An autosomal recessive polymalformative syndrome due to the inability to make cholesterol. Affects the central nervous system (CNS) (white matter) and characterized by growth retardation, developmental delay, severe dysphagia, microcephaly, micrognathia, cleft palate, cataracts, ptosis, polysyndactyly and syndactyly of the second and third toes, and congenital heart defects (transposition of the great vessels is frequent). Congestive heart failure and liver failure are not uncommon.
RSH Syndrome; SLOS I Syndrome; 7-Dehydrocholesterol Reductase Deficiency.
1:20,000 to 1:60,000 live births in the United States among white people. Smith-Lemli-Opitz Syndrome is uncommon in Hispanic population. Carrier frequency for Smith-Lemli-Opitz Syndrome is approximately 1 in 30 in individuals of northern European descent, suggesting a disease incidence between 1:5,000 and 1:18,000 in Europe. Internationally, Smith-Lemli-Opitz Syndrome has been described in patients from the United States, Japan, South America, and Canada.
Results from a mutation in either the DHCR7 (7-dehydrocholesterol-delta7-reductase) gene on 11q12-13. The classic paradigm is an inborn error of metabolism, which includes the accumulation of a toxic precursor (7DHC) leading to the deficiency in production of an essential product (cholesterol). The absence in cholesterol can be implicated in the production of all the anomalies described (polymalformative syndrome) and results in intrauterine growth retardation. Cholesterol is required for normal development because of its involvement in cell and mitochondrial membranes, as well as steroid metabolism and myelination.
As a result of the defect in cholesterol metabolism, serum cholesterol levels are very low and levels of 7-dehydrocholesterol (a cholesterol precursor) are high in serum as well as any other tissue specimens. This biochemical finding associated with the clinical findings confirms the diagnosis of Smith-Lemli-Opitz Syndrome. The mortality/morbidity is associated with stillbirths, or spontaneous abortion, or immediately after birth from multiorgan failure (during the first week of life). Causes of death include pneumonia, lethal congenital heart defect (most often transposition of the great vessels), congestive heart failure (not uncommon), and hepatic failure.
Prognosis is poor. Outcome is correlated to plasma cholesterol concentrations. Plasma cholesterol greater than 1.7 mmol/L has milder features, concentrations less than 0.35 mmol/L are fatal. Neuromuscular: initially hypotonia followed later by hypertonia; mental deficiency can be severe (IQ as low as 20); seizures and generalized nerve demyelination. Cardiovascular: malformations may be present in up to 44% of cases. The incidence of atrioventricular canal defects and anomalous pulmonary venous drainage is relatively high. Craniofacial: microcephaly, strabismus, epicanthic folds, elfin facies, ptosis, low-set ears, and micrognathia may be present. Genital tract: Developmental anomalies of the genital tract (particularly male) are common. Gastrointestinal/Nutrition: feeding difficulties and failure to thrive; Hirschsprung Disease may be more common.