M. Collet

Differential Effects of Oral and Transdermal Estrogen/Progesterone Regimens on Sensitivity to Activated Protein C Among Postmenopausal Women: A Randomized Trial

Objective—Activated protein C (APC) resistance not related to the factor V Leiden mutation is a risk factor for venous thrombosis. Oral estrogen replacement therapy (ERT) has been reported to induce APC resistance. Little is known about the effect of transdermal estrogen. Methods and Results—We enrolled 196 postmenopausal women who were randomly allocated to receive either 1 mg 17&bgr;-estradiol orally (n=63) or 50 &mgr;g 17&bgr;-estradiol transdermally per day (n=68), both associated with 100 mg progesterone daily or placebo (n=65) for 6 months. An activated partial thromboplastin time (APTT)–based test and the effect of APC on thrombin potential (ETP) were used. Oral ERT induced an ETP-based APC resistance compared with both placebo (P =0.006) and transdermal ERT (P <0.001), but there was no significant effect of transdermal ERT compared with placebo (P =0.191). There was no significant effect of ERT on the APTT-based APC sensitivity ratio. Prothrombin fragment 1+2 plasma levels were significantly higher after 6 months of treatment in women allocated to oral ERT compared with those on placebo and transdermal ERT and were positively and significantly correlated with changes in ETP-based APC sensitivity ratio. Conclusions—Our data show that oral, unlike transdermal, estrogen induces APC resistance and activates blood coagulation. These results emphasize the importance of the route of estrogen administration.

Detection of an unexpected subtelomeric 15q26.2 qter deletion in a little girl: Clinical and cytogenetic studies

Unlike the small proximal 15q deletions causing Prader‐Willi and/or Angelman syndrome, distal deletions of the terminal long arm of chromosome 15 have rarely been described. To the best of our knowledge, only four patients with a pure terminal 15q deletion have been documented in the literature. We report here on an unexpected abnormal hybridization pattern for the 15q specific subtelomeric control probe (clone 154P1) of the commercial SNRPN probe in a girl referred for suspicion of Angelman syndrome. Investigation by fluorescent in situ hybridization (FISH) using bacterial artificial chromosome (BAC) clones defined a partial monosomy 15q26.2 → 15qter for a minimal critical region of approximately 5.7 Mb, which is the most distal de novo 15qter deletion reported to date. All the de novo 15qter deletion cases, including ours, presented with pre‐ and post‐natal growth retardation related to the loss of one copy of the IGF1R gene. Based on the comparaison with the previous published cases and owing to the clinical phenotype of our patient, we define a new subtelomeric 15qter syndrome which would be characterized by intrauterine growth retardation and global post‐natal growth failure, variable mental retardation, facial anomalies including relative micrognathia and triangular facies and minor malformations of the extremities including proximally placed thumbs, cubitus valgus, and brachydactyly with tappering of the digits.

Inherited thrombophilias and unexplained pregnancy loss: an incident case-control study.

Summary.  Background: Despite an initial impressive impact, a critical appraisal of the link between pregnancy loss and inherited thrombophilias is currently growing. Furthermore, little is known about the paternal thrombophilic phenotype and pregnancy loss. Objective: We sought an association between unexplained pregnancy loss and parental factor V Leiden (FVL) and Prothrombin G20210A (PTG) mutations. Methods: Design – Incident case–control study. Setting– University Hospital of Brest (France). Patients – Women and their partners from the West Brittany area, consecutively referred for unexplained pregnancy losses (two or more consecutive losses at or before 21 weeks of gestation, or at least one later loss). Controls – Women and their partners with no history of pregnancy loss and at least one normal pregnancy, from the same geographic area, recruited using electoral lists. Statistical analysis – Comparison of FVL and PTG allele frequency between cases and controls using the chi‐square test. Separate analyses were performed according to the type of pregnancy loss (early recurrent or later loss). Results: 311 women (mean age: 32.8) and 284 of their partners were enrolled as cases while 599 women (mean age: 34.3) and 297 of their partners were recruited as controls. The prevalence of female, male or couple thrombophilic mutations was not statistically different between cases and controls whatever the definition of pregnancy loss retained. Conclusions: Presently, there is no clinical indication to routinely test for FVL and likely PTG mutations in women with early recurrent pregnancy loss. Moreover, our results did not reveal that paternal thrombophilic polymorphism should be further explored.

45,X/46,XX mosaicism below 30% of aneuploidy: clinical implications in adult women from a reproductive medicine unit

OBJECTIVE Turners syndrome (TS) is well known, but prognosis for 45,X/46,XX mosaicism below 30% of aneuploidy has not been established. We evaluated differences in clinical features and biological parameters between patients with numerical sex chromosome mosaicism diagnosed incidentally and control women. DESIGN Retrospective observational study of clinical features and biological parameters. METHODS Standard endocrinological and gynecological examination was done and early-follicular-phase blood values were collected from the medical records of women aged 21-43, who were referred to our ward from 1996 to 2006 because of infertility and were karyotyped. Seventy-one women with sex chromosome mosaicism (45,X/46,XX) ranging from 4 to 28% were assigned a chromosomally normal woman (46,XX) matched according to age (n=71). RESULTS In group 45,X/46,XX, 8% or more of aneuploidy accounted for a smaller height compared to controls (P=0.01). Body mass index was increased from 6% of aneuploidy (P=0.02) and was positively correlated to the percentage of 45,X cells (P=0.0001); menarche occurred earlier from 10% of aneuploidy (P=0.01) and was inversely correlated to the percentage of 45,X cells (P=0.045). No difference was found between the groups for FSH, LH, estradiol, inhibin B, and TSH values. Spontaneous abortions were more frequent in case of mosaicism (P=0.01), and recurrence was positively correlated to the percentage of aneuploidy (P=0.008). CONCLUSION Sex chromosome mosaicism is responsible for clinical changes from 6% of aneuploidy, corresponding to the main phenotypical features of TS.

Prenatal Sonographic Patterns in Six Cases of Wolf-Hirschhorn (4p–) Syndrome

This multicentric study presents 6 cases of Wolf-Hirschhorn syndrome (deletion of 4p) detected after a sonographic prenatal diagnosis of early intrauterine growth retardation with fetal abnormalities. Standard karyotyping on regular G-banding during pregnancy was normal in half of the cases. Fortunately, the associated sonographic signs of a typical face, cystic cerebral lesions, midline fusion defects and bilateral renal hypoplasia may help to refine specific indications for high-resolution banding and molecular analysis by in situ hybridization.

Increased thrombin generation measured in the presence of thrombomodulin in women with early pregnancy loss

Compared with 537 parous controls with no history of pregnancy loss, a lower thrombomodulin-related inhibition of the endogenous thrombin potential was measured in 264 cases with previous unexplained pregnancy loss, especially when losses occurred between 9 and 12 weeks of gestation. Adjusting age, protein S, factor VIII, factor V Leiden, and prothrombin G20210A did not change the results.

Nonvisualization of fetal gallbladder increases the risk of cystic fibrosis.

The aim of our study is to evaluate the prevalence of cystic fibrosis (CF) in fetuses referred for genetic testing because of ultrasonographic sign (nonvisualized fetal gallbladder – NVFGB).

Balanced transmission of a paternal complex chromosomal rearrangement involving chromosomes 2, 3, and 18

Balanced Transmission of a Paternal Complex Chromosomal Rearrangement Involving Chromosomes 2, 3, and 18 Audrey Basinko, Aurore Perrin, Huyen Anh Nguyen, Fr ed eric Morel, Marie-Jos ee Le Bris, Anne-H el ene Saliou, Michel Collet, Philippe Parent, Caroline Benech, Sylvia Quemener, Claude Ferec, Nathalie Douet-Guilbert, and Marc De Braekeleer* Laboratoire d’Histologie, d’Embryologie et de Cytog en etique, Facult edeM edecine et des Sciences de la Sant e, Universit e deBrest, Brest, France Laboratoire de Cytog en etique, Centre Hospitalier Universitaire de Brest, Brest, France INSERM U613, Brest, France Service de Gyn ecologie Obst etrique, Centre Hospitalier Universitaire de Brest, Brest, France Service de P ediatrie et de G en etique M edicale, Centre Hospitalier Universitaire de Brest, Brest, France Laboratoire de G en etique Mol eculaire et d’Histocompatibilit e, Centre Hospitalier Universitaire de Brest, Brest, France

Unexplained pregnancy loss: a marker of basal endothelial dysfunction?

OBJECTIVE To compare the microparticle levels of women referred for unexplained pregnancy loss with those of parous controls. DESIGN Incident case-control study. SETTING University medical center. PATIENT(S) 124 women consecutively referred for unexplained pregnancy losses (two or more losses at or before 21 weeks of gestational age, or at least one later loss), and 273 parous women without pregnancy loss. INTERVENTION(S) Numeration of circulating microparticles by flow cytometry after differentiation of subpopulations according to the expression of membrane-specific antigens (CD51, CD144, or CD146 for endothelial, CD41 for platelet, CD45 and CD66b for leukocyte and neutrophil microparticles). MAIN OUTCOME MEASURE(S) Plasma levels of microparticles. RESULTS A relative hypercoagulable state assessed by thrombin generation test had been previously reported in such cases, so we hypothesized that this could be explained by an excess of procoagulant microparticles. The study women displayed statistically significantly lower platelet and higher endothelial microparticle levels than the controls. The parameters of the thrombin generation test were only correlated with the level of endothelial microparticles, with a low coefficient of Speermans correlation (r=0.15). CONCLUSION(S) The difference in microparticle levels between the patients and controls does not clearly explain the hypercoagulable state reported in the patients but could reflect chronic endothelium damage.

DIFFICULT DIAGNOSIS AND MANAGEMENT OF AN HETEROKARYOTYPIC MONOCHORIONIC TWIN PREGNANCY WITH DISCORDANT FETAL SEX AND 45,X/47,XYY KAROTYPES

We report twins for whom ultrasound examinations revealed a Turner syndrome in the female fetus and a normal male fetus. A selective pregnancy termination was decided on the female fetus with hydrops. The death of both twins called in question the chorionic diagnosis. Amniotic fluid cytogenetic analysis revealed a 45,X karyotype in the female twin and a 47,XYY karyotype in the male twin. Molecular cytogenetic analysis on genital and renal cells showed different levels of 45,X/47,XYY mosaicism in both twins; molecular analysis on the amniocytes showed monozygosity. Monozygotic twins with discordant sex are very rare. This study showed the difficult diagnosis and management of a monochorionic twin pregnancy with discordant fetal sex.