Final Diagnosis -- Smith-Lemli-Optiz Syndrome



In 1964, Smith, Lemli, and Opitz described 3 unrelated male children with microcephaly, mental retardation, hypotonia, incomplete development of male genitalia, and dysmorphic facial features including high nasal bridge, long philtrum and board dental ridges(1). The syndrome was first called RSH syndrome, which derived from the surnames of the three families, and later was named Smith-Lemli-Opitz syndrome (SLOS). Cases reported between mid 1960’s and late1970’s suggested that both male and female were affected with a autosomal recessive inheritance pattern, and additional features were blepharoptosis, genital hypoplasia, micrognathia, polydactyly, cleft palate, syndactyly of 2nd and 3rd toes, and a high square forehead.

Smith-Lemli-Opitz syndrome is the third most common autosomal recessive inherited disorder after cystic fibrosis and PKU in North American Caucasian population. It occurs in one in 20,000-40,000 live births, and the estimated carrier frequency is 1 in 100 (2,3). It is unclear that why it was previously under-recognized. This may be due to its recessive inheritance pattern, wide spectrum of clinical presentation, and lack of understanding of the biochemical nature of the syndrome. Recent studies have shown undetectable cholesterol precursors, extremely low serum cholesterol, and low levels of bile acids in the patients. In addition, serum and tissue levels of certain cholesterol biosynthesis intermediates, most notably 7-dehydrocholesterol are markedly increased (4,5). Animal studies showed that the administration of a competitive inhibitor of 7-dehydrocholesterol reductase can reproduce cholesterol abnormalities seen in patients with Smith-Lemli-Opitz syndrome (6). Finally, the reduced enzyme activity has been confirmed with cultured skin fibroblasts from the patients(7,8). These results strongly suggest that the underlying metabolic defect of Smith-Lemli-Opitz syndrome is defective cholesterol synthesis, and the block appeares to be 7-dehydrocholesterol reductase, an essential enzyme which catalyses the reduction of 7-dehydrocholesterol to cholesterol. Chromosomal studies showed that some patients had de novo balanced translocation t (7;20) (q32.1;q13.2) (, and the researchers of these studies proposed that the translocation interrupted the SLOS gene on chromosome 7, while a subtle mutation inactivated the second allele on another chromosome 7 (9,10) . However, to establish the direct link between the Smith-Lemli-Opitz syndrome and 7-dehydrocholesterol reductase gene requires mapping of 7-dehydrocholesterol reductase gene to chr.7q32.1, isolation of the 7-dehydrocholesterol cholesterol gene and identification of its "loss-function mutation(s)".

Cholesterol is a unique compound which is an important precursor for membrane lipids (including CNS myelin), gonadal and adrenal hormones, and bile acids. Therefore, it is not surprising that the inability to synthesis cholesterol would have far-reaching detrimental effects on the CNS, sexual, facial and skeletal development. It is also possible that elevated intermediate metabolites, such as 7-dehydrocholesterol, may have teratogenic effects on varies organ and skeletal development.

Diagnosis of Smith-Lemli-Opitz syndrome should be suspected when a patient presents with a pattern of minor facial anomalies, congenital anomalies of multiple organs, failure to thrive, dysmorphic limb features, and mental retardation. The diagnosis is confirmed by deficiencies of plasma and tissue cholesterol, increased 7-dehydrocholesterol concentrations, and serum 7-dehydrocholesterol is undetectable in normal population. It has been reported that the qualitative and quantitative determinations of cholesterol and 7-dehydrocholerterol levels from plasma can be performed rapidly using liquid chromatography/particle beam interface-mass spectrometry (LC/PB-MS) (11). Cultured fibroblasts from skin biopsy can be used to determine the conversion rate of 7-dehydrocholesterol to cholesterol. Recent studies have shown that synthesis of cholesterol via 7-dehydrocholeterol occurred in the placenta and /or fetus at 10 weeks of gestation. Prenatal diagnosis by quantitation of 7-dehydrocholesterol levels from chorionic villus and amniotic fluid (12,13).

With the advance in understanding of the biochemical mechanism of Smith-Lemli-Opitz syndrome, replacement therapy has been proposed and is currently under active investigation. Dietary intervention has been planned, because of previous success for dietary modification in the treatment of metabolic disorders, such as PKU (restricting the diet to prevent accumulation of harmful precursors) and congenital hypothyroidism (replacement of what is lacking). Current dietary intervention plans focus on providing cholesterol and bile acids in the diet to bypass their metabolic block, and such replacement therapy is under evaluation(14) (

Future studies will focus on identification of chromosomal markers, cloning 7-dehydrocholesterol reductase gene, and characterization of the molecular defect of the 7-dehydrocholesterol reductase gene. Given the relative high frequency of Smith-Lemli-Opitz syndrome (1:20,000-40,000) and high carrier rate (1:100), it is very important to provide effective genetic counseling and accurate molecular diagnosis. The advances in these fields will not only greatly improve genetic counseling and provide accurate molecular diagnosis, but also facilitate the development of enzyme replacement therapy and possible gene therapy.

The diagnosis of case presented was confirmed by the characteristic pattern congenital anomalies and extremely low plasma cholesterol levels. The levels of 7-dehydrocholesterol of blood and skin fibroblast culture have not been performed. The patient’s serum electrolyte abnormalities are likely due to poor feeding and the diarrhea due to bile acids deficiency. Dimercaptosuccinic acid (DMSA) renal scan and abdominal ultrasound were unremarkable. The etiology of the abnormal high plasma renin level, and its relationship with Smith-Lemli-Opitz syndrome is unclear. The patient is now on dietary cholesterol replacement trial, her body weight has been stabilized, however, the long term effectiveness of such dietary replacement therapy is yet to be determined..


  1. Smith DW, Lemli L, Opitz JM. A newly recognized syndrome of multiple congenital anomalies. J. of Pediatr. 64:210-217 1960.
  2. Lowry R, and Young SL. Borderlying normal intelligence in the Smith-Lemli-Opits Syndrome. American Journal of Medical Genetics. 5:137-143 1980.
  3. Opitz JP. RSH/SLO (Smith-Lemli-Opits) syndrom: Historical, Genetic, and Development. American Journal of Medical Genetics. 50:344-346 1994.
  4. Chasalow FI, Blethen SL, Taysi: Possible abnormalities of steroid secretion in children with Smith-Lemli-Opits Syndrome and their parents. Steroid 46:827-843 1985.
  5. Irons M, Elias ER, Salen G, Tint GS, Batta AK: Defective cholesterol synthesis in Smith-Lemli-Opitz syndrome. Lancet 341:1414 1993.
  6. Xu G, Salen G, Shefer S, Ness GC, ChenTS, Zhao Z, and Tint GS: Reproducing abnormal cholesterol biosynthesis as seen in Smith-Lemli-Opits Syndrome by inhibiting the conversion of the 7-dehydrocholesterol to cholesterol in rat. Journal of Clinical Investigation. 95(1):76-81 1995.
  7. Tint GS, Seller M, Hughes-Benzie R, Batta AK, Shefer S, Genest D, Irons M, Elias,E, and Salen G: Markedly increased tissue concentrations of 7-dehydrocholesterol combined with low levels of cholesterol are characteristic of the Smith-Lemli-Opits Syndrome. Journal of Lipid Research 36(1):89-95 1995.
  8. Honda A, Tint GS, Salen, Batta AK, Chen TS, Shefer S: Defective conversion of 7-dehydrocholesterol to cholesterol in cultured skin fibroblasts from Smith-Lemli-Opits Syndrome homozygotes. Journal of Lipid Research 36(7):1595-601 1995.
  9. Wallace M, Zori RT, Whidden E, Gray BA, Williams CA: Smith-Lemli-Opits Syndrome in a female with de novo, balanced translocation involving 7q32: probable disruption of an SLOS gene. American Journal of Medical genetics: 50:368-374, 1994.
  10. Alley TL, Gray BA, Lee SH, Scherer, SW, Tsui LC, Tint GS, Williams CA, Wallace MR: Identification of yeast artificial chromosome clone spanning a translocation breakpoint at 7q32.1 in a Smith-Lemli-Opits Syndrome patient. American Journal of Human Genetics 56:1411-1416, 1995.
  11. Sattler W, Leis HJ, Kostner GM, Malle E: Quantitation of 7-dehydrocholesterol in plasma and amniotic fluid by liquid chromatography/particle beam-mass spectrometry. Rapid Communication Mass Spectrometry 9(13):1288-92. 1995.
  12. Dallaire L. Mitchell G, Giguere, Melancon SB, and Lambert M. Prenatal diagnosis of Smith-Lemli-Opitz syndrome is possible by measurement of 7-dehydrocholesterol in amniotic fluid. Prenatal diagnosis. 15(9):855-8, 1995
  13. Mills K, Mandel H, Montemagno R, Soothill P, and Clayton PT. First trimester prenatal diagnosis of Smith-Lemli-Opitz syndrome. Pediatric Research. 39(5):816-9, 1996.
  14. Irons M, Elias ER, Salen G, Tint GS, Frieden R, Buie TM, Ampola M: Abnormal cholesterol metabolism: report of clinical and biochemical findings in four patients and treatment in one patient. American Journal of Medical Genetic. 50: 347-352, 1994.

Contributed by Jianzhou Wang, MD, PhD., Mohamed A. Virji, MD, PhD and David Finegold, MD.


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