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