Smith-Lemli-Opitz Syndrome Workup

Updated: Sep 24, 2021
  • Author: Robert D Steiner, MD, FAAP, FACMG; Chief Editor: Luis O Rohena, MD, PhD, FAAP, FACMG  more...
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Laboratory Studies


Fetal ultrasonography may reveal anomalies suggestive of Smith-Lemli-Opitz syndrome (SLOS). When clinical suspicion arises, or if Smith-Lemli-Opitz syndrome was present in a previous pregnancy, confirmation of diagnosis is available with measurements of amniotic fluid or chorionic villous 7DHC content. In addition, enzyme activity can be measured in chorionic villi. Mutation analysis for prenatal diagnosis could also be considered, but this is most likely to be helpful if a proband in the family has had previously identified DHCR7 gene mutations.

Confirmatory prenatal diagnostic testing is currently available by genetic mutation analysis.

Low maternal serum unconjugated estriol levels or a pattern of maternal serum triple or quadruple screen markers suggestive of trisomy but with normal karyotype is a marker for Smith-Lemli-Opitz syndrome or steroid sulfatase deficiency. Shackleton reported the unique presence of equine estriols in the maternal urine during pregnancy of a fetus affected by Smith-Lemli-Opitz syndrome, potentially allowing noninvasive prenatal screening for Smith-Lemli-Opitz syndrome. [30]


Smith-Lemli-Opitz syndrome is usually suspected clinically, but the diagnosis must be confirmed by biochemical and/or molecular genetic studies. Plasma total cholesterol and/or low-density lipoprotein (LDL) cholesterol levels may be low but are not universally low. Measurement of plasma sterols, including, at a minimum, cholesterol and 7DHC, is the diagnostic test for Smith-Lemli-Opitz syndrome.

The striking elevation of plasma 7DHC on sterol analysis by gas-liquid chromatography, gas chromatography/mass spectrometry, or tandem mass spectrometry is pathognomonic. The characteristic pattern of low plasma cholesterol levels and the extremely high 7DHC levels define Smith-Lemli-Opitz syndrome. 7DHC is present in plasma in healthy individuals in trace quantities. Cholesterol levels are not always below the reference range; screening by plasma cholesterol measurement alone should be discouraged.

Sterol analysis has proven useful for diagnosing patients with the classical phenotype, prenatal cases identified through maternal serum screening, and patients with more subtle physical findings and intellectual disability. In the United States, a handful of laboratories perform this analysis, and a timely query to the Genetic Testing Registry is extremely useful in identifying laboratories performing this analysis.

Mutational analyses/molecular genetic testing are useful confirmatory tests and important for prenatal diagnosis in a family with a known mutation and, when appropriate, for carrier testing.

Reserve enzyme analysis for atypical cases or cases yielding equivocal results by other methods.

Electrolytes and, possibly, cortisol and adrenocorticotropic hormone (ACTH) may be useful in ruling out adrenal insufficiency.


Imaging Studies

See the list below:

  • Brain MRI or CT scanning may reveal structural brain malformations.

  • Renal ultrasonography may be useful in identifying renal anomalies.

  • Abdominal ultrasonography may help identify or rule out pyloric stenosis.

  • Barium swallow may help identify or rule out pyloric stenosis.

  • Abdominal radiography may be useful when Hirschsprung disease is suspected.

  • Barium enema may be useful when Hirschsprung disease is suspected.

  • Chest radiography is important in looking for congenital heart disease and/or congenital pulmonary abnormalities.

  • Genitourinary ultrasonography may be important in identifying genitourinary anomalies.


Other Tests

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  • Slit lamp examination may reveal strabismus, cataracts, ptosis, and/or optic nerve abnormalities.

  • Developmental or intelligence quotient (IQ) testing may reveal intellectual disability or learning disabilities.



See the list below:

  • Rectal biopsy may be useful when Hirschsprung disease is suspected.

  • Echocardiography and ECG are indicated in every newborn with Smith-Lemli-Opitz syndrome because the incidence of congenital heart disease is quite high.

  • Obtaining a brainstem-evoked response or audiogram is important in Smith-Lemli-Opitz syndrome because hearing loss is not uncommon.

  • Cultured fibroblasts can be used for enzymatic testing to provide diagnostic confirmation in atypical cases. Skin biopsy and enzyme analysis are not normally required when clinical features of Smith-Lemli-Opitz syndrome are present in a patient with elevated levels of 7DHC in the blood.


Histologic Findings

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  • Histologic findings have not generally been useful in the diagnosis of Smith-Lemli-Opitz syndrome, and little literature is available that describes histologic findings in Smith-Lemli-Opitz syndrome. The gross anatomic findings and biochemical findings are of much greater importance.

  • In one case reported by Ness et al, the liver showed severe cholestasis of the hepatocytes, distorted hepatic architecture, septal fibrosis, and extramedullary hematopoiesis. [31] Iron and bilirubin deposition were observed in the hepatocytes. Thymic sections showed marked depletion of thymocytes. The brain was small, weighed 250 g, and showed marked yellow bile staining of the meninges. The gyral pattern was strikingly abnormal. Coronal sections showed mild hydrocephalus with porencephaly, absence of the corpus callosum, and a small hypoplastic cerebellum. Bile staining was present in the basal ganglia and dentate nucleus of the cerebellum, consistent with kernicterus. The cortex corresponding to the grossly abnormal gyral pattern showed abnormal neuronal migration with 4 instead of 6 cortical layers. A severe lack of myelination was also evident using anti-LDL receptor sera.

  • The pancreas in Smith-Lemli-Opitz syndrome may be enlarged and have hyperchromatic nuclei in the islet cells. Severely affected infants have defective or absent pulmonary lobation.