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? Psychosocial 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.