Endocrine Abstracts (2006) 11 P748

Prenatal diagnosis of the “low-oestriol” disorders Smith-Lemli-Opitz syndrome (SLOS), oxidoreductase deficiency (ORD) and sulfatase deficienciy (STSD)

CHL Shackleton1, W Craig2, W Arlt3 & J Marcos1

1Children’s hospital Oakland Research Institute, Oakland, CA, United States; 2Foundation for Blood Research, Scarborough,Maine, United States; 3Division of Medical Sciences, University of Birmingham, Birmingham, United Kingdom.

Introduction: Unconjugated oestriol (uE3) is often measured in maternal serum during second trimester prenatal screening. While oestriol itself has little physiological importance, low values can indicate the presence of a disorder in feto-placental synthesis with potential health implications. Fetal steroids pass through the maternal circulation and into the urine so analysis of maternal fluids can be used for diagnosing causes of low oestriol.

Methods: Samples of urine and serum were obtained from >1,000 pregnant women who exhibited low uE3 (<0.3 MoM). They were primarily from a multicenter study funded to investigate the feasibility of screening for SLOS. After solid phase extraction (SPE) of 1 ml samples, conjugated steroids were hydrolyzed, the free compounds extracted by SPE, derivatized and analyzed by GC/MS. Local ethical committee permissions were obtained for these studies.

Results: SLOS diagnosis was by measuring 7- and 8-dehydro-pregnanetriol and dehydro-oestriol. The key parameter for STS was excessive excretion of 16-hydroxyDHEA sulfate and ORD could be diagnosed by quantifying a pregnenolone metabolite epiallo-pregnanediol. Different quantitative ratios between known steroids (‘precursor metabolite’/‘product metabolite’) have been tested for delineating affected and non-affected pregnancies. Cut-off values for these ratios in urine and serum were established in order to optimize the sensitivity and specificity of the method. The assay false positive rate for SLOS was 0%, and for STS was about 3.2%. The false negative rate for both SLOS and STS was 0%. Through quantifying these selected ratios 5 samples positive for SLOS, and 182 positive for STS were detected. Confirmatory diagnostic data were available through independent laboratory testing and/or postnatal clinical examination for all SLOS cases and 50% of STS cases. Three cases of ORD were found, independent of the primary multi-center program.

Conclusions: For SLOS, STS and ORD non-invasive second trimester diagnosis is readily attainable through GC/MS analysis.

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