| Resumo: |
Disorders of cholesterol biosynthesis have clinical manifestations involving skeleton, eyes, neurologic development, and skin. We describe a patient with congenital cataracts, developmental delay, microcephaly, and low serum cholesterol who developed severe psoriasiform dermatitis and arthralgias beginning at age 3. Her brain MRI indicatedminor gliosis. Quantitative sterol analysis of patient plasma and skin showed marked elevation of 4alpha-methyl- and 4, 4'-dimethylsterols, indicating a deficiency in the first step of sterol C4 demethylation in cholesterol biosynthesis. Molecular studies showed mutations in _SC4MOL_, a gene predicted to encode a sterol C4 methyl oxidase. Thus, our patient has a previously undescribed inborn error of cholesterol biosynthesis. Cellular studies with patient-derived fibroblasts showed higher mitotic rate than control cells in cholesterol-depleted medium, in which _de novo_ cholesterol biosynthesis was increased with the accumulation of methylsterol. Immunologic analyses showed dysregulation of immune-related receptors in the patient and her father. Inhibition of sterol C4 methyl oxidase in human transformed lymphoblasts or in fresh leukocytes induced activation of cell cycle, and immune receptor dysregulation. These findings suggest that methylsterols influence mitotic capacity and immune function. _SC4MOL_ is situated within the psoriasis susceptibility locus _PSORS9_, and is likely a genetic risk factor for common psoriasis.
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