Genodermatoses

Genodermatoses

Neurocutaneous syndromes

Tumor syndromes

Photosensitivity and Premature Aging Syndromes

What to know

Overview

Inheritance pattern

Mutation - what does it do and why does it lead to the clinical findings?

Clinical presentation including neonatal

Key clinical/laboratory features

Associations

Buzzwords

Treatment, particularly if it is unique to the molecular mechanism

Genetics for the dermatologist

Chromosomal inheritance

Ploidy abnormalities: mosaic diploid/triploid mixoploidy
Whole chromosome abnormality: trisomy, monosomy
Structural chromosomal abnormalities: translocation, inversion, duplications, deletions, ring
Submicroscopical copy number abnormalities: contiguous genes syndrome

Mendelian/monogenic diseases = defects in one gene

Polygenic diseases = defects in more than one gene

Complex/multifactorial diseases result from the interaction of environmental & genetic factors

Allelic heterogeneity refers to different clinical entities due to different mutations in the same gene (ex. DSP)

For example, Desmoplakin (DSP) mutations cause

Striate palmoplantar keratoderma
Dilated cardiomyopathy with wooly hair syndrome
Severe dermatitis, multiple allergies and metabolic wasting (SAM) syndrome
Acantholytic EBS
Arrhythmogenic right ventricular cardiomyopathy

Locus (genetic) heterogeneity refers to mutations in different genes that result in the same phenotype

Some diseases, such as EB simplex, that display both allelic and locus heterogeneity

Pleiotropy - a single gene can have varied and multiple effects on different tissues and organs

Patterns of Inheritance

Autossomal dominant → often related to structural proteins (eg. neurofibromin in neurofibromatosis 1, hamartin in tuberous sclerosis)

Autossomal recessive usually involve enzume defect (xeroderma pigmentosum: DNA repair enzymes; oculocutaneous albinism: tyrosinase)

Exceptions to Basic Mendelian Inheritance Patterns

Variable expression

Different degrees of manifestation of a genotype, either between or within families
Examples: broad ranges of severity in Darier disease and neurofibromatosis type 1

Incomplete/reduced penetrance

Not all individuals show a phonotype
AD trait may appear to skip a generation
Examples: hereditary leiomyomatosis and renal cell cancer syndrome

Age-dependent penetrance

Late onset diseases
Examples: late onset in Darier and Hailey Hailey disease

X-inactivation (lyonization) - mosaicismo funcional

Phenotype depends on the proportion of cells expressing the mutant allele
Skewed/non-random-X-inactivation = selection agains cells with mutant allele typically a mosaic distribution
Examples: incontinentia pigmenti

Incontinentia Pigmenti

CHILD Syndrome

Genomic mosaicism: somatic and gonadal

Postzygotic mutation results in a genetically heterogenous organism
Timing of the mutation & the cell types affected determine the extent, distribution and type of clinical findings
A postzygotic mutation is not transmitted to the offspring except if affecting the gonads which may transmit generalized disease to offspring
Examples: PIK3CA/PROS, NF1, epidermolytic ichthyosis (+/- an epidermolytic epidermal nevus reflecting somatic mosaicism in the parent)
Definition of masaic disorder (ERN Skin) - distinguish mosaic disorder from mosaic abnormality

Coexistance of 2 genotypes
Present at birth (some authors like Happle say mosaic disorder can be developped after birth)
Derived from a single zygote
Post zygotic variant has led to the whole disease phenotype
Excludes

Superimposed mosaic manifestions of autosomal dominant disease
Revertant mosaicism

Loss of heterozygosity

AKA type 2 segmental manifestations
A constitutional heterozygous loss-of-function mutation in a tumor suppressor, high risk of tumor formation from a somatic (”second hit”) mutation inactivating the second allele of the same gene
Examples: Skin tumors in hereditary leiomyomatosis and renal cell cancer and basal cell nevus syndrome

Revertant mosaicism

A postzygotic mutation leads to partial or complete recovery of the wild-type phenotype in an area of skin
Examples: several types of EB, ichthyosis with confetti

Ichthyosis en Confetti

Didimose | twin spots | mosaicismo clonal duplo

Recombinação mitótica pós zigótica entre dois loci diferentes de um embrião inicialmete heterozigótico forma dois clones complementares adjacentes
Exemplos

Nevo epidérmico + nevo pigmentado
Cutis tricolor: hiperpigmented and achromic spots. Fenómenos pigmentares opostos
“twin vascular nevi” → justaposição de angioma com nevo anémico