Clinical and biochemical spectrum of patients with RSH/Smith-Lemli- Opitz syndrome and abnormal cholesterol metabolism

Christopher M Cunniff, L. E. Kratz, A. Moser, M. R. Natowicz, R. I. Kelley

Research output: Contribution to journalArticle

181 Citations (Scopus)

Abstract

RSH/Smith-Lemli-Opitz (RSH/SLO) syndrome is an autosomal recessive malformation syndrome recently shown to be associated with a severe deficiency of cholesterol biosynthesis and markedly elevated plasma and tissue levels of 7-dehydrocholesterol (7-DHC), the immediate precursor of cholesterol in the Kandutsch-Russell biosynthetic pathway. Because these biochemical abnormalities permit a reassessment of RSH/SLO on biochemical criteria rather than less specific physical criteria, we review here the clinical and biochemical characteristics of our first 80 patients 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 recognized. These newly recognized atypical RSH/SLO patients included several with no malformations other than syndactyly of the toes and, at the other extreme, patients with frank holoprosencephaly or multiple visceral anomalies who died in utero. Syndactyly of toes 2 and 3 was the most common malformation, occurring in all but one of 80 patients. The best biochemical predictor of clinical severity was the plasma cholesterol level, which decreased with increasing clinical severity. However, at least 10% of patients, including one newborn infant, had normal cholesterol levels at the time of diagnosis and would have been missed without specific quantification of 7-DHC. Not unexpectedly, several patients carrying a clinical diagnosis of RSH/SLO were found to have normal levels of all plasma sterols and apparently normal cholesterol biosynthesis in cultured cells. A comparison of the frequency of anomalies in our biochemically identified patients with similar data from previously reported clinical series suggests that up to 25% of reports of RSH/SLO in the literature may describe genetic conditions other than RSH/SLO with 7-DHC-emia.

Original languageEnglish (US)
Pages (from-to)263-269
Number of pages7
JournalAmerican Journal of Medical Genetics
Volume68
Issue number3
DOIs
StatePublished - 1997
Externally publishedYes

Fingerprint

Smith-Lemli-Opitz Syndrome
Cholesterol
Syndactyly
Toes
Holoprosencephaly
Biosynthetic Pathways
Sterols
Amniotic Fluid
Cultured Cells
Fibroblasts
7-dehydrocholesterol
Newborn Infant

Keywords

  • 7-dehydrocholesterol
  • autosomal recessive inheritance
  • cholesterol metabolism
  • inborn error of metabolism
  • RSH/Smith-Lemli-Opitz syndrome

ASJC Scopus subject areas

  • Genetics(clinical)

Cite this

Clinical and biochemical spectrum of patients with RSH/Smith-Lemli- Opitz syndrome and abnormal cholesterol metabolism. / Cunniff, Christopher M; Kratz, L. E.; Moser, A.; Natowicz, M. R.; Kelley, R. I.

In: American Journal of Medical Genetics, Vol. 68, No. 3, 1997, p. 263-269.

Research output: Contribution to journalArticle

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