Two patients from different families have recently been described as having a deficiency of sterol-C4-methyl oxidase, encoded by the SC4MOL gene. Both patients presented with microcephaly, congenital cataracts, and growth delay in infancy. The first patient (a female), who is now 20 years old, has had severe, diffuse psoriasiform dermatitis everywhere except her palms since she was 6. The second patient, also female, is now 5 and has just started to develop dry skin and hair changes. Quantitative sterol analysis of both patients’ plasma showed marked elevation of 4α-methylsterols and 4,4′-dimethylsterols, indicating a deficiency in the first step of sterol-C4 demethylation in cholesterol biosynthesis.
SC4MOL deficiency is the first autosomal recessive disorder identified in the sterol demethylation complex. Cellular studies with patient-derived fibroblasts have shown higher mitotic rates than control cells in cholesterol-depleted medium, with increased de novo cholesterol biosynthesis and accumulation of methylsterols. Immunologic analyses of granulocytes and B cells from patients and obligate carriers in the patients’ families indicated dysregulation of immune-related receptors. Inhibition of sterol-C4-methyl oxidase in human-transformed lymphoblasts induces activation of the cell cycle. These findings suggest that methylsterols influence mitotic capacity and immune function. SC4MOL is situated within the psoriasis susceptibility locus PSORS9 and may be a genetic risk factor for common psoriasis.
The first patient is a white female who was diagnosed at the age of 15; she had a long-standing history of severe psoriasiform dermatitis affecting her entire body but sparing the palms (Figures 300-1A-C), along with chronic arthralgias, small stature, microcephaly, delayed puberty and intellectual disability.1 Skin was normal at birth and dermatitis was first noted around her umbilicus at the age of 2. It subsequently progressed to her back and trunk with generalization to the remainder of her body by the age of 6. The dermatitis worsens in the winter or when the patient is under stress; it only partially responded to standard anti-inflammatory therapy. Notably, the patient also has a medical history of congenital cataracts, mild developmental delay, microcephaly (at age 13, her head circumference was 53.5 cm, which is under the third percentile for her age and in the 50th percentile for a 7 ½ year old), and failure to thrive. Her height tracked along the third percentile between 9 and 39 months of age, but at age 13, her weight was 28.6 kg (under the third percentile and within the 50th percentile for a 9-year-old), and her height was 140 cm (under the third percentile, and within the 50th percentile for a 10 ½ year old). A skeletal survey showed delayed skeletal maturation, but otherwise there were no diagnostic findings. A skin biopsy showed psoriasiform hyperplasia, dilated capillaries in the dermal papillae, and neutrophils in the epidermis and stratum corneum (Figure 300-1D). Neutrophil elastase staining of neutrophils in the stratum corneum is shown in red in Figure 300-1F...