Epidermolysis bullosa simplex (EBS) is a clinically and genetically heterogeneous group of disorders characterized by recurrent blistering and cleavage within basal keratinocytes. Most forms show autosomal dominant inheritance (see, e.g., 131800, 131760, and 131900), but autosomal recessive inheritance ... Epidermolysis bullosa simplex (EBS) is a clinically and genetically heterogeneous group of disorders characterized by recurrent blistering and cleavage within basal keratinocytes. Most forms show autosomal dominant inheritance (see, e.g., 131800, 131760, and 131900), but autosomal recessive inheritance has been described (Fine et al., 2008).
Fine et al. (1989) reported a kindred in which 4 individuals had localized EBS (see 131800), previously known as the Weber-Cockayne type, inherited in an autosomal recessive pattern. Except for scattered oral erosions in 1 patient, there was ... Fine et al. (1989) reported a kindred in which 4 individuals had localized EBS (see 131800), previously known as the Weber-Cockayne type, inherited in an autosomal recessive pattern. Except for scattered oral erosions in 1 patient, there was no evidence of associated extracutaneous disease. The authors noted the implications for genetic counseling. Hovnanian et al. (1993) reported a consanguineous French family in which 2 sibs had a recessive form of localized EBS. Both had recurrent, painful blistering affecting the lateral, dorsal, and plantar aspects of the feet after walking or minor trauma. Blistering occurred occasionally on the legs and thighs after horseback riding, but the palms and rest of the body were spared. Onset was in early childhood. Focal erythematous and slightly atrophic scars were present on the feet. Hair, nails, teeth, and oral mucosa were normal, and there were no milia. There was no hyperkeratosis of the palms or soles. The disorder did not appear to get better with age, and there was disease exacerbation in the summer. Electron microscopic examination of the skin showed cleavage within basal keratinocytes and no clumping of tonofilaments. The parents were unaffected. Rugg et al. (1994) reported a child with severe generalized epidermal blistering beginning 3 days after birth. Blistering occurred virtually anywhere on the body, including arms, legs, trunk, face, scalp, and oral mucosa. There was no thickening of the palms or soles on examination at age 5 years. The front teeth were discolored and notched, but not pitted, and the fingernails were ridged and of uneven thickness. The tendency to blister had diminished with age. There was no KRT14 expression in the skin, and no intermediate filaments were seen in the basal cells of the epidermis. Neither of the parents, who were related, were affected. Stephens et al. (1995) reported a large family in which generalized EBS of the Koebner type was caused by a heterozygous mutation in the KRT5 gene (K173N; 148040.0006). Due to consanguinity in 1 branch of the family, an affected individual was homozygous for the mutation. However, the phenotype and the ultrastructural findings in this patient were not more severe than those observed in heterozygotes. Stephens et al. (1995) suggested that while the presence of some abnormal KRT5 or KRT14 molecules underlies dominant EBS, the lack of all KRT5 or KRT14 molecules, be they normal or abnormal, appears to underlie recessive EBS. However, homozygous null KRT5 mutations have not been reported in humans to date. Hu et al. (1997) reported a French-Portuguese family with localized EBS (131800) due to a heterozygous mutation in the KRT14 gene (M119I; 148066.0010). Blistering began around 1 year of age and was limited to the hands and feet. There was disease exacerbation in the summer, and the disorder tended to decrease with age. One family member, born of a consanguineous union, was homozygous for the mutation, consistent with autosomal recessive inheritance. This patient had a more severe phenotype, with earlier onset, more generalized blistering, and involvement of the oral, vaginal, and anal mucosa. Since age 14, blistering has been limited to the hands and feet. The distal skin was scarred, all 10 toenails were missing, and small areas of palmar hyperkeratosis were present. Hu et al. (1997) concluded that this mutation acts as a 'partial dominant' in that heterozygotes have milder localized disease and homozygotes have a more severe disease. Yasukawa et al. (2002) reported an unusual Japanese family with both autosomal recessive and dominant inheritance of KRT5 mutations resulting in phenotypic variability. The proband was a man with classic generalized EBS, manifest as blistering of the trunk and extremities, improvement with age, and cytolysis within basal keratinocytes on biopsy. Genetic analysis identified compound heterozygosity for the E170K (148040.0020) and E418K (148040.0021) mutations in the KRT5 gene. His paternal uncle, who had blisters restricted to the palms and soles consistent with localized EBS, was heterozygous for the E170K mutation. The proband's deceased father and paternal grandmother, who were putatively heterozygous for the E170K mutation, also reportedly had localized blistering of the hands and feet. In contrast, 2 unaffected family members were heterozygous for the E418K substitution, implying that it is not pathogenic in isolation. In vitro functional expression studies showed that cells transfected with either mutation developed small ball-like filament aggregates, indicating a disruption of the keratin network, although the effect was more pronounced for the E170K mutation. Expression of both mutant proteins exacerbated the clumping and resulted in significantly more disruption than either alone. These findings were consistent with the marked phenotypic and genotypic variability observed in this family.
In 2 French sibs, born of consanguineous parents, with autosomal recessive EBS, Hovnanian et al. (1993) identified a homozygous mutation in the KRT14 gene (E144A; 148066.0004). The authors predicted that this change in amino acid size, shape, and ... In 2 French sibs, born of consanguineous parents, with autosomal recessive EBS, Hovnanian et al. (1993) identified a homozygous mutation in the KRT14 gene (E144A; 148066.0004). The authors predicted that this change in amino acid size, shape, and hydrophobicity would interfere with K14-K5 heterodimer production essential to keratin formation. In a patient with severe recessive EBS, Chan et al. (1994) identified a homozygous mutation in the KRT14 gene (Y204X; 148066.0006). Each of the unaffected parents, who were related, were heterozygous for the mutation. Skin biopsy of the patient showed lack of a discernible keratin filament network in basal epidermal cells. In a patient with severe recessive EBS, Rugg et al. (1994) identified a homozygous 2-bp deletion in the KRT14 gene (148066.0017).