Homozygous pathogenic variant in the TGM5 gene causing acral peeling skin syndrome type 2

Objectives To provide a detailed description of the clinical case of a patient with recurrent acral erosions since childhood, in whom a homozygous pathogenic variant in the TGM5 gene was identified, and in whom genetic diagnosis made it possible to determine the etiology underlying the clinical presentation. Case presentation We present the case of a 22-year-old male with a history of recurrent acral erosions and blisters since the first month of life, exacerbated by friction and physical exertion. We identified a homozygous pathogenic variant in the TGM5 gene, establishing causality and confirming a genetic diagnosis of Acral Peeling Skin Syndrome type 2 (APSS2), whereas the initial clinical suspicion had been epidermolysis bullosa. Conclusions The identification of pathogenic variants in the TGM5 gene through massively parallel sequencing techniques is crucial to differentiate APSS2 from other blistering disorders, to avoid unnecessary and invasive diagnostic procedures, and to guide appropriate preventive measures, treatment strategies, and individualized patient and family follow-up.