# Handbook of Genetic Counseling/Smith-Lemli-Opitz Syndrome

Smith-Lemli-Opitz Syndrome

## Contracting

* 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%

## Incidence

* 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).

## Testing

* 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
    http://www.smithlemliopitz.org

## References

* 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.

## Notes

The information in this outline was last updated in 2002.