Genetic Investigation Confirms Acral Peeling Skin Syndrome in a Hungarian Family Clinically Diagnosed with Localized Epidermolysis Bullosa Simplex

Introduction: Localized Epidermolysis Bullosa Simplex (EBS, localized form, OMIM 131800) is a rare monogenic skin disease characterized by the development of blisters on the hands and feet. Acral peeling skin syndrome (APSS, OMIM 609796) is a monogenic condition characterized by superficial painless peeling of the skin predominantly on the dorsal aspects of hands and feet. In this study, we investigated a Hungarian patient, whose clinical symptoms suggested the localized form of EBS. Methods: After genomic DNA was isolated from peripheral blood of the patients, mutation analysis of the keratin 5 (KRT5), keratin 14 (KRT14), β4 and α6integrin (ITGB4 and ITGA6) and transglutaminase 5 (TGM5) genes was performed to identify the causative genetic abnormality responsible for the development of the skin symptoms. In silico tools were applied to identify the functional impact of the newly detected mutations. Results: Direct sequencing of the KRT5, KRT14, ITGB4 and ITGA6 genes detected only wild type sequences. Since the clinical symptoms of localized EBS and APSS overlap, mutation screening of the TGM5 gene was also performed. Two missense mutations of the TGM5 gene were detected in heterozygous form: one novel (c.427T > C, p.Trp143Arg) and one recurrent (c.337G > T, p.Gly113Cys). In silico tools suggested that the newly identified variant is a disease causing mutation. Family screening demonstrated that the novel mutation had a paternal origin, and the recurrent mutation a maternal origin. Conclusions: A patient with EBS clinical symptoms carried TGM5 mutations and, in fact, suffered from APSS. Our study provides further insight into the underlying genetic background of patients diagnosed with localized EBS for which the disease-causing mutation could not be identified by the screening the classic EBS genes.