show a characteristic deformation (Spock ears) Frontal bossing and a

saddlebridged nose deformity can occur.

MANAGEMENT

Strict monitoring of body temperature is required for babies in an incubator. Older

children should learn activities with physical cooling measures, such as frequent drinking of

cool liquids, wetting the clothes or wearing special cooling vests and caps.

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X.PORPHYRIAS

PORPHYRIA CUTANEA TARDA

Porphyria cutanea tarda (PCT) is the commonest of all the porphyrias which is

characterized by fragility and blistering of exposed skin.94 Porphyria cutanea tarda results

from deficiency of Uroporphyrinogen Decarboxylase (UROD). It causes an accumulation of

uroporphyrin and some other highly carboxylated porphyrins.

75 percent of patients have the type I (sporadic) form in which the enzyme deficiency

is acquired and limited to hepatocytes, due to inhibition of a normal UROD enzyme 95.25

percent have type II ( familial ) disease where the enzyme deficiency is hereditary, present in

all tissues. It is due to UROD gene mutation. The penetrance of this autosomal dominant inherited form is so low and a family history is present in 7% of cases .Type III disease is rare

which is characterized by a hereditary enzyme deficiency localized to the . The

prevalence varies but in most countries is around 1 in 10 000 .

CLINICAL FEATURES 96

Sporadic PCT presents in middle age while the familial form occur at a younger age. Almost all patients will notice increased fragility on lightexposed skin, particularly the backs of the hands and forearms. The crusts resolve over a few weeks, leaving atrophic scars, milia and often mottled hyper or hypopigmentation and symptoms are generally worse in the summer. Other common features are: patches of scarring alopecia following resolution of bullae on the scalp; hypertrichosis, usually on the upper face and forehead, ears or arms and occasionally affecting the whole body; and hyperpigmentation in a melasmalike pattern on the cheeks and around the eyes, or in a diffuse pattern on lightexposed skin in a reticulate distribution.

Photoinduced onycholysis , accelerated solar elastosis and morphoealike plaques may develop on the head and upper trunk. It has been hypothesized that they arise as a result

48

of the induction of collagen synthesis by uroporphyrin I. On the scalp, the morphoealike

change may cause a scarring alopecia starting in the frontoparietal and occipital areas . 97

CLINICAL VARIANTS

The homozygous form of familial PCT, hepato erythropoietic porphyria

(HEP), is related with over 90% reduction in UROD activity. It causes a severe disease

similar to CEP (Congenital Erythropoietic Porphyria), with photosensitivity during first years

of life causing immediate pain and blisters on sun exposure and mutilating scarring of the face and fingers. Prominent hypertrichosis, fluorescent teeth, eye involvement and shortened distal phalanges also occur. Haemolysis is milder than in CEP, and life expectancy is normal.

DIFFERENTIAL DIAGNOSIS

Variegate Porphyria, Druginduced pseudoporphyria , Renal pseudoporphyria

Heriditary Coproporphyria , lateonset Gunther disease .

INVESTIGATIONS

Biochemical findings

In PCT, the urinary porphyrin concentration is raised, consisting mainly of uroporphyrin.A plasma spectrofl uorimetry peak is seen at 615–620 nm. Isocoproporphyrin accumulates in the faeces. Urine analysis alone is insufficient to diagnose PCT, since some patients with VP have the PCT urine pattern (‘dual porphyria’).98

Histopathology 99

The bullae in PCT are subepidermal with a mild inflammatory infiltrate and

‘festooning’ of dermal papillae into the bullae.Deposition of PASpositive diastaseresistant fibrillary glycoprotein in and around the upper dermal walls with reduplication of the basement membrane is seen . Immunofluorescence reveals IgG, IgM, fibrinogen and complement at the epidermal–dermal junction.

49

Risk factors for the development of PCT

The major risk factors for developing PCT are haemochromatosis,100 hepatitis C

infection, alcohol and oestrogens.

MANAGEMENT

Visible light sunscreens containing titanium dioxide or zinc oxide.Stopping oestrogen

therapy, abstinence from alcohol and treatement of hepatitis C with interferon α.

Definitive treatment is with venesection or lowdose antimalarials 101.

XI.GENETIC BLISTERING DISORDERS

EPIDERMOLYSIS BULLOSA(EB)

Epidermolysis bullosa consists of a group of genetically determined skin fragility disorders characterized by blistering of the skin and mucosae following mild mechanical trauma.

The major forms of epidermolysis bullosa (EB). Level of skin EB type EB subtype Defective protein(s) cleavage Intraepidermal EB simplex Suprabasal EB Transglutaminase5; Simplex Plakophilin1; ;

Keratins 5 and 14; ; Basal EB simplex Exophilin5; Bullous antigen 1/dystonin

Intralamina lucida Junctional EB Junctional EB Laminin332; Type XVII generalized collagen α6, β4, α3 subunits

Type XVII collagen; Junctional EB Laminin332 α6, β4 localized integrin subunits

Sublamina densa Dystrophic EB Dominant Dystrophic EB Type VII collagen

Recessive Dystrophic EB Type VII collagen

Kindler Kindlin1 (Fermitin family Mixed syndrome homologue1)

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JUNCTIONAL EPIDERMOLYSIS BULLOSA(EB)

MOLECULAR PATHOLOGY

Generalized severe junctional EB results from bi allelic lossof function mutations in

one of the LAMA3, LAMB3 or LAMC2 genes .

Similar phenotype of intermediate severity can result from loss of function mutations

in COL17A1 leading to a complete absence of type XVII collagen protein.

Localized forms of junctional EB, inversa subtype result from disruptive mutations in

LAMA3, LAMB3, LAMC2, COL17A1 . Lossoffunction mutations in ITGA6 or ITGB4

(nonsense, frameshift) underlie junctional EB with pyloric atresia.

Almost all variants of junctional EB are characterized by autosomal recessive

inheritance and by formation at the level of the lamina lucida . Conventionally,

junctional EB is divided into two main categories: generalized and localized, each of which

has a number of subtypes. Generalized junctional EB is subdivided into severe, intermediate

and lateonset variants, with either pyloric atresia or respiratory and renal involvement.

Localised junctional EB is subdivided into Localised junctional EB, Localised junctional EB

inversa and Localised junctional EB laryngoonychocutaneous syndrome.

Impact of skin diseases on quality of life

Skin disease, by its visibility, can have a huge impact on quality of life (QoL) at any

age which is very vulnerable. Virtually all aspects of patients' lives can be affected by skin

disease. QoL has been studied for various genodermatological conditions . Dermatology Life

Quality Index (DLQI) was developed by Finlay and Khan in 1994 for the above purpose.

From then QoL assessment studies have been done for few genodermatoses individually.

Quality of life (QoL) assessment is studied in various genodermatoses like congenital

ichthyosis, photodermatoses, neurofibromatosis, tuberous sclerosis, epidermolysis bullosa

and ectodermal dysplasias.

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Why we need to measure Quality of Life?

There are many reasons why it is necessary for dermatologists to assess quality of life in various skin diseases. They are a proof that dermatological conditions which might appear less serious for people are equally serious from patient’s point of view compared to serious systemic diseases. This evidence may be helpful politically and has also been used to strengthen political arguments relating to development of various dermatology services. At the current situation very few clinicians formally assess the QoL of their patients. 102

The Dermatology Life Quality Index (DLQI):

The DLQI consists of 10 questions with simple tick-box answers scored from 0 to

3.103 The mean answer time is taken as two minutes. The DLQI has been described in at least

36 skin diseases in more than 130 articles and published abstracts, in 17 countries and 21 languages. 104Patients with lower impairment of their QoL had more successful treatment than those patients in whom treatment failed.

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AIMS AND OBJECTIVES

AIM:

To estimate the prevalence of genodermatoses and assess the effect of skin diseases on quality of life of the patients.

OBJECTIVES:

. To determine the age and sexwise distribution of Genodermatoses.

. To study the clinical morphology and distribution of lesions.

. To evaluate incidence of associated complications and systemic abnormalities.

. To determine the involvement in other family members.

. To study the functional impairments.

53

MATERIALS AND METHODOLOGY

STUDY DESIGN:

Descriptive Prospective observational study

STUDY POPULATION AND STUDY PERIOD:

Study was conducted in Dermatology department in Tirunelveli Medical

College,Tirunelveli. All patients attending Dermatology OPD and referred cases from co-

operating departments were enrolled in the study over a period of one year after obtaining

clearance from institutional ethical committee.

STUDY MATERIALS AND PROCEDURE:

All patients diagnosed to have genodermatoses irrespective of age and sex were

included in the study.Both written and informed consents were obtained from the patients or

guardian to carry out necessary investigations and to take clinical photographs.

Detailed history regarding age,sex,educational qualification,present and past

illness,family pedigree analysis along with consanguinity were recorded. A detailed physical

examination was performed and dermatological examination regarding morphological

patterns,site of skin lesions were recorded in predesigned proforma.Relevant investigations

were carried out .Patients were managed with appropriate treatment.Dermatology Life

Quality Index(DLQI) questionnaire will be given to the patients. Following that, scores will

be added and effect of their skin disease on their quality of life will be assessed.

STATISTICAL ANALYSIS:

The data collected were entered in Ms Excel and data analysis was done with SPSS software. Summarization and presentation of data were done using proportions and

percentage Numerical data were represented in mean and standard deviation.The p values

less than or 0.05 (P≤ 0.05) were considered as statistically significant.

54

INCLUSION CRITERIA:

Patients with any complaints related to skin,mucosa,hair and nails or clinically detected asymptomatic individuals with features suggesting genodermatoses.

EXCLUSION CRITERIA:

Patients with acquired conditions mimicking genodermatoses like acquired ichthyosis, acquired epidermolysis bullosa acquisita ,xeroderma like pigmentation in solar keratosis etc

55

OBSERVATION AND RESULTS

PREVELANCE

The total number of new cases who attended Dermatology OPD (including referrals

from other departments) during the study period from January 2018 to December 2018 was

15,200 out of which 49 were genodermatoses (0.32%) which accounts to a prevalence of 32 per 1000.

AGE & GENDER WISE DISTRIBUTION

Among the 49 patients,29 patients (59.2%) were males(M) and 20 patients(40.8%) were females(F) with a M:F ratio of 1.45 :1 .The age of the patients ranged from newborn to as old as to 55 years with mean age of 20 years . Eleven patients(22.4%) belong to 0 to 10

years , 21 patients(42.9%) in 11 to 20 years category , 8 patients(16.3) in 21to 30 years , 4

patients(8.2%) belong to 31 to 40 years , 2 patients(4.1%) in 41 to 50 years and 3

patients(22.4%) in 51 to 60 years .Thirteen patients (26.5%)were children(0 to 12 years ) and

19 patients(38.7%) were adolescents (10 to 19 years ) (Figure 1)

Figure 1: Age and gender wise population

12 11 10 10

8 8

6 5 Frequency

4 3 3 2 2 2 2 1 1 1

0 0-10 yrs 11-20 yrs 21-30 yrs 31-40 yrs 41-50 yrs 51-60 yrs Age and gender wise population

Males Females

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EDUCATIONAL PROFILE:

Among the total 49 cases, 44 were educated (89.8%;M:26,F:18) and 5 were

uneducated (10.2%; M:3, F:2) . Among the 13 children 9 were attending school and 4 were

not aged enough to attend school.Among the adolescents and adults one patient was

uneducated and she had low IQ and others were educated. Educational profile was highest in

higher secondary in about 17 patients (34.7% ;M :10, F:7) followed by high school in 11

patients (22.4 %; M:8, F: 3), primary school in 10 patients (20.4%; M:5, F:5 ) and, and middle school going patients were 3(6.1%; M:1, F:2) and 3 graduates (6.1% ;M : 2,F :1).

( Table 1)

Table 1: Educational profile (n=49)

Sl.No Education Males Females N (%)

1 Uneducated 3 2 5(10.2%)

2 Primary school (1st to 5th std) 5 5 10(20.4%)

3 Middle school (6th to 8th std) 1 2 3 (6.1%)

4 High school (9th and 10th std) 8 3 11 (22.4%)

5 Higher secondary (11th and 12th std) 10 7 17 (34.7%)

6 Graduates 2 1 3 (6.1%)

Total 29 20 49

OCCUPATIONAL HISTORY :

Among the 49 cases,20(40.8%) were students of which 13(26.5%) were males and

7(14.3) were females,8(16.3%) were housewives, 6(12.2%) were skilled labourers of which

5(10.2%) were males,one(2.0%) was a female, 5(10.2%) were semiskilled who were males,2

(4.1%)were manual labourers who were males and 8(16.4%) were unemployed of which

4(8.2%) were males and 4(8.2%) were females.(Figure 2)

57

Figure 2 : Occupational History

14 13 12 10 8 8 7 5 5 6 4 4

Frequency 4 2 1 2 0 0 0 0

Occupation

Male Female

PATTERNS OF GENODERMATOSES IN THE STUDY POPULATION

Overall, the most common genodermatoses was Inherited disorders of cornification

(43.8%), followed by hamartoneoplastic syndromes (22.4%), genetic hyperpigmentary disorders (10.2%), porphyrias (6.1%), ectodermal dysplasias(4.1%), disorders of calcification and mineralization(4.1%), viral infections (2%), genetic blistering disorders(2%), tumours of skin appendages (2%), developmental abnormalities of skin(2%) and unclassified (2%).

Among the inherited disorders of cornification , ichthyoses was seen in 18 patients

(37.6%)(ichthyosis vulgaris- 9, lamellar ichthyosis - 4 , erythrokeratoderma variabilis – 2, bullous ichthyosiform erythroderma -1 , harlequin ichthyosis-1 and netherton’s syndrome -1

) and palmoplantar keratoderma with cardiomyopathy ( ) seen in 3 patients

(6.1%)

Among the hamartoneoplastic syndromes , neurofibromatosis is seen in 5 patients

(10.2%) and tuberous sclerosis complex is seen in 6 patients (12.2%) cases.In genetic disorders of pigmentation ,dermatopathia pigmentosa reticularis seen in 3 patients

(6.1%),dyschromatosis symmetrica hereditaria and incontinentia pigmenti seen in one patient

( 2% ).Other diseases are porphyria cutanea tarda in 3(6.1%),X linked ectodermal dysplasia

58 in 2(4.1%),pseudoxanthoma elasticum in 2(4.1%).One case of epidermodysplasia verruciformis ,epidermolysis bullosa junctional,trichoepithelioma,aplasia cutis congenita and cornelia de lange syndrome are seen and each constitutes 2%. (Table 2 )

Table 2: Patterns of genodermatoses in the study population(N=49)

SL GENODERMATOSES MALE FEMALE N (%) NO (%) (%) 1 INHERITED DISORDERS OF 21(43.8%) CORNIFICATION I.Ichthyoses Ichthyosis Vulgaris 5 4 9 Lamellar Ichthyosis 4 0 4 Erythrokeratoderma Variablis 0 2 2 Bullous Ichthyosiform Erythroderma 1 0 1 Netherton Syndrome 1 0 1 Harlequin Ichthyosis 1 0 1 II.Palmoplantar keratoderma with cardiomyopathy Naxos Syndrome 1 2 3 2 HAMARTONEOPLASTIC SYNDROMES 11(22.4%) Neurofibromatosis 2 3 5 Tuberous Sclerosis 1 5 6 3 GENETIC DISORDERS OF 5(10.2%) HYPERPIGMENTATION Dermatopathia Pigmentosa Reticularis 2 1 3 Dyschromatosis Symmetrica Hereditaria 1 0 1 Incontinentia Pigmenti 0 1 1 4 PORPHYRIAS 3(6.1%) Porphyria Cutanea Tarda 3 0 3

5 ECTODERMAL DYSPLASIAS 2(4.1%) X linked Hypohidrotic Ectodermal 2 0 2 Dysplasia 7 DISORDERS OF CALCIFICATION AND 2(4.1%) MINERALIZATION Pseudoxanthoma Elasticum 1 1 2 8 VIRAL INFECTIONS 1(2%) Epidermodysplasia Verruciformis 0 1 1

9 GENETIC BLISTERING DISORDERS 1(2%) Epidermolysis Bullosa Junctional 1 0 1

59

10 TUMOURS OF SKIN APPENDAGES 1(2%) Trichoepithelioma 1 0 1

11 DEVELOPMENTAL ABNORMALITIES 1(2%) OF SKIN Aplasia Cutis Congenita 1 0 1 12 UNCLASSIFIED 1(2%) Cornelia de lange Syndrome 1 0 1

PREVALENCE OF CONSANGUINITY IN DIFFERENT TYPES OF

GENODERMATOSES

In genodermatoses ,17 patients had history of consanguinous marriage and 9 (18%)

patients had history of second degree consanguinous marriage, 6(12%) were males and

3(6%)were females and third degree consanguinous marriage was observed in 8 patients

(16%) of which 5(10%) were males and 3(6%)were females. 32 (66% ) patients had no

history of consanguinous marriage out of which 18(37%) were males and 14(29%) were

females . (Figure 3)

Second degree consanguinity is seen in 3 cases of Naxos syndrome, 2 cases of

lamellar ichthyosis , one case each of ichthyosis vulgaris,dermapathia pigmentosa

reticularis,junctional epidermolysis bullosa and epidermodysplasia verruciformis.

Third degree consanguinity is seen in 2 cases of erythrokeratoderma variabilis,2 cases of ichthyosis vulgaris, one case each of lamellar ichthyosis ,tuberous sclerosis , harlequin ichthyosis and aplasia cutis congenita.

Figure 3 : Prevelance of consanguinity among genodermatosis

40 32 30 18 20 14 Total 9 8

Frequency 6 Male 10 3 5 3 Female 0 Non consanguinous 2nd degree 3rd degree Consanguinity

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FAMILY HISTORY:

Out of the total 49 cases, 17 patients (34.6%) gave positive family history of similar

illness and 32 patients (65.4%) did not have any family history. Positive family history was noted in 8 congenital ichthyosis patients of which 4 were males and 4 were females. 2 cases of erythrokeratoderma variabilis in which sisters are affected and 6 cases of ichthyosis vulgaris in which 2 mothers and their sons, one father and his son where affected. 3 cases of

Naxos syndrome seen in an extended family with siblings (younger brother and his two elder

sisters born to two different mothers were affected) ,2 cases of Tuberous sclerosis (mother

and her daughter) ,2 cases of dermatopathia pigmentosa reticularis(younger brother and elder

sister) and 2 cases of X linked hypohidrotic ectodermal dysplasia (maternal grandfather and

his grandson with skipped generation).In all cases only two generations were affected.

(Table 3)

Table 3: Family History (n=49)

Family history Male Female N(%) Yes 8 9 17(34.6%) No 21 11 32(65.4%) Total 29 20 49

MODE OF INHERITANCE :

Out of the total 49 cases, 22 patients (44.8%) belongs to autosomal dominant trait

(Tuberous sclerosis – 6,Neurofibromatosis – 5,Dermatopathia pigmentosa reticularis –

3,Erythrokeratoderma variabilis – 2,Bullous ichthyosiform erythroderma – 1,Dyschromatosis

symmetrica hereditaria - 1 ,Epidermodysplasia verruciformis - 1,Trichoepithelioma –

1,Cornelia de lange syndrome – 1 and Aplasia cutis congenita – 1)and 15 patients

(30.6%)belongs to autosomal recessive trait(Lamellar Ichthyosis – 4,Naxos syndrome –

3,Porphyria cutanea tarda – 3,Pseudoxanthoma elasticum -2,Harlequin ichthyosis -

1,Netherton syndrome – 1 and Junctional epidermolysis bullosa – 1) , 9 patients (18.3%) to

61

autosomal semidominant type(ichthyosis vulgaris – 9), 2 patients(4.1%) to X linked recessive

(X linked recessive hypohidrotic ectodermal dysplasia – 2) and one patient of incontinentia

pigmenti is of X linked dominant trait(2%).3 cases of ichthyosis vulgaris followed autosomal

semidominant pattern and all other ichthyoses are sporadic.One case of tuberous sclerosis

complex followed autosomal dominant pattern and rest of the tuberous sclerosis complex

and neurofibromatosis were sporadic.Two cases of X linked recessive hypohidrotic

ectodermal dysplasia followed X linked recessive inheritance with skipped generations.Rest

of the diseases were sporadic. (Figure 4)

Figure 4:Mode of Inheritance

25 22

20 15 15 12 12 10 9 10 5 Frequency 4 5 2 2 2 1 0 1 0 0 Autosomal Dominant Autosomal Recessive Autosomal X Linked Dominant X Linked Recessive Semidominant Mode of Inheritance

Total Male Female

DERMATOLOGICAL AND SYSTEMIC ASSOCIATIONS AMONG

GENODERMATOSES:

The dermatological and systemic associations seen with genodermatoses are

depicted in the following table.(Table :4 )

Table 4: Dermatological and Systemic associations among Genodermatoses

Sl.No Disease Dermatological/Systemic Associations 1 Ichthyosis vulgaris Atopy(2) 2 Netherton’ syndrome Atopy(1) 3 Harlequin ichthyosis Developmental delay (1),Mitten hand deformity(1) 4 Naxos syndrome (3),Residual polio with shortened limb(1),Developmental delay (1),Trivial Mitral regurgitation(1)

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5 Neurofibromatosis (1), Focal areas of Signal Hyperintensities(2) 6 Tuberous sclerosis Seizure (2),Subependymal nodules and cortical tubers(2),Renal angiomyolipoma (2) 7 Porphyria Cutanea tarda Kyphoscoliosis and wedge shaped hand (1),Milia (2) 8 X linked hypohidrotic Milia (1) ectodermal dysplasia 9 Incontinentia Pigmenti Peripheral blood eosinophilia(1) 10 Aplasia Cutis congenita Antenatal USG – Fetus papyraceus (1) 11 Cornelia de lange syndrome Developmental delay and ECHO showing Ostium secundum Atrial septal defect(1)

ICHTHYOSES :

Out of 15,200 patients,18 patients (0.11%) found to have congenital ichthyosis and it

constitutes 36.7 % of genodermatoses.

RELATIVE INCIDENCE OF DIFFERENT TYPES OF CONGENITAL

ICHTHYOSIS

Out of 18 patients with congenital ichthyosis, ichthyosis vulgaris accounts for 50% followed by lamellar ichthyosis 22.2%,erythrokeratoderma variabilis constitutes 11.1%

followed by bullous ichthyosiform erythroderma ,harlequin Ichthyosis and netherton’s

syndrome each constitutes 5.6%. (Table 5 )

Table 5 :Relative incidence of different types of congenital Ichthyosis

Sl.No Clinical Types Male Female Total Percentage(n=18) 1 Ichthyosis Vulgaris 5 4 9 50.0% 2 Lamellar Ichthyosis 4 0 4 22.2% 3 ErythrokeratodermaVariablis 0 2 2 11.1% 4 Bullous Ichthyosiform erythroderma 1 0 1 5.6% 5 Netherton Syndrome 1 0 1 5.6% 6 Harlequin Ichthyosis 1 0 1 5.6%

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AGE WISE DISTRIBUTION OF CONGENITAL ICHTHYOSIS

Of the 18 patients, 6 patients (33.3 % ) belong to first decade, 5 patients (27.8%) in second decade , 4 patients (22.2%) in third decade, 2 patients (11.1%) in fifth decade, one patient (5.86%) in sixth decade.(Figure 5)

Figure 5: Age wise distribution of congenital Ichthyosis:

8 6 6 5 5 4 4 4 3

2 2 2 1 1 1 1 1 0 0 0 0 0 0 Frequency 0-10 yrs 11- 20 yrs 21-30 yrs 31- 40 yrs 41-50 yrs 51-60 yrs Age and sex wise distribution

Total Male Female

GENDER WISE INCIDENCE OF DIFFERENT TYPES OF ICHTHYOSIS

Out of 18 patients,12 patients(67%) were males and 6 patients (33%)were females.

Incidence of ichthyosis vulgaris was almost equal in both sexes. All lamellar ichthyosis found only in males. Incidence of Erythro keratoderma variabilis was more in females. Bullous ichthyosiform erythroderma, Harlequin Ichthyosis and Netherton’s syndrome were seen only in males.(Figure 6 )

Figure 6 : Gender wise incidence of different types of ichthyosis

10 9

8 5 6 4 4 4 4 2 2 1 1 1 1 1 1

Frequency 2 0 0 0 0 0 0

Disease

Total Male Female

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AGE OF ONSET OF DIFFERENT TYPE OF ICHTHYOSIS

All cases of ichthyosis vulgaris had age of onset from three to six months. Lamellar

Ichthyosis, Bullous ichthyosiform erythroderma, Netherton syndrome and Harlequin

ichthyosis had onsets since birth and erythrokeratoderma variabilis had late age of onset since

12 years of age(Table 6).

Table 6: Age of onset of different types of ichthyoses

Type of Ichthyosis At Birth – 3 3- 6 months > 1 year Birth months Ichthyosis Vulgaris - 5 4 - Lamellar Ichthyosis 4 - - - ErythrokeratodermaVariablis - - - 2 Bullous Ichthyosiform erythroderma 1 - - - Netherton Syndrome 1 - - - Harlequin Ichthyosis 1 - - -

EVOLUTION OF COLLODION BABY

Out of 4 collodion babies, 100% evolved in to lamellar ichthyosis.Three patients born

of consanguinous marriage with two belonging to 2nd degree and one patient belonging to 3rd

degree. One patient born of non consanguinous marriage.

PREVALENCE OF CONSANGUINITY IN DIFFERENT TYPES OF ICHTHYOSIS

In ichthyosis vulgaris 3(33.3%) patients had history of consanguinity with in 2

patients had history of second degree consanguinous marriage and third degree

consanguinous marriage was observed in one patient and 6 (66% )patients had no history of

consanguinous marriage. and. In lamellar ichthyosis(2 nd degree – 2,3rd degree – 1), harlequin ichthyosis and erythrokeratoderma variabilis all the patients had 3 rd degree consanguinous parents. In bullous ichthyosiform erythroderma and netherton’s syndrome no history of consanguinity was seen.(Table 7)

65

Table 7:Prevelance of consanguinity in different types of ichthyosis

Ichthyoses

Degree of ERYTHRO BULLOUS ICHTHYOSIS LAMELLAR NETHERTON’S HARLEQUIN consangui KERATODERM ICHTHYOSIFORM VULGARIS ICHTHYOSIS SYNDROME ICHTHYOSIS nity A VARIABLIS ERYTHRODERM (Autosomal (Autosomal (Autosomal (Autosomal (Autosomal (Autosomal Semidominant ) Recessive) Recessive) Recessive) Dominant ) Dominant ) N % N % N % N % N % N % No 6 66 1 25 - 1 100 1 100 - 2nd 1 11 2 50 - - - - 3rd 2 22 1 25 2 100 - - 1 100

PREVALANCE OF ICHTHYOSIS IN FAMILY MEMBERS

Out of the total 18 cases, 8 patients (44.4%) gave positive family history of similar

illness out of which 4(22.2%) were males and 4(22.2%) were females and 10 patients

(55.5%) did not have any family history. Out of the 8 cases , 2 cases of erythrokeratoderma

variabilis in which sisters are affected and 6 cases of ichthyosis vulgaris in which 2 mothers

and their sons, one father and his son where affected. (Table 8 )

Table 8: Family history in ichthyosis patients

Family history Males (%) Females (%) Total

Yes 4 4 8 (44.44%)

No 8 2 10 (55.55%)

TYPE OF SCALES

Scaling was observed in all cases. 9(50%) patients presented with fine scales , 4

(22.2%) patients presented with plate like scales , 2 patients(11.1%) with flaky scales ,one

patient (5.6%) with ridged hyperkeratosis,one (5.6%) with double edged scale and one(5.6%)

with coat of armour like scales.These scales are classically seen in their respective diseases

and no variation was observed (Table 9)

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Table 9: Types of scales

Sl.No Type of Scales Type of Ichthyosis No.of Cases(%) 1 Fine Ichthyosis Vulgaris 9(50%) 2 Plate like Lamellar Ichthyosis 4(22.2%) 3 Flaky Erythrokeratoderma variabilis 2(11.1%) 4 Ridged hyperkeratosis Bullous ichthyosiform 1(5.6%) erythroderma 5 Double edged Netherton’s syndrome 1(5.6%) 6 Coat of Armour like Harlequin Ichthyosis 1(5.6%)

HAMARTONEOPLASTIC SYNDROMES

NEUROFIBROMATOSIS(NF)

AGE AND SEX DISTRIBUTION OF NEUROFIBROMATOSIS

Of the 5 cases of NF, all(100%) cases were of type-1.10.2% of total cases were

neurofibromatosis.The age group of patients with neurofibromatosis ranged from 16 to 33

years with the mean age of 26 years.(Table 10)

Table 10 :The Age and Sex Distribution Among Patients With NF ( n=5)

Age in years No. of Cases(n) M(n=2) F(n=3) 0 – 10 yrs 0 0 0 11 – 20 yrs 2(40%) 0 2 21 – 30 yrs 0 0 0 31 – 40 yrs 3(60%) 2 1 Total(n=5) 5(100%) 2(40%) 3(60%)

Clinical presentation:

Highest age incidence was between 31 to 40 years of age.No positive family history was

noted and all are born of non consanguinous marriage.General examination and systemic

examination found to be normal.One patient was affected with seizures(20%).3(60%) patients

were found to have lisch nodules in the eye, all of them bilaterally.

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Dermatological examination: Cutaneous neurofibromas are soft and dome shaped and was observed in all patients (100%). Pigmentary changes in the form of CALM occurred in 5 patients (100%) . Palmar, Axillary and inguinal freckling was noted in 60% of the cases. All of them fulfilled diagnostic criteria for neurofibromatosis with more than two features.

Investigations : All patients underwent CT head and neck examination which were normal 3 patients and two patients(40%) showed Focal areas of Signal Hyperintensities (FASI).

Histopathological Examination showed unencapsulated tumour with pale eosinophilic collagen with spindle shaped cells and wavy nuclei. Few sections showed sebaceous gland and eccrine gland structures within the tumour mass.

TUBEROUS SCLEROSIS (TSC)

AGE AND SEX DISTRIBUTION IN TUBEROUS SCLEROSIS COMPLEX

The total number of cases diagnosed to have tuberous sclerosis were 6 (12.2%) of which one was a male and 5 females. (Table 11). The age of these patients ranged from 7 to

36 years – the mean age being 22 years.

Table -11: Age and sex distribution in tuberous sclerosis complex (n=6)

Age in years No. of Cases(n) M(n=2) F(n=3) 0 – 10 yrs(16.7%) 1 0 1 11 – 20 yrs(33.3%) 2 1 1 21 – 30 yrs(33.3%) 2 0 2 31 – 40 yrs(16.7%) 1 0 1 Total(n=6) 6(100%) 1(16.7%) 5(83.3%)

Clinical Presentation:

The patients presented with seizures in 2 cases (33.3%) and angiofibromas in 5 cases

(83.3%).A positive family history was observed in 2 patients where mother and her daughter

are affected .One patient born of 3 rd degree consanguinous marriage and others were of non

consanguinous marriage.General Examination and ophthalmic examination was normal.

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Dermotological examination :

Angiofibroma was observed in 5 cases (83.3%). Ash leaf macule seen in 3 cases

(50%). Shagreen patch found in 5 cases (83.3%) over the lumbosacral, upper back , thigh and gluteal region and one patient had it in the cheek. Forehead plaque in 2 cases (33.3%),

Koenen’s tumour in 3 cases (50%), CALM in 1 (16.7%), gingival fibroma 3 (50%) and enamel pits in one (16.7%) case.All fulfilled the diagnostic criteria for definite tuberosis sclerosis complex with minimum two major features seen in all patients and minor features seen in 3 patients.

Investigations :

CT Brain, showed both sub-ependymal nodules and cortical tubers in 2 patients(33.3%).USG abdomen was done in all patients out of which 2(33.3%) showed renal angiomylipomas . ECG was normal in all cases.Histopathology of angiofibroma showed pale stained collagen in the upper dermis few blood vessels in the mid dermis,fenestrated and deeply eosin strained collagen in the mid & deeper dermis. Histopathology of shagreen patch showed vertically oriented collagen in the mid & deeper dermis.

PALMOPLANTAR KERATODERMA WITH CARDIOMYOPATHY

NAXOS SYNDROME

Out of the 49 cases who presented with genodermatoses, three cases (6.1%) had

Naxos syndrome among which one was male (17 years) and 2 were females ( 18 & 20 years)

and all belonged to same family.

Clinical Presentation:

All had onset of scaly skin lesions over palms and soles since two years of age and

tiny over the scalp at birth . One female patient was affected by polio with shortening

of right lower limb.

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Family History : All patients belong to same family. All were born of second degree

consanguinous marriage. Their father had 2 wives , both were sisters and one female born to

1st wife and one female and male sibling born to second wife.

General examination : All were moderately built and have pseudoclubbing. Facial

appearance shows sparse eyebrows in all.Systemic examination was normal.

Skeletal Examination : One female patient had residual polio with shortening of right lower

limb. Male patient had Hyperextension at distal phalanx of Index and ring finger with parrot

beaking at index finger.Flexion deformity of middle 3 fingers of both foot.

Dermatological examination: All showed well defined linear hyperkeratotic over palms and

soles with relative sparing of central palm and instep of soles suggestive of striate

keratoderma. Woolly, curled, dry, sparse, rough hair present in all patients .Scalp and eyebrows showed hypotrichosis . Multiple skin coloured horny present diffusely over

back, upperlimb ,lowerlimb in two female patients suggestive of keratosis pilaris.

Investigations: All underwent ECHO and normal in two female patients and male patient

showed trivial mitral regurgitation. Other Investigations were found to be normal.

PORPHYRIAS

PORPHYRIA CUTANEA TARDA

Out of the 49 cases who presented with genodermatoses, three cases (6.1%) were

found to be porphyria cutanea tarda. All were males .

Clinical Presentation:

All presented with fluid filled skin lesions over sun exposed sites with onset from one

year of age in two patients and 4 years of age in one patient which progress to form hypo and

hyperpigmentation followed by scarring in all patients..All had history of photosensitivity

and photophobia .One patient had headache. All patients were born to non consanguinous

marriage.Family history,general and syatemic examination nil significant.

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Ophthalmic Examination :Eye lashes are thick and long.Conjunctival congestion and watering is seen in all of them. Fundus and Other structures found to be normal in all three.

Skeletal Examination : One patient showed kyphosis with stubby shortened digits in both hands.

Teeth examination: Revealed pink red fluorescence in two patients.

Dermatological examination: Revealed multiple varioliform atrophic scars in the exposed areas and hands and feet. Pseudoscleromatous appearance seen. Bullae and erosions seen over both hands.Total nail dystrophy and partial nail dystrophy seen in one patient and other patient had partial nail dystrophy in all fingers .One patient showed milia in ear lobule and other in alae nasi.

Investigations : Urine and serum porphyrin found to negative in one affordable patient. X ray both hands and feet revealed shortening of metacarpals, phalnx and wedge shaped hands.

MRI Brain was found to be normal in one patient who had headache.Histopatholgy shows subepidermal blisters with dermal papillae extending irregularly from the floor of the blister into the blister cavity and pericapillary homogenous eosinophilic material highlighted by

PAS staining is seen. Dermis shows perivascular lymphocytic infiltrate.

GENETIC DISORDERS OF HYPERPIGMENTATION

DERMATOPATHIA PIGMENTOSA RETICULARIS

Out of the 49 patients, three cases (6.1%) were found to be dermatopathia pigmentosa reticularis among which one was female (19 years ) and 2 were males (both are 18 years)

Clinical Presentation:

All presented with dark coloured skin lesions all over the body and the age of the onset was 6 months in one patient and one year in two patients. All had the history of appearance of light coloured skin changes over the dark coloured skin lesions in the adolescent period. All had history of diffuse and one patient had photophobia. One

71 patient born of second degree consanguinous marriage and other two of non consanguinous marriage .

Family History : One female and male were siblings.

Ophthalmic Examination : One patient conjunctival congestion and decreased visual acuity

(6/9) in right eye. Fundus and Other structures found to be normal in all three.

Dermatological examination: Diffuse hyperpigmentation seen all over the body with hypopigmented macules giving the appearance of reticulate pigmentation present over all over the body. .Oral cavity showed hyperpigmentation of hard palate,tongue and buccal mucosa seen.Diffuse hair loss seen in all patients which was shiny, fine ,soft and blackish brown in colour.Nail changes in the form of onycholysis , onychodystrophy seen in all patients.

Investigations : Histopathological section of hyperpigmented macule showed basket weave keratin and exudates in the corneal layer with loss of rete ridges and increased melanin in the basal layer. Superficial dermis shows melanin incontinence and clumps of melanin and with mild perivascular mononuclear cell infiltrate in dermal layer.

DYSCHROMATOSIS SYMMETRICA HEREDITARIA:

One male patient aged 8 years (2 %) was identified to have dyschromatosis symmetrica hereditaria.

Clinical Presentation:

He presented with light coloured skin lesions over the hands and feet since one year of age which was non progressive. He was born of non consanguinous marriage .

Multiple hypo and hyperpigmented macules in a reticulate pattern seen over the dorsal aspect of both hands , feet and knees. Few freckles present over the face. Palms, soles, scalp, hair and nail found to be normal.

72

INCONTINENTIA PIGMENTI:

A 2 days old female baby (2%) found have Incontinentia pigmenti.

Clinical Presentation:

She presented with fluid filled and dark coloured skin lesions all over the body since

birth. No history suggestive of infections, , oligo or polyamnios and no history of

repeated abortions in the mother

Birth History :Term (39 weeks),2nd born female child born by non consanguinous

marriage with birth weight 3.2 kg. No history of similar illness in other family members.

Dermatological examination: Multiple vesicles seen over the scalp,face ,upper chest,arms and

forearm. Nicolsky sign found to be negative. Linear hyperpigmented patches in a blaskhoid

pattern present over arms,forearm,trunk,thighs and legs seen.

Investigations: Basic blood examination showed leucocytosis(15300 cells/cu.mm) and

eosinophilia(12 in differential count) , normal blood sugar and urine examination found to be

normal.

ECTODERMAL DYSPLASIAS

X LINKED HYPOHIDROTIC ECTODERMAL DYSPLASIA

Out of 49 (4.1%) patients , 2 were identified as X linked hypohidrotic ectodermal

dysplasia which consisted of maternal grandfather aged 55 years and his 7 year old grandson .

Clinical Presentation:

Both presented with dry scaly skin lesion all over the body since birth with history of absent sweat, heat intolerance and absent scalp hair ,eyebrows ,body hairs and teeth at birth. History of photosensitivity is seen in grandson .

Teeth examination: Only 4 peg shaped teeths were seen in grandson (Upper right side

– one molar, left side -one molar and one canine , Lower right side – one incisor).Absent teeth in grandfather.

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Dermatological examination: Generalised dry and smooth skin seen. Both had frontal bossing, depressed nasal bridge,prominent lower lips, sparse lustreless ,brown coloured scalp

hair , sparse facial hair with absent eyebrows and eyelashes ,sparse axillary hair, absent body

and pubic hairs. Grandfather presented with milia like papules in the forehead, periorbital

pigmentation and wrinkling in the eyelashes.

DISORDERS OF DERMAL CONNECTIVE TISSUE

PSEUDOXANTHOMA ELASTICUM

Two patients out of 49 (4.1%) were identified as pseudoxanthoma elasticum which

consisted of 14 year old boy and 12 year old girl.

Clinical Presentation:

Both presented with dark coloured skin lesions over the neck since 12 years of age.

History of gradual loosening and wrinkling of skin neck present over the neck. Both were

born of non consanguinous marriage .

Ophthalmic Examination : Fundus examination found to be normal in both. No

evidence of angiod streaks or peau’ d orange appearance.

Dermatological examination: Vaguely defined hyperpigmented skin with wrinkling ,

prominent skin markings and thickening seen over the front of neck. Few tiny yellow

keratotic papules present over the lateral aspect of the neck.

Investigations: Serum calcium and phosphate levels were normal. Histopathological

examination from yellow keratotic papule revealed stratified squamous epithelium with

surface ulceration and dermis showing swollen and abnormal elastic fibres. Von kossa stain

showed calcification of elastic fibres and verhoff van gieson stain showed condensed granular

elastic fibres.

74

VIRAL INFECTIONS

EPIDERMODYSPLASIA VERRUCIFORMIS

One female patient aged 23 years (2 %) was diagnosed to have epidermodysplasia

verruciformis.

Clinical Presentation:

She presented with asymptomatic light coloured skin lesions all over the body for 10

years. She was 2nd born female child , born of 2nd degree consanguinous marriage

Dermatological examination: Multiple hypopigmented scaly macules and thick verrucous plaques seen over the face, front and back of trunk, abdomen, extensors of both forearms knees and legs. Isomorphic phenomenon is seen.

EPIDERMOLYSIS BULLOSA

EPIDERMOLYSIS BULLOSA JUNCTIONAL

One male patient aged 27 years (2 %) was identified to have junctional

epidermolysis bullosa – generalised intermediate type.

Clinical Presentation:

He presented with multiple fluid filled lesions on and off since birth with history of

rupturing of bullae spontaneously in 3 days. History of trauma induced bullae formation and

burning sensation over the erosions were seen. He was born of 2 nd degree consanguinous

marriage.Other systems normal.

Dermatological examination: Multiple clear and haemorrhagic vesicles and bullae ,crusted and healing erosions seen all over the body. Oral cavity showed dental pits.Nails were normal and palmar pits were seen.

Investigations: Skin biopsy showed epidermis with acanthosis,hyperkeratosis and follicular

keratinisation.Subepidermal bullae with upper dermis showing edema,increased vascularity,

75 lymphocytic infiltrates and pigment incontinence.DIF showed no deposition of

IgG,IgA,C3,IgM or fibrin.

TUMOURS OF SKIN APPENDAGES

TRICHOEPITHELIOMA

Out of 49 patients, One male patient aged 53 years (2 %) was diagnosed to have trichoepithelioma..

Clinical Presentation:

He presented with raised asymptomatic skin lesion over the face since 30 years of age. He was born of non consanguinous marriage.

Dermatological examination: Multiple closely set discrete skin coloured papules and nodules seen over forehead, paranasal area, tragus and antihelix of both ears.

Investigations: Histopathology revealed stratified squamous epithelium with underlying dermis showing circumscribed tumour consists of islands and nests of basaloid cells with pilar differentiation and cellular stromal foci of small keratinous seen.

DEVELOPMENTAL ABNORMALITIES OF SKIN

APLASIA CUTIS CONGENITA

A 11 days old male boy a (2 %) was identified to have aplasia cutis congenita with fetus papyraceus.

Clinical Presentation:

He presented with ulcerated skin lesions over both lateral sides of trunk since birth.

There is no evidence of teratogenic drug intake antenatally by mother .

Birth History : Term (38 weeks),1st born male child born by 3rd degree consanguinous marriage with birth weight 2.7 kg.

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Dermatological examination: Bilateral symmetrical irregular stellate scars over lateral chest wall seen. Scalp, nails and mucosa were normal. No congenital abnormities like spina bifida, meningocele, , lung or cardiac anomaly or limb defects in the baby.

Investigations: On reviewing the records antenatal ultrasonography at 12 weeks showed twin intrauterine pregnancy in which one of the twin had no cardiac activity. Repeat ultrasonography at 18 weeks showed single live fetus and reported as vanishing twin pregnancy.

MISCELLANEOUS

CORNELIA DE LANGE SYNDROME WITH HYPOMELANOSIS OF ITO

One male patient aged 17 years (2 %) was identified to have Cornelia de lange syndrome.

Clinical Presentation:

He presented with asymptomatic light coloured skin lesions over the chest since one year of age . History of poor performance at school and delayed milestones seen.He was born of non consanguinous marriage .

General examination : Expressionless face, low set hair line, synorphs,long eyelashes, hypertelorism ,short concave nose, long philtrum ,thin upper vermilion border , simian crease with low pitch and guttural deep voice seen. Moderately built and nourished.

Skeletal Examination : Microcephaly,Upper limb length discrepancy,small hand,short 5 th finger,clinodactyly and hyperextensible knee joints were seen.

Dermatological examination: Macular hypopimented whorls and streaks along the lines of blascko seen in bilateral chest and arms.

Investigations: ECHO showed Atrial Septal defect(Ostium Secundum ) and MRI Brain was found to be normal.

77

EFFECT ON QUALITY OF LIFE AND AFFECTED DOMAINS:

Dermatology Quality of life Index(DLQI) questionarrie is applicable for patients above 16 years of age.The DLQI consists of 10 questions with simple tick-box answers scored from 0 to 3.Minimum score is 0 and maximum score is 30 . “Symptoms and feelings” domain was assessed based on intensity of itching, pain, soreness and embarrassment which consists of 2 questions. “Daily activities” domain by interference with shopping, household works and wearing clothes and it consists of 2 questions, “Leisure” domain by effect on sports, social and leisure activities, and it also consists of 2 questions. “Work and school” domain by interference with work and studies which is a single question. “Personal relationships” domain by problems with partners, close friends or relatives and sexual difficulties and it has two questions. “Treatment “domain by problems faced due to the treatment modality received and it contains one question.

Scores 0 to 1 depicts no effect on quality of life,scores 2 to 5 depicts moderate effect,scores 6 to 10 for moderate effect,score 11 to 20 and 21 to 30 for large effect and very large effect respectively.

Out of the 36 patients (above 16 years of age ),quality of life was not affected in 6 patients (16.7%; M: 4, F: 2) and was affected in remaining 30 patients (83.3%; M: 17, F: 13).

Most of the patients(33.3%) had moderate effect of their diseases on quality of life(as measured by DLQI score) followed by small effect in 30.6%, very large effect in 19.4% patients, with more males affected than females in all categories except for the “moderate effect” category in which both are equal. DLQI scores compared between males and females did not show any statistical significance (p=0.886) (Figure 8 )

The most common domain affected was symptoms and feelings in 83.3 % of patients, followed by daily activities (72.2 %), leisure (58.3 %), personal relationships (47.2%), treatment (41.6 %) ,work and school(13.8%)and no affection in 16.7%. (Figure 9)

78

Out of 30 patients who had “symptoms and feelings “ domain affected, 21 belonging

majorly to ichthyosis ,tuberous sclerosis and neurofibromatosis felt embarrassed due to rough

skin and bizzare appearing lesions and 9 belonging to ichthyosis vulgaris and hypohidrotic

ectodermal dysplasia suffered from itching due to their dry .

Among 26 patients who had “daily activities “domain affected, 15 felt uncomfortable

going out for shopping due to appearance of dry rough skin and fissuring (ichthyosis) and

raised lesions over the face and extremities (neurofibromatosis, trichoepithelioma and

pseudoxanthoma elasticum ,8 had interference due to the clothes they wore due to heat

intolerance( ichthyosis and hypohidrotic ectodermal dysplasia ) and 3 felt that their skin condition interfered with their household works due to keratoderma and fissure(Naxos syndrome) .

In 21 patients who had “leisure” domain affected, 18 felt their social activities were disturbed due to scaly ,nodular and bullous lesions over exposed parts ( neurofibroma,tuberous sclerosis,epidermodysplasia verruciformis and ectodermal dysplasia ) while 3 felt their skin condition interfered with their sports due to heat intolerance and defective sweating(lamellar ichthyosis and ectodermal dysplasia).

Out of 5 patients who had “work and school” domain affected, majority 3 felt their skin condition disturbed their education in school leading to poor performance in school

(Cornelia de lange syndrome, porphyria cutanea tarda) and 2 felt that their skin condition interfered with their occupation due to fissuring and keratoderma . (Ichthyosis vulgaris and

Naxos syndrome ).

There were a total of 17 patients in whom “personal relationships” domain was affected and most of them(12) faced problems with friends or relatives because of their dry skin,raised lesions over exposed parts ( lamellar ichthyosis,neurofibromatosis and tuberous

79 sclerosis ) and 5 of them faced problems with sexual activities due to scaly , nodular and bullous lesions( neurofibroma,tuberous sclerosis and epidermodysplasia verruciformis ).

Among 15 patients who had “treatment “ domain affected, 10 felt their schooling or occupation was affected(ichthyosis vulgaris and lamellar ichthyosis ) because of treatment of their skin diseases, 5 felt that the treatment was time consuming for them(neurofibromatosis and porphyria cutanea tarda.

Figure 8: DLQI SCORE

14 12 12 11

10

8 7 7 6 6 6 Total 6

Frequency Male 4 4 4 Female 4 3 2 2

0 No effect Small effect Moderate effect Large effect DLQI Score

Figure 9 : DOMAINS AFFECTED

35 30 30 26 25 21 17 20 15 15

Frequency 10 5 6 5 0 DLQI Domain Affected

DQLI Domain Affection

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DISEASES WITH HIGH EFFECT ON QUALITY OF LIFE:

Lowest individual score observed in the study was 0 in ichthyosis vulgaris and highest

individual score observed was 13 in neurofibromatosis.The diseases with the high mean

DLQI scores were Junctional epidermolysis bullosa (11.0) and Epidermodysplasia

verruciformis (11.0) followed by Dermatopathia pigmentosa reticularis (10.7 ± 1.2),

porphyria cutanea tarda (10.3 ± 5.0), Hypohidrotic ectodermal dysplasia (9.0), Naxos

disease(8.0 ± 2.8), Tuberous sclerosis(7.6 ± 3.3)ichthyoses (5.2 ± 5.2), neurofibromatosis

(7.4 ± 3.1), Trichoepithelioma(5.0%) (Table 4)

“Symptoms and feelings” was the most common domain affected in all diseases with high

mean DLQI score(Junctional epidermolysis bullosa,Epidermodysplasia verruciformis and

Dermatopathia pigmentosa reticularis) due to their scaly,bullous and pigmentary lesion

causing embarassement ,disturbance in social activities and relationship with friends and

relatives . In addition, “daily activities” domain was also affected in Dermatopathia pigmentosa reticularis and Tuberous sclerosis. “Leisure ” was the most common domain affected in neurofibromatosis and “Personal relationships “was the most common domain affected in epidermodysplasia verruciformis along with “symptoms and feelings” domain.

81

Table 12: Diseases with high mean DLQI score

MEAN DLQI DOMAINS MOST DERMATOSES M F TOTAL SCORE COMMOMLY AFFECTED Junctional Symptoms and feelings,daily 11.0 epidermolysis bullosa 1 0 1 activities Epidermodysplasia Symptoms and feelings, Personal 0 1 1 11.0 verruciformis relationships Symptoms and feelings, daily Dermatopathia 2 1 3 10.7 activities pigmentosa reticularis

Porphyria cutanea 3 0 3 10.3 Symptoms and feelings tarda Hypohidrotic 9.0 1 0 1 Symptoms and feelings ectodermal dysplasia 8.0 Symptoms and feelings,Daily Naxos disease 1 2 3 activities Symptoms and feelings, Tuberous sclerosis 1 4 5 7.6 Treatment 5.2 Symptoms and feelings,Work Ichthyosis 7 4 11 and school 7.4 Neurofibromatosis 2 3 5 Symptoms and feelings, leisure

5.0 Trichoepithelioma 1 0 1 Symptoms and feelings

82

DISCUSSION

Genodermatoses can be broadly classified into three main categories namely single

gene disorders , chromosomal disorders and multifactorial disorders. Most of the

genodermatoses show single gene or Mendelian type of inheritance comprising of autosomal

dominant, autosomal recessive and X-linked recessive type of inheritance. The study of these

dermatoses will be helpful in prenatal diagnosis and genetic counselling. Studies on

genodermatoses are mainly concentrated on individual diseases and there is lack of literature

on study of genodermatoses as a whole including systemic assesment and only few studies

have been done in India.Many disease diagnosis are missed due to lack of facilities and

diagnostic accuracy.So this study is aimed at studying the prevalence and profile of genetic

dermatological conditions and quality of life assessment in patients below 16 years of age.

There were only few studies in literature across the globe depicting patterns of genodermatoses like studies done by Federica Dassoni et al. in paediatric and adults patients at Italian dermatological center in Rome105 and Regina C. betz et al 106. In India there are only few studies which included entire spectrum of genodermatoses.They were studies done by

Sunil kumar et al in paediatric patients at New Delhi107, Farah Sameem et108 al in paediatric

and adults patients at Jammu and Kashmir.None of the above studies assessed the quality of

life in patients and there is only one study, done by Jagannadh et al.,109 which assessed

quality of life affected by skin diseases including genodermatoses, but only in patients of age

16 years and above. Hence our study is aimed to assess effect of skin diseases on quality of

life in genodermatoses patients.

PREVALENCE

In this study,20 different genetic and congenital cutaneous disorders affecting 49

individuals (0.32% of the total caseload) were observed which is in accordance with the study

conducted by Federica Dassoni et al., which was 0.4% where as studies done by Sunil kumar

83 et al., and Farah sameem., et al observed relatively higher prevalence of 0.62% and 0.72% respectively.

AGE & GENDERWISE DISTRIBUTION OF GENODERMATOSES:

In our study mean age of the patients were 20 and males constituted 59.20% and females constituted 40.8% of the study population with M:F ratio of 1.45:1. Farah Sammem et al.,found a similar male preponderance in their study with M:F ratio of 1.17:1 with a mean age of 12 years.

PATTERNS OF GENODERMATOSES IN THE STUDY POPULATION

In our study the most common genodermatoses was ichthyosis seen in 37.6% which is comparable with study conducted by Farah Sammem et al. (33.59%),where as study conducted by Sunil kumar et al107 showed an incidence as high as 55.8%. Comparison of various genodermatoses and their prevalence from studies across the globe were depecited in the following table.(Table 13)

Table 13:Comparison of various genodermatoses and their prevalence from studies across the globe

Sunil Our Farah Sammem et Federica kumar Disorders/Disease Study al(n=128) Dassoni et al et (n=49) (n=122) al(n=34) Ichthyoses 37.6% 33.59% 55.8% 12.2% Harmatoneoplastic 22.4% 15.3% 3% 16.3% syndromes Porphyrias 6.1% 3 % - 2% Other disorders of 6.1% 7% 8% 4% keratinisation Epidermolysis bullosa 2% 9% 9% 4% Hypomelanosis of Ito 2% 1% 3% 3%

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FAMILY HISTORY AND DEGREE OF CONSANGUNITY:

In our study , out of the total 49 cases, 17 patients (34.6%) gave positive family history of similar illness and 32 patients (65.4%) did not have any family history.This is in accordance with the study conducted by Sunil kumar et al ., and Farah sammem et al where they observed positive family history in 32.3 % and 33.5% respectively. In our study 34 % of cases were born of consanguineous marriage in contrast to study done by Farah sameem et al., where it is 57.8 %.

MODE OF INHERITENCE :

In our study 22 patients (44.8%) belongs to autosomal dominant trait and 15 patients

(30.6%)belongs to autosomal recessive trait which is comparable with the study done by

Sunil kumar et al.,107 where he observe it in 50% and 32.3 % respectively and 2 patients(4.1%) affected with X linked recessive trait in our study in contrast to Sunil kumar et al.,107 where he observed it in 17% cases.

ICHTHYOSIS :

In our study , 0.11% of total population found to have congenital ichthyosis and it constitutes 36.7 % of genodermatoses. A study by Wells and Kerr CB et al.,9 showed, that the incidence of ichthyosis vulgaris may be as common as 1 in 250 – 1 in 1000. In this study, the incidence of ichthyosis vulgaris was 1 in 2000 which complies with the above study. A study by Rand et al (187) showed,incidence of lamellar ichthyosis and epidermolytic hyperkeratosis have estimated to occur in 1 in 300,000 population. In our study, incidence of lamellar and epidermolytic hyperkeratosis is seen in 1 in 5000 and 1 in 20000 respectively.

In our study relative incidence of ichthyosis vulgaris was 50 % in our study which is in accordance with Federica Dassoni et al (47.3%)105 and Farah Sammem et al(53.3.%).108Lamellar ichthyosis constitutes about 22.2% which is comparable with study done by Farah Sammem et al(26.6%)108 and it low in study by Sunil kumar et al (5.2%)

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107and high in study by Federica Dassoni et al (46%)105 . Bullous ichthyosiform erythroderma

is seen in 5.6% patients in our study where as Sunil kumar et al (5.2%)107 and Farah Sammem et al(6.6.%)108 observed in these many cases.

Age of onset of ichthyosis vulgaris ranged from 3-6 months in 100% patients. This complies with that of the description about the age of onset of diseases given by Traupe et al

5in the guide to clinical diagnosis of ichthyosis. In Van gysel et al.,110study of follow up of 17

cases of collodion baby, 60-80% of the developed non bullous ichthyosiform

erythroderma and lamellar ichthyosis. In this study,out of 4 cases of collodion babies, 100%

of the patients developed into lamellar ichthyosis where as study in conducted by Sivayadevi

et al there are 70% of cases evolved into lamellar ichthyosis and 30% into non bullous

ichthyosiform erythroderma.111

In our study, in ichthyosis vulgaris, 66% of patients had no history of

consanguinous marriage of the parents and in 34% of patients there is history of

consanguinous marriage was present which is comparable with the study conducted by

Sivayadevi et al (187)where it is seen in 76 % and 24% respectively .In lamellar ichthyosis, 2

nd degree and 3 rd degree consanguinous marriage was present in 50% and 25% of patients where as in study by Sivayadevi et al (187) it is seen in 44% and 55 % respectively.

NEUROFIBROMATOSIS:

Neurofibromatasosis accounts for 10.2% of cases in our study.In this study, all cases(100%) were NF1 which is comparable with the study reported by Huson SM et al.,112which showed a 90% incidence. The most frequent age group affected was 10 to 20

years. The most frequent age group affected was 31 to 40 years where as Friedmann JM

Riccardi et al 43noted most affection in the age group of 11-20 years . There is a female

preponderance (60%) in this as opposed to the studies of Jennifer R. Kam et al., (188) which

indicates equal sex incidence. The most common clinical sign being CALM and mollusca

86

fibrosa (100%). In a study by Neil Gold Berg et al, (188) the incidence of CALM was 69%

CALM were the earliest marker to occur in concurrence with Crow and Schull et al. 113 114

Regarding pigmentary changes, axillary freckling occurred in 60% of cases which is comparable with 70% of axillary freckling by crowe FW et al.35 Incidence of

seizure was 20% which was opposed with 10% incidence in study of Kramer et al. 115 Lisch

nodules has occurred in 60% of cases in contrast to 94– 97% of patients in the literature by

Flueler et al.36

TUBEROUS SCLEROSIS

Tuberous Sclerosis accounts for 12.2% of cases in our study. The common age group

presented was 11 – 20 years with a mean age of 22 years. This is comparable with the study of G. Raghu Rama Rao et al 52which showed mean age of 15.9 years. According to Curallo et

al 116 there is an equal sex incidence, but this study showed a female preponderance. Family

history was positive in 40% in accordance with the study of H. North rup et al.117

Ash leaf macule occurred in 60% as opposed to 80-100% incidence in the study of

Jimbow K et al .50 The commonest cutaneous manifestation was angiofibroma of the face

which was seen in 83.3%. This is comparable with 96% incidence as per the study of

Viamonte et al . (108) Shagreen patch was observed in 83.3% as opposed to 50% reported by

Harris stith et al .(193) The Commonest site of the patch was lumbosacral region in consistent

with the report of Kuntonji et al.(193)

Forehead plaque was seen in 33.3 % which is consistent with that of 36%

incidence in the study of Webb et al.118Koenens tumour was reported in 50% in contrast to

15% incidence in the study of Joswiak et al. (99)The prevalence of CALM was 16.7% as

against the 30% reported by Kuntonji et al.119 Seizures were reported in 33.3% cases as

opposed to 53.33% incidence as per Anisya – Vasanth et al.(195)CNS : Subependymal

nodules and Cortical tubers were seen in 25% of cases as opposed to Curatolo p et al

87

.,116study which revealed 50% incidence. Renal angiomyolipoma was detected in 33.3% in contrast to 60% reported in literature.

NAXOS SYNDROME

6.1% of study patients are involved. Average age of the patients in our study were 18 years where as in study by Baykan et al .,120it was 6 years. In our study , age of onset of

disease was 2 years where as reports by Reena Rai et al 72 and Meera et al121 observed it 1

year of age.History of 2 nd degree consanguinity was observed in our patients which is

similar in case reports by Reena rai et al and Meera et al.Only cutaneous findings and wolly

hair are seen in 3 patients.ECHO showed trivial mitral regurgitation in one patient.No one

showed features of cardiomyopathy.This is in accordance with the reports of Baykan et al120

and Meera et al.121

PORPHYRIA CUTANEA TARDA

6.1% of study patients are found to have porphyria cutanea tarda. All patients

present with blisters in sunexposed areas under 5 years of age where as case report by

Tadjana et al 94observed it in a patient with onset by 8 years of age. Atrophic varioliform

scars ,pseudoscleromatous appearance and milia are observed in all patients and similar

changes are noted by Roopa et al.122. 2 of our patients showed pink coloured fluorescence by

wood’s lamp. Histopathological changes observed by Tadjana et al94 is in accordance with

our study.

DERMATOPATHIA PIGMENTOSA RETICULARIS

6.1% of cases presented with dermatopathia pigmentosa reticularis in which 2

patients were siblings. In our study two siblings affected in same family and similar to case

reports by Aisha Ghias et al.123In our study, all presented with dark coloured skin lesions all

over the body and the age of the onset was 6 months in one patient and one year in two

88

patients which is consistent with the reports by Vinay shanker et al., 124Fahad al saif et

al..125There is history of photophobia in one patient which is not seen in cases of Aisha Ghias et al. 123Diffuse hair loss seen in all patients which was shiny, fine ,soft and blackish brown

in colour.Nail changes in the form of onycholysis , onychodystrophy seen in all

patients.Similar findings were observed by Vinay shanker et al.,124 Fahad al saif et al..125

DYSCHROMATOSIS SYMMETRICA HEREDITARIA:

2% of cases were found to have dyschromatosis symmertrica hereditaria.The age of

onset in our patient was 1 year of age which is consistent with the study by Ami Chia Ying –

Peng et al.,126 where the age of onset ranges from birth to 8 years of age.Our patient born of

non consanguinous marriage where Amia Chia Ying – Peng et al.,126 noted in consanguinity

in 56%.Freckles like macules in the face and multiple hyper and hypopigmented macules are

in our patient and Amia Chia Ying – Peng et al.,126observed this combination of facial freckles and reticulate pigmentation in 40%.

INCONTINENTIA PIGMENTI:

A rare condition which constituted 2% of the study. She presented with fluid filled and dark coloured skin lesions all over the body since birth. Smail Hadj Rabia et al.127 in

their study diagnosed IP in newborn similar to our study. Linear hyperpigmented patches in a

blaskhoid pattern present over arms,forearm,trunk,thighs and legs seen in our study and

similar clinical pattern is observed by T.A.Phan et al.,128 at day 1 of life and they observed it

in 80 % of cases. In our study the onset of IP is in utero and eosinophilia is seen and it is

accordance with study by Yang Yang et al.129

X LINKED HYPOHIDROTIC ECTODERMAL DYSPLASIA

2 patients out of 49 (4.1%) were identified as X linked hypohidrotic ectodermal

dysplasia, which consisted of maternal grandfather and his grandson.Similar familiar occurrence was noted by Karthik hedge et al.,130 and Uday ginjupally et al., 131where three

89

siblings and two siblings are affected respectively. Narrow incisors and conical shaped

canines are seen in our patient which is consistent with Karthik hedge et al. Prominent

everted lips and periorbital pigmentation was observed and similar observation is seen by

Anoop kumar et al.132

PSEUDOXANTHOMA ELASTICUM

4.1% study patients were identified as pseudoxanthoma elasticum.The mean age of onset of disease our patients was 12 years which is in accordance with Weenink et al.133where

as Baglieri et al.134 and Marques et al.,135 observed it by 40 and 42 years respectively.No

family history was observed in our study which is in accordance with studies by Baglieri et

al. 134and Marques et al.,135 . No ocular changes were observed in our cases where Khrifi

Zineb et al.136, observed in 70% of cases. Histopathology and special stains for calcium and elastin confirmed the diagnosis and Weenink et al.,133 noted the similar observation.

EPIDERMODYSPLASIA VERRUCIFORMIS

2 % was diagnosed to have epidermodysplasia verruciformis.The age onset was 10 years of age and she was born of 2 nd degree consanguinous marriage .Donaldson et al.,137

observed late of age of occurrence at 25 years in patient born of non consanguinous parents.

The hypopigmented scaly macules and thick verrucous plaques were in acoradance with

Vohra et al.,138 and Yoshida et al.139

EPIDERMOLYSIS BULLOSA JUNCTIONAL

One case of epidermolysis bullosa junctional (2%) was reported in our study.

Epidermolysis bullosa was seen in 2% cases where as studies by Farah sammem et al

.,108Federica Dassoni et al. 105and Sunil kumar et al .,132observed it in 9%,4 % and 9 %

respectively. Our patient born of 2nd degree consanguinous marriage with no positive family history whereas Caroline et al., (177) seen more patients with positive family history.

Mancuso et al .,140 observed 71 % survival rate of EB Junctional intermediate type.

90

TRICHOEPITHELIOMA

Rare condition which constituted 2% of the study.In our study the age of onset is

about 30 years and had positive family history in two daughters. Ramesh kumar et al 141noted

similar familial occurrence in his patients but with earlier onset of lesions. Aravind karikal et

al., 142observed multiple trichoepitheliomas in a patient similar to our study.

Histopathological findings were in accordance with the study by Sangwaiya et al.143

APLASIA CUTIS CONGENITA

It was observed in 2 % of study group. Incidence is approximately 1-3 out of every

10,000 live births. Sivaprakasam et al.,144observed the usual occurrence of truncal aplasia cutis congenita with fetus papyraceus .In our case USG at 12 weeks showed twin pregnancy with one showing no cardiac activity and at 18 weeks become fetus papyraceus.

Sivaprakasam et al.,144observed at 7 weeks of pregnancy showed a viable twin intrauterine

gestation and at 23 rd week seen a fetus papyraceus in the lower pole of uterus.

CORNELIA DE LANGE SYNDROME WITH HYPOMELANOSIS OF ITO

Rare condition which constituted 2 % of the study.In our study patient was born of

non consanguinous marriage and had no family history which is in accordance with the study

by Kala et al. (216)The history of delayed milestones, and poor performance at school and the

findings of low pitched, growling and gutteral deep voice ,bushy eyebrows long eyelashes

and synophrys were in accoradance with the study by Muhammed et al. 145ECHO showed

Ostium Secundum type of Atrial Septal defect in our patient Chawla et al .,146 observed

perimembranoius ventricular septal defect.

EFFECT OF DERMATOSES ON QUALITY OF LIFE:

Out of the 36 patients (above 16 years of age ),quality of life was not affected in 6

patients (16.7%; M: 4, F: 2) and was affected in remaining 30 patients (83.3%; M: 17, F: 13).

Most of the patients(33.3%) had moderate effect of their diseases on quality of life(as

91

measured by DLQI score) followed by small effect in 30.6%, very large effect in 19.4%

patients, with more males affected than females except for the “moderate effect” category in

which both are equal. DLQI scores compared between males and females did not show any

statistical significance (p=0.886)

The most common domain affected was symptoms and feelings in 83.3 % of patients,

followed by daily activities (72.2 %), leisure (58.3 %), personal relationships (47.2%),

treatment (41.6 %) ,work and school(13.8%)and no affection in 16.7%.

DOMAINWISE EFFECT OF DISEASES ON DLQI:

The common domains affected in the students were “symptoms and feelings” and

“work and school”(diseases are ichthyosis vulgaris,lamellar ichthyosis,neurofibromatosis and

tuberous sclerosis)and in people were “symptoms and feelings” and “daily activities” (naxos syndrome, X linked hypohidrotic dysplasia and epidermodysplasia verruciformis).

The mean DLQI scores of common diseases reported in literature are 9.3 ± 6.5 for

Ichthyosis by Dreyfus et al .,147 8 ± 4 for ectodermal dysplasia by Pavlis et al.,148 10.70 for

epidermolysis bullosa by Horn et al.,1495.13 ± 5.47 for tuberous sclerosis by Crall et al.150

13.0 for porphyria cutanea tarda by C.T Jong et al.151

The most common domains affected for diseases in literature were “symptoms and

feeelings” for ichthyosis (Dreyfus et al.,)147, “symptoms and feelings” and “leisure ” for

neurofibromatosis (Wolkenstein et al.,)152 “symptoms and feelings” for Tuberous sclerosis

(Crall et al.,)150 In the study conducted by Jagannath et al.,109 Dermatology life quality index

(DLQI) analysis showed that majority of the population had small effect on patients life

constituting 47% but in our study most of the patients(33.3%) had moderate effect followed

by small effect in 30.6% . Jagannath et al.,109 observed no effect in 33% but we observed in

16.7% , very large effect is observed in 19.4% patients as opposed to 0.5% by Jagannath et al., 109on patient’s life.

92

SUMMARY

• The total number of new cases were 15,200 out of which 49(0.32%) were diagnosed

to have genodermatoses with a prevalence of 32 per 1000.

• There were 59 % males and 41% females were affected in our study with M:F ratio

of 1.45:1. Most common age group affected was second decade.

• Among the total 49 cases, a total of 44 cases (89.8%)were educated and 5

(10.2%)were uneducated .

• Out of the total cases, most common diseases observed were ichthyoses found in 36.7

% cases, followed by harmatoneoplastic syndromes in 22.4% cases, genetic

hyperpigmentary disorders in 10.2% cases , naxos syndrome in 6.1%, porphyria

cutanea tarda in 6.1% , X linked hypohidrotic ectodermal dysplasia in 4.1% patients,

pseudoxanthoma elasticum in 4.1% patients, epidermodysplasia verruciformis in one

patient, epidermolysis bullosa junctional in one patient, trichoepithelioma in one

patient, aplasia cutis congenita in one patient and cornelia de lange syndrome seen in

one patient with each constituting 2 %.

• About 1/3 rd of cases born of non consanguinous marriage and 2/3 rd of cases born of

consanguinous marriage.

• About 35% of patients had positive family and 65% didn’t have positive family

history.

• Most common age group affected in congenital ichthyosis was first decade.

• All cases were of NF type – 1 with most of the patients in 4 th decade. Palmar,

Axillary and inguinal freckling, Lisch nodules seen in 60% cases and Focal areas of

signal hyperintensities in CT Brain seen in 40% cases.

93

• Tuberous sclerosis was diagnosed in patients aged from 7 to 36 years with the mean

age being 22 years. 33.3% cases showed subependymal nodules,cortical tubers and

renal angiomyolipoma.

• ECHO in one patient with naxos syndrome showed trivial mitral regurgitation.

• Dyschromatosis symmetrica hereditaria seen in a patient with freckles over the face.

• X linked hypohidrotic ectodermal dysplasia seen in 4.1% patients –Maternal

Grandfather and grandson.Only 4 peg shaped teeths are seen in grandson.

• Aplasia cutis congenita with fetus papyraceus seen in one patient detected by

antenatal ultrasonography.

• Cornelia de lange syndrome showed ECHO features of ostium secundum type of

atrial septal defect.

• No chromosomal disorders were observed in our study.

• Quality of life assessment was done in patients above 16 years of age affection is seen

in 83% and not affected in 17%

• About 33.3% had moderate effect of their diseases on quality of life followed by

small effect in 30.6% and very large effect in 19.4% of patients.

• The most common domain affected was “symptoms and feelings” in 83.% ,followed

by “daily activities” (72.%), leisure (58%), personal relationships (47%), treatment

(42%) ,work and school(14%).

• The diseases with the high mean DLQI scores were Junctional epidermolysis bullosa ,

epidermodysplasia verruciformis , dermatopathia pigmentosa reticularis and porphyria

cutanea tarda and hypohidrotic ectodermal dysplasia due to their scaly,bullous and

pigmentary lesion causing embarassement ,disturbance in social activities and

relationship with friends and relatives .

94

CONCLUSION

Our study was aimed to assess the patterns and clinical profile of genodermatoses and their effect on quality of life in hospital setting including all age groups. In our study we found that most common group of diseases were inherited disorders of cornification followed

by harmatoneoplastic syndromes, genetic hyperpigmentary disorders, porphyrias and

ectodermal dysplasias. Most common diseases were ichthyosis vulgaris , tuberous sclerosis

and neurofibromatosis and rare diseases like harlequin ichthyosis, aplasia cutis congenita and

cornelia de lange syndrome .Quality of life was most affected in diseases like

ichthyoses,neurofibromatosis , junctional epidermolysis bullosa and hypohidrotic ectodermal

dysplasia due to their rough,raised,bullous and pigmentary lesion causing embarassement

,disturbance in social activities and relationship with friends and relatives .

Analysis of clinical patterns of genodermatoses with their effect on quality of life

was not done in South India before. There are only very few studies in literature across the

globe depicting patterns of genodermatoses. We compared our study with International and

Indian studies and there is diversity in the study settings ,study population and prevalence of

the diseases..There were studies about patterns of genodermatoses in North India , one

study in paediatric population and other included all age groups and both were done in

hospital setup and they didn’t assess the quality of life.Another study from North Ethiopia studied genodermatoses but they too didn’t assess the quality of life. To the best our knowledge our study is the first of it’s kind to study the patterns of genodermatoses and their

effect on quality of life.In our study most common disease groups affected were ichthyoses followed by hamartoneoplastic syndromes which was consistent with study done in Jammu and Kashmir.But the study done in New Delhi showed increased prevalence of ichthyoses

followed by epidermolysis bullosa and study done in North Ethiopia showed more cases of

95

hamartoneoplastic syndromes followed by ichthyoses. All the studies including our study didn’t do genetic mapping to confirm the disease due to lack of facilities.

Genodermatoses patients and their parents should be counseled about the chronic

nature of the disease, familial involvement ,associated system involvement and available

treatment options because they also have an impact on their quality of life. Early diagnosis

and early intervention can reduce the deformities, improve the quality of life and their

performance in school.We need to do social help and vocational rehabilition for these

patients.The study on genodermatoses will be helpful to know about the inheritance patterns

and appropriate diagnosis will be helpful in prenatal diagnosis in subsequent pregnancies and

also helpful in genetic counselling.

96

LIMITATIONS

 Genetic analysis was not done in our patients to confirm the diagnosis which can be a

platform for further research purposes and steps have been for that.

 Long term followup of the patients will be needed as some of the systemic

manifestations will appear at an later age.

97

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APLASIA CUTIS CONGENITA WITH FETUS PAPYRACEUS

BILATERAL STELLATE SHAPED SCARS OVER TRUNK

BULLOUS ICHTHYOSIFORM ERYTHRODERMA – RIDGED HYPERKERATOTIC SCALES

CORNELIA DE LANGE SYNDROME – EXPRESSIONLESS FACE , SYNOPHRYS AND CLINODACTYLY

DERMATOPATHIA PIGMENTOSA RETICULARIS – RETICULATE PIGMENTATION OVER CHEST,PALMS

RETICULATE PIGMENTATION OVER BUCCAL MUCOSA , TONGUE AND DIFFUSE HAIR LOSS

DYSCHROMATOSIS SYMMETRICA HEREDITARIA JUNCTIONAL EPIDERMOLYSIS BULLOSA

FRECKLES OVER THE FACE BULLAE AND CRUSTED EROSIONS ALL OVER THE BODY

X LINKED HYPOHIDROTIC ECTODERMAL DYSPLASIA – ABSENT TEETH

X LINKED HYPOHIDROTIC ECTODERMAL DYSPLASIA – SPARSE HAIR , EVERTED LIPS

HARLEQUIN ICHTHYOSIS – COAT OF ARMOUR LIKE SCALES,ECTROPION AND ECLABIUM

EPIDERMODYSPLASIA VERRUCIFORMIS

ICHTHYOSIS VULGARIS – FINE SCALES WITH SPARING OF POPLITEAL FOSSA

INCONTINENTIA PIGMENTI – MULTIPLE VESICLES ALONG BLASCHKOID PATTERN

LAMELLAR ICHTHYOSIS – LARGE PLATE LIKE SCALES WITH ECTROPION

NAXOS SYNDROME - WOOLLY HAIR WITH STRIATE PALMOPLANTAR KERATODERMA

FAMILY AFFECTED WITH NAXOS SYNDROME

PSEUDOXANTHOMA –“MOROCCAN LEATHER” APPEARANCE OVER NECK

NEUROFIBROMATOSIS – NEUROFIBROMA , PALMAR FRECKLING

CAFÉ – AU LAIT MACULES

LISCH NODULES TRICHOEPITHELIOMA

TUBEROUS SCLEROSIS – ANGIOFIBROMA AND CONFETTI LIKE MACULES

TSC- FOREHEAD PLAQUE

PERIUNGUAL FIBROMA/ KOENEN’S TUMOUR GINGIVAL FIBROMA

PORPHYRIA CUTANEA TARDA – KYPHOSCOLIOSIS , EROSIONS AND VARIOLIFORM SCARS

VITILIGINOUS MACULES OVER PALMS

DERMATOLOGY LIFE QUALITY INDEX DLQI Hospital No: Date: Name: Score: Address: Diagnosis:

The aim of this questionnaire is to measure how much your skin problem has affected your life OVER THE LAST WEEK. Please tick  one box for each question.

1. Over the last week, how itchy, sore, Very much  painful or stinging has your skin A lot  been? A little  Not at all 

2. Over the last week, how embarrassed Very much  or self conscious have you been because A lot  of your skin? A little  Not at all 

3. Over the last week, how much has your Very much  skin interfered with you going A lot  shopping or looking after your home or A little  garden? Not at all  Not relevant 

4. Over the last week, how much has your Very much  skin influenced the clothes A lot  you wear? A little  Not at all  Not relevant 

5. Over the last week, how much has your Very much  skin affected any social or A lot  leisure activities? A little  Not at all  Not relevant 

6. Over the last week, how much has your Very much  skin made it difficult for A lot  you to do any sport? A little  Not at all  Not relevant 

7. Over the last week, has your skin prevented Yes  you from working or studying? No  Not relevant 

If "No", over the last week how much has A lot  your skin been a problem at A little  work or studying? Not at all 

8. Over the last week, how much has your Very much  skin created problems with your A lot  partner or any of your close friends A little  or relatives? Not at all  Not relevant 

9. Over the last week, how much has your Very much  skin caused any sexual A lot  difficulties? A little  Not at all  Not relevant 

10. Over the last week, how much of a Very much  problem has the treatment for your A lot  skin been, for example by making A little  your home messy, or by taking up time? Not at all  Not relevant  Please check you have answered EVERY question. Thank you. AY Finlay, GK Khan, April 1992 www.dermatology.org.uk, this must not be copied without the permission of the authors. ˆh∫©ıhªı‚ ¡ıÃU¯P uµ Amh¡¯n iG¿U≥I Ìıϧh¿ Gs: ˜uv: ©v®ˆ£s: ˆ£Ø∫: hØU⁄ı]Ï: ïP¡õ:

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©AY Finlay, GK Khan, April 1992, This must not be copied without the permission of the authors. ENGLISH TO TAMIL 22 JANUARY 2008 GENODERMATOSES PROFORMA

Case no: IP/OP no: Date:

Name: Age: Sex:

Address: Mobile No: Informant:

Occupation: Patient - Parents -

Degree of consanguinity: Order of birth:

Pedigree Chart: (With Degree of Consanguinity and Age of the Patient)

HISTORY:

Presenting complaints with duration of each:

Age of Onset:

Progression: h/o scaly skin lesions-

Scaling – age of onset/ distribution

Course of lesion- tends to improve/ persistent/ remission

Seasonal variation- summer / winter exacerbation/ cyclical shedding or peeling h/o raised skin lesions – symptomatic /asymptomatic - h/o asymptomatic light/dark coloured skin lesions – h/o fluid filled lesions – h/o fissures - h/o itching - h/o diminished sweating and heat intolerance – h/o repeated skin infections – h/o photosensitivity/burning sensation - h/s/o atopy/asthma- h/o unprescribed drug intake – h/o native medicine application – h/o oral lesions – h/ o fever /joint pain - h/o swelling in the inguinoscrotal region - h/s/o skeletal abnormalities – h/o difficulty in walking/difficullty in climbing upstairs – h/s/o developmental delay – h/s/o mental retardation- h/o any abnormal movements/restriction of limb movements - h/o speech impairment - h/o learning difficulties – h/o of visual disturbances /photophobia – h/o difficulty in hearing/perception of smell - h/o headache/seizures - h/o cough/cold - h/o chest pain/palpitation/dyspnoea - h/o abdominal pain/vomiting/diarrhoea/malabsorption - h/o loss of weight/loss appetite -

Past History :

History of similar illness in the past k/c/o DM/HT/TB/BA/EPILESY

Birth history : term/preterm/normal labour/assisted/caesarean section, cried immediately after birth APGAR: h/o prematurity / prolonged labour

h/o neonatal resuscitation

Milestones,growth and Development: h/o colloidion appearance/Harlequin fetus/blisters/erythroderma at birth:

Personal History :

Family History :

Contact History :

Menstrual History :

Treatment History :

GENERAL EXAMINATION:

Conscious, oriented, comfortable at rest,

Anaemia, jaundice, cyanosis, clubbing, pedal edema, lymphadenopathy

BP : PR : RR: Temperature :

CVS: RS : P/A: Organomegaly -

CNS: higher function/ speech/ hearing /Nystagmus / hypertonicity / thickened peripheral nerves

Facial Appearance: GROWTH AND DEVELOPMENT STATUS :Physical/Mental

NUTRITIONAL STATUS :

STATURE :

Microcephaly/Cataract/Gait/Bony deformity:

DERMATOLOGICAL EXAMINATION:

Morphology– Patches/ Plaques/ Papules /Nodules/Macules/ Keratoses / blisters / erosion /Ulcers

Nature of Distribution – Patchy /Diffuse /Other patterns

Scales:

present / absent

small/large

White/gray/ light to dark brown /dark

Loose/Flaky / semi-adherent / adherent/powdery/ Branny

Turned up edges( Inward /Outward/double track)

Polygonal / porcupine spine like scale

Lamellar/Warty

Fissures – present/ absent

Erythematous patches – present / absent

Peeling / Ridged hyperkeratosis -

Velvety brown/rough or hyperkeratotic/ lichenification/Erythroderma –

Ectropion/Eclabium/Ear Deformity/Crumbled ears

Eczema/Keratosis pilaris/Impetigo/Fungal Infections/ - ORAL CAVITY EXAMINATION:

GENITAL EXAMINATION: External Appearance/Organ Development /Any Lesions/Testicular descend

SCALP :

Pityriasis amiantacea / matting of hair / alopecia

HAIR :

Hair density - Sparse / total loss / patchy loss/ patterned loss/ normal/ profuse

Hair length :

Hair characteristics - lustreless / shiny / dry/brittle hair

Hair colour –

Hair texture – fine,soft / thick/rough / spongy / wiry / uncombable / unruly/ Lanugo like

Hair pull test –

Other Features:

NAILS: SITES:

nail dystrophy / ridging / subungual hyperkeratosis/onycholysis

hypoplasia of nails/anonychia/onychomedesis/Beau’s lines/pterygium

pigmentation of nails – linear/diffuse/any abnormal colour/whitening of nails

abnormal shape of the nails

PALMS & SOLES: palmoplantar hyperlinearity / blisters / palmoplantar hyperkeratosis / fissures / sclerodactyly / digital contractures / hyperhidrosis

TEETH EXAMINATION:

SKELETAL EXAMINATION:

OPTHALMIC EXAMINATION:

ENT ASSESSMENT:

PSYCHIATRIC ASSESMENT:

NEUROLOGIST OPINION:

CARDIOLOGIST OPINION:

THORACIC PHYSICIAN OPINION:

ENDOCRINOLOGIST OPINION:

DIAGNOSIS:

Provisional :

Final :

INVESTIGATIONS :

I.ROUTINE : DATE:

CBC RBS LFT

TC Urea T.Bilirubin DC Creatinine D.Bilirubin Hb Sr.Sodium I.Bilirubin RBC Sr.Potassium SGOT Platelet SGPT ESR ALP Sr.Protein Sr.Albumin Sr.Globulin II.HAIR MICROSCOPY :

SIMPLE :

TRICHOGRAM:

DERMASCOPY:

III.SKIN BIOPSY:(MORPHOLOGY/SITE/DATE)

IV.IMAGING :(X-RAY,USG,CT,MRI)

V.RELEVANT SYSTEM INVESTIGATIONS :(ECG, ECHO ,EMG )

Other Palms Component Age Educati Occupa Consan Family Birth Seconda Other Axilla/ DQLI Components Diagno Inherit SL NO Name Age Gender Onset complaint Primary Sites Scales Oral Hair Nails and Teeth Eye severely Group on tion guinity history history ry Findings inguinal score affected sis ance s soles affected

1 Lakshmi 20 2 2 4 4 3 2 7 1 1,3 3,4 1,6 8,9,12,1 8 3 4 2 9 3 1 1 1 3 1,2,3 1 1 2 2 Malliga 18 2 2 1 7 3 2 12 1 1,3 3,4 1,6 8,9,12,1 8 3 4 2 9 3 1 1 1 3 1,2,3, 1 1 2 3 Vijai 17 2 1 4 1 3 2 12 1 1,3 3,4 1,6 8,9,12,1 8 3 4 2 9 3 1 1 1 2 1,3,4 1 1 2 4 Sindhamudhar 14 2 1 4 1 4 1 1,3,8 2 1,3,7 2 1,2 18 8 2 1 1 10 3 3 1 5 4 1,2,3,4,5,6 1 2 2 5 Marivannamuthu 7 1 1 2 1 1 1 7,8 2 1,3,7 2 1,2 18 8 2 1 1 1 1 3 1 5 2 2 6 Regina banu 20 2 2 5 3 4 2 12 1 1,3 2,4 1 18 8 6 1 1 1 5 3 1 1 3 1,2,3 1 3 1 7 Siddiqa Parveen 18 2 2 5 7 4 2 12 1 1,3 2,4 1 18 8 6 1 1 1 5 3 1 1 3 1,2,6 1 3 1 8 Narmada 10 1 2 2 1 1 2 10 2 1,4 2 1,6 19 8 3 1 1 1 2 1 1 1 20 5 9 Prince 30 3 1 5 5 4 2 12 1 1,3 2 1 19 8 3 1 1 1 1 1 1 1 1 7 7 20 5 10 Arunkumar 17 2 1 5 1 1 2 1,5,11 2 1,4 3,6,7 3,7 7,8,9,12 8 1 5 2 4 7 1 4 1 4 1,2,3,4,5,6 1 4 2 11 Ganesan 14 2 1 4 1 1 2 8 2 1,3 3,4 13 3 8 1 1 1 1 1 1 1 1 3 1,2,3,6 1 5 2 12 Mary 52 6 2 2 3 1 2 12 1 1,3 2 1 19 8 3 1 1 1 1 1 1 1 1 7 7 20 5 13 Ramesh 33 4 1 4 2 1 2 9 2 1,3 1,2,5 13 6,7,8,9, 1,2,7 1 1 1 1 1 2 1 3 2 1,2,6 6 6 1 14 Paruvadhavardhini 16 2 2 5 1 1 1 12 2 1,4 1,2,4,5 13 2 1,3 1 1 1 1 1 1 1 1 2 1,2,5 1 6 1 15 Sangeeth 17 2 1 5 1 4 2 12 1 1,4 2 1,6 19 8 3 1 1 1 7 1 1 1 2 1,3,5 1 20 5 16 Gopinath 8 1 1 2 1 1 1 5,6 2 1,3 2,3,7 1,3, 18 8 5 1 1 6 1 1 1 1 7 1 17 Sudalaikani 16 2 1 4 1 1 2 12 2 1,3 1,2,3 13 2,3,4,5 1,4 1 1 1 1 1 1 1 1 3 1,2,3,5 1 8 1 18 Esakkiammal 23 3 2 5 3 3 2 12 2 1,3 1,3,4 13 4,5,6,7,8 8 1 1 1 1 1 1 1 1 4 1,2,3,5,6 5 9 1 19 Ramasamy 45 5 1 4 4 1 2 12 1 1,3 2 1 19 8 3 1 1 1 1 1 1 1 1 7 7 20 5 20 Indhumathi 12 2 2 3 1 1 2 3 2 1,3 3,4 13 3 8 1 1 1 1 1 1 1 1 5 2 21 Sivabalasubramanian 18 2 1 5 1 3 2 12 2 1,3 1,2 3,4 ,8,9,12, 8 1 2 2 2,6 6 2 1 1 3 1,2,3,6 1 10 1 22 Nishanth 18 2 1 5 4 1 2 1,6 2 1,3 1,2 7 2,8,9 8 1 1 1 1 1 1 4 1 2 1,2,5 1 4 2 23 Irudhayaraj 25 3 1 6 5 3 2 10 1 1,4 2 1 19 8 3 1 1 1 1 1 1 1 1 7 7 20 5 24 Velayudham 18 2 1 5 1 1 2 11 2 1,3 1,2 13 7,8,9,12 8 1 2 2 4 5 2 1 1 4 1,2,3,5,6 1 10 1 25 B/O Shilpa 2days 1 2 1 7 1 1 12 2 1,4 2,6 1 7,8,9,11 8 3 1 1 1 1 1 1 1 11 3 26 Murugan 53 6 1 4 4 1 2 12 2 1,3 3,5 13 1,2 8 1 1 1 1 1 1 1 1 2 1,2,3 1 12 1 27 Sureshkumar 8 1 1 2 1 1 2 12 2 1,4 1,2 13 2,6,8,9 7 1 1 1 1 1 1 1 1 13 1 28 Josphine 49 5 2 4 3 1 2 12 1 1,3 2 1 19 8 3 1 1 1 1 1 1 1 1 7 7 20 5 29 Rajarathinam 30 3 1 5 4 1 1 4 2 1,4 2,4 1 4,5,6,7,8 8 7 1 2 1 1 1 1 1 3 1,2,5 1 14 2 30 Jagadeeswari 36 4 2 2 3 4 1 12 2 1,3 1,2,3,4 13 6,7,8,9, 4,5,6 1 2,3 1 3 1 1 2 1 2 1,3,5 1 8 1 31 Balasubramanian 3 1 1 1 7 3 1 12 2 1,3,7 2 1 18 8 2 1 1 1 1 1 1 1 2 2 32 Kandhasamy 27 3 1 5 5 1 2 12 2 1,3 2 1 19 8 3 1 1 1 1 1 1 1 2 1,2,6 1 20 5 33 Cherman 20 2 1 3 4 1 2 1,3,5,8,11 2 1,3 1,3,6,7,10 3,4,7 7,8,9,11 8 1 1 1 4 7,8 1 1 1 3 1,2,3,6 1 4 2 34 Santhiya 19 2 2 5 7 1 2 8,9,11 2 1,3 1,2,3 13 4,5,6,7,8 4,5,6 1 2 1 3 5 1 1 1 4 1,2,3,5,6 2 8 1 35 Maridurai 7 1 1 2 1 1 1 1 1 1,4,7 2 1 18 8 3 1 2 1 5,7 1 3 1 15 4 36 Petchiammal 12 2 2 3 1 1 2 12 2 1,4 2 1 19 8 3 1 1 1 1 1 1 1 20 5 37 Nishanthi 30 3 2 2 3 1 1 6,9 1 1,3 1,3,4,5 13 2,4,6,7 4,6 7 2,3 1 1 1 2 1 1 3 1,2,5,6 1 8 1 38 Sundari 7 1 2 2 1 1 2 12 1 1,3 2,3,4 13 2,4,5,9 4,5,6 7 3 1 1 1 1 1 1 8 1 39 Pon aadhavan 4 1 1 1 7 3 1 12 2 1,4,7 2 1 18 8 3 1 1 1 1 3 1 1 2 2 40 Mandhira moorthy 9 1 1 2 1 4 1 7 2 2,4 2 1,6 18 8 4 1 1 12 7 1 1 5 16 2 41 Rajalakshmi 19 2 2 5 1 1 1 12 2 1,3 1,2,3,5 13 ,8,9,12, 1,2,7 7 2 1 1 4 2 1 3 3 1,2,3,5 3 6 1 42 Mari 25 3 2 5 3 1 2 12 2 1,3 3,4 13 2,4,6 2,6 7 3 1 3 1 1 1 1 2 1,2,5 1 8 1 43 Velmurugan 17 2 1 5 7 1 1 6 2 1,3 2 13 4,8 8 7 1 1 1 1 1 1 1 2 1,2,6 1 17 1 44 Kathiresakannan 27 3 1 6 5 3 1 12 2 1,3 6,7 3 18 8 7 1 1 1 8 1 2 1 4 1,2,3,4,5,6 1 18 2 45 Chitrakani 33 4 2 4 3 1 2 12 2 1,4 1,2,5 13 4,5,6,7,8 1,2,7 7 1 1 1 4 2 1 3 2 1,3,5 1 6 1 46 Venkatasubramani 31 4 1 5 5 1 2 12 2 1,3 2,5 13 ,6,7,8,1 1,2 7 1 1 1 4 2 1 1 1 7 7 6 1 47 B/O Kavitha 11 days 1 1 1 7 4 1 12 2 1,3 4 4,7 4,5,6,7 8 7 1 1 1 1 1 1 1 19 1 48 Ramalakshmi 19 2 2 6 1 1 2 11 2 1,3 1,2 13 ,3,4,5,6 8 1 2 2 4 5 2 1 1 4 1,2,3,4,5,6 2 10 1 49 Gandhi 55 6 1 4 2 1 1 1 1 1,3,7 2 1 18 8 3 1 2 1 5,7 1 3 1 3 1,2,3 1 15 4 KEY TO MASTER CHART

Age group

1- 0 to 10 years 2- 11 to 20 years 3 - 21 to 30 years 4 - 31- 40 years 5 – 41- 50 years

6 – 51 – 60 years

Gender

1- Male 2- Female

Education

1- Uneducated, 2 - Primary school (1-5), 3- Middle school (6-8), 4- High school (9,10),

5- Highersecondary (11,12) ,6 - Graduate

Occupation

1 – Student 2 - Manual Labourer , 3 – Housewife 4 - Skilled Worker,5- Semi skilled

6 – Professional 7 – Unemployed

Consanguinity

1- Non consanguineous 2 - 1 st degree 3- 2nd degree 4- 3 rd degree

Onset

1- At birth 2 - After birth

Other complaints

1- Photosensitivity 2 - Unprescribed Drug intake 3- Native medicine application 4- Fever 5- Easy fragility 6- Develepmental delay 7- Difficulty in walking 8- Eye complaints 9- Seizures 10- Atopy 11- Photophobia 12- Nil

Family history

1- Yes 2 - No

Birth History

1- Term 2 - Preterm 3- Normal labour 4- Cesarean

5- Neonatal resuscitation 6- Abnormal milestones 7- Collodion appearance

Primary lesion

1-Macule 2 - Patch 3- Papule 4 - Plaque 5- Nodule 6- Vesicle 7- Bulla 8- Pustule 9- 10- Cyst 11- Petechiae 12- Ecchymosis 13- Nil

Secondary lesion

1- Scale 2 - 3- Erosion 4- 5- Excoriation 6- Fissure 7- Scar 8- Lichenification 9- Poikiloderma 10- Eschar 11- Sclerosis 12- 13- Nil

Sites

1- Scalp 2 - Face 3- Neck 4- Chest 5- Abdomen 6- Upper back 7- Lower back 8- Upper Limb 9- Lower Limb 10- Genitals 11- Gluteal region 12- Palms 13- Soles 14- Axilla 15- Groin 16 -Fingers 17 - Toes 18 – Whole body 19 - Whole body except groin ,flexures, face

Other findings

1- CALM 2 - NF 3- Plex NF 4- Angiofibroma 5- Ash Leaf Macule 6- Shagreen Patch 7- Freckles 8- Nil

Scales

1- Nil 2 - Plate like 3- Fine 4- Coat of Armour like 5- Ridged hyperketosis 6- Flaky 7- Double edge

Oral

1 Normal 2 - Pigmentation 3- Gingival fibroma 4 - Whitish papules 5- Mucosal

Hair

1- Normal 2 - Abnormal

Nails

1- Normal 2 - 3- Koenon tumour 4- Nail dystrophy 5- Nail pitting 6- Onycholysis 7- Hyperpigmentation/ Hypopigmentation 8 - Abnormal shape 9- Nail pallor with pseudoclubbing 10-Half and Half nails 11- Subungual hyperkeratosis 12-

Palms And Soles

1- Normal 2 -Hyperlinearity 3- Palmoplantar keratoderma 4- Freckling 5- Xerosis 6- Hyperpigmentation 7- Fissuring 8-Crusting

Axillary and inguinal

1-Normal 2 – Pigmentation 3-Scaling

Teeth

1- Normal 2- Dental pits 3- Loss of teeth 4- Flourescent teeth

Eyes

1- Normal 2 – Dryness 3- Lisch Nodules 4- Retinal hamartomas 5- Ectropion

DLQI score

1 -> 0- 1 , 2 - > 2-5 , 3 ->6-10 , 4 - >11-20 , 5 - >21-30

Domain severely affected

1- Symptoms and feelings(1,2) 2 - Daily activities(3,4) 3 - Leisure(5,6) 4 - Work and school(7) 5 - Personal relationships(8,9) 6 - Treatment(10) 7 - Not applicable

Diagnosis

1- Naxos Syndrome , 2- Lamellar Ichthyosis , 3 - Erythrokeratoderma Variablis

4- Porphyria Cutanea Tarda 5 - Pseudoxanthoma Elasticum 6 – Neurofibromatosis– 1

7 - Bullous Ichthyosiform Erythroderma 8 -Tuberous Sclerosis Complex

9 - Epidermodysplasia Verruciformis 10- Dermatopathia Pigmentosa Reticularis

11 - Incontinentia Pigmenti 12 – Trichoepithelioma 13- Dyschromatosis Symmetrica

Herediteria 14 - Netherton Syndrome 15- X Linked Hypohidrotic Ectodermal Dysplasia 16 - Harlequin Ichthyosis 17 - Cornelia De Lange Syndrome 18-

Epidermolysis Bullosa Junctional 19- Aplasia Cutis Congenita 20 - Ichthyosis Vulgaris

Inheritance

1- Autosomal Dominant 2- Autosomal Recessive 3- X Linked Dominant 4 - X Linked Recessive 5- Autosomal Semidonant 6 - Nil