SG20 Acral peeling skin syndrome mimicking epidermolysis bullosa simplex

Abstract

Acral peeling skin syndrome (APSS) is a rare autosomal recessive genodermatosis characterized by superficial exfoliation of the ­outermost epidermal layers and acral blistering. Due to overlapping clinical and histopathological features, APSS may be misdiagnosed as epidermolysis bullosa simplex (EBS; now termed KRT5-pEDD-EBS and KRT14-pEDD-EBS). The TGM5 gene encodes the enzyme transglutaminase-5, which maintains stratum corneum integrity. In APSS, a pathogenic variant in TGM5 typically results in cleavage at the junction of the stratum granulosum and stratum corneum. We report a case demonstrating the phenotypic and histopathological overlap in EBS and APSS. This case details an 18-year-old woman with lifelong acral blistering, initially suspected to have EBS, evaluated through clinical assessment, histopathology, immunofluorescence antigen mapping and targeted gene panel sequencing. The patient, conceived via in vitro fertilization to nonconsanguineous parents, presented from birth with recurrent blistering and peeling of the hands and feet in an acral distribution characteristic of EBS. Her past medical history was notable for left Duane anomaly, polydactyly at birth, pyloric stenosis, syndactyly of the toes, and hydronephrosis diagnosed in infancy. Although epidermolysis bullosa has been described in association with pyloric stenosis, the working diagnosis of EBS failed to unify her broader clinical phenotype, including polydactyly and toe webbing. Histopathology demonstrated intraepidermal blistering above the basal layer. Immunofluorescence showed preserved basement membrane zone components with strong keratin 5/6 and keratin 14 staining. Electron microscopy supported EBS due to the basal cell cytoplasm forming the blister floor; however, KRT5 and KRT14 testing done in childhood was negative. In adolescence, worsening acral peeling and subungual haemorrhage prompted further evaluation. Targeted sequencing identified a homozygous pathogenic TGM5 variant (c.337G>T; p.Gly133Cys), confirming APSS. There is a significant phenotypic and histopathological overlap between APSS and EBS, which can lead to prolonged misdiagnosis. Genetic testing is therefore crucial for accurate diagnosis of autoimmune blistering disorders.