Epidermolysis Bullosa Simplex With Mottled Pigmentation

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Retrieved

2019-09-22

Source

Omim

Trials

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Genes

KRT5, KRT14, NAT9, KRT1, EXPH5

Drugs

Allantoin, Allogeneic adipose-derived adult mesenchymal stem cells contained in a fibrin-based bioengineered dermis, Allogeneic human dermal fibroblasts

Allantoin, Allogeneic adipose-derived adult mesenchymal stem cells contained in a fibrin-based bioengineered dermis, Allogeneic human dermal fibroblasts, Allogeneic skin-derived ABCB5-positive mesenchymal stem cells, Bilayer engineered skin composed of keratinocytes (patient autologous) and fibroblasts (donor allogeneic) in a plasma matrix, Diacerein, Dry extract from Betulae cortex (birch bark), Human dermal fibroblasts cultured on a bioresorbable polyglactin mesh, Losartan

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A number sign (#) is used with this entry because of evidence that EBS with mottled pigmentation is caused by heterozygous mutation in the keratin-5 gene (KRT5; 148040) on chromosome 12q13.

Mutation in the same gene causes several other forms of epidermolysis bullosa simplex, including EBS Dowling-Meara type (131760), EBS Koebner type (131900), and EBS Weber-Cockayne type (131800). Similar disorders may also be caused by mutation in the keratin-14 gene (148066).

Clinical Features

Fischer and Gedde-Dahl (1979) reported a Swedish family in which 11 members presented with epidermolysis bullosa simplex with some unusual features, 10 of whom (1 male and 9 females) had a congenital mottled appearance of the skin. Both anomalies were inherited together in an autosomal dominant pattern. Recurrent blistering from birth resembled that of EBS Koebner, but in addition the patients showed 2- to 5-mm hyper- and hypopigmented spots giving the skin, especially of the limbs, a mottled 'dirty' appearance. 'Premature aging of the skin,' mild bruisability of the legs, and longitudinally curved nails were other features. The pigmentary anomaly was delayed in some individuals. Linkage with GPT (138200) on chromosome 8q was excluded. The epidermolysis without dyspigmentation in the eleventh individual suggested to the authors that the syndrome in the other 10 members may be due to genetic linkage of 2 independent genes and not to pleiotropism of a single mutant gene. Matthews and Peachey (1977) reported a father and daughter with EBS with pigmentation and palmar and plantar keratosis; pigmentation was delayed. Reports of other families (Sparrow et al., 1976; Verbov, 1980; Boss et al., 1981) suggested pleiotropism.

Histologically and ultrastructurally, the blistering in EBS with mottled pigmentation closely resembles that found in other EBS subtypes. This is consistent with a disorder of the basal keratinocyte cytoskeleton in which disease-causing mutations have been found within the central rod domains of keratins 5 and 14 (KRT14; 148066) (Irvine et al., 1997).

Glasz-Bona et al. (2010) reported a large 4-generation Hungarian pedigree with EBSMP. There were 10 affected members, 5 of whom were deceased. All had localized blistering and skin fragility in childhood, followed by the development of brownish, lentigo-like mottled pigmentation and hypopigmentation on the trunk and/or extremities during adolescence and adulthood. Two patients also had nail dystrophy.

Molecular Genetics

In 2 unrelated families with EBSMP, Uttam et al. (1996) identified a mutation in the KRT5 gene (P25L; 148040.0009). The same mutation was found in a sporadic case (Irvine et al., 1997) and in 2 additional families (Irvine et al., 2001), increasing the total number of EBSMP kindreds with this mutation to 7.

In affected members of a Hungarian family with EBD-MP, Glasz-Bona et al. (2010) identified a heterozygous P25L mutation in the KRT5 gene.

Animal Model

Roth et al. (2009) found that skin from Krt5-null mice showed increased levels of the inflammatory cytokines MCP1 (CCL2; 158105), CCL19 (602227), and CCL20 (601960), all of which are regulated by NFKB (see 164011) and involved in the recruitment, maturation, and migration of Langerhans cells in the epidermis. These changes were not observed in Krt14-null mice. The number of Langerhans cells were increased 2-fold in epidermis of neonatal Krt5-null mice. In contrast, TNFA (191160) was not changed, demonstrating the specificity of that process. The basal epidermis from Krt5-null mice also showed decreased p120-catenin (CTNND1; 601045). Enhanced Langerhans cell recruitment within the epidermis was found in 5 patients with various forms of EBS due to KRT5 mutations, but not in EBS patients with KRT14 gene mutations. These data provided an explanation for distinct, keratin-type-specific genotype-phenotype correlations in EBS, and suggested that the pathophysiology of EBS involves more than mutant keratins.