Cutaneous mosaicism of lethal mutations

Abstract

The concept of autosomal lethal genes surviving only in a mosaic state was proposed by Happle to explain the genetic basis of several syndromes characterized by (almost always) sporadic occurrence, distribution of lesions in a scattered or asymmetrical pattern, variable extent of involvement, lack of diffuse involvement of entire organs, and equal sex ratio. The mosaic may either arise from a gametic half-chromatid mutation or from an early postzygotic mutation. The purpose of this article is to review current knowledge of the genetics and cutaneous manifestations of some of the birth defects to which the lethal gene concept is thought to apply: the Schimmelpenning (Feuerstein-Mims) syndrome, Proteus syndrome, encephalocraniocutaneous lipomatosis, Sturge-Weber and Klippel-Trenaunay syndrome, cutis marmorata teleangiectatica congenita (van Lohuizen syndrome), and neurocutaneous melanosis.

A Filipino male with encephalocraniocutaneous lipomatosis (Haberland’s syndrome)

“…Individuals with these mutations would be unable to transmit the mutation to their offspring as this would lead to death in-utero. 10 This theory is consistent with the sporadic nature of the disease and the variable severity of manifestations.…”

Large or multiple congenital melanocytic nevi: Occurrence of neurocutaneous melanocytosis in 1008 persons

“…The trait would become manifest only when a postzygotic mutation of the corresponding allele occurred, giving rise to a cell clone displaying allelic loss and forming a The presence of congenital small or medium melanocytic nevi in family members would reflect loss of heterozygosity at the LCMN gene locus, which is occurring in a heterozygous embryo at a later developmental stage. 31 Perhaps this explanation might also account for the occurrence of the skin lesions in these siblings. Persons with head or extremity LCMN experienced very few neurologic complications, with an occurrence of symptomatic NCM of only 0.8% in our database.…”

Depigmented hypertrichosis following Blaschko’s lines associated with cerebral and ocular malformations: a new neurocutaneous, autosomal lethal gene syndrome from the group of epidermal naevus syndromes?

“…The linear distribution of the white patches of the scalp strongly suggests that this is the same naevoid disorder as that on the trunk. 2,4,5 Hypermelanosis of Ito and other linear dyspigmentation can be excluded because there was no epidermal hypo-or hyperpigmentation. The lesional scalp of our patient is different from cases reported in the literature.…”