CLINICAL AND BIOCHEMICAL SPECTRUM OF PATIENTS WITH RSH SMITH-LEMLI-OPITZ SYNDROME AND ABNORMAL CHOLESTEROL-METABOLISM/

RSH/Smith-Lemli-Opitz (RSH/SLO) syndrome is an autosomal recessive mal formation syndrome recently shown to be associated with a severe defic iency of cholesterol biosynthesis and markedly elevated plasma and tis sue levels of 7-dehydrocholesterol (7-DHC), the immediate precursor of cholesterol in the Kandutsch-Russell biosynthetic pathway. Because th ese biochemical abnormalities permit a reassessment of RSH/SLO on bioc hemical criteria rather than less specific physical criteria, we revie w here the clinical and biochemical characteristics of our first 80 pa tients with abnormally increased levels of 7-DHC. The study population included 68 index patients and 12 additional relatives identified by quantification of 7-DHC and cholesterol in plasma, amniotic fluid, or cultured fibroblasts, lymphoblasts, or amniocytes. As demonstrated in other clinical syndromes when redefined biochemically, we have found a wider range of clinical expression of RSH/SLO than previously recogni zed. These newly recognized atypical RSH/SLO patients included several with no malformations other than syndactyly of the toes and, at the o ther extreme, patients with frank holoprosencephaly or multiple viscer al anomalies who died in utero. Syndactyly of toes 2 and 3 was the mos t common malformation, occurring in all but one of 80 patients. The be st biochemical predictor of clinical severity was the plasma cholester ol level, which decreased with increasing clinical severity. However, at least 10% of patients, including one newborn infant, had normal cho lesterol levels at the time of diagnosis and would have been missed wi thout specific quantification of 7-DHC. Not unexpectedly, several pati ents carrying a clinical diagnosis of RSH/SLO were found to have norma l levels of all plasma sterols and apparently normal cholesterol biosy nthesis in cultured cells. A comparison of the frequency of anomalies in our biochemically identified patients with similar data from previo usly reported clinical series suggests that up to 25% of reports of RS H/SLO in the literature may describe genetic conditions other than RSH /SLO with 7-DHC-emia. (C) 1997 Wiley-Liss, Inc.