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

RSH/Smith-Lemli-Opitz (RSH/SLO) syndrome is an autosomal recessive 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. Am. J. Med. Genet. 68: 263–269, 1997. © 1997 Wiley-Liss, Inc.     

Atypical case of Smith-Lemli-Opitz syndrome: Implications for diagnosis

Smith-Lemli-Opitz (SLO) syndrome is an autosomal recessive disorder comprised of recognizable facial abnormalities, growth retardation, and multiple congenital anomalies, commonly involving genitalia, second and third toe syndactyly, and cleft palate. The condition is associated with hypocholesterolemia and elevated levels of 7-dehydrocholesterol (7DHC) resulting from deficient activity of the enzyme 7-dehydrocholesterol reductase. The clinical spectrum of SLO ranges from individuals with mental retardation and minor anomalies to those with major structural defects and early or even prenatal lethality. Low maternal serum unconjugated estriol (uE3) levels and a variety of fetal ultrasound anomalies have been identified in affected pregnancies, and prenatal diagnosis is possible by measurement of amniotic fluid 7DHC levels in pregnancies known to be at risk because of a previously affected child. We report on a pregnancy with low maternal uE3 level, abnormal antenatal ultrasound findings including limb deformities, ventriculomegaly, and hydrops fetalis, and a normal 46,XY karyotype. The infant died at birth. At autopsy the infant had hydrops, unusual face, cleft palate, genital abnormalities, Dandy-Walker malformation, and absence of toe syndactyly. Tests performed on cultured skin fibroblasts showed elevated levels of 7DHC and abnormalities of cholesterol biosynthesis characteristic of the metabolic defect that causes SLO. The atypical findings of hydrops, uncharacteristic facial appearance, and absence of toe syndactyly in this case additionally illustrates the wide phenotypic spectrum of SLO and the need for a high index of suspicion for a disorder with great clinical variability. Identification of another affected pregnancy with a low maternal uE3 level and abnormal fetal ultrasound findings in the presence of a normal karyotype lends additional support for consideration of prenatal biochemical testing for SLO in pregnancies with these findings, including pregnancies not previously known to be at risk. Am. J. Med. Genet. 80:322–326, 1998. © 1998 Wiley-Liss, Inc.     

Difficult prenatal diagnosis in mild Smith-Lemli-Opitz syndrome

Smith-Lemli-Opitz syndrome (SLOS) is an autosomal recessive disorder of cholesterol biosynthesis caused by mutations of the 7-dehydrocholesterol (7DHC) reductase gene (DHCR7). We present our experience with prenatal diagnosis of an affected fetus with a very mild form of SLOS. The mother underwent prenatal diagnosis by chorionic villus (CV) sampling at 11 2/7 weeks because of having two prior affected sons with SLOS. The 7DHC/total-sterol ratio in the fetus was higher than in normal control fetuses but lower than the ratio observed in CV of three other fetuses in whom SLOS was diagnosed prenatally. The pregnancy was terminated at 13 2/7 weeks. The level of 7DHC in amniotic fluid (AF) obtained at the time of pregnancy termination was unequivocally elevated, confirming the diagnosis of SLOS. This report illustrates the difficulties with the interpretation of biochemical prenatal diagnosis based on the determination of 7DHC/total-sterol ratio in CV sample in a case of mild SLOS, whereas biochemical testing of amniotic fluid clearly manifests the biochemical defects of SLOS as early as 13 weeks of gestation.     

Difficult prenatal diagnosis in mild Smith‐Lemli‐Opitz syndrome

Smith‐Lemli‐Opitz syndrome (SLOS) is an autosomal recessive disorder of cholesterol biosynthesis caused by mutations of the 7‐dehydrocholesterol (7DHC) reductase gene (DHCR7). We present our experience with prenatal diagnosis of an affected fetus with a very mild form of SLOS. The mother underwent prenatal diagnosis by chorionic villus (CV) sampling at 11 2/7 weeks because of having two prior affected sons with SLOS. The 7DHC/total‐sterol ratio in the fetus was higher than in normal control fetuses but lower than the ratio observed in CV of three other fetuses in whom SLOS was diagnosed prenatally. The pregnancy was terminated at 13 2/7 weeks. The level of 7DHC in amniotic fluid (AF) obtained at the time of pregnancy termination was unequivocally elevated, confirming the diagnosis of SLOS. This report illustrates the difficulties with the interpretation of biochemical prenatal diagnosis based on the determination of 7DHC/total‐sterol ratio in CV sample in a case of mild SLOS, whereas biochemical testing of amniotic fluid clearly manifests the biochemical defects of SLOS as early as 13 weeks of gestation. Am. J. Med. Genet. 95:396–398, 2000. 2000 Wiley‐Liss, Inc.     

Maternal urinary steroid profiles in prenatal diagnosis of Smith-Lemli-Opitz syndrome: first patient series comparing biochemical and molecular studies

Smith-Lemli-Opitz syndrome (SLOS) is an autosomal recessive disorder caused by reduced activity of 7-dehydrocholesterol (7DHC) reductase, resulting in a decreased level of cholesterol and increased concentrations of 7DHC and 8DHC in body fluids and tissues. Ten pregnancies at 25% risk of SLOS underwent prenatal testing. Diagnostic studies included DHCR7 mutation analysis in chorionic villus samples, amniotic fluid sterol analysis and serial measurements of oestriol (E3), pregnanetriol (PT), 7-dehydropregnanetriol (7DHPT) and 8-dehydroesteriol (8DHE3) concentrations in maternal urine samples obtained between 9 and 20 weeks of gestation. All tests were diagnostic and revealed nine unaffected foetuses (two normal homozygotes and seven DHCR7 heterozygotes) and one affected foetus. In the affected pregnancy, 7DHC and 8DHC in amniotic fluid were 9.87 and 3.7 microg/ml, respectively [reference range (RR) 0.0026 +/- 0.0015 microg/ml and not detectable, respectively] and maternal urinary steroid analyses showed increased ratios of 7DHPT/PT and 8DHE3/E3 of 0.74 and 1.7, respectively (RR 0-0.0147 and 0-0.019). In the heterozygous foetuses, 7DHPT/PT and 8DHE3/E3 ratios did not exceed those found in 48 normal controls. This is the first series of prenatal diagnostic testing for SLOS where non-invasive biochemical testing was performed in tandem with invasive diagnostic testing. We conclude that steroid measurements in maternal urine are a reliable means of prenatal diagnosis for SLOS.     

Variant RSH/Smith-Lemli-Opitz syndrome with atypical sterol metabolism

The RSH/Smith-Lemli-Opitz syndrome (RSH/SLOS) is an autosomal recessive malformation syndrome comprising microcephaly, developmental and growth retardation, characteristic facial anomalies, midline cleft palate, and genital and limb anomalies. Recently, biochemical evidence of an inborn error of cholesterol biosynthesis at the level of 7-dehydrocholesterol (7DHC) reductase was reported in children and adults with RSH/SLOS. We report on two sibs with a variant form of RSH/SLOS whose sterol metabolism in cultured lymphoblasts is abnormal but differs from that of patients with classical RSH/SLOS. The children have relatively mild physical and developmental abnormalities, but a phenotype still consistent with the diagnosis of RSH/SLOS. Their plasma cholesterol levels are only mildly depressed, and they have less markedly increased plasma levels of 7DHC than most patients with classical RSH/SLOS. Cultured lymphoblasts from our patients accumulated 7DHC to the same degree as classical RSH/SLOS lymphoblast when grown with cholesterol-depleted fetal calf serum. However, unlike other RSH/SLOS cells, the increase in cellular 7DHC levels was not suppressed when the cells were grown in the presence of cholesterol from untreated fetal calf serum. The parents' sterol metabolism was also strikingly abnormal in that the levels of 7DHC in their lymphoblasts were markedly elevated compared with those of lymphoblasts from other RSH/SLOS parents. Our findings suggest that these mildly affected RSH/SLOS sibs may have a genetic disorder of sterol metabolism that is related to but biochemically different from classical RSH/SLOS, possibly one affecting intracellular transport of sterols. Am. J. Med. Genet. 78: 413–418, 1998. © 1998 Wiley-Liss, Inc.     

Cholesterol supplementation with egg yolk increases plasma cholesterol and decreases plasma 7‐dehydrocholesterol in Smith‐Lemli‐Opitz syndrome

Smith‐Lemli‐Opitz syndrome (SLOS), an autosomal recessive condition comprising multiple malformations, mental retardation, and growth failure, results from reduced activity of the final enzyme in cholesterol biosynthesis, 7‐dehydrocholesterol Δ⁷‐reductase (DHCR7). Reduced plasma and tissue cholesterol concentrations and accumulation of cholesterol precursors including 7‐dehydrocholesterol (7‐DHC) are characteristic biochemical abnormalities. While it is still unclear what role these potentially toxic precursors have in the pathogenesis of this disorder, the accumulation of 7‐DHC in the brain has been associated with impaired learning in rats and oxidized 7‐DHC has been shown to induce growth retardation in cultured rat embryos. We hypothesized that supplemental dietary cholesterol would increase plasma cholesterol levels and suppress synthesis of 7‐DHC and other abnormal sterols in individuals with SLOS. After baseline sterol levels were obtained, patients were provided supplemental cholesterol as egg yolk. Plasma sterols were analyzed by capillary‐column gas chromatography over time in four children with SLOS. When evaluated at 4–8 weeks after the initiation of cholesterol supplementation, there was a marked increase in mean plasma cholesterol, from 53 mg/dl to 82 mg/dl. While the percent of total sterols as 7‐DHC decreased from 15% to 10%, there was no change in total plasma 7‐DHC levels. However, when evaluated 35–90 weeks after the institution of cholesterol supplementation, mean plasma 7‐DHC decreased, from 11.3 mg/dl to 3.5 mg/dl (−67%, P < 0.05), along with an increase in mean plasma cholesterol from 53 mg/dl to 114 mg/dl (+116%, P < 0.05). These results support the hypothesis that over time dietary cholesterol supplementation from egg yolk increases the plasma cholesterol levels and decreases levels of 7‐DHC which may be toxic. These data have important therapeutic implications in the management of SLOS. Am. J. Med. Genet. 93:360–365, 2000. © 2000 Wiley‐Liss, Inc.     

Sterol concentrations in cultured Smith-Lemli-Opitz syndrome skin fibroblasts: Diagnosis of a biochemically atypical case of the syndrome

The Smith-Lemli-Opitz syndrome is a common birth defect syndrome caused by a deficiency of 7-dehydrocholesterol Δ⁷-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. Am. J. Med. Genet. 68:282–287, 1997. © 1997 Wiley-Liss, Inc.     

Direct analysis of filter paper blood specimens for identification of Smith-Lemli-Opitz syndrome using time-of-flight secondary ion mass spectrometry

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. Am. J. Med. Genet. 68: 300–304, 1997. © 1997 Wiley-Liss, Inc.     

Smith-Lemli-Opitz syndrome

SLO syndrome is an autosomal recessive condition with multiple malformations. This syndrome is ascribed to deficiency of 7 dehydrocholesterol reductase, an enzyme in the cholesterol biosynthetic pathway. The characteristics of this syndrome are facial anomalies, syndactyly of the second and third toe, postaxial polydactyly and genital anomalies with sexual ambiguity. We report a fetal case with intrauterine growth retardation, genital anomalies, multiple malformations with cardiac anomalies, renal aplasia and facial anomalies detected by prenatal ultrasound. Medical abortion was induced at 24 weeks gestation. The diagnosis was considered after complete pathologic examination and biochemical analysis.     

Identification of three patients with a very mild form of Smith-Lemli-Opitz syndrome

Smith-Lemli-Opitz syndrome (SLOS) is an autosomal recessive malformation syndrome characterized by mental retardation, congenital anomalies, and growth deficiency. The syndrome is caused by a block in cholesterol biosynthesis at the level of 7-dehydrocholesterol reductase (7-DHCR), which results in elevated levels of the cholesterol precursor 7-dehydrocholesterol (7-DHC) and its isomer 8-dehydrocholesterol (8-DHC). We report on three patients from two 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 three patients were compound heterozygotes for a novel mutation affecting translation initiation (M1L). Two of them had the common IVS8-1G>C null mutation and the third patient an E448K mutation in the 7-DHCR gene. Our findings emphasize the importance of using a sensitive method for measuring precursors of cholesterol in combination with mutation analysis to analyze patients with only minimal clinical SLOS-like signs.     

Discordant amniotic band sequence in monozygotic twins

Multiple congenital anomalies were identified at 16 weeks gestation in one fetus of an unsuspected twin pregnancy while ultrasound examination was performed before routine genetic amniocentesis. Further sonographic studies documented the amniotic band sequence (ABS) and transient oligohydramnios in the affected fetus. The latter finding supports the theory of amnion rupture followed by amniotic fluid leakage through an ineffective chorion barrier as the pathogenesis of compression related anomalies in this syndrome. Extensive craniofacial involvement including hydrocephalus, encephalocele, and multiple facial clefts in the affected fetus, combined with an erroneous ultrasound diagnosis of ABS in the unaffected twin, created an extremely difficult management and counseling situation. A review of ABS, the embryology of placental membrane development, and a discussion of selective termination procedures are presented.     

Prenatal diagnosis of the RSH/Smith-Lemli-Opitz syndrome

The RSH/Smith-Lemli-Opitz syndrome (RSH/SLOS) is a relatively common, autosomal recessive malformation syndrome comprising distinctive facial, limb and genital anomalies, and mental retardation. Most patients with a clinical diagnosis of RSH/SLOS have a defect of cholesterol biosynthesis at the level of 3beta-hydroxysteroid-delta7-reductase, resulting in a decreased level of cholesterol and an increased level of 7-dehydrocholesterol (7DHC) in body fluids and tissues. We report on our experience with the prenatal diagnosis of RSH/SLOS by quantitative sterol chromatography in amniotic fluid (AF) and chorionic villus (CV). Of 76 AF and nine CV samples analyzed for various indications, 20 were diagnostic of RSH/SLOS based on an increased level of 7DHC in the fluid or tissue. Of 39 fetuses at a 25% risk for RSH/SLOS, 10(25.6%) were affected. Twenty-nine pregnancies not known to be at risk for RSH/SLOS were studied because of either a fetal abnormality characteristic of RSH/SLOS detected by ultrasound, a low maternal serum uE3 level (MSuE3), or both. None of the pregnancies tested, because of a low MSuE3 but lacking a sonographic abnormality characteristic of RSH/SLOS, was affected. However, three of four pregnancies with a low MSuE3 and an RSH/SLOS-type fetal abnormality were positive. RSH/ SLOS was diagnosed in two additional pregnancies on which MSuE3 data were not available but in which fetal anomalies were identified. Of these five RSH/SLOS fetuses identified in pregnancies not otherwise at risk for RSH/SLOS, the presenting sonographic anomaly was either polydactyly, ambiguous genitalia, or both. Evaluation of the biochemical parameters and clinical severity of RSH/SLOS showed that there was an inverse correlation between clinical severity and both the level of AF 7DHC and the level of MSuE3. Based on these earlier and more extensive studies, we conclude that accurate prenatal diagnosis of RSH/ SLOS is possible by sterol analysis of AF and, most likely, CV specimens as well. Furthermore, our findings suggest that MSuE3 levels in combination with sonography may provide useful diagnostic and prognostic information in the absence of a family history of RSH/SLOS.     

Angiomyxoma of the umbilical cord with massive cystic degeneration of Wharton's jelly

Tumors of the umbilical cord, and especially angiomyxomas, are extremely unusual placental lesions. Sonography three weeks after the finding of a slightly elevated amniotic fluid alpha-fetoprotein, detected a cystic lesion of the umbilical cord in a 35-year-old woman at 19.5 weeks gestation. Two prior sonograms had been normal (16.2 and 17.5 weeks gestational age). After delivery of a normal female infant at 38.5 weeks, a pathologic examination revealed an angiomyxoma of the umbilical cord with massive cystic degeneration of Wharton's jelly. The tumor was twice the size of cases cited previously and cystic degeneration was massive. Serial sonography afforded a unique opportunity to study the development of this lesion in utero.     

Nanostructure-initiator mass spectrometry (NIMS) imaging of brain cholesterol metabolites in Smith-Lemli-Opitz syndrome

Cholesterol is an essential component of cellular membranes that is required for normal lipid organization and cell signaling. While the mechanisms associated with maintaining cholesterol homeostasis in the plasma and peripheral tissues have been well studied, the role and regulation of cholesterol biosynthesis in normal brain function and development have proven much more challenging to investigate. Smith–Lemli–Opitz syndrome (SLOS) is a disorder of cholesterol synthesis characterized by mutations of 7-dehydrocholesterol reductase (DHCR7) that impair the reduction of 7-dehydrocholesterol (7DHC) to cholesterol and lead to neurocognitive deficits, including cerebellar hypoplasia and austism behaviors. Here we have used a novel mass spectrometry-based imaging technique called cation-enhanced nanostructure-initiator mass spectrometry (NIMS) for the in situ detection of intact cholesterol molecules from biological tissues. We provide the first images of brain sterol localization in a mouse model for SLOS (Dhcr7^−/−). In SLOS mice, there is a striking localization of both 7DHC and residual cholesterol in the abnormally developing cerebellum and brainstem. In contrast, the distribution of cholesterol in 1-day old healthy pups was diffuse throughout the cerebrum and comparable to that of adult mice. This study represents the first application of NIMS to localize perturbations in metabolism within pathological tissues and demonstrates that abnormal cholesterol biosynthesis may be particularly important for the development of these brain regions.     

Incidence of Smith-Lemli-Opitz syndrome in Ontario, Canada

Smith-Lemli-Opitz syndrome (OMIM 270400) (SLOS) is caused by inherited enzymatic deficiency of 3beta-hydroxysterol-Delta7-reductase (7-dehydrocholesterol-Delta7-reductase, DHCR7). SLOS is diagnosed clinically by the demonstration of elevated levels of 7-dehydrocholesterol (7DHC) in body fluids or tissues. SLOS is associated with mental retardation of variable degree and severe behavior abnormalities. The physical abnormalities range from minor facial anomalies to lethal malformations of the central nervous system, heart, kidneys, and other organs. The exact incidence of SLOS is not known. Although there exist estimates of the incidence of SLOS ranging from 1 in 20,000 to 1 in 60,000, no prospective studies of the incidence of SLOS, based on the clinical data and biochemical diagnosis of SLOS, have been performed. Five unrelated cases of SLOS were diagnosed in Ontario during a 12-month period. The diagnoses were made based on the demonstration of elevated 7DHC in plasma or amniotic fluid. The birth rate for Ontario for that period was 132,000 births. The incidence of SLOS in Ontario was at least 1 in 26,500 pregnancies in 1999-2000. Given that 86% of the population of Ontario is of European origin, the incidence of SLOS in the Ontario population of European origin was at least 1 in 22,700. As infants with mild forms of SLOS born during this period may remain undiagnosed, these numbers likely are underestimates. This observation has implications for prenatal and newborn screening for this potentially treatable inherited disorder.     

Gamma-glutamyl transferase activity in the amniotic fluid of fetuses with chromosomal aberrations and inborn errors of metabolism

The activity of gamma-glutamyl transferase (GGT) was measured in amniotic fluid collected between the 16th and 30th weeks of gestation from 81 pregnancies with fetuses affected by chromosomal aberrations, nine with different types of inborn errors of metabolism, two with hemophilia A and one with fragile X syndrome. The GGT activity was compared with that from 1000 normal pregnancies and deliveries resulting in healthy newborns. Contamination of amniotic fluid by blood did not affect the GGT activity. Pathologically decreased activity was found in 25 of 56 amniotic samples from pregnancies with fetal autosomal chromosomal aberrations (44.6%). It was decreased in 15 of 35 pregnancies with fetal trisomy 21 (43%), in 11 of 19 pregnancies with fetal trisomy 18 (58%), in one of three pregnancies with fetal trisomy 13 and in two pregnancies with fetal trisomy 8 and triploidy, respectively. In only three of 16 pregnancies with fetal sex chromosomal aberrations was the GGT activity low. Increased GGT activity was found in three of six pregnancies with unbalanced structurally rearranged karyotypes of the fetuses. Normal GGT activity was observed in all nine amniotic fluid samples from pregnancies with fetuses affected with different forms of inborn errors of metabolism diseases, in the two pregnancies with hemophilia A and in the pregnancy with a male fetus with fragile X syndrome. These and earlier findings indicate that the GGT activity in amniotic fluid is mostly decreased in pregnancies with severe fetal developmental abnormalities, such as autosomal chromosomal aberrations, which could possibly be secondary to an alteration of the microvillar transport system of GGT to the amniotic fluid.(ABSTRACT TRUNCATED AT 250 WORDS)     

Biochemical variants of Smith-Lemli-Opitz syndrome.

Smith-Lemli-Opitz (SLO or RSH) syndrome is characterized by multiple congenital anomalies, mental retardation, and defective growth; it results from an inherited defect in the biosynthesis of cholesterol. Patients have elevated plasma concentrations of 7-dehydrocholesterol, the immediate biosynthetic precursor of cholesterol and most also have low circulating levels of cholesterol. To understand better the biochemical basis of clinical variability, we evaluated cholesterol biosynthesis in lymphoblasts from 3 unrelated SLOS patients with distinct phenotypes. One patient has "type I SLOS", the second has the more severe "type II SLOS" and the third is classified as atypical and had been postulated to have a defect in sterol transport. The lymphoblasts of each patient show normal subcellular localization of cholesterol and 7-dehydrocholesterol by gradient fractionation. Biochemical differences in the ability of the lymphoblasts to convert 7-dehydrocholesterol to cholesterol are described and correspond to the severity of disease (type II > type I > atypical). Recently, the gene responsible for most SLOS cases (DHCR7) was mapped to chromosome 11 and mutations in DHCR7 were found in each of these patients. The biochemical differences described here likely result from the different mutations observed in DHCR7.     

ADAM sequence and innocent amniotic band: manifestations of early amnion rupture

Thirteen placentas with early amnion rupture (EAR) are described. These placentas were characterized by the absence of amniotic epithelium on the fetal surface, presence of a slightly fibrotic small amniotic band (remnant) attaching to the umbilical cord at the placental end, and the presence of degenerated vernix squamous cells in the fibrous stroma of chorion and amnion. Eight fetuses had ADAM sequence. Six of these fetuses were miscarried between 16 and 28 weeks of gestation. Two affected infants were born alive at gestational ages of 29 and 39 weeks. Five infants were spared by ADAM sequence; two had the umbilical cord strangulated by an amniotic band and were delivered at 27 and 37 weeks. In the 3 infants unassociated with ADAM sequence or strangulation of the umbilical cord, their placentas were interpreted as having innocent amniotic band (IAB) and they were delivered between 32 and 40 weeks. The findings in this study support Torpin's hypothesis that ADAM sequence is a complication of EAR. This ADAM sequence due to simple EAR must be separated from the limb body wall malformation complex because visceral anomalies are uncommon in the former condition but are frequently seen in the latter. In this study the placental pathology of EAR was helpful in confirming the ADAM sequence in the fetus.