Ebook Recent advances in dermatology: Part 1

(BQ) Part 1 book Recent advances in dermatology presents the following contents: Human genome mapping - Relevance to dermatology, relevance to dermatology, neonatal dermatoses an update, aquatic animal bites and stings - an update; drug hypersensitivity syndrome,....

DERMATOLOGY

As medicine is an everyday-changing science with newerresearches and refined clinical experiences, and also in view ofthe possibility of human error, neither the editors nor the authors/nor the publisher warrant that the informations contained in thebook is in every respect accurate or complete, and they disclaimall responsibility for any errors or omissions or for the resultsobtained from use of the information presented in this work.

Associate Editors

Dinesh Hawelia

Consultant DermatologistInstitute of Allergic and Immunologic Skin Diseases

AMRI Hospitals, Salt Lake, Kolkata

Susmit Haldar

Consultant DermatologistCalcutta Skin InstituteInstitute of Allergic andImmunologic Skin Diseases, Kolkata

Assistant Editors

Manas Sen, Nilendu Sarma, Sanjib Chowdhuri, Sudip Kumar Ghosh

Consultant DermatologistsInstitute of Allergic andImmunologic Skin Diseases, Kolkata

Jitendar P Vij

Jaypee Brothers Medical Publishers (P) Ltd

EMCA House, 23/23B Ansari Road, Daryaganj

New Delhi 110 002, India

Phones: +91-11-23272143, +91-11-23272703, +91-11-23282021, +91-11-23245672 Fax: +91-11-23276490, +91-11-23245683

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First Edition: 2007

ISBN 81-8061-896-X

Typeset at JPBMP typesetting unit

Printed at Replika

all the present dermatologists of India,

whose dedication and contribution are leading Indian dermatology scenario towards a brighter future

Aparna Palit

Assistant Professor

Department of Dermatology,

Venereology and Leprology

BLDEA’s SBMP Medical College,

Hospital and Research Centre

Bijapur-586 103, Karnataka

Arun C Inamadar

Professor and Head

Department of Dermatology,

Venereology and Leprology

BLDEA’s SBMP Medical College,

Hospital and Research Centre

of Medical Sciences, Kolkata

7, Bawali Mondal Road,

Kolkata-700026

Balkrishna Nikam

Senior Resident

Department of Dermatology, BYL

Nair Hospital and TN Medical

College

Mumbai Central, Mumbai-400 008

Bibhuti Saha

Associate Professor and Head,

Department of Tropical Medicine

School of Tropical Medicine

G Raghu Rama Rao

Prof and HOD of DermatologyAndhra Medical CollegeVisakhapatnam-530 001

HR Jerajani

Prof and HOD,Dept of DermatologyLTM Medical College and GeneralHospital, Sion

Mumbai-400 022

KK Raja Babu

Prof and HOD (Retd.)Consultant DermatologistA-62, Road No 12Film Nagar, Jubilee HillsHyderabad

Maya Vedamurthy

Consultant DermatologistW-171, Park Road, Anna NagarWest Extn

Chennai-600 101

Meghana Phiske

Lecturer, Dept of DermatologyLTM Medical College and GeneralHospital, Sion

Mumbai-400 022

Nanda Kishore B

Prof and Head,Department of Dermatology,Venereology and LeprologyFather Muller Medical CollegeKankanady, Mangalore-575 002

Niti Khunger

Associate ProfessorDepartment of Skin and STD

VM Medical College and HospitalNew Delhi

C

Patrick Yesudian

Visiting Consultant,

Apollo Hospitals

Prof of Dermatology (Retd.)

Madras Medical College

TN Medical College and

BYL Nair Hospital

Pediatric Dermatology Division

Institute of Child Health

Kolkata

Seema Sainani

Consultant Dermatologist

201, Ramvithal SmrutisadanPlot no 8, 19th Road, Khan WestMumbai

Soumya Panda

Consultant Dermatologist, BelleVue Clinic

Ashok-Swapna122/4, Dr JR Dhar RoadKolkata-700 028

Sujata Sengupta

Assistant ProfessorDepartment of DermatologyRKM Seva Pratisthan andVivekananda Institute1050/1, Survey ParkKolkata-700 075

Sukumar

Associate ProfessorDepartment of DermatologyVenereology and LeprologyFather Muller Medical CollegeKankanady, Mangalore-575 002

Surojit Kumar Biswas

Assistant ProfessorDepartment of DermatologyMidnapore Medical CollegePaschim Midnapore, West Bengal

VR Janaki

Professor and HOD (Retd.)Madras Medical CollegeFlat No 3, Sri Rama BhavanNew No 19, Third StreetAbhiramapuram, Chennai-600 018

Recent Advances in Dermatology, Volume 2 is in the offing with atotally new set of topics in which great amount of advances andresearch has been made in the recent years Authors of this volumeare different from those of the Volume 1 of Recent Advances inDermatology, which was published in 2004.

The topics like Human Genome Mapping, The Th1-Th2 Paradigm

in Dermatology, Paraneoplastic Pemphigus, Role of BiologicalAgents in Management of Psoriosis and APAS are really fascinating.The other interesting subjects discussed are Acute Skin Failure,Psoriatic Arthritis, Cutaneous Manifestations of HIV Infection, etc.The title has also included few topics on Dermatosurgery andCosmetology, e.g update in Vitiligo Surgery and Chemical Peeling.This excellent endeavor will definitely find place in the book-shelves of both senior and junior dermatologists including post-graduate students in this speciality I must express my personalgratitude to all the contributors for their expertise and labor forwriting their articles

Dr Sanjay Ghosh, Editor-in-Chief, of this volume should bespecially congratulated for his commitment, endurance andacademic aptitude for bringing out such a nice volume like the firstone, which is really a hard task to perform I also congratulate histeam of associate and assistant editors for their valuable support inthis project

Time goes on, and that is progress ! — Charles Chaplin (Modified)

When I took the responsibility of editing the first volume of Recent Advances in Dermatology by the request of Jaypee Brothers, theeminent medical publisher of New Delhi, I was not so sure aboutthe collecting of articles in time from the busy and leadingdermatologists of all over India My apprehension was provedwrong later by the prompt response and contribution by the eminentdermatologists sparing their hectic schedule After the publication

of this book I felt some uncertainty about the reader responseespecially where there is a steady decline of book-readership evenglobally by depending on net and other multimedia Here also Iwas astonished and overwhelmed by the response fromdermatologists of all sectors of India and also some other Asiancountries including seniors to juniors, teachers to students,academicians to practising dermatologists

This thrilling experience has given me the impetus to roll theball again and take the pain to edit the second volume of the ‘RecentAdvances in Dermatology’ Like the first volume, I got whole-hearted and warm support again from all the authors whom Iapproached Even some eminent authors personally expressed theireagerness to contribute to this volume I hereby convey my heartfeltthanks to all the contributors of this volume for their earnestinvolvement with the project

Exactly like the previous volume, our book has been planned asacademic project with a view of postgraduate students and practisingdermatologists as target readers Hence the chapters were designed

in a manner, which can provide basic idea of conventionalknowledge along with emitting the rays of recent advancements inthe field of dermatology We, therefore, included similar to the pastvolume, both seniors for their profound experiences and analyticvision as well as younger ones for their unending academicinquisitiveness and knowledge on the subject As we promised inthe last volume, we have changed all the contributors of this volume

to new ones for giving the chance to all academic dermatologists ofIndia by rotation We sincerely apologize to those academicians,

P

whom we could not be able to include even in the second volumebut I firmly assure that we will invite them in the forthcomingvolume of this book.

I pay my deepest respect from the bottom of my heart to

Dr SK Panja and Dr KK Raja Babu for kindly agreeing to write the

‘Foreword’ and ‘Introduction’ respectively for this volume

I acknowledge and express my sincere regards to Mr TarunDuneja, General Manager (Publishing), Jaypee Brothers for hisregular support and co-operations and also express my personalthanks and regards to all the staff of Jaypee Brothers, New Delhiand Kolkata Branches in accomplishing this project I must pay mysincere thanks to Mr Subhrajyoti Bose, who on behalf of me, hasexecuted all the painstaking job of DTP and all other computer worksincluding the graphics of this issue My offer of earnest regardsshould not end here without expressing my indebtedness to myassociate and assistant editors without whom I could not dare totrek in this present difficult journey

Sanjay Ghosh

e-mail:drsanjay1@vsnl.net

1 Introduction: Between Empiricism and Evidence-based Medicine, is there a ‘Middle Road’? 1

KK Raja Babu

2 Human Genome Mapping: Relevance to

Dermatology 9

Sangeeta Amladi, Balkrishna Nikam

3 The Th1-Th2 Paradigm: Relevance to Dermatology 42

6 Acute Skin Failure: Management and

Role of Intensive Skin Care 91

Patrick Yesudian

7 Recent Advances in Paraneoplastic

Pemphigus (PNP) 105

HR Jerajani, Meghana Phiske, Seema Sainani

8 Drug Hypersensitivity Syndrome 129

Arun C Inamadar, Aparna Palit

9 Aquatic Animal Bites and Stings: An Update 142

G Raghu Rama Rao

10 Psoriatic Arthritis 158

Samar Ranjan Pal

11 The Antiphospholipid Antibody Syndrome (APAS):

Relevance to Clinical Dermatology 171

Soumya Panda

12 Mucocutaneous Manifestations of HIV/AIDS 229

Surojit Kumar Biswas, Bibhuti Saha

13 The Newer Biological Agents in the

Treatment of Psoriasis 277

Asok Gangopadhyay, Sujata Sengupta

14 Management of Reactions in Leprosy: An Update 290

Nanda Kishore B, Sukumar

C

15 Drug Interactions: Relevance to

Dermatological Practice 305

Rashmi Sarkar

16 Recent Advances in the Surgical Treatment of Vitiligo 329

Niti Khunger

17 Chemical Peeling: Current Status 341

Maya Vedamurthy, Deepak Vedamurthy

Index 363

‘Nothing is permanent except change’—Heraclitus

(544–483 B.C.)

INTRODUCTION

Empiricism has been the corner stone of dermatological therapy untilrecently and uncontrolled and non-systematically, especiallyanecdotally, gathered data formed the basis of much ofdermatological practice.1 It is true that a great deal of what wepractice today had evolved through empiricism and observation,and sporadically through serendipity Simple beliefs led to simple

‘solutions’, generally based on putative pathophysiological events,without taking in to account the complex nature of the humanorganism and human disease Opinions about the effectiveness oftreatments were sometimes highly opinionated, occasionallybordering on dogma Historically, physicians found answers to theirand their patient’s problems in manuals, textbooks, or in theknowledge and wisdom of their teachers, and their senior andcharismatic colleagues.2 While this was good up to a point, the dearth

of authority and authenticity on such information and absence ofclear therapeutic direction frequently resulted in a wide variation

in clinical practices and in varying and non-optimal outcomes.Further, an individual clinician is likely to see only a limited range

of patients, and distortions that are an inevitable part of unsystematichuman assumptions had affected the conclusions drawn frompersonal observations.3 Empirical therapy was often justified from

Introduction: Between Empiricism and Evidence-based Medicine, is

there a 'Middle Road'?

1

the supposition that better evidence was not available.1 However, it

is fact that empirical therapy still enjoys a great amount of popularity

in the treatment of many skin diseases Examples are legion Theoff-label uses of drugs like dapsone, chloroquine, tetracyclines,thalidomide, etc are too well known to merit a mention here

Evidence-based Medicine (EBM)

Therefore, the need for valid and reproducible data about diagnosis,prognosis, therapy and prevention of diseases in general, hasbothered clinicians for centuries and in 1992, a group led by GordonGuyatt at McMaster University in Canada recognized this need andconsolidated these ideals as evidence-based medicine (EBM) EBM

is the use of current evidence in making decisions about the care ofindividual patients in order to provide them with the best that ispossible.4 Evidence-based medical practice is not new and its earliestorigins could be traced to ancient Chinese medicine EBM representsthe best way of linking and integrating clinical research with clinicalpractice.5 Evidence-based medicine de-emphasizes intuition,unsystematic clinical experience, and pathophysiological rationale

as sufficient grounds for clinical decision-making, and stresses theexamination of evidence from clinical research.6

Practice of evidence-based medicine requires new skills to beacquired by the physician, including efficient literature-searchingand proper evaluation of that literature, but teaching and practice

of such skills have not been traditionally part of medical training.6The clinician is expected to make a critical appraisal of the quality

of evidence, determining its importance and precision, and applying

it to a specific patient The strength or value of the evidence is based

on a series of data: results of systematic reviews of well-designedclinical studies, results of large case series, expert opinion andpersonal experience.7 Of these, systematic reviews are placed at thepinnacle of the evidence hierarchy.8 Literature search and evaluation

in the practice of EBM is bimodal The physician can himself accessand critically evaluate the evidence, like searching databases such

as MEDLINE or EMBASE (if he has the time) or appraise himselfwith the already carried out evaluations and critically judge them(if he doesn’t have the time) Systematic reviews and independently,critically appraised reviews constitute an important facet of the latter.The randomized controlled trials (RCTs) and meta-analyses formthe fulcrum of this evidence Two of the most comprehensive

databases of high quality reviews are the Cochrane Database ofSystematic Reviews, and the Database of Abstracts of Reviews ofEffectiveness Both these resources are found in the Cochrane library,

an electronic publication of the Cochrane collaboration, that isfrequently up-dated as new evidence becomes available.9 Unliketraditional expert reviews, systematic reviews, such as thoseproduced by Cochrane collaboration, summarize accurate, up-to-date, high quality external evidence of the effectiveness ofinterventions for treating and preventing human disease.10 One basicrequirement for practice of EBM is optimal integration of computertechnology into clinical practice Indeed, information technology isthe keystone of evidence-based practice.11

The Case Against EBM

The case against EBM is its undue reliance and emphasis on hard

‘scientific’data, especially its over-dependence on RCTs, and itsalleged tendency to devalue (although EBM proponents deny this)the rich clinical knowledge derived from experience and the detailedstudy of individual patients.12 Furthermore, evidence may not beobtainable in all instances and all therapiesare not studied to thesame extent Critical appraisal of evidence is clearly important butone should not be in the danger of not seeingthe wood for the trees.And the absence of evidence of effectivenessis not the same asabsence of effectiveness.12

It is also suggested that in many RCTs, the upper age limitis 64years for inclusion in the trial In many trials, women of child-bearingage or those who are pregnant are excluded Patients with mixeddiagnosesand co-morbidity are also kept away Drop-outs areanother problem and people may not cooperate for a variety ofreasons It oftenappears that those who are motivated to cooperate

in RCTs arenot a typical cross-section of our patients.12 Efficacy inRCTs is no guarantee of effectivenessin the field, and effectiveness

in the field is no guarantee of effectiveness in the individual patient.Efficacy and effectivenessmay be conflated, to the confusion ofclinicians, researchersand policy-makers.13 Another problem inevaluating data from meta-analyses and systematic reviews is theresults from unpublished studies For any given research area, onecannot tell how manystudies have been conducted but neverreported Easterbrook et al in a careful retrospective study of 487research projects in Oxford, confirmedthe presence of a publication

bias in a cohort of clinicalresearch studies and suggested thatconclusions based onlyon a review of published data should beinterpreted cautiously.14 Caution also needs to be exercised inreading systematic reviews,particularly if the amount of informationfound is small Fewtrials and small numbers lessen the reliability

of a review A curious paradox that can follow theedicts andrestrictions of EBM is pushing more and more patients to seek outcomplementary, alternativeand unevaluated therapies A recentsurvey in the British newspaper ‘Guardian’ revealed that the number

of people using non-conventional treatmentshad doubled in recentyears.12 Moreover, information from EBM can be used to encourageminimalisticpurchasing in the name of evidence Too muchemphasis on a narrow range ofacceptableevidence oversimplifiesthe complex nature of clinicalcare.12

Usefulness of EBM in Clinical Practice

In the absence of definitive evidence of its superiority in improvingpatient outcomes over conventional medicine except in a smallnumber of disease-situations, how useful is EBM to current clinicalpractice? One thing is certain As evidence-based medicine dealsdirectly with the uncertainties of clinical medicine, it has the potentialfor transforming the education and practice of the future generation

of physicians These physicians will continue to face an explodingvolume of literature, rapid introduction of new technologies,deepening concern about burgeoning medical costs, and increasingattention to the quality and outcomes of medical care Until moredefinitive evidence is adduced, adoption of evidence-based medicineshould appropriately be restricted to those who find the rationalecompelling, and thus believe that the use of the evidence-basedmedicine approach is likely to improve clinical care, and to thosewho have the energy, enthusiasm, and resources to use evidence-based medicine in their practices.6 However, there is no doubt thatevidence-based practice is the best way forward for the progress ofmedicine What is heart-warming is that in spite of some of thesefailings, a substantial number of patients in tertiary care hospitalsare shown to receive treatment based on EBM

Evidence-based Dermatology

While the ideals of EBM have been enthusiastically embraced bymany specialties including internal medicine, its acceptance and

incorporation into dermatological practice has been rather slow.15

Dermatology’s frequent use of empirical therapies or use of therapiesbased on uncontrolled, non-systematically gathered or anecdotalevidence perhaps accounts for this delay.4 Furthermore, the upsurge

in clinical research has not been paralleled by methodologicalrefinements, and the quality of RCTs in dermatology seems to fallwell below the usually accepted standards.16 Additionally there are

so many rare diseases in dermatology that RCTs are simplyimpossible A further difficulty of RCTs in dermatology is thevisibility of skin lesions and the possibility that patients tend to self-monitor their illnesses and have their own preconceptions andpreferences about specific treatment modalities.17 A search ofCochrane library uncovered review database entries for only 40 skindisease topics and no entries related to 2 of the 10 most commondiagnoses in dermatology: epidermoid cysts and seborrheickeratoses Another significant barrier to EBM appears to be thepaucity of dermatologists trained in and willing to teach EBM.9 AnEvidence-based Dermatology website (Ebderm.org) was created in

2002 as a guide to evidence-based medicine for practicingdermatologists, residents, and clinical researchers, and is yet tobecome popular

Guidelines of Care

Between the uncertainty of empiricism and hard-to-practice EBM,

is there a ‘middle road’? In 1987, the American Academy ofDermatology (AAD) began developing guidelines of care to aiddermatologists in their clinical practices.18 The mission was topromote high level of clinical expertise, to ensure the higheststandard of care, to provide a review of contemporary medical issues,and to communicate quality dermatological care to external parties.Over the years, the process of guideline development underwent achange and became more refined The initial guidelines of AADwere ‘Consensus guidelines’ and were based on expert opinion.19

For each of the guidelines, an expert panel was assembled to reviewthe relevant literature for that therapeutic area Out of this discussion,guidelines were generated ‘Consensus guidelines’ became popularall over the world and began to be adopted by different countriesand the WHO for different disorders However, limitations of thistype of guidelines became quickly apparent.20 Firstly, the individual

bias of the experts could not be excluded Expert opinion often laggedsignificantly behind conclusive evidence.1 Secondly, the guidelinestended to include many different treatment or therapeutic strategies(although references were provided) creating long lists of possibletherapies without weighting their effectiveness making it difficultfor the clinician to choose the right therapy.18

With the introduction of EBM in the early 1990s, the need for anevidence-based approach in the formulation of guidelines becameobvious.21 This type of approach established criteria for evaluatingthe relevant literature so that conclusions from single case reportstudies and those from large, double-blind, randomized controlledtrials did not get considered equally Evidence-based guidelines alsorecognized the principle of documenting the steps taken during ananalysis so that the process was more open and clearly specified.Although the scientific approach of evidence-based guidelinesappealed to many, the short-comings of this method also soonbecame evident Many clinical subjects in dermatology lackedadequate literature to establish guidelines following the rigid criteria

of evidence-based review of the literature As a result, guidelinescould not be created for many diseases or had only non-specificrecommendations

To overcome these deficits, in 1999, AAD adopted a format inwhich wherever it is necessary, evidence-based approach wassupplemented by expert opinion Guidelines prepared with thisapproach were found to serve as better educational tools in thepractice of dermatology.18 As the proof of the pudding is in eating,what is ultimately important is that the recommended guidelinesshould always be validated in clinical practice

While this was so, the British Association Dermatologists (BAD)started a process of producing guidelines for dermatologists in

1997.22 Strengths of BAD guidelines include the fact that thedevelopment process is overseen by a committee, most of whomare not the authors and also that the entire membership of the BADhas an opportunity to comment on a draft version Another strength

of BAD guidelines is that the authors preparing these are expected

to declare their ‘conflicts of interest.’ These guidelines are generallywritten with practical application in mind, and are specificallytargeted at dermatologists in secondary care BAD guidelines arebased on high-quality evidence if it is available, but they still cover

areas where evidence is scanty or of poor quality The BAD hasfurther refined these guidelines in 2005.23

The Indian Association of Dermatologists, Venereologists andLeprologists (IADVandL) appointed a committee in 2002(ProfVK Sharma, Chair) to formulate treatment guidelines fordermatologists practicing in India The first of the draft guidelines

is expected to be ready this year

CONCLUSION

Clinical guidelines are systematically developed statements to assistclinician and patient decisions about appropriate health care forspecific clinical circumstances They are not same as EBM which isbased on specific and rigid criteria with a de-emphasis on clinicalexpertise They are not empirical, opinionated or non-systematiceither They are expected to integrate best of both the worlds andguide a clinician in his daily practice Explicit and balanced guidelinedevelopment should be able to specify the potential benefits, harms,and costs of available interventions, estimating the possibility ofthe outcomes, and their ‘acceptance’ by the patients Theserequirements are particularly relevant to developing countries likeIndia It, however, should be realized that clinical guidelines areneither protocols of care nor rules of treatment and are to be onlyuseful adjuncts to a clinician’s armamentarium It should ultimately

be left to the individual physician to decide how best to manageindividual patients.24 Clinical guidelines will and must change asnew evidence emerges and should be revised every five years AsNeil Penneys had said ten years ago, medical care is a highly personaland individualized service, the value and success of which can befully assessed only with respect to a particular patient underparticular circumstance.25 How true this is even today!

REFERENCES

1 Williams H, Bigby M In: Williams H, Bigby M, Diepgen T, et al (Eds) Evidence-based Dermatology Bangalore: Prism Books Pvt Ltd, 2003;.9-15.

2 Montori VM, Guyatt GH What is evidence-based medicine and why it should

be practiced? Respir Care 2001:46:1201-11.

3 Dawson N, Arkes HR Systematic errors in medical decision making: Judgment limitations J Gen Intern Med 1987;2:183-7.

4 Bigby M Evidence-based medicine in dermatology Dermatol Clin 2000;18: 261-76.

5 Sackett DL, Rosenberg WMC, Gray JAM, et al Evidence-based medicine: What

it is and what it isn’t BMJ 1996;312:71-2.

6 Users’ guides to evidence-based medicine J Am Med Assn 1992;268:2420-5.

7 Bigby M Evidence-based medicine in a nutshell: A guide to finding and using the best evidence in caring for patients Arch Dermatol 1998;134:609-18.

8 Guyatt GH, Sackett DL, Sinclair JC, et al Users’ guides to the medical literature, IX: A method for grading healthcare recommendations J Am Med Assoc 1995;274:1800-4.

9 Parker ER, Schilling LM, Diba V, et al What is the point of databases of reviews for dermatology if all they compile is “insufficient evidence’ J Am Acad Dermatol 2004;50:635-9.

10 Williams H Where do we go from here? In: Williams H, Bigby M, Diepgen T,

et al, (Eds) Evidence-based Dermatology Bangalore: Prism Books Pvt Ltd, 2003.705-12.

11 Mozlin R Evidence-based medicine Optometry 2000;71:490-500.

12 William DDR, Garner J The case against the ‘evidence’: A different perspective

on evidence-based medicine Br J Psych 2002;180:8-12.

13 Chiesa M, Fonagy P From the efficacy to the effectiveness model in psychotherapy research The APP multicentre project Psychoanalytic Psychotherapy 1999;13:259-72.

14 Easterbrook PJ, Berlin JA, Gopalan R, et al Publication bias in clinical research Lancet 1991;337:867-72.

15 Dellavalle RP, Stegner DL, Deas AM, et al Assessing evidence-based dermatology and evidence-based internal medicine curricula in US residency training programs: A national survey Arch Dermatol 2003;139:369-72.

16 Naldi L The field and its boundaries In: Williams H, Bigby M, Diepgen T,

et al (Eds) Evidence-based Dermatology Bangalore:Prism Books Pvt Ltd, 2003;3-8.

17 Van de Kerkhof PCM, De Hoop D, De Konte J, et al Patient compliance and disease management in the treatment of psoriasis in the Netherlands Dermatology 2000;200:292-8.

18 Abby S, Voorhees V AAD Guidelines of Care: How did we get here and where are we going? J Am Acad Dermatol 2003;48:978-90.

19 Drake LA, Yale KP, Lowery BJ, et al American Academy of Dermatology guidelines of care development and process Arch Dermatol 1997;133:1369- 74.

20 Woolf SH Practice guidelines, a new reality in medicine II Methods of developing guidelines Arch Intern Med 1992;152:946-52.

21 Harbour R5, Miller J A new system for guiding recommendations in based guidelines BMJ 2001;323:334-6.

evidence-22 Cox NH, Williams HC The British Association of Dermatologists therapeutic guidelines: Can we agree? Br J Dermatol 2003;148:621-5.

23 Ormerod AD Recommendations in British Association of Dermatologists guidelines.(Editorial) Br J Dermatol 2005;153:477-8.

24 Sladden MJ, Hull SPM, Wood ML, et al Alopecia areata: The need for guidelines and evidence-based dermatology Br J Dermatol 2005;152:1086-7.

25 Penneys NS Biting the hand that feeds you: An argument against developing organized specialty-wide therapeutic guidelines for dermatological practice.

J Am Acad Dermatol 1995;33: 538-40.

The Human Genome Project (HGP) was established in 1990 as acollaboration between the US Department of Energy (DOE HumanGenome Program) and the National Institutes of Health (NIHNational Human Genome Research Institute).1 The main aims ofthe HGP were to identify all the approximately 20,000 to 25,000 genes

in human DNA, determine the sequences of the 3 billion chemicalbase pairs that make up human DNA, store this information indatabases, improve tools for data analysis and address the ethical,legal, and social issues (ELSI) that may arise from the project.1

This 13-year coordinated effort ended in 2003 with the publication

of the complete Human Genome, although the first analysis of aworking draft was earlier published in 2001 jointly by the HGP andthe privately owned Celera Genomics (Nature Feb 15 2001, ScienceFeb 16 2001).2,3 With an estimated 25,000 to 75,000 genes distributedover 3.2 billion base pairs of DNA, the human genome representsthe largest genome completely sequenced so far The April 11, 2003issue of Science and April 24, 2003 issue of Nature presented a specialcollection of news, view points, and other articles to celebrate 50thanniversary of the publication of Watson and Crick’s model of thestructure of DNA.4,5

The HGP was just the first step in understanding humans at themolecular level Though the project was complete in 2003, manyquestions still remain unanswered, including the function of most

of the estimated 30,000 human genes (The term genome is 75 yearsold and describes an organism’s complete set of genes) Advances

Human Genome Mapping:

Relevance to Dermatology

2

in Structural Genomics, i.e mapping and sequencing of genes on agenome wide scale, has opened up future vistas in the field ofFunctional Genomics, allowing the examination of thousands ofgenes at once using a new technology–DNA microarray or genechip.6

of various disorders that include primary or adjuvant skininvolvement.7

Knowledge of advances in the Human Genome is relevant todermatologists in understanding the genetic/molecular basis andthe variable expression of various genodermatoses It will also help

in understanding of the pathophysiology of inflammatoryimmunological disorders as well as certain skin cancers, thus aiding

in newer treatment options Early detection and new fundamentaldiagnostic approaches using gene chips and therapeutic modalitiesusing gene therapy are now distinct possibililities in the future

Classification of Genetic Skin Disorders

1 Epidermal disorders A Inherited defects in keratin

B Palmoplantar keratodermas

C Follicular hyperkeratoses

D Connexin disorders

E Genetic disorders of pigmentation

F Genetic hair and nail disorders

3 Hereditary cancer syndromes of the skin

4 Genetically determined benign tumors

5 Premature aging syndromes

6 Genetic immunodeficiency syndromes

7 The phakomatoses

8 Chromosomal disorders

9 Genetic inflammatory skin disorders

This article will not deal with chromosomal disorders orinflammatory disorders such as psoriasis, atopic dermatitis, etc.

Table 2.1: Classification of keratin disorders 10,11

Keratin Type Distribution Diseases

K5/K14 Basal layer of epidermis Epidermolysis bullosa simplex K1 Suprabasal layer including BCIE, EHK, Cyclic ichthyosis,

palms and soles EHK, K1 epidermolytic PPK

K 10 Suprabasal layers BCIE, Cyclic ichthyosis with

excluding palms and soles EHK

K9 Epidermis of palms and soles Epidermolytic PPK

K2e Upper spinous layer Ichthyosis bullosa of Siemens K6a/K16 Epidermal appendages Pachyonychia congenita – 1 K6b/K17 Epidermal appendages Pachyonychia congenita – 2 K4/K13 Mucosa White sponge nevus

HHb6/Hb1 Trichocytes Monilethrix

BCIE – Bullous congenital ichthyosiform erythroderma, EHK – Epidermolytic hyperkeratoses, PPK – Palmoplantar Keratodermas

Epidermolysis Bullosa Simplex (EBS)

Epidermolysis bullosa (EB) comprises a heterogenous group ofgenodermatoses characterized by fragility and blistering of the skinassociated with extracutaneous manifestations Based on clinicalseverity, constellation of the phenotypic manifestations and the level

of tissue separation within the cutaneous basement membrane zone(BMZ), EB has been divided into distinct subcategories, viz Simplex(Suprabasal clefting), Junctional (split through dermoepidermaljunction), and Dystrophic (split below dermoepidermal junction).12

Three clinical variants of EBS have been described.12 Cockayne is the least severe form with blistering limited to handsand feet Koebner variant has early onset with more generalized

Weber-blistering in childhood and limited disease in adulthood Summerexacerbations are seen in both the above Dowling-Meara is the mostsevere form with generalized blistering starting early or at birth andassociated with PPK, nail dystrophy, oral mucosal involvement.

At least 10 genes have been well characterized.13 Different types

of mutations, their positions along the affected genes, and theirconsequences at the mRNA and protein levels have resulted in thephenotypic variability and genetic heterogeneity of EBS By andlarge, ‘frameshift’ mutations and mutations in the ‘highly conservedareas’ of genes give rise to severe form of disease, while milderdisease is seen with ‘missense’ mutations and mutations in the otherareas of genes.10 These advances in EB genetics have applicationsfor early and improved diagnosis, molecular classification,prognostic implications, DNA-based prenatal testing in families with

EB as well as genetic counseling

Ichthyoses

This group comprises many diseases with visible scales that can beremoved Previously classified broadly as hyperproliferative orretentive disorders, ichthyoses can now be very well explainableaccording to the candidate genes As many abnormalities still remainunrevealed, clinical classification remains the most useful at preset.10

Broad categorization of ichthyoses would be as those with no majorsystem involvement, and those with major extracutaneous features.Point mutations in the steroid sulfatase gene, located at the end

of short arm of the X chromosome, lead to X linked ichthyosis withlarge dark scales with minimal flexural involvement, often withassociated corneal opacities and cryptorchidism.14 Ultrastructuralstudies in Bullous Congenital Ichthyosiform Erythroderma (BCIE)have shown specific K10 and K1 tonofilament clumping insuprabasal cells of patients with BCIE.9 Several different mutations

in KRT1 and KRT10 were reported Non-Bullous IchthyosiformErythroderma can be distinguished from lamellar ichthyosis type

by high levels of n-alkanes in the scales.15

Ichthyosis Bullosa Siemens, a superficial form of BCIE with mildflexural involvement, correlates with the defect in K2e, which isexpressed in high spinous layers.16 Sprecher et al have reported anunusual mutation in the V2 domain of KRT1 in a single family withIchthyosis Hystrix of Curth-Macklin, a condition showing spikykeratosis all over body, PPK and nail dystrophy.17

Syndromes such as Sjögren-Larsson syndrome are associatedwith fatty alcohol oxidoreductase activity defect, Refsum syndromewith deficiency of phytanic acid hydroxylase, rud syndrome withlack of aryl sulfatase, Dorfman-Chanarin syndrome with a lipidstorage disorder and KID with a connexin disorder (GJB2 genedefect).10 Conradi-Hunerman syndrome (chondrodysplasiapunctata) shows four different types of presentations characterized

by dwarfism, short limbs, cataracts, follicular erythroderma.Recently, this syndrome has been linked to the EBP gene (Emopamilbinding protein) and defect in delta8-delta7 steroid isomerase.18

Keratin–structural Protein Gene Function Defect

a Vorner’s EPPK – defect in K9 (KRT9 gene defect)

b Unna-Thost NEPPK – K1 defect (KRT1 gene defect)

c Diffuse NPPK – K1 defect

d Diffuse NPPK with polycyclic psoriasiform plaques – K1 defect

e PC-1/PC-2 – defects in K6/K16/K17

f PPK associated with EB – defect in K5/K14

Connexin–cellular Communication Molecule Gene Function Defect

a Vohwinkel type of mutilating keratoderma (GJB2 gene defect)

b KID syndrome (GJB2 gene defect)

c Bart-Pumphrey syndrome (GJB2 gene defect)

3 Loricrin–cornified Envelope Gene Function Defect

a Camisa type of Vohwinkel keratoderma (loricrin PPK).(LORICRIN gene)

b BCIE associated PPK (KRT1 gene defect)

c Progressive symmetric keratoderma

Desmoglein, Desmoplakin, Plakoglobulin-cohesion

Molecule Gene Function Defect

a Striate palmoplantar keratoderma (DSP gene defect)

b Carvajal Huerata syndrome

Cathepsin C–transmembrane Signal Molecule

Gene Function Defect

a Papillon-Lefevre syndrome (CSTC gene defect)

b Haim-Munk syndrome (CSTC gene defect)

c Mal de Meleda syndrome (SLURP1 gene defect)

Mitochondrial DNA Defect

Maternally inherited PPK with Deafness (MTTS1 gene defect)

PPK Associated with Inborn Error of Metabolism

Richner-Henhart syndrome (oculocutaneous tyrosinosis) (TAT genedefect)

Besides these, other causes of PPK are Darier’s disese,dyskeratosis congenita, ectodermal dysplasia, ichthyosis hystrix anderythrokeratoderma Much progress in locating the defective gene

on chromosome has been done with the Howel-Evans syndromeand Huriex syndrome, both of these having PPK, autosomaldominant mode of inheritance and cancer association Althoughunderstanding of these molecular bases has increased our ability ofaccurate diagnosis of PPK, treatment of the same still remainsunsatisfactory

Follicular Hyperkeratoses

Darier’s disease is an autosomal dominant condition with completepenetrance and variable expressivity Linkage studies have nowmapped this condition to the long arm of chromosome 12 andmutations in the ATP2A2 gene.21 Both Hailey-Hailey and Darier’sdisease show defect in the ATP-dependent calcium transporterATP2C1 and ATP2A2 gene respectively.22

Connexin Disorders

Over the pastdecade, the molecular basis of most of the disorders ofcornification has been unveiled Among these, a distinct group hasemerged because of primary defects in cell-cell communication due

to faulty gap junction proteins also known as ‘connexins.’11 Thecrucial functional importance of connexins in ectodermal tissues isreflected by the finding that defects in these genes produce a widespectrum of genetic disorders comprising sensorineural hearing loss,disorders of cornification of skin, hair, nail and keratitis To date,mutations in the Connexin genes for Cx26 (GJB2) and less frequentlyCx30 (GJB6) are the principal cause of non-syndromic deafnessworldwide.23

Conditions known to arise from Connexin defects are listedbelow:

Erythrokeratoderma variabilis is a rare genodermatosis characterized

by a unique combination of two distinct morphological features–transient, “migratory” erythematous patches and relativelypersistent hyperkeratoses The disease usually manifests at birth andpersists lifelong with periods of exacerbations and remissions It ispredominantly inherited by autosomal dominant fashion anddiagnostic gene testing is possible (www Genedx.comn)

Vohwinkel syndrome also known as keratoderma hereditaria mutilans,

is a rare autosomal dominant disorder with diffuse, oftentransgradient hyperkeratoses of palms and soles with characteristichoneycomb pattern Other features are constriction bands on thedistal digits, knuckle pads, and starfish-shaped hyperkeratoses withbilateral sensorineural deafness

Bart-Pumphrey syndrome is a rare autosomal dominant variant of PPKcharacterized by knuckle pads, PPK with honeycomb-like surface,leukonychia, and sensorineural deafness

Keratitis-ichthyosis-deafness (KID) syndrome.

Clouston syndrome is hidrotic ectodermal dysplasia characterized byPPK with hypotrichosis, brittle blond hairs as well as progressivenail dystrophy

Oculodentodigital dysplasia

Disorders of Pigmentation

Any defect occurring from the stage of melanocyte development tothe final transfer of the melanin to the keratinocytes can inducepigmentary problems

Hypomelanosis Related to Defect of Embryological

Development of Melanocytes

Piebaldism is a very rare autosomal dominant disorder withcongenital stable fixed patterned leukoderma The topographicaldistribution of the lesions spreading to the anterior part of the trunk,abdomen, extremities and the frontal part of the scalp is characteristic

of the disease The white forelock is the most frequent manifestation.Hyperpigmentation or normal skin islands in the leukodermapatches give mosaic pattern Most patients have a loss of function

or dominant negative mutation of KIT gene which encodes fortyrosine kinase receptor named c-Kit.24 The c-Kit ligand is a stemcell factor, which is involved in proliferation and survival ofmelanoblasts

Waardenburg syndrome (WS) is another rare disorder associatingcongenital white patches with sensorineural deafness (Table 2.2)

Table 2.2: Genes identified in Waardenburg syndrome 25

Disorder Genopathogenesis and phenotype Mapping

WS1 PAX3 (regulates MITF) – white forelock, 2q35-q37.3 AD

white patches, dystopia canthorum and

heterochromia irides with facial abnormalities

and deafness

WS2 MITF (activates transcription of tyrosinase, 3p14.1-p 12.3

mediates survival of melanocytes) – deafness AD/rarely AR and heterochromia irides predominant, no

dystopia, facial abnormalities and less pigmentary

troubles

WS3 PAX3 (regulates MITF) similar to WS1 with more 2q35

severe cutaneous and musculoskeletal troubles AD/AR WS4 EDNRB/EDN3 (embryological development of AR

neurons of ganglions of GIT and melanocytes) – white

forelock, isochromia irides, Hirshprung’s disease

Piebaldism KIT (Proliferation and survival of

melanoblasts) 4q12 AD

Hypomelanosis Related to Defect of Melanogenesis

These disorders involve only pigmentary cells (melanocytes and thecells of the pigmentary retinal epithelium) and includeoculocutaneous albinism (4 types) and ocular albinism.Oculocutaneous albinism (OCA) is characterized by absence ofpigment in hair, skin and eyes along with ocular manifestations likesevere nystagmus, photophobia and reduced visual acuity

Oculocutaneous albinism (OCA) type 1 is due to defect intyrosinase (TYR) gene and is divided into OCA1-A and B types Intype A, there is no tyrosinase activity as mutations occur in all 4functional domains of TYR gene and Type B shows little tyrosinaseactivity as most mutations occur in third functional domain only.OCA 2 is the most common form of OCA Phenotype is similar

to OCA 1 at birth but progressively little amount of pigment isaccumulated in the skin and eyes The disorder results from loss offunction mutation of the P gene, which encodes a melanosomalmembrane that may play a major role in the intracellular transport

of tyrosinase.26 OCA 3 is due to defect in TYR related protein andOCA 4 results from mutations in membrane associated transporterprotein (MATP) gene.26

Hypomelanosis Related to Defect in the Biogenesis of

Melanosomes

Hermansky-Pudlak syndrome—bleeding and lysosomal ceroid storageassociated with partial OCA, bleeding manifestations like epistaxis,gingival bleeding, purpura, genital bleeding are usually not severe.Visceral involvements are interstitial lung fibrosis, granulomatouscolitis and renal failure Disorder is autosomal recessive and seventypes have been described depending on different mutations andphenotypes.27

Chediak-Higashi syndrome—a partial OCA with immunodeficiencyand neurological abnormalities, recurent cutaneous and systemicpyogenic infectioins and severe hemophagocytic lymphopro-liferative syndrome caused by uncontrolled T-cell and macrophageactivation CHS is characterized by the presence of giantmelanosomes in melanocytes and giant inclusion bodies in mostgranulated cells The absence of neutrophil and monocytes migrationand chemotaxis are also noted Disorder results from mutation inCHS 1 gene called LYST.28 The product of this gene is required for

sorting endosomal resident proteins and thus, in vesicular transportand signal transduction.

Hypomelanosis Related to a Defect of Melanosomes Transport

Griscelli-Prunieras syndrome29— is a very rare autosomal recessivedisorder associating hypopigmentation and neurological (GS1) andimmunological (GS2) abnormalities In GS 3 only hypopigmentation

is observed and all phenotypes are characterized by a silvery-grayear and relative skin hypopigmentation Various mutations ondifferent genes have been described

Hypomelanosis Related to Defect of Survival of Melanocytes

Vitiligo—is an acquired cutaneous disorder of pigmentationcharacterized by well circumscribed white cutaneous macules withabsence of melanocytes Several candidate genes have been proposedbut none was really convincing Strong evidence suggests that thevitiligo is an autoimmune disorder and have polygenic multifactorialinheritance.30

Other Hypomelanosis

• Tuberous sclerosis complex

• Pigmentary mosaicism (Hypomelanosis of Ito)

Hypermelanosis

McCune-Albright syndrome: It is a sporadic disease affecting threeareas: The skeleton, the skin, and the endocrine system It ischaracterized by polyostotic fibrous dysplasia, pigmented lesions,and endocrinologic abnormalities including precocious puberty,thyrotoxicosis, pituitary gigantism, and Cushing’s syndrome Theinvolvement of the skin consists of large café au lait spots withirregular margins as opposed to the more outlined cafe au lait spots

in neurofibromatosis This phenotype is associated with mutations

in the GNAS1 gene leading to excess cyclic adnosine phosphatase.31

mono-LEOPARD syndrome (lentigines, electrographic abnormalities, ocularhypertelorism, pulmonary stenosis, abnormal genitalia, retardation

of growth, and deafness): Mutations of PTPN11 may perturb thedevelopmental processes.32

Carney complex : Transmission of lentiginosis with cardiocutaneous

myxomas is autosomal dominant with variable expressivity.Mutation in PRKAR1A gene, which is tumor suppressor gene, isfound in half of the cases.33

Peutz-Touraine-Jeghers syndrome : Characterized by lentiginosis of lips,

buccal mucosa, and digits with hamartomatous polyps ofgastrointestinal tract This is caused by mutation in the gene mapped

in 19p13.3 and encodes serine kinase STK11.34 The pathogenesis is,however, poorly understood

Dyschromatosis symmetrica hereditaria : Characterized by the

association of hypo and hyperpigmented macules mostly on the back

of hands and feet The lesions also appeared on the face andasymptomatic and only skin is involved Recently locus for thisphenotype has been mapped to chromosome 1q21.3 and pathogenicmutations have been identified in DSRAD gene encoding adenosinedeaminase.35 However, pathogenesis of this disorder leading topigmentary abnormality is still unknown

There are still many pigmentary disorders for which the geneticbackground is completely unknown Even if the mutation isdescribed, the pathogenesis of clinical phenotype is still notunderstood The gene involved is identified in only one-third of thecases It is likely that our knowledge of the genes involved inpigmentary disorders will grow in the near future and the betterunderstanding of the molecular mechanisms responsible for thesedisorders will bring new therapeutic approaches

Genetic Hair and Nail Disorders

Hair and nails are skin appendages that share with the otherectodermal tissues a common developmental pathway Inheriteddiseases affecting these two structures, therefore, very often involveepithelial components and present with multiple anomalies,generating both physical and psychological distress among patientsand their families

Hypotrichosis

Loose anagen syndrome: Essential feature is the easy and painlessextraction, by gentle pulling, of clumps of loose anagen hairs

K6hf is the new keratin normally located in companion layer, matrix,and medulla in anagen stage hair follicles and is found to be mutated

in loose anagen syndrome and pseudofolliculitis barbae.36

Monelithrix: Characterized by the appearance of beaded hair shaftsdue to presence of alternating bands of normal and abnormally lowdiameters Hair tends to break at the constricted sites, resulting invarious degrees of alopecia with short and sparse hairs over thescalp Winter et al identified a pathogenic mutation in the hair cortex-specific keratin gene, hHb6.37 Menkes, syndrome is an X-linkeddisorder characterized by neurologic and hair manifestations due

to deleterious mutations in the ATPA7A gene, encoding a copperbinding protein.38

Hypertrichosis

No genes have as yet been identified in the pathogenesis of rarehypertrichotic disorders such as Cornelia de Lange's syndrome,Coffin-Siris syndrome, Ramon's syndrome, CAHMR syndrome,hypertrichosis universalis and trichomegaly

Nail

Nail Patella syndrome39-41 (NPS): It is a dominantly inheritedsyndrome, characterized by a number of nail anomalies ranging fromslight ridging, nail splitting, and nail fragility to generelized nailhypoplasia or aplasia Triangular or V-shaped lunula is particularlytypical The second major feature is absent or hypoplastic patella.Other bony deformities such as iliac horns, elongated radius withhypoplasia of radial head, elbow deformities and rib hypoplasiahave been described Ocular signs include corneal malformations,congenital cataract, iris pigmentations (Lester’s sign) are variablemanifestations Systemically, the NPS patients develop progressiveglomerulopathy manifesting with massive proteinuria andsometimes end-stage renal failure Mutations in the LIM homeboxtranscription factor 1 (LMX1B) gene is located on 9q34.1 LMX1Bwas shown to regulate the expression of collagen IV, a majorcomponent of glomerular basement membrane, thus explainingrenal pathology The protein encoded by this gene is shown to playcentral role in the limb development Some patients with isolatedcongenital nail dysplasia have been shown to carry mutations in

genes known to be associated with complex genodermatoses such

as COL7A1 (dystrophic EB)

Blistering Disorders

EBS, its types and genopathogenesis have been discussed earlier.Junctional Epidermolysis bullosa (JEB) is characterized by blisteringwith atrophic scarring of skin and mucosae, nail dystrophy and lossand abnormal dental enamel Among different clinical forms, lethalHerlitz type is the most severe form inducing death in infancy Othernon-Herlitz forms of JEB are mitis, disentis, inverse and localized.These forms are like Herlitz type but non-lethal Ultrastructurallythe split is within the lamina lucida and the hemidesmosomes arevariably abnormal Absent GB3 antigen, also called as BM600 nicein,

is related to laminin, kalinin and epiligrin BM600 nicein is aglycoprotein with three subunits, the genes for which are located at1q25, 1q32, and 18q11 Lethal JEB can result from mutations in theLAMB3 gene.10,11

Dystrophic Epidermolysis Bullosa (DEB): It shows blisters in the upperdermis In 1978, Bauer et al found increased synthesis of collagenase

in recessive DEB fibroblasts In 1991, Ryynanen et al found closelinkage between dominant DEB and the gene for type VII collagen(COL7A1) in anchoring fibrils.42 However, DEB is not simply acollagen VII deficiency disease; the situation is more complex.Patients with the classical Hallopeau-Siemens recessive DEB developspontaneous blisters, which heal with scarring and milia formation.The fingers and toes become fused by scar tissue leading to mittendeformities (pseudosyndactyly) There are many other types of DEBlike, Pasini, Cockayne-Touraine, Bart, syndrome, pretibial,centripetal, mitis and inverse

Weary Kindler syndrome: It shows mixed features of EB with acralblistering, scarring in infancy and Rothmund-Thomson syndromewith poikiloderma, photosensitivity Initially thought to be a variant

of EB, ultrastructural and molecular genetic studies have confirmed

it to be separate genodermatoses arising from a defect in KIND1gene.43 This gene is a human homologue of the C elegans proteinUnc112, a membrane associated structural/signaling protein thathas been implicated in linking actin cytoskeleton to the extracellularmatrix

Ectodermal Dysplasias

The derivatives of embryonic ectoderm, hair, teeth, nail, and sweatapparatus, are affected in huge variety of conditions More than 117syndromes have been described under ectodermal dysplasia.10

Freire-Maia attempted to classify these disorders using system’, which means disorders are assigned a number according

‘1234-to whether there is involvement of hair (1), teeth (2), nails (3), orsweat glands (4) and are numbered within these categories.44

Ectodermal dysplasias are frequently associated withsensorineural deafness, ocular abnormalities, facial clefting, andskeletal abnormalities, particularly webbing and ectodactyly (lobsterclaw) Palmoplantar keratoderma may occur There is considerableoverlap between different syndromes The only ectodermaldysplasias mapped are the X-linked hypohidrotic ectodermaldysplasia, incontentia pigmenti and Goltz's syndrome

Focal Ectodermal Dysplasia

In these conditions there are discrete areas of ectodermal dysplasia,the rest of the skin being normal

X-linked Hypohidrotic Ectodermal Dysplasia Touraine Syndrome)

(Christ-Siemens-This condition manifest in the boys and is characterized by sparsehair, missing and pointed teeth, dystrophic nails and reducedsweating with hyperpyrexia, which is particularly dangerous ininfancy They have a characteristic face with prominent foreheadand lips; they may be deaf from blockage of external auditory meati

by excessive wax Recurrent chest infections, eczema and atopicmanifestations are known The disease was localized to Xq13.1 fromcytogenetic studies A mutation has now been identified In X-linkedanhidrotic ectodermal dysplasia, the gene located is EDA(Ectodyplasin A protein defect).45

Incontinentia Pigmentii (IP)

A X-linked dominant disorder, usually lethal before birth in males.The gene was mapped to Xp11 and is called as 1KBKG gene Thefunction of this gene is modulation of NF-kappaB signaling

Mutation at Xq28 has also been described in genopathogenesis.46 It

is characterized by skin lesions that follow Blaschko’s lines and aspectrum of other ectodermal, ophthalmic and neurologicmanifestations

Focal Dermal Hypoplasia (Goltz's Syndrome)

Main clinical features are linear areas of pinkish atrophy, which maylook pale on a dark skin, lying along Blaschko’s lines, soft raised,yellowish areas of fat herniation; multiple raspberry-like papillomasaround orifices and in the flexures Gene has been tentativelymapped on Xp22.31 and X-chromosomal mosaicism is attributed tothe genopathogenesis

DERMIS AND ITS DISORDERS

Connective Tissue

Collagen

Ehlers-Danlos syndrome: Characterized by hypermobility of joints,hyperelasticity of skin, easy brusing, poor healing, scar formationand blue sclerae Eleven different variants of the same have beendescribed with known molecular or genetic defect in a few withlimited success (Table 2.3)

Table 2.3: Classification of Ehlers-Danlos syndromes 10

Type Associated features Defect

I Classic type with papyraceous Not known

scars, may rupture the large vessels

II Milder than type I Not known

III Major joint-minor skin involvement Not known

IV Arterial type bruising, rupture of Type III collagen

aneurysms

V Like type II Not known

VI Ocular type, with keratoconus, retinal Lysyl hydroxylase detachment, hemorrhage

VII Extreme joint with hip dislocation Type I collagen

VIII Periodontitis Not known

IX Occipital horns, related to Menkes Copper related disease disease in lysyl oxidase activity

X Bruising, defective platelets Fibronectin

XI Large joint hypermobility Not known

Restrictive dermopathy: Characterized by growth retardation,generalized rigidity of skin, joint contractures and abnormal facieswith small mouth and ectropion There may be abnormal intergrinexpression leading to abnormal collagen bundles arrangement.47

Elastosis perforans serpiginosa: Clinically it presents as red scalypapules arranged in rings or serpiginous fashion, spreadingoutwards to leave atrophic areas of skin, usually on the neck It isassociated with Ehlers-Danlos syndrome type IV (collagen IIIabnormality), Down’s syndrome (which probably involves collagengenes) and pseudoxanthoma elasticum It may be induced bypenicillamine therapy.48

Marfan’s syndrome: Skeletal abnormalities, dislocation of eye lenses,cardiovascular abnormalities attributed to defective fibrillinproduction

Blood Vessels

Hereditary Hemorrhagic Telangiectasia

Recurrent nasal and gut bleeding associated with multipletelangiectasias on lips, tongue, face, hands are seen in this disorder.Systemic involvement may occur with angiodysplasias in brain, liverand pulmonary arteriovenous fistulae leading to dyspnea andcyanosis Those without internal involvement are called ashereditary benign telangiectasias Possible candidate genes arecollagen V and I

Angiokeratoma Corporis Diffusum

Bluish or dark red multiple, grouped angiomas appear on thighs,scrotum, umbilicus at puberty Internally, progressive renal failureleading to death can occur Eyes and autonomous nervous systemmay get involved Galactosidase enzyme deficiency is the cause ofthe syndrome

HEREDITARY CANCER SKIN SYNDROMES

Tumor Prone Skin Disorders

Nevoid Basal Cell Carcinoma Syndrome NBCCS

(Gorlin's Syndrome)

Characterized by shower of skin colored papules resembling cellularnevi (hence nevoid) on trunk, face and epidermoid cysts, dermalcalcinosis, palmar pits Papules may remain static or turn intoinvasive BCC, particularly those on face Skeletal deformities likebifid rib, kyphoscoliosis, pectus excavatum and short fourthmetacarpal may be present Calcinfications of falx cerebri, agenesis

of corpus callosum and medulloblastoma have been described asneurological manifestations No candidate gene has been reported,although NBCCS has been mapped to 9q22.3.50 NBCCS gene seemslikely to function normally as a tumor suppressor, controlling cellgrowth

Multiple Self Healing Squamous Epitheliomas

(Fergusson-Smith Epithelioma)

Lesions usually begin in late teens and occur on sunexposed areas

as minute reddish papules with horny plugs, enlarge over fewweeks, ulcerate and heal with pitted scars Gene predisposing tothis syndrome appears to lie in the region of NBCCS gene(chromosome 9)

Bazex's Syndrome (Follicular Atrophoderma with Basal Cell

tumors at incision sites, multiple osteomas and congenitalhypertrophy of retinal pigmentary epithelium (CHRPE) Genemapping and linkage studies using DNA probes allowspresymptomatic diagnosis with high probability.

Multiple Hamartoma Syndrome (Cowden's Syndrome)

In this syndrome the presence of multiple facial tricholemmomas,extensive verrucous fibromas on the lips and warty acral keratosesand later breast carcinomas, thyroid adenomas and many otherorgans may also be found The gene has been mapped as PTEN/MMAC1 gene on chromosome 10q23.51

DNA Repair and Chromosome Breakage Syndromes

Xeroderma Pigmentosum

The skin appears normal at birth, sun sensitivity becomes obvious

in 1 to 2 years and dryness, atrophy, freckling and telangiectasias ofexposed skin start appearing Cutaneous malignancies soon appear

on the background of damaged skin as actinic keratoses,keratoacanthomas, squamous and basal cell carcinoma, malignantmelanomas The disease advances unpredictably but life expectancy

is much reduced Many die before age of 20 years Associations ofneurological symptoms make up the De Sanctis-Cacchionesyndrome Ultraviolet light damages the DNA by producingpyrimidine cross linkages, which distort DNA Defect in repairingthese damages lead to accumulations of the mutations and cancers.Various groups of XP have been described Group B and H areassociated with Cockayne syndrome, group D is associated withneurological abnormalities and trichothiodystrophy A topicalliposomally delivered UV endonuclease is currently being tested.There are at least 8 genes, corresponding to the various clinicalsubgroups of XP, involved in the pathogenesis.52

Cockayne's Syndrome

Characteristic facies (bird facies) with sunken eyes, large ears andloss of subcutaneous fat and photosensitivity causing pigmentationand scarring characterize the syndrome Other features includedemyelination, optic atrophy, deafness, mental retardation and