Alternative titles; symbols
SNOMEDCT: 43929004; ICD10CM: E78.72; ORPHA: 818; DO: 14692;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 11q13.4 | Smith-Lemli-Opitz syndrome | 270400 | Autosomal recessive | 3 | DHCR7 | 602858 |
A number sign (#) is used with this entry because Smith-Lemli-Opitz syndrome (SLOS) is caused by homozygous or compound heterozygous mutation in the gene encoding sterol delta-7-reductase (DHCR7; 602858), which maps to chromosome 11q13.
Smith-Lemli-Opitz syndrome is an autosomal recessive multiple congenital malformation and mental retardation syndrome. Although historically a clinical distinction was often made between a classic 'type I' disorder and a more severe 'type II' disorder, in reality the syndrome constitutes a clinical and biochemical continuum from mild to severe (Opitz et al., 1987; Cunniff et al., 1997; Kelley, 1998).
The discovery of the deficiency of 7-dehydrocholesterol reductase as a causative factor of the SLO syndrome (Tint et al., 1994) made this syndrome the first true metabolic syndrome of multiple congenital malformations. A multidisciplinary National Institute of Child Health and Human Development (NICHD) conference of the SLO syndrome reviewed different implications of this discovery and proposed further studies in this field. A detailed report on this conference and abstracts of presentations were provided by Opitz and de la Cruz (1994). Observations presented at an NICHD RSH/SLOS conference in September 1995 were reviewed by Kelley (1997). Kelley (1998) referred to SLOS as a metabolic malformation syndrome, but suggested that this may be an exception. Most mutations that had been related to multiple congenital malformation syndromes, i.e., disturbances of the body plan, have not been disorders of intermediary metabolism but, instead, mutations of homeobox genes and other transcriptional regulators and signaling systems.
Opitz et al. (1987) gave a presumedly complete bibliography of the SLO syndrome, which was updated by Opitz et al. (1994) and included almost 200 references. They concluded that lumping SLO syndrome with the Pallister-Hall hamartoblastoma syndrome (PHS; 146510) is not justified. In a given severe case, differentiation from the Meckel syndrome (249000) may be a challenge.
Herman (2003) reviewed the cholesterol biosynthetic pathway and the 6 disorders involving enzyme defects in post-squalene cholesterol biosynthesis: SLOS, desmosterolosis (602398), X-linked dominant chondrodysplasia punctata (CDPX2; 302960), CHILD syndrome (308050), lathosterolosis (607330), and hydrops-ectopic calcification-moth-eaten skeletal dysplasia (HEM; 215140).
The SLOS syndrome was designated RSH syndrome by Smith et al. (1964); the acronym was derived from the surnames of the first 3 families identified with the disorder.
Smith et al. (1964) reported 3 unrelated males with a strikingly similar combination of congenital anomalies: microcephaly, mental retardation, hypotonia, incomplete development of the male genitalia, short nose with anteverted nostrils, and, in 2, pyloric stenosis. A deceased male sib of one of these was probably affected. No parental consanguinity was discovered. Pauli et al. (1997) reassessed 1 of the patients reported by Smith et al. (1964) at age 34 years and described his physical, developmental, and behavioral manifestations. He was indeed found to have a cholesterol biosynthetic defect. A high cholesterol diet had been instituted and appeared to have had a beneficial effect on his behavior.
Pinsky and DiGeorge (1965) reported affected brother and sister. Blair and Martin (1966) also described the condition in brother and sister. The male had hypospadias. Dallaire and Fraser (1966) described affected brothers and noted that blepharoptosis has been a feature of many cases. Lowry et al. (1968) described the combination of micrognathia, polydactyly, and cleft palate, resembling the syndrome known in the German literature as 'Typus Rostockiensis' or 'Ullrich-Feichtiger syndrome' but suggesting the Smith-Lemli-Opitz syndrome with respect to dermatoglyphics. Hoefnagel et al. (1969) and Fried and Fraser (1972) reported cases in adults. Syndactyly of toes 2 and 3 was said to be a frequent finding (Cowell, 1978).
In 3 infants, including a brother and sister, Rutledge et al. (1984) described what they considered to be a 'new' lethal malformation syndrome. External features were mesomelic dwarfism, micrognathia, V-shaped upper lip, microglossia, thick alveolar ridges, ambiguous genitalia, webbed neck, highly arched palate, clubfeet, fused fontanels, inclusion cysts of the tongue, widely spaced nipples, and digital anomalies. Internal findings included oligopapillary renal hypoplasia, severe congenital heart defect, cerebellar hypoplasia, and pulmonary, laryngeal, and gallbladder hypoplasia. Both affected sibs showed polydactyly.
Donnai et al. (1986) reported 3 unrelated infants with moderate limb shortening, joint contractures, and polydactyly. Two with an XY karyotype showed female external genitalia. Internal anomalies included unilobar lungs, hypoplasia of the anterior part of the tongue, and renal hypoplasia. Donnai et al. (1986) suggested that the disorder in their patients and in those reported by Lowry et al. (1968) and Kohler (1983) was not Smith-Lemli-Opitz syndrome, but a distinct disorder for which they suggested the designation Lowry-Miller-MacLean syndrome.
Curry et al. (1987) gave an extensive review of 19 previously unreported patients with the disorder for which they suggested the designation Smith-Lemli-Opitz syndrome type II. Eighteen of their 19 patients had postaxial hexadactyly, 16 had congenital heart defects, 13 had cleft palate, and 10 had cataracts. Unusual findings at autopsy included Hirschsprung disease in 5, unilobar lungs in 6, large adrenals in 4, and pancreatic islet cell hyperplasia in 3. Early lethality was common. They found reports of 19 similar cases in the literature. Their report supported autosomal recessive inheritance by occurrence in 1 pair of sibs in their study and the report of recurrence in 3 of the reported families. Belmont et al. (1987) reported 2 cases of severe lethal SLOS. Eight cases of the same condition were described by Le Merrer et al. (1988), who suggested the designation of 'lethal acrodysgenital dwarfism.' Patients had failure to thrive, facial dysmorphism, ambiguous genitalia, syndactyly, postaxial polydactyly, and internal developmental anomalies such as Hirschsprung disease and cardiac and renal malformations. One of their cases showed parental consanguinity, and in another family 2 sibs were affected.
Failure of masculinization in the SLO syndrome was emphasized by Patterson et al. (1983) and by Greene et al. (1984). Ambiguity of the external genitalia is a frequent feature of males. As shown by the case reported by Scarbrough et al. (1986) and 4 previously reported cases, in extreme instances there is complete failure of development of male external genitalia despite normal XY karyotype. This situation is similar to that in camptomelic dysplasia (114290). In a study of cases from the institution at which SLO syndrome was first described, Joseph et al. (1987) reviewed the genitourinary findings and reported upper urinary tract abnormalities in 57% and genital abnormalities in 71%. Bialer et al. (1987) reported a 46,XY infant with SLO syndrome with female external genitalia, intraabdominal testes with epididymides and deferent ducts, and a normally shaped uterus and vagina, polydactyly, cleft palate, and abnormalities of the kidneys, liver, and lungs. They reviewed 121 cases of SLO syndrome from the literature using a scoring system for severity. In 19 multiplex families, the affected sibs were generally similar in their SLOS scores. Overall degree of severity was positively correlated with genital abnormalities in males, polydactyly, and cleft palate.
On the basis of studies of 2 cases of SLOS, McKeever and Young (1990) raised the question of a primary defect in the fetal adrenals resulting in a combination of low maternal estriol levels, sex reversal, and large adrenal glands in the fetus. Complete absence of lipid was observed in the adrenal cortex of 1 case. They suggested that the apparent suppression of maternal adrenal function in late pregnancy might, however, be secondary to fetomaternal transfer of an adrenal steroid that could not be processed normally by the fetal adrenals.
Lachman et al. (1991) described a phenotypic female with SLOS and a 46,XY karyotype. The child also had clinical hypoglycemia with nesidioblastosis of the pancreas and died on the fifth day of life. An unusually high serum testosterone level suggested a possible defect in testosterone conversion to dihydrotestosterone or a deficiency of end-organ receptors for dihydrotestosterone. In an infant with SLO syndrome and 46,XY karyotype but normal internal and external genitalia of the female type, Fukazawa et al. (1992) found all normal sequences on the Y chromosome, using probes for 26 'loci' including SRY, the presumed gene for testis-determining factor (480000).
Cunniff et al. (1997) reported the clinical and biochemical spectra of 80 patients (68 index cases and 12 family members) with abnormally increased levels of 7-dehydrocholesterol. The phenotypic spectrum ranged from isolated syndactyly of toes 2 and 3 to holoprosencephaly and multiple visceral anomalies resulting in death in utero. Plasma cholesterol concentration was inversely correlated with clinical severity. Little relationship was seen between severity score and 7-dehydrocholesterol concentration. However, 10% of patients had normal serum cholesterol concentrations and would have been missed without quantification of 7-dehydrocholesterol. Syndactyly of toes 2 and 3 was found in 79 of the 80 patients. Johnson (1975) reported 2/3 toe syndactyly in only 73% of his 55 SLO syndrome patients. This finding suggested to Cunniff et al. (1997) that as many as one quarter of previously documented SLOS patients may have had a different genetic disorder.
Ryan et al. (1998) reported a review of all known cases of SLOS in the U. K. A total of 86 cases were initially identified with a diagnosis of SLOS, and a group of 49 with proven 7-dehydrocholesterol reductase deficiency were studied. Thirty-five (71%) were male. Twenty-four individuals were alive at the time of study; 20 had died, including 1 stillbirth, and 5 fetuses had been terminated. The frequent occurrence of hypospadias was thought to account for the high percentage of recognized cases being male. Mental retardation was present in 23 of 25 individuals; photosensitivity in 13 of 24; abnormal sleep pattern in 16 of 23; microcephaly in 32 of 40; short or proximally placed thumbs in 24; and congenital cardiac abnormalities in 18, with an atrioventricular septal defect present in 6. The typical facial appearance was found to become less obvious with age, and 20% of cases did not have 2/3 toe syndactyly. Serum 7-dehydrocholesterol levels did not correlate with clinical severity.
Anderson et al. (1998) reported 2 sibs with variant SLOS and atypical sterol metabolism. Both sibs had mild growth retardation, mild developmental delay, ptosis, micrognathia, and mild syndactyly of toes 2 and 3. They both had low plasma cholesterol, but higher than that typically seen in SLOS patients. In addition, they both had only modest elevations of plasma 7-dehydrocholesterol. The parents had higher 7-dehydrocholesterol/cholesterol ratios compared to those of parents of classic SLOS patients. The authors postulated that this milder phenotype with more severe abnormalities of sterol metabolism in patients and parents may represent a phenocopy of classic SLOS. Alternatively, the Southeastern Cherokee ancestry shared by the parents may have affected the phenotype.
Nowaczyk et al. (1998) reported 2 brothers and their female first cousin, all of nonconsanguineous unions, with mild SLOS. All children had moderate mental retardation and syndactyly of toes 2 and 3, but mild facial abnormalities. The brothers had mild ptosis, anteverted nares, mild micrognathia, and normal genitalia. The girl had mild retrognathia and syndactyly of the second and third toes apparent only from the plantar aspect. The authors suggested that the delay in diagnosis for these children, 31 months for the older brother and 11 years for the cousin, was due to lack of knowledge about SLOS among general and developmental pediatricians. They also suggested that the carrier rate of 1 to 2% among northern European Caucasians may be too low. Nowaczyk et al. (2001) reported the DHCR7 mutations in this family. The brothers' father had the rare thr289-to-ile missense mutation (T289I; 602858.0015). The 2 unrelated mothers were carriers of the common IVS8-1G-C (602858.0001) mutation. All 3 affected cousins had the IVS8-1G-C/T289I genotype. The authors suggested that the observed incidence of IVS8-1G-C homozygotes may be underestimated because of prenatal or perinatal lethality.
Atchaneeyasakul et al. (1998) reviewed the ophthalmologic findings in 8 children with SLOS and documented abnormal concentrations of cholesterol and cholesterol precursors in the ocular tissues in 1 case. The most common ophthalmologic finding was blepharoptosis (6 of 8), with the severity ranging from mild to moderate. None of the patients demonstrated cataracts or amblyopia from blepharoptosis. One patient had a right hypertropia with overaction of the inferior oblique muscle. This patient also had optic atrophy, and a second patient had bilateral optic nerve hypoplasia.
Anstey and Taylor (1999) conducted a questionnaire-based survey to determine the incidence and main features of photosensitivity in SLOS. They confirmed a high incidence, and initial evidence suggested that SLOS may be the first example of an inherited photosensitivity disorder in which sensitivity to UVA is common.
Andersson et al. (1999) described 3 unrelated patients with SLOS who presented with hyponatremia, hyperkalemia, and decreased aldosterone-to-renin ratio. Two patients were newborns, 46,XY with complete failure to masculinize; 1 also had cortisol deficiency. Both died within 10 days of cardiopulmonary complications while on adrenal replacement therapy. The third patient was diagnosed with SLOS at birth and presented with adrenal insufficiency at 7 months; normal serum electrolytes were maintained with mineralocorticoid replacement. Nowaczyk et al. (2001) stated that adrenal insufficiency in the 3 patients reported by Andersson et al. (1999) was thought to be caused by aldosterone deficiency because it responded to mineralocorticoid replacement. They presented a fourth patient with a severe form of SLOS and adrenal insufficiency who had unexplained persistent hypertension, a combination of signs apparently not previously reported in this disorder.
Tierney et al. (2001) used multiple age-dependent questionnaires and telephone interviews to evaluate the behavioral phenotype of 56 subjects with SLOS. They concluded that individuals with SLOS manifest a characteristic behavioral profile of cognitive delay, sensory hyperreactivity, irritability, language impairment, sleep-cycle disturbance, self-injurious behavior, syndrome-specific motor movements, and autism spectrum behaviors (209850). Sikora et al. (2006) used 3 different diagnostic measures of autism, including parental interview, direct observation, and a behavior checklist, to evaluate 14 children with SLOS ranging from 3 to 16 years. Approximately 75% of the children (71 to 86% depending on the evaluation method) had an autism spectrum disorder: about 50% with autistic disorder and the rest with pervasive developmental disorder. The presence or severity of autistic symptoms did not correlate with cholesterol levels. Sikora et al. (2006) suggested a link between cholesterol metabolism and autism.
Irons et al. (1993) reported studies of 2 unrelated female patients, aged 6 months and 10 years, with the SLO syndrome. Plasma cholesterol concentrations in both subjects were very low and 7-dehydrocholesterol was detected in the plasma. (7-Dehydrocholesterol is the penultimate sterol in the Kandutsch-Russell cholesterol biosynthetic pathway.) Cholesterol accounted for only 9% of total fecal neutral sterols, and the feces contained, at best, only trace quantities of bile acids. A defect in cholesterol synthesis was suggested by the abnormally low plasma cholesterol concentrations and fecal excretion, and the accumulation of 7-dehydrocholesterol pointed to a likely defect in the enzyme that reduces the C-7,8 double bond of this intermediate. The reexamination of 2 previously reported patients and the study of 2 new patients by Irons et al. (1994) gave basically the same results, although a girl with more severe clinical manifestations had more pronounced biochemical abnormalities. Reduced myelination in the cerebral hemispheres, cranial nerves, and peripheral nerves is explained by the enzymatic defect. See Tint et al. (1993).
Tint et al. (1995) examined the correlation between severity and outcome on the one hand and plasma sterol levels on the other in 33 patients with SLOS, 24 referred to as having type I and 9 as having type II. All of the patients had markedly reduced activity of the enzyme that converts 7-dehydrocholesterol to cholesterol, but the extent of the block was far more complete in the clinically severe type II. Survival correlated strongly with higher plasma cholesterol concentrations. In contrast, Cormier-Daire et al. (1996) found no such correlation between plasma cholesterol (or 7-DHC) and the severity of SLOS in their 7 patients (5 with SLOS type I and 2 with SLOS type II). Notably, the authors also reported detectable trienol levels in all 7 patients.
Shefer et al. (1995) found a 9-fold reduction of the double bond at C-7 in 7-dehydrocholesterol to yield cholesterol, catalyzed by 7-dehydrocholesterol-delta(7)-reductase, in microsomes from SLOS homozygotes, as compared with controls. This and other results confirmed that lathosterol and 7-dehydrocholesterol are precursors in the pathway of cholesterol biosynthesis and that hepatic microsomal 7-dehydrocholesterol-delta(7)-reductase is the site of the enzyme deficiency in SLO syndrome.
Salen et al. (1996) provided a review of abnormal cholesterol biosynthesis in the SLO syndrome. Seller et al. (1997) illustrated the great usefulness of the biochemical tests for SLOS because of the wide phenotypic variation even between affected sibs. They reported 4 cases illustrating the phenotypic variability.
In lymphoblasts from 3 unrelated SLOS patients with distinct phenotypes, Neklason et al. (1999) found biochemical differences in the ability to convert 7-dehydrocholesterol to cholesterol, which corresponded to the clinical severity of the disease. The authors suggested that the observed biochemical differences likely resulted from different mutations in the DHCR7 gene.
In a patient with SLOS, Honda et al. (2000) found that hepatic microsomal 7-dehydrocholesterol delta-7-reductase activity was less than 1% of control mean. The patient's microsomes also showed decreased cholesterol concentration and markedly increased 7- and 8-dehydrocholesterol concentrations. HMG-CoA synthase and squalene synthase activities in the patient were upregulated to 149% and 532%, respectively, while the activity of HMG-CoA reductase, the rate-limiting enzyme in the pathway, was reduced to 39% of the control mean. The latter observation was supported by the low levels of mevalonic acid in 9 additional SLOS patients. The findings indicated that HMG-CoA reductase was not stimulated in SLOS patients in spite of blocked cholesterol biosynthesis.
In 2 adult brothers formerly described as having SLO syndrome (de Die Smulders and Fryns, 1990), de Die Smulders et al. (1996) reported confirmation of the diagnosis by the finding of low levels of cholesterol (15 to 27% of normal) and very high levels of 7-dehydrocholesterol.
Guzzetta et al. (1996) collected 20 patients suspected of having SLOS by 11 Italian pediatric or clinical genetic centers. In 10 patients, the diagnosis was confirmed biochemically by gas chromatography/mass spectrometry (GC/MS) analysis of serum sterols; the serum sterol profiles in the other 10 patients were normal. A comparison of confirmed SLOS patients to biochemically negative subjects did not identify clinical signs specific for the syndrome. Ultraviolet spectrophotometry measurement of 7-dehydrocholesterol correlated well with GC/MS profiles, showing 100% sensitivity and specificity. Four of 5 patients studied had serum bile acid concentrations below the normal range of controls.
Honda et al. (1997) described a new rapid method for determination of plasma 7-dehydrocholesterol by ultraviolet spectrometry. In addition, Honda et al. (1997) found that analysis of cultured skin fibroblasts that had been exposed to delipidated medium for 4 weeks allowed accurate diagnosis even in atypical cases of SLOS.
Prenatal Diagnosis
Johnson et al. (1994) presented the first report of prenatal diagnosis of SLO syndrome, and described prenatal detection of multiple anomalies in a fetus in which the diagnosis of SLO syndrome was made postnatally.
McGaughran et al. (1994) used biochemical testing for successful prenatal diagnosis of severe SLO syndrome. The first child of the couple requesting prenatal diagnosis had this disorder with multiple external and internal anomalies and died in the neonatal period. Despite apparently normal results of detailed ultrasound scanning in the second pregnancy, that child was also affected and died a few days after birth. Apart from the distinctive facial appearance and body shape, a postmortem examination showed only a cleft of the soft palate and unilobar lungs. During the index pregnancy an amniocentesis was performed at 15 weeks' gestation. Analysis by gas chromatography-mass spectrometry demonstrated an amniotic fluid cholesterol concentration that was low and a 7-dehydrocholesterol concentration that was markedly elevated. The ratio of 7-dehydrocholesterol to cholesterol in plasma from children with this disorder was similar to the ratio in the amniotic fluid of the fetus but much higher than that in plasma from both parents. However, the ratio in plasma from both parents was twice that in plasma from adult controls. Both detailed prenatal scanning and examination of the fetus after termination of the pregnancy demonstrated female external genitalia, a feature of affected male fetuses. The elevated ratio of 7-dehydrocholesterol to cholesterol in the parents suggests the possibility of identifying heterozygotes by this means.
Hyett et al. (1995) found increased nuchal translucency at 11 weeks of gestation, indicating accumulation of fluid in the neck area in a fetus subsequently shown to have SLO syndrome. Because of the association of this defect with chromosomal abnormalities, fetal karyotyping was performed by chorion villus sampling and found to show a normal 46,XY karyotype. Subsequent ultrasound examinations showed resolution of the nuchal fluid, but at 20 weeks the fetal genitalia appeared to be female, an impression confirmed by fetoscopy. Fetal blood sampling confirmed a normal male karyotype. The terminated pregnancy produced a fetus with hypertelorism and hypertrichosis, postaxial polydactyly in one hand, and syndactyly of the second and third toes. A finding of increased levels of 7-dehydrocholesterol in cultured skin fibroblasts confirmed the diagnosis of SLO syndrome.
Dallaire et al. (1995) presented retrospective analyses of amniotic fluid indicating that the prenatal diagnosis of SLO syndrome is possible on the basis of measurements of 7-dehydrocholesterol in amniotic fluid. Amniocentesis had been performed at 17.3 weeks in a pregnancy with severe intrauterine growth retardation (IUGR). The diagnosis of SLO syndrome was suspected in the neonatal period and confirmed by the presence of 7-DHC in the plasma associated with a low total cholesterol concentration. Retrospective analysis of the amniotic fluid sample revealed an elevated level of 7-DHC.
Irons and Tint (1998) concluded that the presence of abnormally elevated levels of 7-DHC in chorionic villus samples and in amniotic fluid is an almost infallible indicator of SLOS. Sterol analysis by gas chromatography/MASS spectroscopy technology was the method used.
Kratz and Kelley (1999) tested 7-dehydrocholesterol levels in 76 amniotic fluid specimens and 9 chorionic villus samples. Of 39 fetuses at 25% risk, 10 (25.6%) were affected. Twenty-nine pregnancies not known to be at risk for SLOS were studied either because of fetal abnormality characteristic of SLOS (polydactyly, ambiguous genitalia, or both) detected by ultrasound, a low maternal serum uE3 (MSuE3), or both. None of the pregnancies with isolated low MSuE3 was affected; 3 of 4 pregnancies with both fetal abnormality and low MSuE3 were affected; 2 additional pregnancies with unavailable MSuE3 and fetal abnormalities were affected. There was an inverse correlation between clinical severity and both amniotic fluid 7-dehydrocholesterol and MSuE3 concentrations.
Shackleton et al. (1999) reported that the equine-type estriols 1,3,5(10),7-estratetraene-3,16-alpha,17-beta-triol (16-alpha-hydroxy-17-beta-dihydroequilin) and 1,3,5(10),6,8-estrapentaene-3,16-alpha,17-beta-triol (16-alpha-hydroxy-17-beta-dihydroequilenin) constituted over half of the estrogens excreted by a woman carrying a fetus with SLOS. Identification of these equine estrogens showed that an estrogen biosynthetic pathway parallel to normal is functional in the fetoplacental unit and uses 7-DHC as precursor, and therefore P450scc (118485), P450c17 (609300), 3-beta-HSD (613890), and P450(arom) (107910) are all active on 7-dehydrometabolites. Women pregnant with affected fetuses have low plasma estriol values (probably due to deficient production of the cholesterol precursor), and this is often a warning sign which instigates further evaluation for SLOS. These findings suggest the potential value of dehydroestriol measurement for noninvasive diagnosis of SLOS at midgestation, in addition to diagnosis that relies on imaging and measurement of 7-DHC levels in amniotic fluid and chorionic villus tissue.
To investigate the antenatal expression of SLO syndrome, Goldenberg et al. (2004) reviewed a series of 30 cases. They found intrauterine growth retardation to be the most frequently detected trait (20/30), either in isolation (9/20) or in association with at least 1 other anomaly (11/20). Goldenberg et al. (2004) concluded that the combination of IUGR with another malformation, including nuchal edema, polydactyly, or a renal, cardiac, or genital malformation, should prompt consideration of the diagnosis of SLO syndrome.
Jezela-Stanek et al. (2006) concluded that steroid measurements in maternal urine are a reliable basis for prenatal diagnosis of SLOS. Ten pregnancies at 25% risk of SLOS underwent prenatal testing.
Cholesterol is an essential nutrient for patients with SLO syndrome. Accumulation of cholesterol precursors, including 7-DHC, may have a role in the pathogenesis of SLO syndrome. The accumulation of 7-DHC in the brain has been associated with impaired learning in rats, and oxidized 7-DHC results in growth retardation in cultured rat embryos (Linck et al., 2000). Treatment with dietary cholesterol supplies cholesterol to the tissues and also reduces the toxic levels of 7-dehydrocholesterol. Kelley (1998) noted that the impact on the families of some SLOS children and adults has been profound when their cholesterol deficiency syndrome was treated. Growth improves, older children learn to walk, and adults speak for the first time in years. Equally important is how much better the children feel. Sometimes after just days or weeks of cholesterol treatment, head banging stops, agitation passes to calm, and older children and adults verbalize how much better they feel.
Irons et al. (1994) reported that treatment of a 1-year-old SLOS patient with exogenous cholesterol (20 to 40 mg/kg/day) in association with ursodeoxycholic acid (15 mg/kg/day) and chenodeoxycholic acid (7 mg/kg/day) resulted in a 3-fold increase of cholesterol compared to pretreatment values; even in this case, however, the levels were below the 5th centile for a normal girl. The status of another patient studied by Irons et al. (1994) improved after the introduction of a special lamb's meat-based formula containing much more cholesterol than other formulas. Administration of cholesterol by mouth in combination with bile salts resulted in growth of SLOS infants and even benefited adults (Opitz, 1996).
Elias et al. (1997) reported the clinical effects of cholesterol supplementation in 6 children with SLOS, ranging in age from birth to 11 years at the onset of therapy in 1994. Their pretreatment cholesterol levels ranged from 8 to 62 mg/dl. Clinical benefits, which were evident even in older patients, included improved growth, more rapid developmental progress, and a lessening of behavioral problems, pubertal progression in older patients, a better tolerance of infection, improvement of gastrointestinal symptoms, and a diminution in photosensitivity and skin rashes. There were no adverse reactions. Irons et al. (1997) and Nwokoro and Mulvihill (1997) also reported clinical improvement in parallel with increase in plasma cholesterol and percent sterol as cholesterol after treatment with cholesterol and/or bile acids in SLOS patients.
Ness et al. (1997) reported markedly increased levels of LDL receptors in the brain and liver of a severely affected SLOS infant, suggesting to them the possibility of treatment by infusion of serum lipoproteins.
Linck et al. (2000) found that treatment of SLOS patients with supplemental cholesterol via egg yolk resulted in an increase in mean serum cholesterol and a decrease in mean serum 7-DHC.
Azurdia et al. (2001) demonstrated objective improvement in photosensitivity after cholesterol supplementation by quantitative phototesting in a 27-year-old male with SLOS. Before treatment, the patient had experienced skin redness and itching within 5 to 10 minutes of sun exposure. After commencing a high cholesterol diet with cholesterol supplements of 70 mg kg/day, increasing to 200 mg kg/day, accompanied by ursodeoxycholic acid 10 mg kg/day, he showed a marked decrease in sensitivity to UVA in the range of 320 to 350 nm.
Wassif et al. (2017) studied the safety and efficacy of simvastatin therapy in 23 patients with mild to typical SLOS using a randomized, double-blind, placebo-controlled trial. This was a crossover trial which consisted of two 12-month treatment phases separated by a 2-month washout period. All patients received cholesterol supplementation during both phases of the trial. No safety issues were identified. Plasma dehydrocholesterol concentrations decreased significantly: 8.9 +/- 8.4% on placebo to 6.1 +/- 5.5% on simvastatin (p less than 0.005). Wassif et al. (2017) observed a trend toward decreased CSF dehydrocholesterol concentrations. A significant improvement (p = 0.017, paired t-test) was observed on the irritability subscale of the Aberrant Behavior Checklist-C when subjects were taking simvastatin. The authors concluded that simvastatin is safe, improves the serum dehydrocholesterol to total sterol ratio, and significantly improves irritability symptoms in patients with mild to classic SLOS.
Noting the cholesterol interacts with hedgehog proteins (SHH, 600725; IHH, 600726), Porter et al. (1996) postulated that there may be defective modification of the hedgehog proteins and perhaps other similarly processed proteins in SLOS. The spectrum of developmental malformations seen in SLO syndrome may be due to loss of hedgehog protein function.
Jiang et al. (2010) compared protein expression in Dhcr7+/+ and Dhcr7-/- brain tissue. One of the proteins identified was cofilin-1 (CFL1; 601442), an actin depolymerizing factor which regulates neuronal dendrite and axon formation. Differential expression of cofilin-1 was due to increased phosphorylation. Phosphorylation of cofilin-1 is regulated by Rho GTPases through Rho-Rock-Limk-Cofilin-1 and Rac/Cdc42-Pak-Limk-Cofilin-1 pathways. Pull-down assays demonstrated increased activation of RhoA (165390), Rac1 (602048), and Cdc42 (116952) in Dhcr7-/- brains, which also resulted in increased phosphorylation of both Limk1 (601329) and Pak1 (602590) in mutant brain tissue. Altered Rho/Rac signaling impairs normal dendritic and axonal formation, and mutations in genes encoding regulators and effectors of the Rho GTPases underlie other human mental retardation syndromes. Thus, Jiang et al. (2010) hypothesized that aberrant activation of Rho/Rac could have functional consequences for dendrite and axonal growth. In vitro analysis of Dhcr7-/- hippocampal neurons demonstrated both axonal and dendritic abnormalities. Jiang et al. (2010) concluded that developmental abnormalities of neuronal process formation may contribute to the neurocognitive deficits found in SLOS and may represent a potential target for therapeutic intervention.
The transmission pattern of SLOS in the patients reported by Wassif et al. (1998) was consistent with autosomal recessive inheritance.
In 3 unrelated patients with SLOS, Wassif et al. (1998) identified 4 different mutations in the DHCR7 gene (602858.0001-602858.0004). Fitzky et al. (1998) identified mutations in the DHCR7 gene (see, e.g., 602858.0009 and 602858.0011) in patients with SLOS.
Yu et al. (2000) reported a simple PCR-based restriction endonuclease digestion assay for rapid detection of a G-to-C transversion in the splice acceptor site of exon 9 (IVS8-1G-C) of DHCR7 (602858.0001). The mutation results in abnormal splicing of exon 9 with a 134-basepair insertion of intron 8 sequences, a resultant frameshift, and a premature translation stop. The authors identified this mutation in 21 of 33 SLOS propositi (21/66 alleles). Since none of their patients was homozygous for the mutation, the authors hypothesized that homozygosity for the mutation may often be prenatally lethal. They also screened unrelated normal individuals for the prevalence of the mutation, including 90 American Caucasians, 120 Finnish Caucasians, 121 Sierra Leone Africans, 95 Han Chinese, and 103 Japanese. One IVS8-1G-C mutation was identified in the American Caucasian population; none was observed in the other populations. Yu et al. (2000) concluded that the IVS8-1G-C transversion is a very common mutation in SLOS patients from the U.S.
Yu et al. (2000) screened an additional 32 patients with SLOS, 28 from the U.S. and 4 from Sweden. Twenty missense mutations, 1 nonsense mutation (602858.0012), and 1 splice site mutation (IVS8-1G-C; 602858.0001) were detected. All probands were heterozygous for mutations. Three mutations accounted for 54% of those observed in their cohort, IVS8-1G-C (22/64 alleles, 34%), T93M (602858.0009) (8/64, 12.5%), and V326L (602858.0011) (5/64, 7.8%). Severity of SLOS was negatively correlated with both plasma cholesterol and relative plasma cholesterol, but not with 7-dehydrocholesterol, the immediate precursor, confirming previous observations. However, no correlation was observed between mutations and phenotype, suggesting that the degree of severity may be affected by other factors. The authors estimated that 33 to 42% of the variation in the SLOS severity score is accounted for by variation in plasma cholesterol, suggesting that factors other than plasma cholesterol are additionally involved in determining severity.
Nowaczyk et al. (2001) described a fetus and 2 newborns with a severe form of SLOS that included holoprosencephaly; all 3 were homozygous for the common DHCR7 mutation, IVS-1G-C (602858.0001), a truncating mutation that is expected to result in virtually absent enzyme activity. Nowaczyk et al. (2001) stated that of 6 previously reported severely affected newborns with SLOS who were homozygous for this mutation, none had holoprosencephaly.
Langius et al. (2003) reported 3 patients from 2 families with a very mild clinical presentation of SLOS. Their plasma cholesterol values were normal and their plasma levels of 7- and 8-DHC were only slightly elevated. In cultured skin fibroblasts, a significant residual 7-DHCR activity was found. All 3 patients were compound heterozygotes for a novel mutation (M1L; 602858.0017) affecting initiation translation. In 2 of the patients, the other mutation present in heterozygous state was the common splice site mutation IVS8-1G-C. The third patient had an E448K missense mutation (602858.0018) in the DHCR7 gene.
Modifier Genes
Witsch-Baumgartner et al. (2004) determined common APOE (107741) and DHCR7 genotypes in 137 unrelated patients with Smith-Lemli-Opitz syndrome and 108 of their parents (59 mothers and 49 fathers). There was a significant correlation between patients' clinical severity scores and maternal APOE genotypes (p = 0.028) but not between severity scores and patients' or paternal APOE genotypes. Presence of the maternal APOE2 allele was associated with a more severe phenotype, and the association persisted after stratification for DHCR7 genotype. Witsch-Baumgartner et al. (2004) suggested that the efficiency of cholesterol transport from the mother to the embryo is affected by maternal APOE genotype, and that APOE plays a role in modulation of embryonic development and malformations.
Koo et al. (2010) reported a girl who had a severe form of SLOS at birth, with multiple congenital anomalies affecting many organ systems. However, after birth, she showed less neurologic impairment than expected. She rolled from side to side at age 7 months, could stand with assistance at 11 months, and gained some fine motor control. Serum 7-dehydrocholesterol was increased at age 4 months but later fell to normal range, and serum cholesterol was normal. Compared to patients with a more severe phenotype and with a less severe phenotype, Koo et al. (2010) observed a discordance in this patient: she was more severely affected, but had a lower 7-dehydrocholesterol/cholesterol ratio, which was usually observed in less severely affected individuals. Genetic analysis identified compound heterozygosity for 2 mutations in the DHCR7 gene: the common IVS8-1G-C splice site mutation (602858.0001) and a splice site mutation in intron 5 (602858.0022). RT-PCR studies of patient fibroblasts showed 3 bands, including a wildtype band, indicating that some residual wildtype protein was produced from the intron 5 mutation. However, patient fibroblasts showed a defect in sterol synthesis in cholesterol-deficient medium. Koo et al. (2010) noted that there is a high need for cholesterol during embryonic development, which may have explained why this child was born with so many abnormalities. After birth, the residual enzyme activity conferred by the intron 5 mutation and the addition of dietary cholesterol may have been sufficient to allow some developmental acquisition.
In British Columbia, Lowry (1982) found the RSH syndrome (Opitz's designation for SLOS) to be the second most frequent recessive disorder (after cystic fibrosis). Chasalow et al. (1985) suggested that the carrier frequency of this disorder may be as high as 1 to 2%.
Tint et al. (1994) estimated the frequency of the SLO syndrome as 1 in 20,000 to 1 in 40,000.
SLOS occurs in relatively high frequency: approximately 1 in 20,000 to 30,000 births in populations of northern and central European background (Ryan et al., 1998).
Nowaczyk et al. (2001) estimated that the incidence of SLOS in the population of European origin in Ontario, Canada, was at least 1 in 22,700. As infants with mild forms of SLOS born during the period of the study may have been undiagnosed, this number was probably an underestimate. The authors suggested that this observation had implications for prenatal and newborn screening.
To determine the carrier frequency of SLOS, Battaile et al. (2001) screened 1,503 anonymous blood samples of random newborn screening blood spot cards from Oregon for the presence of the common SLOS mutation IVS8-1G-C (602858.0001). Sixteen carriers were identified. Since this mutation accounts for about one-third of known SLOS mutations, the calculated carrier frequency for all mutations is 1 in 30, predicting an SLOS incidence between 1 in 1,590 to 1 in 13,500 and suggesting a higher incidence of SLOS than was previously suspected. However, even a slight variation in the frequency of the IVS8-1G-C mutation among SLOS gene mutations would dramatically change the carrier rate.
Witsch-Baumgartner et al. (2001) reported mutation analysis of the DHCR7 gene in 59 SLOS patients; 15 patients were from Poland, 22 from Germany/Austria, and 22 from Great Britain. Mutations were detected on 114 of 118 SLOS chromosomes (96.6%). Altogether, 35 different mutations were identified, but in all 3 populations 3 mutations accounted for more than 50% of SLOS alleles. The mutation spectra were, however, significantly different across these populations. W151X (602858.0010) was the most frequent mutation in the Polish population (33.3%), had an intermediate frequency in German/Austrian patients (18.2%), and was rare in British patients (2.3%). The V326L mutation (602858.0011) showed the same east-west gradient. In contrast, the IVS8-1G-C mutation (602858.0001) was most frequent in Britain (34.1%), intermediate in Germany/Austria (20.5%), and rare in Poland (3.3%). Haplotype analysis using 8 single nucleotide polymorphisms in the coding sequence of the DHCR7 gene gave evidence for both recurrent mutations and founder effects; all IVS8-1G-C and V326L alleles shared the same haplotype, whereas the W151X allele occurred on different haplotypes. Witsch-Baumgartner et al. (2001) concluded that the distribution pattern of DHCR7 mutations in Europe may reflect ancient and modern migrations in Europe.
Witsch-Baumgartner et al. (2008) confirmed the findings of Witsch-Baumgartner et al. (2001) by mutation analysis of 263 European SLOS patients. The mutation spectrum varied significantly between populations, with increased frequency of IVS8-1G-C in the northwest, W151X and V326L in the northeast, and T93M in southern Europe. SLOS was virtually absent in Finland. Haplotype and chimpanzee ortholog analyses indicated that the IVS8-1G-C and Y151X mutations appeared about 3,000 years ago in northwest and northeast Europe, respectively. The T93M mutation probably arose about 6,000 years ago in the eastern Mediterranean region.
Kalb et al. (2012) identified the T93M mutation in 9 (36%) of 26 mutant alleles from 13 Turkish patients with SLO syndrome. Three probands were homozygous for the mutation. No carriers of T93M were identified in 771 control individuals. The allele frequency was estimated to be no more than 1 in 420.
Among 15,825 ethnically diverse individuals screened for Smith-Lemli-Opitz carrier status, Lazarin et al. (2013) identified 232 carriers (1.5%), for an estimated carrier frequency of 1 in 68. Three 'carrier couples' were identified.
Berry et al. (1989) described a family in which a translocation t(7;17)(q34;p13.1) was segregating through 3 generations and by implication in a fourth. The member of the family with an unbalanced translocation involving partial deletion of chromosome 17 had clinical features of the Miller-Dieker syndrome (247200). Four other children with an unbalanced karyotype involving partial deletion of chromosome 7 showed clinical features of SLOS. Berry et al. (1989) postulated that these apparent SLOS cases represent a contiguous gene syndrome in which SLOS or a separate entity closely mimicking SLOS is included.
In a patient with a clinical diagnosis of SLOS type II, Wallace et al. (1994) identified a de novo balanced translocation t(7;20)(q32.1;q13.2) and proposed that the translocation interrupted the SLOS gene on chromosome 7, while a subtle mutation disrupted the other allele. Curry et al. (1987) reported another SLOS type II patient with a balanced translocation involving 7q32. Alley et al. (1995) identified a chromosome 7-specific YAC that spanned the translocation breakpoint, as demonstrated by fluorescence in situ hybridization. Thus the candidate SLOS region could be placed on physical and genetic maps of chromosome 7. Alley et al. (1997) further refined the location of a putative SLOS gene to a 200-kb region of chromosome 7q32.1.
Tint (1993) noted that Suzuki and De Paul (1971) and Roux et al. (1979) found that administration of a pharmacologic inhibitor of the last step in biosynthesis of cholesterol produced physical and physiologic defects in embryonic and fetal rats analogous to those seen in children with the SLO syndrome. A pharmacologic inhibitor of 7-dehydrocholesterol reductase, AY9944, is teratogenic in rats. The use of AY9944 in animals can potentially provide a good model for treatment protocols (Irons et al., 1994). Xu et al. (1995) used a drug, BM15.766, to inhibit 7-dehydrocholesterol reductase in rats. The model was useful for testing different treatment strategies. Stimulating early steps of cholesterol synthesis worsened the biochemical abnormalities, while feeding cholesterol inhibited abnormal synthesis, improved the biochemical abnormalities, and prevented liver damage. Dehart et al. (1997) used BM15.766 to study the teratogenic effects of low cholesterol and high 7-dehydrocholesterol in rats. They found abnormalities similar to those reported in humans with SLOS, including abnormalities of the brain and face. Pathogenesis, observed on gestational day 11 using histologic sections and scanning electron microscopy, involved populations of abnormally rounded-up cells at the rim of the developing forebrain and in the alar plate of the lower midbrain and hindbrain.
Wassif et al. (2001) developed a mouse model of RSH/SLOS by disruption of the 3-beta-hydroxysterol delta-7-reductase gene. As in human patients, the RSH/SLOS mouse had a marked reduction of serum and tissue cholesterol levels and a marked increase of serum and tissue 7-dehydrocholesterol levels. Phenotypic similarities between this mouse model and the human syndrome included intrauterine growth retardation, variable craniofacial anomalies such as cleft palate, poor feeding with an uncoordinated suck, hypotonia, and decreased movement. Neurophysiologic studies showed that although the response of frontal cortex neurons to the neurotransmitter gamma-amino-n-butyric acid was normal, the response of these same neurons to glutamate was significantly impaired.
Cholesterol-enriched lipid rafts play an important role in mast cell activation. Kovarova et al. (2006) observed that mast cells derived from Dhcr7 -/- mice showed constitutive cytokine production and hyperdegranulation after stimulation of Fcer1 (see FCER1A, 147140). Dhcr7-deficient mast cells accumulated 7-DHC in lipid rafts, partially disrupting raft stability and displacing Lyn (165120) protein and activity. Downregulation of Lyn-dependent signaling events, such as phosphorylation of Csk-binding protein (PAG; 605767), was associated with increased Fyn (137025) kinase activity and Akt (164730) phosphorylation. Kovarova et al. (2006) proposed that lipid raft dysfunction in SLOS may explain the observation of allergy in these patients due to increased mast cell sensitivity.
Alley, T. L., Gray, B. A., Lee, S.-H., Scherer, S. W., Tsui, L.-C., Tint, G. S., Williams, C. A., Zori, R., Wallace, M. R. Identification of a yeast artificial chromosome clone spanning a translocation breakpoint at 7q32.1 in a Smith-Lemli-Opitz syndrome patient. Am. J. Hum. Genet. 56: 1411-1416, 1995. Note: Erratum: Am. J. Hum. Genet. 57: 520-521, 1995. [PubMed: 7762564]
Alley, T. L., Scherer, S. W., Huizenga, J. J., Tsui, L.-C., Wallace, M. R. Physical mapping of the chromosome 7 breakpoint region in an SLOS patient with t(7;20)(q32.1;q13.2). Am. J. Med. Genet. 68: 279-281, 1997. [PubMed: 9024559]
Anderson, A. J., Stephan, M. J., Walker, W. O., Kelley, R. I. Variant RSH/Smith-Lemli-Opitz syndrome with atypical sterol metabolism. Am. J. Med. Genet. 78: 413-418, 1998. [PubMed: 9714006] [Full Text: https://doi.org/10.1002/(sici)1096-8628(19980806)78:5<413::aid-ajmg4>3.0.co;2-m]
Andersson, H. C., Frentz, J., Martinez, J. E., Tuck-Muller, C. M., Belliziare, J. Adrenal insufficiency in Smith-Lemli-Opitz syndrome. Am. J. Med. Genet. 82: 382-384, 1999. [PubMed: 10069708]
Anstey, A. V., Taylor, C. R. Photosensitivity in the Smith-Lemli-Opitz syndrome: the US experience of a new congenital photosensitivity syndrome. J. Am. Acad. Derm. 41: 121-123, 1999. [PubMed: 10411425] [Full Text: https://doi.org/10.1016/s0190-9622(99)70420-2]
Atchaneeyasakul, L.-O., Linck, L. M., Connor, W. E., Weleber, R. G., Steiner, R. D. Eye findings in 8 children and a spontaneously aborted fetus with RSH/Smith-Lemli-Opitz syndrome. Am. J. Med. Genet. 80: 501-505, 1998. [PubMed: 9880216] [Full Text: https://doi.org/10.1002/(sici)1096-8628(19981228)80:5<501::aid-ajmg12>3.0.co;2-j]
Azurdia, R. M., Anstey, A. V., Rhodes, L. E. Cholesterol supplementation objectively reduces photosensitivity in the Smith-Lemli-Opitz syndrome. Brit. J. Derm. 144: 143-145, 2001. [PubMed: 11167696] [Full Text: https://doi.org/10.1046/j.1365-2133.2001.03964.x]
Battaile, K. P., Battaile, B. C., Merkens, L. S., Maslen, C. L., Steiner, R. D. Carrier frequency of the common mutation IVS8-1G-C in DHCR7 and estimate of the expected incidence of Smith-Lemli-Opitz syndrome. Molec. Genet. Metab. 72: 67-71, 2001. [PubMed: 11161831] [Full Text: https://doi.org/10.1006/mgme.2000.3103]
Belmont, J. W., Hawkins, E., Hejtmancik, J. F., Greenberg, F. Two cases of severe lethal Smith-Lemli-Opitz syndrome. (Letter) Am. J. Med. Genet. 26: 65-67, 1987. [PubMed: 3812579] [Full Text: https://doi.org/10.1002/ajmg.1320260112]
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. 34: 358-365, 1989. [PubMed: 2596525] [Full Text: https://doi.org/10.1002/ajmg.1320340312]
Bialer, M. G., Penchaszadeh, V. B., Kahn, E., Libes, R., Krigsman, G., Lesser, M. L. Female external genitalia and mullerian duct derivatives in a 46,XY infant with the Smith-Lemli-Opitz syndrome. Am. J. Med. Genet. 28: 723-731, 1987. [PubMed: 3322011] [Full Text: https://doi.org/10.1002/ajmg.1320280320]
Blair, H. R., Martin, J. K. A syndrome characterized by mental retardation, short stature, craniofacial dysplasia, and genital anomalies occurring in siblings. J. Pediat. 69: 457-459, 1966. [PubMed: 5946455] [Full Text: https://doi.org/10.1016/s0022-3476(66)80094-x]
Chasalow, F. I., Blethen, S. L., Taysi, K. Possible abnormalities of steroid secretion in children with Smith-Lemli-Opitz syndrome and their parents. Steroids 46: 827-843, 1985. [PubMed: 3018967] [Full Text: https://doi.org/10.1016/0039-128x(85)90032-7]
Cherstvoy, E. D., Lazjuk, G. I., Nedzved, M. K., Usoev, S. S. The pathological anatomy of the Smith-Lemli-Opitz syndrome. Clin. Genet. 7: 382-387, 1975. [PubMed: 1149307] [Full Text: https://doi.org/10.1111/j.1399-0004.1975.tb00345.x]
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. Europ. J. Pediat. 155: 656-659, 1996. [PubMed: 8839719] [Full Text: https://doi.org/10.1007/BF01957147]
Cotlier, E., Rice, P. Cataracts in the Smith-Lemli-Opitz syndrome. Am. J. Ophthal. 72: 955-959, 1971. [PubMed: 4330375] [Full Text: https://doi.org/10.1016/0002-9394(71)91696-5]
Cowell, H. R. The genetics of foot disorders. Orthop. Rev. 7: 55-58, 1978.
Cunniff, C., Kratz, L. E., Moser, A., Natowicz, M. R., Kelley, R. I. Clinical and biochemical spectrum of patients with RSH/Smith-Lemli-Opitz syndrome and abnormal cholesterol metabolism. Am. J. Med. Genet. 68: 263-269, 1997. [PubMed: 9024557]
Curry, C. J. R., Carey, J. C., Holland, J. S., Chopra, D., Fineman, R., Golabi, M., Sherman, S., Pagon, R. A., Allanson, J., Shulman, S., Barr, M., McGravey, V., Dabiri, C., Schimke, N., Ives, E., Hall, B. D. Smith-Lemli-Opitz syndrome-type II: multiple congenital anomalies with male pseudohermaphroditism and frequent early lethality. Am. J. Med. Genet. 26: 45-57, 1987. [PubMed: 3812577] [Full Text: https://doi.org/10.1002/ajmg.1320260110]
Dallaire, L., Fraser, F. C. The syndrome of retardation with urogenital and skeletal anomalies in siblings. J. Pediat. 69: 459-460, 1966. [PubMed: 5946456] [Full Text: https://doi.org/10.1016/s0022-3476(66)80095-1]
Dallaire, L., Mitchell, G., Giguere, R., Lefebvre, F., Melancon, S. B., Lambert, M. Prenatal diagnosis of Smith-Lemli-Opitz syndrome is possible by measurement of 7-dehydrocholesterol in amniotic fluid. Prenatal Diag. 15: 855-858, 1995. [PubMed: 8559757] [Full Text: https://doi.org/10.1002/pd.1970150911]
Dallaire, L. Syndrome of retardation with urogenital and skeletal anomalies (Smith-Lemli-Opitz syndrome): clinical features and mode of inheritance. J. Med. Genet. 6: 113-120, 1969. [PubMed: 4389828] [Full Text: https://doi.org/10.1136/jmg.6.2.113]
de Die Smulders, C., Fryns, J. P. Smith-Lemli-Opitz syndrome: the changing phenotype with age. Genet. Counsel. 3: 77-82, 1990. [PubMed: 1642814]
de Die Smulders, C., van de Meer, S., Spaapen, L., Fryns, J. P. Confirmation of defective cholesterol biosynthesis in 2 previously described adult sibs with Smith-Lemli-Opitz syndrome. (Letter) Genet. Counsel. 7: 161-162, 1996. [PubMed: 8831138]
Deaton, J. G., Mendoza, L. O. Smith-Lemli-Opitz syndrome in a 23-year-old man. Arch. Intern. Med. 132: 422-426, 1973. [PubMed: 4783024]
Dehart, D. B., Lanoue, L., Tint, G. S., Sulik, K. K. Pathogenesis of malformations in a rodent model for Smith-Lemli-Opitz syndrome. Am. J. Med. Genet. 68: 328-337, 1997. [PubMed: 9024568] [Full Text: https://doi.org/10.1002/(sici)1096-8628(19970131)68:3<328::aid-ajmg15>3.0.co;2-v]
Donnai, D., Young, I. D., Owen, W. G., Clark, S. A., Miller, P. F. W., Knox, W. F. The lethal multiple congenital anomaly syndrome of polydactyly, sex reversal, renal hypoplasia, and unilobular lungs. J. Med. Genet. 23: 64-71, 1986. [PubMed: 3950937] [Full Text: https://doi.org/10.1136/jmg.23.1.64]
Elias, E. R., Irons, M. B., Hurley, A. D., Tint, G. S., Salen, G. Clinical effects of cholesterol supplementation in six patients with the Smith-Lemli-Opitz syndrome (SLOS). Am. J. Med. Genet. 68: 305-310, 1997. [PubMed: 9024564] [Full Text: https://doi.org/10.1002/(sici)1096-8628(19970131)68:3<305::aid-ajmg11>3.0.co;2-x]
Fierro, M., Martinez, A. J., Harbison, J. W., Hay, S. H. Smith-Lemli-Opitz syndrome: neuropathological and ophthalmological observations. Dev. Med. Child Neurol. 19: 57-61, 1977. [PubMed: 844667] [Full Text: https://doi.org/10.1111/j.1469-8749.1977.tb08021.x]
Fitzky, B. U., Witsch-Baumgartner, M., Erdel, M., Lee, J. N., Paik, Y.-K., Glossmann, H., Utermann, G., Moebius, F. F. Mutations in the delta-7-sterol reductase gene in patients with the Smith-Lemli-Opitz syndrome. Proc. Nat. Acad. Sci. 95: 8181-8186, 1998. [PubMed: 9653161] [Full Text: https://doi.org/10.1073/pnas.95.14.8181]
Fried, K., Fraser, W. I. Smith-Lemli-Opitz syndrome in an adult. J. Ment. Defic. Res. 16: 30-34, 1972. [PubMed: 4153066] [Full Text: https://doi.org/10.1111/j.1365-2788.1972.tb01568.x]
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 Paediat. 81: 570-572, 1992. [PubMed: 1392379] [Full Text: https://doi.org/10.1111/j.1651-2227.1992.tb12300.x]
Goldenberg, A., Wolf, C., Chevy, F., Benachi, A., Dumez, Y., Munnich, A., Cormier-Daire, V. Antenatal manifestations of Smith-Lemli-Opitz (RSH) syndrome: a retrospective survey of 30 cases. Am. J. Med. Genet. 124A: 423-426, 2004. [PubMed: 14735596] [Full Text: https://doi.org/10.1002/ajmg.a.20448]
Greene, C., Pitts, W., Rosenfeld, R., Luzzatti, L. Smith-Lemli-Opitz syndrome in two 46,XY infants with female external genitalia. Clin. Genet. 25: 366-372, 1984. [PubMed: 6713715] [Full Text: https://doi.org/10.1111/j.1399-0004.1984.tb02006.x]
Guzzetta, V., De Fabiani, E., Galli, G., Colombo, C., Corso, G., Lecora, M., Parenti, G., Strisciuglio, P., Andria, G., Italian SLOS Collaborative Group. Clinical and biochemical screening for Smith-Lemli-Opitz syndrome. Acta Paediat. 85: 937-942, 1996. [PubMed: 8863875] [Full Text: https://doi.org/10.1111/j.1651-2227.1996.tb14190.x]
Herman, G. E. Disorders of cholesterol biosynthesis: prototypic metabolic malformation syndromes. Hum. Molec. Genet. 12(R1): R75-R88, 2003. [PubMed: 12668600] [Full Text: https://doi.org/10.1093/hmg/ddg072]
Hoefnagel, D., Wurster, D., Pomeroy, J., Benz, R. The Smith-Lemli-Opitz syndrome in an adult. J. Ment. Defic. Res. 13: 249-257, 1969. [PubMed: 5363344] [Full Text: https://doi.org/10.1111/j.1365-2788.1969.tb01089.x]
Honda, A., Batta, A. K., Salen, G., Tint, G. S., Chen, T. S., 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. 68: 288-293, 1997. [PubMed: 9024561] [Full Text: https://doi.org/10.1002/(sici)1096-8628(19970131)68:3<288::aid-ajmg8>3.0.co;2-i]
Honda, A., Tint, G. S., Salen, G., Kelley, R. I., Honda, M., Batta, A. K., Chen, T. S., 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. 68: 282-287, 1997. [PubMed: 9024560]
Honda, M., Tint, G. S., Honda, A., Salen, G., Shefer, S., Batta, A. K., Matsuzaki, Y., Tanaka, N. Regulation of cholesterol biosynthetic pathway in patients with the Smith-Lemli-Opitz syndrome. J. Inherit. Metab. Dis. 23: 464-474, 2000. [PubMed: 10947201] [Full Text: https://doi.org/10.1023/a:1005660130109]
Hyett, J. A., Clayton, P. T., Moscoso, G., Nicolaides, K. H. Increased first trimester nuchal translucency as a prenatal manifestation of Smith-Lemli-Opitz syndrome. Am. J. Med. Genet. 58: 374-376, 1995. [PubMed: 8533850] [Full Text: https://doi.org/10.1002/ajmg.1320580415]
Irons, M. B., Tint, G. S. Prenatal diagnosis of Smith-Lemli-Opitz syndrome. Prenatal Diag. 18: 369-372, 1998. [PubMed: 9602484]
Irons, M., Elias, E. R., Abuelo, D., Bull, M. J., Greene, C. L., Johnson, V. P., Keppen, L., Schanen, C., Tint, G. S., Salen, G. Treatment of Smith-Lemli-Opitz syndrome: results of a multicenter trial. Am. J. Med. Genet. 68: 311-314, 1997. [PubMed: 9024565]
Irons, M., Elias, E. R., Salen, G., Tint, G. S., Batta, A. K. Defective cholesterol biosynthesis in Smith-Lemli-Opitz syndrome. (Letter) Lancet 341: 1414 only, 1993. [PubMed: 7684480] [Full Text: https://doi.org/10.1016/0140-6736(93)90983-n]
Irons, M., Elias, E. R., Tint, G. S., Salen, G., Frieden, R., Buie, T. M., 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. 50: 347-352, 1994. [PubMed: 8209913] [Full Text: https://doi.org/10.1002/ajmg.1320500409]
Jezela-Stanek, A., Malunowicz, E. M., Ciara, E., Popowska, E., Goryluk-Kozakiewicz, B., Spodar, K., Czerwiecka, M., Jezuita, J., Nowaczyk, M. J. M., Krajewska-Walasek, M. Maternal urinary steroid profiles in prenatal diagnosis of Smith-Lemli-Opitz syndrome: first patient series comparing biochemical and molecular studies. Clin. Genet. 69: 77-85, 2006. [PubMed: 16451140] [Full Text: https://doi.org/10.1111/j.1399-0004.2006.00551.x]
Jiang, X.-S., Wassif, C. A., Backlund, P. S., Song, L., Holtzclaw, L. A., Li, Z., Yergey, A. L., Porter, F. D. Activation of Rho GTPases in Smith-Lemli-Opitz syndrome: pathophysiological and clinical implications. Hum. Molec. Genet. 19: 1347-1357, 2010. [PubMed: 20067919] [Full Text: https://doi.org/10.1093/hmg/ddq011]
Johnson, J. A., Aughton, D. J., Comstock, C. H., von Oeyen, P. T., Higgins, J. V., Schulz, R. Prenatal diagnosis of Smith-Lemli-Opitz syndrome, type II. Am. J. Med. Genet. 49: 240-243, 1994. [PubMed: 8116676] [Full Text: https://doi.org/10.1002/ajmg.1320490216]
Johnson, V. P. Smith-Lemli-Opitz syndrome: review and report of two affected siblings. Z. Kinderheilk. 119: 221-234, 1975. [PubMed: 166525] [Full Text: https://doi.org/10.1007/BF00443506]
Joseph, D. B., Uehling, D. T., Gilbert, E., Laxova, R. Genitourinary abnormalities associated with the Smith-Lemli-Opitz syndrome. J. Urol. 137: 719-721, 1987. [PubMed: 3560332] [Full Text: https://doi.org/10.1016/s0022-5347(17)44188-7]
Kalb, S., Caglayan, A. O., Degerliyurt, A., Schmid, S., Ceylaner, S., Hatipoglu, N., Hinderhofer, K., Rehder, H., Kurtoglu, S., Ceylaner, G., Zschocke, J., Witsch-Baumgartner, M. High frequency of p.thr93met in Smith-Lemli-Opitz syndrome patients in Turkey. (Letter) Clin. Genet. 81: 598-601, 2012. [PubMed: 22211794] [Full Text: https://doi.org/10.1111/j.1399-0004.2011.01750.x]
Kelley, R. I. A new face for an old syndrome. (Editorial) Am. J. Med. Genet. 68: 251-256, 1997. [PubMed: 9024554] [Full Text: https://doi.org/10.1002/(sici)1096-8628(19970131)68:3<251::aid-ajmg1>3.0.co;2-p]
Kelley, R. I. RSH/Smith-Lemli-Opitz syndrome: mutations and metabolic morphogenesis. (Editorial) Am. J. Hum. Genet. 63: 322-326, 1998. [PubMed: 9683618] [Full Text: https://doi.org/10.1086/301987]
Kenis, H., Hustinx, T. W. A familial syndrome of mental retardation in association with multiple congenital anomalies resembling the syndrome of Smith-Lemli-Opitz. Maandschr. Kindergeneesk. 35: 37-48, 1967. [PubMed: 6047019]
Kohler, H. G. Familial neonatally lethal syndrome of hypoplastic left heart, absent pulmonary lobation, polydactyly, and talipes, probably Smith-Lemli-Opitz (RSH) syndrome. Am. J. Med. Genet. 14: 423-428, 1983. [PubMed: 6859093] [Full Text: https://doi.org/10.1002/ajmg.1320140304]
Koo, G., Conley, S. K., Wassif, C. A., Porter, F. D. Discordant phenotype and sterol biochemistry in Smith-Lemli-Opitz syndrome. Am. J. Med. Genet. 152A: 2094-2098, 2010. [PubMed: 20635399] [Full Text: https://doi.org/10.1002/ajmg.a.33540]
Kovarova, M., Wassif, C. A., Odom, S., Liao, K., Porter, F. D., Rivera, J. Cholesterol deficiency in a mouse model of Smith-Lemli-Opitz syndrome reveals increased mast cell responsiveness. J Exp. Med. 203: 1161-1171, 2006. [PubMed: 16618793] [Full Text: https://doi.org/10.1084/jem.20051701]
Kratz, L. E., Kelley, R. I. Prenatal diagnosis of the RSH/Smith-Lemli-Opitz syndrome. Am. J. Med. Genet. 82: 376-381, 1999. [PubMed: 10069707]
Lachman, M. F., Wright, Y., Whiteman, D. A. H., Herson, V., Greenstein, R. M. Brief clinical report: a 46,XY phenotypic female with Smith-Lemli-Opitz syndrome. Clin. Genet. 39: 136-141, 1991. [PubMed: 1849804] [Full Text: https://doi.org/10.1111/j.1399-0004.1991.tb03000.x]
Langius, F. A. A., Waterham, H. R., Romeijn, G. J., Oostheim, W., de Barse, M. M. J., Dorland, L., Duran, M., Beemer, F. A., Wanders, R. J. A., Poll-The, B. T. Identification of 3 patients with a very mild form of Smith-Lemli-Opitz syndrome. Am. J. Med. Genet. 122A: 24-29, 2003. [PubMed: 12949967] [Full Text: https://doi.org/10.1002/ajmg.a.20207]
Lazarin, G. A., Haque, I. S., Nazareth, S., Iori, K., Patterson, A. S., Jacobson, J. L., Marshall, J. R., Seltzer, W. K., Patrizio, P., Evans, E. A., Srinivasan, B. S. An empirical estimate of carrier frequencies for 400+ causal Mendelian variants: results from an ethnically diverse clinical sample of 23,453 individuals. Genet. Med. 15: 178-186, 2013. [PubMed: 22975760] [Full Text: https://doi.org/10.1038/gim.2012.114]
Le Merrer, M., Briard, M. L., Girard, S., Mulliez, N., Moraine, C., Imbert, M. C. Lethal acrodysgenital dwarfism: a severe lethal condition resembling Smith-Lemli-Opitz syndrome. J. Med. Genet. 25: 88-95, 1988. [PubMed: 2831368] [Full Text: https://doi.org/10.1136/jmg.25.2.88]
Linck, L. M., Lin, D. S., Flavell, D., Connor, W. E., Steiner, R. D. Cholesterol supplementation with egg yolk increases plasma cholesterol and decreases plasma 7-dehydrocholesterol in Smith-Lemli-Opitz syndrome. Am. J. Med. Genet. 93: 360-365, 2000. [PubMed: 10951458] [Full Text: https://doi.org/10.1002/1096-8628(20000828)93:5<360::aid-ajmg4>3.0.co;2-p]
Lowry, R. B., Miller, J. R., MacLean, J. R. Micrognathia, polydactyly and cleft palate. J. Pediat. 72: 859-861, 1968. [PubMed: 5652614] [Full Text: https://doi.org/10.1016/s0022-3476(68)80441-x]
Lowry, R. B. Personal Communication. Calgary, Alberta, Canada 1982.
Lowry, R. B. Variability in the Smith-Lemli-Opitz syndrome: overlap with the Meckel syndrome. (Editorial) Am. J. Med. Genet. 14: 429-433, 1983. [PubMed: 6859094] [Full Text: https://doi.org/10.1002/ajmg.1320140305]
McGaughran, J., Donnai, D., Clayton, P., Mills, K. Diagnosis of Smith-Lemli-Opitz syndrome. (Letter) New Eng. J. Med. 330: 1685-1686, 1994. [PubMed: 8177281]
McKeever, P. A., Young, I. D. Smith-Lemli-Opitz syndrome II: a disorder of the fetal adrenals? J. Med. Genet. 27: 465-466, 1990. [PubMed: 2395167] [Full Text: https://doi.org/10.1136/jmg.27.7.465]
Neklason, D. W., Andrews, K. M., Kelley, R. I., Metherall, J. E. Biochemical variants of Smith-Lemli-Opitz syndrome. Am. J. Med. Genet. 85: 517-523, 1999. [PubMed: 10405455] [Full Text: https://doi.org/10.1002/(sici)1096-8628(19990827)85:5<517::aid-ajmg18>3.0.co;2-1]
Ness, G. C., 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. 68: 294-299, 1997. [PubMed: 9024562] [Full Text: https://doi.org/10.1002/(sici)1096-8628(19970131)68:3<294::aid-ajmg9>3.0.co;2-m]
Nevo, S., Benderly, A., Levy, J., Katznelson, M. B.-M. Smith-Lemli-Opitz syndrome in an inbred family. Am. J. Dis. Child. 124: 431-433, 1972. [PubMed: 5056882] [Full Text: https://doi.org/10.1001/archpedi.1972.02110150129021]
Nowaczyk, M. J. M., Farrell, S. A., Sirkin, W. L., Velsher, L., Krakowiak, P. A., Waye, J. S., Porter, F. D. Smith-Lemli-Opitz (RHS) syndrome: holoprosencephaly and homozygous IVS8-1G-C genotype. Am. J. Med. Genet. 103: 75-80, 2001. [PubMed: 11562938] [Full Text: https://doi.org/10.1002/1096-8628(20010915)103:1<75::aid-ajmg1502>3.0.co;2-r]
Nowaczyk, M. J. M., Heshka, T., Eng, B., Feigenbaum, A. J., Waye, J. S. DHCR7 genotypes of cousins with Smith-Lemli-Opitz syndrome. Am. J. Med. Genet. 100: 162-163, 2001. [PubMed: 11298379] [Full Text: https://doi.org/10.1002/ajmg.1227]
Nowaczyk, M. J. M., McCaughey, D., Whelan, D. T., Porter, F. D. Incidence of Smith-Lemli-Opitz syndrome in Ontario, Canada. Am. J. Med. Genet. 102: 18-20, 2001. Note: Erratum: Am. J. Med. Genet. 104: 184 only, 2001. [PubMed: 11471166] [Full Text: https://doi.org/10.1002/1096-8628(20010722)102:1<18::aid-ajmg1376>3.0.co;2-e]
Nowaczyk, M. J. M., Siu, V. M., Krakowiak, P. A., Porter, F. D. Adrenal insufficiency and hypertension in a newborn infant with Smith-Lemli-Opitz syndrome. Am. J. Med. Genet. 103: 223-225, 2001. [PubMed: 11745994] [Full Text: https://doi.org/10.1002/ajmg.1545.abs]
Nowaczyk, M. J. M., Whelan, D. T., Hill, R. E. Smith-Lemli-Opitz syndrome: phenotypic extreme with minimal clinical findings. Am. J. Med. Genet. 78: 419-423, 1998. [PubMed: 9714007] [Full Text: https://doi.org/10.1002/(sici)1096-8628(19980806)78:5<419::aid-ajmg5>3.0.co;2-g]
Nwokoro, N. A., Mulvihill, J. J. Cholesterol and bile acid replacement therapy in children and adults with Smith-Lemli-Opitz (SLO/RSH) syndrome. Am. J. Med. Genet. 68: 315-321, 1997. [PubMed: 9024566] [Full Text: https://doi.org/10.1002/(sici)1096-8628(19970131)68:3<315::aid-ajmg13>3.0.co;2-w]
Opitz, J. M., de la Cruz, F. Cholesterol metabolism in the RSH/Smith-Lemli-Opitz syndrome: summary of an NICHD conference. Am. J. Med. Genet. 50: 326-338, 1994. [PubMed: 7632194] [Full Text: https://doi.org/10.1002/ajmg.1320500406]
Opitz, J. M., Penchaszadeh, V. B., Holt, M. C., Spano, L. M., Smith, V. L. Smith-Lemli-Opitz (RSH) syndrome bibliography: 1964-1993. Am. J. Med. Genet. 50: 339-343, 1994. [PubMed: 8209911] [Full Text: https://doi.org/10.1002/ajmg.1320500407]
Opitz, J. M., Penchaszadeh, V. B., Holt, M. C., Spano, L. M. Smith-Lemli-Opitz (RSH) syndrome bibliography. Am. J. Med. Genet. 28: 745-750, 1987. [PubMed: 3322013] [Full Text: https://doi.org/10.1002/ajmg.1320280324]
Opitz, J. M. Personal Communication. Helena, Montana 2/24/1996.
Patterson, K., Toomey, K. E., Chandra, R. S. Hirschsprung disease in a 46,XY phenotypic infant girl with Smith-Lemli-Opitz syndrome. J. Pediat. 103: 425-427, 1983. [PubMed: 6886911] [Full Text: https://doi.org/10.1016/s0022-3476(83)80422-3]
Pauli, R. M., Williams, M. S., Josephson, K. D., Tint, G. S. Smith-Lemli-Opitz syndrome: thirty-year follow-up of 'S' of 'RSH' syndrome. Am. J. Med. Genet. 68: 260-262, 1997. [PubMed: 9024556] [Full Text: https://doi.org/10.1002/(sici)1096-8628(19970131)68:3<260::aid-ajmg3>3.0.co;2-q]
Pinsky, L., DiGeorge, A. M. A familial syndrome of facial and skeletal anomalies associated with genital abnormality in the male and normal genitals in the female: another cause of male pseudohermaphroditism. J. Pediat. 66: 1049-1054, 1965. [PubMed: 14288458] [Full Text: https://doi.org/10.1016/s0022-3476(65)80091-9]
Porter, J. A., Young, K. E., Beachy, P. A. Cholesterol modification of hedgehog signaling proteins in animal development. Science 274: 255-258, 1996. Note: Erratum: Science 274: 1597 only, 1996. [PubMed: 8824192] [Full Text: https://doi.org/10.1126/science.274.5285.255]
Roux, C., Horvath, C., Dupuis, R. Teratogenic action and embryo lethality of AY 9944R: prevention by a hypercholesterolemia-provoking diet. Teratology 19: 35-38, 1979. [PubMed: 88081] [Full Text: https://doi.org/10.1002/tera.1420190106]
Rutledge, J. C., Friedman, J. M., Harrod, M. J. E., Currarino, G., Wright, C. G., 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. Am. J. Med. Genet. 19: 255-264, 1984. [PubMed: 6507477] [Full Text: https://doi.org/10.1002/ajmg.1320190208]
Ryan, A. K., Bartlett, K., Clayton, P., Eaton, S., Mills, L., Donnai, D., Winter, R. M., Burn, J. Smith-Lemli-Opitz syndrome: a variable clinical and biochemical phenotype. J. Med. Genet. 35: 558-565, 1998. [PubMed: 9678700] [Full Text: https://doi.org/10.1136/jmg.35.7.558]
Salen, G., Shefer, S., Batta, A. K., Tint, G. S., Xu, G., Honda, A., Irons, M., Elias, E. R. Abnormal cholesterol biosynthesis in the Smith-Lemli-Opitz syndrome. J. Lipid Res. 37: 1169-1180, 1996. [PubMed: 8808751]
Scarbrough, P. R., Huddleston, K., Finley, S. C. An additional case of Smith-Lemli-Opitz syndrome in a 46,XY infant with female external genitalia. J. Med. Genet. 23: 174-175, 1986. [PubMed: 3712395] [Full Text: https://doi.org/10.1136/jmg.23.2.174]
Seller, M. J., Flinter, F. A., Docherty, Z., Fagg, N., Newbould, M. Phenotypic diversity in the Smith-Lemli-Opitz syndrome. Clin. Dysmorph. 6: 69-73, 1997. [PubMed: 9018421]
Shackleton, C. H. L., Roitman, E., Kratz, L. E., Kelley, R. I. Equine type estrogens produced by a pregnant woman carrying a Smith-Lemli-Opitz syndrome fetus. J. Clin. Endocr. Metab. 84: 1157-1159, 1999. [PubMed: 10084612] [Full Text: https://doi.org/10.1210/jcem.84.3.5660]
Shefer, S., Salen, G., Batta, A. K., Honda, A., Tint, G. S., Irons, M., Elias, E. R., Chen, T. C., Holick, M. F. Markedly inhibited 7-dehydrocholesterol-delta(7)-reductase activity in liver microsomes from Smith-Lemli-Opitz homozygotes. J. Clin. Invest. 96: 1779-1785, 1995. [PubMed: 7560069] [Full Text: https://doi.org/10.1172/JCI118223]
Sikora, D. M., Pettit-Kekel. K., Penfield, J., Merkens, L. S., Steiner, R. D. The near universal presence of autism spectrum disorders in children with Smith-Lemli-Opitz syndrome. Am. J. Med. Genet. 140A: 1511-1518, 2006. [PubMed: 16761297] [Full Text: https://doi.org/10.1002/ajmg.a.31294]
Smith, D. W., Lemli, L., Opitz, J. M. A newly recognized syndrome of multiple congenital anomalies. J. Pediat. 64: 210-217, 1964. [PubMed: 14119520] [Full Text: https://doi.org/10.1016/s0022-3476(64)80264-x]
Suzuki, K., De Paul, L. D. Cellular degeneration in developing central nervous system of rats produced by hypocholesteremic drug AY9944. Lab. Invest. 25: 546-555, 1971. [PubMed: 4331663]
Tierney, E., Nwokoro, N. A., Porter, F. D., Freund, L. S., Ghuman, J. K., Kelley, R. I. Behavior phenotype in the RSH/Smith-Lemli-Opitz syndrome. Am. J. Med. Genet. 98: 191-200, 2001. [PubMed: 11223857] [Full Text: https://doi.org/10.1002/1096-8628(20010115)98:2<191::aid-ajmg1030>3.0.co;2-m]
Tint, G. S., Irons, M., Elias, E. R., Batta, A. K., Frieden, R., Chen, T. S., Salen, G. Defective cholesterol biosynthesis associated with the Smith-Lemli-Opitz syndrome. New Eng. J. Med. 330: 107-113, 1994. [PubMed: 8259166] [Full Text: https://doi.org/10.1056/NEJM199401133300205]
Tint, G. S., Salen, G., Batta, A. K., Shefer, S., Irons, M., Ampola, M., Frieden, R. Abnormal cholesterol and bile acid synthesis in an infant with a defect in 7-dehydrocholesterol (7DHC)-lambda-7 reductase. (Abstract) Gastroenterology 104: 1008A, 1993.
Tint, G. S., Salen, G., Batta, A. K., Shefer, S., Irons, M., Elias, E. R., Abuelo, D. N., Johnson, V. P., Lambert, M., Lutz, R., Schanen, C., Morris, C. A., Hoganson, G., Hughes-Benzie, R. Correlation of severity and outcome with plasma sterol levels in variants of the Smith-Lemli-Opitz syndrome. J. Pediat. 127: 82-87, 1995. [PubMed: 7608816] [Full Text: https://doi.org/10.1016/s0022-3476(95)70261-x]
Tint, G. S. Cholesterol defect in Smith-Lemli-Opitz syndrome. (Letter) Am. J. Med. Genet. 47: 573-574, 1993. [PubMed: 8256825] [Full Text: https://doi.org/10.1002/ajmg.1320470429]
Wallace, M., Zori, R. T., Alley, T., Whidden, E., Gray, B. A., Williams, C. A. 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. 50: 368-374, 1994. [PubMed: 8209918] [Full Text: https://doi.org/10.1002/ajmg.1320500414]
Wassif, C. A., Kratz, L., Sparks, S. E., Wheeler, C., Bianconi, S., Gropman, A., Calis, K. A., Kelley, R. I., Tierney, E., Porter, F. D. A placebo-controlled trial of simvastatin therapy in Smith-Lemli-Opitz syndrome. Genet. Med. 19: 297-305, 2017. [PubMed: 27513191] [Full Text: https://doi.org/10.1038/gim.2016.102]
Wassif, C. A., Maslen, C., Kachilele-Linjewile, S., Lin, D., Linck, L. M., Connor, W. E., Steiner, R. D., Porter, F. D. Mutations in the human sterol delta-7-reductase gene at 11q12-13 cause Smith-Lemli-Opitz syndrome. Am. J. Hum. Genet. 63: 55-62, 1998. [PubMed: 9634533] [Full Text: https://doi.org/10.1086/301936]
Wassif, C. A., Zhu, P., Kratz, L., Krakowiak, P. A., Battaile, K. P., Weight, F. F., Grinberg, A., Steiner, R. D., Nwokoro, N. A., Kelley, R. I., Stewart, R. R., Porter, F. D. Biochemical, phenotypic and neurophysiological characterization of a genetic mouse model of RSH/Smith-Lemli-Opitz syndrome. Hum. Molec. Genet. 10: 555-564, 2001. [PubMed: 11230174] [Full Text: https://doi.org/10.1093/hmg/10.6.555]
Weber, J. W., Schwarz, H. Der typus Rostockiensis Ullrich-Feichtiger Dyskraniopygophalangie. Helv. Paediat. Acta 15: 163-170, 1960. [PubMed: 13843313]
Witsch-Baumgartner, M., Ciara, E., Loffler, J., Menzel, H. J., Seedorf, U., Burn, J., Gillessen-Kaesbach, G., Hoffmann, G. F., Fitzky, B. U., Mundy, H., Clayton, P., Kelley, R. I., Krajewska-Walasek, M., Utermann, G. Frequency gradients of DHCR7 mutations in patients with Smith-Lemli-Opitz syndrome in Europe: evidence for different origins of common mutations. Europ. J. Hum. Genet. 9: 45-50, 2001. [PubMed: 11175299] [Full Text: https://doi.org/10.1038/sj.ejhg.5200579]
Witsch-Baumgartner, M., Gruber, M., Kraft, H. G., Rossi, M., Clayton, P., Giros, M., Haas, D., Kelley, R. I., Krajewska-Walasek, M., Utermann, G. Maternal apo E genotype is a modifier of the Smith-Lemli-Opitz syndrome. J. Med. Genet. 41: 577-584, 2004. [PubMed: 15286151] [Full Text: https://doi.org/10.1136/jmg.2004.018085]
Witsch-Baumgartner, M., Schwentner, I., Gruber, M., Benlian, P., Bertranpetit, J., Bieth, E., Chevy, F., Clusellas, N., Estivill, X., Gasparini, G., Giros, M., Kelley, R. I., and 17 others. Age and origin of major Smith-Lemli-Opitz syndrome (SLOS) mutations in European populations. J. Med. Genet. 45: 200-209, 2008. [PubMed: 17965227] [Full Text: https://doi.org/10.1136/jmg.2007.053520]
Xu, G., Salen, G., Shefer, S., Ness, G. C., Chen, T. S., Zhao, Z., Tint, G. S. Reproducing abnormal cholesterol biosynthesis as seen in the Smith-Lemli-Opitz syndrome by inhibiting the conversion of 7-dehydrocholesterol to cholesterol in rats. J. Clin. Invest. 95: 76-81, 1995. [PubMed: 7814648] [Full Text: https://doi.org/10.1172/JCI117678]
Yu, H., Lee, M.-H., Starck, L., Elias, E. R., Irons, M., Salen, G., Patel, S. B., Tint, G. S. Spectrum of delta(7)-dehydrocholesterol reductase mutations in patients with the Smith-Lemli-Opitz (RSH) syndrome. Hum. Molec. Genet. 9: 1385-1391, 2000. Note: Erratum: Hum. Molec. Genet. 9: 1903 only, 2000. [PubMed: 10814720] [Full Text: https://doi.org/10.1093/hmg/9.9.1385]
Yu, H., Tint, G. S., Salen, G., Patel, S. B. Detection of a common mutation in the RSH or Smith-Lemli-Opitz syndrome by a PCR-RFLP assay: IVS8-1G-C is found in over sixty percent of US propositi. Am. J. Med. Genet. 90: 347-350, 2000. [PubMed: 10710236] [Full Text: https://doi.org/10.1002/(sici)1096-8628(20000214)90:4<347::aid-ajmg16>3.0.co;2-7]