Clinical characteristics.

Smith-Lemli-Opitz syndrome (SLOS) is a congenital multiple-anomaly / cognitive impairment 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 restriction, 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; individuals with normal development and only minor malformations have been described.

Diagnosis/testing.

The diagnosis of SLOS is established in a proband with suggestive clinical features and elevated 7-dehydrocholesterol level and/or by identification of biallelic pathogenic variants in DHCR7 by molecular genetic testing. 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.

Management.

Treatment of manifestations: While no long-term 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 are indicated for identified disabilities. Consultation with a nutritionist and consideration of hypoallergenic or elemental formulas in infants; gastrostomy as needed for feeding; neonatal cholestatic liver disease often resolves with cholesterol and/or bile acid therapy. A trial of melatonin or another hypnotic may be considered for those with sleep disturbance. Orthotics, tendon release surgery, or Botox^® as needed. Proper clothing and sunscreen with UVA and UBV protection for photosensitivity. Routine treatment for gastroesophageal reflux, pyloric stenosis, Hirschsprung disease, constipation, recurrent otitis media, hearing loss, cataracts, ptosis, strabismus, psychiatric disturbance/behavioral issues, seizures, cleft palate, dental anomalies, congenital heart defects, hearing loss, limb defects, and adrenal insufficiency, including stress-related doses of steroids during illness and other physical stress.

Surveillance: Routine health supervision including monitoring of growth parameters, nutritional status, developmental progress, behavior, stooling pattern, changes in tone, seizures (if present), and movement disorders at each visit; 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; screening for vision problems and hearing loss annually in childhood; dental evaluations twice yearly starting at age three years; assessment for signs of puberty and rate of pubertal progression starting at age ten years; monitor for gonadal location and signs/symptoms of urinary tract infection as clinically indicated.

Agents/circumstances to avoid: Treatment with haloperidol or other drugs in the same class. Psychotropic drugs (trazodone, aripirazole) that elevate 7-DHC 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 pathogenic variants in the family are known. Prenatal testing for a pregnancy at increased risk is possible using biochemical testing or molecular genetic testing if the pathogenic variants in the family are known.

Suggestive Findings

Smith-Lemli-Opitz syndrome should be suspected in individuals with the following clinical features and laboratory findings.

Clinical 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 restriction / short stature
• Intellectual disability
• Hypospadias in males
• Cleft palate
• Postaxial polydactyly

Laboratory findings

• Elevated serum concentration of 7-dehydrocholesterol (7-DHC) as defined by the laboratory
  Note: (1) 7-DHC concentration is usually measured in blood samples, but can be measured in other tissues. In rare instances, serum concentrations of 7-DHC and cholesterol can be in the normal ranges and a strong clinical suspicion of SLOS may require sterol analysis from cultured fibroblasts or confirmatory genetic testing [Koo et al 2010]. (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 typically do not have the physical features of SLOS, but may be tested for SLOS because of neurocognitive issues. (3) Different laboratories may report results in different units. Laboratories in the US report results as milligrams per deciliter (mg/dL) or micrograms per milliliter (μg/mL); European laboratories most often report results as millimoles per liter (mmol/L). Thus, direct comparison of values between laboratories requires caution.
• Low serum concentration of cholesterol. Serum concentration of cholesterol in unaffected and affected individuals can overlap, particularly when the affected individuals are older or have a milder phenotype.
  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.

Establishing the Diagnosis

The diagnosis of Smith-Lemli-Opitz syndrome is established in a proband with suggestive clinical features and elevated 7-dehydrocholesterol level AND/OR biallelic pathogenic variants in DHCR7 identified by molecular genetic testing (see Table 1).

Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing, multigene panel) and comprehensive genomic testing (chromosomal microarray analysis, exome sequencing, exome array, genome sequencing) depending on the phenotype.

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of Smith-Lemli-Opitz syndrome is broad, individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those in whom the diagnosis of Smith-Lemli-Opitz syndrome has not been considered are more likely to be diagnosed using genomic testing (see Option 2).

Clinical Description

Severe Smith-Lemli-Opitz syndrome (SLOS) is characterized by prenatal and postnatal growth restriction, 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 [Nowaczyk & Irons 2012]. 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.

Growth

• Prematurity and breech presentation are common. Neonates frequently have poor suck, irritability, and failure to thrive.
• Children and adults with SLOS are generally smaller than average with severe failure to thrive.
  • Growth parameters are typically 2 SD or more below the mean for age or, in less affected children, for family background.
  • Congenital, static microcephaly is also common.

Feeding difficulties/gastrointestinal issues. Infants with SLOS frequently have feeding problems secondary to a combination of hypotonia, oral-motor incoordination, gastrointestinal problems and formula intolerance.

• In general, infants with more severe congenital anomalies have more feeding problems.
• Constipation is a common problem and may be related to hypotonia, dysmotility, and/or hypomotility.
• Gastroesophageal reflux is also common in infancy and improves with age in some individuals.
• 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].
• Pyloric stenosis and Hirschsprung disease are rare findings.

Development and behavior

• 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 2017].
• Behavior signs/symptoms include the following:
  • Sensory hyperreactivity
  • Irritability
  • Sleep cycle disturbance
    Many individuals require very little sleep, often only a few hours per night [Zarowski et al 2011].
  • Self-injurious behavior (hand biting and/or head banging)
  • Autism spectrum behaviors (46%-53%)
  • Temperament dysregulation
  • Social and communication deficits [Diaz-Stransky & Tierney 2012, Thurm et al 2016]
• Depression and other psychiatric problems have been reported in older individuals.

Neurologic issues. Hypotonia, which is common in young children, affects feeding and delays motor development.

• Older children often exhibit hypertonia.
• Seizures can occur, but are not more common than in the general population.

Neuroimaging. Individuals with SLOS commonly have anomalies involving the midline and para-midline structures of the brain [Lee et al 2013]. Developmental abnormalities of the central nervous system include the following [Nowaczyk & Irons 2012, Lee et al 2013]:

• Abnormalities of myelination
• Ventricular dilatation
• Malformations of the corpus callosum and/or cerebellum
• Dandy-Walker malformation and its variants
• Holoprosencephaly (5%) [Weaver et al 2010]

Skin. 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 individuals 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.

Anomalies of the genitalia. Many 46,XY individuals with severe manifestations of SLOS have extreme undervirilization of the external genitalia, resulting in female external genitalia (termed "sex reversal"). Approximately 20%-25% of individuals with SLOS described in the literature have a 46,XY karyotype with a female phenotype [Lin et al 1997].

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.

• Hypospadias and/or bilateral cryptorchidism occurs 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].
• Other findings include:
  • Persistent urogenital sinus and posterior labial fusion without clitoromegaly in a female with an XX karyotype [Chemaitilly et al 2003];
  • Precocious puberty in affected girls [Irons, unpublished].

Renal anomalies. 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.

Oral

• Cleft palate is present in 40%-50% of affected individuals and may contribute to feeding and growth problems.
• Dental anomalies include oligo- and polydontia, enamel hypoplasia, tooth crowding, agenesis of teeth, marked curve of Spee (occlusal curvature), and widely spaced incisors [Muzzin & Harper 2003, Rojare et al 2019].

Characteristic facial features include narrow forehead, epicanthal folds, ptosis, short nose with anteverted nares, short mandible with preservation of jaw width, and nevus simplex (sometimes also referred to as capillary hemangioma or nevus flammeus) over the nasal root that extends onto the glabella [Nowaczyk et al 2012].

• The ears are low set and posteriorly rotated, but can be otherwise normal [Nowaczyk et al 2012].
• 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].

Ophthalmologic findings. Congenital cataracts are present in approximately 20% of affected individuals [Cunniff et al 1997, Lin et al 1997]. Cataracts may also develop acutely [Goodwin et al 2008]. Other ophthalmologic manifestations [Atchaneeyasakul et al 1998]:

• Ptosis
• Strabismus
• Optic atrophy
• Optic nerve hypoplasia

Cardiac anomalies. Up to 50% of affected individuals have an identified cardiac defect with an increased incidence of atrioventricular canal defects and anomalous pulmonary venous return. Pulmonary stenosis has also been reported [Prosnitz et al 2017, Nasr et al 2019]

Respiratory. 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 [Quélin et al 2012].
• An increased frequency of upper- and/or lower-respiratory infections is seen, particularly in infancy and early childhood.

Musculoskeletal findings. Y-shaped syndactyly of the second and third toes is the most common (though not universal) finding.

• Postaxial, bilateral foot 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]. Some individuals with a more severe phenotype also have postaxial bilateral polydactyly of the hands.
• 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.

Ears and hearing. Recurrent otitis media and conductive hearing loss have been reported in a majority of infants and children with SLOS.

Endocrinologic issues. 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].

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 number and severity of congenital anomalies [Tint et al 1995, Yu et al 2000, Waterham & Hennekam 2012]. Mortality is particularly high in the group of individuals with the lowest cholesterol concentrations (~10 mg/dL).

Genotype-Phenotype Correlations

A strict genotype-phenotype correlation is difficult because most affected individuals are compound heterozygotes.

• In general, individuals who are homozygous for two null alleles, such as the common c.964-1G>C or p.Trp151Ter variants, have a severe phenotype.
• A detailed evaluation of 207 individuals with SLOS showed that the most severe phenotypes were observed in individuals with two null variants or with two variants in loop 8-9 (amino acids 352-411), while those with one or two pathogenic variants in loop 1-2 (amino acids 59-94 and amino acids 119-151 respectively) or one pathogenic variant in the N-terminus (amino acids 1-37) have milder phenotypes [Waterham & Hennekam 2012].

However, the significant variation seen in severity, even among individuals with similar pathogenic variants, suggests influences on phenotype other than the DHCR7 pathogenic variant [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

SLOS may also be referred to as RSH syndrome or SLO syndrome.

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

In North America, the birth prevalence of SLOS is estimated at 1:40,000 live births [Cross et al 2015], although it should be noted that affected females, who lack the genital abnormalities seen in affected males, are underascertained. The carrier frequency in North America is estimated at 1% [Cross et al 2015]. SLOS is less common in individuals of Asian or African ancestry [Wright et al 2003].

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with Smith-Lemli-Opitz syndrome (SLOS), the evaluations summarized in Table 4 (if not performed as part of the evaluation that led to the diagnosis) are recommended.