Smith-Lemli-Opitz-syndrome

Smith-Lemli-Opitz syndrome is an autosomal recessively inherited disorder. A severe defect in cholesterol biosynthesis has been identified leading to abnormally low plasma cholesterol levels and elevated levels of the cholesterol precursor 7-dehydrocholesterol, the result of deficiency of 7-dehydrocholesterol reductase. We describe one such child with Smith-Lemli-Opitz syndrome. This child had clinical features similar to Smith-Lemli-Opitz syndrome like facial dysmorphism and cardiac and renal anomalies with failure to thrive.     

Possible abnormalities of steroid secretion in children with Smith-Lemli-Opitz syndrome and their parents

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

Smith-Lemli-Opitz syndrome: the changing phenotype with age.

In this report we present follow up data of two brothers with Smith-Lemli-Opitz syndrome. The changes with ageing are striking and few of the typical SLO traits are still present, which makes it extremely difficult to make the diagnosis Smith-Lemli-Opitz syndrome at adult age.     

Editor's preface

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.     

The Smith-Lemli-Opitz syndrome with a G303R/R352W mutation: in an extremely irritable child responsive to cholesterol supplementation

Smith-Lemli-Opitz syndrome(SLOS) is a hereditary disorder of cholesterol biosynthesis. It is characterized by growth deficiency, mental retardation and multiple congenital anomalies, including a typical facial appearance, cleft palate, syndactyly, and a variety of central nervous system and/or major congenital malformations. There are very few reports of the Smith-Lemli-Opitz syndrome in Korean children. Here, we report on a girl with a G303R/R352W mutation. The patient was extremely irritable; assessment of the severity of the irritability included severity scoring and the amount of sleep. Cholesterol supplementation was started with egg yolks, and the irritability improved.     

Molecular genetics of the Smith-Lemli-Opitz syndrome and postsqualene sterol metabolism.

The Smith-Lemli-Opitz syndrome is a disorder of morphogenesis resulting from an enzymatic defect in the last step of cholesterol metabolism (reduction of 7-dehydrocholesterol). Analysis of the defective gene and identification of mutations therein have paved the way for the study of the molecular genetics of the disorder which is caused by numerous different mutations. Future efforts should identify a postulated intracellular signalling activity of sterol intermediates, isolate proteins that govern the sterol traffic between intracellular compartments, structurally characterize the enzyme delta 7-sterol reductase defective in the Smith-Lemli-Opitz syndrome and investigate the pathomechanism of sterol depletion-induced dysmorphogenesis.     

Synthesis of [3alpha-3H]cholesta-5,8-dien-3beta-ol and tritium-labeled forms of other sterols of potential importance in the Smith-Lemli-Optiz syndrome

Five unsaturated sterols relevant to the Smith-Lemli-Opitz syndrome have been prepared in high radiochemical purity with a tritium label at the 3alpha position. Swern oxidation of cholesta-5,8-dien-3beta-ol and other unlabeled C27 sterols afforded the corresponding 3-ketosteroids, and reduction with tritiated NaBH4 gave the desired 3alpha-3H sterols, with double bonds at the delta(5,8), delta(5,8(14)), delta(6,8), delta(6,8(14)), and delta8 positions. High radiochemical purity of the tritiated sterols was demonstrated by normal phase, reversed phase, and silver-ion (Ag+) high-performance liquid chromatography (HPLC). In the course of this work, we developed a medium-pressure variant of Ag+-HPLC for purifying radiolabeled samples, documented significant isotopic fractionation of the 3alpha-tritiated sterols and their acetates on Ag+-HPLC, and discovered unexpected effects of a delta(8(14)) bond on the conformation of 3-keto-delta5-steroids. The synthetic and analytical methodologies described herein should provide a sound basis for investigating the origin and metabolism of sterols involved in the Smith-Lemli-Opitz syndrome and in late stages of cholesterol biosynthesis.     

An unrecognized etiology of sexual ambiguity: Smith-Lemli-Opitz syndrome or a new entity?

The authors report three cases of a new syndrome which characteristic anomalies are facial dysmorphism with anteverted nose, down slanting palpebral fissures, ptosis, severe microretrognatia, polydactyly. The authors insist on the particular severe genital anomalies, the failure to thrive and the constant lethal issue. The authors discuss the diagnosis of Smith-Lemli-Opitz syndrome and suggest the possibility of a new entity always confounded with others associations characterized by a polydactyly and a sexual reversion in male.     

Smith-Lemli-Opitz syndrome: evaluation of the correlations between individual traits as an approach to the study of heterogeneity

A computer analysis was used to study heterogeneity of the Smith-Lemli-Opitz syndrome (SLOS) with or without certain anomalies and to determine intrafamilial phenotypical variability. The analysis of 83 SLOS cases showed significant differences in average values of intragroup similarity, estimated for the cases with cleft palate and without it and those with or without polydactyly. The degree of intragroup similarity in familial cases appeared to be twice as high as in sporadic ones. These data confirm the hypothesis on genetic heterogeneity of SLOS with some allelic forms.     

The roles of cis-inactivation by Notch ligands and of neuralized during eye and bristle patterning in Drosophila

Background  

Normal post-squalene cholesterol biosynthesis is important for mammalian embryonic development. Neonatal mice lacking functional dehydrocholesterol Δ7-reductase (Dhcr7), a model for the human disease of Smith-Lemli-Opitz syndrome, die within 24 hours of birth. Although they have a number of biochemical and structural abnormalities, one cause of death is from apparent respiratory failure due to developmental pulmonary abnormalities.     

Adrenal insufficiency and abnormal genitalia in a 46XX female with Smith-Lemli-Opitz syndrome

OBJECTIVE: To report the first case of a 46XX female infant with Smith-Lemli-Opitz syndrome (SLOS), adrenal insufficiency and abnormal genitalia. METHODS: The patient was assessed for hormonal status on day 4 and 6 months later and was followed-up from the study time (2.5 years of age). RESULTS: The patient had a persistent urogenital sinus, posterior labial fusion without clitoromegaly. She presented with a salt-wasting syndrome on day 4. Adrenal insufficiency was confirmed. Adrenal androgen levels, including 17-hydroxyprogesterone and 11-deoxycortisol were moderately elevated. CONCLUSION: Children with SLOS should be assessed for adrenal insufficiency. In female infants, abnormal external genitalia can be observed even if the precise mechanism behind these abnormalities is yet to be determined.     

Smith‐Lemli‐Opitz syndrome in trisomy 13: How does the mix work?

BACKGROUND: Trisomy 13 and Smith-Lemli-Opitz syndrome (SLOS) are both well-recognized multiple congenital anomaly/mental retardation syndromes. CASE: In this report we describe a male newborn with trisomy 13 who also has features of SLOS, such as 2/3 toe syndactyly and a shawl-like scrotum. Biochemical analysis was consistent with SLOS, and limited molecular analysis revealed 1 mutation in the DHCR7 gene. CONCLUSIONS: The challenges in establishing the diagnosis of SLOS in this patient are presented and the unique coexistence of the 2 major malformation syndromes is discussed. Given the overlapping phenotype of the 2 syndromes, our report should encourage further research on cholesterol biosynthesis in patients with trisomy 13.     

Disorders of post-squalene cholesterol biosynthesis leading to human dysmorphogenesis.

Insights in molecular developmental biology in animals and humans are facilitating the understanding of pathophysiologic mechanisms in dysmorphogenesis or abnormalities in normal embryologic structural development. A milestone was recognition of the role of shh in morphogenesis of craniofacial structures, especially the development of holoprosencephaly. The dependence of hedgehog morphogens on cholesterol modification for normal hedgehog signaling function has particular relevance to disorders of cholesterol synthesis which manifest dysmorphogenesis. Four human disorders of morphogenesis (Smith-Lemli-Opitz syndrome, desmosterolosis, X-linked chondrodysplasia punctata, CHILD syndrome) have recently been shown to be caused by sterol abnormalities resulting from cholesterol biosynthesis enzyme deficiencies. This review summarizes the clinical, biochemical and molecular data in these disorders with an emphasis on understanding the pathophysiology of dysmorphogenesis.     

The function of cholesterol in embryogenesis

Cholesterol is critical in embryonic development. Inhibition of cholesterol synthesis in experimental animals has caused a birth defect called holoprosencephaly (HPE), which is evidenced by cyclopia (one eye in the middle of the face), monorhinia (protruding single nose above the eye), absence of the pituitary gland, and central nervous system (CNS) abnormalities. In humans, an inherited defect in the cholesterol-synthesizing enzyme 7-dehydrocholesterol reductase depletes cholesterol and results in human HPE, termed Smith-Lemli-Opitz syndrome. In its most severe form, the syndrome leads to cyclopia, monorhinia, and lack of separation of cerebral hemispheres. The cause of the syndrome is a defect in a protein coded by the gene Sonic hedgehog (SHH). The protein SHH is expressed in the notochord of the CNS in the early embryo and is activated by being cleaved autocatalytically, with simultaneous covalent attachment of cholesterol to the N-terminal fragment, which is secreted by cells of the mesoderm layer, signaling the establishment of the neural midline cells. Thus, cholesterol is essential for proper signaling in the development of the normal embryo.     

Diagnosis of human fetal abnormalities by fetography.

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

Associated malformations in cases with congenital diaphragmatic hernia

The etiology of congenital diaphragmatic hernia (CDH) is unclear and its pathogenesis is controversial. Because previous reports have inconsistently noted the type and frequency of malformations associated with CDH, we assessed these associated malformations ascertained between 1979 and 2003 in 334,262 consecutive births. Of the 115 patients with the most common type of CDH, the posterolateral, or Bochdalek-type hernia, 70 (60.8%) had associated malformations. These included: chromosomal abnormalities (n = 21, 30.0%); non-chromosomal syndromes (Fryns syndrome, fetal alcohol syndrome, De Lange syndrome, CHARGE syndrome, Fraser syndrome, Goldenhar syndrome, Smith-Lemli-Opitz syndrome, multiple pterygium syndrome, Noonan syndrome, and spondylocostal dysostosis); malformation sequences (laterality sequence, ectopia cordis); malformation complexes (limb body wall complex) and non syndromic multiple congenital anomalies (MCA) (n = 30, 42.9%). Malformations of the cardiovascular system (n = 42, 27.5%), urogenital system (n = 27, 17.7%), musculoskeletal system (n = 24, 15.7%), and central nervous system (n = 15, 9.8%) were the most common other congenital malformations. We observed specific patterns of malformations associated with CDH which emphasizes the need to evaluate all patients with CDH for possible associated malformations. Geneticists and pediatricians should be aware that the malformations associated with CDH can often be classified into a recognizable malformation syndrome or pattern (57.1%).     

Biochemical and genetic aspects of 7-dehydrocholesterol reductase and Smith-Lemli-Opitz syndrome

In recent years, several inherited human disorders caused by defects in cholesterol biosynthesis have been identified. These are characterized by malformations, multiple congenital anomalies, mental and growth retardation and/or skeletal and skin abnormalities indicating a pivotal role of cholesterol in morphogenesis and embryonic development. The first recognized and most common of these developmental disorders is Smith-Lemli-Opitz syndrome, an autosomal recessive trait caused by mutations in the DHCR7 gene resulting in a deficiency of the encoded sterol Delta(7)-reductase, alternatively called 7-dehydrocholesterol reductase (EC 1.3.1.21). This enzyme catalyzes the final step in cholesterol biosynthesis, which is the reduction of the Delta(7) double bond of 7-dehydrocholesterol to produce cholesterol.     

Direct duplication 2p14→2p23

Summary A malformed male newborn was first diagnosed as having Smith-Lemli-Opitz syndrome. Extensive cytogenetic studies, including Q, G, C, R and T banding and BudR treatment, were applied, finally leading the authors to conclude that the patient had a partial 2p trisomy caused by direct duplication 2p142p23. This was a de novo chromosome abnormality, as both parents had normal karyotypes.     

Identification of a yeast artificial chromosome clone spanning a translocation breakpoint at 7q32.1 in a Smith-Lemli-Opitz syndrome patient.

Smith-Lemli-Opitz syndrome (SLOS) is a mental retardation/multiple congenital anomaly syndrome. The gene(s) involved has not been mapped or cloned, but, recently, a biochemical abnormality in cholesterol biosynthesis has been shown to occur in most SLOS patients. The defect is suspected to occur in the penultimate step of the cholesterol pathway, involving the enzyme 7-dehydrocholesterol reductase, which has not been isolated. On the basis of the hypothesis that a de novo balanced translocation [t(7;20)(q32.1;q13.2)] in an SLOS patient directly interrupts the SLOS gene, positional cloning techniques are being employed to localize and identify the SLOS gene. We report the identification of a chromosome 7-specific YAC that spans the translocation breakpoint, as detected by FISH. This is the first study narrowing a candidate SLOS region and placing it on physical and genetic maps of the human genome.