GENETICS IN DERMATOLOGY

GENETICS (Gk: Genesis – Origin)

The branch of biology that deals with heredity, especially the mechanisms of hereditary transmission and the variation of inherited characteristics among similar or related organisms

HUMAN GENOME ORG

GENETICS : PRINCIPLES

• GENE (Grk ‘Genea’ – Descent) Basic Unit of Heredity Info to Build / Maintain Cells & Transfer traits to Offspring

Sequence of DNA bases

GENETICS : PRINCIPLES• CHROMOSOME Storage Units of Genes

Females 23 Homologous Pairs 22 AUTO + 01 ALLO each Somatic Cell 22 Homologous + 01 Heterologous pair - Males

GENE LOCUS

Genes arranged inspecific location onChromosome - LOCI

GENETICS : PRINCIPLES

ALLELE - Alternative genes at Single Locus

HETEROZYGOUS (Aa) HOMOZYGOUS (AA)

GENETICS : PRINCIPLES

GENOTYPE - Inherited Instructions within an Organism’s genetic code; Blueprint, Constant, Str / Func

PHENOTYPE - Observable traits like Morphology, Properties, Changes with Environmental Influence &

Developmental Conditions

Differ due to

PENETRANCE

Proportion of individuals who carry a disease causing mutated gene and exhibit the clinical phenotype over a defined period.

Failure to exhibit Phenotype even though they carry the affected gene; this condition is termed as REDUCED / INCOMPLETE PENETRANCE

AD Dis e.g. TUBEROUS SCLEROSIS

GENETICS : PRINCIPLES

DOMINANT ALLELES - Phenotypic Expression with Heterozygous Allele

RECESSIVE ALLELES - Phenotypic Expression only with Homozygous Alleles

GENETIC HETEROGENICITY

• EXACT CLINICAL PHENOTYPES due to several Gene Mutations

• LAMELLAR ICHTHYOSIS

Mut in TGM-1 / ABCA12 / CYP4F22

CLINICAL HETEROGENICITY

• Mut in Single-Gene-Locus Several Phenotypic Variants

E.g. Mut in Connexin 26 causing Vohwinkel Syn Keratitis-ichthyosis-deafness (KID) Syn

MOSAICISM

Presence in an individual of 2 (or more) genetically distinct cell populations derived from the same homozygous zygote.

Functional Mosaicism - Normal Human Female with 46, XX (One X Chr inactivated during Embryogenesis by Lyonization into Barr Body)

MITOSIS

Cellular Growth / Repair / Asexual Reproduction

1 Parent Cell 2 Diploid Cells (2n)

Identical Daughter Cells

MEIOSIS

Sexual Reproduction / Production of Gametes

1 Parent Cell 4 Haploid Cells (n)

Daughter Cells different from Parent Cells

Chromosomal Cross-Over

CELL DIVISION

NOSOLOGY (Gk ; Nosos + Logos)

•FAMILIAL - ‘Clustering’ Higher Prevalence in relatives than population

eg HAILEY-HAILEY DIS

•CONGENITAL - present since Birth +/- Genetic -Developmental Defects- Infectious (RUBELLA) Insult (AMNIOTIC BAND SYN)

NOSOLOGY

POLYGENIC

Multifactorial

Multiple Genes + Environmental Influences

ATOPIC DERMATITIS PSORIASIS VULGARIS

GENODERMATOSES

• INHERITED DISORDERS

Alteration in Function of SINGLE GENE

Typical Inheritance Patterns AD / AR / XD / XR

AUTOSOMAL DOMINANTBoth Sexes

HeterozygousFor Abn Allele‘AFFECTED’

50% Transmission (Average)Positive Family History

AUTOSOMAL DOMINANT

Acute intermittent porphyria PBG

Ichthyosis (some forms) FILAGGRIN

Neurofibromatosis NF1

Tuberous sclerosis TSC1/2

Hereditary haemorrhagic telangiectasia ENG

AUTOSOMAL RECESSIVEBoth Sexes

Homogenous forAbn Allele is‘AFFECTED’

25% Transmission

No Family History (Carriers)

AR

Consanguinous Marriages / Ethnic Groups(Isolated Allele Groups)

Increased Risk of Carrier Parents

Risk of Affected Individual (25%)

AUTOSOMAL RECESSIVE (AR)

Epidermolysis bullosa DSP

Severe Ichthyosis ABCA12

Acrodermatitis enteropathica SLC39A4

Phenylketonuria PAH

Xeroderma pigmentosum XPA/B/C/D

X-LINKED DOMINANTHemizygous MaleHeterozygous Female

Affected Male to Daughters

Affected Female To 50% eachSon/Daughter

X-LINKED DOMINANT (XD)

Incontinentia pigmenti NEMO

Oro-facial-digital syndrome OFD1

X-LINKED RECESSIVEUsually Males

Atavistic

No Father to Son

Carrier Mother : SONOne Daughter Carrier

X-LINKED RECESSIVE (XR)

Anhidrotic ectodermal dysplasia EDA

Fabry’s disease A-GAL A

Menke’s syndrome ATP7A

Ocular albinism GPR143

CHROMOSOMAL DISORDERS

DEFECTS :

Change in no of Chr (ANEUPLOIDY)

Monosomy - TURNER’S SYN

Trisomy - DOWN’S EDWARD’S PATAU’S

CHROMOSOMAL DISORDERSDEFECTS :

Chr Str Rearrangement

Deletion - CRI-DU-CHAT Translocation - BURKITT’S LYMPHOMA Non-Dysjunction - KLEINFELTER’S DOWN’S

CHROMOSOMAL DISORDERS

• DEFECTS based on Chromosomes involved

AUTOSOMES SEX CHROMOSOMES

DOWN’S / EDWARD’S TURNER’S / KLEINFELTERS

PATAU’S / CRI-DU-CHAT FRAGILE-X / XXY / XXYY /CHR 4p DEL / CHR 18q DEL XXXXY

DOWN’S SYN

47, XX(XY), +21 1:700 LB ‘MONGOLIAN SYN’

DS – SYSTEMIC MANIFEST

DS – DERMAT MANIFEST

Birth - Soft, Velvety Skin 5 and 10 YO - Dry / Less Elastic15 YO – Generalized Xerosis20 YO - Patchy Lichenidication

Folliculitis Assoc with Malassezia Furfur; Responsive to ItraconazleAssoc with

DS – DERMAT MANIFEST

Fine, Hypopigmented Hair

Assoc with Alopecia Arreata

Recurrent Skin infections, Angular Cheilitis

Assoc with Onychomycosis

OTHER AUTOSOMAL DIS

EDWARD’S SYN 47,XX(XY),+18 Hypomelanosis

CRI-DU-CHAT SYN 46,XX(XY),-5p Premature Greying of Hair

LONG-ARM-DELETION-18 46,XX(XY),-18qEczema (25%)

TURNER’S SYN

45,XO 1:2500 LBs

TURNER’S SYN-MANIFEST

TURNER’S SYN-DERMAT FEATURES

• Hypoplastic Nails

• Keloidal Tendency

• Melanocytic Naevi Melanoma

KLEINFELTER’S SYNDROME

• 47,XXY 1:600 LBs

• Assoc with SLE INCONTINENTIA PIGMENTI LIVEDOID VASCULITIS LEG ULCERS

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