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Smith-Lemli-Opitz Syndrome.

Authors

Nowaczyk MJM1.

Source

GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2019.
1998 Nov 13 [updated 2013 Jun 20].

Author information

1
Associate Professor, Molecular Medicine & Pathology and Pediatrics, CCMG Program Director, Pediatrician and Clinical Geneticist, McMaster University, Hamilton, Canada

Excerpt

CLINICAL 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 pathogenic variants are known to cause SLOS. Sequence analysis of DHCR7 detects approximately 96% of known pathogenic variants.

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 pathogenic variants in the family are known. Prenatal testing for pregnancies at risk is possible using biochemical testing or molecular genetic testing if the pathogenic variants in the family are known.

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