Microcephaly, Congenital Cataract, And Psoriasiform Dermatitis

A number sign (#) is used with this entry because of evidence that microcephaly, congenital cataract, and psoriasiform dermatitis (MCCPD) is caused by homozygous or compound heterozygous mutation in the SC4MOL gene (MSMO1; 607545) on chromosome 4q32.

Description

SC4MOL deficiency represents an inborn error of cholesterol metabolism that is characterized by accumulation of a large amount of methylsterols, particularly dimethylsterols, in affected patients. The associated features of immune dysregulation, skin disease, and growth delay can be at least partially corrected with cholesterol and statin supplements (He et al., 2014).

Clinical Features

He et al. (2011) reported a 15-year-old girl who presented at age 13 years for evaluation of severe ichthyosiform erythroderma affecting the entire body but sparing the palms. Her skin was normal at birth, but periumbilical dermatitis was noted when she was 2 years old; dermatitis then spread to her back and trunk and ultimately to the remainder of her body by age 6. The dermatitis worsened in winter or with stress, and at one point almost completely normalized. There was no long-term response, however, to traditional therapies for psoriasis. Skin histology showed psoriasiform hyperplasia with CD68 (153634)-negative lipid-laden foamy cells in the dermis. The patient also exhibited microcephaly, congenital cataracts, mild developmental delay, and failure to thrive. Serum lipid profile showed persistently low total cholesterol, HDL, and LDL, with normal triglycerides and VLDL. A cholesterol biosynthesis defect was suspected, and plasma sterol analysis showed a 20-fold increase in 4-alpha-monomethyl sterols and a 500-fold increase in 4,4-prime-dimethyl sterols. No 4-carboxylmethylsterol or 4-methylsterone was detected in patient skin or plasma. Methylsterols were markedly elevated in patient fibroblasts compared to controls, and the level of methylsterols increased when the patient cells were grown in cholesterol-depleted medium. Experiments with culture medium were consistent with a block at the step of sterol-C4-methyl oxidase (607545) in the cholesterol synthesis pathway. Vockley et al. (2011) stated that at age 15, the patient exhibited delayed puberty. She had received 2 years of treatment with an oral statin and supplementation of cholesterol and bile acids, following which her plasma methylsterol levels normalized, her weight and linear growth improved dramatically, and her arthralgias resolved. Application of a topical statin plus cholesterol suspension resulted in marked improvement of her skin disease. In addition, analysis of immunocyte profiles before and after therapy revealed a significant reduction in granulocyte activation after treatment, approaching levels seen in her heterozygous parents. Vockley et al. (2011) also reported a girl with microcephaly, developmental delay, congenital cataracts, and joint contractures that were most marked in the lower extremities. (The same girl was later reported by He et al., 2014). The authors noted that although her skin appeared normal, she had increased expression of CD25 (IL2RA; 147730) and TLR2 (603028) in leukocytes and IgD receptors in the B-cell population that was similar to the original patient.

Molecular Genetics

In a 15-year-old girl with microcephaly, congenital cataract, severe psoriasiform dermatitis, and elevated methylsterols, who was negative for mutation in the NSDHL gene (300275), He et al. (2011) sequenced the candidate gene SC4MOL and identified compound heterozygosity for 2 missense mutations, H173Q (607545.0001) and Y244C (607545.0002). Each parent was heterozygous for 1 of the mutations, which were not found in 2,876 alleles from population controls or in public variant 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.

In a 5-year-old Hispanic girl with microcephaly, congenital cataract, and elevated methylsterols, previously reported by Vockley et al. (2011), He et al. (2014) identified homozygosity for a missense mutation in the SC4MOL gene (G115R; 607545.0003). Her parents were heterozygous for the mutation. The authors noted that although the patient was beginning to develop dry skin and hair changes, she had never exhibited a marked psoriasiform rash.