P18 KLICK syndrome is a hyperproliferative inflammatory skin disorder

• Published in: British journal of dermatology (1951) 2023-07, Vol.189 (1), p.e21-e21
• Main Authors: Cherry, Hannah, Parsons, Maddy, Rastrick, Joe, Hardman-Smart, Jonathan, DiMeglio, Paola, McGrath, John
• Format: Article
• Language: English
• ISSN: 0007-0963; 1365-2133
• DOI: 10.1093/bjd/ljad174.039

Keratosis linearis with ichthyosis congenita and sclerosing keratoderma (KLICK) syndrome is an ultra-rare genodermatosis. Clinical manifestations include linear hyperkeratotic papules in the flexures, palmoplantar keratoderma and pseudoainhum. To date, all affected individuals carry a homozygous pathogenic variant, c.-95delC in POMP, which encodes for proteasome maturation protein. Disease pathophysiology is not well understood, resulting in nonspecific and limited treatment options. However, clinically, the phenotype shows erythema and inflammation, indicating that there may be uncharacterized inflammatory pathways in KLICK syndrome, similar to some other ichthyoses. The aim of this work was to characterize KLICK syndrome at the cellular and molecular level. A lesional skin biopsy was obtained, following informed consent, from a 32-year-old woman with KLICK syndrome. Sanger sequencing confirmed the presence of the homozygous single nucleotide deletion in the 5′ untranslated region in POMP. Skin architecture was assessed using immunostaining, which revealed dynamic proliferative keratinocytes, precocious expression of involucrin and loricrin, and retention of loricrin in the stratum corneum. Lymphocytic infiltrates in the upper dermis were suggestive of inflammation and imaging mass cytometry was used to visualize and identify the immune subsets present. RNA sequencing revealed dysregulated pathways relating to keratinocyte differentiation, keratinization, cornification, and interferon signalling. Functional classification of differentially expressed genes using PANTHER additionally implicated WNT signalling, EGFR signalling and inflammatory signalling pathways as dysregulated in KLICK syndrome. KLICK syndrome can therefore be characterized as a hyperproliferative inflammatory skin disorder. Using a reverse transcriptomics approach, epidermal growth factor receptor (EGFR) inhibition and phosphoinositide 3-kinase (PI3K) inhibition were identified as potential treatment options that warrant further investigation. 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.