Pierangela De Biasio

Sonographic and molecular diagnosis of thanatophoric dysplasia type I at 18 weeks of gestation

Thanatophoric dysplasia is the most common type of lethal skeletal dysplasia. It can usually be diagnosed with ultrasound, but differential diagnosis with other osteochondrodysplasias is not always possible. Mutations in the fibroblast growth factor receptor 3 (FGFR3) gene have been demonstrated to cause two distinct subtypes of the disorder. We describe a case of thanatophoric dysplasia type I diagnosed at 18 weeks of gestation by ultrasonography. Genomic DNA obtained by chorionic villus sampling showed a C to G substitution at position 746 in the FGFR3 gene, resulting in a Ser249Cys substitution already known to be associated with type I disease. Implications for perinatal management are discussed. Copyright

Previously undescribed nonsense mutation in SHH caused autosomal dominant holoprosencephaly with wide intrafamilial variability

Holoprosencephaly (HPE) is the most common developmental defect of the forebrain and midface in humans, with a frequency of 1/16,000 live births. Different genes are implicated in the pathogenesis of HPE; these include SHH, ZIC2, SIX3, TGIF, and human DKK1. We describe here a family with recurrence of autosomal dominant HPE in different members showing a wide clinical variability. The mother presents a single central maxillary incisor and mild hypotelorism as signs of the diseases, while three of her sons were affected by HPE. By direct sequencing and restriction analysis of exon 2 of the SHH gene, we have identified a previously undescribed nonsense mutation at codon 128 (W128X). The identification of this mutation allowed us to give a prenatal diagnosis in this family and confirms a wide intrafamilial variabilty in the phenotypic spectrum.

Comparison of first trimester, second trimester and integrated Down's syndrome screening results in unaffected pregnancies.

Abstract Our aim was to compare the results of first trimester combined test, second trimester triple test, and integrated test in the same pregnant population. We retrospectively studied 927 women, all giving birth to an unaffected baby except for two cases of Downs syndrome. The women underwent a nuchal translucency ultrasound measurement and a blood sampling for pregnancy-associated plasma protein A and free β-hCG subunit (free total chorionic gonadotropin subunit) assay in the first trimester of pregnancy. A second trimester biochemical screening (α-fetoprotein, unconjugated oestriol and total hCG) was performed later. The correlations between each pair of markers and between each marker level and maternal age were calculated. No marker showed significant correlation with any other or with maternal age, with the obvious exception of free β-hCG subunit and total hCG. The false-positive rate (cut-off level: 1 in 350 at term) was 1.5% for the first trimester test, 3.6% for the second trimester test and 0.54% for the integrated test. In 10/14 pregnancies, the increased risk in the first trimester was not confirmed neither in the second trimester nor by the integrated test. In 29/33 women with an increased risk in the second trimester, the first trimester and the integrated test results were discordant. The absence of correlation among different marker levels suggests that the information supplied by the first and second trimester tests is different. Integrating first and second trimester markers in a single test could pose the ethical problem of withholding first trimester results and thus denying the possible advantages of an earlier pregnancy termination.

Acute Premature Constriction of the Ductus Arteriosus after Maternal Self-Medication with Nimesulide

Objective: To describe clinical findings in a case of premature ductal constriction associated with maternal use of nimesulide, a cyclo-oxygenase type-2 inhibitor. Methods: Case report. Results: A mother self-administered nimesulide at 39 weeks of gestation due to lower back pain. Less than 24 h later premature ductal constriction was diagnosed by echocardiography following a suspicious fetal heart rate recording with baseline tachycardia and absent accelerations. Conclusion: In a term pregnancy, nimesulide administration can rapidly cause premature ductal constriction. This condition may induce abnormalities in the fetal heart rate trace.

Maternal plasma DNA testing for aneuploidy in pregnancies achieved by assisted reproductive technologies

Purpose:We sought to compare measurements of circulating cell-free DNA as well as Down syndrome test results in women with naturally conceived pregnancies with those conceived using assisted reproductive technologies.Methods:Data regarding assisted reproductive technologies were readily available from seven enrollment sites participating in an external clinical validation trial of nested case/control design. Measurements of circulating cell-free fetal and total DNA, fetal fraction (ratio of fetal to total DNA), chromosome-specific z-scores, and karyotype results were available for analysis.Results:Analyses were restricted to 632 euploid (5.2% assisted reproductive technologies) and 73 Down syndrome (13.7% assisted reproductive technologies), including 16 twin pregnancies. No differences were found for fetal or total circulating cell-free DNA, or for the fetal fraction in euploid (P = 0.70) or Down syndrome (P = 0.58) pregnancies by method of conception. There appeared to be systematic z-score reductions for chromosomes 21, 18, and 13 in assisted reproductive technologies versus natural euploid pregnancies (P = 0.048, 0.0032, and 0.36, respectively).Conclusion:Assisted reproductive technologies and naturally conceived pregnancies contribute similar levels of circulating cell-free DNA into maternal circulation. Small differences in the z-scores of pregnancies achieved by assisted reproductive technologies were observed and do not appear to be test-related artifacts. However, the findings need confirmation before any consideration of changes to testing and reporting protocols.Genet Med 16 5, 419–422.

Stepwise sequential screening for trisomy 21 in assisted reproduction pregnancies

We offered a modified stepwise sequential integrated screening for Down syndrome to 72 singleton and 16 twin pregnancies obtained with assisted reproductive techniques, observing no cases of trisomy 21 and obtaining a false positive rate of 10% in singleton and 7% in twin pregnancies. In our population, this approach for regulating access to invasive karyotyping can avoid a substantial number of unnecessary procedures, comparing favourably with current practice even in spontaneous pregnancies.