ESDR262 - The Role of Cholesterol in Rare Inflammatory Skin Disease

Inflammatory linear verrucous epidermal naevus (ILVEN) is a rare congenital disease characterised by Blaschko-linear erythematous scaly skin. It is highly pruritic, disfiguring, and notoriously treatment-resistant. The genetic basis is heterogeneous: causes so far established are a single case of GJA1- and two of CARD14- mosaicism. However, clinical overlap with the skin lesions of CHILD syndrome led us to hypothesise that there may be a common biological pathway abnormality in ILVEN skin centred on cholesterol metabolic pathways. Ten patients with ILVEN and no other clinical features (GJA1 and CARD14 wildtype) and ten healthy controls (excess normal skin from surgery) were recruited and biopsied. Deep whole exome sequencing of affected skin revealed that two patients had unsuspected CHILD syndrome (Congenital Hemidysplasia, Ichthyosiform Erythroderma and Limb Defects) with germline NSDHL variants. Keratinocytes were cultured and HPV immortalised, then characterised using proliferation assays, Filipin III staining and highly optimised 2-dimensional Gas-Chromatography mass spectrometry. Strikingly, mean total cholesterol levels and three sterol intermediates in the cholesterol synthesis pathway were significantly reduced in the patient group compared to controls. In parallel we observed significant hyper-proliferation in patient keratinocytes at baseline compared to controls, which was rescued by addition of cholesterol in isolation and with the addition of Simvastatin. Treatment in clinic with topical 2% cholesterol + 2% lovastatin was effective in both patients with CHILD syndrome as previously shown, and partial correction in two further patients without a known genetic disorder of cholesterol metabolism. These findings identify a significant role for cholesterol levels in the pathogenesis of ILVEN and raise important questions about the regulation of inflammatory skin disease by lipid metabolic pathways.