A number sign (#) is used with this entry because of evidence that autosomal recessive localized or generalized intermediate epidermolysis bullosa simplex-3 with BP230 deficiency (EBS3) is caused by homozygous or compound heterozygous mutation in the DST (BPAG1) gene (113810) on chromosome 6p12.

Localized or generalized intermediate epidermolysis bullosa simplex-3 with BP230 deficiency (EBS3) is a mild autosomal recessive dermatologic disorder characterized by trauma-induced blistering mainly occurring on the feet and ankles. Ultrastructural analysis of skin biopsy shows abnormal hemidesmosomes with poorly formed inner plaques (summary by Liu et al., 2012).

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

Groves et al. (2010) reported a 38-year-old Kuwaiti man, born of consanguineous parents, with epidermolysis bullosa simplex. He had a lifelong history of trauma-induced spontaneous blisters and erosions particularly affecting his ankles and feet, although the face, trunk, and more proximal limbs were also affected. Blisters and erosions healed without delay, scarring, or milia formation. He also had nail dystrophy and moderate dental caries, but hair was normal and there was no history of mucosal blistering. Electron microscopic analysis of a skin biopsy showed discrete abnormalities of hemidesmosomes, with poorly formed inner plaques leading to a lucent zone between keratin filaments and outer hemidesmosomal plaques, which showed no gross abnormalities. Immunofluorescence staining showed absence of BPAG1-e at the dermal-epidermal junction and in keratinocytes. There was also decreased immunoreactivity for beta-4-integrin (ITGB4; 147557), PLEC1 (601282), and COL17A1 (113811). The patient's 4 sibs, parents, and 2 children had no skin abnormalities. In addition to skin blistering, the patient had CADASIL (125310) resulting from a heterozygous mutation in the NOTCH3 gene (600276).

Liu et al. (2012) reported a 34-year-old Iranian woman with a lifelong skin blistering disorder that was worse during the summer and after trauma, such as at sites of friction from clothing. Blistering occurred mainly on the ankles, feet, dorsal aspects of the hands, and elbows. She had no hair, nail, mucosal, or genital involvement. Subtle atrophic scarring was present on the shins, ankles, elbows, dorsal aspects of the hands, and lower back. Electron microscopy of skin biopsy showed abnormal hemidesmosomes with poorly formed inner plaques and a lucent zone between keratin filament sand outer hemidesmosomal plaques. The keratin filaments extended to where the inner plaques should be, but did not associate with any attachment structures. Immunostaining for BPAG1-e showed complete absence of the protein in the patient's skin sample. Her father and 2 of her 3 children also had mild blistering, but skin biopsies and DNA were not available from those individuals. None of the individuals had neurologic abnormalities.

Ganani et al. (2021) described 5 patients from 3 families with localized EBS and mutation in the DST gene. Family A was a consanguineous Israeli family of Iraqi origin in which 2 sisters, 48 and 49 years of age, had childhood onset of blisters, primarily of the feet and hands as well as other areas of mechanical pressure. Other features included postinflammatory hypopigmentation, delayed wound healing, calluses, and asymptomatic plantar keratoderma, and 1 of the sisters had nail dystrophy. On examination, both had clear fluid-filled bullae, on the dorsum of a foot and on a finger. Skin biopsy from the edge of a blister revealed subepidermal separation with positive collage IV (see 120130) staining at the base of the blister. Their father and paternal grandmother also reported recurrent blisters. In family B, 4 Israeli sibs of Indian descent had EBS, of which 2 were available for study. One was a 58-year-old woman who had blisters mainly of the lower extremities following friction or mechanical pressure from age 10 years. She also reported nail dystrophy, pressure-induced calluses, and postinflammatory hypopigmentation. Her 70-year-old brother first noted acral blisters involving the soles around age 20 years; examination showed fluid-filled bullae at the right medial ankle and dorsal aspect of the feet. In family C, also Israeli of Indian origin, the proband was an 8-year-old boy who developed blistering over the lower legs and feet at 3 years of age. Examination showed remnants of blisters on the dorsum of the right foot with residual postinflammatory hypopigmentation. The authors noted that the findings in these patients showed phenotypic variability, including atypically large bullae on the dorsal aspect of the feet, as well as variable ages at presentation, even within the same family.

The transmission pattern of EBSB2 in the family reported by Groves et al. (2010) was consistent with autosomal recessive inheritance.

In a Kuwaiti man with epidermolysis bullosa simplex, Groves et al. (2010) identified a homozygous truncating mutation in the DST gene (Q1124X; 113810.0002).

In a 34-year-old Iranian woman from a consanguineous family with epidermolysis bullosa simplex, Liu et al. (2012) identified a homozygous truncating mutation in the DST gene (R1249X; 113810.0003).

By whole-exome and direct sequencing, Ganani et al. (2021) identified biallelic mutations in the DST gene in affected members of 3 Israeli families with localized EBS: in family A, 2 sisters of Iraqi descent were homozygous for the previously reported Q1124X mutation (113810.0002); in family C, an 8-year-old boy of Indian origin was homozygous for a 1-bp duplication (113810.0006); and in family B, a brother and sister of Indian origin were compound heterozygous for the same 1-bp duplication and a 1-bp deletion (113810.0007). Haplotype analysis did not support the existence of a founder mutation in the 2 families of Indian origin. Familial segregation was not reported.