Pediatric Summary Report

Secondary Findings in Pediatric Subjects

Non-diagnostic, excludes newborn screening & prenatal testing/screening

• Status (Pediatric): Passed (Consensus scoring is Complete)
• Curation Status (Pediatric): Released - Under Revision 1.0.0
• Status (Adult): Incomplete (Consensus scoring is Incomplete)
• GENE/GENE PANEL: DHCR7
• Condition: Smith-Lemli-Optiz Syndrome
• Mode(s) of Inheritance: Autosomal Recessive

Actionability Assertion

• DHCR7 ⇔ 0010035 (smith-lemli-opitz syndrome; slos): Assertion Pending

Actionability Rationale

This topic was initially scored prior to development of the process for making actionability assertions. The Actionability Working Group decided to defer making an assertion until after the topic could be reviewed through the update process.

Final Consensus Scores

Gene Condition Pairs: DHCR7 ⇔ 0010035 (OMIM:270400)

Outcome / Intervention Pair	Severity	Likelihood	Effectiveness	Nature of the Intervention	Total Score
Impaired development / Dietary cholesterol supplementation	2	3C	0C	3	8CC
Impaired growth / Dietary cholesterol supplementation	1	3C	1N	3	8CN

1. What is the nature of the threat to health for an individual carrying a deleterious allele?

Prevalence of the Genetic Condition

The birth prevalence of Smith-Lemli-Opitz syndrome (SLOS) varies depending on geographic region. In North America, prevalence is 1:40,000-1:60,000 live births. In middle Europe, prevalence is 1:20,000-1:60,000. In Eastern European population, prevalence may be as high as 1:16,000. In African or Asian populations, SLOS has been rarely reported. [1, 2, 3]

Clinical Features

SLOS is a congenital multiple-anomaly/cognitive impairment syndrome caused by an abnormality in cholesterol metabolism resulting from deficiency of 7-dehydrocholesterol (7-DHC) reductase. The clinical spectrum is wide; individuals with normal development and only minor malformations have been described. While present at birth, SLOS may be detected in later childhood or adulthood in mild forms. It is characterized by prenatal and postnatal growth restriction, microcephaly, moderate-to-severe intellectual disability, and multiple major and minor malformations. Children and adults are generally smaller than average and may demonstrate failure to thrive. Developmental abnormalities of the central nervous system include abnormalities of the midline and para-midline structures of the brain. Cognitive function can range, from no impairment to severe intellectual disability. Behavior signs/symptoms are varied and may include sensory hyperreactivity, irritability, self-injurious behavior, autism spectrum behaviors, and social and communication deficits. Depression and other psychiatric problems have been reported in older individuals. Genital anomalies in 46,XY males include undervirilization of the external genitalia resulting in female-appearing external genitalia, hypospadias, and/or bilateral cryptorchidism. 46,XX females may have bicornuate uterus, septate vagina, posterior labial fusion without clitoromegaly, and precocious puberty. Musculoskeletal findings often include 2-3 syndactyly of the toes and rarely polydactyly. Photosensitivity can be severe and result from even brief exposure to sunlight. Other malformations include cleft palate, cardiac defects, renal anomalies, liver disease, ophthalmologic manifestations, and dental anomalies. Because cholesterol is a precursor of steroid hormones (including cortisol, aldosterone, and testosterone), endocrine problems (including electrolyte abnormalities, hypoglycemia, hypertension, adrenal insufficiency, low testosterone) can be seen. Individuals with SLOS have distinctive facial features. [1, 2, 3, 4, 5]

Natural History

Prognosis in SLOS depends on the severity of the disease and on the associated malformations. Severe prenatal manifestations may result in death in the neonatal period. Heart disease and brain malformations may be lethal. Many individuals live into adulthood. Mildly affected individuals may be able to live and work relatively independently. Studies have identified a weak inverse correlation between serum concentration of cholesterol and number and severity of congenital anomalies. Mortality is particularly high in the group of individuals with the lowest cholesterol concentrations. [1, 3]

2. How effective are interventions for preventing harm?

Patient Management

The following evaluations are recommended after diagnosis of SLOS is made:
• Assessment of growth including weight, length/height and head circumference
• Gastroenterology/nutrition/feeding team evaluation
• AST, ALT, and bilirubin concentrations
• Developmental assessment
• Neuropsychiatric evaluation
• Neurologic evaluation
• Physical examination of the external genitalia
• Renal ultrasound
• Clinical assessment for cleft palate
• Ophthalmologic evaluation
• Orthopedics/physical medicine & rehabilitation/PT/OT evaluation
• Audiologic evaluation
• Testosterone levels in males
• Consultation with clinical geneticist and/or genetic counselor
• Family support/resources . (Tier 4) [1]

Treatment of most manifestations associated with SLOS (e.g., gastrointestinal issues, behavioral issues, congenital heart defects) is symptomatic and based on standard of care. (Tier 4) [1, 2]

Cholesterol supplementation should be considered in all individuals with SLOS to increase cholesterol and decrease 7-DHC and 8-DHC levels and because it may result in clinical improvement and has minimal side effects. The impact of cholesterol supplementation has not generally been evaluated in randomized placebo-controlled studies. One trial of 14 children (aged 2 months to 15 years) with SLOS reported an average 164% increase in plasma cholesterol following dietary therapy for 6-15 months. However, no significant change in 7-DHC or 8-DHC was detected. Another trial of 4 children (aged 6 weeks to 28 months) with SLOS reported significant decreases in both 7-DHC (mean 67% decreased) and 8-DHC (mean 50% decrease) at 35 weeks. The beneficial effects of cholesterol supplementation on varied clinical outcomes are far from established. In six patients followed for 2 years (aged birth to 11 years), clinical improvement in growth (acceleration in weight, height and head circumference) and neurodevelopmental status (a more rapid rate of progress) was observed. Other observational studies have documented improvements after cholesterol supplementation for the following: improved growth, reduced photosensitivity, increased nerve conduction velocity, improved tone, achievement of ambulation, developmental cognitive and behavioral changes. The only published double blind, placebo-controlled trial of cholesterol supplementation, performed in 10 individuals (aged 4.6 years to 19.9 years), found no measurable reduction of behavioral abnormalities over a period of about 2.5 months. A second unblinded study reported that 6 years of supplementation in 14 children with SLOS did not improve developmental progress. (Tier 3) [1]

The safety and efficacy of simvastatin therapy in patients with SLOS was assessed in a randomized, double-blind, placebo-controlled trial that noted improvement in the levels of 7-DHC and the 7-DHC/cholesterol ratio and significant improvement (p=0.017) on the irritability subset of the Aberrant Behavior Checklist-C when individuals were on simvastatin. However, while simvastatin appears to be safe in individuals with SLOS in this study, it is not a generally recommended therapy. (Tier 3) [1]

Surveillance

The following surveillance is recommended in individuals with SLOS:
• Feeding: Measurement of growth parameters and evaluation of nutritional status and safety of oral intake (each visit)
• Gastrointestinal: Monitor for constipation (each visit) and assessment of cholesterol, serum concentration of 7-DHC, and serum amino transferases (AST and ALT) (every 3-4 months in 1st few years of life, 2x/year thereafter)
• Development: Monitor developmental progress and educational needs (age appropriate development ≥2x/year until age 3 years; annually thereafter)
• Psychiatric/behavioral: Behavioral assessment for anxiety, attention and aggressive or self-injurious behavior (each visit)
• Neurologic: Assess for new manifestations such as seizures, changes in tone, movement disorders (each visit)
• Musculoskeletal: Physical medicine, PT/OT assessment of mobility, self-help skills (each visit)
• Genitourinary: Monitor for urinary tract infections and gonadal location (as clinically indicated)
• Dental: Evaluation by dentist (frequency - ≥2x/year starting at age 3 years)
• Endocrine: Assessment for signs of puberty and progression through puberty (start at age 10 until adulthood)
• Other: Assess family need for social work support (eg – palliative/respite care, home nursing, other local resources) and care coordination (each visit). (Tier 4) [1]

Circumstances to Avoid

Treatment with haloperidol may exacerbate the biochemical sterol abnormalities in individuals with SLOS and cause an increase in symptoms. Other drugs in this class will cause the same change in sterol levels. Other psychotropic drugs shown to elevate 7-DHC are trazodone and aripiprazole. Thus, one must weigh the benefit of such medications against the potential negative side effects. (Tier 3) [1]

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. (Tier 4) [1]

3. What is the chance that this threat will materialize?

Mode of Inheritance

Autosomal Recessive [1, 2, 3, 4]

Prevalence of Genetic Variants

The population prevalence of DHCR7 pathogenic variants was not available. However, the carrier frequency in North America is estimated as 1%. In addition, up to 99% of patients with SLOS are estimated to have at least one pathogenic variant in DHCR7. (Tier 3) [1]

A study among 262,399 individuals undergoing expanded carrier screening reported carrier frequencies of 1 in 43 in Ashkenazi Jewish and 1 in 54 in Northern European populations indicating the carrier frequency may be closer to 2%. (Tier 5) [6]

Penetrance

The plasma cholesterol concentration is decreased in most patients with SLOS, however, 10% have normal cholesterol levels. (Tier 3) [1, 3]

The frequency of some features of SLOS have been reported:
• Autism spectrum disorders: 46-75%
• Congenital heart defect: 50%
• Hypospadias and/or bilateral cryptorchidism (in males): 50%
• Postaxial polydactyly: 25%-50%
• External female genitalia with a 46,XY karyotype: 20%-25%
• Cataract (may be congenital or develop acutely): 20%
• Holoprosencephaly: 5% (Tier 3) [1]

The frequency of some features of SLOS have been reported:
• 2-3 toe syndactyly: >99%
• Growth restriction: >90%
• Anteverted nares: 90%
• Microcephaly: 80%-84%
• Cleft palate: 40%-50%
• Bifid uvula: 33%
• Hypotonia: 40%-50%
• Renal anomalies: 25% (Tier 4) [1, 2]

Relative Risk

Information on relative risk was not available for the Pediatric context.

Expressivity

The significant variation seen in severity, even among individuals with similar pathogenic variants, suggests influences on phenotype other than DHCR7 pathogenic variants. (Tier 3) [1, 3]

Clinical variability is noted even within families, as siblings with SLOS have been reported with medical and developmental problems of different degrees. (Tier 4) [1]

4. What is the Nature of the Intervention?

Nature of Intervention

Cholesterol supplementation can include egg yolk or crystalline cholesterol in an oil-based or aqueous solution. Cholesterol supplementation is reported to have minimal side effects. [1]

5. Would the underlying risk or condition escape detection prior to harm in the setting of recommended care?

Chance to Escape Clinical Detection

Affected females, who lack the genital abnormalities seen in affected males, may be under-ascertained. In addition, the spectrum of phenotype is wide and mild cases may be under-ascertained. (Tier 4) [1, 3]

Mildly affected patients may have 7-DHC concentrations in the upper normal range and only marginally elevated 8-DHC concentrations. Very rarely, even patients with a classical phenotype have borderline sterol concentrations. (Tier 3) [1, 3]

Date of Search: 06.03.2020

Reference List

1. Nowaczyk MJM, Wassif CA. Smith-Lemli-Opitz Syndrome. GeneReviews®. (Year1993)

2. Smith-Lemli-Opitz syndrome. Orphanet encyclopedia, http://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=en&Expert=818

3. Witsch-Baumgartner M, Sawyer H, Haas D. Clinical utility gene card for: Smith-Lemli-Opitz Syndrome [SLOS]. Eur. J. Hum. (Genet)

4. Online Medelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. DEAFNESS, AUTOSOMAL RECESSIVE 57; DFNB57. MIM: 618003: 2018 Jun 04. World Wide Web URL: http://omim.org.

5. Online Medelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. 7-DEHYDROCHOLESTEROL REDUCTASE; DHCR7. MIM: 602858: 2015 Oct 12. World Wide Web URL: http://omim.org.

6. Lazarin GA, Haque IS, Evans EA, Goldberg JD. Smith-Lemli-Opitz syndrome carrier frequency and estimates of in utero mortality rates. Prenat. (Diagn)