A rule concerning the segmental manifestation of autosomal dominant skin disorders. Review of clinical examples providing evidence for dichotomous types of severity

Allelic loss underlies type 2 segmental Hailey-Hailey disease, providing molecular confirmation of a novel genetic concept

“…However, several recent reports indicate that exceptions to this rule exist. On rare occasions, the disorder may show a band-like or otherwise segmental arrangement reflecting mosaicism (4,5).…”

“…According to a new genetic concept we postulated, 2 different types of segmental manifestation can be distinguished in autosomal dominant skin diseases ( Figure 1) (4,5). Type 1 reflects heterozygosity for a de novo postzygotic mutation occurring at an early stage of embryogenesis.…”

“…The cutaneous lesions within the affected segments show a degree of severity similar to that of the nonsegmental phenotype caused by a germline mutation. Outside the segmental areas, the skin is both clinically and genetically normal (4,5).…”

“…A postzygotic mutation occurring at an early developmental stage would result in loss of heterozygosity (LOH) and give rise, in a segmental area, to a homozygous or hemizygous state of the underlying mutation. Clinically, this would be reflected by rather pronounced segmental lesions being superimposed on the ordinary nonsegmental phenotype (4,5). The concept of type 2 segmental involvement, however, has so far not been proven at the cellular and molecular level.…”

Early history of neurofibromatosis type 2 and related forms: earliest descriptions of acoustic neuromas, medical curiosities, misconceptions, landmarks and the pioneers behind the eponyms

“…MPNSTs/NF1, NF2 or schwannomatosis), the degree of involvement (generated by the supposed MPNST or (plexiform) schwannomas in the neck and thigh was very pronounced and superimposed on an ordinary trait (i.e. NF1, NF2 or schwannomatosis), thus resembling the so-called type 2 segmental manifestations of autosomal dominant traits [34,36] (i.e. a very pronounced (segmental) involvement limited to a restricted area of the body superimposed on the non-segmental phenotype vs. the type 1 segmental manifestations, which are characterised by a true mosaic/localised form of a disease) [35,64,67,68,70].…”