NOTCH2 related disorders: Description and review of the fetal presentation.

Signs of skeletal dysplasias are relatively common in fetuses with abnormal ultrasound (US) findings. The diversity of congenital skeletal disorders, the possibility of late-onset severe phenotypes and overlapping syndromes can be a challenge in the way of diagnosis, even if prenatal high-throuput sequencing allows for a better diagnosis, prognosis and genetic counseling. Hajdu-Cheney spectrum pathologies are rarely described in prenatal, and the signs associated remain poorly known, and do not include specific postnatal signs as acro-osteolysis and premature osteoporosis. We hereby report a couple for whom a medical termination of pregnancy was performed because a severe polymalformative syndrome associating severely short limbs with bowed long bones, severe cardiopathy, hyperechogenic kidneys and dysmorphism. After fetopathological and radiological examinations, Exome Sequencing (ES) was performed and revealed a de novo truncating mutation in the last exon of NOTCH2, responsible for Hajdu-Cheney or Serpentine Fibula Polycystic Kidney syndromes.

Tunneling Splittings in Water Clusters from Path Integral Molecular Dynamics.

We present calculations of tunneling splittings in selected small water clusters, based on a recently developed path integral molecular dynamics (PIMD) method. The ground-rotational-state tunneling motions associated with the largest splittings in the water dimer, trimer, and hexamer are considered, and we show that the PIMD predictions are in very good agreement with benchmark quantum and experimental results. As the tunneling spectra are highly sensitive to both the details of the quantum dynamics and the potential energy surface, our calculations are a validation of the MB-Pol surface as well as the accuracy of PIMD. The favorable scaling of PIMD with system size paves the way for calculations of tunneling splittings in large, nonrigid molecular systems with motions that cannot be treated accurately by other methods, such as the semiclassical instanton.

Tunneling splittings from path-integral molecular dynamics using a Langevin thermostat.

We report an improved method for the calculation of tunneling splittings between degenerate configurations in molecules and clusters using path-integral molecular dynamics (PIMD). Starting from an expression involving a ratio of thermodynamic density matrices at the bottom of the symmetric wells, we use thermodynamic integration with molecular dynamics simulations and a Langevin thermostat to compute the splittings stochastically. The thermodynamic integration is performed by sampling along the semiclassical instanton path, which provides an efficient reaction coordinate as well as being physically well-motivated. This approach allows us to carry out PIMD calculations of the multi-well tunneling splitting pattern in the water dimer and to refine previous PIMD calculations for one-dimensional models and malonaldehyde. The large (acceptor) splitting in the water dimer agrees to within 20% of benchmark variational results, and the smaller splittings agree to within 10%.

Diagnostic yield of chromosomal microarray analysis in fetuses with isolated increased nuchal translucency: a French multicenter study.

OBJECTIVE: To determine the frequency and nature of copy number variants (CNVs) identified by chromosomal microarray analysis (CMA) in a large cohort of fetuses with isolated increased nuchal translucency thickness (NT) ≥ 3.5 mm. METHODS: This was a retrospective, multicenter study, including 11 French hospitals, of data from the period between April 2012 and December 2015. In total, 720 fetuses were analyzed by rapid aneuploidy test and the fetuses identified as euploid underwent CMA. CNVs detected were evaluated for clinical significance and classified into five groups: pathogenic CNVs; benign CNVs; CNVs predisposing to neurodevelopmental disorders; variants of uncertain significance (VOUS); and CNVs not related to the phenotype (i.e. incidental findings). RESULTS: In 121 (16.8%) fetuses, an aneuploidy involving chromosome 13, 18 or 21 was detected by rapid aneuploidy test and the remaining 599 fetuses were euploid. Among these, 53 (8.8%) had a CNV detected by CMA: 16/599 (2.7%) were considered to be pathogenic, including 11/599 (1.8%) that were cryptic (not visible by karyotyping); 7/599 (1.2%) were CNVs predisposing to neurodevelopmental disorders; and 8/599 (1.3%) were VOUS. Additionally, there was one (0.2%) CNV that was unrelated to the reason for referral diagnosis (i.e. an incidental finding) and the remaining 21 were benign CNVs, without clinical consequence. Interestingly, we identified five genomic imbalances of the 1q21.1 or 15q11.2 regions known to be associated with congenital heart defects. CONCLUSION: Our study demonstrates the benefit of CMA in the etiological diagnosis of fetuses with isolated increased NT. It is worth noting that most (69%) of the detected pathogenic CNVs were cryptic. Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd.

Perspectives: using polymer modeling to understand the formation and function of nuclear compartments.

Compartmentalization is a ubiquitous feature of cellular function. In the nucleus, early observations revealed a non-random spatial organization of the genome with a large-scale segregation between transcriptionally active-euchromatin-and silenced-heterochromatin-parts of the genome. Recent advances in genome-wide mapping and imaging techniques have strikingly improved the resolution at which nuclear genome folding can be analyzed and have revealed a multiscale spatial compartmentalization with increasing evidences that such compartment may indeed result from and participate to genome function. Understanding the underlying mechanisms of genome folding and in particular the link to gene regulation requires a cross-disciplinary approach that combines the new high-resolution techniques with computational modeling of chromatin and chromosomes. In this perspective article, we first present how the copolymer theoretical framework can account for the genome compartmentalization. We then suggest, in a second part, that compartments may act as a "nanoreactor," increasing the robustness of either activation or repression by enhancing the local concentration of regulators. We conclude with the need to develop a new framework, namely the "living chromatin" model that will allow to explicitly investigate the coupling between spatial compartmentalization and gene regulation.

[What signs should you look for ultrasound (2D/3D) to affirm the good location of tubal implants? About a retrospective study of 92 cases]. / Quels signes échographiques doit-on rechercher (2D/3D) pour affirmer la bonne localisation des implants tubaires ? À propos d'une étude rétrospective de 92 cas.

OBJECTIVE: The aim of this study is to propose an analysis of the route and the curvature of the Essure® system in 3D ultrasound to determine their correct location so as not to miss a tubal perforation. METHODS: This is a retrospective single center study during 2 years analyzing 92 3D ultrasound performed by a single sonographer. Implant placement was performed by different operators. One prescribed 3D ultrasound control in case of difficulties with the installation; other indications where systematics. RESULTS: The Essure®'s position is right in 79% of cases. Twenty-eight implants appear incorrectly positioned on ultrasound 3D positioning. Abnormalities found are those described by the classification proposed in the literature. In one case, the curvature of the implant, not taking into account this classification, allowed to evoke a tubal perforation. Among the 28 cases of non-visualized implants in place, 3 cases of wrong position of the implant were confirmed by additional examinations (laparoscopy or HSG). For 14 cases, the ASP or HSG disproved the wrong position of the implants. In other cases, we did not have other complementary examinations. CONCLUSION: Ultrasonography 3D seems to be the method of choice to control implants for simple implementation and good reproducibility. However, the interpretation of 3D ultrasound images is sometimes difficult. The study of the curvature of the implant should be systematically analyzed not to miss a tubal perforation.

[Correlation between antenatal ultrasound and postnatal diagnosis in cleft lip or palate: A retrospective study of 44 cases]. / Corrélation anté- et postnatale dans le cadre de fentes du palais primaires ou secondaires : étude rétrospective de 44 cas.

OBJECTIVES: Anomalies of the maxillofacial development concern 1 for 700 births. About 30% of prenatal diagnoses of isolated primary cleft palate or associated with a cleft of secondary palate will be corrected in postnatal. This retrospective observational study was designed to compare the antenatal data and postnatal diagnosis regarding a series of clefts. MATERIALS AND METHODS: All children born between 1 December 2009 and 31 January 2014 in a prenatal diagnostic reference center and having a cleft palate were included. Newborns with an abnormality associated with the cleft were excluded. A comparison was made between the data in the antenatal ultrasound reports and postnatal those described by the surgeon during surgery. RESULTS: Forty-four children were included and three infants were excluded due to associated anomalies. Of those 41 children, 27 children have been screened. Ultrasound and clinical diagnosis was the same for 23 cases (85.2%) and inaccurate for 4 patients (14.8%). In case of primary cleft palate prenatal diagnosis was performed to 19 cases of 21 (90.5%), but only 8 of 20 if only secondary cleft palate (42.1%) including 7 with a Pierre-Robin sequence. DISCUSSION: Antenatal screening sensitivity of primary and secondary cleft palate increase in recent years with a rate of 85.2% in our series. By contrast, diagnosis of isolated secondary cleft palate seems to be more difficult and 3D ultrasound does not always improve screening performance. CONCLUSION: Ultrasound 2D seem sufficient for screening of primary and secondary cleft palate. The 3D ultrasound may be useful for a better representation of the cleft for future parents. The same language concerning the classification of the clefts facilitates harmonization of reporting and understanding between professionals. The presence of the maxillofacial surgeon ultrasound room would allow the sonographer to direct its ultrasound accurately or improve its learning curve.

[Beckwith-Wiedemann syndrome: What do you search in prenatal diagnosis? About 14 cases]. / Le syndrome de Beckwith-Wiedemann : que faut-il rechercher en anténatal? À propos d'une série de 14 cas.

OBJECTIVES: Beckwith-Wiedemann syndrome (BWS) is the most common overgrowth syndrome and has an incidence of 1/13,700. The majority of the cases are diagnosed after birth. Patients with BWS have an increased risk of neonatal hypoglycemia and embryonal tumors development in childhood. We wanted to identify the ultrasound signs that must alert physicians to prepare best perinatal management strategies. METHODS: We conducted a retrospective study of a population of 14 cases of BWS diagnosed in perinatal period; four of them were detected prenatally by ultrasound. The anomalies signs described in prenatal were analyzed and compared with the clinical features of the postnatal period. RESULTS: The major features reported were represented by macrosomia for 71.4% with an increase of abdominal circumference, and macroglossia for 78.6%. The minor features were various with 64% of visceromegaly (nephromegaly and/or hepatomegaly), 50% of hydramnios and for 80% of male children a genital anomaly (crytorchidism and/or hypospadias). CONCLUSION: This study identified some prenatal ultrasound signs that should alert the clinician to the possibility of BWS. A genetic conseling, after confirmation by molecular diagnosis, could be proposed in a near future in prenatal, and could improve postnatal management strategies for these affected children at high postnatal risk.

[Rare case of bilateral pulmonary agenesis and prenatal diagnosis]. / Diagnostic anténatal d'une agénésie pulmonaire bilatérale : une observation exceptionnelle.

Bilateral pulmonary agenesis (BPA) is a rare congenital lung malformation. The prognosis is severe as it is incompatible with extra-uterine life. Although multiple prenatal imaging modalities are developed, the prenatal diagnosis of BPA remains problematic. We report a case of BPA observed in our unity and for which the diagnosis was not clearly identified during the evaluation. This report illustrates the need to consider all the imaging aspects and particularly during US examination suspecting BPA.

[When should evoke prenatal paternal uniparental disomy 14?]. / Quand faut-il évoquer en anténatal une disomie uniparentale paternelle 14 ?

The paternal uniparental disomy 14 is a rare malformation syndrome whose postnatal pathognomonic sign is the deformation of the rib as coat hanger. In prenatal, ultrasonographic signs are major recurrent polyhydramnios, a narrow thorax and deformed long bones short and sometimes other anomalies including ends. The authors report one rare case of prenatal paternal uniparental disomy 14 with the deformation of the rib as coat hanger. Prenatally, the narrow deformed thorax can be searched by ultrasound three-dimensional (3D) and/or helical CT and thus represent an aid to prenatal diagnosis.

[Epidermolysis bullosa simplex congenital antenatal discovery and contribution of 3D ultrasound]. / Épidermolyse bulleuse simplex congénitale de découverte anténatale et apport de l'échographie 3D.

Epidermolysis bullosa (EB) comprises a heterogeneous group of genodermatoses whose prognosis is variable. The diagnosis is suggested by prenatal ultrasound at signs, especially for junctional EB with pyloric atresia. The authors report a case of antenatal image limited skin undermining highlighted by the ultrasound three-dimensional (3D) in connection with a diagnosis of a congenital epidermolysis simplex confirmed postnatal period.

Overexpression of copper transporter CTR1 in the brain barrier of North Ronaldsay sheep: implications for the study of neurodegenerative disease.

Age-related regulatory failure of the brain barrier towards the influx of redox metals such as copper and iron may be associated with the pathological changes that characterize dementias such as Alzheimer's diseases (ADs) and amyotrophic lateral sclerosis (ALS). The integrity of the brain barrier to regulate copper in the brain is maintained by the complex interplay of membrane-located transporters, of which copper transporter 1 (CTR1) exerts a defining role. North Ronaldsay (NR) sheep are a primitive breed that have adapted to a copper-deficient environment by an enhanced uptake of the metal, resulting in copper overload in the liver and brain. This study reports that CTR1 is overexpressed in both the blood-brain barrier (BBB) and the blood-cerebrospinal fluid barrier (BCB) of adult NR sheep when compared with a domesticated breed. The excess copper is stored ultimately in astrocytes as non-injurious copper-metallothionein (MT). NR sheep have apparently retained an immature regulatory setting for CTR1 in the BBB, promoting facilitated copper uptake into the brain. This putative failure of maturation of CTR1 allows insight into the regulatory control of brain copper homeostasis, whereby the BBB and BCB act in concert to sequester excess copper and protect neurons from injury. The elevated copper content of the ageing human brain may derive from a dysregulation of CTR1 at the brain barrier, with a return to the default (immature) setting and implications for neurodegenerative disease.

[Interest of 3D ultrasound in the follow-up of tubal sterilizations: case report of a rare tubal perforation]. / Intérêt de l'échographie en 3 dimensions dans le suivi des stérilisations tubaires : à propos d'un cas rare de perforation.

The Essure™ system's effectiveness is based on the follow-up at three months. The challenge is to find a minimally invasive imaging technique to locate the devices. Therefore, many authors recommend three-dimensional ultrasound in first-line. We report here an exceptional case of tubal perforation for which ultrasound failed to diagnose. Until then, only three cases have been reported in the literature, noting the difficulty to diagnose this complication. Indeed, although ultrasound is described as reliable, reproducible and non-radiating, it is a dynamic examination, operator dependent, exposing to the risk of misinterpretation.

[Facial coloboma: report of an exceptional prenatal case and interest of three-dimensional ultrasonography]. / Colobome facial: à propos d'une observation anténatale précoce exceptionnelle; apport de l'échographie en 3-dimensions.

We report a rare case of Tessier no. 4 craniofacial cleft diagnosed by ultrasound imaging at 10 weeks' gestation. Tessier no. 4 craniofacial cleft is a very rare and complex congenital abnormality, characterized by an oblique orbitomaxillary facial cleft. Prenatal diagnosis of orofacial clefting is usually done at midtrimester of pregnancy, based on careful sonographic examination of the fetal face. However conventional 2D ultrasound is limited in screening isolated cleft palate and defects of the secondary palate. Thus, 3D ultrasound shows a greater sensitivity in a referred population and antenatal evaluation of facial clefs.

[Does the sickle cell trait (heterozygous carrier status) confer protection against malaria?]. / L'hémoglobine S protège-t-elle du paludisme ?

The high frequency of the gene for sickle-cell hemoglobin in malaria-endemic regions is believed to be due to an advantage in surviving malaria. We report the case of a woman with both malaria and hemoglobin S.

[Hemophagocytic syndrome due to Herpes simplex virus after hysteroscopy]. / Syndrome d'activation macrophagique à Herpes simplex virus après hystéroscopie.

Hemophagocytic syndrome is an uncommon but life-threatening complication of Herpes simplex virus type 1 or 2 infection. Diagnosis is difficult to establish given the low specificity of clinical and biological signs.