Pattern of secretion of pregnancy-associated plasma protein-A (PAPP-A) during pregnancies complicated by fetal aneuploidy, in vivo and in vitro

International audienceBackground: Pregnancy-associated placental protein-A (PAPP-A) is a metalloprotease which circulates as an hetero-tetramer in maternal blood. Its maternal serum concentration in fetal trisomy 21 is decreased during the first trimester, so that PAPP-A is a useful screening biomarker. However, the regulation of PAPP-A placental secretion is unclear. We therefore investigated the secretion of PAPP-A in pregnancies complicated by fetal aneuploidies, both in vivo and in vitro.Methods: Maternal serum collected between 10 WG and 33 WG during 7014 normal pregnancies and 96 pregnancies complicated by fetal trisomy 21, 18, and 13 were assayed for PAPP-A using the Immulite 2000xpi system®. The pregnancies were monitored using ultrasound scanning, fetal karyotyping and placental analysis. Villous cytotrophoblasts were isolated from normal and trisomic placenta and cultured to investigate PAPP-A secretion in vitro (n=6).Results: An increased nuchal translucency during the first trimester is a common feature of many chromosomal defect but each aneuploidy has its own syndromic pattern of abnormalities detectable at the prenatal ultrasound scanning and confirmed at the fetal examination thereafter. PAPP-A levels rise throughout normal pregnancy whereas in trisomy 21, PAPP-A levels were significantly decreased, but only during the first trimester. PAPP-A levels were decreased in trisomy 13 and sharply in trisomy 18, whatever the gestational age. In vitro, PAPP-A secretion was decreased in aneuploidy, and associated with decreased hCG secretion in Trisomy 21 and 18. These biochemical profiles did not appear to be linked to any specific histological lesions affecting the placenta.Conclusions: These profiles may reflect different quantitative and qualitative placental dysfunctions in the context of these aneuploidies

Prenatal diagnosis of Niemann-Pick type C disease: Current strategy from an experience of 37 pregnancies at risk

Thirty-seven pregnancies at risk for Niemann-Pick type C disease were monitored by study of cultured amniotic fluid cells (8 cases) or chorionic villus cells (29 cases) in 23 couples over the period 1984–91. An early protocol combined determination of sphingomyelinase activity with electron microscopy. The current strategy, based on the demonstration of specific abnormalities in intracellular processing of exogenous cholesterol, combines the study of the early phase (first 6 h) of LDL-induced cholesteryl ester formation and the histochemical evaluation (filipin staining after 24 h of LDL uptake) of the LDL-induced accumulation of unesterified cholesterol. Thirteen fetuses were predicted to be affected. Confirmation of the diagnosis was made by study of cholesterol processing in fetal skin fibroblast cultures and/or by demonstration of a characteristic lipid storage in fetal liver, already present at 14 w gestation. Definition of the biochemical phenotype (classical, variant, or intermediate) of the index case, with regard to cholesterol-processing abnormalities, is an absolute prerequisite to adequate genetic counseling in a given family. Prenatal diagnosis has now proved a safe procedure in the predominant (approximately 85%) group of families with the classical phenotype

Large-Scale Deletions and SMADIP1 Truncating Mutations in Syndromic Hirschsprung Disease with Involvement of Midline Structures

Hirschsprung disease (HSCR) is a common malformation of neural-crest–derived enteric neurons that is frequently associated with other congenital abnormalities. The SMADIP1 gene recently has been recognized as disease causing in some patients with 2q22 chromosomal rearrangement, resulting in syndromic HSCR with mental retardation, with microcephaly, and with facial dysmorphism. We screened 19 patients with HSCR and mental retardation and eventually identified large-scale SMADIP1 deletions or truncating mutations in 8 of 19 patients. These results allow further delineation of the spectrum of malformations ascribed to SMADIP1 haploinsufficiency, which includes frequent features such as hypospadias and agenesis of the corpus callosum. Thus, SMADIP1, which encodes a transcriptional corepressor of Smad target genes, may play a role not only in the patterning of neural-crest–derived cells and of CNS but also in the development of midline structures in humans

A French multicenter study of over 700 patients with 22q11 deletions diagnosed using FISH or aCGH

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