Under-recognition of acral peeling skin syndrome: 59 new cases with 15 novel mutations

Summary Background Acral peeling skin syndrome (APSS) is a rare skin fragility disorder usually caused by mutations in the transglutaminase 5 gene (TGM5). Methods We investigated the mutation spectrum of APSS in the U.K., Germany and Poland. Results We identified 59 children with APSS from 52 families. The phenotype was readily recognizable, with some variation in severity both within and between families. Most cases had been misdiagnosed as the localized form of epidermolysis bullosa simplex (EBS‐loc). Eighteen different TGM5 mutations were identified, 15 of which were novel. Eight mutations were unique to a single family, nine each occurred in two families, while the common p.Gly113Cys mutation linked to a second missense variant p.Thr109Met occurred in 47 of the 52 families and was homozygous in 28. Most patients were of nonconsanguineous white European origin. Conclusions We propose that APSS is under‐reported and widely misdiagnosed as EBS‐loc, with significant counselling implications as APSS is autosomal recessive while EBS‐loc is dominant. We recommend screening for TGM5 mutations when EBS‐loc is suspected but not confirmed by mutations in KRT5 or KRT14. Our report trebles the number of known TGM5 mutations. It provides further evidence that p.Gly113Cys is a founder mutation in the European population. This is consistent with the striking ethnic distribution of APSS in U.K., where the majority of patients are of nonconsanguineous white European origin, in contrast to the pattern of other recessive skin disorders. What's already known about this topic? Acral peeling skin syndrome (APSS), caused by transglutaminase 5 (TGM5) mutations, resembles localised epidermolysis bullosa simplex (EBS‐loc). The common TGM5 mutation p.Gly113Cys is recurrent in Europeans. What does this study add? We report 15 novel TGM5 mutations. Unlike the pattern of other recessive skin disorders in the U.K., APSS is associated with European ancestry and not consanguinity, consistent with a European founder mutation. APSS is under‐recognized and commonly misdiagnosed as EBS‐loc.