Childhood Degenerative & Metabolic Disorders

Updated 05.05.2023
Released 11.28.1994
Expires For CME 05.05.2026

Smith-Lemli-Opitz syndrome

Author: Martina Witsch-Baumgartner PhD

Editor: Deepa S Rajan MD

Introduction

Overview

Smith-Lemli-Opitz syndrome is an autosomal recessive multiple congenital malformation syndrome that is associated with intellectual disability. The primary defect is the deficiency of 7-dehydrocholesterol reductase. This leads to an accumulation of 7- and 8-dehydrocholesterol and a lack of cholesterol. The latter is mainly involved in embryonic development. The distinctive malformations observed are characteristic facial features (such as anteverted nares), hypospadias, and 2-3 toe syndactyly. There is significant phenotypic variation in expressivity, and individuals have been described with normal development and only minor malformations. The incidence of Smith-Lemli-Opitz syndrome is about 1:15,000 to 1:60,000. Pathogenic mutations are maintained in the Leiden Open Variation database with links to possible modifier genes. There are still very limited studies about cholesterol therapies and improvement of phenotype by HMG-CoA-reductase inhibitors such as simvastatin.

Key points

	• Smith-Lemli-Opitz syndrome is an autosomal recessive metabolic malformation and intellectual disability syndrome due to cholesterol deficiency.
	• Mutation spectra are known in a variety of different populations, and pathogenic variants are maintained in the Leiden Open Variation database, HGMD, and in ClinVar).
	• There is a large spectrum of phenotype variability. This is due in part to the type of mutations in the DHCR7 gene, the genotype present in the individual, and modifying factors, such as the maternal apo E genotype.
	• Smith-Lemli-Opitz syndrome is primarily diagnosed by clinical presentation, including typical malformations, 2-3 toe syndactyly, and elevated 7-dehydrocholesterol.
	• There is no curative therapy for Smith-Lemli-Opitz syndrome presently.
	• Studies confirm that neuroleptic medications (eg, aripiprazole and cariprazine) lead to an elevation of 7-dehydrocholesterol in the brain of offspring and, hence, should be avoided during pregnancy (36; 37).

Historical note and terminology

In the 1960s, Smith-Lemli-Opitz syndrome (SLOS) was first described in three male patients by the pediatricians David W Smith, Luc Lemli, and John Opitz of the University of Wisconsin, U.S. (101). The syndrome was initially named RSH, a nondescriptive acronym of the first letters of the original patients’ surnames. It was a clinical description of patients who all had microcephaly and hypogonadism.

Thirty years later, Tint and colleagues published their measurements of neutral sterols in the plasma of five patients with Smith-Lemli-Opitz syndrome and found abnormally low concentrations of cholesterol but greater than 1000-fold increases in the level of 7-dehydrocholesterol, the immediate precursor of cholesterol in the Kandutsch-Russell pathway for biosynthesis of cholesterol (42; 110). This step in the biosynthesis of cholesterol is catalyzed by the delta 7-dehydrocholesterol reductase (96). Subsequently, the underlying DHCR7 gene was identified and cloned in 1998 (75).

More than 550 DHCR7 mutations have been described so far in individuals with Smith-Lemli-Opitz syndrome (see LOVD, HGMD, and ClinVar) (116; 119; 23; 122; 124; 131; 84; 130; 118). All patients with elevated levels of 7-dehydrocholesterol were shown to be compound heterozygous for two DHCR7 mutations or homozygous (personal communication).

Comparison between the clinical phenotype described by severity scores (63) and the corresponding biochemical data and their genotypes demonstrates a clear genotype-phenotype correlation (124). Possible phenotypic modifiers may include the maternal apo E genotype (123). The maternal apo E2 genotypes have been associated with a severe Smith-Lemli-Opitz syndrome phenotype, whereas apo E genotypes without the E2 allele have been associated with a milder phenotype. Another modifier of Smith-Lemli-Opitz syndrome associated with viability of patients with Smith-Lemli-Opitz syndrome is the maternal ABCA1 genotype (64), but the size of HDL particles may also influence the maternal transport of cholesterol to the fetus (44).

The HUGO Gene Nomenclature Committee symbol is DHCR7. The genomic sequence source is NG_012655.2. The transcript reference sequence now used for nomenclature of mutations in the DHCR7 gene is NM_001360.3 (MANE transcript) and LRG_340_t1 (see http://www.lrg-sequence.org and https://www.ncbi.nlm.nih.gov/refseq/MANE/).

Clinical manifestations

Presentation and course

	• Cardinal malformations are 2-3 toe syndactyly; 46,XY sexual ambiguity; hypospadias; cryptorchidism; cleft soft palate, microcephaly, and characteristic facies with anteverted nares, broad, flat nasal bridge, epicanthal folds, blepharoptosis, abnormal (low-set) pinnae, broad alveolar ridges, small tongue, and micrognathia.
	• Less frequent physical findings include cataracts, postaxial polydactyly, prenatal growth retardation, renal dysplasia, adrenal hyperplasia, abnormal pulmonary lobation, and Hirschsprung disease.

Rossi and colleagues (90) reported liver involvement in about 16% of individuals with Smith-Lemli-Opitz syndrome. Liver disease occurs in two main patterns: progressive cholestasis and stable isolated hypertransaminasemia. Holoprosencephaly is a rare feature in Smith-Lemli-Opitz syndrome but demonstrates the common pattern of midline defects seen in this syndrome. Holoprosencephaly is found in Smith-Lemli-Opitz syndrome if the individual is homozygous for null mutations. Synophthalmia was shown once in a patient with Smith-Lemli-Opitz syndrome with holoprosencephaly (121).

Cognitive ability typically ranges from borderline intellectual performance to severe intellectual disability, though mild forms of Smith-Lemli-Opitz syndrome have been described in individuals with normal intellectual function (76; 22; 26). A novel study showed nearly normal IQ in nine of 145 examined patients with Smith-Lemli-Opitz syndrome (27).

Other prominent features include behavioral problems such as hyperactivity and self-injurious behavior, irritability, sleep cycle disturbances (reduced total sleep time), autistic behaviors, and social and communication deficits (132; 24). A study demonstrated associative relationships between cholesterol levels and sleep disturbance in youth with Smith-Lemli-Opitz syndrome and explained how cholesterol levels may contribute to the behavioral phenotype (33).

The diagnostically most important physical findings have been organized into a severity scoring system that can be used for the diagnosis of Smith-Lemli-Opitz syndrome by clinical criteria alone (08; 63). However, with the discovery of abnormal sterol biosynthesis in essentially all patients (53), the major criterion for the diagnosis of Smith-Lemli-Opitz syndrome has become increased plasma or tissue levels of 7-dehydrocholesterol. The primary and secondary biochemical abnormalities now associated with Smith-Lemli-Opitz syndrome include low plasma and tissue levels of cholesterol; increased plasma and tissue levels of 7-dehydrocholesterol and two related isomers; increased plasma levels of lathosterol (some patients); decreased plasma, urinary, and biliary levels of normal bile acids; increased plasma, urinary, and biliary levels of abnormal bile acids (typically, monounsaturated relative to normal species); low or low normal levels of sex steroids; increased plasma gonadotropin levels (some patients); abnormal species (monounsaturated) of 17-hydroxysteroids; and low maternal levels of estriol, a fetal sterol product, during pregnancy.

The dietary intake of cholesterol has only a marginal effect on lowering 7-dehydrocholesterol levels (103). Therefore, the presence of 7-dehydrocholesterol is an absolute criterion for the clinical diagnosis of Smith-Lemli-Opitz syndrome.

Immunodeficiency is not usually recognized as a feature of Smith-Lemli-Opitz syndrome, and the frequently observed infections in patients with Smith-Lemli-Opitz syndrome have historically been attributed to decreased patient mobility and reduced respiratory effort. But it seems that immunodeficiency may be a feature of the syndrome (07; 02; 80).

An overview of gonadal germ cell tumor predisposition and differences of sex development concluded that although 74% of patients with Smith-Lemli-Opitz syndrome showed genital anomalies, gonadal cell tumors were reported in only two reports (88).

Interestingly, a study about growth deficiency (below 3rd percentile) in patients with Smith-Lemli-Opitz syndrome showed that growth is linear with advancing age, and the deficiency was smaller in patients with genotype null/TM (91).

An overview on clinical manifestations is provided in GeneReviews^® (80).

Prognosis and complications

Many children with Smith-Lemli-Opitz syndrome die in the newborn period from complications of internal malformations, especially of the central nervous system, heart, and kidneys. Pulmonary insufficiency is also a common cause of death. A study of genotype-phenotype correlation demonstrated that the severely affected patients nearly always have homozygosity or compound heterozygosity for null mutations, including c.964-1G>C (p.?) and c.452G>A (p.Trp151*) (122).

Furthermore, severe hypotonia with breech presentation often complicates delivery and adds to the child's medical problems. Nevertheless, the majority of affected children survive with various degrees of developmental delay and failure-to-thrive. All affected children and adults have intellectual disability. Although sometimes the retardation is profound, development in other affected individuals is comparable to that of Down syndrome. Also, borderline normal intelligence has been recorded in some of the most mildly affected children (70; 124; 50). The mildest case published so far is of a pregnant woman with Smith-Lemli-Opitz syndrome (26). She showed typical congenital anomalies in a very mild form, including submucosal cleft palate, small mouth, and 2-3 toe syndactyly. She had no other malformations, and she had normal intellect.

Interestingly, cholesterol levels and 7DHC were elevated during the pregnancy of another pregnant woman. Despite the predicted phenotype based on her genotype (c.964-1G> C; c.1083C> G, p.(Phe361Leu)), her mild clinical phenotype is likely explained by a polymorphism c.1773C>T (rs688) in the LDLR gene (NM_000527.4) that appears to increase the total LDL cholesterol level (133).

Another mildly affected patient with Smith-Lemli-Opitz syndrome with subtle anomalies of the genitourinary system associated with mild dysmorphic features and mild intellectual disability was described carrying the mutation p.(Phe174Ser) (112).

At birth and in early infancy, the major clinical problems are surgical in nature, including cataract removal, cleft palate repair, hypospadias repair or more substantial urogenital reconstruction, and colectomy and colostomy for Hirschsprung disease. Other more chronic medical problems include epilepsy in fewer than half of the children, photosensitivity, and spasticity. Muscle tone typically is reduced in the newborn period, but often evolves into spasticity in late infancy or childhood.

Mildly affected patients with Smith-Lemli-Opitz syndrome may show phenotypes that improve over time (13).

Clinical vignette

A typical course of a Smith-Lemli-Opitz syndrome case is described by Löffler and colleagues (69). In another example of typical familial Smith-Lemli-Opitz syndrome, a brother and sister are described (18).

A girl was born at 38 weeks’ gestation with birth weight in the tenth percentile, length shorter than the third percentile, and head circumference in the third percentile. She had generalized hydrops; microcephaly; short neck; ptosis; upturned nose with flat, broad nasal bridge; low-set abnormally modulated ears; long philtrum; retrognathia; hypoplastic tip of tongue; cleft hard palate; unilateral postaxial hexadactyly; bilateral short, broad, overriding big toes; and 2-3 toe clinodactyly, with minimal partial cutaneous syndactyly. Additionally, the girl showed severe valvular aortic stenosis, hypoplastic aortic arch, biventricular hypertrophy, atrial septal defect, patent ductus arteriosus, pulmonary hypertension, agenesis of the left kidney, and a hypoplastic right kidney. Brain imaging identified hypoplasia of the splenium and rostrum of the corpus callosum. Neonatally, the infant developed a volvulus of the sigmoid. After abdominal surgery, respiratory distress increased, and she died at the age of 19 days. She carried a homozygous DHCR7c.452G>A (p.Trp151*) pathogenic variant.

However, intrafamilial variability of phenotype presentation is described in a family where two pregnancies showed holoprosencephaly and one child presented only with short stature, cleft palate, imperforate anus, and mild language delay with subtle dysmorphic features (105). 7-DHC was not elevated at 1 year of age. DHCR7 genotype in these cases was c.964-1G>C and c.1039G>A.

Biological basis

Etiology and pathogenesis

Pathophysiology. The underlying defect in Smith-Lemli-Opitz syndrome is the lack of cholesterol. Cholesterol plays critical roles in embryonic development, in maintaining the integrity of cellular membranes, myelin, and signal transduction via lipid rafts, and in the metabolism of steroid hormones, oxysterols, and bile acids. Effects of 7-dehydrocholesterol (7DHC) and its possible effect of substitution of cholesterol are not well known, and a toxic effect of 7DHC and its derivatives have not been excluded (61). In plasma of patients with Smith-Lemli-Opitz syndrome, novel hydroxy-8-dehydrocholesterol has been detected: either 24- or 25-hydroxy-8-dehydrocholesterol, which are not detectable in control samples (38). As there are many functions of cholesterol, it is likely that there are multiple pathogenetic mechanisms that underlie the clinical problems in Smith-Lemli-Opitz syndrome. In embryonic development, a major player is the sonic hedgehog (SHH) signal cascade. It is involved in pattern formation of the central nervous system, facial structures, and limbs. Mutations in sonic hedgehog cause holoprosencephaly, which is also found in patients with Smith-Lemli-Opitz syndrome (55). Sonic hedgehog is cholesterol modified, secreted from a signaling cell, and binds to a receptor called patched (PTCH). PTCH regulates transmembrane signaling in the responding cell by modulating the function of a protein called smoothened (SMO). Cooper and colleagues have shown in mice fibroblasts that reduced sterols inhibit SMO (17). The amino terminus of the sterol reductase likely interacts directly with SMO to regulate sonic hedgehog signaling (58). Additionally, it has been demonstrated that PTCH-mediated transport of vitamin D3 modulates SMO function (09). Furthermore, inhibition of SMO by vitamin D3 and inactivation of SHH signaling reduces the DHCR7 activity (50% of control activity) (134). It is important to note that although 7DHC is a precursor of vitamin D, Rossi and colleagues did not find vitamin D deficiency in individuals affected by Smith-Lemli-Opitz syndrome (89).

Phosphorylation of 7-dehydrocholesterol reductase by kinases regulates the activity. This leads to increase of vitamin D as was demonstrated by Prabhu and colleagues (86). If the amino acid is mutated, p.Ser14Ala phosphorylation is no longer possible; in this case, DHCR7 activity is decreased.

The possibility of toxic effects of the cholesterol precursor 7DHC was investigated by Jiang and colleagues by quantitative proteomics analysis, and they demonstrated that differential expression of proteins is influenced by decreased cholesterol levels as well as increased 7DHC (47). At least 42 proteins showed differential expression. It seems that altered nonsterol isoprenoid synthesis contributes to defects in intracellular trafficking and cytoskeletal function. Furthermore, the known toxin 7-ketocholesterol, which is directly synthesized from 7DHC, is a strong inhibitor of cytochrome P450 7A1, and it exerts significant biological activities on the regulation of cholesterol homeostasis, cytotoxicity, apoptosis, induction of inflammation, and growth inhibition (98). 3β,5α-dihydroxycholest-7-en-6-one (DHCEO) and 7-ketocholesterol have also been shown to cause retinal degeneration in rats (30; 127; 128). The common feature of UV photosensitivity in individuals with Smith-Lemli-Opitz syndrome may also be a result of oxidative stress due to accumulation of 7DHC or its derived metabolites (114).

In astrocytes of DHCR7-deficient mice, an aberrant expression of glial fibrillary acidic protein (GFAP) and cellular hypertrophy might contribute to astrocyte-microglia crosstalk (32). This represents a role for cholesterol metabolism within the astrocyte-microglia immune axis and has implications for other neurologic diseases.

A potential regulator of cholesterol homeostasis identified by Christodoulou and colleagues is TMEM147 (14); it interacts with the lamin B receptor. When downregulated, the expression of lamin B receptor and DHCR7 is decreased.

Mutations in the DHCR7 gene are causal for Smith-Lemli-Opitz syndrome (28). Computational studies have shown that pathogenic DHCR7 mutations are localized more frequently in transmembrane regions and at the binding site (OMIM * 602858) (85).

Cell biology. Lipid rafts are specialized microdomains that are essential for the assembly of signaling molecules. They also influence membrane fluidity and trafficking of membrane proteins, and they regulate different cellular processes, such as neurotransmission and receptor trafficking. Substitution of cholesterol by 7DHC in these lipid rafts alters protein composition and stability (52; 73). It was shown in Smith-Lemli-Opitz syndrome membranes that fluidity of the membrane was increased (113). In synthetic membranes with 7DHC, atypical membrane organization appears to lead to functional defects in IgE receptor-mediated mast cell degranulation and cytokine production (62), NMDA receptor function (117), and serotonin receptor ligand binding (100). In iPSC model it was shown that specific DHCR7 mutations lead to accumulation of 7DHC, which deregulates the Wnt/β-catenin pathway and results in precocious neural differentiation (31).

Epidemiology

The incidence of this syndrome in European populations is estimated to be 1:15,000 to 1:40,000 (82; 12; 54). The incidence in Poland is reportedly 1:4000 (15). There are ethnic groups with a lower incidence or no known cases of Smith-Lemli-Opitz syndrome, such as Africans and Chinese (131). In Japan, where Smith-Lemli-Opitz syndrome is estimated to be rare, c.1055G>A (p.Arg352Gln) is the most frequent mutation (111; 72). Another DHCR7 mutation, c.1325A>G (p.His442Arg), has also been reported in a Japanese case (104). Two Korean patients with Smith-Lemli-Opitz syndrome have rare DHCR7 mutations: p.(Pro227Ser) (c.679C> T), p.(Gly303Arg) (c.907G> A), p.(Lys376Argfs*37) (c.1127_1128delA), and p.(Arg352Trp) (c.1054C> T) (49; 56).

Carrier frequencies vary in different populations, ranging from 1 in 180 in African Americans up to 1 in 43 in Ashkenazi Jews (65).

The incidence estimates are likely biased by several factors: (1) in most studies the diagnosis was only clinical without biochemical confirmation, (2) patients at both ends of the clinical spectrum may escape diagnosis, and (3) few studies had systematically recruited all patients with Smith-Lemli-Opitz syndrome from a geographic area or population. When only biochemically confirmed Smith-Lemli-Opitz syndrome was considered, a much lower incidence rate of 1 in 60,000 was found (92; 54). Several studies estimate the number of carriers in diverse populations yielding a frequency for the most common mutation (c.964-1G> C, former name: IVS8-1G> C) of 1 in 100 in European Caucasians, in Western Europe, and in North America (120). The overall carrier frequency for any DHCR7 mutation is 1 in 30 (06; 79), and the incidence is 1 in 1700 to 1 in 13,400. This discrepancy between calculated and observed incidences is explained by undiagnosed mild cases, misdiagnosed severe cases, death prior to diagnosis, or fetal loss. Data from next generation sequencing (NGS) of 17,836 chromosomes revealed a carrier frequency of 1.01% (21). A summary about the age and origin of the most frequent Smith-Lemli-Opitz syndrome mutations shows effects of random drift and founder mutations in the history of the syndrome (125).

Differential diagnosis

Typical clinical features of Smith-Lemli-Opitz syndrome include multiple malformations such as polydactyly, hypospadias, cleft palate, and 2-3 toe syndactyly. This constellation of malformations was described in patients with squalene synthase deficiency (16), which concerns the first step of cholesterol biosynthesis. Mutations in the FDFT1 gene are responsible, and the consequence is the accumulation of farnesyl pyrophosphate. Otherwise, they are rarely seen together in other syndromes, though other syndromes may be considered, such as Smith-Magenis syndrome, a variety of chromosomal aneuploidy syndromes (trisomies 13 and 18), pseudotrisomy 13 syndrome, Cornelia de Lange syndrome, Simpson-Golabi-Behmel syndrome, and Pallister-Hall syndrome. Occasionally, other syndromes due to sterol synthesis defects may be difficult to distinguish from Smith-Lemli-Opitz syndrome, including desmosterolosis, lathosterolosis, and X-linked chondrodysplasia punctata.

Confusing conditions

As the clinical manifestations of Smith-Lemli-Opitz syndrome are broad and specific, there are few other conditions that display comparable symptomatic features. However, other syndromes show overlapping signs. For example, polydactyly may occur in other conditions such as Meckel syndrome and Pallister-Hall syndrome. Two-three toe syndactyly may be present in male EBP disorder with neurologic defects syndrome and in lathosterolosis, which are both also sterol metabolic disorders, and in squalene synthase deficiency. Features of desmosterolosis, also a sterol metabolic disorder, include ambiguous genitalia, cleft palate, and microcephaly. However, all of these disorders show additional symptoms that distinguish them from Smith-Lemli-Opitz syndrome.

Associated or underlying disorders

The human cholesterol biosynthesis pathway is the background for many different vitally important formation pathways, eg, steroid hormones, vitamin D, and bile acids. The cholesterol biosynthesis pathway and resulting disorder depends on the deficient enzyme.

Enzyme deficiency	Disorder
Mevalonate kinase	Mevalonic aciduria Hyper-IgD syndrome
Squalene synthase	Squalene synthase deficiency
Lanosterol synthase	Alopecia-mental retardation syndrome Hypotrichosis
3 beta-hydroxysteroid-delta14-sterol reductase	Hydrops-ectopic calcification-moth-eaten, or Greenberg, skeletal dysplasia
3 beta-hydroxysteroid dehydrogenase	Congenital hemidysplasia with ichthyosiform erythroderma and limb defects
3 beta-hydroxysteroid-delta8-delta7-sterol isomerase	Chondrodysplasia punctata 2, X-linked
3 beta-hydroxysteroid-delta5-desaturase	Lathosterolosis
Desmosterol-delta24-reductase	Desmosterolosis

A more recently described syndrome phenotypically resembling Smith-Lemli-Opitz syndrome is the Alazami syndrome due to LARP7 mutations (34).

Diagnostic workup

Clinical diagnosis. New technologies regarding automated image analysis for the recognition of syndromes are developing and are valuable for diagnosis of Smith-Lemli-Opitz syndrome, too (see Face2Gene) (83). The clinical evaluation of patients suspected of having Smith-Lemli-Opitz syndrome should include measurement of growth parameters and physical examination to note polydactyly, syndactyly, genitourinary malformations, and other congenital anomalies, as well as neurologic findings like hypotonia. Additional assessments should include an ophthalmologic evaluation, a developmental assessment, a renal and abdominal ultrasound to identify potential internal anomalies, and an echocardiogram to delineate cardiac defects. Rectal and sigmoidal biopsy for diagnosis of Hirschsprung disease may also be indicated for patients with intestinal motility problems. Very mildly affected patients may show only mild intellectual disability (27), autistic behavior, and characteristic facial features, but they almost always have 2-3 toe syndactyly (11; 45; 50; 26).

When the only clinical indication is an autism spectrum disorder, there is no indication for biochemical testing of 7-dehydrocholesterol or genetic testing (51).

Prenatal diagnosis. If polydactyly is seen prenatally, it is often isolated but might also be due to trisomy 13 syndrome, Meckel-Gruber syndrome, diabetic embryopathy, Carpenter syndrome, Pallister-Hall syndrome, or Greig cephalopolysyndactyly (102).

Biochemical diagnosis. The measurement of 7-dehydrocholesterol for biochemical diagnosis of the syndrome can be performed in plasma or any tissue sample by gas chromatography (53). Methods have been established to get easier, more reliable, and fast quantification of cholesterol and 7-dehydrocholesterol even out of dried blood samples (35). Measurement of 7-dehydrochoelsterol is even possible to perform from the hair of individuals (71).

Molecular diagnosis. Nearly all patients demonstrate pathogenic DHCR7 variants on both alleles (Witsch-Baumgartner et al unpublished data).

In ClinGen’s listing of actionable secondary findings, DHCR7 is recommended, but dependent on phenotypic output, and not as screening (40).

Management

Genetic counseling. Each sibling of a patient with Smith-Lemli-Opitz syndrome carries a 25% risk of also being affected, a 50% chance of being a carrier of a DHCR7 mutation, and a 25% chance of being an unaffected noncarrier. Carrier detection is possible if the pathogenic variants in the family are known, or if the partner of an unaffected individual is a carrier. Prenatal testing for pregnancies at increased risk due to known familial genetic disease and also by prenatal ultrasound is possible using biochemical testing or molecular genetic testing (93).

As Smith-Lemli-Opitz syndrome is a possible cause of recurrent pregnancy loss, the American College of Obstetricians and Gynecologists recommends that genetic counselors offer carrier screening for DHCR7 mutations to patients in the preconception and prenatal period (74).

Drug treatment. Treatments are focused on mitigating the deficiency of cholesterol as well as the increase of 7DHC. Most patients with Smith-Lemli-Opitz syndrome get dietary cholesterol supplementation. This treatment is limited because cholesterol does not cross the blood-brain barrier. The accumulation of 7DHC is treated by an HMG-CoA-reductase inhibitor, simvastatin, with the aim to inhibit the synthesis pathway. Additionally, the advantage of simvastatin is that it crosses the blood-brain barrier. The outcomes of these approaches are very controversial. Observation studies report improved growth, increased socialization, decreased irritability and aggression, increased alertness, decreased photosensitivity, decreased infections, improved hearing, and improved muscle tone and strength (25; 41). Another study on the age of initiation of cholesterol therapy showed that therapy started before the age of 5 resulted in fewer features of autism when compared to a group of patients that initiated treatment after 5 years of age (108). Unfortunately, a longitudinal study on developmental progress in children with Smith-Lemli-Opitz syndrome who were receiving cholesterol supplementation showed no significant improvement (99). This conclusion is supported by Tierney and colleagues, who showed lack of behavioral improvement from dietary cholesterol (107). However, larger studies and outcomes of lifelong dietary cholesterol supplementation are still lacking.

A study utilizing statins to reduce the frequency and the severity of neurobehavioral abnormalities in Smith-Lemli-Opitz syndrome is underway (03). A review of all studies done on potential effects of statin therapies in people with Smith-Lemli-Opitz syndrome show very few effects on neurobehavioral manifestations, but some evidence for adverse effects (04).

As it seems that retinal degeneration is due to 7DHC and derived oxysterols accumulation, Fliesler and colleagues used a rat treatment model and found a positive effect of a combined treatment with cholesterol supplementation together with antioxidants (vitamin E and C) and sodium selenite (29). Koczok and colleagues showed that supplementation of vitamin E in a cholesterol supplemented diet led to improved aggression, self-injury, irritability, hyperactivity, attention deficit, repetitive behavior, sleep disturbance, skin photosensitivity or eczema in three out of six patients (57).

Simvastatin therapy in two patients with Smith-Lemli-Opitz syndrome improved the DHC/cholesterol ratio in plasma and cerebral fluid (48). Although simvastatin treatment in combination with cholesterol supplementation resulted in increased sterol levels in 39 patients with Smith-Lemli-Opitz syndrome, there was no beneficial effect on anthropometric measurements or behavior (39).

Wassif and colleagues performed a randomized, placebo-controlled trial regarding safety and efficacy of simvastatin therapy; they evaluated 23 patients with mild to typical Smith-Lemli-Opitz syndrome (115). Simvastatin was shown to be relatively safe, improved the serum dehydrocholesterol-to-total sterol ratio, and significantly improved irritability symptoms in patients with mild to classic Smith-Lemli-Opitz syndrome.

Supplementation of bile acids that can be reduced in patients with Smith-Lemli-Opitz syndrome has been discussed but not recommended (41; 81; 54).

Treatment trials may be tracked utilizing biomarkers such as 7-dehydrocholesterol and 8-dehydrocholesterol (and their ratio to cholesterol). These markers have been shown to be correlated with the level of cognitive and adaptive functioning in Smith-Lemli-Opitz syndrome, especially regarding cognitive abilities (106).

Korade and colleagues observed different effects on sterol metabolism using psychotropic drugs; aripiprazole, haloperidol, and trazodone increased circulating 7DHC and 8DHC levels, whereas clozapine, escitalopram/citalopram, lamotrigine, olanzapine, and risperidone did not (60; 59). They recommended not prescribing drugs that increase 7DHC levels during pregnancy. This was also shown for cariprazine and aripiprazole (36; 37). They also concluded that as 1% to 3% of the patient population carries heterozygous DHCR7 mutations, women should avoid taking cariprazine and aripiprazole as therapy, especially during nursing and pregnancy.

Lifestyle adjustments. Apart from nutritional treatment, the management of children and adults with Smith-Lemli-Opitz syndrome is essentially symptomatic management of the clinical problems associated with their individual malformations and the provision of specialized educational and behavioral management resources.

Surgery. A large proportion of children have major feeding problems, including primary swallowing dysfunction, gastroesophageal reflux, pyloric stenosis, and various degrees of colonic aganglionosis. Surgical management is often required for these problems. Medical management for renal dysplasia and insufficiency may be required in the more severely affected patients. Another problem in a small percentage (less than 10%) of patients is cholestatic liver disease, possibly caused by or influenced by abnormal bile acid species produced from 7-dehydrocholesterol (77).

Gene therapy. First attempts with a human DHCR7 construct in adeno-associated virus (AAV) vector in juvenile and newborn mice by intravenous injection showed in the liver increase of DHCR7 mRNA expression and increased liver cholesterol levels. Unfortunately, this treatment did not affect brain cholesterol levels, but it affected weight gain (129).

Pulmonary vein stenosis occurs in patients with Smith-Lemli-Opitz syndrome. Five of 170 subjects with pulmonary vein stenosis were diagnosed with Smith-Lemli-Opitz syndrome and died at 2, 3, and 11 months. Patients with pulmonary vein stenosis should be screened for Smith-Lemli-Opitz syndrome. In all newly diagnosed patients with Smith-Lemli-Opitz syndrome, echocardiogram should be obtained. The pathophysiology of pulmonary vein stenosis is not yet understood and requires further studies (87).

Outcomes

Simvastatin treatment is controversial. Although simvastatin treatment in combination with cholesterol supplementation may increase sterol levels in patients with Smith-Lemli-Opitz syndrome, there has been no beneficial effect on anthropometric measurements or behavior (39). However, simvastatin was also shown to be relatively safe, improved the serum dehydrocholesterol-to-total sterol ratio, and significantly improved irritability in patients with mild to classic Smith-Lemli-Opitz syndrome (115).

Apart from nutritional treatment, the management of children and adults with Smith-Lemli-Opitz syndrome is essentially symptomatic management of the clinical problems associated with their individual malformations and the provision of specialized educational and behavioral management resources.

Special considerations

Pregnancy

The first description of a pregnancy in an individual with very mild Smith-Lemli-Opitz syndrome without any complication resulted in a healthy child delivered by cesarean section (26).

The developing embryo or fetus with Smith-Lemli-Opitz syndrome appears to be largely dependent for synthesizing its own cholesterol for prenatal growth and development, but maternal transport of cholesterol is also present (126). Indeed, the malformations characteristic of Smith-Lemli-Opitz syndrome date to as early as 6 weeks' gestation.

Prenatal diagnosis may be made by measurement of increased levels of 7-dehydrocholesterol in amniotic fluid, (01; 109), chorion villi (95; 63; 78), or by molecular diagnosis (12; 68) is available. In two cases preimplantation molecular diagnosis was performed with successful pregnancies (67).

Abnormal sterol composition has also been demonstrated in cultured chorionic villus cells and directly in villus material. Although prevention of CNS malformations has been accomplished in the rat model (AY-9944) for Smith-Lemli-Opitz syndrome by feeding pregnant rats high cholesterol diets (05), it is not known whether similar malformations could be prevented in humans. Antenatal treatment of Smith-Lemli-Opitz syndrome by cholesterol supplementation is feasible and results in improvement in fetal plasma cholesterol levels and fetal red cell volume (43).

An important finding that may allow more frequent prenatal diagnosis of Smith-Lemli-Opitz syndrome in pregnancies not known to be at risk is that the majority of mothers carrying affected fetuses have had abnormally low levels of estriol, a fetal sterol product that is commonly monitored during pregnancy as a sign of fetal viability (97; 46). Some affected pregnancies have been associated with low levels of all three elements of the "triple screen" in pregnancy: (1) estriol, (2) alpha-fetoprotein, and (3) human chorionic gonadotropin. Shackleton and colleagues demonstrated in a large, multicenter study that maternal urinary dehydroestriol, 7-dehydropregnanetriol, or 8-dehydropregnenetriol could be used as a noninvasive test between the 14th and 22nd week of gestation (94). Abnormal results for these tests, as well as increased nuchal translucency (68), should now be considered an indication to measure amniotic fluid levels of 7-dehydrocholesterol or to perform immediate molecular analysis. Craig and colleagues performed prenatal routine screening of 7-dehydrocholesterol in maternal urine or serum. Among over 1 million pregnancies, 739 were screen positive. Of those, two Smith-Lemli-Opitz syndrome cases were identified and 69 cases had major fetal abnormalities (19). In the Czech Republic, 456 fetuses with high risk for Smith-Lemli-Opitz syndrome were detected by a screening of unconjugated estriol; Smith-Lemli-Opitz syndrome was confirmed in five of those fetuses, and 11 fetuses were carriers (10).

The latest studies confirm these observations. In a mouse model, Genaro-Mattos and colleagues showed the strongest effect of cariprazine and of aripiprazole on the brains of Dhcr7^+/- pups born to Dhcr7^+/- dams (36; 37). They concluded that as 1% to 3% of the patient population carry heterozygous DHCR7 mutations, women should avoid taking cariprazine and aripiprazole as therapy, especially during nursing and pregnancy.

Anesthesia

Smith-Lemli-Opitz syndrome can pose potential problems during anesthesia. Intubation may be extremely difficult due to the Pierre-Robin sequence associated with the disorder. Indeed, hypoxia following tube dislodgement was a contributory factor in the death of one patient (20). Additionally, there may be complications associated with the patient's specific malformations, such as heart defects. Theoretically, there may be a decreased ability to accommodate the stress of anesthesia and surgery in affected patients with especially low cholesterol levels because of decreased synthesis of corticosteroids and mineralocorticoids; however, there has been no published report of this.

Cancer

In bladder cancer, there is some evidence that DHCR7 is upregulated and DHCR7 deficiency might decrease tumorigenesis in vitro (66).

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Smith-Lemli-Opitz syndrome

Associated Disorders

Autism
Cataracts
Cleft palate
Congenital heart disease
Hirschsprung disease
- Holoprosencephaly
- Hypospadias
- Intellectual disability

Differential Diagnosis

squalene synthase deficiency
Smith-Magenis syndrome
variety of chromosomal aneuploidy syndromes
trisomies 13 and 18
pseudotrisomy 13 syndrome
- Cornelia de Lange syndrome
- Simpson-Golabi-Behmel syndrome
- Pallister-Hall syndrome
- desmosterolosis
- lathosterolosis
- X-linked chondrodysplasia punctata

Also Relevant

Cerebellar hypoplasia, dysplasia, and enlargement
Chondrodystrophies
Holoprosencephaly
Intellectual disability
Meckel-Gruber syndrome
- Microcephaly

Clinical Categories

Childhood Degenerative & Metabolic Disorders

Smith-Lemli-Opitz syndrome

Introduction

Overview

Key points

Historical note and terminology

Clinical manifestations

Presentation and course

Prognosis and complications

Clinical vignette

Biological basis

Etiology and pathogenesis

Epidemiology

Prevention

Differential diagnosis

Confusing conditions

Associated or underlying disorders

Diagnostic workup

Management

Outcomes

Special considerations

Pregnancy

Anesthesia

Cancer

References

Contributors

Author

Editor

Former Authors

Patient Profile

ICD & OMIM codes

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Hyperargininemia

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