A number sign (#) is used with this entry because of evidence that autosomal recessive generalized intermediate epidermolysis bullosa simplex 5D (EBS5D) is caused by homozygous or compound heterozygous mutation in the PLEC gene (601282) on chromosome 8q24.

Autosomal recessive generalized intermediate epidermolysis bullosa simplex 5D (EBS5D) is characterized by generalized skin blistering that heals with scarring and hyperpigmentation. Nail dystrophy is severe. Mucous membranes, heart, and muscle are spared (Gostynska et al., 2015).

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

Gostynska et al. (2015) reported 2 sisters from a consanguineous Turkish family who had skin blistering with sparing of the mucous membranes as well as severe nail dystrophy, without cardiac or skeletal muscle involvement, and mutation in the PLEC gene. The proband, first examined at 27 years of age, had developed mild foot blisters after walking at 1.5 years of age. Fingernails and toenails were dystrophic by 3 years of age. Blistering became generalized with pruritus during puberty at age 14, and lesions healed with scarring and hyperpigmentation. Examination revealed excoriated and verrucous papules and intact blisters, most pronounced on the distal extremities, as well as focal plantar hyperkeratosis and severely dystrophic nails. Teeth and hair were normal. Her 26-year-old sister had a similar history and distribution of progressive skin lesions but displayed less pronounced hyperkeratotic papules and plantar hyperkeratosis, possibly due to having less pruritus. Neurologic and cardiologic evaluation in the older sister revealed no evidence of muscular dystrophy or cardiac pathology; neither sister exhibited any signs of muscular dystrophy or cardiomyopathy at 29 and 30 years of age, respectively. Immunofluorescence antigen mapping of lesional skin showed a thin granular lining of keratin staining on the blister floor, revealing very low intraepidermal cleavage in basal cells, consistent with EBS. Transmission electron microscopy showed hypoplastic hemidesmosomes and intraepidermal pseudojunctional cleavage, with the plasma membrane of basal cells visible on the blister floor.

Tu et al. (2020) reported 2 unrelated patients who had generalized EBS with nail dystrophy and mutation in the PLEC gene. The 31-year-old woman and 18-year-old man both had generalized erythematous blistering and erosions since birth, with hyperpigmented patches on the trunk and extremities. Both had blisters within the oral cavity, palmoplantar keratoderma, and dystrophy of all 20 nails. Neither had muscle weakness, hoarseness, ocular lesions, or other extracutaneous manifestations. Transmission electron microscopy showed hypoplastic hemidesmosomes in both patients; the woman also had focal reduplication of the lamina densa and the man had vesicles in basal cells. Immunofluorescence studies showed near-complete absence of plectin at the dermoepidermal junction.

The transmission pattern of EBS5D in the family reported by Gostynska et al. (2015) was consistent with autosomal recessive inheritance.

In 2 sisters with EBS and nail dystrophy (EBSND) from a consanguineous Turkish family, Gostynska et al. (2015) analyzed the candidate gene PLEC1 and identified homozygosity for a nonsense mutation (R16X; 601282.0014) present only in the 1a isoform. Quantitative RT-PCR of cultured skin keratinocytes from the sisters showed reduced transcription of 1a compared to controls. Because isoform 1a is not expressed in either striated or cardiac muscle tissue, Gostynska et al. (2015) stated that they did not expect muscular dystrophy or cardiomyopathy to develop in these patients.

By whole-exome sequencing (WES) evaluating 21 known EBS-associated genes in a 31-year-old woman with EBSND, Tu et al. (2020) identified compound heterozygosity for a nonsense mutation (R2319X; 601282.0013) and a missense mutation (L319P; 601282.0015) in the PLEC gene. WES in a similarly affected unrelated 18-year-old man revealed compound heterozygosity for the same L319P mutation and a nonsense mutation (W936X; 601282.0016). Sanger sequencing confirmed segregation in the families.