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Smith-Lemli-Opitz syndrome

Orpha number ORPHA818
Synonym(s) 7-dehydrocholesterol reductase deficiency
RSH syndrome
SLOS
Prevalence Unknown
Inheritance Autosomal recessive
Age of onset Infancy
Neonatal
ICD-10
  • Q87.1
ICD-O -
OMIM
UMLS
  • C0175694
  • C2713347
MeSH
  • D019082
MedDRA -

Summary

Smith-Lemli-Opitz syndrome (SLOS) is characterized by multiple congenital anomalies, intellectual deficit, and behavioral problems. SLOS is most common in central and northern Europe with an estimated incidence of around 1/ 20,000 to 1/ 40,000 births. The disease is present at birth, but may be detected in later childhood or adulthood in mild forms. Patients present with growth retardation and intellectual deficit. Behavioral problems include multiple autistic traits, hyperactivity, self-injurious behavior and sleep disturbances. The structural brain anomalies may include hypoplasia or absence of the corpus callosum, and holoprosencephaly. Microcephaly (80% of cases), bitemporal narrowing, ptosis, a broad nasal bridge, short nasal root, anteverted nares (90% of cases), a small chin, and micrognathia are common craniofacial features. Occasionally, cataract, strabismus, and nystagmus are observed. Other clinical features include cleft palate or bifid uvula (1/3 of patients), photosensitivity, rhizomelia and postaxial polydactyly of the hands or feet, syndactyly of the 2nd and 3rd toes (95% of cases), and short and proximally placed thumbs. Genital anomalies (small penis, hypospadias, ambiguous genitalia) are frequent in males (70% of cases). Cardiovascular anomalies (atrial and ventricular septal defects, patent ductus arteriosus, atrioventricular canal) can be present. Gastrointestinal anomalies including poor feeding, gastroesophageal reflux, pyloric stenosis, malrotation, and colonic aganglionosis are frequent. SLOS is due to an inborn error of cholesterol synthesis and is caused by mutations in the DHCR7 gene (11q13.4) leading to deficiency of the enzyme 3 beta-hydroxysterol-delta 7-reductase that converts 7-dehydrocholesterol (7DHC) to cholesterol. Transmission is autosomal recessive. Diagnosis is based on the detection of elevated 7DHC levels in plasma or tissues. Mutation analysis confirms the diagnosis. Imaging studies (CT, MRI, echocardiogram) may be performed to detect malformations. The differential diagnosis includes lathosterolosis, desmosterolosis, Dubowitz syndrome, Cornelia De Lange syndrome, oculo-digito-esophago-duodenal syndrome, Noonan syndrome, Pallister-Hall syndrome, trisomy 13 and trisomy 18 (see these terms), and pseudotrisomy 13. Prenatal diagnosis may be suspected at fetal ultrasonography and should be confirmed by analysis of amniotic fluid or chorionic villous samples, measurements of 7DHC content and mutation analysis if DHCR7 mutations have already been identified in the family. Management is symptomatic and most patients are treated with dietary cholesterol supplementation. Treatment trials are underway investigating combined treatment with cholesterol supplementation and a HMG CoA reductase inhibitor (simvastatin). Surgery is proposed in case of secondary problems due to malformations. Prognosis depends on the severity of the disease and on the associated malformations. Heart disease and brain malformations may be lethal. Some individuals live into adulthood. Mildly affected individuals may be able to live and work in a group home setting.

Expert reviewer(s)

  • Dr Simona BIANCONI
  • Dr Forbes PORTER

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Detailed information

Summary information
Practical genetics
  • EN (2008,pdf)
Guidance for genetic testing
  • EN (2013,pdf)
Clinical genetics review
  • EN (2013)
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