Ichthyosis Bullosa Of Siemens

A number sign (#) is used with this entry because ichthyosis bullosa of Siemens (IBS) is caused by heterozygous mutation in the KRT2 gene (600194) on chromosome 12q13.

Clinical Features

Schnyder (1970) concluded that the bullous type of ichthyosis, called ichthyosis bullosa of Siemens (Siemens, 1937), represents a distinct entity. IBS is a rare autosomal dominant disorder that is highly penetrant and clinically evident from birth. In affected individuals, the clinical findings are similar to those of epidermolytic hyperkeratosis (EHK; 113800). IBS patients are born with a generalized reddening of the skin (erythema) and widespread blistering. In later weeks, they develop large, dark gray hyperkeratoses predominantly on their arms and legs and particularly on the flexural areas where the hyperkeratoses have a lichenified appearance (Traupe et al., 1986; Steijlen et al., 1990). The skin on the limbs of these patients bruises easily and blisters are readily induced by mild physical trauma. The condition usually improves with age so that in most middle-aged patients the hyperkeratosis and keratotic lichenification is limited to the flexural folds of the major joints. As is the case for EHK and most autosomal dominant disorders, IBS patients exhibit a wide variability in the severity of their symptoms. Siemens (1937), who first made the distinction between EHK and IBS, noted that the skin of IBS patients was unusually fragile and had a tendency to shed the outer layers of the epidermis, producing localized denuded areas. He applied the term 'Mauserung' (molting) to this distinctive clinical finding. Siemens' work was largely overlooked until Traupe et al. (1986) reported histologic and ultrastructural findings on a second family with IBS.

In a family with IBS reported by Steijlen et al. (1990), affected individuals had brownish rippled hyperkeratosis and superficial blistering from early childhood. Blistering was more pronounced during hot and humid weather and could be provoked by mild trauma. Erythroderma had never been present in any of the affected persons. Skin lesions were localized, especially on the extensor surfaces of the arms and legs and around the umbilicus, knees, and ankles. In the hyperkeratotic regions, superficially denuded areas were present. Occasionally, fresh blisters ranging in size from 0.5 to 2 cm appeared. On ultrastructural examination of the skin, keratinocytes in the upper spinous layer displayed aggregates of tonofilaments forming V shapes or shells around the nuclei.

Ichthyosis Exfoliativa

Ichthyosis exfoliativa is an autosomal dominant skin disorder described by Vakilzadeh and Kolde (1991) in a single family. The clinical manifestations were similar to those of IBS, but the histologic features of epidermolytic hyperkeratosis were absent. The patients showed dark gray hyperkeratotic lesions with denuded areas. Superficial blistering occurred spontaneously, especially during the summer, but occurred also after trivial trauma. There was no history of erythroderma. On electron microscopic examination, it was said that 'the number of tonofilaments and keratohyaline granules were markedly reduced with no grouping of the tonofilaments.'

Nomenclature

Epidermolytic hyperkeratosis is a histopathologic characteristic of a variety of monogenic keratinization disorders comprising bullous congenital ichthyosiform erythroderma of Brocq, epidermolytic palmoplantar keratoderma of Vorner (EPPK; 144200), ichthyosis hystrix of Curth-Macklin (IHCM; 146590), and ichthyosis bullosa of Siemens. The term epidermolytic hyperkeratosis is also used to refer to the diseases themselves.

Mapping

In the family with IBS reported by Steijlen et al. (1990), Steijlen et al. (1994) demonstrated linkage of the disorder to the region of chromosome 12 in which the keratin type II gene cluster is located. The keratin type I gene cluster on chromosome 17 was excluded.

Steijlen et al. (1994) demonstrated that ichthyosis exfoliativa in the family reported by Vakilzadeh and Kolde (1991) was also linked to the region of chromosome 12 carrying the type II keratin gene cluster.

Molecular Genetics

In 2 families originally diagnosed as having EHK and in 4 families diagnosed with IBS, Rothnagel et al. (1994) identified heterozygous mutations at the same codon in the highly conserved C terminus of the rod domain of keratin 2e (E493D, 600194.0001 and E493K, 600194.0002), thus revealing a mutation hotspot. These results allow a differential diagnosis to be made between IBS and EHK at the DNA level. Rothnagel et al. (1994) suggested that patients thought to have EHK who lack keratin-1 (KRT1; 139350) or keratin-10 (KRT10; 148080) mutations should be reexamined for mutations in the KRT2E gene. McLean et al. (1994) identified the E493K mutation in the KRT2E gene in 2 unrelated British families.

In the family with ichthyosis exfoliativa reported by Vakilzadeh and Kolde (1991), Kremer et al. (1994) detected heterozygosity for the E493K mutation in the KRT2E gene that had previously been found in families with IBS, suggesting that the disorders may be the same.