A number sign (#) is used with this entry because generalized severe epidermolysis bullosa simplex-2A (EBS2A) is caused by heterozygous mutation in the KRT5 gene (148040) on chromosome 12q13.

Another form of generalized severe EBS, EBS1A (131760), is caused by mutation in the KRT14 gene (148066).

Generalized severe epidermolysis bullosa simplex-2A (EBS2A) is an autosomal dominant skin disorder characterized by extensive intraepidermal blistering after minor mechanical stress from the time of birth with herpetiform marginal spreading and central healing. Oral mucosal involvement, nail dystrophy, onychogryposis, formation of milia, and palmoplantar hyperkeratosis are common features. Blistering is more frequent in warm weather and generally improves with advancing age. The 'severe' subtype of EBS was previously known as the Dowling-Meara type (EBSDM). In addition to the intraepidermal blister formation after minor mechanical stress common to all forms of EBS, skin biopsies from patients with the severe EBS subtype show aggregation and clumping of basal keratins on electron microscopy, resulting in a total collapse of the keratin cytoskeleton of basal keratinocytes (summary by Muller et al., 1999).

For a discussion of genetic heterogeneity of the subtypes of EBS, see EBS1A (131760).

Nomura et al. (1996) reported a Japanese boy with EBS Dowling-Meara (EBSDM) and mutation in the KRT5 gene who developed blisters over the entire body after birth. At 6 days of age, extensive blisters and erosions were present over the entire body and in oral mucous membranes. On clinical grounds, the more severe EB subtypes junctional (see 226650) or dystrophic (see 131750) were suspected. After a few months, palmar and plantar hyperkeratosis developed, as well as deformities on all nails. There was no family history of blistering disease. Electron microscopy revealed blisters within basal cells and clumping of tonofilaments characteristic of EBSDM.

Rugg et al. (1999) studied a family of French ancestry with EBS Dowling-Meara type and mutation in the KRT5 gene. All affected individuals had suffered since birth from recurrent and general blistering after mild physical trauma. Blistering was nonscarring and occurred at any body site, but predominantly on hands, elbows, feet, knees, and face. Oral blistering was sometimes noted. Moderate hyperkeratosis of palms and soles was present in several affected individuals. Disease exacerbation was observed during the summer. No milia were noted, and hair, nails, and teeth were normal. Electron microscopic examination of a skin biopsy obtained after rubbing an intact area showed cleavage within the basal keratinocytes with clumping of keratin filaments.

Muller et al. (1999) reported a 38-year-old woman with a mutation in KRT5 who had been affected since birth by generalized blister formation with herpetiform spreading and central healing. Hemorrhagic blisters occurred on the trunk, palms and soles, face, and in oral mucosa after minor trauma. Palmar and plantar hyperkeratoses existed before walking, and plantar hyperkeratoses were painful in periods of blistering. Subungual blisters and irregular nail plate thickening were present. Although some improvement was noted after age 4 years, recurrent generalized blistering occurred into adulthood. Blistering in the basal layer and clumping of basal keratins seen on electron microscopy permitted the diagnosis of EBSDM.

Shemanko et al. (2000) described a female infant (patient 2) with Dowling-Meara EBS and mutation in the KRT5 gene who had a hoarse cry, a feature not well documented in Dowling-Meara EBS but usually associated with junctional EB. At birth, patient 2 had blisters on palms and soles, and within hours blistering had spread to involve the tongue, buccal mucosa, periungual regions, and large areas of skin. By 3 weeks of age she had developed stridor and a hoarse cry, which was present until about the age of 2 years. Laryngoscopy was not undertaken. At the age of 19 months, the child developed a widespread cutaneous herpes simplex infection, requiring inpatient treatment with systemic aciclovir. At 5 years of age, the patient was developing normally despite the persistence of widespread herpetiform blistering.

Glu477 to Lys Mutation

Sathishkumar et al. (2016) and Lalor et al. (2019) reported patients with particularly severe generalized EBS, including skin loss requiring intensive care; several patients died in the first months of life. All of these patients carried a E477K mutation in KRT5 (see MOLECULAR GENETICS).

Sathishkumar et al. (2016) reported 7 children and 1 adult with severe generalized EBS. All 7 children had extensive skin loss at birth and required intensive medical care, and 5 of them died within the first 6 months of life, having received parenteral feeding, opiate analgesia, and antibiotics until death. Of the 2 surviving infants, one was a 4-year-old girl, and the other was still hospitalized at day 86 of life, with hoarseness, feeding difficulties, and recurrent skin infections. Four of the deceased infants had no family history of EBS, but 1 had an affected mother who had severe blistering in childhood and in adulthood experienced marked palmoplantar keratoderma with significant pain and recurrent infections restricting mobility, as well as severe periodontal disease.

Lalor et al. (2019) reported 6 children with severe generalized EBS. All 6 patients had severe generalized blistering and aplasia cutis and required intensive care after birth, and 1 child died at age 1 month due to sepsis. Blistering improved with age, and surviving children developed a distinctive reticulated skin pattern that was erythematous, hyperpigmented, or both, with round blanched patches of skin centrally. Most patients had severe onychodystrophy with moderate to severe palmoplantar hyperkeratosis. Often there was severe neonatal oral blistering and poor weight gain, necessitating gastrostomy tube placement. Two patients had broncho- and/or laryngomalacia, requiring tracheostomy. In addition, most patients had multiple developmental delays, beyond what might be expected for a chronically ill child. The authors noted that the reticulated pattern of pigmentation in these patients appeared to be distinct and perhaps pathognomonic, and stated that it was different from the pigmentation observed in EBS with mottled pigmentation (EBSMP; 131960).

The transmission pattern of EBS2A in the families reported by Lane et al. (1992) and Rugg et al. (1999) was consistent with autosomal dominant inheritance. The heterozygous mutations in the KRT5 gene that were identified in patients with EBS2A by Nomura et al. (1996) and Muller et al. (1999) occurred de novo.

In a large family with Dowling-Meara EBS, Lane et al. (1992) identified a heterozygous mutation in the KRT5 gene (E475G; 148040.0001) that segregated with the disorder in an autosomal dominant pattern.

In a Japanese patient with EBSDM, Nomura et al. (1996) detected a de novo heterozygous missense mutation in the KRT5 gene (148040.0008).

In affected members of a large French family with Dowling-Meara EBS, Rugg et al. (1999) identified a heterozygous splice site mutation in the KRT5 gene (148040.0011), resulting in a deletion of the last 5 amino acids of the H1 head domain and the first 17 amino acids of the conserved N-terminal end of the 1A rod domain, including the first 2 heptad repeats and the helix initiation peptide.

In a 5-year-old girl with Dowling-Meara EBS and a hoarse cry, Shemanko et al. (2000) identified a heterozygous missense mutation in the KRT5 gene (S181P; 148040.0012).

In a 38-year-old German woman with EBSDM, Muller et al. (1999) detected a heterozygous nonsense mutation in the KRT5 gene (E477X; 148040.0015). The patient's unaffected parents, 2 sisters, and son did not carry the mutation.

Glu477 to Lys Mutation

Sathishkumar et al. (2016) reviewed a cohort of 37 newborns with generalized severe EBS, reported to the National Health Service of the UK over a 15-year period, 33 of whom underwent genetic analysis. Of those 33 patients, 17 had mutations in the KRT5 gene, 15 had mutations in KRT14, and 1 had a mutation in both KRT5 and KRT14. Seven children, including 5 who died in infancy and 1 who remained hospitalized at almost 3 months of age, were heterozygous for an E477K substitution in the KRT5 gene (148040.0025). The E477K variant occurred de novo in all but 1 of the children, who had an affected mother. Sathishkumar et al. (2016) noted that the E477K variant had been reported previously in 10 cases of generalized severe EBS, but clinical information was limited and mortality data were not reported. The authors suggested that the E477K variant might predispose to a severe and potentially lethal form of generalized severe EBS, noting that survivors were likely to be overrepresented if some affected neonates died before genetic studies were performed and the mutation occurred de novo.

Lalor et al. (2019) ascertained 6 children from national or local epidermolysis bullosa databases, from the United States, Italy, Germany, Finland, and Chile, in whom Sanger sequencing had revealed heterozygosity for the E477K mutation in the KRT5 gene. All were severely affected and 1 infant died. In 5 patients, the mutation was demonstrated to have arisen de novo; genetic analysis had not yet been performed in the parents of the sixth patient.

In a 15-year review of all infants born with generalized severe EBS and notified to the National Health Service of the UK, Sathishkumar et al. (2016) identified 37 cases. Genetic analysis in 33 of those cases showed KRT5 mutations in 17, KRT14 mutations in 15, and mutations in both KRT5 and KRT14 in 1 patient. The authors noted that generalized severe EBS was associated with KRT5 and KRT14 mutations involving the highly conserved ends of the alpha-helical rod domain, the helix boundary motifs, whereas mutations outside the helix boundary motifs were associated with milder EBS phenotypes. In addition, clinical severity had been reported to be associated with the nature of the amino acid change, with changes in polarity or acidity being associated with more severe phenotypes.

Kim et al. (2017) screened 52 Australian patients with EBS for mutations in the KRT5 and KRT14 genes and identified 32 different mutations in 39 pedigrees. The authors found that mutations causing localized EBS occurred sporadically across the KRT5 and KRT14 peptides. Mutations resulting in generalized severe EBS were most commonly clustered at the helix boundary motifs, the helix initiation (HIP) and termination (HTP) regions, which are critical for normal keratin formation. In most other cases phenotypes correlated with the location of the mutations and were in agreement with previous reports.