• Peter R Hull, Angela Hobbs, Shaun Aron, and Michele Ramsay.
• Division of Dermatology, Department of Medicine, Royal University Hospital, University of Saskatchewan, Canada. peter.hull@usask.ca.
• S. Afr. Med. J. 2013 Oct 11; 103 (12 Suppl 1): 961-5.

AbstractKeratolytic winter erythema (KWE), also known as Oudtshoorn skin disease, is characterised by a cyclical disruption of normal epidermal keratinisation affecting primarily the palmoplantar skin with peeling of the palms and soles, which is worse in the winter. It is a rare monogenic, autosomal dominant condition of unknown cause. However, due to a founder effect, it occurs at a prevalence of 1/7 200 among South African Afrikaans-speakers. In the mid-1980s, samples were collected from affected families for a linkage study to pinpoint the location of the KWE gene. A genome-wide linkage analysis, using microsatellite markers, identified the KWE critical region on chromosome 8p23.1-p22. Subsequent genetic studies focused on screening candidate genes in this critical region; however, no pathogenic mutations that segregated exclusively with KWE were identified. The cathepsin B (CTSB) and farnesyl-diphosphate farnesyltransferase 1 (FDFT1) genes revealed no potentially pathogenic variants, nor did they show differential gene expression in affected skin. Mutation detection in additional candidate genes also failed to identify the KWE-associated variant, suggesting that the causal variant may be in an uncharacterised functional region. Bioinformatic analysis revealed highly conserved regions within the KWE critical region and a custom tiling array was designed to cover this region and to search for copy number variation. Although the study did not identify a variant that segregates exclusively with KWE, it provided valuable insight into the complex KWE-linked region. Next-generation sequencing approaches are being used to comb the region, but the causal variant for this interesting hyperkeratotic palmoplantar phenotype still remains elusive. 

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