Keratosis linearis with ichthyosis congenita and sclerosing keratoderma (KLICK) syndrome is an ultra-rare autosomal recessive genodermatosis. Clinical manifestations include linear hyperkeratotic papules in the flexures, palmoplantar keratoderma and pseudoainhum. To date, all affected individuals carry a homozygous mutation, c.-95delC in POMP, which encodes for proteasome maturation protein. Disease pathophysiology is not well understood and there are no approved therapies. However, literature indicates that KLICK syndrome, like some other ichthyoses, may involve uncharacterised inflammatory pathways. Following written consent, a lesional skin biopsy was obtained from a 32-year-old female with KLICK syndrome. Sanger sequencing confirmed the presence of the homozygous 5’ UTR mutation in POMP, and transcriptomic RNA sequencing methods were used to identify key affected pathways. Skin architecture was assessed by histological and immuno-staining. Immunofluorescence microscopy revealed dynamic proliferative keratinocytes, precocious expression of involucrin and loricrin, with retention of loricrin in the stratum corneum. In addition, lymphocytic infiltrates were detected in the upper dermis providing evidence of inflammation. KLICK syndrome can therefore be characterised as a hyperproliferative inflammatory skin disorder. To overcome challenges surrounding limited patient material, induced pluripotent stem cells (iPSCs) were successfully derived from dermal fibroblasts using a non-integrative mRNA-based reprogramming method. Pluripotency was confirmed by immunofluorescent staining and germ-layer formation by tri-lineage differentiation. Patient derived iPSCs will facilitate further research into epithelial dysregulation by organotypic skin modelling. Understanding the pathobiology of KLICK syndrome may yield novel mechanisms driving inflammatory skin disease, which may be therapeutically targetable in patients with currently limited treatment options.

Keratosis linearis with ichthyosis congenita and sclerosing keratoderma (KLICK) syndrome is an ultra-rare autosomal recessive genodermatosis. Clinical manifestations include linear hyperkeratotic papules in the flexures, palmoplantar keratoderma and pseudoainhum. To date, all affected individuals carry a homozygous mutation, c.-95delC in _POMP_, which encodes for proteasome maturation protein. Disease pathophysiology is not well understood and there are no approved therapies. However, literature indicates that KLICK syndrome, like some other ichthyoses, may involve uncharacterised inflammatory pathways. Following written consent, a lesional skin biopsy was obtained from a 32-year-old female with KLICK syndrome. Sanger sequencing confirmed the presence of the homozygous 5’ UTR mutation in _POMP_, and transcriptomic RNA sequencing methods were used to identify key affected genes. Skin architecture was assessed by histological and immuno-staining. Immunofluorescence microscopy revealed dynamic proliferative keratinocytes, precocious expression of involucrin and loricrin, with retention of loricrin in the stratum corneum. In addition, lymphocytic infiltrates were detected in the upper dermis providing evidence of inflammation. Transcriptomics revealed a large number of upregulated genes in KLICK syndrome relating to keratinisation and innate immune signalling. Genes of interest with relevant biology have been selected for further validation. KLICK syndrome can therefore be characterised as a hyperproliferative inflammatory skin disorder. Understanding the pathobiology of KLICK syndrome may yield novel mechanisms driving inflammatory skin disease, which may be therapeutically targetable in patients with currently limited treatment options.

ESDR206 - KLICK syndrome is a hyperproliferative inflammatory skin disorder.

The scientific meeting of the European Society for Dermatological Research (ESDR) is held yearly, usually in September. With an international attendance of more than 1000 skin scientists from around the globe, the four-day event includes short oral presentations from peer-reviewed abstracts, keynote lectures from international experts, sponsored symposia, satellite programs, educational events as well as an important focus on posters, networking and building collaborations amongst scientists. For more information about this year’s meeting visit our website.