VARIANT RSH SMITH-LEMLI-OPITZ-SYNDROME WITH ATYPICAL STEROL-METABOLISM/

The RSH/Smith-Lemli-Opitz syndrome (RSH/SLOS) is an autosomal recessiv e malformation syndrome comprising microcephaly, developmental and gro wth retardation, characteristic facial anomalies, midline cleft palate , and genital and limb anomalies. Recently, biochemical evidence of an inborn error of cholesterol biosynthesis at the level of 7-dehydrocho lesterol (7-DHC) reductase was reported in children and adults with RS H/SLOS, We report on two sibs with a variant form of RSH/SLOS whose st erol metabolism in cultured lymphoblasts is abnormal but differs from that of patients with classical RSH/SLOS, The children have relatively mild physical and developmental abnormalities, but a phenotype still consistent with the diagnosis of RSH/SLOS, Their plasma cholesterol le vels are only mildly depressed, and they have less markedly increased plasma levels of 7DHC than most patients with classical RSH/SLOS, Cult ured lymphoblasts from our patients accumulated 7DHC to the same degre e as classical RSH/SLOS lymphoblast when grown with cholesterol-deplet ed fetal calf serum, However, unlike other RSH/SLOS cells, the increas e in cellular 7DHC levels was not suppressed when the cells were grown in the presence of cholesterol from untreated fetal calf serum, The p arents' sterol metabolism was also strikingly abnormal in that the lev els of 7DHC in their lymphoblasts were markedly elevated compared with those of lymphoblasts from other RSH/SLOS parents. Our findings sugge st that these mildly affected RSH/SLOS sibs may have a genetic disorde r of sterol metabolism that is related to but biochemically different from classical RSH/SLOS, possibly one affecting intracellular transpor t of sterols, (C) 1998 Wiley-Liss, Inc.