Smith-Lemli-Opitz Syndrome Clinical Presentation

Updated: Apr 01, 2015
  • Author: Robert D Steiner, MD; Chief Editor: Luis O Rohena, MD  more...
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The following signs and symptoms may be noted:

  • Lethargy
  • Obtundation or coma
  • Respiratory failure
  • Hearing loss
  • Visual loss
  • Vomiting
  • Feeding difficulties
  • Failure to thrive
  • Constipation
  • Cyanosis
  • Congestive heart failure
  • Photosensitivity

Neuropsychiatric and neurodevelopmental abnormalities are common and include variable mental retardation, aberrant behavior, and autism.

  • The aberrant behavior of the older child can include antisocial, self-destructive, and violent acts or withdrawal, self-stimulation, and frank autism. Indeed, autism is quite common in Smith-Lemli-Opitz syndrome (SLOS). [18]
  • The risk for neuropsychiatric disorders also appears to be increased in adults with Smith-Lemli-Opitz syndrome.


Intrauterine growth retardation (IUGR) is common, as is short stature or abnormally low weight for height, altered muscle tone (hypotonia), and often a distinctive shrill cry.

Growth charts for SLOS have been published. [19] Rarely, hydrops fetalis occurs.

Congenital anomalies evident upon physical examination may include the following:

  • Microcephaly
  • Intracranial germinoma [20]
  • Broad nasal tip with anteverted nostrils
  • Micrognathia
  • Ptosis of eyelids
  • Epicanthal folds
  • Strabismus
  • Cataracts (may also develop postnatally [21] )
  • Broad maxillary alveolar ridges
  • Slanted or low-set ears
  • Syndactyly of second and third toes
  • Postaxial polydactyly
  • Hypospadias or cryptorchidism in males and, occasionally, complete sex reversal (ie, 46,XY females)
  • Cleft palate
  • Heart murmur or cyanosis or respiratory distress secondary to congenital cardiac defects
  • Respiratory distress secondary to pulmonary anomalies

Considerable phenotypic variance may be present within affected families, between individuals, and over time in the neonate, infant, child, and adult with Smith-Lemli-Opitz syndrome. Mildly affected individuals may exhibit only subtle dysmorphic facies and learning disabilities, whereas severely affected individuals may have complete sex reversal, lethal cardiac and brain malformations, microcephaly, cleft palate, and multiorgan system failure.



Analysis of family pedigrees has revealed that Smith-Lemli-Opitz syndrome is transmitted in an autosomal recessive fashion as an multiple congenital anomaly (MCA)/MR syndrome. Three different groups reported the molecular genetic basis for Smith-Lemli-Opitz syndrome simultaneously.

Smith-Lemli-Opitz syndrome is caused by mutations in the DHCR7 gene, the gene that codes for the enzyme DHCR7 that normally converts 7DHC to cholesterol in the final step of the cholesterol synthetic pathway. Mapping of the DHCR7 gene established the chromosomal position on band 11q12.13. Subsequent mutational analyses by several groups have identified a wide variety of different mutations within the DHCR7 gene, with several common mutations. [22]

Most patients with Smith-Lemli-Opitz syndrome have proven to be compound heterozygotes. This genetic heterogeneity points to possible phenotype-genotype corollaries.

The cause of the intellectual disability, behavioral abnormalities, and malformations is unclear, but cholesterol deficiency, accumulation of potentially toxic precursors, and/or oxysterols or esterified oxysterols may be implicated. [23]