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1/70. adrenal insufficiency in smith-lemli-opitz syndrome.

    We describe three unrelated patients with adrenal insufficiency and RSH or smith-lemli-opitz syndrome (SLOS), a disorder due to deficient synthesis of cholesterol. These patients presented with hyponatremia, hyperkalemia, and decreased aldosterone-to-renin ratio, which is a sensitive measure of the renin-aldosterone axis. All patients had profound serum total cholesterol deficiency (14-31 mg/dl) and marked elevation of 7-dehydrocholesterol (10-45 mg/ dl). Two patients were newborn infants with 46, XY karyotypes and complete failure to masculinize; one of these patients also had cortisol deficiency. Both patients died within 10 days of birth of cardiopulmonary complications while on adrenal replacement therapy. The third patient diagnosed with SLOS at birth presented at age 7months with fever and diarrhea and was noted to have profound hyponatremia. This patient is maintaining normal serum electrolytes on mineralocorticoid replacement. We conclude that adrenal insufficiency may be a previously undetected and treatable manifestation in SLOS. We hypothesize that deficiency of cholesterol, an adrenal hormone precursor, may lead to insufficient synthesis of adrenal steroid hormones. ( info)

2/70. prenatal diagnosis of smith-lemli-opitz syndrome in a pregnancy with low maternal serum oestriol and a sex-reversed fetus.

    A cytogenetically normal male fetus was subsequently found to have female external genitalia, a cardiac malformation and mid-trimester intra-uterine growth retardation by ultrasound examination. The maternal serum oestriol level was low. The combination of low oestriol and sonographic findings suggested Smith Lemli Opitz syndrome (SLO), which was confirmed by a markedly increased amniotic fluid level of 7-dehydrocholesterol. We review the differential diagnosis of apparent sex reversal in a fetus and low maternal serum oestriol level. To further examine the specificity of low maternal oestriol level as a marker for SLO a follow-up study of 12141 pregnancies screened for down syndrome using three biochemical markers: alpha-fetoprotein, beta-human chorionic gonadotrophin and oestriol was performed. 26 pregnancies had an oestriol level that was 0.25 MoM or less. SLO was not diagnosed clinically in any of the liveborn children ascertained through a low maternal oestriol level. Nine of the pregnancies ended in spontaneous miscarriage. Although the frequency of SLO in pregnancies with low maternal oestriol levels or sex-reversed fetuses is unknown, the diagnosis of SLO should, nevertheless, be considered in both clinical settings. ( info)

3/70. Equine type estrogens produced by a pregnant woman carrying a smith-lemli-opitz syndrome fetus.

    The equine-type estriols 1,3,5(10),7-estratetraene-3,16alpha,17beta-triol (16alpha-hydroxy-17beta-dihydroequilin) and 1,3,5(10),6,8-estrapentaene-3,16alpha,17beta-triol (16alpha-hydroxy-17beta-dihydroequilenin) constituted over half of the estrogens excreted by a woman carrying a smith-lemli-opitz syndrome (SLOS) affected fetus. The steroids were characterized by gas chromatography-mass spectrometry (GC/MS), and mass spectra of the dehydro estriols as trimethylsilyl ethers are illustrated. SLOS is associated with 7-dehydrocholesterol (7DHC), delta 7-reductase deficiency; the enzyme catalyzing the final step in cholesterol biosynthesis. Identification of these equine estrogens show that an estrogen biosynthetic pathway parallel to normal is functional in the feto-placental unit and uses 7DHC as precursor, therefore P450scc, P450c17, and 3betaHSD and P450arom are all active on 7-dehydrometabolites. patients 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. The estriol deficiency is not quantitatively made up by the dehydrometabolites, and the combined excretion was found to be about one-third of the mean of gestational age matched controls. The importance of these findings lies in the potential value of dehydroestriol measurement for non-invasive diagnosis of SLOS at mid-gestation. Currently diagnosis relies on imaging, since SLOS is a malformation syndrome, and measurement of 7DHC levels in amniotic fluid and chorionic villus tissue. ( info)

4/70. smith-lemli-opitz syndrome presenting with persisting nuchal oedema and non-immune hydrops.

    smith-lemli-opitz syndrome (SLO) is a recognized clinical entity with distinctive anomalies. Recently it has been shown that a specific defect in cholesterol metabolism, 7-dehydroxycholesterol reductase deficiency, causes the multiple abnormalities seen in SLO. There have been two reports of first-trimester nuchal translucency associated with SLO. We report two cases of SLO in the third trimester, one with persisting nuchal oedema and the other presenting with hydrops. These findings may explain a proportion of the perinatal loss associated with this syndrome. ( info)

5/70. Antenatal therapy of smith-lemli-opitz syndrome.

    OBJECTIVES: smith-lemli-opitz syndrome (SLOS) is a recessively inherited disorder caused by an inborn error of cholesterol metabolism that results in deficiency of cholesterol and accumulation of the cholesterol precursor, 7-dehydrocholesterol (DHC) and its epimer, 8-DHC. Affected patients present with congenital anomalies, growth restriction, and mental retardation. Postnatal treatment with cholesterol supplementation has been shown to improve plasma sterol levels and has resulted in improved growth and development in many patients. We hypothesized that prenatal supplementation of cholesterol could potentially arrest some of the adverse consequences of cholesterol deficiency at an earlier stage of development. methods: SLOS was diagnosed in the third trimester in a fetus initially identified by sonography with intrauterine growth restriction and ambiguous genitalia and confirmed by elevated levels of 7- and 8-DHC in amniotic fluid. Antenatal supplementation of cholesterol was provided by fetal intravenous and intraperitoneal transfusions of fresh frozen plasma (cholesterol level = 219 mg/dl). RESULTS: The in utero transfusions resulted in increased levels of fetal cholesterol, as measured in blood samples obtained by cordocentesis. In addition, fetal red cell mean corpuscular volume rose, which further indicated that the exogenous cholesterol was incorporated into the fetal erythrocytes. CONCLUSIONS: Antenatal treatment of SLOS by cholesterol supplementation is feasible and results in improvement in fetal plasma cholesterol levels and fetal red cell volume. SLOS may be added to the growing list of human genetic disorders for which prenatal diagnosis is available and therapeutic intervention may be possible. ( info)

6/70. bile acid synthesis in the smith-lemli-opitz syndrome: effects of dehydrocholesterols on cholesterol 7alpha-hydroxylase and 27-hydroxylase activities in rat liver.

    The smith-lemli-opitz syndrome (SLOS) is a congenital birth defect syndrome caused by a deficiency of 3beta-hydroxysterol Delta(7)-reductase, the final enzyme in the cholesterol biosynthetic pathway. The patients have reduced plasma and tissue cholesterol concentrations with the accumulation of 7-dehydrocholesterol and 8-dehydrocholesterol. bile acid synthesis is reduced and unnatural cholenoic and cholestenoic acids have been identified in some SLOS patients. To explore the mechanism of the abnormal bile acid production, the activities of key enzymes in classic and alternative bile acid biosynthetic pathways (microsomal cholesterol 7alpha-hydroxylase and mitochondrial sterol 27-hydroxylase) were measured in liver biopsy specimens from two mildly affected SLOS patients. The effects of 7- and 8-dehydrocholesterols on these two enzyme activities were studied by using liver from SLOS model rats that were treated with the Delta(7)-reductase inhibitor (BM15.766) for 4 months and were comparable with more severe SLOS phenotype in plasma and hepatic sterol compositions. In the SLOS patients, cholesterol 7alpha-hydroxylase and sterol 27-hydroxylase were not defective. In BM15.766-treated rats, both enzyme activities were lower than those in control rats and they were competitively inhibited by 7- and 8-dehydrocholesterols. Rat microsomal cholesterol 7alpha-hydroxylase did not transform 7-dehydrocholesterol or 8-dehydrocholesterol into 7alpha-hydroxylated sterols. In contrast, rat mitochondrial sterol 27-hydroxylase catalyzed 27-hydroxylation of 7- and 8-dehydrocholesterols, which were partially converted to 3beta-hydroxycholestadienoic acids. Addition of microsomes to the mitochondrial 27-hydroxylase assay mixture reduced 27-hydroxydehydrocholesterol concentrations, which suggested that 27-hydroxydehydrocholesterols were further metabolized by microsomal enzymes. These results suggest that reduced normal bile acid production is characteristic of severe SLOS phenotype and is caused not only by depletion of hepatic cholesterol but also by competitive inhibition of cholesterol 7alpha-hydroxylase and sterol 27-hydroxylase activities by accumulated 7- and 8-dehydrocholesterols. Unnatural bile acids are synthesized mainly by the alternative pathway via mitochondrial sterol 27-hydroxylase in SLOS. ( info)

7/70. smith-lemli-opitz syndrome: a treatable inherited error of metabolism causing mental retardation.

    smith-lemli-opitz syndrome, a syndrome of multiple malformations and mental retardation that for years was relegated to the atlases of genetic esoterica, was recently found to be a relatively common inborn error of metabolism. The underlying defect is absent or deficient activity of 7-dehydrocholesterol- delta 7-reductase, the enzyme catalysing the final step of cholesterol synthesis. The discovery of the biochemical defect causing smith-lemli-opitz syndrome has resulted in the development of a diagnostic test and a potentially beneficial treatment (dietary cholesterol supplementation). Infants and young children with the syndrome have shown marked improvement in growth, behaviour and general health after receiving cholesterol therapy; older children and adults have shown some improvement in development and intellectual functioning. Despite the excitement these developments have elicited among geneticists and biochemists, this syndrome remains relatively unknown to many primary care physicians. Increased awareness of smith-lemli-opitz syndrome is needed to identify affected patients so that they and their families can benefit from appropriate treatment and genetic counselling. ( info)

8/70. Beneficial effects of dietary supplementation in a disorder with defective synthesis of cholesterol. A case report of a girl with smith-lemli-opitz syndrome, polyneuropathy and precocious puberty.

    In 1993 the Smith-Lemli-Opitz (SLO) syndrome, known as a malformation syndrome characterized by certain stigma, turned out to be a metabolic disease with a defect in the last step of cholesterol biosynthesis. This led to the possibility of identifying affected individuals by biochemical methods and of increasing understanding of pathogenic mechanisms. Hopes of influencing the effects of the metabolic defect by dietary supplementation were raised and reports with some benefits of treatment have been published. This is a report of a 12-y-old girl with the SLO syndrome in an apparently progressive form. In addition to typical signs and well-known symptoms she has a verified polyneuropathy and precocious puberty. She has been treated with cholesterol and bile acids for 3 y, during which time the progressive course has been arrested. A notable effect has been the improvement of her polyneuropathy, verified by measurement of nerve conduction velocities. Possible mechanisms involved in the pathogenesis of her precocious puberty are discussed. ( info)

9/70. smith-lemli-opitz syndrome: in vivo and in vitro study of testicular function in a prepubertal patient with ambiguous genitalia.

    The pathogenesis of the development of ambiguous genitalia reported in some 46,XY patients with smith-lemli-opitz syndrome is not understood. Presumably, it is related to the 7-dehydrocholesterol reductase deficiency present in these patients. In this study we have evaluated testicular function, both in vivo and in vitro, in a 46,XY patient with ambiguous genitalia, reared as a girl. The diagnosis was based on clinical features, low serum cholesterol and high serum 7-dehydrocholesterol levels. serum hormone values, determined during the first month of age, showed normal basal testosterone (1.95 ng/ml), LH (0.91 U/l) and FSH (2.51 U/l). However, serum testosterone did not increase after hCG administration (1.98 ng/ml). On the other hand, the patient had a positive biological response to exogenous testosterone (decrease in sex hormone-binding globulin serum levels). She was orchidectomized at the age of 33 mo. Testicular cells were dispersed and maintained in culture for 6 d. These cells showed a very good capacity to secrete testosterone into the culture medium (X /- SD, 26.1 /- 11.7 vs. 4.36 /- 1.70 pmol/10(6) cells/24 h in a control group of testicular cells prepared from testes collected at necropsy). The patient's cells failed to respond to LH stimulation (18.6 /- 4.0 pmol/10(6) cells/24 h), although they did respond to other stimuli. It is concluded that the severe cholesterol deficiency of this patient did not impair the capacity of the testes to synthesize testosterone. However, the LH/hCG receptor or its subsequent message was activated neither in vivo nor in vitro. This finding suggests that the foetal testes might have failed to respond to placental hCG at the time of male external genital differentiation. This failure could have been responsible for the ambiguous genitalia present in this patient. ( info)

10/70. Fetal demise with smith-lemli-opitz syndrome confirmed by tissue sterol analysis and the absence of measurable 7-dehydrocholesterol Delta(7)-reductase activity in chorionic villi.

    smith-lemli-opitz syndrome (SLOS), an autosomal recessive condition with multiple malformations, mental retardation, and growth failure, results from markedly reduced activity of the final enzyme in the cholesterol biosynthetic pathway, 7-dehydrocholesterol Delta(7)-reductase (DHCR7). We diagnosed SLOS in a fetus following intrauterine demise at 32 weeks' gestation. Chorionic villus (CV) sampling had been performed at 30 weeks because oligohydramnios and atrioventricular septal defect were noted on fetal ultrasound. On fetal post-mortem examination, a midline U-shaped soft palate cleft, micrognathia, postaxial polydactyly of the fingers with single transverse palmar creases bilaterally, and cutaneous syndactyly of toes two-three bilaterally suggested SLOS. We hypothesized that SLOS could be confirmed by analysis of tissue sterols despite extensive autolysis, and by measurement of enzyme activity in CV cells. Measurement of DHCR7 activity in CV cells was undertaken using ergosterol as a substrate. CV cells were unable to convert any ergosterol to brassicasterol after a 72 h incubation period while control CV cells reduced 12.6-71.8% of ergosterol to brassciasterol in a 72 h period. SLOS was confirmed by measurement of elevated 7-dehydrocholesterol (7-DHC) in the CV cells. Measurements of sterols were made in multiple fetal tissues. All tissues analysed showed elevated 7-DHC with markedly increased 7-DHC/cholesterol ratios. ( info)
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