Hamilton, Luke
Salamat, Bita
Hamby, Tyler
Brautbar, Ariel
Wilson, Don


Journal Title

Journal ISSN

Volume Title



INTRODUCTION Smith-Lemli-Opitz syndrome (SLOS) is an autosomal recessive disorder due to mutations in the DHCR7 gene, impairing 7-dehydrocholesterol reductase (DHCR7) and cholesterol synthesis. Patients typically present with low cholesterol and high 7DHC (7-dehydrocholesterol, a toxic precursor) levels, although these values may be normal. SLOS is characterized by distinctive facial and autistic features. Severity depends on baseline cholesterol levels from fractional synthesis by DHCR7 with wildtype-like activity. We present a case and current management recommendations. CASE PRESENTATION A 15-yr-old male with SLOS was referred for short stature and delayed puberty. He has a history of a cleft palate repair, hemangioma removal, gastrostomy button placement, hypospadias, and umbilical hernia repairs. A younger brother, suspected to have SLOS, died young. Physical exam revealed a height and weight st percentile, coarse facial hair, dental dysplasia and malalignment, widely spaced nipples, a broad chest, an undescended left testicle, and global delays. Laboratory results included normal LDL-C (low-density lipoprotein cholesterol) levels of 84 mg/dL (ref. range/dL), atypical of SLOS. He is thought to have residual wildtype-like DHCR7 activity. RESULTS Cholesterol supplements may improve clinical symptoms with minimal side effects. However, studies with standardized methods analyzing cognitive impairment have shown no improvements. Because cholesterol does not cross the blood-brain-barrier (BBB), CSF cholesterol and 7DHC are not altered after supplements. Studies of simvastatin (crosses the BBB), however, have shown improved CSF cholesterol and 7DHC levels, and developmental and behavioral symptoms in mild SLOS (recognized by the Aberrant Behavior Checklist-Community irritability score). Although simvastatin inhibits HMG-CoA reductase, it is hypothesized that the paradoxical elevation in CSF cholesterol is due to increased expression of mutant DHC7R with wildtype-like activity, from increased synthesis of the regulatory protein SREBP2 by simvastatin. CONCLUSION SLOS is an autosomal recessive disorder that impairs DHCR7 function. Severity is dependent on cholesterol and 7DHC levels. Management with cholesterol supplementation may not alleviate SLOS-related developmental deficits. Simvastatin, however, may be helpful and should be considered for patients with mild presentations of SLOS that have residual wildtype-like activity of DHCR7.