Ichthyosis bullosa of Siemens: report of a family with evidence of a keratin 2e mutation, and a review of the literature

Abstract

We report a large family with ichthyosis bullosa of Siemens (IBS) including eight affected members spanning three generations. The classical features of the disease were consistently observed with blistering, superficial peeling of the skin, and localized lichenified hyperkeratosis mainly confined to the limbs. Phenotypic variation, however, was also observed with some individuals exhibiting unusual clinical features. Specifically, the index patient was erythrodermic at birth; she subsequently developed a widespread pustular eruption. Erythroderma is classically absent in IBS and pustulation is very unusual. She also had hypertrichosis of the limbs, as did an affected female first cousin. This has not previously been reported in IBS. Electron microscopy showed complex aggregates of keratin in the spinous and granular layers associated, in places, with remarkably little cell lysis. Sequencing of genomic DNA revealed a mutation (E493K) in keratin 2e. A review of the literature on IBS indicates that E493K is the most commonly reported mutation to date and might represent a mutational hotspot for this disease.

Molecular and diagnostic aspects of genetic skin fragility

“…So far, 13 different missense mutations have been described (HGMD, http:// archive.uwcm.ac.uk/uwcm/mg/hgmd0.html). The mutation p.E493K, located at the end of the rod domain, is by far the most frequent mutation in this disorder [33]. …”

An autosomal recessive exfoliative ichthyosis with linkage to chromosome 12q13

“…Lack of tenderness in the denuded areas also suggests that dermal papillae are not fully exposed in the denuded areas. In the other variants of exfoliative ichthyoses the cleavage occurs in more superficial layers: in the stratum corneum in PSS, 19,20 in granular or upper spinous layers in IBS, ADIE or AEI 4,6 , 12 . Aggregates of keratin filaments in basal keratinocytes have not been reported in other exfoliative ichthyoses.…”

“…Peeling of skin is found in several congenital ichthyosiform dermatoses: epidermolytic hyperkeratosis (EHK), 1 ichthyosis bullosa of Siemens (IBS), 2 peeling skin syndrome (PSS), 3 as well as in two less clearly defined ichthyoses—annular epidermolytic ichthyosis 4,5 (AIE) and autosomal dominant ichthyosis exfoliativa 6 (ADIE). Mutations in keratins were found in EHK (K1 and K10), 7,8 in AEI (K10) 5 and in IBS and ADIE (K2e) 9–12 . In the heterogeneous group of PSS, the gene loci are still unknown.…”

A boy with persistent ‘atopic eczema’ resistant to conventional topical therapies

“…Clinically IBS had a milder phenotype than BCIE, and erythroderma was not a feature, although an erythrodermic case of IBS has been described. 2 Subsequently, in 1994 IBS was discovered to be due to mutations in the keratin 2e gene (KRT2E; OMIM 600194), which is expressed in the uppermost spinous layers but mainly in the granular layer, as opposed to the classical or Broq variant of BCIE, which is due to KRT1 and KRT10 mutations, 3 both expressed in the suprabasal layers. IBS is a rare condition with 17 kindreds and only 6 sporadic cases reported in the past 70 years, but the true figure is likely to be higher, as many IBS cases are mild and therefore probably underreported.…”