Description) Smith-Lemli-Opitz syndrome (SLOS) is a devastating birth defect associated with mental retardation and multiple physical malformations. Since it is an enzymatic disorder of cholesterol synthesis (7-dehydrocholesterol-7-reductase deficiency) it is likely that steroid hormone synthesis by the adrenal glands and gonads is impacted because all such compounds utilize cholesterol as precursor. SLOS patients may have quantitatively compromised steroid synthesis because of cholesterol deficiency, and in addition novel steroids with unknown pharmacological properties may be produced which retain ring B unsaturation. This application addresses such issues through a study of serum and urinary steroids. About 30 patients are routinely studied for short periods at the NIH and these will be the subjects of the study. The investigators have evidence that 7-dehydrocholesterol overproduced in the disorder can act as precursor for novel C21, C19, and C18 steroids that are produced in adrenals and gonads. Once confirmed structures of urinary metabolites of such compounds have been obtained, it will be possible to state which (if not all) steroid biosynthetic enzymes accept 7- and 8- dehydrocholesterol as precursor. Information on specific steroids produced in SLOS will permit easy diagnosis, maybe leading to future pre- and postnatal screening. Furthermore, is the quantitative production of steroid hormone metabolites reduced in SLOS? If so, does this suggest adrenal insufficiency? The investigators will measure 40 steroid metabolites in urine and relate their excretions to those of age matched controls and to serum hormone measurements obtained in a separate study. In addition, cholesterol is routinely given to SLOS patients for beneficial effect on behavior and growth. Does the cholesterol partially work through the adrenal steroid mechanism by contributing to hormonal synthesis? The investigators will measure steroid hormone metabolites before and after cholesterol administration and determine if there has been a measurable increase in hormonal metabolites concomitant with decreased dehydrometabolite excretion. Finally, if ring B dehydrosteroids are produced, is the ratio of the individual dehydrometabolites to corresponding conventional metabolites related to the dehydrocholesterol to cholesterol ratio and clinical severity?
