Handbook of Genetic Counseling/Smith-Lemli-Opitz Syndrome

Smith-Lemli-Opitz Syndrome


  • Make small talk and establish rapport with the family.
  • Elicit the family's concerns. What issues would you like to discuss today?
  • Briefly outline the topics to be covered during the visit.

Eliciting Interim History

  • Interim Family History:
  • Have there been any new births, deaths, or diagnoses in the family?
  • Is there any consanguinity in the family?



Genetic Etiology

  • Autosomal recessive inheritance
  • Caused by a deficiency of the enzyme 7DHCR, the final enzymatic step in the cholesterol biogenesis pathway.
  • Molecular Genetics
  • The gene encoding 7DHCR is located at 11q12-13, and is named DHCR7.
  • 19 different mutations have been reported (including 13 missense, 5 frameshift, and 1 nonsense mutation).
  • Milder phenotypes can be seen if the mutation renders the enzyme partially active.
  • The mechanism leading to the manifestations seen appears to be the result of a deficiency in cholesterol.
  • Cholesterol is a critical component of myelin and other CNS proteins
  • Cholesterol is also a precursor to the sex steroids, estrogen and testosterone, thus hypocholesterolemia results in a deficiency of these hormones.
  • The derangement of sterol composition in the cell membranes may result in abnormal cell-to-cell interactions in the developing embryo. (? Explains polydactyly and cleft palate and growth deficiency seen in some??)
  • Penetrance:
  • 100% penetrant with variable expressivity

Recurrence Risks

  • The risk of recurrence is 25%


  • The incidence is estimated to be 1:40,000- 1:60,000
  • The carrier frequency is approximately 1:122
  • More common in people of European background, and has been seen rarely in those of African American and Asian descent.
  • There is an excess of males diagnosed with Smith-Lemli-Opitz syndrome (bias of ascertainment as a result of hypogenetalism seen in boys).

Diagnostic Criteria and Clinical Features

  • Diagnosis is usually made based on the recognition of a constellation of characteristic clinical features, with diagnostic confirmation based on measurement of elevated 7DHC in plasma or other tissues.
  • The cardinal features include:
  • Prenatal growth deficiency with subsequent failure to thrive
  • Developmental delay/ mental retardation (moderate to severe)
  • Poor muscle tone (hypotonia)
  • Characteristic facies (change with age and are difficult to recognize in adulthood)
  • Microcephaly with narrow bifrontal diameter
  • Ptosis (50%)
  • Down-slanting palpebral fissures
  • Short nose with depressed nasal bridge, with anteverted nares
  • Low set and posteriorly rotated ears
  • Retrognathia
  • Cleft palate (37-52%)
  • Cardiac defects (36-38%)
  • AV canal defects, and total anomalous pulmonary venous return defects
  • Gastrointestinal anomalies (25%)
  • Pyloric stenosis, malrotation, Hirschsprung disease
  • Polydactyly
  • Cutaneous 2-3 toe syndactyly (90%)
  • Genital abnormalities (70%)
  • Hypospadias, cryptorchidism, micropenis, hypoplastic scrotum, and microutethra.
  • Upper tract anomalies (57%) include hydronephrosis, renal cystic dysplasia, renal duplication, renal agenesis, and reflux.

Occasional Abnormalities

  • Seizures
  • Demyelination in the cerebral hemispheres, cranial nerves, and peripheral nerves.
  • Cataracts
  • Dislocation of the hip

Natural History

  • Congenital onset
  • Many are born in breech presentation
  • Stillbirth and early neonatal death are not uncommon
  • Feeding difficulty and vomiting, hypotonia, and irritable behavior with shrill screaming have been frequently reported problems in infancy
  • Of those who survive, 20% die within the first year.
  • Death is commonly related to pneumonia
  • The degree of mental deficiency is usually moderate to severe (adults described had IQ's in the 20's).


  • Diagnostic:
  • Increased 7DHC levels in blood or other tissues
  • Clinical evaluation
  • Prenatal:
  • Measurement of elevated 7DHC in amniotic fluid or chorionic villi
  • Carrier testing:
  • Not currently available
  • Differences of 7DHC in heterozygotes is indistinguishable from homozygotes (normal).
  • With the discovery of the gene, it is hoped that mutation analysis will assist in heterozygote identification.

Surveillance, Management, and Treatment Options

  • Growth and Feeding:
  • Adequate caloric intake should be ensured.
  • Consideration should be given to cholesterol supplementation to improve weight gain.
  • Oral-motor training with OT to help patient take food orally
  • G-tube to assist in feeding if oral intake is not adequate
  • Development and behavior
  • EI, special education programs, and therapies to enhance the developmental potential of the patient.
  • Supervised setting for adults (group home) - improved behavior and development has been noted in patients receiving cholesterol supplementation
  • Craniofacial
  • Cleft palate repair at age 12-18 months
  • Ophthalmologic
  • If there is a suggestion of visual compromise from ptosis, cataracts, or any other abnormality, referral to an ophthalmologist is recommended.
  • Cardiovascular
  • Specific to malformation identified
  • Special consideration should be given in those cases where prognosis is poor.
  • Gastrointestinal
  • Surgical referral and standard treatment for each specific condition
  • Genitourinary
  • Ultrasound of urinary tract at diagnosis
  • Treatment is dependent upon the condition identified
  • Repair of hypospadias
  • Observe boys with cryptorchidism to see if spontaneous descent occurs
  • Determine chromosomal sex if ambiguous genitalia is present.
  • Musculoskeletal
  • Simple excision of supernumerary digits
  • Skin
  • Cholesterol treatment has been reported to cause a decrease in photosensitivity and skin rashes.
  • Limit length of sun exposure to avoid sun photosensitivity

Differential Diagnosis

  • Chromosomal abnormalities including Trisomy 18 (Growth deficiency, cleft palate, and DD) and Trisomy 13 (Growth retardation, polydactyly, and DD)
  • Noonan syndrome (short stature, DD, cardiac defects, cryptorchidism)

Support Groups

  • Smith-Lemli-Opitz/RSH Foundation
P.O. Box 212
Georgetown, MA 01833
(978) 352-5885
Contact person: Cynthia Gold
email: info@smithlemliopitz.org


  • Cunniff C, Chapter 21. (2001). Management of Genetic Syndromes. Ed. Cassidy SB and Allanson JE. New York: John Wiley and Sons.
  • www.geneclinics.org
  • Jones KL (1997). Smith's Recognizable Patterns of Human Malformation. Philadelphia: W.B. Saunders Company.



The information in this outline was last updated in 2002.