The diagnosis of SLOS in often first raised on the basis of the characteristic phenotype. Confirmation of the diagnosis requires analysis of sterols in Wood, tissue, amniotic fluid, or chorionic villus with subsequent identification of the characteristic sterol profile, which includes elevation of the cholesterol precursors 7-DHC and 8-DHC. usually in the presence of decreased levels of cholesterol (Tint et al.. 1994, 1995b; Kelley, 1995). Most patients will have decreased cholesterol levels in blood or other body tissues: however, there have been patients with mild or variant forms of the condition who have normal cholesterol levels but elevation of 7-DHC and K-DHC. Therefore, measurement of sterols by gas-chruinatography (CiC) or by GC/inass spectrometry (MS), which can separate the sterols and measure each independently, is necessary for a proper diagnostic evaluation as it is the elevation of 7and K-DHC that confirms the diagnosis of SLOS. Measurement of cholesterol by the method employed in most hospital laboratories will not identify all patients as this measure* Mai cholesterol (cholesterol plus the precursors), which can result in cholesterol levels in the normal range. Patients with variant forms of SLOS have also presented with normal sterol profiles in blood but accumulation of sterol precursors in fibroblasts or lympboblasts (Anderson et al., 1998). In cases where blood is not available, tissue can be sent for sterol analysis. Sterols from tissue from stored pathologic specimens, either fro/en tissue or tissue blocks, can also be extracted for diagnostic testing.
Other laboratory testing should include analysis of electrolytes, glucose, and indices of liver function to evaluate for the presence of cholestasis or coagulopathy in a severely affected newborn and endocrine hormonal testing for Cortisol deficiency or abnormal male steroid hormones. Newborn screening for SI-OS has not been possible as an easily implemented. reproducible technique for identification of 7-DHC or 8DHC from filter paper-dried blood spots has not been established. However, time-of-flight secondary ion MS to measure the cholesterol/dehydro cholesterol ratio (Zimmerman et al.. 1997), measurement of 7-DHC and 8-DHC by GC/MS (Stan* and Lovgren. 2000). and measurement of the 7-DHCVcholcstcrol ratio by electrospray ionization tandem MS (Johnson et al.. 2001). all from dried blood spots, ate promising techniques for future use.
Carrier Testing Carrier detection by biochemical analysis is more problematic. Obligate carriers do not have significantly lower cholesterol levels or significantly higher levels of 7-DHC or X-DHC than noncarriers (Irons, unpublished; Nowac/.yk et al.. 2(XH)a). eliminating sterol analysis of plasma as a potential test for carrier detection. Cairier detection i* possible either by measurement of DHCR7 activity (Shefer et al.. 1097) or by measurement of the rate of reduction of the ergo-»terol C-7 douhie bond (Honda el al., 1993) in cultured skin fibroblasts, although neither technique js readily available and both may potentially miss some carriers due to overlap of activity into the normal range Molecular analysis of l)HCK7 gene mutations will provide the easiest and most reliable method of carrier detection.