This study aims to evaluate the efficacy of routinely identifying Smith-Lemli-Opitz Syndrome (SLOS) prenatally. This serious inherited metabolic disorder (birth prevalence 1:20,000) is characterized by moderate to severe mental retardation and congenital anomalies. Two circumstances now make it possible to carry out the proposed intervention trial. First, the cause of SLOS is now known to be a defect in the conversion of 7-dehydrocholesterol to cholesterol. This discovery makes it possible to confirm the diagnosis biochemically by measuring cholesterol precursors in the serum of affected individuals and in amniotic fluid. Secondly, the array of maternal serum analytes currently measured routinely to screen for Down syndrome in 2,000,000 U.S. pregnancies annually includes unconjugated estriol (uE3). This analyte requires cholesterol as a precursor, and its concentration in maternal serum is lower when the fetus has SLOS. The major barrier to identifying SLOS prenatally is the absence of sound screening methodology that takes into account the detection rate, the false positive rate, and the prevalence. The investigators have developed a model, based on actual data from SLOS pregnancies, and propose to test it in 1,000,000 pregnancies in which maternal serum uE3 (and other) measurements are currently being done routinely. The screening false positive rate is projected to be 0.2 percent, the detection rate 57 percent, and the odds of being affected given a positive result 1:70. These rates all compare favorably with routine prenatal screening tests. Diagnostic testing in amniotic fluid is highly reliable and will correctly identify the affected and unaffected pregnancies. In the proposed trial, the investigators will introduce this SLOS model into several major U.S. prenatal screening centers, and develop informational materials for both physicians and patients. Diagnostic testing will be provided by participating expert laboratories. It will also be possible, for the first time, to determine whether SLOS diagnostic studies can be carried out in maternal urine, rather than amniotic fluid, thereby avoiding invasive procedures. The study will also aid in refining prevalence estimates by race and ethnicity, and will determine whether several rare disorders in the cholesterol biosynthetic pathway would be detectable.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Project (R01)
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Epidemiology and Disease Control Subcommittee 2 (EDC)
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Oster-Granite, Mary Lou
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Foundation for Blood Research
United States
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Marcos, Josep; Craig, Wendy Y; Palomaki, Glenn E et al. (2009) Maternal urine and serum steroid measurements to identify steroid sulfatase deficiency (STSD) in second trimester pregnancies. Prenat Diagn 29:771-80
Shackleton, Cedric H L; Marcos, Josep; Palomaki, Glenn E et al. (2007) Dehydrosteroid measurements in maternal urine or serum for the prenatal diagnosis of Smith-Lemli-Opitz syndrome (SLOS). Am J Med Genet A 143A:2129-36
Craig, Wendy Y; Haddow, James E; Palomaki, Glenn E et al. (2007) Major fetal abnormalities associated with positive screening tests for Smith-Lemli-Opitz syndrome (SLOS). Prenat Diagn 27:409-14
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