In a 15-year-old girl with microcephaly, congenital cataracts, severe psoriasiform dermatitis, and elevated methylsterols (MCCPD; 616834), He et al. (2011) identified compound heterozygosity for 2 mutations in the SC4MOL gene: a c.519T-A transversion (c.519T-A, NM_006745) in exon 4, resulting in a his173-to-gln (H173Q) substitution, and a c.731A-G transition in exon 6 of the SC4MOL gene, resulting in a tyr244-to-cys (Y244C; 607545.0002) substitution. Both substitutions are located at highly conserved residues, within the second and fourth metal-binding domains, respectively. Each parent was heterozygous for 1 of the mutations, which were not found in 2,876 alleles from population controls or in the dbSNP or 1000 Genomes Project databases. Plasma methylsterol levels were increased in the parents, though to a lesser degree than in the patient, suggesting a subclinical effect in the heterozygous state. Analysis of cell proliferation in patient fibroblasts showed increased cell division compared to control cells when cultured in cholesterol-restricted medium. Immunologic analysis revealed that activated CD16+ (146740) granulocytes were increased 30- and 20-fold in the patient and her father, respectively, compared to controls. In addition, there were 30- and 15-fold increases in the numbers of TLR2+ (603028)/TLR4- (603030) granulocytes in the patient and her father. He et al. (2011) noted that upregulation of TLR2 but not TLR4 was typical in patients with psoriasis or psoriatic arthritis and stated that it likely reflects dysregulation of the immune response following normal bacterial infections. Expression of the granulocyte-specific CD16B (610665) isoform was also markedly downregulated in the patient and her father, suggesting a defect in phagocytic function. Serum cytokine profiles showed that the levels of a number of proinflammatory cytokines and chemokines associated with granulocyte and monocyte activation were increased in the patient, and to a lesser extent in her father.
