Handbook of Genetic Counseling/Smith-Lemli-Opitz Syndrome
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- 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??)
- 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
- 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
- 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 
- Demyelination in the cerebral hemispheres, cranial nerves, and peripheral nerves.
- 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).
- Increased 7DHC levels in blood or other tissues
- Clinical evaluation
- 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
- Cleft palate repair at age 12-18 months
- If there is a suggestion of visual compromise from ptosis, cataracts, or any other abnormality, referral to an ophthalmologist is recommended.
- Specific to malformation identified
- Special consideration should be given in those cases where prognosis is poor.
- Surgical referral and standard treatment for each specific condition
- 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.
- Simple excision of supernumerary digits
- 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: firstname.lastname@example.org
- Cunniff C, Chapter 21. (2001). Management of Genetic Syndromes. Ed. Cassidy SB and Allanson JE. New York: John Wiley and Sons.
- 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.