Erythrokeratolysis hiemalis (EH) also known as keratolytic winter erythema is a rare dominantly inherited disorder of cornification. It manifests with recurrent episodes of skin peeling and palmoplantar erythema, often more visible during the winter season. EH was recently found to be caused by genomic duplications in a non-coding region which regulates CTSB, a gene encoding the cysteine protease Cathepsin B. As a consequence, Cathepsin B expression is increased which in turn causes EH. We aimed at identifying the genetic defect underlying an atypical disorder of cornification in a family featuring severe diffuse transgradient hyperkeratosis involving the palms and soles accompanied by mild diffuse redness of the palms. Pedigree analysis suggested autosomal dominant inheritance. Whole exome sequencing revealed a heterozygous missense mutation in CTSB, encoding Cathepsin B. The mutation affects a highly conserved residue and is predicted to be pathogenic. Protein modelling indicated that the mutation is likely to lead to increased endopeptidase Cathepsin B activity. Accordingly, using a reporter expressing the mutation, we found that it indeed results in increased Cathepsin B activity. Moreover, Cathepsin B expression was increased in a biopsy sample obtained from the patient. In summary, we report the identification of the first gain-of-function missense mutation in CTSB which was found to be associated with an atypical EH-like phenotype.

Expanding the clinical spectrum of erythrokeratolysis hiemalis