Handbook of Genetic Counseling/Smith-Lemli-Opitz Syndrome

Smith-Lemli-Opitz Syndrome

Contracting

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

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).

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.

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

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.

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

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)

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.