Aalfs CM, Hennekam RC, Wanders RJ, Jira PE, Pilon JW, Wijburg FA.
[Smith-Lemli-Opitz syndrome; a special defect in cholesterol metabolism]. [Dutch].
Ned Tijdschr Geneeskd 1996;140:1463-1466.
In a male neonate dysmaturity, microcephalia, a high nasal bridge, a long philtrum, broad dental ridges, schisis of the palatum molle, retrognathia, a small penis with a chorda, a small scrotum, bilateral inguinal hernia and bilateral syndactyly of the second and third toes were observed. The presence of the Smith-Lemli-Opitz (SLO) syndrome was suspected. By gas chromatography a severely decreased plasma cholesterol level (0.27 mmol/l) was found and an increased plasma 7-dehydrocholesterol level (0.24 mmol/l). The SLO syndrome is caused by a block in the cholesterol biosynthesis due to the autosomal recessive deficiency of 7-dehydrocholesterol reductase. The patient's condition improved with use of a cholesterol-enriched diet.

Abuelo DN, Tint GS, Kelley R, Batta AK, Shefer S, Salen G.
Prenatal detection of the cholesterol biosynthetic defect in the Smith-Lemli-Opitz syndrome by the analysis of amniotic fluid sterols.
Am J Med Genet 1995;56:281-285.
The Smith-Lemli-Opitz (SLO or RSH) syndrome is an autosomal recessive disorder characterized by a recognizable pattern of minor facial anomalies, congenital anomalies of many organs, failure to thrive, and mental retardation. Its cause is a defect in cholesterol biosynthesis characterized by abnormally low plasma cholesterol levels and concentrations of the cholesterol precursor 7-dehydrocholesterol (7DHC) elevated up to several thousand-fold above normal. We used capillary column gas-chromatography to quantify sterols in amniotic fluid, amniotic cells, plasma, placenta, and breast milk from a heterozygous mother who had previously given birth to an affected son and in cord blood and plasma from her affected newborn daughter. The cholesterol concentration in amniotic fluid at 16 weeks gestation was normal, but 7DHC, normally undetectable, was greatly elevated. In cultured amniocytes, the level of 7DHC was 11% of total cholesterol, similar to cultured fibroblasts from patients with SLO syndrome. At 38 weeks, a girl with phenotype consistent with the syndrome was born. Cholesterol concentrations were abnormally low in cord blood and in the baby's plasma at 12 weeks, while levels of 7DHC were grossly elevated, confirming the prenatal diagnosis. The mother's plasma cholesterol increased steadily during gestation but remained below the lower 95% limit reported for normal control women. We conclude that it is now possible to detect the SLO syndrome at 16 weeks gestation by analyzing amniotic fluid sterols.

Acosta PB.
RSH/SLO (Smith-Lemli-Opitz) syndrome: designing a high cholesterol diet for the SLO syndrome.
Am J Med Genet 1994;50:358-363.
A high cholesterol diet has been suggested to help prevent the poor reproductive outcomes found in heterozygote carriers of fetuses affected with the Smith-Lemli-Opitz (SLO) syndrome. The theory has also been presented that a high cholesterol medical food may enhance myelination of the central nervous system of the infant and prevent demyelination in the child and adult with SLO. Clinical studies are required to test this hypothesis and to determine the optimal composition of such medical foods. FDA requires proof of efficacy and controls nutrient composition, ingredients, and label claims of medical foods.

Akl KF, Khudr GS, Der Kaloustian VM, Najjar SS.
The Smith-Lemli-Opitz syndrome. Report of a consanguineous Arab infant with bilateral focal renal dysplasia.
Clin Pediatr (Phila) 1977;16:665-668.

Alley TL, Gray BA, Lee SH, Scherer SW, Tsui LC, Tint GS, Williams CA, Zori R, Wallace MR.
Identification of a yeast artificial chromosome clone spanning a translocation breakpoint at 7q32.1 in a Smith-Lemli-Opitz syndrome patient [published erratum appears in Am J Hum Genet 1995 Aug;57(2):520-1].
Am J Hum Genet 1995;56:1411-1416.
Smith-Lemli-Opitz syndrome (SLOS) is a mental retardation/multiple congenital anomaly syndrome. The gene(s) involved has not been mapped or cloned, but, recently, a biochemical abnormality in cholesterol biosynthesis has been shown to occur in most SLOS patients. The defect is suspected to occur in the penultimate step of the cholesterol pathway, involving the enzyme 7-dehydrocholesterol reductase, which has not been isolated. On the basis of the hypothesis that a de novo balanced translocation [t(7;20)(q32.1;q13.2)] in an SLOS patient directly interrupts the SLOS gene, positional cloning techniques are being employed to localize and identify the SLOS gene. We report the identification of a chromosome 7-specific YAC that spans the translocation breakpoint, as detected by FISH. This is the first study narrowing a candidate SLOS region and placing it on physical and genetic maps of the human genome.

Alley TL, Scherer SW, Huizenga JJ, Tsui LC, Wallace MR.
Physical mapping of the chromosome 7 breakpoint region in an SLOS patient with t(7;20) (q32.1;q13.2).
Am J Med Genet 1997;68:279-281.
Smith-Lemli-Opitz syndrome (SLOS) is an autosomal recessive disorder characterized by multiple congenital anomalies and mental retardation. SLOS has an associated defect in cholesterol biosynthesis, but the molecular genetic basis of this condition has not yet been elucidated. Previously our group reported a patient with a de novo balanced translocation [t(7;20)(q32.1;q13.2)] fitting the clinical and biochemical profile of SLOS. Employing fluorescence in situ hybridization (FISH), a 1.8 Mb chromosome 7-specific yeast artificial chromosome (YAC) was identified which spanned the translocation breakpoint in the reported patient. The following is an update of the on-going pursuit to physically and genetically map the region further, as well as the establishment of candidate genes in the 7q32.1 breakpoint region.

Andresen BS, Bross P, Jensen TG, Knudsen I, Winter V, Kolvraa S, Bolund L, Gregersen N.
Molecular diagnosis and characterization of medium-chain acyl-CoA dehydrogenase deficiency. [Review].
Scand J Clin Lab Invest Suppl 1995;220:9-25.
Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency is the most common defect in mitochondrial beta-oxidation in humans. It is an autosomal recessive disorder which usually presents in infancy. The disease manifests itself in periods of metabolic stress to the beta-oxidation system and may be fatal. Four years ago we identified a prevalent disease-causing mutation (G985) which causes an amino acid change (K304E) in the mature MCAD protein. Using a Polymerase Chain Reaction (PCR) based assay for this mutation we have demonstrated: 1. that the G985 mutation is present in 90% of the disease alleles from patients from all over the world; 2. that the allele frequency of G985 in the general population from most European countries is very high (the carrier frequency ranges from 1/68 to 1/333); 3. that MCAD deficiency is not, as has previously been suggested, related to Sudden Infant Death Syndrome (SIDS). Moreover, investigation by Restriction Fragment Length Polymorphism (RFLP) analysis of several families with diagnosed MCAD deficiency revealed that the G985 mutation is only present in chromosomes of a particular RFLP haplotype, suggesting a common chromosomal background for this mutation. The other mutations in the MCAD gene are distributed to all known MCAD RFLP haplotypes. Because 80% of the patients are homozygous for the G985 mutation, DNA based diagnosis of most patients is now fast and easy. In order to make DNA based diagnosis possible for the remaining 20% of patients we have set up PCR/solid-phase based semi-automated sequencing of all 12 exons of the MCAD gene. We have so far identified the mutation in 33 of 45 non-G985 homozygous families with verified MCAD deficiency, thereby bringing the number of known mutations in the MCAD gene up to 26. In order to investigate in detail the molecular defects of the mutant MCAD proteins we overexpressed them in COS-7 and in an E. coli based expression system with and without co-overexpression of the molecular chaperones GroES and GroEL. The expression studies revealed that the primary effect of all the identified mutations is on formation of correct enzyme structure, and does not directly affect the catalytically active regions of the enzyme. We find that our diagnostic set up, consisting of an initial testing by the G985 assay, followed by semi-automated sequencing of DNA from those patients who were indicated to be compound heterozygous, is an important improvement to the diagnosis of MCAD deficiency.(ABSTRACT TRUNCATED AT 400 WORDS) [References: 64]

Antoniades K, Peonidis A, Pehlivanidis C, Kavadia S, Panagiotidis P.
Craniofacial manifestations of Smith-Lemli-Opitz syndrome: case report.
Int J Oral Maxillofac Surg 1994;23:363-365.
The Smith-Lemli-Opitz syndrome is characterized by striking craniofacial features, microcephaly, mental deficiency, growth retardation, 2-3 syndactyly of the feet, and genital malformations. We present a patient and discuss dentofacial aspects of the syndrome.

Appelkvist EL, Reinhart M, Fischer R, Billheimer J, Dallner G.
Presence of individual enzymes of cholesterol biosynthesis in rat liver peroxisomes.
Arch Biochem Biophys 1990;282:318-325.
Cholesterol biosynthesis by isolated rat liver peroxisomes was examined. Labeling of cholesterol from [3H]-mevalonate in the presence of peroxisomes required the addition of cytosol, since peroxisomes, like microsomes, apparently possess only those enzymes of cholesterol biosynthesis subsequent to the steps involving farnesyl-PP. Under the conditions employed the amounts of 4,4-dimethyl and desmethyl sterols generated by peroxisomes were equal to or exceeded those produced by the microsomes. In addition, marker enzyme analysis demonstrated minimal microsomal contamination in the peroxisomal fraction. The metabolite patterns observed by HPLC after incubation of these two fractions with [3H]mevalonate were different. Dihydrolanosterol oxidase, steroid-14-reductase, steroid-8-isomerase, and steroid-3- ketoreductase activities were present in peroxisomes. Separation of peroxisomes into membranes and contents revealed that all the synthesizing activities are associated with the membrane fraction. 7 alpha-Hydroxylase, which catalyzes the first step in the biosynthesis of bile acids, was also present in peroxisomes, but it remains to be clarified to what extent peroxisomal cholesterol is a substrate for bile acid synthesis.

Armendares S, Carnevale A, Del Castillo V, Najar Aparicio A.
[Smith-Lemli-Opitz syndrome: description of 2 affected brothers, clinical characterization and hereditary mechanism]. [Spanish].
Rev Invest Clin 1973;25:129-142.

Axelson M.
Occurrence of isomeric dehydrocholesterols in human plasma.
Journal of Lipid Research 1991;32:1441-1448.

Barbu V, Roux C, Dupuis R, Gardette J, Maziere JC.
Teratogenic effect of AY 9944 in rats: Importance of the day of administration and maternal plasma cholesterol level.
Proceedings of the Society for Experimental Biology & Medicine 1984;176:54-59.
An inhibitor of cholesterol synthesis, AY 9944 (trans-1,4-bis(2-chlorobenzylaminomethyl) cyclohexane dihydrochloride) is teratogenic. A single dose of AY 9944 (50 mg/kg or 75 mg/kg) given to Wistar pregnant rats on the second, fourth, sixth, seventh, or eighth day of gestation induced malformations such as holoprosencephaly. They were often limited to isolated pituitary agenesis. The highest percentage of holoprosencephalic fetuses was found when AY 9944 was given on the fourth day of gestation. Whatever the dose and the day of administration, the lower the maternal plasma cholesterol level, the more frequent were holoprosencephalic fetuses. Therefore, it is suggested that the decrease in maternal plasma cholesterol level is at least one of the factors provoking holoprosencephaly.

Barbu V, Roux C, Lambert D, Dupuis R, Gardette J, Maziere JC, Maziere C, Elefant E, Polonovski J.
Cholesterol prevents the teratogenic action of AY 9944: Importance of the timing of cholesterol supplementation to rats.
Journal of Nutrition 1988;118:774-779.
These studies were conducted to determine whether dietary cholesterol supplementation could prevent fetal malformations induced by the amphipathic drug AY 9944, which is well known as a cholesterol biosynthesis inhibitor, and to investigate whether the plasma maternal sterol level and the nature of the sterols found in treated Wistar rats could explain this prevention. Pituitary agenesis was the most constant element of holoprosencephaly when AY 9944 was administered on d 4 of gestation at two dosages, 50 or 75 mg/kg. The rate of malformed fetuses was dose related. A strong negative correlation was established between maternal plasma sterol levels on d 10 of gestation (day of pituitary gland formation) and the rate of fetal anomalies (r = -0.97, P less than 0.01). Supplementation of AY 9944-treated rats with cholesterol had an obvious preventive action on fetal malformations. When cholesterol was added to the diet the same day as AY 9944 treatment and maintained until d 15, the prevention of malformations was almost complete. When the supplementation was initiated later, the prevention of anomalies decreased. The nature of plasma maternal sterols shows that the cholesterol supplementation modifies significantly the ratio of cholesterol to 7-dehydrocholesterol in treated rats. Therefore, maternal plasma sterol perturbations may play a role in the teratogenic action of AY 9944.

Bardelli AM, Lasorella G, Barberi L, Vanni M.
Ocular manifestations in Kniest syndrome, Smith-Lemli-Opitz syndrome, Hallermann-Streiff-Francois syndrome, Rubinstein-Taybi syndrome and median cleft face syndrome.
Ophthalmic Paediatr Genet 1985;6:343-347.
In the pathology of malformations it is only in very few cases possible to identify a complete syndromal picture; the authors present some multimalformative syndromes, observed in the past few years at the Department of Pediatric Ophthalmology of the University of Siena. The ocular findings are reported and discussed in relation with the general features in order to make a correct diagnosis.

Barness LA.
Nutritional requirements of infants and children with respect to cholesterol and related compounds. [Review] [18 refs].
Am J Med Genet 1994;50:353-354.
Cholesterol is an enigmatic, essential metabolite. Breast milk contains significant quantities of cholesterol, yet human infants thrive on cholesterol-free diets. Recommendations to lower serum cholesterol are widespread, yet low serum cholesterol is associated with poorly understood morbidity. Serum cholesterol is increased with diets high in fat, yet dietary cholesterol has relatively little effect on serum concentrations. Smith-Lemli-Opitz syndrome, marked with extremely low serum cholesterol, may serve as a human model for the evaluation of absorption and metabolism of dietary cholesterol. [References: 18]

Batta AK, Salen G, Tint GS, Shefer S.
Identification of 19-nor-5,7,9(10)-cholestatrien-3 beta-ol in patients with Smith-Lemli-Opitz syndrome.
J Lipid Res 1995;36:2413-2418.
We have identified the third unknown sterol in the plasma and tissues of Smith-Lemli-Opitz homozygotes as 19-nor-5,7,9(10)-cholestatrien-3 beta-ol. The structure was established from capillary gas-liquid chromatography retention index and characteristic fragmentation pattern by mass spectrometry that were identical to a synthetic reference standard. Evidence is presented that 19-nor-5,7,9(10)-cholestatrien-3 beta-ol is not an artifact formed during the chemical isolation of the relatively unstable 7-dehydrocholesterol. It is possible that 19-nor-5,7,9(10)-cholestatrien-3 beta-ol may contribute to the clinical abnormalities in patients with Smith-Lemli-Opitz syndrome.

Batta AK, Tint GS, Shefer S, Abuelo D, Salen G.
Identification of 8-dehydrocholesterol (cholesta-5,8-dien-3 beta-ol) in patients with Smith-Lemli-Opitz syndrome.
J Lipid Res 1995;36:705-713.
Cholesta-5,8-dien-3 beta-ol (8-dehydrocholesterol) and cholesta-5,7-dien-3 beta-ol (7-dehydrocholesterol) were isolated from the fecal neutral sterol fraction from homozygotes with Smith-Lemli-Opitz syndrome. The structures of the sterols were conclusively established from their mass spectra and 1H and 13C nuclear magnetic resonance spectra. It is probable that 8-dehydrocholesterol arises from 7-dehydrocholesterol and is not a direct precursor of cholesterol.

Batta AK, Salen G.
Abnormal cholesterol biosynthesis produced by AY 9944 in the rat leads to skeletal deformities similar to the Smith-Lemli-Opitz syndrome [editorial; comment]. [Review] [8 refs].
J Lab Clin Med 1998;131:192-193.

Bellknap WM, Dietschy JM.
Sterol synthesis and low-density lipoprotein clearance in vivo in the pregnant rat, placenta, and fetus.
Journal of Clinical Investigation 1988;82:2077-2085.
Whereas the greatest relative increase in body mass occurs during the third trimester of fetal life, the source of the cholesterol that supports this growth is uncertain. These studies used [3H]water and 125I-cellobiose-labeled low density lipoproteins to quantitate absolute rates of cholesterol acquisition in vivo by the fetus of the rat. Preliminary studies demonstrated that [3H]water administered intravenously to the mother rapidly equilibrated with the body pool of water in the fetus and that 22-microgram atoms of H from the water pool were incorporated into each micromole of newly synthesized cholesterol. After administration of [3H]water to pregnant rats, the rates of sterol synthesis per 100 g of whole body weight were severalfold higher in the fetus than in the dams. Individual organs of the dam such as the liver, however, had much higher synthetic rates than those in the fetus. When maternal hepatic cholesterol synthesis was suppressed by cholesterol feeding, newly synthesized cholesterol disappeared from the maternal blood yet there was essentially no change in the rate of appearance of newly synthesized sterol in the fetus, placenta, and fetal membranes. The placenta did take up low density lipoproteins at rates equal to about one-third of that seen in the maternal liver, but none of the apolipoprotein or cholesterol was transferred to the fetus. These studies indicate that the rat fetus receives little or no cholesterol from the mother but, rather, satisfies its need for cholesterol during fetal development through local synthesis. Furthermore, the fetal membranes appear to be an important site for sterol synthesis in the fetal compartment.

Belmont JW, Hawkins E, Hejtmancik JF, Greenberg F.
Two cases of severe lethal Smith-Lemli-Opitz syndrome.
Am J Med Genet 1987;26:65-67.

Berry R, Wilson H, Robinson J, Sandlin C, Tyson W, Campbell J, Porreco R, Manchester D.
Apparent Smith-Lemli-Opitz syndrome and Miller-Dieker syndrome in a family with segregating translocation t(7;17)(q34;p13.1).
Am J Med Genet 1989;34:358-365.
We describe a family in which one male infant presented with Miller-Dieker syndrome and four male relatives had a phenotype similar to the Smith-Lemli-Opitz (SLO) syndrome. High resolution cytogenetic analysis on the child with Miller-Dieker syndrome showed 46,XY,-17,+der17t(7;17)(q34:p13.1). Paternal chromosomes showed a balanced translocation: 46,XY,t(7;17)(q34:p13.1). The paternal grandmother had a history of multiple miscarriages, and a paternal uncle had two sons who died neonatally. Chromosomes on these children and their father had originally been reported as normal. There was also a paternal cousin to the father of the propositus who had had two sons with similar clinical findings. A diagnosis of SLO syndrome was considered. Image enhancement techniques on previous suboptimal preparations on these four children documented the subtle unbalanced translocation 46,XY,-7,+der7t(7;17)(q34:p13.1). Subsequent high resolution analysis on one of these four children who was still living confirmed this chromosome constitution. It is postulated that these apparent SLO cases may represent a contiguous gene syndrome in which SLO or a separate entity closely mimicking the syndrome in included.

Bialer MG, Penchaszadeh VB, Kahn E, Libes R, Krigsman G, Lesser ML.
Female external genitalia and mullerian duct derivatives in a 46,XY infant with the smith-lemli-Opitz syndrome. [Review] [21 refs].
Am J Med Genet 1987;28:723-731.
We report on a 46,XY newborn infant with Smith-Lemli-Opitz (SLO) syndrome with female external genitalia, intraabdominal testes with epididymides and deferent ducts and a normally shaped uterus and vagina. Polydactyly, cleft palate, and several internal organ malformations were also present, and the patient died shortly after birth. Data on six reported male infants with SLO syndrome and female external genitalia suggest a correlation between degree of genital involvement and overall degree of severity. Scoring systems to quantify overall degree of severity (SLO score) and degree of genital involvement in males (genital score) were devised and applied to 122 reported cases from the literature. Statistical analyses showed a unimodal distribution of the SLO severity scores, and positive correlations between the SLO score and the genital score in males, the presence of polydactyly, and the presence of cleft palate. In 19 multiplex families the affected sibs were generally similar in their SLO scores. The above analyses suggest that the wide phenotypic variability in the SLO syndrome is determined by variable expressivity of the same entity as opposed to genetic heterogeneity. The observed phenotypic correlations naturally determine that males with complete feminization are among the more severe patients and tend to have polydactyly and cleft palate. [References: 21]

Biesecker LG, Kang S, Schaffer AA, Abbott M, Kelley RI, Allen JC, Clericuzio C, Grebe T, Olney A, Graham JM, Jr.
Exclusion of candidate loci and cholesterol biosynthetic abnormalities in familial Pallister-Hall syndrome.
J Med Genet 1996;33:947-951.
Pallister-Hall syndrome (PHS) was originally described in 1980 in six sporadic cases of children with structural anomalies including hypothalamic hamartoma, polydactyly, imperforate anus, and renal and pulmonary anomalies. In 1993, the first familial cases were reported, including affected sibs and vertical transmission. Three of these families are sufficiently large to allow initial evaluation by linkage studies to candidate genes or loci. We have evaluated candidate loci for PHS based on three clinical observations. The first is a patient with PHS-like malformations, including a hypothalamic hamartoma, and an unbalanced translocation involving 7q and 3p. The second is a family with familial PHS where the founder's father had an autosomal dominant hand malformation previously mapped to 17q. The third is the phenotypic overlap of PHS and Smith-Lemli-Opitz syndrome. In this report, we exclude these loci as candidates for linkage to the PHS phenotype on the basis of lod scores of less than-2.0. We conclude that hypothalamic hamartoma is not specific to PHS and that the dominant hand malformation in one of the families was a coincidence. To evaluate the relationship of PHS to Smith-Lemli-Opitz syndrome, we analysed levels of cholesterol and intermediate metabolites of the later stages of cholesterol biosynthesis. There is no evidence of a generalised disorder of cholesterol biosynthesis in patients with familial PHS. On genetic and biochemical grounds, we conclude that PHS and Smith-Lemli-Opitz syndrome are not allelic variants of a single locus.

Blair HR, Martin JK.
A syndrome characterized by mental retardation, short stature, craniofacial dysplasia, and genital anomalies occurring in siblings.
Journal of Pediatrics 1966;69:457-459.

Bronshtein M, Riechler A, Zimmer EZ.
Prenatal sonographic signs of possible fetal genital anomalies.
Prenat Diagn 1995;15:215-219.
The sonographic markers of female and male external genitalia have been documented in early and late gestation. The aim of the present study was to report our experience of possible sonographic markers of fetal genital anomalies. Sonography was performed with a vaginal probe in early gestation and an abdominal sector scanner in advanced gestation. The following genital anomalies were observed: hypospadias, epispadias, ambiguous genitalia, and testicular feminization or Smith-Lemli-Opitz syndrome. It is therefore concluded that prenatal diagnosis of some genital anomalies is now possible.

Bundey S, Smyth HG.
Three sisters with the Smith-Lemli-Opitz syndrome.
J Ment Defic Res 1974;18:51-61.

Calvani M, Tirasacchi V, Toscano V, Bellussi A, Fortuna C.
[Early the larche and hyperprolactinemia in the Smith-Lemli-Opitz syndrome]. [Italian].
Minerva Pediatr 1979;31:1721-1732.

Camera G.
[A typical case of Smith-Lemli-Opitz syndrome: nosologic problems and overlapping syndromes]. [Italian].
Pathologica 1990;82:539-542.
A male infant, born to consanguineous parents, with typical clinical findings of the Smith-Lemli-Opitz syndrome (SLOS) is reported. Nosologic controversies and overlapping syndromes with SLOS are discussed.

Canick JA, Abuelo DN, Bradley LA, Tint GS.
Maternal serum marker levels in two pregnancies affected with Smith-Lemli-Opitz syndrome [letter].
Prenat Diagn 1997;17:187-189.

Carr BR, Parker CR, Jr., MacDonald PC, Simpson ER.
Metabolism of high density lipoprotein by human fetal adrenal tissue.
Endocrinology 1980;107:1849-1854.
The role of lipoproteins as a source of the cholesterol utilized for steroidogenesis by human fetal adrenal (HFA) tissue was investigated previously. It was found that low density lipoprotein (LDL) was the lipoprotein preferred as a source of cholesterol for steroidogenesis by the HFA. [125I]Iodo-LDL was taken up and degraded by HFA tissue in organ culture, and the degradation of [125I]iodo-LDL was stimulated when ACTH (1 microgram X ml-1) was present in the culture medium. Others have shown that high density lipoprotein (HDL) is utilized as a source of cholesterol for steroidogenesis by rat adrenocortical cells in vitro and by the adrenals of the adult rat in vivo. In the present investigation we evaluated the metabolism of [125I]iodo-HDL by HFA tissue. [125I]iodo-HDL uptake by the HFA tissue increased in a linear manner with time and as the concentration of [125I]iodo-HDL in the culture medium was increased. However, there was little degradation of [125I]iodo-HDL by HFA. Moreover, preincubation of HFA tissue in medium containing ACTH (1 microgram X ml-1) or HDL, in various concentrations, did not affect the rate of uptake and degradation of [125I]iodo-HDL. The rate of degradation of [125I]iodo-LDL was found to decrease to low levels as the concentration of nonradiolabeled LDL in the culture medium was increased, whereas nonradiolabeled HDL had little effect on the degradation of [125I]iodo-LDL. HFA tissue fragments were incubated in medium containing ACTH plus lipoprotein-poor serum (LPPS) alone or LPPS plus HDL in various concentrations (50-1000 microgram X ml-1). The medium was changed daily and assayed for dehydroisoandrosterone sulfate and cortisol. In the presence of HDL, steroid secretion rates were no greater than those attained by HFA maintained in medium containing LPPS. It is concluded that the HFA utilizes cholesterol derived from LDL for steroidogenesis and that HDL is not metabolized efficiently by the human fetal adrenal.

Carr BR, Porter JC, MacDonald PC, Simpson ER.
Metabolism of low density lipoprotein by human fetal adrenal tissue.
Endocrinology 1980;107:1034-1040.

Carr BR, Simpson ER.
Lipoprotein utilization and cholesterol synthesis by the human fetal adrenal gland. [Review] [126 refs].
Endocr Rev 1981;2:306-326.
A model proposed for regulation of steroidogenesis, lipoprotein utilization and cholesterol metabolism in HFA tissue is presented in Fig 17. We envision that the role of ACTH and cAMP in steroidogenesis and cholesterol metabolism is as follows. ACTH binds to specific receptors on the surface of the cells of the HFA gland and as a consequence, adenylate cyclase is activated, leading to increased formation of cAMP. cAMP causes activation of protein kinase that leads, presumably, to phosphorylation of specific proteins. This leads to the initiation of reactions that give rise to increased activity of key enzymes and levels of proteins involved in adrenal cholesterol metabolism. Presumably, the action of ACTH causes an increase in the activity of cholesterol side chain cleavage, the rate-limiting step in the conversion of cholesterol to steroid hormones. We suggest that once the mitochondrial cholesterol side-chain cleavage system is fully activated by ACTH, the supply of cholesterol to the mitochondria becomes rate-limiting for steroidogenesis. To meet this demand for cholesterol, a further action of ACTH results in an increase in the number of LDL receptors. LDL binds to specific receptors on the cell surface that are localized in coated pits. LDL is internalized by a process of adsorptive endocytosis and the internalized vesicles fuse with lysosomes and the protein component of LDL is hydrolyzed by lysosomal proteolytic enzymes to amino acids. The cholesteryl esters of LDL also are hydrolyzed to give rise to fatty acids and cholesterol. The liberated cholesterol is available for utilization in the biosynthesis of steroid hormones and other cellular processes. In addition, ACTH stimulates the activity of HMG CoA reductase and, thus, the rate of de novo cholesterol biosynthesis. In this way sufficient cholesterol is obtained to provide for precursor cholesterol to maintain the high rate of steroid synthesis by the HFA. HDL is not utilized as a source of cholesterol by the HFA. Because of the rapid rate of utilization of LDL by the HFA, fetal plasma levels of LDL are low and the activity of the HFA is a primary determinant of these levels. Thus, in the case of anencephaly, in which the activity of the adrenal is very low, plasma levels of LDL are 2--3 times higher than in normal fetuses, whereas plasma HDL levels are similar. In addition, in the normal neonate plasma LDL levels rise rapidly after birth, and this event is coincident with the involution of the fetal zone of the adrenal. The fetal liver is likely to be the major source ultimately of the LDL-cholesterol utilized by the HFA. Consequently, factors that regulate cholesterol and lipoprotein synthesis in the fetal liver may, in turn, affect the steroidogenic activity of the HFA through regulation of the supply of cholesterol precursor. Thus, if trophic factors for the HFA other than ACTH exist, an important site of their action might be the fetal liver, rather than a direct action to influence the rate of synthesis of steroids by the fetal adrenal. [References: 126]

Carr BR, Simpson ER.
Cholesterol synthesis in human fetal tissues.
Journal of Clinical Endocrinology and Metabolism 1982;55:447-452.

Casamassima AC, Mamunes P, Gladstone IM, Jr., Solomon S, Moncure C.
A new syndrome with features of the Smith-Lemli-Opitz and Meckel-Gruber syndromes in a sibship with cerebellar defects.
Am J Med Genet 1987;26:321-336.
The Smith-Lemli-Opitz syndrome (SLOS) and the Meckel syndrome (MS) have been regarded as separate autosomal recessive entities. Recently, overlap of these two syndromes has been discussed. A sibship containing a probable new syndrome with features reminiscent of the SLOS and the MS is presented. The literature is reviewed with regard to the frequency of various malformations in these syndromes. Clinical manifestations and cerebellar abnormalities in these sibs are similar to those described in the Joubert syndrome (JS). These three cases may represent a new syndrome with features in common with SLOS, MS, and JS resulting from the same mutant gene, which exhibits considerable pleiotropy.

Cass D.
Aganglionosis: associated anomalies.
J Paediatr Child Health 1990;26:351-354.
In a series of 21 patients with aganglionosis there were five with associated anomalies (24%). These included trisomy 21, Smith-Lemli-Opitz syndrome type II, persistent Mullerian duct syndrome, supernumerary digits and segmental hypopigmentation. This high incidence may be due to sample bias, but clinicians are encouraged to carefully follow their aganglionic patients as there may be under-reporting of associated anomalies. Knowledge of these anomalies can help in the management of individual patients and subsequent pregnancies. In addition these diverse associated anomalies suggest that as well as sometimes being part of a vagal neural crest deficiency, aganglionosis can be part of a generalized mesenchymal defect in embryonic development. There are probably several genes involved.

Cenedella RJ.
Cholesterol and cataracts. [Review] [158 refs].
Surv Ophthalmol 1996;40:320-337.
Inherited defects in enzymes of cholesterol metabolism and use of drugs which inhibit lens cholesterol biosynthesis can be associated with cataracts in animals and man. The basis of this relationship apparently lies in the need of the lens to satisfy its sustained requirement for cholesterol by on-site synthesis, and impairing this synthesis can lead to alteration of lens membrane structure. Lens membrane contains the highest cholesterol content of any known membrane. The Smith-Lemli-Opitz syndrome, mevalonic aciduria, and cerebrotendinous xanthomatosis all involve mutations in enzymes of cholesterol metabolism, and affected patients can develop cataracts. Two established models of rodent cataracts are based on treatment with inhibitors of cholesterol biosynthesis. The long-term ocular safety of the very widely used vastatin class of hypocholesterolemic drugs is controversial. Some vastatins are potent inhibitors of cholesterol biosynthesis by animal lenses, can block cholesterol accumulation by these lenses and can produce cataracts in dogs. Whether these drugs inhibit cholesterol biosynthesis in human lenses at therapeutic doses is unknown. Results of clinical trials of 1-5 years duration in older patient populations indicate high ocular safety. However, considering the slow life-long growth of the lens and its continuing need for cholesterol, longterm safety of the vastatins should perhaps be viewed in units of 10 or 20 years, particularly with younger patients. [References: 158]

Chakanovskis JE, Sutherland GR.
The Smith-Lemli-Opitz syndrome in a profoundly retarded epileptic boy.
J Ment Defic Res 1971;15:153-162.

Chambers CM, McLean MP, Ness GC.
Smith-Lemli-Opitz syndrome produced in rats with AY 9944 treated by intravenous injection of lipoprotein cholesterol.
Am J Med Genet 1997;68:322-327.
A limitation to treating Smith-Lemli-Opitz infants by giving dietary cholesterol is their impaired ability to absorb cholesterol due to a deficiency of bile acids. Since intravenously administered lipoprotein cholesterol should not require bile acids for uptake into tissues, we tested the effects of this form of cholesterol on tissue cholesterol and 7-dehydrocholesterol levels in an animal model of SLO, created by feeding rats 0.02% AY 9944. Intravenous administration of 15 mg of bovine cholesterol supertrate twice daily increased serum cholesterol levels from 11 to over 250 mg/dl. This treatment increased liver cholesterol levels from 309 to over 900 micrograms/g and lowered hepatic 7-dehydrocholesterol levels from 1546 to 909 micrograms/g. A combination of iv cholesterol and 2% dietary cholesterol was most effective as it raised hepatic cholesterol levels to 1950 micrograms/g, which is 50% above normal. 7-Dehydrocholesterol levels were decreased to 760 micrograms/g. Similar responses were seen for heart, lung, kidney, and testes. Brain sterol levels were not significantly affected. AY 9944 caused a modest increase in hepatic HMG-CoA reductase activity. Administration of dietary cholesterol together with iv cholesterol lowered hepatic HMG-CoA reductase activity to barely detectable levels. The data indicate that the combination of iv and dietary cholesterol was most effective in raising cholesterol levels, lowering 7-dehydrocholesterol levels, and inhibiting de novo cholesterol biosynthesis.

Chang DT, Lopez A, von Kessler DP, Chiang C, Zhao R, Seldin MF, Fallon JF, Beachy PA.
Products, genetic linkage and limb patterning activity of a murine hedgehog gene.
Development 1994;120:3339-3353.

Chasalow FI, Blethen SL, Taysi K.
Possible abnormalities of steroid secretion in children with Smith-Lemli-Opitz syndrome and their parents.
Steroids 1985;46:827-843.
In early infancy, two unrelated children with Smith-Lemli-Opitz syndrome were found to have elevated levels of androgen sulfates. When the steroid conjugates in the serum of normal infants were hydrolyzed and chromatographed on Sephadex LH-20, 4 androgen containing peaks (I, II, III, IV) were found. In the serum from these two infants with Smith-Lemli-Opitz syndrome, Peaks I and III were increased, but Peaks II and IV were absent. The parents of the two children, and of three additional unrelated children with Smith-Lemli-Opitz syndrome, had exaggerated 17-hydroxyprogesterone responses to an intravenous bolus of ACTH. These findings suggest that a defect in steroid metabolism may be linked to the Smith-Lemli-Opitz syndrome.

Cherstvoy ED, Lazjuk GI, Lurie IW, Nedzved MK, Usoev SS.
The pathological anatomy of the Smith-Lemli-Opitz syndrome.
Clin Genet 1975;7:382-387.
Two cases of the Smith-Lemli-Opitz syndrome are described, together with the autopsy findings. In both cases, the typical appearance and visceral malformations were present. Hypoplasia of the frontal lobes and corpus callosum, and aplasia of the splenium constitute abnormalities of the brain which may be useful in the diagnosis of this disorder at autopsy. The autosomal recessive mode of inheritance of this syndrome was confirmed.

Cherstvoy ED, Lazjuk GI, Ostrovskaya TI, Shved IA, Kravtzova GI, Lurie IW, Gerasimovich AI.
The Smith-Lemli-Opitz syndrome. A detailed pathological study as a clue to a etiological heterogeneity.
Virchows Arch A Pathol Anat Histopathol 1984;404:413-425.
An analysis of 33 autopsied cases with the Smith-Lemli-Opitz syndrome (including 8 cases from our practice) is presented. Polydactyly in dead SLOS children was found in 51% (17/33) of cases and occurred significantly more often in this group than in the whole group of SLOS (20-22%). Certain morphological differences in the type of renal, cerebral, pulmonary and pancreatic anomalies indicate the existence of two phenotypically similar SLOS: 1) with polydactyly; 2) without it. The presented data initiate SLOS heterogeneity.

Clayton P, Mills K, Keeling J, FitzPatrick D.
Desmosterolosis: a new inborn error of cholesterol biosynthesis [letter; comment].
Lancet 1996;348:404.

Cooper MK, Porter JA, Young KA, Beachy PA.
Plant-derived and synthetic teratogens inhibit the ability of target tissues to respond to Sonic hedgehog signaling.
Science (U.S.A.) 1998;280:1603-1607.

Cormier-Daire V, Wolf C, Munnich A, Le Merrer M, Nivelon A, Bonneau D, Journel H, Fellmann F, Chevy F, Roux C.
Abnormal cholesterol biosynthesis in the Smith-Lemli-Opitz and the lethal acrodysgenital syndromes.
Eur J Pediatr 1996;155:656-659.
The Smith-Lemli-Opitz syndrome (SLO) is an autosomal recessive disorder characterized by dysmorphic facial features with abnormal limbs and genitalia. Two forms have been recognized based on clinical course and severity: the classical SLO (type I) and the lethal acrodysgenital syndrome (type II). Type I SLO has been recently ascribed to a defect in cholesterol synthesis. Taking advantage of a series of seven patients including five type I and two type II SLO, we describe micrognathia, severe microcephaly, major ante and post natal growth retardation and feeding difficulties as consistent features in the disease. In addition, we give support to the presence of abnormal cholesterol levels in the lethal acrodysgenital syndrome but find no correlation between plasma sterol levels and the clinical severity of the disease. CONCLUSION: The identification of the same biochemical defect in both types of Smith-Lemli-Opitz Syndrome suggests that despite major discrepancies in clinical course and severity, type I and type II SLo are probably allelic disorders.

Cotlier E, Rice P.
Cataracts in the Smith-Lemli-Opitz syndrome.
Am J Ophthalmol 1971;72:955-959.

Cruz MLA, Wong WW, Mimouni F, Hachey DL, Setchell KDR, Klein PD, Tsang RC.
Effects of infant nutrition on cholesterol synthesis rates.
Pediatric Research 1994;35:135-140.
Nutrient effects on cholesterol fractional synthesis rates (FSR) in infancy by stable isotope determination have not been studied. We hypothesized that FSR is significantly reduced with high dietary cholesterol and phytoestrogen intake and increased with low dietary cholesterol and phytoestrogen intake. We prospectively studied 33 term male infants exclusively fed human milk (high cholesterol, low phytoestrogen, n = 12), cow milk-based formula (low cholesterol, low phytoestrogen, n = 8), soy milk-based formula (zero cholesterol, high phytoestrogen, n = 7), or soy milk-based formula modified to contain cholesterol (low cholesterol, high phytoestrogen, n = 6) during the first 4 mo of life. Cholesterol FSR was determined from rate of incorporation of deuterium into erythrocyte membrane cholesterol, and urinary isoflavone excretion (an index of dietary phytoestrogen exposure) was measured by gas chromatography-mass spectrometry. Significant differences in cholesterol FSR were found. FSR (%/d) was lowest in human milk (2.62 +/- 0.38), highest in soy milk-based formula (9.40 +/- 0.51), and intermediate in cow milk-based and modified soy milk-based formula (6.90 +/- 0.48 and 8.03 +/- 0.28, respectively), p < 0.0001. Cholesterol FSR was significantly lower in modified soy milk-based compared with soy milk-based formula, p < 0.05. We also show for the first time that dietary phytoestrogens are absorbed and excreted by the infant fed soy protein-based formula. Urinary isoflavone excretion was inversely related to cholesterol FSR, but it was not significantly related to serum cholesterol concentration. We conclude that the type of infant nutrition and dietary cholesterol are major factors influencing cholesterol fractional synthesis rates in infancy

Cunniff C, Kratz LE, Moser A, Natowicz MR, Kelley RI.
Clinical and biochemical spectrum of patients with RSH/Smith-Lemli-Opitz syndrome and abnormal cholesterol metabolism.
Am J Med Genet 1997;68:263-269.
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.

Curry CJ, Carey JC, Holland JS, Chopra D, Fineman R, Golabi M, Sherman S, Pagon RA, Allanson J, Shulman S, et al.
Smith-Lemli-Opitz syndrome-type II: multiple congenital anomalies with male pseudohermaphroditism and frequent early lethality.
Am J Med Genet 1987;26:45-57.
In 1964, Smith et al described a syndrome of microcephaly, growth and mental retardation, unusual facial appearance, syndactyly of toes 2 and 3, and genital abnormalities. Major structural malformations and early death have been uncommon in the many subsequent literature reports. We report on 19 infants with a phenotype we propose to call Smith-Lemli-Opitz syndrome (SLOS)-Type II, in which major structural abnormalities, male pseudohermaphroditism, and early lethality are common. Of these 19 patients, 18 had postaxial hexadactyly, 16 had congenital heart defect, 13 had cleft palate, and 10 had cataracts. Unusual findings seen in these patients at autopsy included Hirschsprung "disease" in five patients, unilobated lungs in six, large adrenals in four, and pancreatic islet cell hyperplasia in three. Comparison of our cases to 19 similar literature cases suggests the existence of a distinct phenotype that may be separate from SLOS as originally described. It is also inherited as an autosomal recessive, as documented by occurrence in one pair of sibs in this study and recurrence in three reported families.

Dallaire L, Fraser FC.
The syndrome of retardation with urogenital and skeletal anomalies in siblings.
Journal of Pediatrics 1966;69:459-460.

Dallaire L.
Syndrome of retardation with urogenital and skeletal anomalies (Smith-Lemli-Opitz syndrome): clinical features and mode of inheritance.
J Med Genet 1969;6:113-120.

Dallaire L, Mitchell G, Giguere R, Lefebvre F, Melancon SB, Lambert M.
Prenatal diagnosis of Smith-Lemli-Opitz syndrome is possible by measurement of 7-dehydrocholesterol in amniotic fluid.
Prenat Diagn 1995;15:855-858.
Amniocentesis was performed at 17.3 weeks in a pregnancy with severe intrauterine growth retardation. Cytogenetic studies on amniocytes were normal, 46,XX, and the pregnancy was continued. The diagnosis of Smith-Lemli-Opitz syndrome was suspected in the neonatal period and confirmed by the presence of 7-dehydrocholesterol (7-DHC) in the plasma (0.4 mmol/l, normal = not detectable) associated with a low total cholesterol concentration (0.4 mmol/l, normal = 2.56 +/- 0.23). Retrospective analysis of the amniotic fluid sample revealed an elevated level of 7-DHC (0.022 mmol/l; normal = undetectable). Therefore measurement of 7-DHC levels in amniotic fluid during the second trimester of pregnancy is useful for the prenatal diagnosis of Smith-Lemli-Opitz syndrome in families at risk and should be considered in cases of severe growth retardation of unknown aetiology for which amniotic fluid is available and in which a normal chromosomal pattern in amniocytes is present.

de Die-Smulders C, Fryns JP.
Smith-Lemli-Opitz syndrome: the changing phenotype with age.
Genet Couns 1992;3:77-82.
In this report we present follow up data of two brothers with Smith-Lemli-Opitz syndrome. The changes with ageing are striking and few of the typical SLO traits are still present, which makes it extremely difficult to make the diagnosis Smith-Lemli-Opitz syndrome at adult age.

De Die-Smulders C, Van de Meer S, Spaapen L, Fryns JP.
Confirmation of defective cholesterol biosynthesis in 2 previously described adult sibs with Smith-Lemli-Opitz syndrome [letter].
Genet Couns 1996;7:161-162.

De Fabiani E, Caruso D, Cavaleri M, Galli Kienle M, Galli G.
Cholesta-5,7,9(11)-trien-3 beta-ol found in plasma of patients with Smith-Lemli-Opitz syndrome indicates formation of sterol hydroperoxide.
J Lipid Res 1996;37:2280-2287.
The Smith-Lemli-Opitz syndrome (SLOS) is an autosomal recessive disorder characterized by accumulation of cholesta-5,7-dien-3 beta-0l caused by a deficiency of the enzyme desaturating this sterol to cholesterol. In addition to other unusual sterols recently found in plasma of patients with SLOS, namely cholesta-5,8-dien-3 beta-ol and 19-nor-cholesta-5,7,9 (10)-trien-3 beta-ol we have detected a trienol and we describe here its identification as cholesta-5,7,9 (11)-trien-3 beta-ol by GC-MS and by comparison with a synthetic standard. We tested the possibility that the trienol may be formed by radical oxidation of cholesta-5,7-dien-3 beta-ol accumulated in plasma of patients with SLOS because it is known to be formed by decomposition of 7-hydroperoxy-cholesta-5,8-dien-3 beta-ol, which is a product of cholesta-5,7-dien-3 beta-ol photooxidation. Incubation of cholesta-5,7-dien-3 beta-ol with rat liver microsomes in the presence of ADP/Fe2+ and NADPH gave rise to a number of oxygenated sterols. Among these, analysis by particle-beam LC-MS under CI conditions indicated the presence of 7-hydroperoxy-cholesta-5,8-dien-3 beta-ol and of cholesta-5,7,9(11)-trien-3 beta-ol which is known to derive from the oxidation of the 7-hydroperoxide. From these results we conclude that cholesta-5,7-dien-3 beta-ol accumulated in tissues of patients with SLOS may be oxidized by oxygen radicals giving rise to oxygenated sterols. Some of these compounds may be toxic and may contribute to worsen the pathological picture in patients with SLOS.

de Jong G, Kirby PA, Muller LM.
RSH (Smith-Lemli-Opitz) syndrome: "severe" phenotype with ectrodactyly.
Am J Med Genet 1998;75:283-287.
We describe the antenatal ultrasound findings of growth retardation, oligohydramnios, mesomelic limb shortness, and cardiac, renal, and hand defects in a fetus who was postnatally diagnosed as having RSH ("Smith-Lemli-Opitz") syndrome. An unusual finding was ectrodactyly of both hands.

de la Torre Verdu M, Vazquez Lopez M, Carrasco Marina L, Giros ML, Quijano Roy S, Arregui Sierra A.
[Smith-Lemli-Opitz syndrome: abnormal cholesterol biosynthesis]. [Spanish].
An Esp Pediatr 1997;46:617-620.

Degenhardt F, Muhlhaus K.
[Delayed bone growth as a sonographic sign in the early detection of Smith-Lemli-Opitz syndrome]. [German].
Z Geburtshilfe Perinatol 1988;192:169-172.
The Smith-Lemli-Opitz syndrome was first described in 1964. It is inherited as an autosomal recessive trait. Characteristic manifestations are abnormalities of the facial skull, a delayed growth, lazy feeder, zygodatly and a cryptorchism in males. The case of a girl is presented born with this syndrome likewise her sister. Diagnosis was confirmed in the 30th gestational week by means of ultrasound. A retardation of bony growth and telltale signs of this syndrome were observed. At birth length of diaphysis differed 5 weeks compared with standard.

Dehart DB, Lanoue L, Tint GS, Sulik KK.
Pathogenesis of malformations in a rodent model for Smith-Lemli-Opitz syndrome.
Am J Med Genet 1997;68:328-337.
The fact that Smith-Lemli-Opitz syndrome (SLOS), a syndrome comprising major malformations involving a number of organ systems, results from an abnormality in cholesterol biosynthesis, was discovered only recently. Utilizing a drug (BM 15.766) to inhibit the same step in cholesterol biosynthesis as is abnormal in those affected with SLOS, we have developed a rat model that presents with abnormalities observed as early as gestational day 12 that appear to be consistent with some of those subsequent malformations that comprise the human syndrome. Abnormalities of the brain and face include deficiency in the midline region of the upper face, narrowing of the forebrain hemispheres and of the cerebral aqueduct, and deficiency in the developing lower jaw. Associated pathogenesis, as observed on gestational day 11 in histological sections and with scanning electron microscopy, involves abnormal cell populations at the rim of the developing forebrain and in the alar plate of the lower midbrain and hind-brain. The affected cells appear abnormally rounded up, having apparently lost their normal cell contacts. The potential basis for the selective vulnerability of this cell population and the impact of its vulnerability relative to subsequent dysmorphogenesis is discussed.

Delattre P.
[Smith-Lemli-Opitz syndrome. Apropos of a further case]. [French].
Lille Med 1974;19:18-21.

Domenici R, Fiorini V, Giorgi F.
[Smith-Lemli-Opitz syndrome. Case report and differential diagnosis]. [Italian].
Minerva Pediatr 1982;34:709-714.

Donnai D, Young ID, Owen WG, Clark SA, Miller PF, Knox WF.
The lethal multiple congenital anomaly syndrome of polydactyly, sex reversal, renal hypoplasia, and unilobular lungs.
Journal of Medical Genetics 1986;23:64-71.
Three cases are reported of a lethal multiple congenital anomaly syndrome. The infants had moderate limb shortening, joint contractures, polydactyly, and the two with male karyotypes had female external genitalia. Internal anomalies included unilobular lungs, hypoplasia of the anterior portion of the tongue, and renal hypoplasia.

Donnai D, Burn J, Hughes H.
Smith-Lemli-Opitz syndromes: do they include the Pallister-Hall syndrome?
Am J Med Genet 1987;28:741-743.

Donnenfeld AE, Zackai EH, McDonald DM, Aquino R, Emanuel BS.
De novo 2q+ masquerading as Smith-Lemli-Opitz syndrome.
J Med Genet 1987;24:436-439.
We report a female infant diagnosed shortly after birth as having Smith-Lemli-Opitz syndrome. Despite previously reported normal G banded karyotypes, a high resolution banded chromosome analysis identified 46,XX,2q+. The importance of attention to established features of clinical syndromes, as well as persistence in investigation when diagnostic uncertainties exist, are discussed.

Dunin-Wasowicz D, Krajewska-Walasek M, Rowecka-Trzebicka K, Gurkau-Malecha M, Gutkowska A, Chrzanowska K.
[Diagnosis of Edwards syndrome in newborns]. [Polish].
Pediatr Pol 1995;70:865-874.
Congenital malformations most useful for the diagnosis of trisomy 18 in the first days of life were defined based on observations of newborns with Edwards syndrome treated at the Child Health Center in 1992-1994. Intrauterine growth retardation, facial skeleton dysmorphy, congenital heart malformation, mainly VSD, extremity malformations, especially of the palms and feet found in the newborn suggest a diagnosis of Edwards syndrome. The need to differentially diagnose trisomy 18 with autosomal recessive syndrome TAR, Roberts and Smith-Lemli-Opitz is stressed.

Dzarlieva R, Duma H, Cvetkovski P, Urumova E.
The Smith-Lemli-Opitz syndrome in a five months old child.
God Zb Med Fak Skopje 1977;23:253-261.

Elias ER, Irons M.
Abnormal cholesterol metabolism in Smith-Lemli-Opitz syndrome. [Review] [27 refs].
Curr Opin Pediatr 1995;7:710-714.
Smith-Lemli-Opitz syndrome (SLOS) is a common autosomal recessive disorder. Children with SLOS present with specific facial dysmorphism and have multiple congenital anomalies including cleft palate, congenital heart disease, genitourinary anomalies, and limb abnormalities. They also manifest severe failure to thrive and mental retardation. A metabolic defect at the final step in the cholesterol biosynthetic pathway has been described in SLOS patients. This defect results in markedly reduced cholesterol levels and abnormal accumulation of cholesterol precursors, particularly 7-dehydrocholesterol. This newly described metabolic defect in humans is one of only a few metabolic errors known to cause multiple birth defects. The biochemical profile of reduced plasma cholesterol levels in association with markedly elevated levels of the cholesterol precursor 7-dehydrocholesterol is now used to confirm the diagnosis of SLOS, which was formerly made on purely clinical grounds. This biochemical abnormality has been confirmed in dozens of patients with SLOS in both the United States and Europe. The severe cholesterol deficiency seen in these patients has multiple effects on health and early childhood development, because cholesterol is an essential component of many cell functions, which explains many of the clinical findings seen in SLOS. [References: 27]

Elias ER, Irons MB, Hurley AD, Tint GS, Salen G.
Clinical effects of cholesterol supplementation in six patients with the Smith-Lemli-Opitz syndrome (SLOS).
Am J Med Genet 1997;68:305-310.
We describe the clinical effects of cholesterol supplementation in 6 children with the RSH-"Smith-Lemli-Opitz" syndrome (SLOS). The children ranged in age from birth to 11 years at the onset of therapy, with pretreatment cholesterol levels ranging from 8 to 62 mg/dl. Clinical benefits of therapy were seen in all patients, irrespective of age at onset of treatment, or severity of cholesterol defect. Effects of treatment included improved growth, more rapid developmental progress, and a lessening of problem behaviors. Pubertal progression in older patients, a better tolerance of infection, improvement of gastrointestinal symptoms, and a diminution in photosensitivity and skin rashes were also noted. There were no adverse reactions to treatment with cholesterol. This preliminary study suggests that cholesterol supplementation may be of benefit to patients with the SLOS.

Ericsson J, Appelkvist EL, Thelin A, Chojnacki T, Dallner G.
Isoprenoid biosynthesis in rat liver peroxisomes. Characterization of cis-prenyltransferase and squalene synthetase.
J Biol Chem 1992;267:18708-18714.
Isolated peroxisomes were able to utilize [3H]isopentenyl diphosphate to synthesize farnesyl diphosphate, which then was utilized as substrate by both the peroxisomal squalene synthetase and cis- prenyltransferase. The specific activity of squalene synthetase in peroxisomes was as high as in microsomes, i.e. 160 pmol/mg of protein/min. If NADPH was omitted from the assay medium, presqualene diphosphate accumulated, which indicates that the reaction occurs in two steps, as in microsomes. In the presence of NADPH, incorporation from [3H]farnesyl diphosphate was stimulated 3-fold, and the major products were squalene and cholesterol. The specific activity of cis- prenyl-transferase in peroxisomes was 4-fold higher than in microsomes, i.e. 456 pmol of isopentenyl diphosphate incorporated/mg of protein/h. There were two major products formed from farnesyl diphosphate and [3H] isopentenyl diphosphate, i.e. trans,trans,cis-geranylgeranyl diphosphate and long chain polyprenyl diphosphates. The polyprenyl diphosphates had the same chain length distribution as that of dolichol derivatives in rat liver, with the dominating polyisoprenes being C90 and C95. In contrast to the microsomal enzyme, peroxisomal cis- prenyltransferase did not require detergents for optimal activity. The enzyme was associated primarily with the peroxisomal membrane after sonication of the peroxisomes.

Farese RV, Jr., Ruland SL, Flynn LM, Stokowski RP, Young SG.
Knockout of the mouse apolipoprotein B gene results in embryonic lethality in homozygotes and protection against diet-induced hypercholesterolemia in heterozygotes.
Proc Natl Acad Sci USA 1995;92:1774-1778.
Apolipoprotein B is synthesized by the intestine and the liver in mammals, where it serves as the main structural component in the formation of chylomicrons and very low density lipoproteins, respectively. Apolipoprotein B is also expressed in mammalian fetal membranes. To examine the consequences of apolipoprotein B deficiency in mice, we used gene targeting in mouse embryonic stem cells to generate mice containing an insertional disruption of the 5' region of the apolipoprotein B gene. Mice that were heterozygous for the disrupted apolipoprotein B allele had an approximately 20% reduction in plasma cholesterol levels, markedly reduced plasma concentrations of the pre-beta and beta-migrating lipoproteins, and an approximately 70% reduction in plasma apolipoprotein B levels. When fed a diet rich in fat and cholesterol, heterozygous mice were protected from diet-induced hypercholesterolemia; these mice, which constitute an animal model for hypobetalipoproteinemia, should be useful for studying the effects of decreased apolipoprotein B expression on atherogenesis. The breeding of heterozygous mice yielded no viable homozygous apolipoprotein B knockout mice. Most homozygous embryos were resorbed by midgestation (before gestational day 11.5); several embryos that survived until later in gestation exhibited exencephalus. The embryonic lethal phenotype was rescued by complementation with a human apolipoprotein B transgene--i.e., human apolipoprotein B transgenic mice that were homozygous for the murine apolipoprotein B knockout mutation were viable. Our findings indicate that apolipoprotein B plays an essential role in mouse embryonic development.

Fehlow P.
[Contribution to the differential diagnosis of Smith-Lemli-Opitz syndrome]. [German].
Padiatr Grenzgeb 1988;27:331-335.

Fehlow P, Walther F.
[Primary hypogonadism associated with neuropsychiatric disorders]. [German].
Arztl Jugendkd 1991;82:93-102.
Among 43 female patients aged 17-46 years, most with severe oligophrenia, there were 4 with primary hypogonadism (olfactory-genital dysplasia, Smith-Lemli-Opitz syndrome and lastly a Kanner syndrome). The incidence of genital underdevelopment is assumed to be higher among mentally retarded female patients. In cases of hypogonadism and hypogenitalism a search should always be made for possible mental and neurological disorders.

Fehlow P, Walther F.
[Hirschsprung-Galant infantilism]. [German].
Padiatr Grenzgeb 1991;30:245-252.
Report about a 17 1/2 year-old girl with severe mental retardation, dwarfism, hypogenitalism and short segment type of HIRSCHSPRUNG's disease, abortive SMITH-LEMLI-OPITZ syndrome is supposed. Literature about etiology and genetics of HIRSCHSPRUNG's disease is reviewed.

Fierro M, Martinez AJ, Harbison JW, Hay SH.
Smith-Lemli-Opitz syndrome: neuropathological and ophthalmological observations.
Dev Med Child Neurol 1977;19:57-62.
The case of a three-year-old boy with the Smith-Lemli-Opitz syndrome is reported. In addition to the constellation of skeletal and genital anomalies classically described in this syndrome, this patient had spontaneous opsoclonus-like eye movements, strabismus, lack of visual following responses and of opticokinetic reflexes. At autopsy the cerebellar vermis was found to be absent. There were retinal hemangiomas. Microscopical examinations showed loss of Purkinje cells and extensive neuronal degeneration within dentate nuclei, associated with patchy demyelination of cerebellar peduncles and central white matter. These findings may contribute to the explanation of the pathophysiology of opsoclonus and some of the neuro-ophthalmological findings.

Fine RN, Gwinn JL, Young EF.
Smith-Lemli-Opitz syndrome. Radiologic and postmortem findings.
Am J Dis Child 1968;115:483-488.

Finley SC, Finley WH, Monsky DB.
Cataracts in a girl with features of the Smith-Lemli-Opitz syndrome.
J Pediatr 1969;75:706-707.

FitzPatrick DR, Keeling JW, Evans MJ, Kan AE, Bell JE, Porteous ME, Mills K, Winter RM, Clayton PT.
Clinical phenotype of desmosterolosis.
Am J Med Genet 1998;75:145-152.
We describe a child with lethal multiple malformations and generalised accumulation of desmosterol. The infant had macrocephaly, a hypoplastic nasal bridge, thick alveolar ridges, gingival nodules, cleft palate, total anomalous pulmonary venous drainage, ambiguous genitalia, short limbs, and generalised osteosclerosis. Gas chromatography-mass spectrometry demonstrated an abnormal accumulation of desmosterol in kidney, liver. and brain. Higher than normal levels of the same sterol were detected in plasma samples obtained from both parents. The biochemical phenotype in this infant is highly suggestive of a novel inborn error of cholesterol biosynthesis caused by an autosomal recessive deficiency of 3betahydroxysterol-delta24-reductase. A phenotypic overlap of this case with Raine syndrome was noted; however, desmosterol accumulation was not found on postmortem tissue samples from a previously reported case of this disorder.

Franceschini P, Franceschini D.
[Low cholesterol and pathological manifestations: Smith-Lemli-Opitz syndrome (letter)]. [Italian].
Minerva Pediatr 1994;46:579-580.

Freedman RA, Baum JL.
Postlenticular membrane associated with Smith-Lemli-Opitz syndrome.
Am J Ophthalmol 1979;87:675-677.
A 6-day-old boy with Smith-Lemli-Opitz syndrome developed bilateral cataracts, posterior synechiae, and a dense postlenticular membrane. No other signs of inflammation were noted that could account for the development of either the posterior synechiae or membrane. To our knowledge, this is the first published report of such an associated membrane.

Fried K, Fraser WI.
Smith-Lemli-Opitz syndrome in an adult.
J Ment Defic Res 1972;16:30-34.

Fukazawa R, Nakahori Y, Kogo T, Kawakami T, Akamatsu H, Tanae A, Hibi I, Nagafuchi S, Nakagome Y, Hirayama T.
Normal Y sequences in Smith-Lemli-Opitz syndrome with total failure of masculinization.
Acta Paediatr 1992;81:570-572.
We report an infant with characteristics of Smith-Lemli-Opitz syndrome who had anteverted nostrils, apparently low-set ears, micrognathia, high-arched palate, cleft palate, growth and psychomotor retardation, hypotonia, poor suck, cerebral hypotrophy and double renal pelvis and ureter. An EEG showed spike waves in the right temporal area. The patient appeared to have normal internal and external genitalia of the female type. Both ovaries were dysplastic. The karyotype was 46,XY. All of 26 loci on the Y chromosome were positive including SRY, a candidate gene for TDF.

Garcia CA, McGarry PA, Voirol M, Duncan C.
Neurological involvement in the Smith-Lemli-Opitz syndrome: clinical and neuropathological findings.
Dev Med Child Neurol 1973;15:48-55.

Gellis SS, Feingold M.
Picture of the month. Smith-Lemli-Opitz syndrome.
Am J Dis Child 1968;115:603-604.

Gemme G, Bonioli E, Ruffa G, Sbolgi P.
[Smith-Lemli-Opitz syndrome. Description of 2 cases and review of the literature]. [Italian].
Minerva Pediatr 1978;30:805-810.

Gill DG, Blair AL.
Smith-Lemli-Opitz syndrome: two further cases.
Ir Med J 1975;68:33-36.

Gomez de Terreros I, Cintado Bueno C, Ariza Almeida S, Gonzalez Meneses A.
[Smith-Lemli-Opitz syndrome. Cardiologic considerations (author's transl)]. [Spanish].
An Esp Pediatr 1975;8:689-694.
A new case of the Smith-Lemli-Opitz Syndrome is reported, associated with a type of congenital cardiopathy not described previously in this syndrome.

Gracia R, Nieto JA, Nistal M, Iturriaga R, Lledo G, Barrio R, Lama R.
[Aniridia associated with gonadoblastoma in Smith-Lemli-Opitz syndrome (author's transl)]. [Spanish].
An Esp Pediatr 1976;9:19-24.
One case of bilateral "in situ" gonadoblastoma associated with aniridia and Smith-Lemli-Opitz syndrom is reported. This observation confirms the incidence of gonadoblastoma in intersex patients. Coincidence of this tumor and aniridia is considered by the authors as previously unreported.

Greenberg F, Gresik MV, Carpenter RJ, Law SW, Hoffman LP, Ledbetter DH.
The Gardner-Silengo-Wachtel or genito-palato-cardiac syndrome: male pseudohermaphroditism with micrognathia, cleft palate, and conotruncal cardiac defect.
Am J Med Genet 1987;26:59-64.
We report on two sib fetuses with similar abnormalities detected prenatally by ultrasound. The first fetus had micrognathia, was without cleft palate, and had low-set ears, double outlet right ventricle with a ventricular septal defect, and 46,XY gonadal dysgenesis. The second sib fetus was born with cleft lip and palate, micrognathia, transposition of the great vessels, ventricular septal defect, a right-sided aorta arch, and bilateral cystic kidneys with hypospadias. We were able to identify 11 additional cases in the literature with similar findings. We think this set of defects is a recognizable syndrome that appears to be inherited either as an autosomal recessive or as an X-linked recessive and may overlap with the Smith-Lemli-Opitz syndrome.

Greene C, Pitts W, Rosenfeld R, Luzzatti L.
Smith-Lemli-Opitz syndrome in two 46,XY infants with female external genitalia.
Clin Genet 1984;25:366-372.
Two infants with features of the Smith-Lemli-Opitz (SLO) syndrome were found to have a 46,XY karyotype and female external genitalia. Autopsies showed normal testes for age with normal Wolffian duct structures and without Mullerian duct derivatives. This failure of masculinization of the external genitalia is an unusual finding and may represent the extreme of a spectrum of the genital anomalies commonly seen in males with this autosomal recessive syndrome. An endocrine evaluation on one of these infants at 3 months suggested unusually low testosterone production and meagre response to stimulation with human chorionic gonadotropin (hCG). The failure of complete masculinization of external genitalia in some cases of SLO syndrome may be due to inadequate testosterone production in utero.

Guzzetta V, De Fabiani E, Galli G, Colombo C, Corso G, Lecora M, Parenti G, Strisciuglio P, Andria G.
Clinical and biochemical screening for Smith-Lemli-Opitz syndrome. Italian SLOS Collaborative Group.
Acta Paediatr 1996;85:937-942.
Smith-Lemli-Opitz syndrome (SLOS) is a multiple congenital anomalies/mental retardation disorder possibly due to a defect of delta 7-sterol reductase, leading to low plasma cholesterol levels and to the accumulation of 7-dehydrocholesterol (7-DHC) and other cholesterol precursors. This study aimed to identify clinical features that could potentially be specific indicators for the clinical diagnosis of SLOS, and to test the reliability of ultraviolet spectrophotometry (UVS) as a biochemical screening procedure for the syndrome. Twenty patients with clinical suspicion of SLOS, referred to 11 Italian paediatric and clinical genetic centres, were collected during 1994. In 10 patients the diagnosis was confirmed biochemically by gas chromatography/mass spectrometry (GC/MS) analysis of serum sterols, whereas in the other 10 patients the serum sterol profiles were normal. A comparison between confirmed SLOS patients and biochemically negative subjects did not show clinical signs specific for the syndrome. UVS measurement of 7-DHC correlated well with GC/MS profiles, showing 100% sensitivity and specificity. Four out of five patients had serum bile acid concentrations below the normal range of controls.

Haji-Michael PG, Hatch DL.
Smith-Lemli-Opitz syndrome and malignant hyperthermia [letter; comment].
Anesth Analg 1996;83:200.

Hanissian AS, Summitt RL.
Smith-Lemli-Opitz syndrome in a negro child.
J Pediatr 1969;74:303-305.

Harbin RL, Katz JI, Frias JL, Rabinowicz IM, Kaufman HE.
Sclerocornea associated with the Smith-Lemli-Opitz syndrome.
Am J Ophthalmol 1977;84:72-73.
A 2,000-g infant boy had many features of the Smith-Lemli-Opitz syndrome (prenatal growth deficiency and developmental retardation, microcephaly with unusual facies, hypospadias, and feeding difficulties) as well as sclerocornea. The association of this rare eye finding with this rare congenital syndrome is unique. Successful penetrating keratoplasty was performed in one eye at 8 months of age.

Hasui M, Saito C, Kasama T, Taki T, Yachie A.
[Identification of impaired cholesterol biosynthesis in a Japanese patient of Smith-Lemli-Opitz syndrome]. [Japanese].
No To Hattatsu 1997;29:61-66.
We reported the decreased level of cholesterol as well as the elevated levels of 7- and 8-dehydrocholesterol in the serum and erythrocytes of a Japanese patient with Smith-Lemli-Opitz syndrome. These findings suggested that the detection of these precursors of cholesterol synthesis should become an important biochemical parameter for this syndrome in which clinical features are not always obvious.

Henkel KE, Pfeiffer RA, Stoss H.
[Genetic morphological fatal syndrome. Smith-Lemli-Opitz syndrome]. [German].
Pathologe 1993;14:91-92.

Herman TE.
[Smith-Lemli-Opitz syndrome type II. Contribution of imaging]. [French].
J Radiol 1993;74:593-596.
Smith-Lemli-Opitz syndrome, type II, is a very rare congenital condition which has been fatal in all reported cases. The imaging findings can be diagnostic. A rapid and accurate diagnosis is very important to the effected infant and the parents in this autosomal recessive condition.

Herman TE, Siegel MJ, Lee BC, Dowton SB.
Smith-Lemli-Opitz syndrome type II: report of a case with additional radiographic findings.
Pediatr Radiol 1993;23:37-40.
A phenotypically female infant with 46-XY chromosomes was found to have Smith-Lemli-Opitz syndrome, type II a rare congenital malformation syndrome with many features of the more common classic Smith-Lemli-Opitz syndrome. The patient's skeletal survey revealed characteristic and previously undescribed skeletal anomalies which are reported. In addition a lipoma of the pituitary gland was found on magnetic resonance imaging. This lesion is particularly interesting given the hypothesized steroid abnormality in Smith-Lemli-Opitz, type II syndrome, the sexual ambiguity of males with this syndrome and the similarity of this syndrome to the Pallister-Hall syndrome which characteristically has a hamartoblastoma of the hypothalamus.

Hill S, Creasy M, Bundey S.
A family with three sisters with the 4p- syndrome, originally reported as suffering from the Smith-Lemli-Opitz syndrome.
J Ment Defic Res 1991;35:76-80.
The authors further describe investigations of a family originally reported by Bundey & Smyth in 1974 with a diagnosis of the Smith-Lemli-Opitz syndrome. Chromosome studies performed for the fourth time revealed that the mother had a presumptive t(4;22) translocation. The importance of reviewing earlier diagnoses, including repeating the chromosome studies if indicated, in order to arrive at a more accurate diagnosis is stressed. It is also important to provide the cytogenetics laboratory with clues to any possible clinically-recognisable chromosome syndrome, and to be prepared to examine the chromosomes of the parents of the affected case, even if the patient's karyotype appears normal. In this particular family, the correct diagnosis in the affected girls led to a realization that their brother had a 50% risk of producing unbalanced offspring.

Hobbins JC, Jones OW, Gottesfeld S, Persutte W.
Transvaginal ultrasonography and transabdominal embryoscopy in the first-trimester diagnosis of Smith-Lemli-Opitz syndrome, type II.
Am J Obstet Gynecol 1994;171:546-549.
OBJECTIVE: Our goal was to demonstrate the efficacy of transabdominal embryoscopy in the first trimester of pregnancy. STUDY DESIGN: A patient at risk for Smith-Lemli-Opitz syndrome, type II, was referred for prenatal diagnosis at 11 weeks 5 days of gestation. RESULTS: A transvaginal ultrasonographic examination revealed the presence of a nuchal membrane and bilateral polydactyly. A transabdominal embryoscopy confirmed the diagnosis of polydactyly. The patient had an unremarkable postprocedure course before termination of pregnancy 5 days later. In a second pregnancy embryoscopy revealed a normal fetal hand despite a suggestion on transvaginal ultrasonography that there was polydactyly. On the basis of this information the patient elected to continue the pregnancy, and a normal baby was delivered at 35 weeks. CONCLUSION: This case validates the efficacy of noninvasive and invasive techniques, used adjunctively, in the first-trimester diagnosis of a lethal fetal condition composed of subtle phenotypic manifestations.

Hodge VJ, Gould SJ, Subramani S, Moser HW, Krisans SK.
Normal cholesterol synthesis in human cells requires functional peroxisomes.
Biochemical Biophysical Research Communications 1991;181:537-541.

Hoefnagel D, Wurster D, Pomeroy J, Benz R.
The Smith-Lemli-Opitz syndrome in an adult male.
J Ment Defic Res 1969;13:249-257.

Hoffmann G, Gibson KM, Brandt IK, Bader PI, Wappner RS, Sweetman L.
Mevalonic aciduria - an inborn error of cholesterol and non-sterol isoprene biosynthesis.
New England Journal of Medicine 1986;314:1610-1614.

Honda A, Tint GS, Salen G, Batta AK, Chen TS, Shefer S.
Defective conversion of 7-dehydrocholesterol to cholesterol in cultured skin fibroblasts from Smith-Lemli-Opitz syndrome homozygotes.
J Lipid Res 1995;36:1595-1601.
The Smith-Lemli-Opitz syndrome is a common birth defect syndrome characterized biochemically by low plasma cholesterol levels and high concentrations of the cholesterol precursor 7-dehydrocholesterol. The present study was undertaken to prove that the enzyme defect is at the step in which 7-dehydrocholesterol is converted into cholesterol and to establish a new biochemical method for the diagnosis of this disease. We assayed the latter part of the cholesterol biosynthetic pathway by incubating [3H]lathosterol (the immediate precursor of 7-dehydrocholesterol) with cultured skin fibroblasts from 15 homozygous patients, 14 obligate heterozygous parents, and 8 controls, and measuring its conversion to 7-dehydrocholesterol and cholesterol. The formation of cholesterol from lathosterol in parents was not significantly different from that in controls. In contrast, cells from patients made very little cholesterol (P < 0.0001, patients vs. parents or vs. controls) but readily converted lathosterol to 7-dehydrocholesterol. The defect was especially profound in a subgroup of 8 of the most severely clinically affected patients, as virtually no label was detected in the cholesterol fraction. These results provide compelling evidence that 1) this disease is caused by a primary defect in 7-dehydrocholesterol delta 7-reductase, an essential enzyme in the biosynthesis of cholesterol; 2) the most clinically severe form of the syndrome may be associated with the most inhibited enzyme; and 3) the enzyme lathosterol 5-desaturase that converts lathosterol to 7-dehydrocholesterol is fully intact. The present method using fibroblast and amniocyte cultures establishes it as a useful procedure for the biochemical diagnosis of this syndrome.

Honda M, Tint GS, Honda A, Batta AK, Chen TS, Shefer S, Salen G.
Measurement of 3 beta-hydroxysteroid delta 7-reductase activity in cultured skin fibroblasts utilizing ergosterol as a substrate: a new method for the diagnosis of the Smith-Lemli-Opitz syndrome.
J Lipid Res 1996;37:2433-2438.
A new sensitive and specific method for the evaluation of 3 beta-hydroxysteroid delta 7-reductase activity, the defective enzyme in the Smith-Lemli-Opitz (SLO) syndrome, is described. The assay is based on the use of gas chromatography-mass spectrometry with selected-ion monitoring to measure the mass of brassicasterol (ergosta-5,22-dien-3 beta-ol) produced by the incubation of ergosterol (ergosta-5,7,22-trien-3 beta-ol) with cultured human skin fibroblasts. Although the conversion of ergosterol to brassicasterol was slower than the transformation of [3H]7-dehydrocholesterol to [3H] cholesterol, cells from control subjects produced brassicasterol efficiently. In contrast, cells form SLO patients produced very little brassicasterol (P < 0.0001, patients vs. parents or vs. controls). These results indicate that the reduction of ergosterol can be used as an assay for 3 beta-hydroxysteroid delta 7-reductase in human skin fibroblasts, which avoids the many problems caused by the instability and lack of availability of radiolabeled 7-dehydrocholesterol. The present method made it possible to diagnose the SLO syndrome with high sensitivity and reliability using a commercially available compound.

Honda A, Tint GS, Shefer S, Batta AK, Honda M, Salen G.
Effect of YM 9429, a potent teratogen, on cholesterol biosynthesis in cultured cells and rat liver microsomes.
Steroids 1996;61:544-548.
YM 9429 (cis-1-[4-(p-menthan-8-yloxy)phenyl]piperidine) is a hypolipidemic agent with a potent and specific teratogenicity, inducing cleft palate and skeletal variations in rats. Since cleft palate is generally observed in the Smith-Lemli-Opitz syndrome, a common syndrome of multiple congenital anomalies caused by reduced activity of 7-dehydrocholesterol delta 7-reductase (3 beta-hydroxysteroid delta 7-reductase), the final enzyme in the cholesterol biosynthetic pathway, YM 9429 was suspected of being an inhibitor of this enzyme. To prove this hypothesis, YM 9429 was added to cultured human skin fibroblasts and to cultured Morris hepatoma cells and incubated with [5-3H]mevalonolactone. After 24 h, radiolabeled 7-dehydrocholesterol accumulated in the cells, whereas the formation of radiolabeled cholesterol was markedly reduced. The results indicate that YM 9429 inhibits the conversion of 7-dehydrocholesterol to cholesterol catalyzed by the microsomal enzyme 7-dehydrocholesterol delta 7-reductase. In rat liver microsomes, the mode of inhibition was found to be noncompetitive, with a Ki of 40 microM. These results suggest that YM 9429 induced developmental abnormalities in rats by the same mechanism as the Smith-Lemli-Opitz syndrome. This compound might be useful for studying the pathogenesis of anomalies in animal models of the Smith-Lemli-Opitz syndrome.

Honda A, Shefer S, Salen G, Xu G, Batta AK, Tint GS, Honda M, Chen TC, Holick MF.
Regulation of the last two enzymatic reactions in cholesterol biosynthesis in rats: effects of BM 15.766, cholesterol, cholic acid, lovastatin, and their combinations.
Hepatology 1996;24:435-439.
The Smith-Lemli-Opitz syndrome is a common inherited birth disorder caused by markedly reduced 7-dehydrocholesterol delta 7-reductase activity, the final enzyme in the cholesterol biosynthetic pathway. BM 15.766 (4-[2-[1-(4-chlorocinnamyl)piperazin-4-yl]ethyl]-benzoic acid) inhibits 7-dehydrocholesterol delta 7-reductase activity, reduces plasma cholesterol levels, and increases 7-dehydrocholesterol levels to reproduce the biochemical abnormalities of the syndrome in rats. Cholesterol, cholic acid, and lovastatin, alone or in combinations, were fed to rats given BM 15.766, and hepatic activities of the last two enzymes in the cholesterol biosynthetic pathway, lathosterol 5-dehydrogenase and 7-dehydrocholesterol delta 7-reductase, were measured. After feeding BM 15.766, hepatic 7-dehydrocholesterol delta 7-reductase activity decreased by 77% while lathosterol 5-dehydrogenase activity tended to increase, so that the ratio of 5-dehydrogenase to delta 7-reductase activities increased from 0.33 to 2.8. In BM 15.766-fed rats, treatment with cholesterol suppressed both 5-dehydrogenase and delta 7-reductase activities by 76% and 66%, respectively, and decreased the 5-dehydrogenase: delta 7-reductase activities ratio from 2.8 to 2.2. In contrast, treatment with cholic acid and BM 15.766 further inhibited delta 7-reductase activity by 67% without changing significantly the 5-dehydrogenase activity that had increased the ratio to 5.5. Combining BM 15.766 with lovastatin increased 5-dehydrogenase activity fivefold but did not change delta 7-reductase activity, raising the ratio to 14.3. In BM 15.766-treated rats, the first and last two enzymatic reactions in the cholesterol biosynthetic pathway catalyzed by 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, lathosterol 5-dehydrogenase, and 7-dehydrocholesterol delta 7-reductase are down-regulated by cholesterol. Thus, only cholesterol and not cholic acid or lovastatin could reduce elevated plasma 7-dehydrocholesterol levels induced by BM 15.766.

Honda A, Batta AK, Salen G, Tint GS, Chen TS, Shefer S.
Screening for abnormal cholesterol biosynthesis in the Smith-Lemli-Opitz syndrome: rapid determination of plasma 7-dehydrocholesterol by ultraviolet spectrometry.
Am J Med Genet 1997;68:288-293.
The Smith-Lemli-Opitz syndrome (SLOS) is a common condition caused by deficiency of 7-dehydrocholesterol delta 7-reductase. The syndrome can usually be diagnosed by demonstrating markedly increased plasma concentrations of the cholesterol precursor, 7-dehydrocholesterol. We describe a simple and rapid method for detection of plasma 7-dehydrocholesterol by use of ultraviolet (UV) spectrometry. Lipids were extracted from plasma by addition of ethanol and n-hexane, and the n-hexane phase was directly subjected to spectrometry. The absorption maxima characteristics of 7-dehydrocholesterol (lambda max 271, 282, and 294 nm) were observed in patients' plasma but not in controls. For quantitative measurements, absorbance at 282 nm was used. Since this absorbance is the sum of the absorbance derived from 7-dehydrocholesterol and background absorbance, the concentrations of 7-dehydrocholesterol in various plasma samples were quantified by subtracting estimated background absorbance at 282 nm from observed absorbance at 282 nm. The results correlated well with total (free plus esterified) 7-dehydrocholesterol concentrations measured by gas-liquid chromatographic method. The UV spectrometric assay was sensitive enough to detect increased 7-dehydrocholesterol in cultured skin fibroblasts from patients grown in delipidated medium. The present method will make it possible to screen plasma or fibroblasts to detect the syndrome rapidly in general clinical laboratories.

Honda A, Tint GS, Salen G, Kelley RI, Honda M, Batta AK, Chen TS, Shefer S.
Sterol concentrations in cultured Smith-Lemli-Opitz syndrome skin fibroblasts: diagnosis of a biochemically atypical case of the syndrome.
Am J Med Genet 1997;68:282-287.
The Smith-Lemli-Opitz syndrome is a common birth defect syndrome caused by a deficiency of 7-dehydrocholesterol delta 7-reductase, an essential enzyme in the biosynthesis of cholesterol. The syndrome can usually be diagnosed easily from the plasma markers of markedly elevated 7-dehydrocholesterol and reduced cholesterol concentrations. However, atypical cases with normal plasma levels of cholesterol with only moderately elevated 7-dehydrocholesterol have been reported. To establish a sensitive method for the biochemical diagnosis of the atypical cases of the syndrome, we measured sterol concentrations of cultured skin fibroblasts. 7-Dehydrocholesterol concentrations in patients' fibroblasts grown in the presence of 10% fetal bovine serum were significantly higher than those in controls and parents (P < 0.0005), but they were not elevated proportionately as much as in plasma. To re-produce the accumulation of 7-dehydrocholesterol, the cells were exposed to delipidated medium to induce sterol biosynthesis. After 4 weeks, 7-dehydrocholesterol concentrations in patients' fibroblasts increased from 2.8 +/- 0.3% to 34 +/- 3% of total sterols (cholesterol + 7-dehydrocholesterol + 8-dehydrocholesterol). The increase was also observed in fibroblasts from an atypical patient who has a normal plasma cholesterol level and a 7-dehydrocholesterol concentration of only 0.15 mg/dl. In contrast, cells from parents and controls accumulated very little 7-dehydrocholesterol (< 1% of total sterols). These results demonstrate that cultured fibroblasts exhibit abnormally high accumulation of 7-dehydrocholesterol after cells are exposed to delipidated medium not only in typical patients, but also in an atypical case. The present method is a sensitive procedure for the biochemical diagnosis of this syndrome.

Honda M, Tint GS, Honda A, Nguyen LB, Chen TS, Shefer S.
7-Dehydrocholesterol down-regulates cholesterol biosynthesis in cultured Smith-Lemli-Opitz syndrome skin fibroblasts.
J Lipid Res 1998;39:647-657.
The Smith-Lemli-Opitz syndrome (SLOS) is a common birth defect-mental retardation syndrome caused by a defect in the enzyme that reduces 7-dehydrocholesterol to cholesterol. Because of this block, patients' plasma cholesterol levels are generally low while 7-dehydrocholesterol concentrations are markedly elevated. In addition, plasma total sterols are abnormally low and correlate negatively with the percent of 7-dehydrocholesterol (r = -0.65, P < 0.0001) suggesting that 7-dehydrocholesterol might inhibit the activity of HMG-CoA reductase. Cultured skin fibroblasts from SLOS patients grown in fetal bovine serum or for 1 day in delipidated medium contain little 7-dehydrocholesterol (3 +/- 1% of total sterols) and HMG-CoA reductase activities are indistinguishable from that measured in control cells. However, raising the 7-dehydrocholesterol concentration to 20 +/- 3% of total sterols, equal to the mean proportion in plasma of SLOS patients, by either growing cells for 1 week in delipidated medium or adding 20 microg/ml 7-dehydrocholesterol directly to the cells reduced HMG-CoA reductase activities from 74 +/- 7 to 9 +/- 2 pmol/min per mg protein, or from 92 +/- 22 to 16 +/- 4 pmol/min per mg protein, respectively (P < 0.01). In contrast, adding 20 microg/ml cholesterol evoked a 2- to 4-fold lesser suppression of activity (39 +/- 8 pmol/min per mg protein, P < 0.05, vs. 7-dehydrocholesterol). HMG-CoA synthase and LDL binding were inhibited equally by 7-dehydrocholesterol and cholesterol. Ketaconazole prevented the down-regulation of HMG-CoA reductase by 7-dehydrocholesterol, suggesting that an hydroxylated derivative of 7-dehydrocholesterol may be especially important in suppressing cholesterol synthesis. These results demonstrate that 7-dehydrocholesterol, perhaps as an hydroxylated derivative(s), is a very effective feedback inhibitor of HMG-CoA reductase.

Hyett JA, Clayton PT, Moscoso G, Nicolaides KH.
Increased first trimester nuchal translucency as a prenatal manifestation of Smith-Lemli-Opitz syndrome.
Am J Med Genet 1995;58:374-376.
Routine ultrasound examination at 11 weeks of gestation in a woman with no family history of genetic disease demonstrated increased accumulation of fluid in the fetal nuchal region. In view of the association of this defect with chromosomal abnormalities, fetal karyotyping was performed by chorion villus sampling and this demonstrated a normal 46,XY karyotype. Subsequent scans showed resolution of the nuchal fluid, and at the 20-week scan the fetal genitalia appeared to be female. Fetal blood sampling confirmed a normal male karyotype and fetoscopy confirmed the presence of female external genitalia. The parents elected to terminate the pregnancy, and postmortem findings were indicative of Smith-Lemli-Opitz syndrome. This was confirmed by the finding of increased levels of 7-dehydrocholesterol in cultured skin fibroblasts.

Ieshima A.
[Smith Lemli-Opitz syndrome]. [Review] [16 refs] [Japanese].
Ryoikibetsu Shokogun Shirizu 1996:302-304.

Ieshima A.
[Smith Lemli-Opitz syndrome]. [Review] [16 refs] [Japanese].
Ryoikibetsu Shokogun Shirizu 1996;15:302-304.

Irons M, Elias ER, Salen G, Tint GS, Batta AK.
Defective cholesterol biosynthesis in Smith-Lemli-Opitz syndrome [letter] [see comments].
Lancet 1993;341:1414.

Irons M, Elias ER, Tint GS, Salen G, Frieden R, Buie TM, Ampola M.
Abnormal cholesterol metabolism in the Smith-Lemli-Opitz syndrome: report of clinical and biochemical findings in four patients and treatment in one patient.
Am J Med Genet 1994;50:347-352.
We report on four patients with the Smith-Lemli-Opitz (SLO) syndrome who appear to have a defect in cholesterol biosynthesis. The initial results of therapy of one of the patients with cholesterol and bile acids to correct her metabolic abnormalities are described. This finding provides a biochemical marker to help in the diagnosis of this syndrome, may provide insight into the pathogenesis of this disorder, and have therapeutic and prenatal diagnostic implications as well.

Irons M, Elias ER, Abuelo D, Bull MJ, Greene CL, Johnson VP, Keppen L, Schanen C, Tint GS, Salen G.
Treatment of Smith-Lemli-Opitz syndrome: results of a multicenter trial.
Am J Med Genet 1997;68:311-314.
Patients with the RSH or Smith-Lemli-Optiz syndrome (SLOS) have an inborn error of cholesterol biosynthesis which results in a deficiency of cholesterol and an elevation of the cholesterol precursor, 7-dehydrocholesterol. A treatment protocol consisting of administration of cholesterol +/- bile acids was initiated in an attempt to correct the biochemical abnormalities seen. Fourteen patients (8 female, 6 male: ages 2 months to 15 years) have now been treated for 6-15 months. Three patients received cholesterol alone, while 11 patients received cholesterol and one or more bile acids. Biochemical improvement in sterol levels and in the ratio of cholesterol to total sterols was noted in all patients. The most marked improvement was noted in patients presenting with initial cholesterol levels < 40 mg/dl. No toxicity was observed. Clinical improvement in growth and neurodevelopmental status was also observed.

Irons MB, Tint GS.
Prenatal diagnosis of Smith-Lemli-Opitz syndrome. [Review] [16 refs].
Prenat Diagn 1998;18:369-372.

Iros JE, Sanchez GH.
[Smith-Lemli-Opitz syndrome]. [Spanish].
Arch Argent Pediatr 1970;68:23-28.

Itokazu N, Ohba K, Sonoda T, Ohdo S.
[Infantile spasms in monozygotic twins with Smith-Lemli-Opitz syndrome type I]. [Review] [22 refs] [Japanese].
No To Hattatsu 1992;24:485-490.
Monozygotic twins with Smith-Lemli-Opitz syndrome who developed infantile spasms were presented. They were the result of the first full-term pregnancy of non-consanguineous parents. They had following abnormalities: marked growth and developmental retardation, congenital heart disease, light brown hair which is rare in Japanese, small dolichocephaly, hypertelorism, anteverted nostrils, micrognathia, hypospadias and shawl scrotum. The cranial MRI showed the delayed myelination of occipital lobe. As far as we could review published reports, we were unable to find other report on monozygotic twins having the Smith-Lemli-Opitz syndrome. [References: 22]

Jira P, Wevers R, de Jong J, Rubio-Gozalbo E, Smeitink J.
New treatment strategy for Smith-Lemli-Opitz syndrome [letter].
Lancet 1997;349:1222.

Jira PE, de Jong JG, Janssen-Zijlstra FS, Wendel U, Wevers RA.
Pitfalls in measuring plasma cholesterol in the Smith-Lemli-Opitz syndrome.
Clin Chem 1997;43:129-133.
Correct quantitative results for plasma cholesterol, 7-dehydrocholesterol (7-DHC), and 8-dehydrocholesterol (8-DHC) are invaluable for making the correct diagnosis in patients with the Smith-Lemli-Opitz syndrome (SLO) and for biochemical monitoring of these patients during therapy. The enzymatic method for cholesterol measurement based on cholesterol oxidase gives falsely high values for plasma cholesterol in samples from patients with SLO. Both 7-DHC and 8-DHC contribute substantially to the test result, given that they are accepted substrates of cholesterol oxidase. All cholesterol methods making use of this enzyme are expected to give unreliable results with plasma samples from SLO patients. Cholesterol values found with these methods may be low-normal in individual cases with SLO. Therefore, other techniques for measuring cholesterol, 7-DHC, and 8-DHC, e.g., gas chromatography, should be used for diagnosing these patients and for follow-up during therapy. However, a normal value for plasma cholesterol, as obtained by gas chromatography, does not exclude SLO. The diagnosis should always be confirmed or excluded by testing for the presence of high concentrations of 7-DHC and 8-DHC in plasma. We found that one patient with a severe form of the disease had a plasma cholesterol concentration of 20 micromol/L-to our knowledge, the lowest value ever recorded in a human being.

Johnson VP.
Smith-Lemli-Opitz syndrome: review and report of two affected siblings.
Z Kinderheilkd 1975;119:221-234.
This paper reports two siblings with the Smith-Lemli-Opitz syndrome and reviews the literature on the subject. SLOS is a syndrome of multiple congenital anomalies with mental and growth retardation, unusual facies, genito-urinary and hand and foot abnormalities inherited as an autosomal recessive trait.

Johnson JA, Aughton DJ, Comstock CH, von Oeyen PT, Higgins JV, Schulz R.
Prenatal diagnosis of Smith-Lemli-Opitz syndrome, type II [see comments].
Am J Med Genet 1994;49:240-243.
Smith-Lemli-Opitz syndrome, type II (SLOS-II) is a severe autosomal recessive disorder characterized by a distinctive face, unusual cleft palate, postaxial polydactyly, congenital heart defects, renal anomalies, and male pseudohermaphroditism. We present the first report of prenatal diagnosis of SLOS-II, as well as an additional report of prenatal detection of multiple anomalies, in which a positive diagnosis of SLOS II was made postnatally. In neither case was the pregnancy known prospectively to be at risk for SLOS-II. In the former case, targeted sonographic examination at 31 weeks of gestation showed intrauterine growth retardation, atrioventricular septal defect, mesomelic shortening of the arms, small kidneys, overlapping fingers, and female external genitalia; a 46,XY chromosome constitution had been ascertained previously. A provisional diagnosis of SLOS-II was made prenatally. In the latter case, targeted sonographic examination at 18 weeks of gestation showed severe oligohydramnios, atrioventricular septal defect, and Dandy-Walker malformation. The kidneys and bladder were not visualized. The chromosome constitution was 46,XX. The diagnosis of SLOS-II was made postnatally. In both cases, additional findings compatible with SLOS-II were noted postnatally. Prenatal detection of congenital heart defects and renal abnormalities, in combination with certain additional findings (most notably, female external genitalia in the presence of a 46,XY karyotype, polydactyly, disproportionately short limbs, or intrauterine growth retardation) and a normal karyotype, suggests the diagnosis of SLOS-II, and warrants further investigation.

Joseph DB, Uehling DT, Gilbert E, Laxova R.
Genitourinary abnormalities associated with the Smith-Lemli-Opitz syndrome.
J Urol 1987;137:719-721.
The Smith-Lemli-Opitz syndrome is characterized by mental retardation, hypotonia, facial dysmorphism and abnormalities of the limbs, genitalia and kidneys. Since the latter 2 features have not been emphasized in the urological literature, the experience from the institution at which the syndrome was first described is reviewed and an illustrative case is reported. Upper urinary tract abnormalities were noted in 57 per cent and genital abnormalities in 71 per cent of the children evaluated.

Judge CG, Chakanovskis JE, Sutherland GR.
The Smith-Lemli-Opitz syndrome.
Med J Aust 1971;2:145-147.

Juttnerova V, Balicek P.
[The Smith-Lemli-Opitz syndrome in a 2-months-old boy]. [Czech].
Sb Ved Pr Lek Fak Karlovy Univerzity Hradci Kralove Suppl 1977;20:473-477.

Kandutsch AA, Russell AE.
Preputial gland tumor sterols. III. A metabolic pathway from lanosterol to cholesterol.
Journal of Biological Chemistry 1960;235:2256-2261.

Karsten J, Kosztolanyi G.
Smith-Lemli-Opitz syndrome in siblings.
Acta Paediatr Hung 1992;32:127-134.
This paper presents two brothers with incomplete expression of the Smith-Lemli-Opitz syndrome. A definite diagnosis, made after the birth of the second child, could only be reached when the clinical features of both patients were combined.

Kelley RI.
Quantification of 3-methylglutaconic acid in urine, plasma, and amniotic fluid by isotope-dilution gas chromatography/mass spectrometry.
Clin Chim Acta 1993;220:157-164.
A method is described for quantification of the trace metabolite, 3-methylglutaconic acid, by isotope-dilution gas chromatography/mass spectrometry using synthetic 3-[2,4,6-13C3]methylglutaconic acid. Results are shown for quantification of 3-methylglutaconic acid in plasma, urine, cerebrospinal fluid and amniotic fluid for both normal controls and patients with different forms of 3-methylglutaconic aciduria. A simple method for the synthesis and purification of 3-[2,4,6-13C3]methylglutaconic acid is also described.

Kelley RI.
Diagnosis of Smith-Lemli-Opitz syndrome by gas chromatography/mass spectrometry of 7-dehydrocholesterol in plasma, amniotic fluid and cultured skin fibroblasts.
Clin Chim Acta 1995;236:45-58.
A method is described for quantification of 7-dehydrocholesterol (7DHC) and other neutral sterols by gas chromatography/mass spectrometry for diagnosis of Smith-Lemli-Opitz syndrome, an apparent primary defect of cholesterol biosynthesis associated with low plasma levels of cholesterol and high levels of its precursor, 7DHC. Results are summarized for specimens from normal controls and from 40 patients with Smith-Lemli-Opitz syndrome (SLOS). Whereas the concentration of 7DHC (as a combined peak of 7DHC and iso-7DHC) in normal infant plasma was found to be 0.10 +/- 0.05 (S.D.) microgram/ml, the level in patients with SLOS ranged from 2.7 to 470 micrograms/ml, or from 10 to more than 2000 times the upper limit of normal. Patients with milder type I SLOS as well as those with the more severe type II SLOS were found to have the same sterol abnormality. Although most infants with SLOS had plasma cholesterol levels lower than 400 micrograms/ml (40 mg/dl), several older children with only mildly increased levels of 7DHC had normal plasma cholesterol levels. Diagnostically useful, comparably increased levels of 7DHC were found in amniotic fluid and cultured skin fibroblasts from patients with SLOS. More mildly increased levels of 7DHC were also found in both plasma and cultured skin fibroblasts of SLOS heterozygotes. The method described uses capillary columns and GC/MS instrumentation available in most biochemical genetics laboratories and should prove useful not only for diagnosis and prenatal diagnosis of Smith-Lemli-Opitz syndrome, but also for identification of other possible inborn errors of sterol biosynthesis.

Kelley RI, Kratz L.
3-methylglutaconic acidemia in Smith-Lemli-Opitz syndrome.
Pediatr Res 1995;37:671-674.
The branched-chain organic acid, 3-methylglutaconic acid, is an intermediate (as the CoA thioester) in the leucine degradative pathway as well as the mevalonate shunt, a pathway that links isoprenoid metabolism with mitochondrial acetyl-CoA metabolism. Because the majority of patients with abnormal 3-methylglutaconic aciduria or acidemia appear to have normal leucine metabolism, we have speculated that some patients with 3-methylglutaconic aciduria may have defects of polyisoprenoid or sterol biosynthesis leading to overflow of isoprenoid precursors to 3-methylglutaconate via the mevalonate shunt. We therefore measured plasma levels of 3-methylglutaconic acid in patients with a known defect of sterol biosynthesis, Smith-Lemli-Opitz syndrome, and found that the patients with the lowest cholesterol levels had abnormally increased plasma levels of 3-methylglutaconic acid, similar in magnitude to those of patients with idiopathic 3-methylglutaconic aciduria. This finding suggests that some patients with unexplained 3-methylglutaconic aciduria may have defects of isoprenoid or sterol biosynthesis underlying their abnormal organic aciduria.

Kelley RL, Roessler E, Hennekam RC, Feldman GL, Kosaki K, Jones MC, Palumbos JC, Muenke M.
Holoprosencephaly in RSH/Smith-Lemli-Opitz syndrome: does abnormal cholesterol metabolism affect the function of Sonic Hedgehog?
Am J Med Genet 1996;66:478-484.
The RSH/Smith-Lemli-Opitz syndrome (RSH/SLOS) is an autosomal recessive malformation syndrome associated with increased levels of 7-dehydro-cholesterol (7-DHC) and a defect of cholesterol biosynthesis at the level of 3 beta-hydroxy-steroid-delta7-reductase (7-DHC reductase). Because rats exposed to inhibitors of 7-DHC reductase during development have a high frequency of holoprosencephaly (HPE) [Roux et al., 1979], we have undertaken a search for biochemical evidence of RSH/SLOS and other possible defects of sterol metabolism among patients with various forms of HPE. We describe 4 patients, one with semilobar HPE and three others with less complete forms of the HPE sequence, in whom we have made a biochemical diagnosis of RSH/SLOS. The clinical and biochemical spectrum of these and other patients with RSH/SLOS suggests a role of abnormal sterol metabolism in the pathogenesis of their malformations. The association of HPE and RSH/SLOS is discussed in light of the recent discoveries that mutations in the embryonic patterning gene, Sonic Hedgehog (SHH), can cause HPE in humans and that the sonic hedgehog protein product undergoes autoproteolysis to form a cholesterol-modified active product. These clinical, biochemical, and molecular studies suggest that HPE and other malformations in SLOS may be caused by incomplete or abnormal modification of the sonic hedgehog protein and, possible, other patterning proteins of the hedgehog class, a hypothesis testable in somatic cell systems.

Kempen HJM, Glatz JFC, Gevers-Leuven JA, van der Voort HA, Katan MB.
Serum lathosterol is an indicator of whole-body cholesterol synthesis in humans.
Journal of Lipid Research 1988;29:1149-1156.

Kenis H, Hustinx TW.
A familial syndrome of mental retardation in association with multiple congenital anomalies resembling the syndrome of Smith-Lemli-Opitz.
Maandschr Kindergeneeskd 1967;35:37-48.

Kim EH, Boutwell WC.
Smith-Lemli-Opitz syndrome associated with Hirschsprung disease, 46,XY female karyotype, and total anomalous pulmonary venous drainage [letter].
J Pediatr 1985;106:861.

Kofer J.
[Differential diagnosis of mentally retarded children--report of 2 cases on the Smith-Lemli-Opitz syndrome (letter)]. [Czech].
Cesk Pediatr 1976;31:465-466.

Kohler HG.
Brief clinical report: familial neonatally lethal syndrome of hypoplastic left heart, absent pulmonary lobation, polydactyly, and talipes, probably Smith-Lemli-Opitz (RSH) syndrome.
Am J Med Genet 1983;14:423-428.
Two siblings, one a male pseudohermaphrodite and the other female, died on the first day of life. In both instances pregnancy was complicated by polyhydramnios. At autopsy each was found to have multiple abnormalities, some concordant, others discordant. The concordant ones were hypoplastic left-heart complex, absent pulmonary lobation, polydactyly, bilateral talipes, and, on microscopic examination, some large atypical cells in the pancreatic islets. Chromosome cultures failed to grow. As far as is known parents were unrelated. Autosomal recessive inheritance is considered a possible cause, and the infants are thought to have the most severe form of the so-called Smith-Lemli-Opitz (RSH) Syndrome.

Kolf-Clauw M, Chevy F, Wolf C, Siliart B, Citadelle D, Roux C.
Inhibition of 7-dehydrocholesterol reductase by the teratogen AY9944: a rat model for Smith-Lemli-Opitz syndrome.
Teratology 1996;54:115-125.
Our aim is to verify the validity of a rat model proposed for Smith-Lemli-Opitz (SLO) syndrome, a developmental disorder characterized by a defect in 7-dehydrocholesterol-delta 7 (7DHC)-reductase and by facial dysmorphism close to the holoprosencephaly caused by the teratogen AY9944. We investigated the sterol profile in rats treated with AY9944 blocking 7DHC-reductase. AY9944 was given orally to rats on gestation day 3 (D3). The sera were sampled for kinetic data on D3, D6, D9, D12, and D21. Cholesterol was measured in parallel by the routine enzymatic method and by the gas chromatography/mass spectrometry (GC-MS) procedure used in SLO diagnosis. In addition to sterols, we dosed steroid hormones punctually on D4 and on D10, and examined D21 fetuses in other animals. The enzymatic method was not specific for cholesterol, and measured 70% pure 7DHC added to a normal serum. On D21, 77% live fetuses showed pituitary agenesis. Cholesterol was rapidly reduced by more than 50% on D6 involving an accumulation of 7DHC, 8DHC, and trienols, as identified in SLO-affected children. The most abundant 7DHC reached a maximum from D9 to D12, equaling cholesterol on D9 (11 mg/dl). On D10, the magnitudes of hypocholesterolemic and of 7DHC accumulation were found to be dose-dependent. Progesterone was reduced as early as 24 hr after treatment and dropped to 40% of the levels in the controls on D10, correlating to the decrease in cholesterolemia. This rat model reproduces the same biochemical perturbations as seen in SLO, strongly suggesting that aberrant sterols (7DHC, 8DHC, or nortrienol) may contribute to the developmental defects.

Kolf-Clauw M, Chevy F, Siliart B, Wolf C, Mulliez N, Roux C.
Cholesterol biosynthesis inhibited by BM15.766 induces holoprosencephaly in the rat.
Teratology 1997;56:188-200.
To confirm that blocking 7-dehydrocholesterol delta 7 reductase (7DHC reductase), as observed in Smith-Lemli-Opitz syndrome (SLOS), induces craniofacial defects, we tested BM15.766, which blocks 7DHC reductase but is chemically unrelated to the holoprosencephaly-inducing teratogen AY9944. Rats were given BM15.766 either in methylcellulose from days (D) 1 through D11 (3 treated groups: protocol A) or in olive oil from D4 through D7 (300 mg/kg/d: protocol B). The sera were sampled on D0, D3, and D5 or D6, D10, D14, and D21 to measure cholesterol and dehydrocholesterols in all groups and steroid hormones in protocol B. D21 fetuses showed the holoprosencephaly spectrum of malformations and the treated dams low cholesterol and accumulation of 7DHC, 8DHC, and trienols, as in SLOS-affected children. In the 3 dosage groups the malformations were dose-related and enzymatic cholesterol decreased to a plateau. The DHC reached 25-44% of the total sterols in the dams. In protocol B, one-third of the BM15.766-treated fetuses presented facial malformations and almost two-thirds pituitary agenesis. On D10, cholesterol reached a minimum and the DHC a maximum while estradiol 17 beta and progesterone were lowered, the latter decreasing in correlation with cholesterolemia. A sterol profile similar to that previously observed after AY9944 associated with a similarly high incidence of pituitary agenesis confirmed that time-limited inhibition of 7DHC reductase induces holoprosencephaly and that pituitary agenesis is the minor form of holoprosencephaly.

Kolf-Clauw M, Chevy F, Ponsart C.
Abnormal cholesterol biosynthesis as in Smith-Lemli-Opitz syndrome disrupts normal skeletal development in the rat [see comments].
J Lab Clin Med 1998;131:222-227.
Smith-Lemli-Opitz syndrome (SLOS) in human infants is a common autosomal recessive malformation syndrome (estimated incidence, 1:20,000). It is characterized clinically by congenital anomalies, especially craniofacial and limb defects, and biochemically by a defect in 7-dehydrocholesterol-delta7-reductase activity (7DHC-reductase), the final enzyme in cholesterol biosynthesis. In previous studies, early administration of the 7DHC-reductase inhibitor AY9944 to pregnant rats resulted in a high frequency of holoprosencephaly, relevant to craniofacial anomalies of SLOS. In order to test the effect of AY9944 on limb development, we treated dams on gestation day 7 (GD7), which delays the biochemical defect to about GD13 to GD14. Sera were sampled on GD12, GD14, and GD21 and cholesterol and dehydrocholesterols (7DHC and 8DHC) were measured by gas-chromatography-mass spectrometry (GC-MS), as for the diagnosis of SLOS. GD21 fetuses were examined for gross malformations and skeletal development. In treated dams, the SLOS biochemical marker 7DHC accounted for one fourth and one third of total sterols, respectively, on GD12 and GD14, and cholesterolemia on these two gestation days was reduced by 50% and 43%, respectively, as compared with control values. This maternal metabolic defect was associated with decrease in fetal weight and delayed ossification. In addition, scapular malformations were observed in four fetuses from three litters. The malformations could have been caused by the same mechanism as holoprosencephaly after early treatment with AY9944. These cholesterol-deficiency-based malformations could have a common cause in the abnormal expression of Hedgehog or other developmental gene proteins, and may thus explain various congenital polymalformative syndromes in humans, including SLOS.

Komatsu H, Tosaki Y, Ogli K, Yokono S.
[Anesthetic management of a patient with Smith-Lemli-Opitz syndrome]. [Japanese].
Masui 1987;36:1450-1453.

Krajewska-Walasek M.
One more case of a severe lethal condition resembling the Smith-Lemli-Opitz, type II syndrome.
Genet Couns 1991;2:221-225.
A male child with a lethal multiple congenital anomaly syndrome of facial dysmorphism, ambiguous genitalia, syndactyly and postaxial polydactyly is presented. He had findings consistent with the diagnosis of Smith-Lemli-Opitz type II syndrome. Similar changes were observed in his elder sister, who died when she was 2 months old. On the basis of this familial observation the nosology of Smith-Lemli-Opitz syndrome is discussed.

Kretzer FL, Hittner HM, Mehta RS.
Ocular manifestations of the Smith-Lemli-Opitz syndrome.
Arch Ophthalmol 1981;99:2000-2006.
To our knowledge, this article describes the first ocular histopathologic condition of a Smith-Lemli-Opitz proband, despite almost 60 clinical histories that exist in the literature. The sole retinal abnormality in this 1-month-old infant with congenital bilateral cataracts is the extensive dropout of peripheral ganglion axons with incipient optic nerve demyelination. Unusual amorphous cytoplasmic masses that are continuous with photoreceptor discs are prominent aspects of the peripheral subretinal space. The morphological data imply that the localized mitochondrial disintegration is restricted to the corneal endothelium and retinal pigment epithelium and is an important element in the etiology. All children who fail to thrive with vomiting, are mentally deficient, have anteverted nostrils, broad maxillary alveolar ridges, syndactyly of the second and third toes, and ambiguous genitalia should be carefully screened for incipient corneal endothelial changes, mild cataracts, and peripheral retinal changes.

Lachman MF, Wright Y, Whiteman DA, Herson V, Greenstein RM.
Brief clinical report: a 46,XY phenotypic female with Smith-Lemli-Opitz syndrome.
Clin Genet 1991;39:136-141.
A phenotypic female infant with Smith-Lemli-Opitz (SLO) syndrome was found to have a 46,XY karyotype. Autopsy showed normal tests for age and normal Wolffian duct structures. The serum testosterone level was unusually high, suggesting that the failure of virilization of the external genitalia in the child might be due to a defect in testosterone conversion to dihydrotestosterone or a lack of end-organ receptors for the same. An additional feature not previously described in association with SLO syndrome was present, which was clinical hypoglycemia with nesidioblastosis.

Lacombe D, Battin J.
Gonadal function in Smith-Lemli-Opitz syndrome [letter; comment].
Am J Med Genet 1993;45:119.

Lange Y.
Cholesterol movement from plasma membrane to rough endoplasmic reticulum. Inhibition by progesterone.
J Biol Chem 1994;269:3411-3414.
The effect of progesterone on the movement of sterols from the cell surface to the rough endoplasmic reticulum (ER) was examined in rat hepatoma cells. Plasma membranes were labeled exogenously with [3H]cholesterol or [3H]zymosterol. Translocation of the labeled sterols to the rough ER was inferred from their conversion to [3H]cholesteryl esters and [3H]cholesterol, respectively. Progesterone inhibited both of these reactions by more than 90%. The concentration for half-maximal inhibition was 0.7 microgram/ml. Progesterone did not inhibit acyl- CoA:cholesterol acyltransferase activity itself, since the steroid had no effect on the esterification of [3H]cholesterol synthesized in vitro in the rough ER from [3H]zymosterol. Moreover, the small amount of [3H]cholesterol synthesized from plasma membrane [3H]zymosterol in progesterone-treated intact cells was esterified at the same fractional rate as cholesterol in control cells. Subcellular fractionation of cells pulse-labeled with [3H]cholesterol and treated with progesterone suggested that the block in plasma membrane cholesterol transfer to the rough ER occurred at the level of the plasma membrane.

Lanoue L, Dehart DB, Hinsdale ME, Maeda N, Tint GS, Sulik KK.
Limb, genital, CNS, and facial malformations result from gene/environment-induced cholesterol deficiency: further evidence for a link to sonic hedgehog.
Am J Med Genet 1997;73:24-31.
Low cholesterol levels produced by treating cholesterol deficient mutant mice with a cholesterol synthesis inhibitor (BM 15.766) between days 4 to 7 of pregnancy resulted in malformations consistent with those in the Smith-Lemli-Opitz syndrome (SLOS). Facial anomalies in mildly affected gestational day 12 mouse embryos included a small nose and long upper lip; in more severely affected embryos, the facial and forebrain anomalies are representative of holoprosencephaly. Additionally, abnormalities of the mid- and hind-brain were observed and included stenosis of the cerebral aqueduct at the level of the isthmus and apparent absence of the organ progenitor for the cerebellar vermis. Although not previously directly linked to cholesterol deficiency in experimental animals, limb and external genital defects were a notable outcome in this multifactorially-based cholesterol deficiency model. The results of this study provide new evidence supporting an important role for cholesterol in early embryonic development, provide additional support for the hypothesis that this role may involve the function of specific gene products, such as sonic hedgehog (shh) signaling protein, and provide a description of the pathogenesis of some of the characteristic malformations in SLOS.

Le Merrer M, Briard ML, Chauvet ML.
[An unrecognized etiology of sexual ambiguity: Smith-Lemli-Opitz syndrome or a new entity?]. [French].
J Genet Hum 1987;35:187-193.
The authors report three cases of a new syndrome which characteristic anomalies are facial dysmorphism with anteverted nose, down slanting palpebral fissures, ptosis, severe microretrognatia, polydactyly. The authors insist on the particular severe genital anomalies, the failure to thrive and the constant lethal issue. The authors discuss the diagnosis of Smith-Lemli-Opitz syndrome and suggest the possibility of a new entity always confounded with others associations characterized by a polydactyly and a sexual reversion in male.

Le Merrer M.
Acrodysgenital dwarfism or Smith-Lemli-Opitz type II syndrome [letter].
Clin Genet 1991;40:252.

Lee JJ, von Kessler DP, Parks S, Beachy PA.
Secretion and localized transcription suggest a role in positional signaling for products of the segmentation gene hedgehog.
Cell 1992;71:33-50.

Lendvai D, Castello MA, Ballati G.
[Two malformative syndromes possibly unifiable: Ullrich-Feichtiger and Smith-Lemli-Opitz syndromes. Case report]. [Italian].
Minerva Pediatr 1969;21:56-61.

Lin AE, Ardinger HH, Ardinger RH, Jr., Cunniff C, Kelley RI.
Cardiovascular malformations in Smith-Lemli-Opitz syndrome. [Review] [102 refs].
Am J Med Genet 1997;68:270-278.
We reviewed 215 patients (59 new, 156 from the literature) with Smith-Lemli-Opitz syndrome (SLOS), and found that 95 (44%) had a cardiovascular malformation (CVM). Classifying CVMs by disordered embryonic mechanisms, there were 5 (5.3%) class 1 (ectomesenchymal tissue migration abnormalities), 56 (58.9%) class II (abnormal intracardiac blood flow), 25 (26.3%) class IV (abnormal extracellular matrix), and 5 (5.3%) class V (abnormal targeted growth). Comparing the frequencies of individual CVMs in this series with a control group (the Baltimore-Washington Infant Study), there were 6 individual CVMs which showed a significant difference from expected values. When frequencies of CVMs in SLOS were analyzed by mechanistic class, classes IV and V were significantly more frequent, and class I significantly less frequent, than the control group. Although CVMs in SLOS display mechanistic heterogeneity, with an overall predominance of class II CVMs, the developmental error appears to favor alteration of the cardiovascular developmental mechanisms underlying atrioventricular canal and anomalous pulmonary venous return. This information should assist the clinical geneticist evaluating a patient with possible SLOS, and should suggest research direction for the mechanisms responsible for the SLOS phenotype. [References: 102]

Lipson A, Hayes A.
Smith-Lemli-Opitz syndrome and Hirschsprung disease [letter].
J Pediatr 1984;105:177.

Llirbat B, Wolf C, Chevy F, Citadelle D, Bereziat G, Roux C.
Normal and inhibited cholesterol synthesis in the cultured rat embryo.
J Lipid Res 1997;38:22-34.
The Smith-Lemli-Opitz syndrome-affected fetus presents a deficiency in delta7-dehydrocholesterol reductase, the last enzymatic step in the cholesterol biosynthesis pathway. Development of the abnormal human fetus takes place in a normal environment as the heterozygous mother's cholesterolemia remains normal. An animal model for this disease has been obtained from the offspring of pregnant rats treated with "distal" inhibitors of delta7-dehydrocholesterol reductase, AY-9944 or BM15766. In the animal model, embryonic development occurs in a disturbed environment characterized by hypocholesterolemia and accumulation of delta7-dehydrocholesterol and delta8-dehydrocholesterol in the maternal serum. The purpose of the present study was to assess, in cultured rat embryos at early developmental stages, the relative contributions of exogenous and de novo synthesized cholesterol in the total embryonic cholesterol, according to the conditions of normal and altered de novo biosynthesis. Cultured rat embryos are able to synthesize cholesterol as shown by 13C-incorporation into cholesterol from 13C-labeled precursors added to the culture medium. De novo cholesterol biosynthesis is altered by addition to the culture medium of AY-9944 which inhibits the delta7-dehydrocholesterol reductase and the delta8-delta7-sterol isomerase as suggested by the emergence of characteristic aberrant sterols in the embryonic tissues. Cholesterol-rich serum used for embryo culture alters the pattern in a way that confirms that the rat embryos are able to import exogenous cholesterol which down-regulates de novo cholesterol biosynthesis. Exogenous cholesterol substitutes for the deficit in a manner efficient enough to prevent the embryonic abnormalities induced by AY-9944.

Lowry RB, Miller JR, MacLean JR.
Micrognathia, polydactyly, and cleft palate.
Journal of Pediatrics 1968;72:859-861.

Lowry RB, Yong SL.
Borderline normal intelligence in the Smith-Lemli-Opitz (RSH) syndrome.
Am J Med Genet 1980;5:137-143.
We report two sibs with the Smith-Lemli-Opitz (RSH) syndrome and intelligence in the borderline normal range. The proposita has all the features of the syndrome; however, her brother shows fewer signs, indicating that considerable variability of expression may exist for this autosomal recessive trait. Nearly all previous cases had severe to profound mental retardation. The incidence of the syndrome in British Columbia is approximately 1/40,000 live births, giving a heterozygote frequency of about 1/100.

Lowry RB.
Editorial comment: variability in the Smith-Lemli-Opitz syndrome: overlap with the Meckel syndrome.
Am J Med Genet 1983;14:429-433.

Lund E, Starck L, Venizelos N.
Detection of defective 3 beta-hydroxysterol delta 7-reductase activity in cultured human fibroblasts: a method for the diagnosis of Smith-Lemli-Opitz syndrome.
J Inherit Metab Dis 1996;19:59-64.
Patients with the autosomal recessive disorder Smith-Lemli-Optiz syndrome (SLO) have recently been shown to have markedly increased tissue levels of certain cholesterol biosynthesis intermediates, most notably 7-dehydrocholesterol. The findings strongly suggest a block in the step that catalyses reduction of 7-dehydrocholesterol to cholesterol. The accumulation of 7-dehydrocholesterol can generally easily be detected in serum by gas chromatography-mass spectrometry. However, it could not be totally ruled out that SLO patients with less severe enzyme defects could escape detection by this method. A more direct way of diagnosing a defect in 7-dehydrocholesterol reduction would be to assay the conversion of 7-dehydrocholesterol to cholesterol in cultured fibroblasts from patients with suspected SLO. In the present work, an assay for the conversion of [3H]lathosterol to [3H]cholesterol in cultured human fibroblasts is described. Lathosterol is the immediate precursor of 7-dehydrocholesterol in the cholesterol biosynthetic pathway and was chosen for the assay instead of 7-dehydrocholesterol owing to the difficulty in preparation and handling of the latter compound. Fibroblasts from control subjects converted [3H]lathosterol to [3H]cholesterol efficiently, whereas in fibroblasts from SLO patients the conversion did not go beyond 7-dehydrocholesterol. It is concluded that the present method is useful for the diagnosis of SLO.

Marion RW, Alvarez LA, Marans ZS, Lantos G, Chitayat D.
Computed tomography of the brain in the Smith-Lemli-Opitz syndrome.
J Child Neurol 1987;2:198-200.
Computed tomographic (CT) scans of the brain in a child with Smith-Lemli-Opitz syndrome revealed enlargement of the ventricular system, hypoplasia of the cerebellum, and abnormal thickening of the gray matter, consistent with pachygyria. These findings have been previously noted in autopsies performed on patients with this disorder. We conclude that CT scanning is a valuable tool in the evaluation of children suspected of having the Smith-Lemli-Opitz syndrome.

McGaughran J, Donnai D, Clayton P, Mills K.
Diagnosis of Smith-Lemli-Opitz syndrome [letter; comment].
N Engl J Med 1994;330:1685-1686; discussion 1687.

McGaughran JM, Clayton PT, Mills KA, Rimmer S, Moore L, Donnai D.
Prenatal diagnosis of Smith-Lemli-Opitz syndrome.
Am J Med Genet 1995;56:269-271.
An abnormality in cholesterol synthesis was described recently in the Smith-Lemli-Opitz (SLO) syndrome. Here we describe how the application of this finding has enabled an accurate prenatal diagnosis. We also discuss the possible use of this test in detecting heterozygotes.

McKeever PA, Young ID.
Smith-Lemli-Opitz syndrome. II: A disorder of the fetal adrenals?
J Med Genet 1990;27:465-466.
Two cases of Smith-Lemli-Opitz syndrome type II are presented. During the late stages of both pregnancies maternal oestriol levels were unrecordable and there was evidence of suppression of maternal adrenal function. We speculate on the existence of a primary defect in the fetal adrenals.

Meinecke P, Blunck W, Rodewald A.
Smith-Lemli-Opitz syndrome.
Am J Med Genet 1987;28:735-739.

Merrer ML, Briard ML, Girard S, Mulliez N, Moraine C, Imbert MC.
Lethal acrodysgenital dwarfism: a severe lethal condition resembling Smith-Lemli-Opitz syndrome. [Review] [34 refs].
J Med Genet 1988;25:88-95.
We report eight cases of a lethal association of failure to thrive, facial dysmorphism, ambiguous genitalia, syndactyly, postaxial polydactyly, and internal developmental anomalies (Hirschsprung's disease, cardiac and renal malformation). This syndrome is likely to be autosomal recessive and resembles Smith-Lemli-Opitz (SLO) syndrome. However, the lethality, the common occurrence of polydactyly, and the sexual ambiguity distinguishes this condition from SLO syndrome. A review of published reports supports the separate classification of this syndrome for which we propose the name lethal acrodysgenital dwarfism. [References: 34]

Metzke H, Lassig W, Kohler H.
[Smith-Lemli-Opitz syndrome]. [German].
Padiatr Padol 1972;7:259-266.

Mills K, Mandel H, Montemagno R, Soothill P, Gershoni-Baruch R, Clayton PT.
First trimester prenatal diagnosis of Smith-Lemli-Opitz syndrome (7-dehydrocholesterol reductase deficiency).
Pediatr Res 1996;39:816-819.
In Smith-Lemli-Opitz syndrome (SLOs), 7-dehydrocholesterol (7-DHC) accumulated because there is a block in the pathway for synthesis of cholesterol via 7-DHC. Prenatal diagnosis of SLOs has been achieved by analysis of 7-DHC in amniotic fluid obtained at 16-18 wk from pregnancies at risk. The purpose of this study was to investigate 7-DHC and cholesterol concentrations in chorionic villus (CV) samples with a view to performing first trimester prenatal diagnosis. Using a sensitive gas chromatography-mass spectrometry assay it was possible to detect 7-DHC in CV samples obtained as early as 7 wk of gestation. The ration of 7-DHC to cholesterol in placental tissue was shown to be relatively constant over the gestational period of 7-18 wk. We therefore proceeded to analyze the 7-DHC/cholesterol ration in CV samples taken at 10-12 wk of gestation from three pregnancies at risk for SLOs. The results were as follows: patient A, 1.10 x 10(-3); patient B, 1.80 x 10(-3); patient C, 0.091; control range for CVS (8-12 wk), 3.10 x 10(-4) to 1.62 x 10(-3) (mean +/- 2SD; n = 5). The fetus of patient C was diagnosed as affected by SLOs, and the parents requested termination. Analysis of cultured skin fibroblasts confirmed the diagnosis. Pregnancies A and B were diagnosed unaffected, and this was confirmed first by amniocentesis and then by the birth of normal infants at term. We conclude that synthesis of cholesterol via 7-DHC is occurring in the placenta and/or fetus at 10 wk of gestation and that prenatal diagnosis by CV biopsy is possible.

Ming JE, Roessler E, Muenke M.
Human developmental disorders and the Sonic hedgehog pathway [In Process Citation].
Mol Med Today 1998;4:343-349.
Sonic hedgehog (Shh) is a morphogen that is crucial for normal development of a variety of organ systems, including the brain and spinal cord, the eye, craniofacial structures, and the limbs. Mutations in the human SHH gene and genes that encode its downstream intracellular signaling pathway cause several clinical disorders. These include holoprosencephaly (HPE, the most common anomaly of the developing forebrain), nevoid basal cell carcinoma syndrome, sporadic tumors, including basal cell carcinomas, and three distinct congenital disorders: Greig syndrome Pallister-Hall syndrome, and isolated postaxial polydactyly. These conditions caused by abnormalities in the SHH pathway demonstrate the crucial role of SHH in complex developmental processes, and molecular analyses of these disorders provide insight into the normal function of the SHH pathway in human development.

Mizushima A, Satoyoshi M.
[Unusual responses of muscular rigidity and hypothermia to halothane and succinylcholine; a case report of Smith-Lemli-Opitz (SLO) syndrome]. [Japanese].
Masui 1988;37:1118-1123.

Moebius FF, Bermoser K, Reiter RJ, Hanner M, Glossmann H.
Yeast sterol C8-C7 isomerase: identification and characterization of a high-affinity binding site for enzyme inhibitors.
Biochemistry 1996;35:16871-16878.
The yeast gene ERG2 encodes a sterol C8-C7 isomerase and is essential for ergosterol synthesis and cell proliferation. Its striking homology with the so-called sigma1 receptor of guinea pig brain, a polyvalent steroid and drug binding protein, suggested that the yeast sterol C8-C7 isomerase (ERG2) carries a similar high affinity drug binding domain. Indeed the sigma ligands [3H]haloperidol (Kd = 0.3 nM) and [3H]ifenprodil (Kd = 1.4 nM) bound to a single population of sites in ERG2 wild type yeast microsomes (Bmax values of 77 and 61 pmol/mg of protein, respectively), whereas binding activity was absent in strains carrying ERG2 gene mutations or disruptions. [3H]Ifenprodil binding was inhibited by sterol isomerase inhibitors such as fenpropimorph (Ki = 0.05 nM), tridemorph (Ki = 0.09 nM), MDL28,815 (Ki = 0.44 nM), triparanol (Ki = 1.5 nM), and AY-9944 (Ki = 5.8 nM). [3H]Haloperidol specifically photoaffinity-labeled a protein with an apparent molecular weight of 27400, in agreement with the molecular mass of the sterol C8-C7 isomerase (24900 Da). 9E10 c-myc antibodies specifically immunoprecipitated the c-myc tagged protein after [3H]haloperidol photolabeling, unequivocally proving that the drug binding site is localized on the ERG2 gene product. Haloperidol, trifluperidol, and ifenprodil inhibited the growth of Saccharomyces cerevisiae and reduced the ergosterol content of cells grown in their presence. Our results demonstrate that the yeast sterol C8-C7 isomerase has a polyvalent high-affinity drug binding site similar to mammalian sigma receptors and that in yeast sigma ligands inhibit sterol biosynthesis.

Moebius FF, Striessnig J, Glossmann H.
The mysteries of sigma receptors: new family members reveal a role in cholesterol synthesis. [Review].
Trends Pharmacol Sci 1997;18:67-70.

Moebius FF, Fitzky BU, Lee JN, Paik YK, Glossmann H.
Molecular cloning and expression of the human delta7-sterol reductase.
Proc Natl Acad Sci U S A 1998;95:1899-1902.
Inhibitors of the last steps of cholesterol biosynthesis such as AY9944 and BM15766 severely impair brain development. Their molecular target is the Delta7-sterol reductase (EC, suspected to be defective in the Smith-Lemli-Opitz syndrome, a frequent inborn disorder of sterol metabolism. Molecular cloning of the cDNA revealed that the human enzyme is a membrane-bound protein with a predicted molecular mass of 55 kDa and six to nine putative transmembrane segments. The protein is structurally related to plant and yeast sterol reductases. In adults the ubiquitously transcribed mRNA is most abundant in adrenal gland, liver, testis, and brain. The Delta7-sterol reductase is the ultimate enzyme of cholesterol biosynthesis in vertebrates and is absent from yeast. Microsomes from Saccharomyces cerevisiae strains heterologously expressing the human cDNA remove the C7-8 double bond in 7-dehydrocholesterol. The conversion to cholesterol depends on NADPH and is potently inhibited by AY9944 (IC50 0.013 microM), BM15766 (IC50 1.2 microM), and triparanol (IC50 14 microM). Our work paves the way to clarify whether a defect in the delta7-sterol reductase gene underlies the Smith-Lemli-Opitz syndrome.

Morell P, Jurevics H.
Origin of cholesterol in myelin.
Neurochem Res 1996;21:463-470.
We review some of the older literature concerning metabolic turnover of cholesterol in the nervous system. The overall picture is that incorporation of radioactive precursors into brain cholesterol is roughly proportional to the rate of myelination and that, once incorporated, radioactive cholesterol is relatively stable metabolically. We outline a strategy for demonstrating the source (local synthesis or uptake from circulation) of cholesterol in brain. The experimental design involves determining the rate of accumulation of cholesterol; this is calculated as the increasing amounts of sterol in brain at successive time intervals during development. The rate of appearance of newly synthesized cholesterol is determined from incorporation of radioactivity from 3H20 (injected i.p. several hours prior to sacrifice) into cholesterol. The radioactivity associated with the sterol fractions and the specific activity of body water determined from the serum can be used to calculate the absolute amount of sterol newly synthesized during the time when 3H20 was present. The results obtained demonstrated that all of the bulk cholesterol accumulating in brain can be accounted for by newly synthesized cholesterol. None of the radioactive cholesterol came from the circulation, since cholesterol feeding suppressed cholesterol biosynthesis in the liver and specific radioactivity of circulating cholesterol was negligible. Thus, almost all cholesterol accumulating in brain during development is locally synthesized.

Morris MD, Chiakoff IL.
Concerning incorporation of labeled cholesterol, fed to mothers, into brain cholesterol of 20-day-old suckling rats.
Journal of Neurochemistry 1961;8:226-229.

Mucke J, Sandig KR, Bruckner HG.
[Variability of the Smith-Lemli-Opitz syndrome. Report on 2 additional cases]. [German].
Padiatr Grenzgeb 1977;16:221-228.

Munoz Calvo MT, Cenal Gonzalez MJ, Parra Martinez I, Hervas Olivares F, Nieto Cuartero JA, Lestache RG.
[Smith-Lemli-Opitz Syndrome; endocrinologic study (author's transl)]. [Spanish].
An Esp Pediatr 1981;15:498-502.
A case of Smith-Lemli-Opitz syndrome is reported in an 8 year old boy of related parents. He presented clinical features of the syndrome, with a normal male karyotype, distal axial triradii and increased number of whorl dermatoglyphic. Cerebral T.A.C. revealed an hypodensity zone in the left cerebral hemisphere. Authors studied the hypotalamo-pituitary axis finding a normal secretion of FSH and LH. The secretion of TSH and PRL under TRH stimulation showed an enhanced response. Plasma GH response to insulin induced hypoglycemia plus L-arginine was within normal limits.

Nagao M, Iwadate K, Zhang WD, Takahashi H, Yamada Y, Suzuki H, Takatori T.
[An autopsy case of Smith-Lemli-Opitz syndrome]. [Japanese].
Nippon Hoigaku Zasshi 1994;48:274-278.
A 17 month-old girl was found dead in her bed. The findings of a juditial autopsy revealed that she had a cleft palate, low-set and accessory ears, and syndactyly of right and left second and third toes and right third and fourth toes. Her birth size was small and subsequently she failed to thrive. Organ anomaly, such as atriaol septal defect, accessory spleens, and uterus bicornis bicollis were found. From these findings, this case was diagnosed as a Smith-Lemli-Opitz syndrome.

Naoumova RP, Marais AD, Mountney J, Firth JC, Rendell NB, Taylor GW, Thompson GR.
Plasma mevalonic acid, an index of cholesterol synthesis in vivo, and responsiveness to HMG-CoA reductase inhibitors in familial hypercholesterolaemia.
Atherosclerosis 1996;119:203-213.
Fasting plasma mevalonic acid (MVA), an indicator of in vivo cholesterol synthesis, was measured in 35 patients with familial hypercholesterolaemia (FH) of whom 7 were treated with pravastatin 10- 40 mg/day, 7 with simvastatin 10-40 mg/day and 21 with atorvastatin 80 mg/day. Reductions in low density lipoprotein (LDL) cholesterol and MVA on maximal dose therapy differed significantly between the three drugs: 34.7%, 42.9% and 54.0% (P = 0.0001), and 31.6%, 48.9% and 58.8% (P = 0.004), respectively. Patients on atorvastatin were subdivided according to whether their reduction in LDL cholesterol on treatment was above or below the mean percentage change for the whole group. Basal values of LDL cholesterol did not differ significantly, but above average responders had a significantly higher mean pre-treatment level of MVA (6.2 +/- 0.60 vs. 4.3 +/- 0.61 ng/ml, P < 0.05) than below average responders. When all three drug groups were pooled above average responders showed a significantly greater absolute decrease in MVA on treatment than below average responders (3.85 +/- 0.48 vs. 2.33 +/- 0.40 ng/ml, P < 0.05). However, there was no significant correlation between the magnitude of the decreases in LDL cholesterol and MVA. These findings suggest that FH patients who responded well to statins had a higher basal level of plasma MVA, i.e. a higher rate of cholesterol synthesis, which was more susceptible to pharmacological inhibition. The more marked cholesterol lowering effect of atorvastatin 80 mg/day presumably reflects, at least in part, its ability to inhibit HMG-CoA reductase to a greater extent than maximal recommended doses of pravastatin and simvastatin of 40 mg/day.

Natowicz MR, Evans JE.
Abnormal bile acids in the Smith-Lemli-Opitz syndrome.
Am J Med Genet 1994;50:364-367.
The urinary bile acids from four patients with Smith-Lemli-Opitz (SLO) syndrome were analyzed by continuous flow fast atom bombardment mass spectrometry. Two types of abnormalities were noted: (1) a deficiency of normal bile acids (cholenoates) and (2) the presence of abnormal species postulated to be cholenoates and cholestenoates. The finding of abnormal urinary bile acids in children with SLO syndrome led to further investigation of the cholesterol metabolic pathway and to the delineation of a new inborn error of metabolism, deficient conversion of 7-dehydrocholesterol to cholesterol [Irons et al., 1993]. The abnormalities of urinary bile acids, if confirmed by further structural analyses and studies of additional patients, provide an explanation for various aspects of the gastro-intestinal abnormalities and growth retardation noted in SLO syndrome and suggest that exogenous bile acid replacement may play an important role in the therapy of patients with this syndrome.

Ness GC, Lopez D, Borrego O, Gilbert-Barness E.
Increased expression of low-density lipoprotein receptors in a Smith-Lemli-Opitz infant with elevated bilirubin levels.
Am J Med Genet 1997;68:294-299.
We report on an infant girl with severe RSH or Smith-Lemli-Opitz syndrome with hyperbilirubinemia. The infant died at age 2 months. Sterol analysis of liver and brain tissues showed marked elevations of 7-dehydrocholesterol with decreased levels of cholesterol. Immunocytochemical analysis demonstrated remarkable increases in low-density lipoprotein (LDL) receptors in these tissues, indicative of a deficiency in available cholesterol for tissue needs.

Neuhauser G.
[Smith-Lemli-Opitz-syndrome (RSH-syndrome)]. [German].
Hippokrates 1975;46:507-509.

Nevo S, Benderly A, Levy J, Katznelson MB.
Smith-Lemli-Opitz syndrome in an inbred family.
Am J Dis Child 1972;124:431-433.

Newbould MJ, Lendon M, Barson AJ.
Oligohydramnios sequence: the spectrum of renal malformations.
Br J Obstet Gynaecol 1994;101:598-604.
OBJECTIVE: To assess the value of the autopsy findings on a series of infants dying with features of the oligohydramnios sequence, with particular reference to anomalies of the renal tract. DESIGN: Retrospective review. SETTING: Pathology departments serving three maternity units in Manchester. SUBJECTS: Eighty-nine infants having an autopsy examination between 1976 and 1990. RESULTS: Thirty-two (34%) infants had bilateral renal agenesis, 30 (34%) had bilateral cystic dysplasia, eight (9%) had unilateral agenesis with unilateral cystic dysplasia, four (4%) had renal histology characteristic of a recessively inherited disorder (two cases of renal tubular dysgenesis and two cases of autosomal recessive (infantile) polycystic disease), nine (10%) had minor urinary tract anomalies, and three (3%) had morphologically normal renal tracts. Forty-eight (54%) infants had congenital abnormalities other than those resulting from oligohydramnios sequence; most commonly, these were anomalies of the sporadic VATER association, but in four infants the extra renal anomalies present allowed recognition of a recessively inherited syndrome (Meckel's in three cases, Smith-Lemli-Opitz in one). CONCLUSIONS: A detailed autopsy is vital in assessment of infants with oligohydramnios sequence resulting from a congenital abnormality of the kidneys or urinary tract. This applies equally to second trimester fetuses following miscarriage or therapeutic abortion, to stillborn infants, or to neonatal deaths.

Nikonovich Iu B, Kaurov BA, Lur'e IV.
[Smith-Lemli-Opitz syndrome: evaluation of the correlations between individual traits as an approach to the study of heterogeneity]. [Russian].
Tsitol Genet 1987;21:57-60.
A computer analysis was used to study heterogeneity of the Smith-Lemli-Opitz syndrome (SLOS) with or without certain anomalies and to determine intrafamilial phenotypical variability. The analysis of 83 SLOS cases showed significant differences in average values of intragroup similarity, estimated for the cases with cleft palate and without it and those with or without polydactyly. The degree of intragroup similarity in familial cases appeared to be twice as high as in sporadic ones. These data confirm the hypothesis on genetic heterogeneity of SLOS with some allelic forms.

Nishio M, Murata M, Kusakawa S.
[Case of Smith-Lemli-Opitz syndrome with atrial heart septal defect]. [Japanese].
Nippon Shonika Gakkai Zasshi 1970;74:675-681.

Norgard M, Yankowitz J, Rhead W, Kanis AB, Hall BD.
Prenatal ultrasound findings in hydrolethalus: continuing difficulties in diagnosis.
Prenat Diagn 1996;16:173-179.
We present the prenatal ultrasound findings in a case of hydrolethalus. This case illustrates ongoing problems in differentiating hydrolethalus, both pre- and postnatally, from other midline malformation syndromes including Pallister-Hall, Smith-Lemli-Opitz, pseudo-trisomy 13, oral facial-digital syndrome, and Meckel syndrome. Hydrolethalus can also be difficult to distinguish from certain skeletal dysplasias such as the short rib-polydactyly syndromes and campomelic dysplasia. Tests which can aid in diagnosis are presented.

Nwokoro NA, Hyde B, Mulvihill JJ.
Smith-Lemli-Opitz syndrome: biochemical before clinical diagnosis; early dietary management.
Am J Med Genet 1994;50:375-376.
Pursuit of a possible metabolic basis for an unrecognized pattern of multiple congenital anomalies in a newborn girl led to the detection of a huge elevation of plasma 7-dehydrocholesterol at age 8 months. The biochemical findings and the evolving clinical picture led to the diagnosis of Smith-Lemli-Opitz syndrome at age 11 months. High cholesterol diet may have improved the rate of developmental progress.

Nwokoro NA, Mulvihill JJ.
Cholesterol and bile acid replacement therapy in children and adults with Smith-Lemli-Opitz (SLO/RSH) syndrome.
Am J Med Genet 1997;68:315-321.
Tint et al. [N Engl J Med 1994, 330:107-113], working with blood samples from the Smith-Lemli-Opitz syndrome (SLOS) patients of Irons and Elias showed the biochemical basis of this disorder to be a cholesterol biosynthesis defect [Irons et al., Lancet, 1993, 341:1414]. Based on this finding, clinical protocols for cholesterol and bile acid replacement therapy were established in a few centers including the University of Pittsburgh. We report our experience with bile acid and/or cholesterol replacement therapy in six patients with SLOS, now aged 3-27 years, with a confirmed biochemical diagnosis. Levels of plasma cholesterol and 7-dehydrocholesterol were correlated with periodic clinical evaluations over 8-27 months of therapy. There was a marked improvement in the growth of all the children. There was also an increase in the plasma cholesterol level in all the children and an overall increase in their percent sterol as cholesterol. Subjective improvement was also noted in their development. Although there was no significant change in the plasma cholesterol level of the older patients, there was a marked improvement in their behavior and in their quality of life.

Oostra RJ, Baljet B, Schutgens RB, Hennekam RC.
Smith-Lemli-Opitz syndrome diagnosed in a 130-year-old anatomical specimen.
Am J Med Genet 1997;68:257-259.
The Museum Vrolik collection of human anatomy comprises 360 recently re-described specimens with congenital anomalies. The external findings in one of these specimens, originally described by Willem Vrolik (1801-1863) 130 years ago, were suggestive of Smith-Lemli-Opitz (SLO) syndrome. Cholesterol synthesis was analyzed in skin biopsies, obtained from the suspected SLO specimen and a control specimen. The cholesterol levels in the SLO specimen and in the control specimen were in the proportion of 1 to 45. This confirms the diagnosis in this specimen which, to our knowledge, represents the oldest known case of SLO syndrome.

Oostra RJ, Baljet B, Dijkstra PF, Hennekam RC.
Congenital anomalies in the teratological collection of Museum Vrolik in Amsterdam, The Netherlands. I: Syndromes with multiple congenital anomalies [see comments].
Am J Med Genet 1998;77:100-115.
The Museum Vrolik collection of the Department of Anatomy and Embryology of the University of Amsterdam, founded by Gerardus Vrolik (1775-1859) and his son Willem Vrolik (1801-1863), consists of more than 5,000 thousand specimens of human and animal anatomy, embryology, pathology, and congenital anomalies. Recently, the collection of congenital anomalies was recatalogued and redescribed according to contempory syndromological views. The original descriptions, as far as preserved, were compared with the clinical and radiographical findings. In 13 specimens the following multiple congenital anomalies (MCA) syndromes were diagnosed: acrofacial dysostosis, Apert syndrome, Brachmann-De Lange syndrome, ichthyosis congenita gravis, Jarcho-Levin syndrome, Meckel syndrome, oro-facio-digital syndrome type IV, Roberts syndrome, Smith-Lemli-Opitz syndrome, Treacher Collins syndrome, and trisomy 13. It appeared that the founders of the museum studied and described several of these syndromes many years before they became established as such. In some specimens a reliable diagnosis is still pending. The use of additional diagnostical techniques, such as MRI, CT scanning, and fluorescence in situ hybridization, in these specimens is currently being investigated.

Opitz JM, Zellweger H, Shannon WR, Ptacek LJ.
The RSH syndrome. "The First Conference on the Clinical Delineation of Birth Defects. Part II: Malformation Syndromes." 1969; BD:OAS V(2):43-52.

Opitz JM, Penchaszadeh VB, Holt MC, Spano LM.
Smith-Lemli-Opitz (RSH) syndrome bibliography.
Am J Med Genet 1987;28:745-750.

Opitz JM, de la Cruz F.
Cholesterol metabolism in the RSH/Smith-Lemli-Opitz syndrome: summary of an NICHD conference [see comments].
Am J Med Genet 1994;50:326-338.
During the evolution of multicellularity and attendant processes of development, cholesterol played a key role in the formation of the plasma membrane and outer mitochondrial membrane of every cell in the organism. Later functions include pivotal involvement in steroid, bile acid, and vitamin D metabolism and myelination of the nervous system. In the CNS myelination does not begin until the third trimester, and subcortical myelination not until after birth. The cholesterol of the cell membrane of the ovum is maternally derived. It is not known when the zygote begins making its own cholesterol during morphogenesis and histogenesis, but it must occur early to keep up with the dramatic rate of cell division in the embryo. Thus, it is a startling surprise that human embryos and fetuses apparently able to synthesize little cholesterol (because of a presumed defect of the delta 5,7-sterol, delta 7-reductase that converts 7-dehydrocholesterol (7-DHC) into cholesterol) frequently live to term and, rarely, may be so mildly affected as to attend school with only mild MR. The discovery by G. Stephen Tint and his co-workers of the apparent 7-DHC reductase deficiency makes the RSH (Smith-Lemli-Opitz) syndrome the first true metabolic malformation syndrome. A teratological animal model which has been known for 30 years now appears applicable to the RSH/SLO syndrome. A multidisciplinary NICHD conference held on September 20-21, 1993 reviewed the numerous implications of this discovery and agreed unanimously that research in this field be given highest priority in order to better understand cholesterol synthesis in the mammalian brain, cholesterol transport from mother to embryo and fetus, pre- and postnatal metabolic compensation in structure and function for a profound block in cholesterol synthesis, the nature of the blood-brain barrier for cholesterol, treatment of affected infants, children, and adults, structure and genetic specification of a 7-DHC reductase enzyme (which has never been purified:) and its evolution, the variability of the syndrome and whether it is genetically homo- or heterogeneous, the population genetics of the RSH syndrome, possible selective advantages (or disadvantages) of heterozygotes, and means of newborn screening, carrier detection, and prenatal diagnosis.

Opitz JM.
RSH/SLO ("Smith-Lemli-Opitz") syndrome: historical, genetic, and developmental considerations. [Review] [27 refs].
Am J Med Genet 1994;50:344-346.
Thirty years after the publication of Smith et al. [1964: J Pediatr 64:210-217] of 3(4) cases of the RSH/SLO ("Smith-Lemli-Opitz") syndrome and after the publication by Roux [1964: Arch Franc Pediatr 21:451-464] on the teratogenic action of Triparanol, a defect of cholesterol metabolism was discovered by Tint and his co-workers in the blood of the patients of Irons and Elias [Irons et al., 1993: Lancet 341:1414]. In this manner, the RSH syndrome has been identified as another metabolic multiple congenital anomalies/mental retardation (MCA/MR) syndrome (prototype Zellweger syndrome) in which deficient cholesterol synthesis must be held responsible for all parts of the syndrome, including blastogenetic and organogenetic malformations, minor anomalies, more or less severe abnormalities of CNS and PNS structure and function, postnatal failure to thrive, and, in some cases, stillbirth or infancy/childhood death. [References: 27]

Opitz JM, Penchaszadeh VB, Holt MC, Spano LM, Smith VL.
Smith-Lemli-Opitz (RSH) syndrome bibliography: 1964-1993.
Am J Med Genet 1994;50:339-343.

Ostergaard GZ, Nielsen H, Friis B.
Defective monocyte oxidative metabolism in a child with Smith-Lemli-Opitz syndrome.
Eur J Pediatr 1992;151:291-294.
We present a patient with Smith-Lemli-Opitz syndrome with immunodeficiency. The patient suffered numerous infectious episodes, atopic dermatitis and wheezing. Immunological investigations demonstrated severely reduced oxidative burst-responsiveness of the blood monocytes, whereas chemotaxis, phagocytosis and interleukin-1 production were normal. Tests of neutrophils and lymphocytes were normal excluding previously described immune deficiency disorders. The father proved to have diminished monocyte oxidative metabolism as well, whereas the mother had normal monocyte function. The genetic and immunological aspects are discussed in relation to the syndrome.

Pankau R, Partsch CJ, Funda J, Sippell WG.
Hypothalamic-pituitary-gonadal function in two infants with Smith-Lemli-Opitz syndrome [see comments].
Am J Med Genet 1992;43:513-516.
We report on the hypothalamic-pituitary-gonadal function in 2 male infants with the Smith-Lemli-Opitz (SLO or RSH) syndrome. Both infants had abnormal external genitalia. Basal and LHRH stimulated plasma gonadotropins were normal for age (1 month). Plasma testosterone, androstenedione, and dehydroepiandrosterone sulfate were normal for age and sex. Some forms of congenital adrenal hyperplasia (17,20-desmolase deficiency, 17 alpha-hydroxylase deficiency, and 3 beta-hydroxysteroid dehydrogenase deficiency) were ruled out by hormonal studies. The endocrinological findings indicate a normal hypothalamic-pituitary-gonadal function and a normal adrenal steroid biosynthesis in these 2 patients. A partial androgen receptor defect causing the genital malformations seems possible in one patient. Whether 5 alpha-reductase deficiency is the cause of the male pseudohermaphroditism in SLO syndrome remains the subject of future studies.

Park SC, Needles CF, Dimich I, Sussman L.
Congenital heart disease in an infant with the Smith-Lemli-Opitz syndrome.
J Pediatr 1968;73:896-902.

Parker TS, McNamara DJ, Brown CD, Kolb R, Ahrens EH, Jr., Alberts AW, Tobert J, Chen J, De Schepper PJ.
Plasma mevalonate as a measure of cholesterol synthesis in man.
J Clin Invest 1984;74:795-804.
Measurement of mevalonic acid (MVA) concentrations in plasma or 24-h urine samples is shown to be useful in studies of the regulation of 3- hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase and cholesterol synthesis. Plasma MVA concentrations, measured either at 7-9 a.m. after an overnight fast, or throughout the 24-h cycle, were compared with cholesterol synthesis rates that were measured by the sterol balance method: plasma MVA concentrations were directly related to the rate of whole body cholesterol synthesis (r = 0.972; p less than 0.001; n = 18) over a tenfold range of cholesterol synthesis rates. Moreover, hourly examination of MVA concentrations throughout the day demonstrated that interventions such as fasting or cholesterol feeding cause suppression of the postmidnight diurnal rise in plasma MVA concentrations, with little change in the base-line of the rhythm. Thus, the daily rise and fall of plasma MVA appears to reflect changes in tissues and organs, such as the liver and intestine, that are known to be most sensitive to regulation by fasting or by dietary cholesterol. The hypothesis that short-term regulation of HMG-CoA reductase in tissues is quickly reflected by corresponding variations in plasma MVA was tested by using a specific inhibitor of HMG-CoA reductase, mevinolin, to block MVA synthesis. Mevinolin caused a dose-dependent lowering of plasma MVA after a single dose; and in patients who received the drug twice a day for 4 wk, it decreased 24-h urinary MVA output. Significant lowering of plasma cholesterol was achieved through administration of mevinolin at doses that only moderately limit MVA production.

Parnes S, Hunter AG, Jimenez C, Carpenter BF, MacDonald I.
Apparent Smith-Lemli-Opitz syndrome in a child with a previously undescribed form of mucolipidosis not involving the neurons.
Am J Med Genet 1990;35:397-405.
A diagnosis of Smith-Lemli-Opitz syndrome was made shortly after birth in a small-for-dates infant, on the basis of a characteristic face, penoscrotal hypospadias, bilateral postaxial hexadactyly, and bilateral syndactyly of toes 2-3. The clinical course was marked by failure to thrive, severe delay, refractory myoclonic jerks beginning at age 2 months, and increasing hepatosplenomegaly. He developed corneal clouding and increased gingival hypertrophy and died at age 18 weeks. Autopsy disclosed widespread storage of mucopolysaccharides and lipids within the macrophages and, to a lesser extent, parenchymal cells, of all organ systems. There was extensive demyelination of the cerebral white matter, and dystrophic calcification in the cerebrum, cerebellum, and brainstem. There was no evidence of primary neuronal involvement in the storage. Although the chance concurrence of 2 uncommon diseases is rare, a causal link between the clinical anomalies and the storage disorder cannot be argued convincingly on the basis of one case. Careful pathologic studies of other children who die with clinical signs compatible with Smith-Lemli-Opitz syndrome are indicated.

Partridge WM, Mietus LJ.
Palmitate and cholesterol transport through the blood-brain barrier.
Journal of Neurochemistry 1980;34:463-466.

Patriarca PL, Manzia S.
[Smith-Lemli-Opitz syndrome (case report)]. [Italian].
Minerva Pediatr 1972;24:670-674.

Patsner B, Mann WJ, Chumas J.
Malignant mixed germ cell tumor of the ovary in a young woman with Smith-Lemli-Opitz syndrome.
Gynecol Oncol 1989;33:386-388.
The first known case of a malignant germ cell tumor of the ovary occurring in a patient with Smith-Lemli-Opitz syndrome is reported.

Patterson K, Toomey KE, Chandra RS.
Hirschsprung disease in a 46,XY phenotypic infant girl with Smith-Lemli-Opitz syndrome.
J Pediatr 1983;103:425-427.

Pauli RM, Williams MS, Josephson KD, Tint GS.
Smith-Lemli-Opitz syndrome: thirty-year follow-up of "S" of "RSH" syndrome.
Am J Med Genet 1997;68:260-262.
We have reassessed patient "S," one of the first 3 individuals recognized to have Smith-Lemli-Opitz (or RSH) syndrome, at age 34 years, and we describe his physical, developmental, and behavioral manifestations. This reassessment provides formal evidence that this individual has the cholesterol biosynthetic defect which is thought to be the cause of Smith-Lemli-Opitz syndrome. Dietary manipulation appears to have had a beneficial effect on the patient's behavior and suggests that even in adults with this condition, dietary cholesterol supplementation may be indicated.

Penchaszadeh VB.
The nosology of the Smith-Lemli-Opitz Syndrome.
Am J Med Genet 1987;28:719-721.

Penzien JM, Hoffmann GF.
MRI in Smith-Lemli-Opitz syndrome type 1 [letter; comment].
Childs Nerv Syst 1997;13:505-506.

Petersen WC, Crouch ER, Jr.
Anesthesia-induced rigidity, unrelated to succinylcholine, associated with Smith-Lemli-Opitz syndrome and malignant hyperthermia [see comments].
Anesth Analg 1995;80:606-608.

Pfeiffer RA, Slavaykoff H.
[Is there a syndrome of Ullrich and Feichtiger?(Author's transl)]. [German].
Klin Padiatr 1975;187:176-180.
Report on two siblings having died during the first days of life who exhibited a syndrome of polydactyly, renal aplasia and inter-sexual genitalia, and in one child an additional cleft palate and coarctation of the aorta with VSD. It shares several features with the syndrome of Smith-Lemli and Opitz. The syndrome of Ullrich and Feichtiger which had been taken into consideration earlier sould be rejected as a clinical and etiological entity.

Pfohl M, Naoumova RP, Neuwirth C, Sussekov A, Smykowski J, Rendell NB, Taylor GW, Seif FJ, Thompson GR.
Upregulation of cholesterol synthesis after acute reduction of low density lipoprotein by apheresis in normocholesterolaemic subjects: evidence for a threshold effect.
Atherosclerosis 1997;135:257-262.
The influence of low density lipoproteins (LDL) in the plasma on the regulation of cholesterol biosynthesis is not clear. We studied the changes in plasma mevalonic acid (MVA) concentration and the lathosterol/cholesterol (L/C) ratio, which are well established indices of whole body cholesterol synthesis, in four normocholesterolaemic subjects after each had undergone LDL apheresis on two occasions. LDL apheresis of 75% of the calculated plasma volume reduced LDL- cholesterol by 44% to 1.5 +/- 0.2 mmol/l without changing plasma MVA levels or L/C ratios. Apheresis of 125% of the calculated plasma volume decreased plasma LDL-cholesterol by 69% to 0.9 +/- 0.2 mmol/l, with significant increases in plasma MVA and L/C ratio on the day after the procedure. These results imply that LDL-cholesterol is an integral part of the sterol regulatory pool and suggest that plasma levels cannot be lowered below 1-1.4 mmol/l in normal subjects without upregulating cholesterol biosynthesis.

Pfohl M, Naoumova RP, Kim KD, Thompson GR.
Use of cholesterol precursors to assess changes in cholesterol synthesis under non-steady-state conditions [In Process Citation].
Eur J Clin Invest 1998;28:491-496.
BACKGROUND: Quantification of plasma levels of an early and late intermediate on the cholesterol pathway, mevalonic acid (MVA) and lathosterol respectively, provides a useful method of estimating cholesterol synthesis in humans. The aim of this study was to assess further their roles as indices of cholesterol synthesis under non- steady-state conditions. METHODS: The short-term effects of pharmacological inhibition of 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA) reductase on both variables were determined in four normolipidaemic subjects during and after treatment with simvastatin 20 mg daily. Plasma MVA was measured using gas chromatography-mass spectrometry, and lathosterol using gas chromatography. RESULTS: A single dose of 20 mg of simvastatin decreased plasma MVA after 2 h and decreased the lathosterol-cholesterol (L/C) ratio after 4 h. Treatment with simvastatin 20 mg daily for 9 days decreased both variables by approximately 50%, the nadir of plasma MVA occurring on the second day and of the L/C ratio on the fifth day, and resulted in a 39% reduction in low-density lipoprotein (LDL)-cholesterol. After discontinuing simvastatin, there were rebounds in plasma MVA and the L/C ratio to above basal levels but not in LDL cholesterol or apolipoprotein B (apoB), the latter continuing to decrease for a further 2 days. CONCLUSION: These results suggest that simvastatin rapidly down- regulates cholesterol synthesis, which is then up-regulated when the drug is withdrawn.

Pierquin G, Peeters P, Roels F, Vamos E, Brucher JM, Tint GS, Honda A, Van Regemorter N.
Severe Smith-Lemli-Opitz syndrome with prolonged survival and lipid abnormalities.
Am J Med Genet 1995;56:276-280.
We have studied a girl with multiple congenital anomalies, growth and mental deficiency, characteristic facial anomalies, cataracts, cerebellar atrophy, and severe hypocholesterolemia. Death occurred at age 7 years. After excluding several syndromes, i.e., peroxisomal disorders, mevalonic acidaemia, and Marinesco-Sjogren syndrome, it is concluded that this girl had severe Smith-Lemli-Opitz Syndrome (SLOS) with exceptionally long survival. This diagnosis was confirmed through assay of 7-dehydrocholesterol in cultured fibroblasts.

Pietrzyk JJ, Majerska B, Pieniazek M.
[Smith-Lemli-Opitz syndrome in a female newborn infant]. [Polish].
Pediatr Pol 1983;58:663-666.

Pinsky L, DiGeorge AM.
A familial syndrome of facial and skeletal anomalies associated with genital abnormality in the male and normal genitals in the female.
Journal of Pediatrics 1965;66:1049-1054.

Porter JA, Young KE, Beachy PA.
Cholesterol modification of Hedgehog signaling proteins in animal development.
Science 1996;274:255-259.

Repetto M, Maziere JC, Citadelle D, Dupuis R, Meier M, Biade S, Quiec D, Roux C.
Teratogenic effect of the cholesterol synthesis inhibitor AY 9944 on rat embryos in vitro.
Teratology 1990;42:611-618.
AY 9944 [trans-1,4-bis(2-chlorobenzylaminomethyl) cyclohexane dihydrochloride] is an amphiphilic cationic molecule. This chemical is an established inhibitor of cholesterol synthesis and is teratogenic in rats. The mechanisms of this teratogenicity remain to be clarified. This study used cultured rat whole embryos to ascertain whether AY 9944 had a direct effect on embryos, or whether its action was indirect, via the maternal cholesterol metabolism. Four experimental conditions were investigated: (A) controls; (B) 10 day untreated embryos were cultured in serum of treated rats; (C) 10 day untreated embryos were cultured in serum containing added AY 9944 (0-1,000 micrograms/ml); and (D) 10 day embryos from females treated on day 4 of gestation were cultured in normal serum. In group B there was no growth retardation; some slight nonspecific abnormalities were not significant. In group C, direct addition of AY 9944 to culture medium retarded growth and differentiation in a dose-dependent manner. No malformation was observed, but histological examinations showed numerous areas of cell necrosis, especially in the CNS. In group D, not only was growth retardation observed, but also characteristic malformations of AY 9944 teratogenesis, including pituitary agenesis. These results show that AY 9944 teratogenicity is initiated prior to day 10.

Retbi JM, Limal JM, Boutignon H, Rosenstein-Retbi J, Dayras JC.
[Smith-Lemli-Opitz syndrome with male pseudohermaphroditism. A case report with endocrinological study (author's transl)]. [French].
Ann Pediatr (Paris) 1981;28:55-58.

Robinson CD, Perry LW, Barlee A, Mella GW.
Smith-Lemli-Opitz syndrome with cardiovascular abnormality.
Pediatrics 1971;47:844-847.

Roessler E, Belloni E, Gaudenz K, Jay P, Berta P, Scherer SW, Tsui L, Muenke M.
Mutations in the human Sonic Hedgehog gene cause holoprosencephaly.
Nature Genetics 1996;14:357-360.

Roessler E, Belloni E, Gaudenz K, Vargas F, Scherer SW, Tsui LC, Muenke M.
Mutations in the C-terminal domain of Sonic Hedgehog cause holoprosencephaly.
Hum Mol Genet 1997;6:1847-1853.
Holoprosencephaly (HPE) is the most common brain anomaly in humans, involving abnormal formation and septation of the developing central nervous system. Among the heterogeneous causes of HPE, mutations in the Sonic Hedgehog (SHH) gene have been shown to result in an autosomal dominant form of the disorder. Here we describe a total of five different mutations in the processing domain encoded by exon 3 of SHH in familial and sporadic HPE. This is the first instance in humans where SHH mutations in the domain responsible for autocatalytic cleavage and cholesterol modification of the N-terminal signaling domain of the protein have been observed.

Roessler E, Muenke M.
Holoprosencephaly: a paradigm for the complex genetics of brain development [In Process Citation].
J Inherit Metab Dis 1998;21:481-497.
Holoprosencephaly (HPE) is the most common major developmental defect of the forebrain in humans. Clinical expression is variable, ranging from a small brain with a single cerebral ventricle and cyclopia to clinically unaffected carriers in familial HPE. Significant aetiological heterogeneity exists in HPE and includes both genetic and environmental causes. Recently, defects in the cell signalling pathway involving the Sonic Hedgehog (SHH) gene, as well as defects in the cholesterol biosynthesis, have been shown to cause HPE in humans. These discoveries and current genetic approaches serve as a paradigm for studying normal and abnormal brain morphogenesis.

Rossiter JP, Hofman KJ, Kelley RI.
Smith-Lemli-Opitz syndrome: prenatal diagnosis by quantification of cholesterol precursors in amniotic fluid.
Am J Med Genet 1995;56:272-275.
Until recently, the diagnosis of Smith-Lemli-Opitz syndrome (SLOS), an autosomal recessive malformation/mental retardation syndrome, was made on the basis of clinical criteria alone. As a result, prenatal diagnosis has been possible only if sonography disclosed distinct fetal malformations in a subsequent pregnancy. However, the recent description of increased levels of 7-dehydrocholesterol (cholesta-5,7-dien-3 beta-ol) in patients with SLOS, most likely caused by a deficiency of 3 beta-hydroxysteroid-delta 7-reductase, has provided an apparently reliable biochemical marker for diagnosis of SLOS. To determine if this abnormality of sterol metabolism has utility for prenatal diagnosis of SLOS, we measured the levels of neutral sterols in stored amniotic fluid samples from two SLOS pregnancies. In both cases, the diagnosis of SLOS was made in the neonatal period by clinical criteria and the finding of markedly increased levels of 7-dehydrocholesterol in plasma. Quantitative analysis by gas chromatography of sterols extracted from the amniotic fluid of both pregnancies revealed similar, markedly increased levels of 7-dehydrocholesterol and its precursor, lathosterol (cholest-7-en-3 beta-ol), both of which were undetectable in reference amniotic fluids. These findings suggest that abnormalities of cholesterol biosynthesis in SLOS may be sufficiently expressed in fetal life to permit prenatal diagnosis of this disorder by measurement of 7-dehydrocholesterol in amniotic fluid.

Roux C, Horvath C, Dupuis R.
Teratogenic action and embryo lethality of AY 9944R. Prevention by a hypercholesterolemia-provoking diet.
Teratology 1979;19:35-38.
Embryomortality and teratogenesis provoked by inhibitors of cholesterol synthesis are well demonstrated. Teratogenic action is particularly reflected by holoprosencephalies, but also by uro-genital abnormalities. A hypercholesterolemia-provoking diet has been shown to be completely effective for preventing holoprosencephaly, but only partially so for preventing the uro-genital malformations and fetal mortality. It is thus possible that the two types of abnormalities are governed by different mechanisms. In addition, the diet itself, whose hypercholesterolemic effect is considerable, has certain disadvantages. It seems to have a certain effect on fetal mortality and could be responsible for several uro-genital malformations. This deserves further study.

Roux C, Dupuis R, Horvath C, Talbot JN.
Teratogenic effect of an inhibitor of cholesterol synthesis (AY 9944) in rats: Correlation with maternal cholesterolemia.
Journal of Nutrition 1980;110:2310-2312.
The teratogenic action of AY 9944, an inhibitor of cholesterol synthesis, was previously shown. Its prevention by simultaneous administration of cholesterol led to the hypothesis that this action is correlated with the decrease in cholesterol. The present investigation demonstrates that there is an inverse correlation between holoprosencephalic type of malformations and maternal cholesterolemia and that, in Wistar rats, 0.30 g/liter of cholesterolemia is a threshold under which these malformations can be observed.

Roux C, Wolf C, Llirbat B, Kolf M, Mulliez N, Taillemite JL, Cormier V, Le Merrer M, Chevy F, Citadelle D.
[Cholesterol and development]. [Review] [19 refs] [French].
C R Seances Soc Biol Fil 1997;191:113-123.
The teratogenic action of distal inhibitors of cholesterol synthesis has been known for some time. The induced malformations are of a particular type: they include holoprosencephalies. Recently these observations have solicited increased interest due to: 1/ the discovery in 1993 of a similar form of inhibition of cholesterol synthesis which is responsible for a human malformation syndrome, Smith-Lemli-Opitz; 2/ the demonstration of the involvement of the Sonic Hedgehog gene in normal development of prosencephalon and the description of the mode of action of the protein Shh: autoprocessing followed by "cholesterolisation". [References: 19]

Ruan B, Pang J, Wilson WK, Schroepfer Jr. GJ.
Concerning the thermolability of cholesta-5,8-dien-3ß-ol, a sterol that accumulates in blood and tissues in a human genetic developmental disorder.
Bioorganic & Medicinal Chemistry Letter 1996;6:2421-2424.

Rudney H, Sexton RC.
Regulation of cholesterol biosynthesis.
Annual Review of Nutrition 1986;6:245-272.

Rutledge JC, Friedman JM, Harrod MJ, Currarino G, Wright CG, Pinckney L, Chen H.
A "new" lethal multiple congenital anomaly syndrome: joint contractures, cerebellar hypoplasia, renal hypoplasia, urogenital anomalies, tongue cysts, shortness of limbs, eye abnormalities, defects of the heart, gallbladder agenesis, and ear malformations.
American Journal of Medical Genetics 1984;19:255-264.
Three cases of a lethal malformation syndrome with severe visceral anomalies were seen in two families and include one pair of sibs. The predominating external manifestations are mesomelic dwarfism, micrognathia, V-shaped upper lip, microglossia, thick alveolar ridges, ambiguous genitalia, webbed neck, highly arched palate, clubfeet, fused fontanelles, inclusion cysts of the tongue, four-finger creases, digital anomalies, apparently low-set ears, widely spaced nipples, and dislocated thighs and forearms. The internal findings include oligopapillary renal hypoplasia, severe congenital heart defect, cerebellar hypoplasia, pulmonary hypoplasia, hypoplastic larynx, and hypoplastic gallbladder. Other findings from the two autopsies and one clinical investigation not documented in all three patients include unilobar lungs, hydrocephalus, cataracts, microphthalmia, polydactyly, islet cell hyperplasia, suprapubic skin crease, urethral anomalies, and a decreased number of turns of the cochlea. The hypoplasia seen in the several affected organs is similar to the disordered development seen in experimental models of branching epithelial morphogenesis in which mesenchymal-epithelial interaction has been disrupted.

Ruvalcaba RH, Reichert A, Smith DW.
Smith-Lemli-Opitz syndrome. Case report.
Arch Dis Child 1968;43:620-623.

Salbert BA, Schwartz ID, Grunt JA.
Sex reversal in an infant with Smith-Lemli-Opitz syndrome, type II: evidence for 5-alpha reductase deficiency.
J Pediatr Endocrinol Metab 1996;9:67-69.

Salen G, Tint GS, Xu G, Batta AK, Irons M, Elias ER.
Abnormal cholesterol biosynthesis in the Smith-Lemli-Opitz syndrome.
Ital J Gastroenterol 1995;27:506-508.
We measured plasma sterol concentrations in 7 homozygotes with the Smith-Lemli-Opitz syndrome, 5 heterozygotes and rats treated with BM 15.766, the competitive inhibitor of 7-dehydrocholesterol 7-reductase. Low cholesterol associated with markedly elevated 7-dehydrocholesterol concentrations were detected in the plasma of all homozygotes and inhibitor-treated rats. Heterozygotes were clinically normal and, like control subjects, showed only trace amounts of 7-dehydrocholesterol in plasma. We conclude that the Smith-Lemli-Opitz syndrome is due to an inherited defect in 7 dehydrocholesterol 7-reductase which causes the accumulation of 7-dehydrocholesterol and a deficiency of cholesterol in the plasma, a biochemical abnormality that can be reproduced in rats treated with BM 15.766.

Salen G, Shefer S, Batta AK, Tint GS, Xu G, Honda A.
Abnormal cholesterol biosynthesis in sitosterolaemia and the Smith-Lemli-Opitz syndrome. [Review] [25 refs].
J Inherit Metab Dis 1996;19:391-400.
We investigated the enzyme defects in two inherited disorders of cholesterol biosynthesis: sitosterolaemia and the Smith-Lemli-Opitz syndrome. In sitosterolaemic homozygotes, plasma plant sterols (sitosterol and campesterol) concentrations are elevated because of enhanced intestinal absorption and diminished removal. Underlying these changes is very low cholesterol biosynthesis to provide extra sterol for cell growth. Extremely reduced activities of HMG-CoA reductase, the rate-controlling enzyme for cholesterol biosynthesis, caused by deficient HMG-CoA reductase mRNA is responsible and is the suspected inherited abnormality. The Smith-Lemli-Opitz syndrome is caused by a block in the last reaction in the cholesterol biosynthetic pathway, the conversion of 7-dehydrocholesterol to cholesterol, which is catalysed by 7-dehydrocholesterol delta 7-reductase. As a result, low plasma and tissue cholesterol with high 7-dehydrocholesterol levels are found in homozygotes, who show characteristic phenotypes of mental retardation, facial dysmorphism, and organ and limb congenital anomalies. Similar biochemical findings are produced in rats fed BM 15,766, an inhibitor of 7-dehydrocholesterol delta 7-reductase. Interestingly, feeding cholesterol can suppress abnormal cholesterol biosynthesis and improve symptoms in homozygotes and rats fed BM 15,766. [References: 25]

Salen G, Shefer S, Batta AK, Tint GS, Xu G, Honda A, Irons M, Elias ER.
Abnormal cholesterol biosynthesis in the Smith-Lemli-Opitz syndrome. [Review] [64 refs].
J Lipid Res 1996;37:1169-1180.
The Smith-Lemli-Opitz syndrome is caused by an inherited defect in 7-dehydrocholesterol-delta7-reductase, the enzyme that catalyzes the last reaction in cholesterol biosynthesis, the conversion of 7-dehydrocholesterol to cholesterol. As a result, deficient cholesterol is produced and the precursor 7-dehydrocholesterol and derivatives (8-dehydrocholesterol and 19-nor-5,7,9(10)-cholestatrien-3 beta-ol) accumulate. Tissues (especially brain) deprived of cholesterol, or because of the deposited sterol precursors and derivatives, develop abnormally and function poorly. Replacement with dietary cholesterol may help correct the biochemical defects and improve symptoms. [References: 64]

Sattler W, Leis HJ, Kostner GM, Malle E.
Quantification of 7-dehydrocholesterol in plasma and amniotic fluid by liquid chromatography/particle beam-mass spectrometry as a biochemical diagnostic marker for the Smith-Lemli-Opitz syndrome.
Rapid Commun Mass Spectrom 1995;9:1288-1292.
The qualitative and quantitative determination of cholesterol and 7-dehydrocholesterol (7-DHC) in plasma as a biochemical diagnostic marker for the Smith-Lemli-Opitz syndrome by liquid chromatography/particle beam interface-mass spectrometry (LC/PB-MS) is presented. Baseline separation of cholesterol and 7-DHC is achieved on a silica column with hexane+ethanol (99: 1 v/v) as mobile phase within a 10 min analysis. Recoveries of cholesterol and 7-DHC in a simple two-phase extraction system are nearly 100%. The absolute limit of detection using LC/PB-MS is approximately 10 ng. The method presented allows extraction, analysis and quantification of cholesterol and 7-DHC within 15 min without the necessity of sample derivatization.

Scarbrough PR, Huddleston K, Finley SC.
An additional case of Smith-Lemli-Opitz syndrome in a 46,XY infant with female external genitalia.
J Med Genet 1986;23:174-175.
Ambiguity of the external genitalia has been frequently documented in male patients classified as the Smith-Lemli-Opitz (SLO) syndrome. Four previous case reports suggest that in extreme cases of the SLO syndrome there may be complete lack of development of the male external genitalia even in the presence of a normal male 46,XY karyotype. We present an additional case of a phenotypically female infant with dysmorphic features compatible with SLO syndrome and a 46,XY chromosome complement.

Schechter R, Torfs CP, Bateson TF.
The epidemiology of infantile hypertrophic pyloric stenosis.
Paediatr Perinat Epidemiol 1997;11:407-427.
Infants with infantile hypertrophic pyloric stenosis (IHPS) born from 1983 to 1988 and recorded in the California Birth Defects Monitoring Program (CBDMP) database were compared with their birth cohort by demographic characteristics and selected associated birth defects. We identified 1963 cases of IHPS for a cumulative incidence of 1.9 per 1000 livebirths. The cumulative incidence per 1000 livebirths was 2.4 in White, 1.8 in Hispanic, 0.7 in Black, and 0.6 in Asian infants. Between weeks 3-12 after birth, 1871 (95%) IHPS cases were diagnosed. Premature infants were diagnosed with IHPS later than term or post-term infants. The incidence of IHPS declined for those born to maternal age groups of > or = 25 years and, independently, for successive birth ranks. The probandwise concordance rate for IHPS in monozygous twins was less than unity (0.25-0.44), although higher than the concordance for dizygous twins (0.05-0.10). The incidence of Smith-Lemli-Opitz syndrome (SLO) diagnosed in infants with IHPS (3 of 1963) was 157-fold higher than the incidence of SLO diagnosed in the CBDMP population. IHPS occurs in all of the largest racial and ethnic groups in California, most frequently in White and Hispanic infants. Pyloric stenosis presents only within a brief phase of development, which may be delayed in premature infants. A predominant discordance of disease state in monozygous twins implies an aetiological role for undetermined environmental factors. The association between SLO, caused by deficient cholesterol synthesis, and IHPS deserves additional study. Infants with suspected SLO require close observation for the onset of IHPS.

Scherer SW, Soder S, Duvoisin RM, Huizenga JJ, Tsui LC.
The human metabotropic glutamate receptor 8 (GRM8) gene: a disproportionately large gene located at 7q31.3-q32.1.
Genomics 1997;44:232-236.
Metabotropic glutamate receptors (GRMs), which constitute a family of genes, are neurotransmitter receptors that respond to glutamate stimulations by activating GTP-binding proteins and modulating second-messenger cascades. Pharmacological and expression studies of the rodent Grm8 gene suggest it could be a presynaptic receptor modulating glutamate release at the axon terminals. To study human GRM8, we have determined its nucleotide sequence and genomic organization. While the coding region of the gene spans only 2.3 kb, the gene encompasses approximately 1000 kb of DNA at the boundary of the q31.3-q32.1 bands of chromosome 7. This observation is relevant to the study of Smith-Lemli-Opitz syndrome and an autosomal dominant form of retinitis pigmentosa (RP10), since they map to the same region. Copyright 1997 Academic Press.

Schroepfer GJ, Jr.
Sterol biosynthesis.
Annu Rev Biochem 1981;50:585-621.

Schroepfer GJ, Jr.
Sterol biosynthesis.
Annu Rev Biochem 1982;51:555-585.

Schumacher H.
[The Smith-Lemli-Opitz-syndrome]. [German].
Z Kinderheilkd 1969;105:88-98.

Seedorf U, Walter M, Assmann G.
Diagnosis of Smith-Lemli-Opitz syndrome [letter; comment].
N Engl J Med 1994;330:1686-1687.

Seedorf U, Fobker M, Voss R, Meyer K, Kannenberg F, Meschede D, Ullrich K, Horst J, Benninghoven A, Assmann G.
Smith-Lemli-Opitz syndrome diagnosed by using time-of-flight secondary-ion mass spectrometry.
Clin Chem 1995;41:548-552.
We describe a rapid and sensitive method involving time-of-flight secondary-ion mass spectrometry (TOF-SIMS) for specific laboratory diagnosis of the Smith-Lemli-Opitz syndrome, which is characterized by massive (approximately 1000-fold) accumulation of the biosynthetic cholesterol precursor 7-dehydrocholesterol. Minute amounts of blood (1-50 microL) were extracted with n-hexane, and aliquots were analyzed by TOF-SIMS. 7-Dehydrocholesterol and its isomers were detected at 491.3 mass units ([M + 107Ag]+) and cholesterol at 495.3 mass units ([M + 109Ag]+). Quantitation of 7-dehydrocholesterol and cholesterol was achieved after saponification and addition of stigmasterol as internal standard. Whereas 7-dehydrocholesterol and isomeric dehydrocholesterol were not detectable in controls, the patients revealed concentrations ranging between 0.84 and 1.25 mmol/L. Comparison with results obtained by gas chromatography indicated that quantitation by TOF-SIMS yielded the sum of 7-dehydrocholesterol, isomeric dehydrocholesterol II, and sterol III, the latter two also being increased in the patients. Consistent with quantitation by gas chromatography, the cholesterol concentrations in the patients ranged between 1.54 and 2.12 mmol/L (controls: 6.10 +/- 1.37 mmol/L).

Seemanova E, Voriskova M.
[Smith-Lemli-Opitz syndrome in an infant]. [Czech].
Cesk Pediatr 1974;29:504-506.

Seller MJ, Russell J, Tint GS.
Unusual case of Smith-Lemli-Opitz syndrome "type II".
Am J Med Genet 1995;56:265-268.
We describe a fetus with abnormalities suggestive, but not typical, of severe Smith-Lemli-Opitz syndrome (SLO). Biochemical studies demonstrated that there was a defect of cholesterol biosynthesis similar to that recently discovered in children with SLO. The findings in this fetus extend even further the wide spectrum of abnormalities of the SLO phenotype, and emphasize that a genetic pathological examination and biochemical studies should always be undertaken on atypical cases, especially fetuses.

Seller MJ, Flinter FA, Docherty Z, Fagg N, Newbould M.
Phenotypic diversity in the Smith-Lemli-Opitz syndrome.
Clin Dysmorphol 1997;6:69-73.
The phenotype of four cases of Smith-Lemli-Opitz syndrome (SLO) with proven defects in cholesterol biosynthesis are compared, and shown to be markedly disparate even between sibs, and demonstrate the dilemma for the clinician. The advent of a biochemical test for SLO has been enormously valuable in determining which patients are truly affected by the condition, but because of the wide phenotypic variation, a diagnosis on clinical features alone remains problematic.

Sharp P, Haan E, Fletcher JM, Khong TY, Carey WF.
First-trimester diagnosis of Smith-Lemli-Opitz syndrome.
Prenat Diagn 1997;17:355-361.
We report here the prenatal diagnosis of Smith-Lemli-Opitz (SLO) syndrome in the first trimester by direct measurement of 7-dehydrocholesterol (7-DHC) in a chorionic villus (CV) biopsy. The proband was diagnosed clinically at birth and the diagnosis was confirmed biochemically by demonstrating elevated 7-DHC in plasma. The family pursued prenatal diagnosis in their fourth, fifth, and sixth pregnancies. The fourth pregnancy spontaneously miscarried at 9 weeks' gestation. Analysis in both direct and cultured curetting tissue (identified as similar to CV tissue) showed an abnormal tissue neutral sterol pattern with an elevated 7-DHC concentration. The fifth pregnancy also miscarried spontaneously at 9 weeks but no tissue of unequivocal fetal origin could be identified to allow biochemical investigation. In the sixth pregnancy, ultrasound examination at the time of CV sampling showed a thickened nuchal fold. Direct analysis of the CV sample revealed elevated levels of 7-DHC consistent with the diagnosis of SLO. The pregnancy was terminated and both fetal tissue and cultured fetal cells showed marked increases in 7-DHC, confirming the prenatal diagnosis.

Shefer S, Salen G, Batta AK, Honda A, Tint GS, Irons M, Elias ER, Chen TC, Holick MF.
Markedly inhibited 7-dehydrocholesterol-delta 7-reductase activity in liver microsomes from Smith-Lemli-Opitz homozygotes.
J Clin Invest 1995;96:1779-1785.
We investigated the enzyme defect in late cholesterol biosynthesis in the Smith-Lemli-Opitz syndrome, a recessively inherited developmental disorder characterized by facial dysmorphism, mental retardation, and multiple organ congenital anomalies. Reduced plasma and tissue cholesterol with increased 7-dehydrocholesterol concentrations are biochemical features diagnostic of the inherited enzyme defect. Using isotope incorporation assays, we measured the transformation of the precursors, [3 alpha- 3H]lathosterol and [1,2-3H]7-dehydrocholesterol into cholesterol by liver microsomes from seven controls and four Smith-Lemli-Opitz homozygous subjects. The introduction of the double bond in lathosterol at C-5[6] to form 7-dehydrocholesterol that is catalyzed by lathosterol-5-dehydrogenase was equally rapid in controls and homozygotes liver microsomes (120 +/- 8 vs 100 +/- 7 pmol/mg protein per min, P = NS). In distinction, the reduction of the double bond at C-7 [8] in 7-dehydrocholesterol to yield cholesterol catalyzed by 7-dehydrocholesterol-delta 7-reductase was nine times greater in controls than homozygotes microsomes (365 +/- 23 vs 40 +/- 4 pmol/mg protein per min, P < 0.0001). These results demonstrate that the pathway of lathosterol to cholesterol in human liver includes 7-dehydrocholesterol as a key intermediate. In Smith-Lemli-Opitz homozygotes, the transformation of 7-dehydrocholesterol to cholesterol by hepatic microsomes was blocked although 7-dehydrocholesterol was produced abundantly from lathosterol. Thus, lathosterol 5-dehydrogenase is equally active which indicates that homozygotes liver microsomes are viable. Accordingly, microsomal 7-dehydrocholesterol-delta 7-reductase is inherited abnormally in Smith-Lemli-Opitz homozygotes.

Shefer S, Salen G, Honda A, Batta A, Hauser S, Tint GS, Honda M, Chen T, Holick MF, Nguyen LB.
Rapid identification of Smith-Lemli-Opitz syndrome homozygotes and heterozygotes (carriers) by measurement of deficient 7-dehydrocholesterol-delta 7-reductase activity in fibroblasts.
Metabolism 1997;46:844-850.
To extend the enzyme deficiency in Smith-Lemli-Opitz syndrome (SLOS) to extrahepatic tissues, 7-dehydrocholesterol-delta 7-reductase activity was measured in fibroblasts from 10 controls, five SLOS homozygotes, and five obligate heterozygotes. In cells grown almost to confluence in cholesterol-containing medium (4 mg/dL), the conversion of [1,2-3H]7-dehydrocholesterol to cholesterol (7-dehydrocholesterol-delta 7-reductase activity) was 3.8 times higher in control than in homozygote cells and 2.2 times higher than in heterozygote cells. After 24 hours' exposure of the fibroblasts to cholesterol-deficient medium supplemented with lovastatin, 7-dehydrocholesterol-delta 7-reductase activity increased twofold in controls, but did not change significantly in either heterozygous or homozygous cells. In contrast, the activities of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase and lathosterol 5-dehydrogenase, two key enzymes that precede 7-dehydrocholesterol-delta 7-reductase in the cholesterol biosynthetic pathway, and low-density lipoprotein (LDL) receptor-mediated binding were equal in control, homozygote, and heterozygote fibroblasts. Further, HMG-CoA reductase activity and LDL receptor-mediated binding increased after exposure of the cells to cholesterol-deficient medium. Fibroblast cholesterol concentrations were approximately equal, although homozygote cells contained 30 times more 7-dehydrocholesterol. Thus, markedly reduced 7-dehydrocholesterol-delta 7-reductase activity that cannot be upregulated after exposure of the cells to cholesterol-deficient medium is diagnostic for the biochemical defect in SLOS. Significantly reduced enzyme activity between the levels in controls and homozygotes without accumulation of 7-dehydrocholesterol in fibroblasts identified heterozygotes.

Silve S, Dupuy PH, Ferrara P, Loison G.
Human lamin B receptor exhibits sterol C14-reductase activity in Saccharomyces cerevisiae.
Biochim Biophys Acta 1998;1392:233-244.
Lamin B receptor (LBR), a nuclear protein of avian and mammalian cells, contains an hydrophobic domain that shares extensive structural similarities with the members of the sterol reductase family. To test if the sterol-reductase-like domain of LBR could be enzymatically competent, several sterol reductase-defective strains of Saccharomyces cerevisiae were transformed with a human-LBR expressing vector. LBR production did not change the ergosterol biosynthesis defect in an erg4 mutant impaired in sterol C24(28) reductase. In contrast, the sterol C14 reduction step and ergosterol prototrophy were restored in LBR- producing erg24 transformants which lack endogenous sterol C14 reductase. To test the effects of C14 reductase inhibitors on LBR activity, we constructed EMY54, an ergosterol-requiring strain that is devoid of both sterol C8-C7 isomerase and sterol C14 reductase activities. EMY54 cells recovered the capability of synthesizing ergost- 8-en-3beta-ol upon transformation with a vector that expressed either yeast sterol C14 reductase or hLBR. In addition, growth in sterol-free medium was restored in these transformants. Sterol biosynthesis and proliferation of LBR-producing cells were found to be highly susceptible to fenpropimorph and tridemorph, but only moderately susceptible to SR 31747. Our results strongly suggest that hLBR is a sterol C14 reductase.

Sinclair L, Brown J, Winterborn MH.
Smith-Lemli-Opitz syndrome.
Proc R Soc Med 1969;62:907-908.

Singer LP, Marion RW, Li JK.
Limb deficiency in an infant with Smith-Lemli-Opitz syndrome.
Am J Med Genet 1989;32:380-383.
We describe a 46,XY newborn infant with Smith-Lemli-Opitz syndrome (SLOS) with multiple congenital anomalies including female external genitalia, a testis palpable in each labium majus, a cone-shaped cervix, and normal vagina. Additional anomalies included cleft palate, total anomalous pulmonary venous return, and striking limb defects (ectrodactyly of the left upper limb, radial aplasia, and monodactyly of the right upper limb). To our knowledge, this is the first report of SLOS associated with limb deficiency and the third associated with total anomalous pulmonary venous return. Our patient demonstrates that limb deficiencies may be a rare component manifestation in this syndrome of multiple congenital anomalies.

Smith DW, Lemli L, Opitz JM.
A newly recognized syndrome of multiple congenital anomalies.
Journal of Pediatrics 1964;64:210-217.

Smithells RW.
Smith-Lemli-Opitz syndrome.
Dev Med Child Neurol 1968;10:663-665.

Sood S, Giacoia GP, Tunnessen WW, Jr.
Picture of the month. Smith-Lemli-Opitz syndrome.
Arch Pediatr Adolesc Med 1994;148:1189-1190.

Sotnikova EN, Zhordania RV, Bukhny AE, Durnov LA, Pogosiants EE.
[Genetics of nephroblastoma. II. The incidence of developmental defects and dysplastic and asymmetrical traits in children with nephroblastoma]. [Russian].
Genetika 1983;19:323-330.
The frequency of developmental defects and displasticity characters in children with nephroblastoma was determined in two groups--with early, up to 2 years manifestation of the tumor (ENB), in 40 patients, and with advanced nephroblastoma (ANB), in 59 patients (manifestation of the disease after 2 years). The data were correlated with control groups adequate for age (130 children). The frequency of serious developmental defects was higher in ANB group (20%) than in ENB group (7%). Over a half of developmental defects were hemihypertrophy and doubling of organs. One case of a child with the combination of nephroblastoma and Smith-Lemli-Opitz syndrome was defined. In ANB group an increased frequency of asymmetry in the conjugate organs (foot, hand, middle finger, ears) was found. Its direction is correlated with tumor localization (tumor site). In ENB group no analogous effect was shown. The data obtained present phenotype characteristics of groups with early and late manifestation of the disease which are probably different in their genesis and thus, their identification is necessary for the adequate medicogenetic consultation (examination).

Srsen S.
Smith-Lemli-Opitz syndrome: report of a new case and review of the literature.
Acta Paediatr Acad Sci Hung 1972;13:301-308.

Srsen S.
[Discussion contribution to the article of E. Seemanova and M. Voriskova "Smith-Lemli-Opitz syndrome in the infant" (Cs. Pediat. 29, 1974, 9 p. 504-6]. [Slovak].
Cesk Pediatr 1975;30:306-308.

Stamellos KD, Shackelford JE, Tanaka RD, Krisans SK.
Mevalonate kinase is localized in rat liver peroxisomes.
Journal of Biological Chemistry 1992;267:5560-5568.

Starck L, Bjorkhem I, Lund E, von Dobeln U.
[New possibilities for children with Smith-Lemli-Opitz syndrome. A cholesterol synthesis defect discovered]. [Review] [14 refs] [Swedish].
Lakartidningen 1995;92:3325-3326, 3329.

Stewart FJ, Nevin NC, Dornan JC.
Prenatal diagnosis of Smith-Lemli-Opitz syndrome [letter; comment].
Am J Med Genet 1995;56:286-287.

Strauss E.
One-eyed animals implicate cholesterol in development [news; comment].
Science 1998;280:1528-1529.

Suzumori K, Yagami Y.
Diagnosis of human fetal abnormalities by fetography.
Teratology 1975;12:303-309.
Being able to detect fetal abnormalities that may be associated with hydramnios would be extremely useful, especially when diabetes mellitus, Rh isoimmunization, and multiple pregnancy are ruled out. For this purpose the new technique of fetography, consisting of injecting a small amount of 2 radioque media (liposoluble and hydrosoluble), was used. Four out of 6 fetuses were correctly predicted to be abnormal. They were 1 case of esophageal atresia, 1 of suspicious chromosomal abnormality (after birth it was confirmed as having the Smith-Lemli-Opitz syndrome), and 2 of trisomy 18. It is felt that this simple technique should be used as an aid to the obstetrician faced with the problem of determining the basis of unexplained hydramnios.

Thompson E, Baraitser M.
An autosomal recessive mental retardation syndrome with hepatic fibrosis and renal cysts.
Am J Med Genet 1986;24:151-158.
Two sisters had developmental retardation and congenital hepatic fibrosis. One, 23 years old, had facial anomalies reminiscent of Smith-Lemli-Opitz syndrome, ocular coloboma, and hypoplastic kidneys with a single cyst. The other sister died at 18 months and had an encephalocele and cystically dilated collecting ducts in the renal medulla. Although the manifestations in these two sisters are similar to the Smith-Lemli-Opitz and Meckel syndromes respectively, there are sufficient differences to suggest that they had a separate autosomal recessive MCA-MR syndrome.

Thompson E, Baraitser M.
Nosology of Smith-Lemli-Opitz syndrome [letter]. [Review] [3 refs].
Am J Med Genet 1987;28:733-734.

Tint GS.
Cholesterol defect in Smith-Lemli-Opitz syndrome [letter].
Am J Med Genet 1993;47:573-574.

Tint GS, Irons M, Elias ER, Batta AK, Frieden R, Chen TS, Salen G.
Defective cholesterol biosynthesis associated with the Smith-Lemli-Opitz syndrome [see comments].
N Engl J Med 1994;330:107-113.
BACKGROUND. The Smith-Lemli-Opitz syndrome (frequency, 1:20,000 to 1:40,000) is defined by a constellation of severe birth defects affecting most organ systems. Abnormalities frequently include profound mental retardation, severe failure to thrive, and a high infant-mortality rate. The syndrome has heretofore been diagnosed only from its clinical presentation. METHODS. Using capillary-column gas chromatography-mass spectrometry, we measured the sterol composition of plasma, erythrocytes, lens, cultured fibroblasts, and feces from five children with the syndrome (three girls and two boys). RESULTS. Plasma cholesterol levels were abnormally low (8 to 101 mg per deciliter [0.20 to 2.60 mmol per liter]) in every patient, being well below the 5th percentile for age- and sex-matched controls. Concentrations of the cholesterol precursor 7-dehydrocholesterol (cholesta-5,7-dien-3 beta-ol), which was not detectable in most of our controls, were elevated (11 to 31 mg per deciliter) more than 2000-fold above normal and were similar to the levels of cholesterol in all tissues from all patients. An isomeric dehydrocholesterol with a structure similar to that of 7-dehydrocholesterol was also detected. CONCLUSIONS. The combination of abnormally low plasma cholesterol levels and a high concentration of the cholesterol precursor 7-dehydrocholesterol points to a major block in cholesterol biosynthesis at the step in which the C-7(8) double bond of 7-dehydrocholesterol is reduced, forming cholesterol. The block may be sufficient to deprive an embryo or fetus of cholesterol and prevent normal development, whereas the incorporation of 7-dehydrocholesterol into all membranes may interfere with proper membrane function.

Tint GS, Salen G, Batta AK, Shefer S, Irons M, Elias ER, Abuelo DN, Johnson VP, Lambert M, Lutz R, et al.
Correlation of severity and outcome with plasma sterol levels in variants of the Smith-Lemli-Opitz syndrome.
J Pediatr 1995;127:82-87.
OBJECTIVES: To determine whether type I and the more severe type II variant of Smith-Lemli-Opitz syndrome have the same metabolic defect and to learn which plasma sterol measurements best predict survival. METHODS: Plasma sterols were measured in 33 individuals (24 type I, 9 type II) with a clinical diagnosis of the syndrome. RESULTS: Cholesterol levels were abnormally low (61 +/- 34 mg/dl) in type I subjects, whereas concentrations of the cholesterol precursor 7-dehydrocholesterol and its isomer 8-dehydrocholesterol were elevated 40- to 10,000-fold. Plasma cholesterol levels were significantly lower and total dehydrocholesterol levels higher in type II than in type I. Six children with the type II variant died by 13 weeks with mean plasma cholesterol levels 6.2 +/- 3.1 mg/dl, versus 17 +/- 11 mg/dl in the three surviving children with type II (p < 0.05). No child with a cholesterol level 7 mg/dl or less lived longer than 13 weeks. CONCLUSIONS: Patients with type I and type II variants of Smith-Lemli-Opitz syndrome have markedly reduced activity of the enzyme that converts 7-dehydrocholesterol to cholesterol, but the extent of the block is far more complete in type II. Survival correlates strongly with higher plasma cholesterol concentrations.

Tint GS, Seller M, Hughes-Benzie R, Batta AK, Shefer S, Genest D, Irons M, Elias E, Salen G.
Markedly increased tissue concentrations of 7-dehydrocholesterol combined with low levels of cholesterol are characteristic of the Smith-Lemli-Opitz syndrome.
J Lipid Res 1995;36:89-95.
The Smith-Lemli-Opitz syndrome is an autosomal recessive birth defect (frequency 1:20,000-1:40,000) that results in profound mental retardation, physical deformities, and failure to thrive. It is characterized biochemically by low plasma cholesterol and greatly elevated levels of two dehydrocholesterols, one of which is the cholesterol precursor 7-dehydrocholesterol. To determine whether the block in cholesterol biosynthesis affects tissue sterols, we assayed several organs from two affected individuals, a female who died at 27 hours and a 20-week male fetus. Cholesterol concentrations in abdominal wall, adrenal gland, and kidney from two or three unaffected fetuses, who served as controls, averaged 2.0, 1.5, and 1.4 mg/g wet weight, compared to 0.08, 0.44, and 0.14, respectively, for the homozygous fetus. Cerebral cortex cholesterol concentrations were 2.2 mg/g for two 20-22-week fetal controls but only 0.21 and 0.09 mg/g, respectively, for the homozygous child and fetus. Similarly, tissue cholesterol levels were abnormally low in the homozygous child being less than 1 mg/g in liver, adipose, thymus, muscle, and adrenal and 6.2 mg/dl in plasma. Dehydrocholesterols could not be detected by conventional means in any controls but were elevated enough in tissues from affected individuals to make total sterol concentrations nearly normal. These results suggest that a defect in 3 beta-hydroxysterol delta 7-reductase leads to both a profound lack of cholesterol and its replacement by dehydrocholesterols. Such a combination may be lethal in the most severely affected individuals.

Tint GS, Honda A, Honda M, Batta AK, Salen G, Chen TS, Xu G, Shefer S.
7­dehydrocholesterol and cholesterol biosynthesis in cultured cells (abstract).
American Journal of Medical Genetics 1996.

Tint GS, Batta AK, Xu G, Shefer S, Honda A, Irons M, Elias ER, Salen G.
The Smith-Lemli-Opitz syndrome: a potentially fatal birth defect caused by a block in the last enzymatic step in cholesterol biosynthesis. [Review] [135 refs].
Subcell Biochem 1997;28:117-144.

Tomaraei SN, Sarkar B, Bansali A, Marwaha RK.
Smith-Lemli-Opitz syndrome.
Indian J Pediatr 1993;60:143-145.

Trasimeni G, Di Biasi C, Iannilli M, Orlandi L, Boscherini B, Balducci R, Gualdi GF.
MRI in Smith-Lemli-Opitz syndrome type I [see comments].
Childs Nerv Syst 1997;13:47-49.
We describe a single case of a polymalformational syndrome in which the MR findings were of great help in the final diagnosis of Smith-Lemli-Opitz syndrome (SLOS) type I. MRI was performed for evaluation of the brain morphology since the clinical and laboratory findings were suggestive but not unequivocally indicative of SLOS. MRI findings of frontal lobe hypoplasia, cortical migration defect, and abnormalities of median line structures prompted the final diagnosis of SLOS.

Tsukahara M, Fujisawa K, Yamamoto K, Hasui M, Saito C, Yamamaka T, Honda A, Honda M, Tint GS, Salen G, Opitz JM.
Smith-Lemli-Opitz syndrome in Japan [letter; comment].
Am J Med Genet 1998;75:118-119.

Tzouvelekis G, Antoniades K, Batma A, Nanas C.
Smith-Lemli-Opitz syndrome in female, monozygotic twins.
Clin Genet 1991;40:229-232.
A pair of monozygotic female twins with SLO syndrome is presented. We have found only one paper in the literature that referred to twins with this rare syndrome. The multiple congenital defects in these cases, consist of limb and genital abnormalities, retardation of growth, mental deficiency, craniofacial defects and abnormal neurological status.

Ullrich K, Koch HG, Meschede D, Flotmann U, Seedorf U.
Smith-Lemli-Opitz syndrome: treatment with cholesterol and bile acids [letter].
Neuropediatrics 1996;27:111-112.

van Rooij A, Nijenhuis AA, Wijburg FA, Schutgens RB.
Highly increased CSF concentrations of cholesterol precursors in Smith-Lemli-Opitz syndrome.
J Inherit Metab Dis 1997;20:578-580.
The Smith-Lemli-Opitz syndrome is a genetic disorder characterized by typical clinical features including reduced myelination of both brain and peripheral nervous system and defective cholesterol biosynthesis. In patients this results in very low cholesterol concentrations and accumulation of cholesterol precursors in plasma, tissues, cultured cells and faeces. We now show that the cholesterol concentration in CSF of Smith-Lemli-Opitz patients is markedly decreased and that 7- and 8-dehydrocholesterol concentrations are highly increased in comparison to controls. Moreover, dietary treatment of patients with cholesterol seems not to affect CSF cholesterol concentration.

Verloes A, Ayme S, Gambarelli D, Gonzales M, Le Merrer M, Mulliez N, Philip N, Roume J.
Holoprosencephaly-polydactyly ('pseudotrisomy 13') syndrome: a syndrome with features of hydrolethalus and Smith-Lemli-Opitz syndromes. A collaborative multicentre study. [Review] [34 refs].
J Med Genet 1991;28:297-303.
A syndrome of holoprosencephaly and postaxial polydactyly, associated with hydrocephalus, heart defect, adrenal hypoplasia, and other visceral malformations, has been observed in five unrelated children with normal chromosomes. Clinical overlap with lethal acrodysgenital dwarfism (Smith-Lemli-Opitz syndrome type II) and hydrolethalus syndrome is discussed. Recessive inheritance seems likely. [References: 34]

Verloes A, Gillerot Y, Langhendries JP, Fryns JP, Koulischer L.
Variability versus heterogeneity in syndromal hypothalamic hamartoblastoma and related disorders: review and delineation of the cerebro-acro-visceral early lethality (CAVE) multiplex syndrome. [Review] [45 refs].
Am J Med Genet 1992;43:669-677.
We report on a case of neonatal hypothalamic hamartoblastoma with holoprosencephaly, Hirschsprung disease, and tetramelic postaxial polydactyly. Twenty-seven previous cases of congenital hypothalamic embryonic tumours with associated congenital defects are reviewed. A classification in isolated, associated, and syndromal forms is proposed. The difficulties encountered in differential diagnosis between the syndromal form (mainly represented by the Pallister-Hall syndrome) and related diseases as Smith-Lemli-Opitz type II, holoprosencephaly-polydactyly, orofaciodigital type VI and hydrolethalus syndromes are outlined. Two pathogenic mechanisms are discussed: a classical pleiotropic model and single sequence model. The latter is sufficient to delineate syndromal hypothalamic hamartoblastoma. With the former, syndromal hypothalamic hamartoblastoma cannot be clearly recognized in the absence of a CNS tumour, a child with syndromal hypothalamic hamartoblastoma cannot be reliably diagnosed as Pallister-Hall rather than another MCA syndrome, and, ultimately, the existence of Pallister-Hall syndrome could be questioned, as it could only be the extreme expression of one or several other syndromes. As this hypothesis cannot be proven or disproven at this point, the authors suggest creating the concept of multiplex phenotype. "Cerebro-Acro-Visceral Early lethality multiplex syndrome" is suggested to encompass all the ambiguous cases. Within this complex, an operative classification key is proposed. [References: 45]

Verloes A.
Numerical syndromology: a mathematical approach to the nosology of complex phenotypes.
Am J Med Genet 1995;55:433-443.
Numerical taxonomy is defined by Sneath and Sokal as the grouping of taxonomic units on the basis of their character states by numerical methods of multivariate data analysis, and syndromology as the study of multiple congenital anomaly (MCA) syndromes and of their nosology. We present here an application of those methods to the analysis of overlapping syndromes. The main advantage of numerical taxonomy is that it allows simultaneous objective and unweighted analysis of multiple traits, giving the possibility to test mathematically the clinical hypotheses about the heterogeneity between closely resembling syndromes and uncovering objective patterns of anomalies, to be compared with the subjective pattern recognition process which characterizes most of the diagnostic approach in syndromology. In this paper, we explored 5 syndromes whose most severe expression belongs to the cerebroacrovisceral early lethality (CAVE) phenotype: hydrolethalus, severe Smith-Lemli-Opitz, orofaciodigital type VI (Varadi-Papp), holoprosencephaly-polydactyly, and Pallister-Hall syndromes. Fifty-five published cases, including many overlapping cases, were submitted to principal factor analysis followed by hierarchical clustering and graphical scaling. Results show that the 5 syndromes clearly constitute independent phenotypic entities, that some of the original diagnoses have to be reconsidered, and that many of the overlapping cases may be unambiguously set in one category. Hypothalamic hamartoblastoma appears to be a nonspecific dysplasia occurring in any of the 5 disorders.

Wallace M, Zori RT, Alley T, Whidden E, Gray BA, Williams CA.
Smith-Lemli-Opitz syndrome in a female with a de novo, balanced translocation involving 7q32: probable disruption of an SLOS gene.
Am J Med Genet 1994;50:368-374.
A 3-month-old infant girl had manifestations of the Smith-Lemli-Opitz syndrome (SLOS) including typical positional anomalies of the limbs, apparent Hirschsprung disease, cataracts, ptosis, anteverted nares, cleft of the posterior palate, small tongue, broad maxillary alveolar ridges, and abnormally low serum cholesterol levels. Chromosomal analysis showed a de novo balanced translocation interpreted as 46,XX,t(7;20)(q32.1;q13.2). We hypothesize that the translocation breakpoint in this case interrupts one SLOS allele and that the other allele at the same locus has a more subtle mutation that was inherited from the other parent. This case, as well as cytogenetic observations in other SLOS cases, suggests that SLOS could be due to autosomal recessive mutation at a gene in 7q32.

Wanders RJ, Romeijn GJ, Wijburg F, Hennekam RC, de Jong J, Wevers RA, Dacremont G.
Smith-Lemli-Opitz syndrome: deficient delta 7-reductase activity in cultured skin fibroblasts and chorionic villus fibroblasts and its application to pre- and postnatal detection.
J Inherit Metab Dis 1997;20:432-436.

Warburg M, Bugge M, Brondum-Nielsen K.
Cytogenetic findings indicate heterogeneity in patients with blepharophimosis, epicanthus inversus, and developmental delay.
J Med Genet 1995;32:19-24.
Three unrelated, mentally retarded boys with typical blepharophimosis-ptosis-epicanthus inversus syndrome (BPES) were found to have chromosomal aberrations. One of them had a del(3)(p25), another patient had a de novo translocation t(2; 3), which after high resolution banding combined with chromosome painting was interpreted to be unbalanced with a loss of band q23. The third patient had a del(7)(q34). The phenotypes of the two patients with chromosome 3 related syndromes were similar, but the third also had genital malformations resembling the Smith-Lemli-Opitz syndrome. This patient had a palatal ridge, and a single mesial maxillary tooth suggesting the holoprosencephaly sequence, but CT scans of the brain were normal.

Weed M, Mundlos S, Olsen BR.
The role of sonic hedgehog in vertebrate development. [Review] [53 refs].
Matrix Biol 1997;16:53-58.
Members of the hedgehog family are important signalling molecules during embryonic development. One member, Sonic hedgehog, is expressed in embryonic structures such as the zone of polarizing activity in the posterior limb bud, the notochord, and the floor plate of the neural tube, where it plays a role in patterning of the embryo. Sonic hedgehog is synthesized as an inactive precursor which must be proteolytically cleaved and modified by the addition of a cholesterol moiety to become active as a signalling molecule. In this processing, the C-terminal region of Sonic hedgehog serves as both the endoprotease and a cholesterol transferase. The importance of cholesterol for Sonic hedgehog function may explain many of the profound developmental defects caused by perturbations of cholesterol metabolism. The receptor for Sonic hedgehog is Patched, a multi-pass transmembrane protein which forms a complex with Smoothened Mutations in Patched are associated with basal cell naevus syndrome, while mutations in Sonic hedgehog cause holoprosencephaly. Downstream targets of Sonic hedgehog signalling are transcription factors like Gli3, responsible for Greigs polycephalosyndactyly in humans and Hoxd13, responsible for polysyndactyly. [References: 53]

Weiss MC, Baumgart E, Fahimi HD, Pill H, Rebel W, Hartig F.
[Elevation of 7-dehydrocholesterol concentrations in serum and liver and pericentral peroxisome proliferation in hepatocytes of rats after inhibition of cholesterol biosynthesis by BM 15,766]. [German].
Berl Munch Tierarztl Wochenschr 1995;108:66-69.
Sprague-Dawley rats of both sexes were treated for three months with BM 15,766, an inhibitor of cholesterol biosynthesis in conjunction with standard or high-fat and high-cholesterol diets. In serum and livers of all drug-treated rats lowered cholesterol concentration associated with an increase of 7-dehydrocholesterol (7-DHC) was found. Electron microscopy of the liver showed a distinct proliferation of peroxisomes and an increase of dumb-bell shaped mitochondria in the pericentral zone 3. Abnormal-shaped peroxisomes with DAB-negative loops attached to their membranes were found in the intermediate zone 2. These alterations were more accentuated in drug-treated rats fed standard diet, then in treated rats receiving a high-fat and high-cholesterol diet. The observations demonstrate, that the increase of 7-DHC is due to the inhibition of 7-DHC-delta 7-reductase by BM 15.766 and emphasize the zonal heterogeneity of hepatocytes. The relevance of these observations for the investigation of the human Smith-Lemli-Opitz syndrome, in which also decreased plasma-cholesterol levels and an increase of 7-DHC were reported, is discussed.

Wolf C, Chevy F, Pham J, Kolf-Clauw M, Citadelle D, Mulliez N, Roux C.
Changes in serum sterols of rats treated with 7-dehydrocholesterol-delta 7-reductase inhibitors: comparison to levels in humans with Smith-Lemli-Opitz syndrome.
J Lipid Res 1996;37:1325-1333.
The impaired conversion of 7-dehydrocholesterol to cholesterol, as a result of a permanent inhibition of the activity of 7-dehydrocholesterol-delta 7-reductase, has been reported in the Smith-Lemli-Opitz (SLO) syndrome (1, 2). For the purpose of experimental teratology, an animal disease model consisting of the offspring of pregnant rats treated with AY 9944 or BM 15766, inhibitors of 7-dehydrocholesterol-delta 7-reductase, was established. The present study compares the profiles of sterols in rat serum, obtained after transient treatment with inhibitors, with profiles of sterols obtained from patients with the permanent enzyme defect. AY 9944 (single dose of 50, 75, or 100 mg/kg) or BM 15766 (60, 75, or 90 mg/kg per day for 11 days) induces hypocholesterolemia and accumulation of 7-dehydrocholesterol and aberrant sterols in rat serum. The aberrant sterols in the treated rats are similar to those detected in human SLO patients by gas chromatography coupled to mass spectrometry (1, 3, 4) and were identified as 7- and 8-dehydrocholesterol, two trienols (I and II), and 19-nor-5,7,9(10)-cholestatrien-3 beta-ol. The time- and dose-dependences of the biochemical alterations are compared to the teratogenic abnormalities induced by inhibitors. The dietary cholesterol supplementation that suppresses embryo malformations induced by AY 9944 prevents severe hypocholesterolemia and decreases the aberrant sterol levels. As a function of time after intoxication, the 8-dehydrocholesterol to 7-dehydrocholesterol ratio increases, suggested that 8-dehydrocholesterol is derived from the gradual conversion of the accumulated 7-dehydrocholesterol. The ratio of 8-dehydrocholesterol to 7-dehydrocholesterol is higher in human SLO than in the animal disease model. This may be explained by a permanent block in 7-dehydrocholesterol-delta 7-reductase in SLO compared to a transient inhibition of this enzyme in the animal model.

Worthington S, Goldblatt J.
Smith-Lemli-Opitz syndrome: further delineation of the phenotype.
Clin Dysmorphol 1997;6:263-266.

Wulfsberg EA, Curtis J, Jayne CH.
Chondrodysplasia punctata: a boy with X-linked recessive chondrodysplasia punctata due to an inherited X-Y translocation with a current classification of these disorders. [Review] [46 refs].
Am J Med Genet 1992;43:823-828.
Chondrodysplasia punctata (CDP) is a heterogeneous group of rare bone dysplasias characterized by punctate calcification of cartilage. The punctate calcifications are non-specific and have been seen in a wide variety of disorders including the Zellweger syndrome, warfarin, dilantin, alcohol and rubella embryopathies, vitamin-K-epoxide-reductase deficiency, chromosome trisomies 18 and 21, the Smith-Lemli-Opitz syndrome, prenatal infectious chondritis, hypothyroidism, and other rare disorders. We report on a boy with short stature, developmental delay, nasal hypoplasia, telebrachydactyly, hypoplastic genitalia, CDP, ichthyosis, hypoplastic genitalia, and a 46-X,+der(X),t(X;Y)(p22.31;q11.21), Y karyotype. Genomic DNA probe analysis was interpreted as showing that the translocation breakpoint was within the X-linked Kallmann syndrome gene. We review a current classification of these disorders that includes 3 well-defined single gene disorders. These include an autosomal recessive rhizomelic type with early lethality, an X-linked dominant type with presumed male lethality, and an X-linked recessive type that has only been described as part of a contiguous gene deletion syndrome. [References: 46]

Xu G, Salen G, Shefer S, Ness GC, Chen TS, Zhao Z, Tint GS.
Reproducing abnormal cholesterol biosynthesis as seen in the Smith-Lemli-Opitz syndrome by inhibiting the conversion of 7-dehydrocholesterol to cholesterol in rats [see comments].
J Clin Invest 1995;95:76-81.
The Smith-Lemli-Opitz syndrome is a recessive inherited disorder characterized by neurologic developmental defects and dysmorphic features in many organs. Recently, abnormal cholesterol biosynthesis with impaired conversion of 7-dehydrocholesterol to cholesterol has been discovered in homozygotes. To reproduce the biochemical abnormality, BM 15.766, a competitive inhibitor of 7-dehydrocholesterol-delta 7-reductase, the enzyme that catalyzes the conversion of 7-dehydrocholesterol into cholesterol was fed by gavage to rats. After 14 d, plasma cholesterol concentrations declined from 48 mg/dl to 16 mg/dl and 7-dehydro-cholesterol levels rose from trace to 17 mg/dl. Hepatocytes surrounding the central vein developed balloon necrosis. Stimulating cholesterol synthesis with cholestyramine followed by BM 15.766 produced an additional 40% decline (P < 0.05) in plasma cholesterol and 34% increase in 7-dehydrocholesterol levels compared to the inhibitor alone. Adding 2% cholesterol to the diet during the second week of BM 15.766 treatment increased plasma cholesterol threefold and decreased 7-dehydrocholesterol concentrations 55%. Hepatic 3-hydroxy-3-methylglutaryl co-enzyme A (HMG-CoA) reductase activity increased 73% with a 3.9-fold rise in mRNA levels but cholesterol 7 alpha-hydroxylase activity decreased slightly though mRNA levels increased 1.4 times with BM 15.766 treatment. These results demonstrate that BM 15.766 is a potent inhibitor of 7-dehydrocholesterol-delta 7-reductase. The model reproduces abnormal cholesterol biosynthesis as seen in the Smith-Lemli-Opitz syndrome and is useful to test different treatment strategies. Stimulating early steps of cholesterol synthesis worsens the biochemical abnormalities while feeding cholesterol inhibits abnormal synthesis, improves the biochemical abnormalities and prevents liver damage.

Xu G, Salen G, Shefer S, Ness GC, Chen TS, Zhao Z, Salen L, Tint GS.
Treatment of the cholesterol biosynthetic defect in Smith-Lemli-Opitz syndrome reproduced in rats by BM 15.766.
Gastroenterology 1995;109:1301-1307.
BACKGROUND & AIMS: The Smith-Lemli-Opitz syndrome is a recessive inherited disorder characterized by neurological developmental defects and dysmorphic features with a defect in cholesterol synthesis at the conversion of 7-dehydrocholesterol to cholesterol. BM 15.766 inhibits 7-dehydrocholesterol-delta 7-reductase and reproduces the biochemical defect. The aim of this study was to investigate the effects of cholesterol, cholic acid, and lovastatin feeding on rats fed BM 15.766. METHODS: Plasma cholesterol and 7-dehydrocholesterol concentrations were related to the hepatic 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase. RESULTS: With the inhibitor treatment, plasma cholesterol concentrations decreased 67%; 7-dehydrocholesterol concentrations increased from trace to 17 mg/dL; and hepatic HMG-CoA reductase activity and messenger RNA levels were stimulated 74% and two times, respectively. In inhibitor-treated rats, feeding cholesterol increased plasma cholesterol concentrations 3.7 times, decreased 7-dehydrocholesterol concentrations 88%, and reduced elevated HMG-CoA reductase activity and messenger RNA levels 74% and 49%. Feeding cholic acid increased plasma cholesterol without reducing 7-dehydrocholesterol concentrations. The combination of cholic acid and cholesterol enhanced plasma cholesterol 9.5 times without decreasing 7-dehydrocholesterol levels. Feeding lovastatin depressed plasma cholesterol further without reducing 7-dehydrocholesterol levels. CONCLUSIONS: Cholesterol is essential to correct abnormal cholesterol synthesis induced by BM 15.766 in rats by expanding the pool and inhibiting HMG-CoA reductase. Neither cholic acid nor lovastatin are effective separately, but cholic acid plus cholesterol may offer some additional benefit.

Yang SP, Bidichandani SI, Figuera LE, Juyal RC, Saxon PJ, Baldini A, Patel PI.
Molecular analysis of deletion (17)(p11.2p11.2) in a family segregating a 17p paracentric inversion: implications for carriers of paracentric inversions.
Am J Hum Genet 1997;60:1184-1193.
A male child with multiple congenital anomalies initially was clinically diagnosed as having Smith-Lemli-Opitz syndrome (SLOS). Subsequent cytogenetic studies revealed an interstitial deletion of 17p11.2, which is associated with Smith-Magenis syndrome (SMS). Biochemical studies were not supportive of a diagnosis of SLOS, and the child did not display the typical SMS phenotype. The father's karyotype showed a paracentric inversion of 17p, with breakpoints in p11.2 and p13.3, and the same inversion was also found in two of the father's sisters. FISH analyses of the deleted and inverted 17p chromosomes indicated that the deletion was similar to that typically seen in SMS patients and was found to bracket the proximal inversion breakpoint. Available family members were genotyped at 33 polymorphic DNA loci in 17p. These studies determined that the deletion was of paternal origin and that the inversion was of grandpaternal origin. Haplotype analysis demonstrated that the 17p11.2 deletion arose following a recombination event involving the father's normal and inverted chromosome 17 homologues. A mechanism is proposed to explain the simultaneous deletion and apparent "reinversion" of the recombinant paternal chromosome. These findings have implications for prenatal counseling of carriers of paracentric inversions, who typically are considered to bear minimal reproductive risk.

Yunis E, Gonzalez J, Zuniga R, Torres de Caballero OM, Mondragon A.
Direct duplication 2p14 to 2p23.
Hum Genet 1979;48:241-244.
A malformed male newborn was first diagnosed as having Smith-Lemli-Opitz syndrome. Extensive cytogenetic studies, including Q, G, C, R and T banding and BudR treatment, were applied, finally leading the authors to conclude that the patient had a partial 2p trisomy caused by direct duplication 2p14 to 2p23. This was a de novo chromosome abnormality, as both parents had normal karyotypes.

Zellweger H, Bardach J, Bordwell J, Williams K.
The short arm deletion syndrome of chromosome 4 (4p- syndrome).
Arch Otolaryngol 1975;101:29-32.
Partial deletion of the short arm of chromosome 4 (4p-) represents another (rare) cause of cleft lip and cleft palate. Further characteristic manifestations of the syndrome (also called Wolf or Wolf-Hirschhorn syndrome) are growth failure, microcephaly, prominent glabella, hypertelorism, beaked nose, poorly differentiated and low set ears, cardiac and renal malformation and hypospadias. Life expectancy is often shortened. The 4p- syndrome has many features in common with another deletion syndrome, the cri-du-chat syndrome, and also with the Smith-Lemli-Opitz syndrome. The latter is a hereditary condition with normal karyotype. The cri-du-chat syndrome is characterized by a peculiar high-pitched, mewing cry and can be differentiated from the Wolf syndrome by the different staining characteristics (banding) of chromosomes 4 and 5.

Zimmerman PA, Hercules DM, Naylor EW.
Direct analysis of filter paper blood specimens for identification of Smith-Lemli-Opitz syndrome using time-of-flight secondary ion mass spectrometry.
Am J Med Genet 1997;68:300-304.
In this study, time-of-flight secondary ion mass spectrometry was used to distinguish between blood of normal infants and that of individuals with Smith-Lemli-Opitz (SLO) syndrome. SLO syndrome results in an abnormally low concentration of blood cholesterol and an elevated concentration of 7-dehydrocholesterol. Blood was spotted on filter paper and analyzed directly with no extractions or separations. Results showed that using ratios of fragment ions for cholesterol/dehydrocholesterol, patients with SLO and normal individuals could be unambiguously distinguished. Unknown samples from 28 individuals were obtained and identified correctly.

Zizka J, Maresova J, Kerekes Z, Nozicka Z, Juttnerova V, Balicek P.
Intestinal aganglionosis in the Smith-Lemli-Opitz syndrome.
Acta Paediatr Scand 1983;72:141-143.

Zucker JM, Job JC, Rossier A.
[A new variety of dystrophic intra-uterine nanism: Smith, Lemli and Opitz syndrome]. [French].
Ann Pediatr (Paris) 1967;14:2409-2411.

Zucker JM, Job JC, Rossier A.
[A new variety of dystrophic intra-uterine nanism: Smith, Lemli and Opitz syndrome]. [French].
Ann Pediatr 1967;14:2409-2411.