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Smith-Lemli-Opitz Syndrome

Synonyms: RSH Syndrome, SLO Syndrome, SLOS
, MD, FRCPC, FCCMG, FACMG
Associate Professor, Molecular Medicine & Pathology and Pediatrics
CCMG Program Director
Pediatrician and Clinical Geneticist
McMaster University
Hamilton, Canada

Initial Posting: ; Last Update: June 20, 2013.

Summary

Disease characteristics. Smith-Lemli-Opitz syndrome (SLOS) is a congenital multiple anomaly syndrome caused by an abnormality in cholesterol metabolism resulting from deficiency of the enzyme 7-dehydrocholesterol (7-DHC) reductase. It is characterized by prenatal and postnatal growth retardation, microcephaly, moderate to severe intellectual disability, and multiple major and minor malformations. The malformations include distinctive facial features, cleft palate, cardiac defects, underdeveloped external genitalia in males, postaxial polydactyly, and 2-3 syndactyly of the toes. The clinical spectrum is wide and individuals have been described with normal development and only minor malformations.

Diagnosis/testing. The diagnosis of SLOS relies on clinical suspicion and detection of elevated serum concentration of 7-DHC. Although serum concentration of cholesterol is usually low, it may be in the normal range in approximately 10% of affected individuals, making it an unreliable test for screening and diagnosis. DHCR7 is the only gene in which mutations are known to cause SLOS. Sequence analysis of DHCR7 detects approximately 96% of known mutations.

Management. Treatment of manifestations: While no dietary studies on cholesterol supplementation have been conducted in a randomized fashion, cholesterol supplementation may result in clinical improvement. Early intervention and physical/occupational/speech therapies for identified disabilities; consultation with a nutritionist; gastrostomy as needed for feeding; routine treatment for pyloric stenosis, gastroesophageal reflux, constipation, recurrent otitis media, cataracts, ptosis, and/or strabismus. Neonatal cholestatic liver disease often resolves with cholesterol and/or bile acid therapy. Orthotics, tendon release surgery, or Botox® as needed; proper clothing and sunscreen with UVA and UBV protection for photosensitivity.

Prevention of secondary complications: Treatment with stress-related doses of steroids during illness and other stress; attention to airway management and other potential complications during anesthesia.

Surveillance: Routine health supervision including history, physical examination, monitoring of growth parameters; age-appropriate developmental assessment; nutritional assessment; monitoring of cholesterol, serum concentration of 7-DHC, and serum amino transferases (ALT and AST) every three to four months in the first few years of life and twice yearly thereafter.

Agents/circumstances to avoid: Treatment with haloperidol or other drugs in the same class. Psychotropic drugs (trazodone, aripirazole) that elevate 7DHC should be used with caution; extended sun exposure should be avoided.

Evaluation of relatives at risk: Testing of all sibs so that cholesterol supplementation can begin as soon as possible after birth.

Other: For severely affected infants, consider surgical management of congenital anomalies (e.g., cleft palate, congenital heart disease, genital anomalies) as for any other severe, usually lethal disorder.

Genetic counseling. SLOS is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier detection is possible if the disease-causing mutations in the family are known. Prenatal testing for pregnancies at risk is possible using biochemical testing or molecular genetic testing if the disease-causing mutations in the family are known.

Diagnosis

Clinical Diagnosis

Clinical diagnostic criteria have not been established for Smith-Lemli-Opitz syndrome (SLOS). A pattern of congenital anomalies suggests the diagnosis. The following are the most commonly observed features:

  • Characteristic facial features (narrow forehead, epicanthal folds, ptosis, short mandible with preservation of jaw width, short nose, anteverted nares, and low-set ears)
  • 2-3 syndactyly of the toes (minimal to Y-shaped)
  • Microcephaly
  • Growth retardation/short stature
  • Intellectual disability
  • Hypospadias in males
  • Cleft palate
  • Postaxial polydactyly

Testing

Decreased activity of the enzyme 7-dehydrocholesterol (7-DHC) reductase results in failure to convert 7-DHC to cholesterol [Irons et al 1993, Irons et al 1994, Tint et al 1994, Elias & Irons 1995]:

  • Serum concentration of 7-DHC. The diagnostic test is an elevation of serum concentration of 7-DHC as defined by the laboratory for a given patient.

    Note: (1) 7-DHC concentration is usually measured in blood samples, but can be measured in other tissues. (2) Some individuals on psychotropic medications can have elevated 7-DHC levels secondary to the medication, giving rise to false-positive test results. Such individuals rarely have the physical features of SLOS, but may be tested for SLOS because of neurocognitive issues; molecular genetic testing and/or fibroblast testing is needed to clarify the diagnosis. (3) Different laboratories may report results in different units. Laboratories in the US report results as milligrams per deciliter or micrograms per milliliter; European laboratories most often report results as millimoles per liter. Thus, direct comparison of values between laboratories requires caution.
  • Serum concentration of cholesterol. Although most affected individuals have hypocholesterolemia, serum concentration of cholesterol values in normal and affected individuals can overlap, particularly when the affected individuals are older or have a milder phenotype [Kelley 1995]. Because normal serum concentrations of cholesterol change with age, values must be considered in the context of the individual.

    Note: Serum concentration of cholesterol determined by the method employed in most hospital laboratories, which measures total cholesterol (cholesterol plus the precursors), does not identify all individuals with SLOS because total cholesterol levels can be in the normal range.

Carrier detection

  • Because of considerable overlap between the ranges of serum concentration of cholesterol and 7-DHC in carriers and non-carriers, carrier status cannot be determined by measuring the serum concentration of either compound.
  • However, biochemical testing of fibroblasts has been successful in carrier detection [Shefer et al 1997].
  • Carrier testing is also possible by molecular genetic analysis if the disease-causing mutations in the family are known.

Molecular Genetic Testing

Gene. DHCR7, encoding 7-DHC reductase [Fitzky et al 1998, Wassif et al 1998, Waterham et al 1998], is the only gene in which mutations are known to cause SLOS.

Clinical testing

Table 1. Summary of Molecular Genetic Testing Used in Smith-Lemli-Opitz Syndrome

Gene 1Test MethodMutations Detected 2Mutation Detection Frequency by Test Method 3
DHCR7Sequence analysisSequence variants 496% 5, 6
Sequence analysis of select exonsSequence variants in exons 4-9 4Unknown
Targeted mutation analysisMutations in testing panels (variable by laboratory)100% for the mutations in the panel
Deletion/duplication analysis 7Exon and whole-gene deletions/duplicationsMultiple exon deletions 8

1. See Table A. Genes and Databases for chromosome locus and protein name.

2. See Molecular Genetics for information on allelic variants.

3. The ability of the test method used to detect a mutation that is present in the indicated gene

4. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

5. Waterham & Hennekam [2012]

6. Most of the affected individuals studied have two detectable mutations; rare individuals had only one detectable mutation [Waterham & Hennekam 2012].

7. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.

8. Weaver et al [2010], Aradhya et al [2012]

Testing Strategy

To confirm/establish the diagnosis in a proband with equivocal biochemical test results. Molecular genetic testing of DHCR7 is generally considered a second-tier test and may be useful in instances in which serum concentration of 7-DHC is difficult to interpret, or in which only DNA from the affected individual is available.

Carrier testing for at-risk relatives requires molecular genetic testing; prior identification of the disease-causing mutations in the family is necessary.

Note: Carriers are heterozygotes for an autosomal recessive disorder and are not at risk of developing the disorder.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require molecular genetic testing; prior identification of the disease-causing mutations in the family is necessary.

Clinical Description

Natural History

Severe Smith-Lemli-Opitz syndrome (SLOS) is characterized by prenatal and postnatal growth retardation, microcephaly, moderate to severe intellectual disability, and multiple major and minor malformations including characteristic facial features, cleft palate, abnormal gingivae, cardiac defects, hypospadias, ambiguous genitalia (failure of masculinization of male genitalia), postaxial polydactyly, and 2-3 toe syndactyly [Cunniff et al 1997, Ryan et al 1998, Krajewska-Walasek et al 1999, Kelley & Hennekam 2000]. Individuals with milder forms may have only subtle facial characteristics, hypotonia, 2-3 toe syndactyly, and mild to no intellectual disability. Clinical variability is noted even within families as sibs with SLOS have been reported with medical and developmental problems of different degrees.

Prematurity and breech presentation are common. Neonates frequently have poor suck, irritability, and failure to thrive [Pinsky & DiGeorge 1965].

Infants with SLOS frequently have feeding problems secondary to a combination of hypotonia, oral-motor incoordination, and gastrointestinal problems that include dysmotility, hypomotility, gastrointestinal reflux, constipation, and formula intolerance. In general, infants with the more severe phenotype have more feeding problems. Children and adults with SLOS are generally smaller than average.

Pyloric stenosis and Hirschsprung disease have been reported [Dallaire & Fraser 1966, Patterson et al 1983, Lipson & Hayes 1984]. Constipation is a common problem. Liver disease is variable and can range from severe cholestasis (generally in those who are more severely affected) to mild/moderate stable elevation of serum amino transferases [Rossi et al 2005].

Cognitive function ranges from borderline intellectual capability to severe intellectual disability. Low normal intellectual function can be seen in individuals with mild forms of SLOS [Mueller et al 2003, Eroglu et al 2011].

Behavioral signs/symptoms include sensory hyperreactivity, irritability, sleep cycle disturbance, self-injurious behavior (hand biting and/or head banging), autism spectrum behaviors (46%-53%), temperament dysregulation, and social and communication deficits [Tierney et al 2000, Diaz-Stransky & Tierney 2012]. Many individuals require very little sleep, often only a few hours per night [Zarowski et al 2011].

Depression and other psychiatric problems have been reported in older individuals.

Individuals with SLOS commonly have anomalies involving the midline and para-midline structures of the brain [Lee et al, in press]. Developmental abnormalities of the central nervous system include microcephaly (80%-84%), abnormalities of myelination, ventricular dilatation, malformations of the corpus callosum and/or cerebellum, Dandy-Walker malformation and its variants, and holoprosencephaly (5%) [Ryan et al 1998; Kelley & Hennekam 2000; Caruso et al 2004; Lee et al, in press]. Approximately 5% of individuals with SLOS have holoprosencephaly [Chasalow et al 1985, Kelley et al 1996, Weaver et al 2010]. Hypotonia, which is common in young children, affects feeding and delays motor development. Older children often exhibit hypertonia.

Photosensitivity, which is commonly seen in SLOS, appears to be UVA mediated [Anstey 2001]. Photosensitivity can be severe and can result from even brief exposure to sunlight. Many children cannot tolerate any exposure to sunlight; others can tolerate varying periods of exposure if properly clothed and protected with a UVA- and UVB-protection sunscreen.

Hypospadias and/or bilateral cryptorchidism occur in 50% of reported males with SLOS [Gorlin et al 1990, Lin et al 1997]. Bicornuate uterus and septate vagina have been noted in 46,XX females [Lowry et al 1968]. Because genital abnormalities are easier to recognize in males than females, males are more likely than females to be evaluated for a diagnosis of SLOS [Pinsky & DiGeorge 1965, Dallaire & Fraser 1966, Gorlin et al 1990]. Other findings include persistent urogenital sinus and posterior labial fusion without clitoromegaly in a female with an XX karyotype [Chemaitilly et al 2003] and precocious puberty in girls with SLOS [Starck et al 1999; Irons, unpublished].

Since the report of Curry et al [1987], it has been recognized that many 46,XY individuals with severe manifestations of SLOS have extreme undermasculinization of the external genitalia, resulting in female external genitalia (termed "sex reversal"). Lin et al [1997] reported that 20%-25% of individuals with SLOS described in the literature have a 46,XY karyotype with a female phenotype.

Characteristic facial features include narrow forehead, epicanthal folds, ptosis, short nose with anteverted nares, short mandible with preservation of jaw width, and capillary hemangioma over the nasal root that extends onto the glabella [Nowaczyk et al 2012]. The ears are low set and are posteriorly rotated, but can be otherwise normal [Nowaczyk et al 2012]. Cleft palate is present in 40%-50% of affected individuals reported [Johnson 1975, Cunniff et al 1997] and may contribute to feeding and growth problems. The neck is often short with redundant skin at the nape. The characteristic facial appearance may be subtle in some individuals, but when assessed objectively, is present even in the least severely affected individuals; the severity of the dysmorphic features correlates with the severity of both the biochemical and physical abnormalities [Nowaczyk et al 2012].

Congenital cataracts are present in approximately 20% of affected individuals [Finley et al 1969, Cunniff et al 1997, Lin et al 1997]. Cataracts may also develop acutely [Goodwin et al 2008]. Other ophthalmologic manifestations include ptosis, strabismus, optic atrophy, and optic nerve hypoplasia [Atchaneeyasakul et al 1998].

Cunniff et al [1997] and Lin et al [1997] reported that up to 50% of the affected individuals in their cohorts had an identified cardiac defect. They also reported an increased incidence of atrioventricular canal defects and anomalous pulmonary venous return when compared with an unselected series of individuals with SLOS [Park et al 1968, Lin et al 1997].

Cardiorespiratory problems can occur secondary to malformations of the heart or respiratory tract, including the trachea or larynx. Abnormal pulmonary lobation and pulmonary hypoplasia are common in more severely affected individuals [Donnai et al 1986, Bialer et al 1987, Curry et al 1987, Quélin et al 2012]. An increased frequency of upper- and/or lower-respiratory infections is seen particularly in infancy and early childhood.

Approximately 25% of affected individuals have renal anomalies, most commonly renal hypoplasia or agenesis, renal cortical cysts, hydronephrosis, and structural anomalies of the collecting system [Curry et al 1987, Ryan et al 1998, Kratz & Kelley 1999, Nowaczyk et al 2001].

Y-shaped syndactyly of the second and third toes is the most common, but not universal, finding. Postaxial polydactyly is present in one quarter to one half of all affected individuals [Gorlin et al 1990, Cunniff et al 1997, Lin et al 1997]. Less common findings include hypoplastic or short thumbs and thenar hypoplasia. The index finger often has a subtle “zig-zag” appearance secondary to misalignment of the phalanges [Nowaczyk & Irons 2012]. Less common are clinodactyly, hammer toes, and dorsiflexed halluces [Pinsky & DiGeorge 1965, Opitz 1969].

Because cholesterol is a precursor of steroid hormones, including cortisol, aldosterone, and testosterone, endocrine problems (including electrolyte abnormalities, hypoglycemia, and hypertension) can be seen. Adrenal insufficiency can result in severe electrolyte abnormalities [Chemaitilly et al 2003]. Low serum concentrations of testosterone have been seen in severely affected males [Chasalow et al 1985].

Other medical/dental issues include recurrent otitis media, splenomegaly, and hearing loss (both conductive and sensorineural). Seizures can occur, but are not more common than in the general population.

Genotype-Phenotype Correlations

Biochemical. Although strict correlations between the serum concentration of cholesterol and clinical outcome are not possible, most studies have identified an inverse correlation between serum concentration of cholesterol and clinical severity [Tint et al 1995, Cunniff et al 1997, Yu et al 2000, Waterham & Hennekam 2012]. Mortality is particularly high in the group of individuals with the lowest cholesterol concentrations (~10 mg/dL).

Molecular genetic. A strict genotype-phenotype correlation is difficult because most affected individuals are compound heterozygotes. However, a severe phenotype has been described in homozygotes for the two functional null alleles c.832-1G>C (IVS8-1G>C, the intron 8 splice acceptor) and p.Trp151*, and for the missense mutation p.Arg404Cys [Witsch-Baumgartner et al 2000]. A detailed evaluation of 207 individuals with SLOS showed that the most severe phenotypes were observed in individuals with two null mutations or with two mutations in loop 8-9, while those with one or two mutations in loop 1-2 or one mutation in the N-terminus have milder phenotypes [Waterham & Hennekam 2012]. However, the significant variation seen in severity, even among individuals with similar mutations, suggests significant influences on phenotype other than the DHCR7 mutation [Porter 2000]. One important factor may include transport of cholesterol from the mother to the fetus early in pregnancy. A more severe phenotype has been seen in offspring of women who have an APOE E2 allele [Witsch-Baumgartner et al 2004, Woollett 2005], which may interfere with binding of apo E-containing maternal lipoproteins in the placenta.

Nomenclature

Curry et al [1987] described 19 infants with a severe form of SLOS that included cleft palate, cardiac defects, and early lethality. This disorder was termed Smith-Lemli-Opitz syndrome type II. With the advent of laboratory testing for SLOS, it has become apparent that SLOS type II is not biochemically distinct, but rather represents the more severe end of the spectrum of the SLOS phenotype.

Prevalence

The birth prevalence of SLOS is estimated to be approximately 1:20,000 to 1:40,000 live births [Tint et al 1994, Nowaczyk et al 2001, Nowaczyk et al 2004]; in individuals of northern or central European ancestry, it has also been variably estimated to range from 1:10,000 to 1:60,000 [Porter 2000]. SLOS is less common in individuals of Asian or African ancestry [Wright et al 2003].

Affected females, who lack the genital abnormalities seen in affected males, are under-ascertained.

In an investigation of 1503 random blood samples from newborn screening blood spots, 16 samples had the intron 8 splice acceptor mutation. This information was used to calculate a carrier frequency of approximately 1:30, with a predicted prevalence of SLOS between 1:1,590 and 1:13,500 [Battaile et al 2001]. A higher figure for affected individuals than what is observed clinically may be explained by an increased incidence of intrauterine fetal demise or neonatal death in severely affected individuals or under-reporting of more mildly affected individuals who lack physical findings suggestive of SLOS.

Differential Diagnosis

Although many malformation syndromes share at least some of the clinical features of SLOS (e.g., polydactyly, hypospadias, cleft palate), they rarely have more than two of these features in common. In particular, the Y-shaped 2-3 toe syndactyly, present in most individuals with SLOS, is rarely seen in other disorders. The biochemical findings (Clinical Diagnosis) should allow for ready differentiation between individuals with SLOS and those with conditions that are clinically and biochemically similar.

Biochemically, only SLOS presents with elevated 7DHC and low or low normal plasma cholesterol. Other sterol metabolic disorders present with distinct patterns of sterol abnormalities and are unlikely to be confused with SLOS. Of other sterol synthesis defects, only desmosterolosis (macrocephaly/microcephaly, hypoplastic nasal bridge, thick alveolar ridges, gingival nodules, cleft palate, total anomalous pulmonary venous drainage, ambiguous genitalia, short limbs, and generalized osteosclerosis), lathosterolosis (microcephaly, narrow forehead, depressed nasal bridge, cleft palate, hepatic steatosis, and hematologic anomalies), and hemizygous EBP deficiency (in males; X-linked chondrodysplasia punctata) may be difficult to distinguish clinically from SLOS; however, the pattern of biochemical anomalies is distinct from those observed in SLOS.

Disorders with similar clinical findings include the following:

  • Trisomy 13 syndrome (holoprosencephaly, cleft lip and cleft palate, cardiac defects, polydactyly)
  • Trisomy 18 syndrome (growth retardation, characteristic facial appearance, short sternum, cardiac defects, camptodactyly, early lethality)
  • Dubowitz syndrome (growth retardation, blepharophimosis, toe syndactyly, eczema, immune deficiency)
  • Meckel-Gruber syndrome (encephalocele, cystic renal disease, polydactyly)
  • Noonan syndrome (growth retardation, downslanting palpebral fissures, broad posterior neck, pulmonic stenosis, hypospadias)
  • Simpson-Golabi-Behmel syndrome (macrosomia, facial clefts, polydactyly)
  • Pseudotrisomy 13 syndrome (holoprosencephaly, polydactyly)
  • Pallister-Hall syndrome (hypothalamic hamartoblastoma, polydactyly)
  • Nguyen syndrome [Nakane et al 2005]

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with Smith-Lemli-Opitz syndrome (SLOS), the following evaluations are recommended:

  • Physical examination with special attention to growth parameters, congenital anomalies, and neurologic findings (hypotonia/hypertonia, seizures)
  • Developmental assessment
  • Ophthalmologic evaluation for strabismus, cataracts, and functional eye problems
  • Cardiac evaluation (ECG and echocardiogram) for congenital defects
  • Musculoskeletal evaluation for delineation of syndactyly, polydactyly, abnormalities of tone, and need for ankle-foot orthoses (AFOs) or other orthotics
  • Genitourinary examination for anomalies of external genitalia in males and females
  • Evaluation for functional problems of the gastrointestinal system by history and, if indicated, studies for pyloric stenosis and gastroesophageal reflux. Particular attention should also be given to stooling pattern, abdominal distention, or other signs of possible bowel obstruction, particularly in children with a more severe phenotype, because of their risk for Hirschsprung disease.
  • Nutritional assessment for feeding problems and poor weight gain
  • Possible MRI or other cranial imaging to evaluate for holoprosencephaly and/or other brain anomalies
  • Renal ultrasound evaluation for renal anomalies
  • Hearing evaluation for either sensorineural or conductive hearing loss
  • Laboratory evaluation including glucose and electrolytes (for adrenal insufficiency), serum concentrations of amino transferases and bilirubin (for cholestatic liver disease), and testosterone in males
  • Medical genetics consultation

Treatment of Manifestations

Cholesterol Supplementation

Devising a treatment strategy for SLOS has been difficult as all factors contributing to the clinical phenotype are not yet known with certainty. It is likely that both low cholesterol levels and elevation of the cholesterol precursors 7-DHC and 8-DHC contribute to many of the clinical findings in affected individuals. Therefore, treatment strategies to date have focused on supplying exogenous cholesterol (either as egg yolks or as crystalline cholesterol in either an oil-based or aqueous suspension) in an attempt to raise cholesterol levels and secondarily decrease the levels of the precursors 7-DHC and 8-DHC. In general, affected individuals with a more severe biochemical defect require larger doses of cholesterol.

It should be emphasized that dietary studies on cholesterol supplementation have not been conducted in a randomized fashion.

There are multiple reports of dietary cholesterol treatment for SLOS [Elias et al 1997, Irons et al 1997, Linck et al 2000, Chan et al 2009]. Improved growth [Elias et al 1997, Irons et al 1997], reduced photosensitivity [Azurdia et al 2001, Starck et al 2002a], and increased nerve conduction velocity [Starck et al 2002a] have been objectively documented. However, dietary therapy does not appear to increase the levels of cholesterol in CSF to effect therapeutic effects [van Rooij et al 1997]. There is objective evidence that cholesterol supplementation may alleviate skin photosensitivity [Azurdia et al 2001]. Additional studies have shown improved tone and achievement of ambulation as well as developmental cognitive and behavioral changes [Irons et al 1997, Tierney et al 2000, Tierney et al 2001]. However, these studies did not have well-defined clinical outcome measures [Svoboda et al 2012].

Nonetheless, cholesterol supplementation should be considered in all individuals with SLOS because it may result in clinical improvement and has minimal side effects [Elias et al 1997, Nwokoro & Mulvihill 1997, Battaile & Steiner 2000].

Other Treatments

Referral to appropriate early intervention and physical/occupational/speech therapies is often required for identified disabilities.

Many infants have difficulty with suck and/or swallow and may require gastrostomy for feeding and support of a nutritionist to help monitor caloric intake and growth. Infants with severe feeding problems generally require the insertion of gastrostomy tubes and/or the use of hypoallergenic, elemental formulas. Because children with SLOS have low muscle mass, careful monitoring of weight gain and growth is necessary so that overconsumption of calories does not lead to obesity.

For those with frequent vomiting or apparent gastroesophageal reflux, a diagnosis of pyloric stenosis should be considered and treated as in the general population. Gastrointestinal reflux and/or constipation require treatment by a gastroenterologist.

Neonatal cholestatic liver disease often resolves with cholesterol and/or bile acid therapy.

Surgical repair may be required for cataracts, ptosis, and/or strabismus.

Syndactyly of hands and/or feet and/or polydactyly may require surgical repair.

Orthopedic management of the early hypotonia and later hypertonia includes the use of AFOs and other orthotics, as well as physical and occupational therapy.

Tendon release surgery or Botox® therapy may be indicated in older children with significant hypertonia.

Dental management can be challenging. Proper positioning, choice of dental devices, and sedation techniques need to be considered [Muzzin & Harper 2003].

Recurrent otitis media may require tympanostomy tube placement.

Photosensitivity can be severe and many children cannot tolerate any exposure to sunlight; others can tolerate varying periods of exposure if properly clothed and protected with a UVA- and UVB-protection sunscreen.

Prevention of Secondary Complications

In severely affected individuals, treatment with stress steroids in doses customarily used for children with congenital adrenal hyperplasia (see 21-Hydroxylase-Deficient Congenital Adrenal Hyperplasia) is recommended during periods of illness, stress, or prolonged decrease in oral intake [Bianconi et al 2011].

Anesthetic problems including muscular rigidity and malignant hyperthermia have been reported [Choi & Nowaczyk 2000]. Airway management during anesthesia may be challenging; use of a laryngeal mask airway has been successful [Leal-Pavey 2004, Matveevskii et al 2006].

Surveillance

Routine health supervision by a physician familiar with SLOS, its complications, and its treatment includes the following:

  • History, physical examination, and monitoring of growth parameters, with the frequency to be determined by the severity of the child's condition
  • Age-appropriate developmental assessment at least twice a year until age three years and annually thereafter
  • Nutritional assessment at least every three to four months until age two years and twice yearly thereafter
  • Monitoring of cholesterol, serum concentration of 7-DHC, and serum amino transferases (ALT and AST) every three to four months in the first few years of life and twice yearly thereafter

Agents/Circumstances to Avoid

Treatment with haloperidol, which has a high affinity for the DHCR7 substrate binding site, may exacerbate the biochemical sterol abnormalities in individuals with SLOS and cause an increase in symptoms. It is likely that other drugs in this class will cause the same change in sterol levels [Kelley & Hennekam 2000]. Other psychotropic drugs shown to elevate 7DHC are trazodone and aripiprazole (Abilify®) [Hall et al 2013]. Thus, one must weigh the benefit of such medications against the potential negative side effects. As many individuals with SLOS do require psychotropic medications, close monitoring of clinical signs/symptoms and serum concentration of 7-DHC is recommended.

Photosensitivity can be severe and extended periods of sun exposure should be avoided, as severe sunburn can occur with only limited exposure; however, limited sun exposure is possible for some affected individuals as long as protective clothing is worn and a sunscreen with UVA and UVB properties is used.

Evaluation of Relatives at Risk

All sibs should be tested by measurement of 7DHC concentration in plasma or amniotic fluid (prenatally). In cases of borderline 7DHC concentration, molecular genetic testing is indicated. Caution must be exercised in interpreting elevated 7DHC concentration in individuals treated with haloperidol, aripiprazole, and tradozone [Hall et al 2013].

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

No current guidelines exist for the management of pregnant women with SLOS, as to date only one affected woman with a successful pregnancy has been identified [Ellingson et al, submitted].

Therapies Under Investigation

Jira et al [2000] used the HMG-CoA reductase inhibitor simvastatin to treat two affected individuals for 14 and 23 months, resulting in normalization of cholesterol levels and a decrease of plasma precursors by 28% and 33%. Improvement in the precursor/cholesterol ratio in the cerebrospinal fluid was also found. Morphometric parameters improved in both individuals, and no adverse side effects were observed. However, these studies were not reproduced by subsequent investigations by Haas et al [2007] and Chan et al [2009].

Starck et al [2002b] treated two affected individuals with simvastatin, cholesterol supplementation, and bile acids and found reduction in absolute and relative serum concentration of 7-DHC. However, in one of these individuals, simvastatin was discontinued after hepatotoxic side effects and increased photosensitivity were observed.

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.

Other

For more severely affected infants with SLOS, the issues of surgical management of congenital anomalies such as cleft palate, congenital heart disease, and genital anomalies need to be considered as they would be in any other infant with a severe, usually lethal disorder.

Reassignment of sex of rearing for infants with a 46,XY karyotype and female genitalia may not always be appropriate because most will have early death, and the process of gender reassignment can be highly disruptive to a family already coping with the difficult issues of having a child with a genetic disorder characterized by life-threatening medical complications.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Smith-Lemli-Opitz syndrome (SLOS) is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

  • The parents of a proband are obligate carriers, and, therefore, carry one mutant allele.
  • Carriers are asymptomatic.

Sibs of a proband

  • At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
  • Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.
  • Heterozygotes (carriers) are asymptomatic.

Offspring of a proband. Individuals with severe SLOS have not been reported to reproduce; however, fertility does not appear to be reduced in mildly affected individuals with SLOS. A woman with SLOS who was not diagnosed until her pregnancy as having SLOS gave birth to a normal child [Ellingson et al, submitted].

Other family members of a proband. Each sib of a proband's parents is at a 50% risk of being a carrier.

Carrier Detection

Carriers for SLOS cannot be identified using serum biochemical testing.

Carrier detection is possible in at-risk relatives when both DHCR7 disease-causing mutations have been identified in an affected family member.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Family planning

  • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are carriers, or are at risk of being carriers.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

High-risk pregnancies. For pregnancies known to be at 25% risk for SLOS based on family history, the finding of abnormal concentration of 7-DHC levels in amniotic fluid obtained by amniocentesis usually performed at approximately 15 to 18 weeks' gestation [Abuelo et al 1995, Dallaire et al 1995, Rossiter et al 1995, Griffiths et al 2008] or in tissue obtained from chorionic villus samples (CVS) at approximately ten to 12 weeks' gestation [Mills et al 1996, Sharp et al 1997] is diagnostic. Caution should be exercised in diagnosing individuals with a family history of a mild variant form of SLOS. In this situation, demonstration of the enzyme deficiency in cultured amniocytes will be required.

If the two disease-causing mutations in DHCR7 have been identified in the proband, molecular genetic testing may be used in place of biochemical testing or to clarify indeterminate results [Loeffler et al 2002, Waye et al 2007].

Sonographic prenatal detection of SLOS is possible in affected fetuses with multiple congenital anomalies. Intrauterine growth retardation (IUGR) is common in fetuses with SLOS. Facial features of SLOS can be observed as early as 18 weeks’ gestation [Nowaczyk & Irons 2012, Quelin et al 2012]. However, ultrasound examination may be normal, especially in cases with mild SLOS [Goldenberg et al 2004].

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Low-risk pregnancies. In pregnancies in which no family history of SLOS exists, certain findings in the fetus could prompt consideration of SLOS. For example:

  • The combination of low concentrations of unconjugated estriol, HCG, and alpha-fetoprotein on routine maternal serum testing at 15 to 20 weeks' gestation could suggest the possible diagnosis of SLOS [Rossiter et al 1995]. However, data are currently insufficient to make specific recommendations about which pregnancies to investigate for SLOS when results of maternal serum screening tests are abnormal. Palomaki et al [2002] examined a prenatal screening model based on second-trimester maternal serum concentration of alpha-fetoprotein, human chorionic gonadotropin, and unconjugated estriol. They found that a cutoff risk level of one in 50 would result in the detection of 62% of affected pregnancies, while 0.34% of normal pregnancies would screen positive. The positive predictive value of such a screening test is approximately 1% (1 in 90).
  • Low maternal serum concentrations of unconjugated estriol alone may warrant further investigation, especially when associated with abnormal ultrasonographic findings suggestive of SLOS.
  • Fetal ultrasound examination. Prenatal findings of SLOS may include intrauterine growth retardation, major malformations of the brain, heart, kidneys, or limbs, and ambiguous genitalia, especially female-appearing genitalia or severe hypospadias in an XY fetus. Other nonspecific findings may include increased nuchal translucency, cystic hygroma, nonimmune hydrops, and cleft palate. However, although abnormal findings on ultrasound examination can be seen in fetuses with SLOS, no pattern is pathognomonic. Furthermore, ultrasound examination may be normal. Goldenberg et al [2004] found that intrauterine growth restriction (IUGR), the most frequent ultrasound finding, was detected in 67% of affected fetuses; IUGR was an isolated finding in 45% and associated with at least one other anomaly in 55%. Ultrasound examinations were considered normal in 17%; early detection of multiple malformations was only noted in 10% [Goldenberg et al 2004]. Quélin et al [2012] found that the pattern of anomalies in fetuses diagnosed with SLOS differed from the individuals diagnosed postnatally.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the disease-causing mutations have been identified [Liss et al 2008].

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A. Smith-Lemli-Opitz Syndrome: Genes and Databases

Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B. OMIM Entries for Smith-Lemli-Opitz Syndrome (View All in OMIM)

270400SMITH-LEMLI-OPITZ SYNDROME; SLOS
6028587-@DEHYDROCHOLESTEROL REDUCTASE; DHCR7

Normal allelic variants. DHCR7 contains nine exons and eight introns and spans 14,100 base pairs; exons 3-9 encode the protein 7-dehydrocholesterol reductase [Witsch-Baumgartner et al 2001]. The gene has an open reading frame of 1425 nucleotides.

Pathologic allelic variants. More than 150 mutations have been described [Waterham & Hennekam 2012] (see Table 2). They include 130 missense, eight nonsense, and five splice site mutations, eight deletions, two insertions, and one indel.

The most frequently found abnormal allele (28.2%) is c.832-1G>C (IVS8-1G>C), a splice site acceptor mutation in the last base of intron 8 that leads to an alternative upstream cryptic splice acceptor site. This results in the insertion of 134 base pairs of intronic sequence into the DHCR7 mRNA, resulting in a frameshift and a premature stop codon. The resulting protein product is non-functional (null mutation).

Other common abnormal alleles and their estimated frequencies include p.Thr93Met (10.4%), p.Trp151* (6.0%), p.Arg404Cys (5.2%), p.Val326Leu (5.0%), p.Arg352Trp (3.2%), p.Glu448Lys (3.2%), p.Gly410Ser (2.2%), p.Arg242Cys (1.8%), p.Ser169Leu (1.7%), p.Phe302Leu (1.3%), and p.Arg242His (1.0%). The 12 mutations account for 69.2% of reported alleles [Correa-Cerro & Porter 2005].

Approximately 84% of mutations are missense mutations distributed among all coding exons, in addition to a relatively few nonsense mutations, splicing defects, insertions, and deletions, which presumably result in loss of enzymatic activity and represent functional null alleles [Waterham & Hennekam 2012]. It has been hypothesized that mutations that are not found by routine testing methods are regulatory mutations that affect either transcription or stability of the DHCR7 mRNA [Correa-Cerro & Porter 2005].

Table 2. DHCR7 Pathologic Allelic Variants Discussed in This GeneReview

DNA Nucleotide Change
(Alias 1)
Protein Amino Acid ChangeReference Sequence
c.278C>Tp.Thr93MetNM_001360​.2
c.452G>Ap.Trp151*
c.506C>Tp.Ser169Leu
c.724C>Tp.Arg242Cys
c.725G>Ap.Arg242His
c.906C>Gp.Phe302Leu
c.976G>Tp.Val326Leu
c.1054C>Tp.Arg352Trp
c.1210C>Tp.Arg404Cys
c.1228G>Ap.Gly410Ser
c.832-1G>C
(IVS8-1G>C)
--
c.1342G>Ap.Glu448Lys

Note on variant classification: Variants listed in the table have been provided by the author(s). GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1. Variant designation that does not conform to current naming conventions

Normal gene product. The gene has an open reading frame of 1425 nucleotides and encodes a 475-amino acid polypeptide with a predicted molecular weight of 54.5 kd [Porter 2000]. The normal gene product is 7-dehydrocholesterol (7-DHC) reductase (3β-hydroxysteroid-Δ7-reductase), the last enzymatic step in cholesterol biosynthesis [Irons et al 1993, Irons et al 1994, Tint et al 1994, Elias & Irons 1995], which catalyzes the conversion of 7-DHC to cholesterol.

Abnormal gene product. Decreased function of 7-DHC reductase fails to convert 7-DHC to cholesterol, resulting in elevation of the cholesterol precursors 7-DHC and 8-DHC and generally decreased levels of cholesterol.

References

Medical Genetic Searches: A specialized PubMed search designed for clinicians that is located on the PubMed Clinical Queries page Image PubMed.jpg

Literature Cited

  1. Abuelo DN, Tint GS, Kelley R, Batta AK, Shefer S, Salen G. Prenatal detection of the cholesterol biosynthetic defect in the Smith- Lemli-Opitz syndrome by the analysis of amniotic fluid sterols. Am J Med Genet. 1995;56:281–5. [PubMed: 7778590]
  2. Anstey A. Photomedicine: lessons from the Smith-Lemli-Opitz syndrome. J Photochem Photobiol B. 2001;62:123–7. [PubMed: 11566274]
  3. Aradhya S, Lewis R, Bonaga T, Nwokekeh N, Stafford A, Boggs B, Hruska K, Smaoui N, Compton JG, Richard G, Suchy S. Exon-level array CGH in a large clinical cohort demonstrates increased sensitivity of diagnostic testing for Mendelian disorders. Genet Med. 2012;14:594–603. [PubMed: 22382802]
  4. Atchaneeyasakul LO, Linck LM, Connor WE, Weleber RG, Steiner RD. Eye findings in 8 children and a spontaneously aborted fetus with RSH/Smith-Lemli-Opitz syndrome. Am J Med Genet. 1998;80:501–5. [PubMed: 9880216]
  5. Azurdia RM, Anstey AV, Rhodes LE. Cholesterol supplementation objectively reduces photosensitivity in the Smith-Lemli-Opitz syndrome. Br J Dermatol. 2001;144:143–5. [PubMed: 11167696]
  6. Battaile KP, Battaile BC, Merkens LS, Maslen CL, Steiner RD. Carrier frequency of the common mutation IVS8-1G>C in DHCR7 and estimate of the expected incidence of Smith-Lemli-Opitz syndrome. Mol Genet Metab. 2001;72:67–71. [PubMed: 11161831]
  7. Battaile KP, Steiner RD. Smith-Lemli-Opitz syndrome: the first malformation syndrome associated with defective cholesterol synthesis. Mol Genet Metab. 2000;71:154–62. [PubMed: 11001806]
  8. Bialer MG, Penchaszadeh VB, Kahn E, Libes R, Krigsman G, Lesser ML. Female external genitalia and müllerian duct derivatives in a 46,XY infant with the smith-lemli-Opitz syndrome. Am J Med Genet. 1987;28:723–31. [PubMed: 3322011]
  9. Bianconi SE, Connely SK, Keil MF, Sinaii N, Rother KI, Porter FD, Stratakis CA. Adrenal function in Smith-Lemli-Opitz syndrome. Am J Med Genet A. 2011;155A:2732–38. [PMC free article: PMC3488380] [PubMed: 21990131]
  10. Caruso PA, Poussaint TY, Tzika AA, Zurakowski D, Astrakas LG, Elias ER, Bay C, Irons MB. MRI and 1H MRS findings in Smith-Lemli-Opitz syndrome. Neuroradiology. 2004;46:3–14. [PubMed: 14605787]
  11. Chan YM, Merkens LS, Connor WE, Roullet JB, Penfield JA, Jordan JM, Steiner RD, Jones PJ. Effects of dietary cholesterol and simvastatin on cholesterol synthesis in Smith-Lemli-Opitz syndrome. Pediatr Res. 2009;65:681–5. [PMC free article: PMC2780332] [PubMed: 19430384]
  12. Chasalow FI, Blethen SL, Taysi K. Possible abnormalities of steroid secretion in children with Smith-Lemli-Opitz syndrome and their parents. Steroids. 1985;46:827–43. [PubMed: 3018967]
  13. Chemaitilly W, Goldenberg A, Baujat G, Thibaud E, Cormier-Daire V, Abadie V. Adrenal insufficiency and abnormal genitalia in a 46XX female with Smith-Lemli-Opitz syndrome. Horm Res. 2003;59:254–6. [PubMed: 12714790]
  14. Choi PT, Nowaczyk MJ. Anesthetic considerations in Smith-Lemli-Opitz syndrome. Can J Anaesth. 2000;47:556–61. [PubMed: 10875719]
  15. Correa-Cerro LS, Porter FD. 3beta-hydroxysterol Delta7-reductase and the Smith-Lemli-Opitz syndrome. Mol Genet Metab. 2005;84:112–26. [PubMed: 15670717]
  16. Cunniff C, Kratz LE, Moser A, Natowicz MR, Kelley RI. Clinical and biochemical spectrum of patients with RSH/Smith-Lemli- Opitz syndrome and abnormal cholesterol metabolism. Am J Med Genet. 1997;68:263–9. [PubMed: 9024557]
  17. Curry CJ, Carey JC, Holland JS, Chopra D, Fineman R, Golabi M, Sherman S, Pagon RA, Allanson J, Shulman S. et al. Smith-Lemli-Opitz syndrome-type II: multiple congenital anomalies with male pseudohermaphroditism and frequent early lethality. Am J Med Genet. 1987;26:45–57. [PubMed: 3812577]
  18. Dallaire L, Fraser FC. The syndrome of retardation with urogenital and skeletal anomalies in siblings. J Pediatr. 1966;69:459–60. [PubMed: 5946456]
  19. Dallaire L, Mitchell G, Giguere R, Lefebvre F, Melancon SB, Lambert M. Prenatal diagnosis of Smith-Lemli-Opitz syndrome is possible by measurement of 7-dehydrocholesterol in amniotic fluid. Prenat Diagn. 1995;15:855–8. [PubMed: 8559757]
  20. Diaz-Stransky A, Tierney E. Cognitive and behavioral aspects of Smith-Lemli-Opitz syndrome. Am J Med Genet C Semin Med Genet. 2012;160C:295–300. [PubMed: 23042585]
  21. Donnai D, Young ID, Owen WG, Clark SA, Miller PF, Knox WF. The lethal multiple congenital anomaly syndrome of polydactyly, sex reversal, renal hypoplasia, and unilobular lungs. J Med Genet. 1986;23:64–71. [PMC free article: PMC1049544] [PubMed: 3950937]
  22. Elias ER, Irons M. Abnormal cholesterol metabolism in Smith-Lemli-Opitz syndrome. Curr Opin Pediatr. 1995;7:710–4. [PubMed: 8776024]
  23. Elias ER, Irons MB, Hurley AD, Tint GS, Salen G. Clinical effects of cholesterol supplementation in six patients with the Smith-Lemli-Opitz syndrome (SLOS). Am J Med Genet. 1997;68:305–10. [PubMed: 9024564]
  24. Ellingson M, Wick M, White W, Raymond K, Saenger A, Wassif C, Porter F, Babovic-Vuksanovic D. Pregnancy in an individual with mild Smith-Lemli-Opitz syndrome. Submitted. [PMC free article: PMC3883898] [PubMed: 23790112]
  25. Eroglu Y, Nguyen-Driver M, Freeman K, Merkens L, Merkens M, Roullet JB, Elias E, Sarphare G, Porter FD, Tierney E, Steiner S. Smith-Lemli-Opitz syndrome with normal IQ. Denver, CO: Pediatric Academic Societies and Asian Society for Pediatric Research Joint Meeting. 2011.
  26. Finley SC, Finley WH, Monsky DB. Cataracts in a girl with features of the Smith-Lemli-Opitz syndrome. J Pediatr. 1969;75:706–7. [PubMed: 5809847]
  27. Fitzky BU, Witsch-Baumgartner M, Erdel M, Lee JN, Paik YK, Glossmann H, Utermann G, Moebius FF. Mutations in the Delta7-sterol reductase gene in patients with the Smith-Lemli-Opitz syndrome. Proc Natl Acad Sci U S A. 1998;95:8181–6. [PMC free article: PMC20950] [PubMed: 9653161]
  28. Goldenberg A, Wolf C, Chevy F, Benachi A, Dumez Y, Munnich A, Cormier-Daire V. Antenatal manifestations of Smith-Lemli-Opitz (RSH) syndrome: a retrospective survey of 30 cases. Am J Med Genet A. 2004;124A:423–6. [PubMed: 14735596]
  29. Goodwin H, Brooks BP, Porter FD. Acute postnatal cataract formation in Smith-Lemli-Opitz syndrome. Am J Med Genet A. 2008;146A:208–11. [PubMed: 18076100]
  30. Gorlin RJ, Cohen MM Jr, Levin LS. Syndromes of the Head and Neck. 3 ed. New York, NY: Oxford University Press; 1990:890-5.
  31. Griffiths WJ, Wang Y, Karu K, Samuel E, McDonnell S, Hornshaw M, Shackleton C. Potential of sterol analysis by liquid chromatography-tandem mass spectrometry for the prenatal diagnosis of Smith-Lemli-Opitz syndrome. Clin Chem. 2008;54:1317–24. [PMC free article: PMC2533047] [PubMed: 18556335]
  32. Haas D, Garbade SF, Vohwinkel C, Muschol N, Trefz FK, Penzien JM, Zschocke J, Hoffmann GF, Burgard P. Effects of cholesterol and simvastatin treatment in patients with Smith-Lemli-Opitz syndrome (SLOS). J Inherit Metab Dis. 2007;30:375–87. [PubMed: 17497248]
  33. Hall P, Michels V, Gavrilov D, Matern D, Oglesbee D, Raymond K, Rinaldo P, Tortorelli S. Aripiprazole and trazodone cause elevations of 7-dehydrocholesterol in the absence of Smith-Lemli-Opitz Syndrome. Mol Genet Metab. 2013 [PubMed: 23628460]
  34. Irons M, Elias ER, Abuelo D, Bull MJ, Greene CL, Johnson VP, Keppen L, Schanen C, Tint GS, Salen G. Treatment of Smith-Lemli-Opitz syndrome: results of a multicenter trial. Am J Med Genet. 1997;68:311–4. [PubMed: 9024565]
  35. Irons M, Elias ER, Salen G, Tint GS, Batta AK. Defective cholesterol biosynthesis in Smith-Lemli-Opitz syndrome. Lancet. 1993;341:1414. [PubMed: 7684480]
  36. Irons M, Elias ER, Tint GS, Salen G, Frieden R, Buie TM, Ampola M. Abnormal cholesterol metabolism in the Smith-Lemli-Opitz syndrome: report of clinical and biochemical findings in four patients and treatment in one patient. Am J Med Genet. 1994;50:347–52. [PubMed: 8209913]
  37. Jira PE, Wevers RA, de Jong J, Rubio-Gozalbo E, Janssen-Zijlstra FS, van Heyst AF, Sengers RC, Smeitink JA. Simvastatin. A new therapeutic approach for Smith-Lemli-Opitz syndrome. J Lipid Res. 2000;41:1339–46. [PubMed: 10946022]
  38. Johnson VP. Smith-Lemli-Opitz syndrome: review and report of two affected siblings. Z Kinderheilkd. 1975;119:221–34. [PubMed: 166525]
  39. Kelley RI. Diagnosis of Smith-Lemli-Opitz syndrome by gas chromatography/mass spectrometry of 7-dehydrocholesterol in plasma, amniotic fluid and cultured skin fibroblasts. Clin Chim Acta. 1995;236:45–58. [PubMed: 7664465]
  40. Kelley RI, Hennekam RC. The Smith-Lemli-Opitz syndrome. J Med Genet. 2000;37:321–35. [PMC free article: PMC1734573] [PubMed: 10807690]
  41. Kelley RL, Roessler E, Hennekam RC, Feldman GL, Kosaki K, Jones MC, Palumbos JC, Muenke M. Holoprosencephaly in RSH/Smith-Lemli-Opitz syndrome: does abnormal cholesterol metabolism affect the function of Sonic Hedgehog? Am J Med Genet. 1996;66:478–84. [PubMed: 8989473]
  42. Krajewska-Walasek M, Gradowska W, Ryzko J, Socha P, Chmielik J, Szaplyko W, Kasprzyk J, Gorska B, Szreter M, Wolski J, Rysiewski H, Malunowicz EM, Gregorek H, Michalkiewicz J, Pietraszek E, Szaplyko J. Further delineation of the classical Smith-Lemli-Opitz syndrome phenotype at different patient ages: clinical and biochemical studies. Clin Dysmorphol. 1999;8:29–40. [PubMed: 10327249]
  43. Kratz LE, Kelley RI. Prenatal diagnosis of the RSH/Smith-Lemli-Opitz syndrome. Am J Med Genet. 1999;82:376–81. [PubMed: 10069707]
  44. Leal-Pavey YR. Use of the LMA classic to secure the airway of a premature neonate with Smith-Lemli-Opitz syndrome: a case report. AANA J. 2004;72:427–30. [PubMed: 15633366]
  45. Lee R, Conley S, Gropman A, Porter F, Baker E. Brain magnetic resonance imaging findings in Smith-Lemli-Opitz syndrome. Am J Med Genet. in press [PMC free article: PMC3787998] [PubMed: 23918729]
  46. Lin AE, Ardinger HH, Ardinger RH, Cunniff C, Kelley RI. Cardiovascular malformations in Smith-Lemli-Opitz syndrome. Am J Med Genet. 1997;68:270–8. [PubMed: 9024558]
  47. Linck LM, Lin DS, Flavell D, Connor WE, Steiner RD. Cholesterol supplementation with egg yolk increases plasma cholesterol and decreases plasma 7-dehydrocholesterol in Smith-Lemli-Opitz syndrome. Am J Med Genet. 2000;93:360–5. [PubMed: 10951458]
  48. Lipson A, Hayes A. Smith-Lemli-Opitz syndrome and Hirschsprung disease. J Pediatr. 1984;105:177. [PubMed: 6737144]
  49. Liss J, Lukaszuk K, Bruszczyńska A, Szczerkowska Z, Rebala K. Pregnancy and life after preimplantation genetic diagnosis of Smith-Lemli-Opitz syndrome. Fertil Steril. 2008;90:2011. [PubMed: 18442819]
  50. Loeffler J, Utermann G, Witsch-Baumgartner M. Molecular prenatal diagnosis of Smith-Lemli-Opitz syndrome is reliable and efficient. Prenat Diagn. 2002;22:827–30. [PubMed: 12224080]
  51. Lowry RB, Miller JR, MacLean JR. Micrognathia, polydactyly, and cleft palate. J Pediatr. 1968;72:859–61. [PubMed: 5652614]
  52. Matveevskii A, Berman L, Sidi A, Gravenstein D, Kays D. Airway management of patient with Smith-Lemli-Opitz syndrome for gastric surgery: case report. Paediatr Anaesth. 2006;16:322–4. [PubMed: 16490099]
  53. Mills K, Mandel H, Montemagno R, Soothill P, Gershoni-Baruch R, Clayton PT. First trimester prenatal diagnosis of Smith-Lemli-Opitz syndrome (7- dehydrocholesterol reductase deficiency). Pediatr Res. 1996;39:816–9. [PubMed: 8726234]
  54. Mueller C, Patel S, Irons M, Antshel K, Salen G, Tint GS, Bay C. Normal cognition and behavior in a Smith-Lemli-Opitz syndrome patient who presented with Hirschsprung disease. Am J Med Genet A. 2003;123A:100–6. [PMC free article: PMC1201564] [PubMed: 14556255]
  55. Muzzin KB, Harper LF. Smith-Lemli-Opitz syndrome: a review, case report and dental implications. Spec Care Dentist. 2003;23:22–7. [PubMed: 12887150]
  56. Nakane T, Hayashibe H, Nakazawa S. An MCA/MR syndrome with hypocholesterolemia due to familial hypobetalipoproteinemia: report of a second patient with Nguyen syndrome. Am J Med Genet A. 2005;137A:305–7. [PubMed: 16088930]
  57. Nowaczyk MJ, Irons MB. Smith-Lemli-Opitz syndrome:phenotype, natural history and epidemiology. Am J Med Genet C Semin Med Genet. 2012;160C:250–62. [PubMed: 23059950]
  58. Nowaczyk MJ, McCaughey D, Whelan DT, Porter FD. Incidence of Smith-Lemli-Opitz syndrome in Ontario, Canada. Am J Med Genet. 2001;102:18–20. [PubMed: 11471166]
  59. Nowaczyk MJ, Tan M, Hamid JS, Allanson JE. Smith-Lemli-Opitz syndrome: Objective assessment of facial phenotype. Am J Med Genet. 2012;158A:1020–8. [PubMed: 22438180]
  60. Nowaczyk MJ, Zeesman S, Waye JS, Douketis JD. Incidence of Smith-Lemli-Opitz syndrome in Canada: results of three-year population surveillance. J Pediatr. 2004;145:530–5. [PubMed: 15480380]
  61. Nwokoro NA, Mulvihill JJ. Cholesterol and bile acid replacement therapy in children and adults with Smith-Lemli-Opitz (SLO/RSH) syndrome. Am J Med Genet. 1997;68:315–21. [PubMed: 9024566]
  62. Opitz JM. The RSH Syndrome. Birth Defects. 1969;5:167–9.
  63. Palomaki GE, Bradley LA, Knight GJ, Craig WY, Haddow JE. Assigning risk for Smith-Lemli-Opitz syndrome as part of 2nd trimester screening for Down's syndrome. J Med Screen. 2002;9:43–4. [PubMed: 11943798]
  64. Park SC, Needles CF, Dimich I, Sussman L. Congenital heart disease in an infant with the Smith-Lemli-Opitz syndrome. J Pediatr. 1968;73:896–902. [PubMed: 4386913]
  65. Patterson K, Toomey KE, Chandra RS. Hirschsprung disease in a 46,XY phenotypic infant girl with Smith-Lemli-Opitz syndrome. J Pediatr. 1983;103:425–7. [PubMed: 6886911]
  66. Pinsky L, DiGeorge AM. A familial syndrome of facial and skeletal anomalies associated with genital abnormality in the male and normal genitals in the female: another cause of male pseudohermaphroditism. J Pediatr. 1965;66:1049–54. [PubMed: 14288458]
  67. Porter FD. RSH/Smith-Lemli-Opitz syndrome: a multiple congenital anomaly/mental retardation syndrome due to an inborn error of cholesterol biosynthesis. Mol Genet Metab. 2000;71:163–74. [PubMed: 11001807]
  68. Quélin C, Loget P, Verloes A, Bazin A, Bessières B, Laquerrière A, Patrier S, Grigorescu R, Encha-Razavi F, Delahaye S, Jouannic JM, Carbonne B, D'Hervé D, Aubry MC, Macé G, Harvey T, Ville Y, Viot G, Joyé N, Odent S, Attié-Bitach T, Wolf C, Chevy F, Benlian P, Gonzales M. Phenotypic spectrum of fetal Smith-Lemli-Opitz syndrome. Eur J Med Genet. 2012;55:81–90. [PubMed: 22226660]
  69. Rossi M, Vajro P, Iorio R, Battagliese A, Brunetti-Pierri N, Corso G, Di Rocco M, Ferrari P, Rivasi F, Vecchione R, Andria G, Parenti G. Characterization of liver involvement in defects of cholesterol biosynthesis: long-term follow-up and review. Am J Med Genet A. 2005;132A:144–51. [PubMed: 15580635]
  70. Rossiter JP, Hofman KJ, Kelley RI. Smith-Lemli-Opitz syndrome: prenatal diagnosis by quantification of cholesterol precursors in amniotic fluid. Am J Med Genet. 1995;56:272–5. [PubMed: 7778588]
  71. Ryan AK, Bartlett K, Clayton P, Eaton S, Mills L, Donnai D, Winter RM, Burn J. Smith-Lemli-Opitz syndrome: a variable clinical and biochemical phenotype. J Med Genet. 1998;35:558–65. [PMC free article: PMC1051366] [PubMed: 9678700]
  72. Sharp P, Haan E, Fletcher JM, Khong TY, Carey WF. First-trimester diagnosis of Smith-Lemli-Opitz syndrome. Prenat Diagn. 1997;17:355–61. [PubMed: 9160388]
  73. Shefer S, Salen G, Honda A, Batta A, Hauser S, Tint GS, Honda M, Chen T, Holick MF, Nguyen LB. Rapid identification of Smith-Lemli-Opitz syndrome homozygotes and heterozygotes (carriers) by measurement of deficient 7-dehydrocholesterol-delta 7-reductase activity in fibroblasts. Metabolism. 1997;46:844–50. [PubMed: 9225842]
  74. Starck L, Bjorkhem I, Ritzen EM, Nilsson BY, von Dobeln U. 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. Acta Paediatr. 1999;88:729–33. [PubMed: 10447131]
  75. Starck L, Lovgren-Sandblom A, Bjorkhem I. Cholesterol treatment forever? The first Scandinavian trial of cholesterol supplementation in the cholesterol-synthesis defect Smith-Lemli-Opitz syndrome. J Intern Med. 2002a;252:314–21. [PubMed: 12366604]
  76. Starck L, Lovgren-Sandblom A, Bjorkhem I. Simvastatin treatment in the SLO syndrome: a safe approach? Am J Med Genet. 2002b;113:183–9. [PubMed: 12407710]
  77. Svoboda MD, Christie JM, Eroglu Y, Freeman KA, Steiner RD. Treatment of Smith-Lemli-Opitz syndrome and other sterol disorders. Am J Med Genet C Semin Med Genet. 2012;160C:285–94. [PMC free article: PMC3890258] [PubMed: 23042642]
  78. Tierney E, Nwokoro NA, Kelley RI. Behavioral phenotype of RSH/Smith-Lemli-Opitz syndrome. Ment Retard Dev Disabil Res Rev. 2000;6:131–4. [PubMed: 10899806]
  79. Tierney E, Nwokoro NA, Porter FD, Freund LS, Ghuman JK, Kelley RI. Behavior phenotype in the RSH/Smith-Lemli-Opitz syndrome. Am J Med Genet. 2001;98:191–200. [PubMed: 11223857]
  80. Tint GS, Irons M, Elias ER, Batta AK, Frieden R, Chen TS, Salen G. Defective cholesterol biosynthesis associated with the Smith-Lemli-Opitz syndrome. N Engl J Med. 1994;330:107–13. [PubMed: 8259166]
  81. Tint GS, Salen G, Batta AK, Shefer S, Irons M, Elias ER, Abuelo DN, Johnson VP, Lambert M, Lutz R. et al. Correlation of severity and outcome with plasma sterol levels in variants of the Smith-Lemli-Opitz syndrome. J Pediatr. 1995;127:82–7. [PubMed: 7608816]
  82. van Rooij A, Nijenhuis AA, Wijburg FA, Schutgens RB. Highly increased CSF concentrations of cholesterol precursors in Smith-Lemli-Opitz syndrome. J Inherit Metab Dis. 1997;20:578–80. [PubMed: 9266395]
  83. Wassif CA, Maslen C, Kachilele-Linjewile S, Lin D, Linck LM, Connor WE, Steiner RD, Porter FD. Mutations in the human sterol delta7-reductase gene at 11q12-13 cause Smith-Lemli-Opitz syndrome. Am J Hum Genet. 1998;63:55–62. [PMC free article: PMC1377256] [PubMed: 9634533]
  84. Waterham HR, Hennekam RC. Mutational spectum of Smith-Lemli-Opitz syndrome. Am J Med Genet C Semin Med Genet. 2012;160C:263–84. [PubMed: 23042628]
  85. Waterham HR, Wijburg FA, Hennekam RC, Vreken P, Poll-The BT, Dorland L, Duran M, Jira PE, Smeitink JA, Wevers RA, Wanders RJ. Smith-Lemli-Opitz syndrome is caused by mutations in the 7- dehydrocholesterol reductase gene. Am J Hum Genet. 1998;63:329–38. [PMC free article: PMC1377322] [PubMed: 9683613]
  86. Waye JS, Eng B, Nowaczyk MJ. Prenatal diagnosis of Smith-Lemli-Opitz syndrome (SLOS) by DHCR7 mutation analysis. Prenat Diagn. 2007;27:638–40. [PubMed: 17441222]
  87. Weaver DD, Solomon BD, Akin-Samson K, Kelley RI, Muenke M. Cyclopia (synophthalmia) in Smith-Lemli-Opitz syndrome: First reported case and consideration of mechanism. Am J Med Genet C Semin Med Genet. 2010;154C:142–5. [PMC free article: PMC2815131] [PubMed: 20104611]
  88. Witsch-Baumgartner M, Fitzky BU, Ogorelkova M, Kraft HG, Moebius FF, Glossmann H, Seedorf U, Gillessen-Kaesbach G, Hoffmann GF, Clayton P, Kelley RI, Utermann G. Mutational spectrum in the Delta-7-sterol reductase gene and genotype-phenotype correlation in 84 patients with Smith-Lemli-Opitz syndrome. Am J Hum Genet. 2000;66:402–12. [PMC free article: PMC1288092] [PubMed: 10677299]
  89. Witsch-Baumgartner M, Gruber M, Kraft HG, Rossi M, Clayton P, Giros M, Haas D, Kelley RI, Krajewska-Walasek M, Utermann G. Maternal apo E genotype is a modifier of the Smith-Lemli-Opitz syndrome. J Med Genet. 2004;41:577–84. [PMC free article: PMC1735869] [PubMed: 15286151]
  90. Witsch-Baumgartner M, Loffler J, Utermann G. Mutations in the human DHCR7 gene. Hum Mutat. 2001;17:172–82. [PubMed: 11241839]
  91. Woollett LA. Maternal cholesterol in fetal development: transport of cholesterol from the maternal to the fetal circulation. Am J Clin Nutr. 2005;82:1155–61. [PubMed: 16332646]
  92. Yu H, Tint GS, Salen G, Patel SB. Detection of a common mutation in the RSH or Smith-Lemli-Opitz syndrome by a PCR-RFLP assay: IVS8-G—>C is found in over sixty percent of US propositi. Am J Med Genet. 2000;90:347–50. [PubMed: 10710236]
  93. Zarowski M, Vendrame M, Irons M, Kothare SV. Prevalence of sleep problems in Smith-Lemli-Opitz syndrome. Am J Med Genet A. 2011;155A:1558–62. [PubMed: 21626671]

Suggested Reading

  1. Bukelis I, Porter FD, Zimmerman AW, Tierney E. Smith-Lemli-Opitz syndrome and autism spectrum disorder. Am J Psychiatry. 2007;164:1655–61. [PubMed: 17974928]
  2. Ko JS, Choi BS, Seo JK, Shin JY, Chae JH, Kang GH, Lee R, Ki CS, Kim JW. A novel DHCR7 mutation in a Smith-Lemli-Opitz syndrome infant presenting with neonatal cholestasis. J Korean Med Sci. 2010;25:159–62. [PMC free article: PMC2799999] [PubMed: 20052364]
  3. Tierney E, Conley SK, Goodwin H, Porter FD. Analysis of short-term behavioral effects of dietary cholesterol supplementation in Smith-Lemli-Opitz syndrome. Am J Med Genet A. 2010;152A:91–5. [PMC free article: PMC2799534] [PubMed: 20014133]
  4. Witsch-Baumgartner M, Schwentner I, Gruber M, Benlian P, Bertranpetit J, Bieth E, Chevy F, Clusellas N, Estivill X, Gasparini G, Giros M, Kelley RI, Krajewska-Walasek M, Menzel J, Miettinen T, Ogorelkova M, Rossi M, Scala I, Schinzel A, Schmidt K, Schönitzer D, Seemanova E, Sperling K, Syrrou M, Talmud PJ, Wollnik B, Krawczak M, Labuda D, Utermann G. Age and origin of major Smith-Lemli-Opitz syndrome (SLOS) mutations in European populations. J Med Genet. 2008;45:200–9. [PubMed: 17965227]

Chapter Notes

Author History

Christopher M Cunniff, MD, FACMG; University of Arizona Colleges of Medicine and Science (1998-2007)
Mira Irons, MD, FACMG, FAAP; Harvard Medical School (2007-2013)
Tracey L Kurtzman; University of Arizona College of Medicine (1998-2001)
Malgorzata JM Nowaczyk, MD, FRCPC, FCCMG, FACMG (2013-present)

Revision History

  • 20 June 2013 (me) Comprehensive update posted live
  • 24 October 2007 (me) Comprehensive update posted to live Web site
  • 11 February 2004 (me) Comprehensive update posted to live Web site
  • 6 November 2001 (me) Comprehensive update posted to live Web site
  • 13 November 1998 (pb) Review posted to live Web site
  • 20 April 1998 (cc) Original submission by TL Kurtzman, BA and C Cunniff, MD
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