eMedicine Specialties > Pediatrics: Genetics and Metabolic Disease > Genetics

Smith-Lemli-Opitz Syndrome: Differential Diagnoses & Workup

Author: Robert D Steiner, MD, Professor, Departments of Pediatrics and Molecular and Medical Genetics, Vice Chair for Research, Department of Pediatrics, Oregon Health & Science University; Director and Consulting Staff, Metabolic Bone Disease Clinic, Shriner's Hospital and Doernbecher Children's Hospital; Co-Director: Pediatric and Child Health Research, Oregon Clinical and Translational Research Institute (CTSA).
Contributor Information and Disclosures

Updated: May 12, 2009

Differential Diagnoses

Adrenal Hypoplasia
Hirschsprung Disease
Adrenal Insufficiency
Hydrops Fetalis
Ambiguous Genitalia and Intersexuality
Hypospadias
Androgen Insensitivity Syndrome
Jaundice, Neonatal
Cholestasis
Malnutrition
Cleft Lip and Palate
Microphallus
Cognitive Deficits
Neonatal Sepsis
Congenital Adrenal Hyperplasia
Pervasive Developmental Disorder
Denys-Drash Syndrome
Pervasive Developmental Disorder: Autism
Extremely Low Birth Weight Infant
Pierre Robin Malformation
Failure to Thrive
Short Stature
Fulminant Hepatic Failure
Trisomy 18
Gastroesophageal Reflux
Growth Failure
Hearing Impairment

Other Problems to Be Considered

Abetalipoproteinemia
Chromosome anomaly
Cryptorchidism
Growth retardation
Hydrolethalus syndrome
Hypobetalipoproteinemia
Language disorder, expressive
Language disorder, mixed
Language disorder, receptive
Meckel syndrome
Pallister-Hall syndrome
Steroid sulfatase deficiency
Ullrich-Feichtiger syndrome

Workup

Laboratory Studies

  • Prenatal
    • 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 in only a few laboratories.
    • 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.15
  • Postnatal
    • Smith-Lemli-Opitz syndrome is usually suspected clinically, but biochemical studies are necessary for confirmation of diagnosis. 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 least 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 or gas chromatography/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 mental retardation (MR). In the United States, a handful of laboratories perform this analysis, and a timely query to GeneTests is extremely useful in identifying laboratories performing this analysis.
    • Mutational analyses have revealed considerable heterogeneity, rendering impractical mutational analysis as initial testing for diagnostic purposes at this point, although molecular genetics testing may prove useful for prenatal diagnosis via chorionic villous sampling (CVS) or amniocentesis in a specific family with a known mutation.
    • 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

  • 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

  • Slit lamp examination may reveal strabismus, cataracts, ptosis, and/or optic nerve abnormalities.
  • Developmental or intelligence quotient (IQ) testing may reveal MR or learning disabilities.

Procedures

  • 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

  • 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.16 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.

More on Smith-Lemli-Opitz Syndrome

Overview: Smith-Lemli-Opitz Syndrome
Differential Diagnoses & Workup: Smith-Lemli-Opitz Syndrome
Treatment & Medication: Smith-Lemli-Opitz Syndrome
Follow-up: Smith-Lemli-Opitz Syndrome
Multimedia: Smith-Lemli-Opitz Syndrome
References
Further Reading
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Keywords

Smith-Lemli-Opitz syndrome, SLOS, RSH syndrome, multiple congenital anomalies/mental retardation syndrome, MCA/MR, congenital malformations, dysmorphic facial features, microcephaly, toe syndactyly, learning disabilities, behavioral disabilities, DHCR7 gene, inborn error of metabolism, cyanosis, congestive heart failure, constipation, toxic megacolon, electrolyte disturbances, failure to thrive, cataracts, optic nerve abnormalities, pneumonia, lethal congenital heart defect, hepatic failure, lethargy, respiratory failure, intrauterine growth retardation, IUGR, hydrops fetalis, micrognathia, ptosis of eyelids, strabismus, hypospadias, cryptorchidism, cleft palate, treatment, diagnosis

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Contributor Information and Disclosures

Author

Robert D Steiner, MD, Professor, Departments of Pediatrics and Molecular and Medical Genetics, Vice Chair for Research, Department of Pediatrics, Oregon Health & Science University; Director and Consulting Staff, Metabolic Bone Disease Clinic, Shriner's Hospital and Doernbecher Children's Hospital; Co-Director: Pediatric and Child Health Research, Oregon Clinical and Translational Research Institute (CTSA).
Robert D Steiner, MD is a member of the following medical societies: American Academy of Pediatrics, American Association for the Advancement of Science, American College of Medical Genetics, American Society of Human Genetics, Oregon Medical Association, Society for Inherited Metabolic Disorders, Society for Pediatric Research, Society for the Study of Inborn Errors of Metabolism, and Western Society for Pediatric Research
Disclosure: Genzyme Honoraria Speaking and teaching; Genzyme Grant/research funds Other; Shire Honoraria Speaking and teaching; Actelion Honoraria Speaking and teaching; Biomarin Honoraria Speaking and teaching; Biomarin Consulting fee Consulting

Medical Editor

Elaine H Zackai, MD, Professor of Pediatrics, Professor of Obstetrics and Gynecology, Professor of Pediatrics in Human Genetics, University of Pennsylvania School of Medicine; Director, Clinical Genetics Center, University of Pennsylvania; Senior Physician and Director of Clinical Genetics, The Children's Hospital of Philadelphia
Elaine H Zackai, MD is a member of the following medical societies: American Cleft Palate/Craniofacial Association, American College of Medical Genetics, and American Society of Human Genetics
Disclosure: Nothing to disclose.

Pharmacy Editor

Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine
Disclosure: Pfizer Inc Stock Investment from financial planner; Avanir Pharma Stock Investment from financial planner ; WebMD Salary and stock Employment and investment from financial planner

Managing Editor

Robert Anthony Saul, MD, Clinical Professor, Department of Pediatrics, University of South Carolina; Senior Clinical Geneticist, Greenwood Genetic Center
Robert Anthony Saul, MD is a member of the following medical societies: American Academy of Pediatrics, American College of Medical Genetics, and American College of Physician Executives
Disclosure: Nothing to disclose.

CME Editor

Daniel Rauch, MD, FAAP, Director, Pediatric Hospitalist Program, Associate Professor, Department of Pediatrics, New York University School of Medicine
Daniel Rauch, MD, FAAP is a member of the following medical societies: Ambulatory Pediatric Association, American Academy of Pediatrics, and Society of Hospital Medicine
Disclosure: Baxter Honoraria Consulting

Chief Editor

Bruce Buehler, MD, Professor, Department of Pediatrics, Pathology and Microbiology, Executive Director, Hattie B Munroe Center for Human Genetics and Rehabilitation, University of Nebraska Medical Center
Bruce Buehler, MD is a member of the following medical societies: American Academy for Cerebral Palsy and Developmental Medicine, American Academy of Pediatrics, American Association on Mental Retardation, American College of Medical Genetics, American College of Physician Executives, American Medical Association, and Nebraska Medical Association
Disclosure: Nothing to disclose.

 
 
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