Midgestational maternal urine steroid markers of fetal Smith-Lemli-Opitz (SLO) syndrome (7-dehydrocholesterol 7-reductase deficiency)

Smith-Lemli-Opitz syndrome (SLOS) is a malformation syndrome associated wit h 7-dehydrocholesterol (7DHC) 7-reductase deficiency. Although SLOS can be detected in an affected fetus before midpregnancy by measurement of 7DHC le vels in amniotic fluid or chorionic villus cells, a noninvasive, more routi ne method is needed. Accordingly, this study was instigated to search for s pecific steroids in maternal urine in an affected pregnancy that reflect th e 7-reductase deficiency of the fetus, ie, steroids retaining 7,8-unsaturat ion. Steroids were characterized by gas chromatography/mass spectrometry af ter urinary extraction, conjugate separation, and derivatization. Most ster oids in maternal urine from a patient carrying a SLOS fetus were identified as progesterone metabolites, and these were entirely conventional, showing no evidence of additional unsaturation. Unsaturated homologues of the cort isol metabolites were also not detected. However, unsaturated homologues of pregnane-3,16,20-triols and pregnane-3,17,20-triol were found. Most likely , these are 7,8-unsaturated homologues, but 8,9-unsaturation is also possib le because of the known activity of Delta(7)-Delta(8)-isomerase on 7DHC, wh ich results in 8DHC being a prominent sterol in SLOS. Among these novel hum an steroids, the following were provisionally characterized: 5 beta-pregn-7 (or 8)-ene-3 alpha,17 alpha,20 alpha-triol, 5 beta-pregn-7(or 8)-ene-3 alph a,16 alpha,20 alpha-triol, and 5 alpha-pregn-7(or 8)-ene-3,16 alpha,20 alph a-triol. Confirmation of the position of unsaturation will require steroid synthesis. These novel steroids are not present in normal pregnancy urine a nd, therefore, are valuable for prenatal diagnosis of SLOS. In addition, se parate studies have shown that 5 beta-pregn-7(or 8)-ene-3 alpha,17 alpha,20 alpha-triol is present in urine of children and adults with SLOS, and so i s a useful analyte for confirmation of the disorder throughout life. (C) 19 99 Published by Elsevier Science Inc. All rights reserved.