Smith-Lemli-Opitz Research Articles

Síndrome de Smith-Lemli-Opitz. Anomalía en la síntesis de colesterol

Smith-Lemli-Opitz (SLO) es un síndrome debido a la deficiencia de la 7- dehidrocolesterol reductasa (DHCR7). DHCR7 cataliza principalmente la reducción del 7-dehidrocolesterol (7DHC) en colesterol. En SLO, esto se traduce en la disminución del colesterol y el aumento de los niveles de 7DHC, tanto durante el desarrollo embrionario y después del nacimiento. Las malformaciones que se encuentran en SLO puede ser consecuencia de la disminución del colesterol, aumento de 7DHC o una combinación de estos dos factores. Objetivo: Describir los aspectos clínicos y diagnósticos de un paciente con SLO y hacer una revisión actualizada del tema. Caso clínico: El reporte de caso se basa en datos recopilados en la historia clínica del paciente. Destacándose la presencia de bajo peso y talla. Microcefalia con dismorfias faciales como frente estrecha, hipotelorismo, epicanto bilateral, filtrum largo, comisuras bucales hacia abajo, paladar ojival y micrognatia. También micropene, hipospadia y criptorquidia bilateral, clinodactilia de 5to dedo bilateral, braquidactilia con pulgares de implantación proximal en manos y sindactilia parcial bilateral entre 2do y 3er dedo de los pies. Hipotonía generalizada y retraso del desarrollo psicomotor. Conclusión: Ante la presencia de un paciente con rasgos fenotípicos característicos de este síndrome y con niveles bajos del colesterol sérico, se debe sospechar en la posibilidad de SLO como diagnóstico.

PP-015 Complex partnership between paediatricians and hospital pharmacists

BackgroundHospital pharmacists face many daily challenges including supplying medicinal products for children. Lack of paediatric drugs encourages hospital pharmacists to act. The University of Debrecen has 150 paediatric beds.PurposeTo present...

G36 Palliative Care in Neonates with Antenatally and Postnatally Diagnosed Congenital Heart Disease

IntroductionThe RCPCH1 and BAPM2 have issued guidance on palliative care for neonates with life limiting conditions. There is no reference to congenital heart disease (CHD).MethodsWe reviewed 7 babies with CHD...

Meckel Gruber Syndrome

Dear Sir, We are reporting a case of Meckel-Gruber Syndrome (MGS), which was identified by its typical structural anomalies and supported by a history of consanguinity. MGS, which was originally described by Meckel in 1822 and later by Gruber [1], is caused by the failure of mesodermal induction. Of the 200 cases which have been reported so far, the highest incidence has been observed in the Gujarati Indians, with 1 affected birth per 1,300 (carrier rate 1 in 18) [2]. MGS is a lethal, rare and autosomal recessive condition that commonly occurs in association with chromosome 17 [2]. This syndrome is characterised by cystic kidneys, occiptal encephalocele and post axial polydactly. Two out of the three major anomalies are sufficient for the definitive diagnosis. Many congenital anomalies are present, of which the most striking is occipital encephalocele [3]. This cconsists of extrusion of parts of the brain parenchyma that is fully covered by a dural sac. A 16–year–old primigravida presented in labour at 32 weeks of gestation with a preterm, premature rupture of membranes. A routine ultrasonography, which was done at 20 weeks, had diagnosed a foetus with several structural malformations that were suspected to be lethal. She continued the pregnancy on religious grounds. The ultrasonogram showed occipital encephalocele, polydactyly, oligohydramnios and cystic dysplasia of both kidneys. There was no history which was suggestive of an infectious origin for the malformations, but a genetic cause was suspected, as the patient had a consanguineous marriage. She delivered a 1.5 kg male foetus vaginally that had an occipital encephalocele [Table/Fig-1], a bell-shaped chest, a protuberant abdomen and post axial polydactyly of both hands and the left leg [Table/Fig-2]. On abdominal examination large masses were found, which were palpable in the lumbar regions. The baby died 2 hours after birth. A postmortem examination confirmed herniation of the brain and that both kidneys had multiple small cysts. A genetic analysis could not be done, as patient was unable to afford this investigation. The intra–natal and post–natal periods of the mother went on uneventfully. Based on the presence of classical features, a diagnosis of MGS was suggested. [Table/Fig-1]: Occipital encephalocele [Table/Fig-2]: Bell-shaped chest, protuberant abdomen and post axial polydactyly In MGS, the incidence of occipital encephalocele and post-axial polydactyly is 60% -80% and 55%-75%, respectively [2]. Renal disorders are noted in 95-100% of the cases. In this case, a foetal renal disorder like cystic dysplasia of bilateral kidneys was noted during autopsy; central nervous system defects and skeletal system malformations which included micrognathia were also present. In MGS most of the infants with are stillborns or they die hours or days after birth, the implicated cause being dysplastic kidneys that result in oligohydramnios, which ultimately leads to foetal pulmonary hypoplasia [2]. The longest known survivor lived only till 4 months [4]. The possible differential diagnoses are trisomy13, autosomal dominant polycystic kidney disease(PKD) and autosomal recessive Smith-Lemli-Opitz (SLO) syndrome [5]. In view of the high recurrence rates of MGS, subsequent pregnancies should be properly investigated by first trimester ultrasound scans, with an early recourse to a chorionic villus biopsy or amniocentesis, if it is needed. Though neonatal autopsy and genetic studies are gold standards for the diagnosis, detecting two out of the three major anomalies in the foetus, as has been mentioned above, is also sufficient for clinicians to arrive at a definitive diagnosis and for counselling the patients likewise in such hospital set-ups where neither is possible.

A patient with Smith–Lemli–Opitz syndrome: novel mutation of the DHCR7 gene and effects of therapy with simvastatin and cholesterol supplement

The Smith-Lemli-Opitz (SLO) syndrome is a multiple congenital anomaly with mental retardation due to a decreased or lack of activity of 7-dehydrocholesterol reductase as a consequence of mutations of the DHCR7 gene. This paper describes a special patient with SLO syndrome. Laboratory examination showed low cholesterol (2.77 mmol/L) and increased 7-dehydrocholesterol level (102 mg/L). Molecular genetic analysis revealed a compound heterozygosity c.964-1G>C/p.G366V (c.G1370T) of the proband. The p.G366V is a novel mutation of the DHCR7 gene with guanine by thymine nucleotide exchange resulting in glycin by valin amino acid exchange in the dehydrocholesterol reductase enzyme. Simvastatin (0.2 mg/kg/day) and cholesterol replacement therapy (150-250 mg/kg/day) led to significant improvement in the patient's laboratory findings (7-dehydrocholesterol, cholesterol) as well as in his behavior and gross motor function. Our patient demonstrates that the c.964-1G>C/p.G366V (c.G1370T) genotype of combined heterozygosity is associated with a typical form of SLO syndrome along with moderately altered laboratory findings and a favorable biochemical response to cholesterol and simvastatin treatment.

Prenatal Diagnosis of Smith–Lemli–Opitz Syndrome

Smith–Lemli–Opitz (SLO) syndrome is an autosomal recessive multiple congenital malformation syndrome due to mutations in the 7-DHCR gene. The presented boy was diagnosed prenatally with multiple congenital malformations and confirmed as SLO by autopsy and molecular diagnosis. Interestingly in this boy prenatal MRI revealed a dilated duodenum, pointing towards intestinal dysmotility which is common in SLO.

Sensorineural hearing-loss in the Smith–Lemli-Opitz syndrome

Sensorineural hearing-loss in the Smith–Lemli-Opitz syndrome

Sensorineural hearing-loss in the Smith–Lemli-Opitz syndrome

Summary The Smith–Lemli-Opitz (SLO) syndrome is an autosomal recessive disorder caused by a mutation in the 7-dehydrocholesterol reductase gene, which in turn provokes a defect in cholesterol biosynthesis. SLO is characterised by a specific physical, behavioural and developmental pattern, and the main clinical features include minor facial anomalies, multiple congenital anomalies, failure to thrive and mental retardation. This report describes a case in a newborn child with the typical clinical signs and symptoms of SLO syndrome, who was also affected by profound bilateral sensorineural deafness, and revises the literature suggesting that audiological examination of patients with SLO syndrome may be useful.

Epistatic interactions with a common hypomorphicRET allele in syndromic Hirschsprung disease

Hirschsprung disease (HSCR) stands as a model for genetic dissection of complex diseases. In this model, a major gene, RET, is involved in most if not all cases of isolated (i.e., nonsyndromic) HSCR, in conjunction with other autosomal susceptibility loci under a multiplicative model. HSCR susceptibility alleles can harbor either heterozygous coding sequence mutations or, more frequently, a polymorphism within intron 1, leading to a hypomorphic RET allele. On the other hand, about 30% of HSCR are syndromic. Hitherto, the disease causing gene has been identified for eight Mendelian syndromes with HSCR: congenital central hypoventilation (CCHS), Mowat-Wilson (MWS), Bardet-Biedl (BBS), Shah-Waardenburg (WS4), cartilage-hair-hypoplasia (CHH), Smith-Lemli-Opitz (SLO), Goldberg-Sprintzsen (GSS), and hydrocephalus due to congenital stenosis of the aqueduct of sylvius (HSAS). According to the HSCR syndrome, the penetrance of HSCR trait varies from 5 to 70%. Trisomy 21 (T21) also predisposes to HSCR. We were able to collect a series of 393 patients affected by CCHS (n = 173), WS4 (n = 24), BBS (n = 51), MWS (n = 71), T21 (n = 46), and mental retardation (MR) with HSCR (n = 28). For each syndrome, we studied the RET locus in two subgroups of patients; i.e., with or without HSCR. We genotyped the RET locus in 393 patients among whom 195 had HSCR, and compared the distribution of alleles and genotypes within the two groups for each syndrome. RET acts as a modifier gene for the HSCR phenotype in patients with CCHS, BBS, and Down syndrome, but not in patients with MWS and WS4. The frequent, low penetrant, predisposing allele of the RET gene can be regarded as a risk factor for the HSCR phenotype in CCHS, BBS, and Down syndrome, while its role is not significant in MWS and WS4. These data highlight the pivotal role of the RET gene in both isolated and syndromic HSCR.

Antenatal manifestations of Smith-Lemli-Opitz (RSH) syndrome: a retrospective survey of 30 cases.

Smith-Lemli-Opitz (SLO) syndrome or RSH syndrome is an autosomal recessive multiple malformation, and mental retardation syndrome ascribed to 7-dehydrocholesterol reductase deficiency, and usually diagnosed in the early postnatal period. Reviewing a series of 30 cases of SLO, we have investigated the variable antenatal expression of the disorder. Intrauterine growth retardation (IUGR) was the most frequent detectable trait (20/30). IUGR was either isolated (9/20) or associated with at least one other anomaly (11/20), including nuchal edema, renal, cardiac, cerebral malformations, genital anomalies, or polydactyly. In this last group, 3/11 presented with multiple malformations (> or =3 anomalies). In 5/30 cases, isolated nuchal edema (3/30), and isolated cardiac (1/30) or renal malformations (1/30) were the only detectable anomalies. Ultrasound findings were considered normal in 5/30 cases and were abnormal in 25/30 cases (83%), but early detection of multiple malformations was rare (3/30, 10%). We suggest giving consideration to a more systematic sterol analysis when dealing with IUGR, especially when associated anomalies are detected.

Metabolic disorders and mental retardation.

The metabolic and anatomical substrate of most forms of mental retardation is not known. Because the basis of normal brain function is not sufficiently understood, the basis of abnormal function is understood poorly. Even in disorders where the fundamental biochemical defect is known, such as phenylketonuria (PKU) and other enzyme defects, the exact basis for brain dysfunction is uncertain. The outcome for treated PKU, galactosemia, homocystinuria, and lysosomal disorders is not yet optimal. The various forms of nonketotic hyperglycinemia often respond poorly to current therapy. Less familiar disorders, with or without seizures, such as deficient synthesis of serine or creatine and impaired glucose transport into the brain, and disorders with variable malformations, such as Smith-Lemli-Opitz (SLO) syndrome and the congenital disorders of glycosylation (CDGs), may initially be thought to be a nonspecific form of developmental delay. Less familiar disorders, with or without seizures and disorders with variable malformations may initially be thought to be a nonspecific form of developmental delay. Simple tests of urine, blood, and cerebrospinal fluid may lead to a diagnosis, accurate genetic counseling, and better treatment. Metabolic brain imaging (magnetic resonance spectroscopy (MRS)) has also helped to reveal biochemical abnormalities within the brain.

Circonstances cliniques du diagnostic du syndrome de Smith-Lemli-Opitz et tentatives de corrélation phénotype-génotype : à propos de 45 cas

Introduction. – SLO (Smith-Lemli-Opitz) syndrome is an autosomal recessive multiple congenital malformations syndrome, including mental retardation, failure to thrive, craniofacial abnormalities, incomplete development of male genitalia, limb anomalies and various internal organ abnormalities. This syndrome is caused by a deficiency of cholesterol biosynthesis at the distal step of 7–dehydrocholesterol reductase ( 7DHCR). Patients and methods. – We have reviewed 45 cases of SLO syndrome and showed the large clinical spectrum of this syndrome. Results. – The prenatal diagnosis should be considered when dealing with antenatal growth retardation and visceral malformations. At birth, a normal weight does not systematically exclude the diagnosis. Diagnosis was more difficult for older children especially for girls and should be suspected on the association of mental retardation, autism, short stature and microcephaly. We found a correlation between low plasmatic cholesterol measurement and clinical severity. Phenotype-genotype correlation was difficult to establish. However, homozygosity for IVS8-1G>C splice site mutation was associated with severe phenotype. Conclusion. – Better understanding of the 7DHCR gene regulation factors and of the compensatory mechanism of foeto-maternal cholesterol transfer are necessary to explain the wide clinical spectrum of the SLO syndrome.

Blocking cholesterol synthesis impairs acquisition of the classically conditioned eyeblink response.

Smith-Lemli-Opitz (SLO) syndrome is a congenital disorder characterized by severe mental retardation. Patients with SLO lack 7-dehydrocholesterol (7 dH) reductase, which catalyzes the last step of cholesterol synthesis. Administration of an agent that blocks 7 dH cholesterol reductase, BM 15.766 (BM), leads to a biochemical profile which resembles that of SLO patients, i.e., lower plasma, liver, and brain cholesterol levels accompanied by the appearance of the precursors 7 dH and 8 dH cholesterol. In this article we address the functional consequences of chronic BM treatment on new motor learning by assessing acquisition of the classically conditioned eyeblink response. Just-weaned rats were fed BM by gavage for four months, with half of these rats given exogenous cholesterol during the last two months of BM treatment. Acquisition of the eyeblink response was impaired in BM-treated rats. Impaired acquisition of the eyeblink response was not accompanied by alterations in responsiveness to either the conditioned or unconditioned stimulus. Exogenous cholesterol, a clinically relevant countertreatment, failed to correct for the learning impairment produced by BM treatment. Chronic treatment with a cholesterol synthesis-blocking agent impaired associative learning in just-weaned rats.

Photosensitivity in the Smith-Lemli-Opitz syndrome: The US experience of a new congenital photosensitivity syndrome

Photosensitivity has been briefly mentioned in several publications on the Smith-Lemli-Opitz (SLO) syndrome, an autosomal recessive mental retardation syndrome. We conducted a questionnaire-based survey to determine the incidence and main features of photosensitivity in SLO. We confirmed a high incidence, and initial evidence suggests that SLO may be the first example of an inherited photosensitivity disorder in which sensitivity to UVA is common. (J Am Acad Dermatol 1999;41:121-3.)

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. □Cholesterol, cholesterol and bile acid treatment, polyneuropathy, precocious puberty, Smith‐Lemli‐Opitz syndrome

Midgestational maternal urine steroid markers of fetal Smith–Lemli–Opitz (SLO) syndrome (7-dehydrocholesterol 7-reductase deficiency)

Smith–Lemli–Opitz syndrome (SLOS) is a malformation syndrome associated with 7-dehydrocholesterol (7DHC) 7-reductase deficiency. Although SLOS can be detected in an affected fetus before midpregnancy by measurement of 7DHC levels in amniotic fluid or chorionic villus cells, a noninvasive, more routine method is needed. Accordingly, this study was instigated to search for specific steroids in maternal urine in an affected pregnancy that reflect the 7-reductase deficiency of the fetus, ie, steroids retaining 7,8-unsaturation. Steroids were characterized by gas chromatography/mass spectrometry after urinary extraction, conjugate separation, and derivatization. Most steroids in maternal urine from a patient carrying a SLOS fetus were identified as progesterone metabolites, and these were entirely conventional, showing no evidence of additional unsaturation. Unsaturated homologues of the cortisol metabolites were also not detected. However, unsaturated homologues of pregnane-3,16,20-triols and pregnane-3,17,20-triol were found. Most likely, these are 7,8-unsaturated homologues, but 8,9-unsaturation is also possible because of the known activity of Δ 7-Δ 8-isomerase on 7DHC, which results in 8DHC being a prominent sterol in SLOS. Among these novel human steroids, the following were provisionally characterized: 5β-pregn-7(or 8)-ene-3α,17α,20α-triol, 5β-pregn-7(or 8)-ene-3α,16α,20α-triol, and 5α-pregn-7(or 8)-ene-3,16α,20α-triol. Confirmation of the position of unsaturation will require steroid synthesis. These novel steroids are not present in normal pregnancy urine and, therefore, are valuable for prenatal diagnosis of SLOS. In addition, separate studies have shown that 5β-pregn-7(or 8)-ene-3α,17α,20α-triol is present in urine of children and adults with SLOS, and so is a useful analyte for confirmation of the disorder throughout life.

Prenatal diagnosis of Smith-Lemli-Opitz syndrome via an abnormal maternal serum screen

Smith-Lemli-Opitz (SLO) syndrome is an autosomal recessive disorder which results from a defect in cholesterol biosynthesis. The finding of elevated levels of cholesterol precursors is diagnostic of SLO. There have been few reported cases of the prenatal diagnosis of SLO in the presence of a non-contributory family history. Abnormal triple screen, sex discrepancy, and polydactyly led to such a diagnosis in this case.L.M. was a 29 year old G2 P1 ABO who presented at 17.1 weeks gestation due to a positive maternal serum triple screen which estimated a midtrimester risk for fetal trisomy 18 of 1/15. The triple screen was reported as follows: MSAFP 0.44 MOM; ESTRIOL 0.43 MOM; HCG 0.35 MOM at 16.1 weeks. The couple opted for amniocentesis which resulted in a normal 46,XY karyotype. Due to a suspicion of early IUGR, a repeat ultrasound examination was performed at 20.1 weeks gestation, revealing a discrepancy between observed fetal sex and karyotype, post-axial polydactyly of both feet and the left hand, and growth lag. A repeat amniocentesis was performed to confirm fetal sex. L.M. was counseled regarding the sonographic and biochemical evidence that was suggestive of SLO. She elected to terminate the pregnancy. Amniotic fluid analysis subsequently revealed that 7-dehydrocholesterol (7-DHC) was greater than 800-fold increased in comparison to control; conversion of ergosterol to brassicasterol (estimating 7-DHC reductase activity) was 0.5% in fetal fibroblasts (control 15-35%, n=2), verifying SLO. Features consistent with SLO reported on autopsy included ambiguous genitalia with micropenis, severe hypospadias, and bifid scrotum. There was left hand post-axial polydactyly, bilateral post-axial polydactyly of the feet, and partial syndactyly of the second and third toes bilaterally. Facial dysmorphia included a broad nasal tip and anteverted nares, broad maxillary alveolar ridges, with a high arched hard palate and a soft palate cleft.This case demonstrates a possible role for triple screen, particularly uE3 analysis, in the detection of fetuses at risk for SLO.

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.

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.

Smith-Lemli-Opitz Syndrome

Two sibs, a male aged 3 years and female aged 7 months, with a variant of Smith-Lemli-Opitz (SLO) syndrome and atypical sterol metabolism are reported from the Kennedy Krieger Institute, Johns Hopkins University, Baltimore, MD.