De novo variants in SP9 cause a novel form of interneuronopathy characterized by intellectual disability, autism spectrum disorder, and epilepsy with variable expressivity.

PURPOSE: Interneuronopathies are a group of neurodevelopmental disorders characterized by deficient migration and differentiation of gamma-aminobutyric acidergic interneurons resulting in a broad clinical spectrum, including autism spectrum disorders, early-onset epileptic encephalopathy, intellectual disability, and schizophrenic disorders. SP9 is a transcription factor belonging to the Krüppel-like factor and specificity protein family, the members of which harbor highly conserved DNA-binding domains. SP9 plays a central role in interneuron development and tangential migration, but it has not yet been implicated in a human neurodevelopmental disorder. METHODS: Cases with SP9 variants were collected through international data-sharing networks. To address the specific impact of SP9 variants, in silico and in vitro assays were carried out. RESULTS: De novo heterozygous variants in SP9 cause a novel form of interneuronopathy. SP9 missense variants affecting the glutamate 378 amino acid result in severe epileptic encephalopathy because of hypomorphic and neomorphic DNA-binding effects, whereas SP9 loss-of-function variants result in a milder phenotype with epilepsy, developmental delay, and autism spectrum disorder. CONCLUSION: De novo heterozygous SP9 variants are responsible for a neurodevelopmental disease. Interestingly, variants located in conserved DNA-binding domains of KLF/SP family transcription factors may lead to neomorphic DNA-binding functions resulting in a combination of loss- and gain-of-function effects.

Is laterality of congenital diaphragmatic hernia a reliable prognostic factor? French national cohort study.

OBJECTIVES: The objective of this study was to assess whether the laterality of congenital diaphragmatic hernia (CDH) was a prognostic factor for neonatal survival. METHODS: This was a cohort study using the French national database of the Reference Center for Diaphragmatic Hernias. The principal endpoint was survival after hospitalization in intensive care. We made a comparative study between right CDH and left CDH by univariate and multivariate analysis. Terminations and stillbirths were excluded from analyses of neonatal outcomes. RESULTS: A total of 506 CDH were included with 67 (13%) right CDH and 439 left CDH (87%). Rate of survival was 49% for right CDH and 74% for left CDH (P < .01). Multivariate analysis showed two factors significantly associated with mortality: thoracic herniation of liver (OR 2.27; IC 95% [1.07-4.76]; P = .03) and lung-to-head-ratio over under expected (OR 2.99; IC 95% [1.41-6.36]; P < .01). Side of CDH was not significantly associated with mortality (OR 1.87; IC 95% [0.61-5.51], P = .26). CONCLUSION: Rate of right CDH mortality is more important than left CDH. Nevertheless after adjusting for lung-to-head-ratio and thoracic herniation of liver, right CDH does not have a higher risk of mortality than left CDH.

Prenatal therapy with pyrimethamine + sulfadiazine vs spiramycin to reduce placental transmission of toxoplasmosis: a multicenter, randomized trial.

BACKGROUND: The efficacy of prophylaxis to prevent prenatal toxoplasmosis transmission is controversial, without any previous randomized clinical trial. In France, spiramycin is usually prescribed for maternal seroconversions. A more potent pyrimethamine + sulfadiazine regimen is used to treat congenital toxoplasmosis and is offered in some countries as prophylaxis. OBJECTIVE: We sought to compare the efficacy and tolerance of pyrimethamine + sulfadiazine vs spiramycin to reduce placental transmission. STUDY DESIGN: This was a randomized, open-label trial in 36 French centers, comparing pyrimethamine (50 mg qd) + sulfadiazine (1 g tid) with folinic acid vs spiramycin (1 g tid) following toxoplasmosis seroconversion. RESULTS: In all, 143 women were randomized from November 2010 through January 2014. An amniocentesis was later performed in 131 cases, with a positive Toxoplasma gondii polymerase chain reaction in 7/67 (10.4%) in the pyrimethamine + sulfadiazine group vs 13/64 (20.3%) in the spiramycin group. Cerebral ultrasound anomalies appeared in 0/73 fetuses in the pyrimethamine + sulfadiazine group, vs 6/70 in the spiramycin group (P = .01). Two of these pregnancies were terminated. Transmission rates, excluding 18 children with undefined status, were 12/65 in the pyrimethamine + sulfadiazine group (18.5%), vs 18/60 in the spiramycin group (30%, P = .147), equivalent to an odds ratio of 0.53 (95% confidence interval, 0.23-1.22) and which after adjustment tended to be stronger (P = .03 for interaction) when treatment started within 3 weeks of seroconversion (95% confidence interval, 0.00-1.63). Two women had severe rashes, both with pyrimethamine + sulfadiazine. CONCLUSION: There was a trend toward lower transmission with pyrimethamine + sulfadiazine, but it did not reach statistical significance, possibly for lack of statistical power because enrollment was discontinued. There were also no fetal cerebral toxoplasmosis lesions in the pyrimethamine + sulfadiazine group. These promising results encourage further research on chemoprophylaxis to prevent congenital toxoplasmosis.

Ex utero intrapartum technique (EXIT): Indications, procedure methods and materno-fetal complications - A literature review.

A congenital malformation of the head, neck or thorax can lead to upper airway compression with a risk of asphyxia or neonatal death. To secure and protect the upper airway, the Ex Utero Intrapartum Therapy (EXIT) procedure has been developed. The procedure allows delivery of the fetus via a hysterotomy while relying on the placenta as the organ of respiration for the fetus prior to clamping of the umbilical cord. A high level of expertise is necessary for successful completion of the EXIT procedure, which is not void of maternal and fetal risks. In this literature review, we present the indications, procedure methods and materno-fetal complications associated with the EXIT procedure.

Prenatal diagnosis of Desbuquois dysplasia type 1 by whole exome sequencing before the occurrence of specific ultrasound signs.

Desbuquois dysplasia is a very severe and sometimes lethal form of osteochondrodysplasia characterized by prenatal onset of severe micromelic short stature, joint laxity with multiple joint dislocations, specific radiographic features, and facial dysmorphism. Here, we report a case for which whole exome sequencing allowed early prenatal diagnosis of Desbuquois dysplasia before the detection of characteristic ultrasound signs of the disease.

Medical Termination Of Pregnancy For Psychosocial Reasons.

The requesting of medical termination of pregnancy (MTP) for psychosocial reasons invites several questions concerning progress in medicine as well raising necessary and legitimate ethical questions. The law currently permits MTP for maternal reasons at any stage of pregnancy if the woman's health is at a significant risk. However, conceptions of mental health risks remain a grey area and present difficulties in terms of psychiatric assessment. When dealing with a patient suffering from a psychiatric disorder, questions must be asked on the reasons behind the request as well as questions concerning free and clear consent. It must also be taken into account that the progressive nature of pregnancy means patient care must be provided relatively quickly. These cases invite discussion on medical decisions, on both a moral and rational level, and the legitimacy of the basis on which the medical decision is taken in the context of MTP for psychosocial reasons.

Management of fetal goiters: 6-year retrospective observational study in three prenatal diagnosis and treatment centers of the Pays De Loire Perinatal Network.

Introduction: The incidence of fetal goiters is reported to be around 1 per 40,000 births. The risk of complications is first of all obstetric, directly related to goiter size, but it may also affect longer term fetal and child development, depending on whether the goiter is due to hypo- or hyperthyroidism. Management is multidisciplinary, but not yet consensual and not always optimal by either endocrinologists or obstetricians.Objectives: The principal objective of this retrospective study was to analyze the data that enabled the physicians to assess whether the goiter was hypo- or hyperthyroid and then to analyze the obstetric practices used in the Pays de Loire network to describe in detail the tools used to diagnose and characterize the goiters and the management chosen in these cases. The secondary objectives are to assess, in our small cohort, the effectiveness of the in utero treatments provided, based on the examination of the children at birth and their outcome at 6 months of life, and to suggest a strategy for monitoring these women at risk that takes current guidelines into consideration.Materials and methods: This multicenter retrospective study covers a 6-year period and focused on the prenatal diagnosis centers (CPDPN) of the Pays de Loire perinatal network: in Nantes, Angers, and Le Mans. The network is responsible for around 42,000 births a year, and the study included 17 women, for a prevalence of 1 per 15,000 births.Results: Ten of the 17 fetuses had a hypothyroid goiter, 4 a hyperthyroid goiter, and 3 normal thyroid findings on fetal blood sample (FBS). For four women, these goiters were secondary to fetal dyshormonogenesis, for 9 more to Graves disease with TSH receptor antibodies (TRAb), and for four women to thyrotoxicosis at the start of pregnancy, managed by synthetic antithyroid drugs. Two newborns had severe complications associated with maternal transmission of Graves disease (TRAb positive at birth): one with exophthalmos and one with neonatal tachycardia. The other 14 had normal psychomotor development at 6 months, based on a clinical examination by a pediatric endocrinologist; only one child was lost to follow-up.Conclusion: Together, ultrasound and multidisciplinary expertise (of an endocrinologist and an obstetrician experienced with this disease) remain the best means for avoiding, or otherwise for accurately characterizing fetal goiter. An ultrasound diagnostic score, of the type proposed by Luton et al. in 2009, may make it possible to homogenize practices and thus to defer or delay the - currently too common - performance of invasive FBS procedures, which must remain rare in this management to limit comorbidities. A threshold TRAb value (>5 IU/l) makes it possible to define this group of women as at risk of fetal and neonatal hyperthyroidism and thus requiring close monitoring. The value of prenatal intra-amniotic thyroxine treatment for hypothyroid goiters (including dyshormonogenesis) remains to be demonstrated.

Pregnancy outcome in Turner syndrome: A French multi-center study after the 2009 guidelines.

OBJECTIVE: This study aimed to assess the application of the French guidelines for pregnancies in Turner syndrome (TS) and their impact on perinatal prognosis. STUDY DESIGN: We performed a French multi-center retrospective study (14 centers), including TS pregnant patients (spontaneously or by Assisted Reproductive Technology (ART)) between January 2006 and July 2017. Only clinical pregnancies were analyzed. The adjustment of medical follow-up modalities to French guidelines was evaluated for all pregnancies after 2009. Pregnancies from oocyte donation (OD) after 2009 were compared to those of a cohort of TS pregnancies obtained by OD before 2009, which were reported by the French Study Group for Oocyte Donation. RESULTS: One hundred seventy pregnancies in 103 patients were included: 35 spontaneous, 5 by means of intra-conjugal ART, and 130 with OD. No serious maternal complications were observed. We reported two stillbirths and one intra uterine fetal death. The French guidelines were partially respected. The preconceptional assessment was carried out in 74% of cases. Cardiology follow-up during pregnancy was performed in accordance with guidelines in 74% of patients. Postpartum cardiac ultrasonography was performed in 45% of pregnancies but only in 11% within 8 days post-partum. When compared to the 2009 historical cohort, the rates of high blood pressure (19% vs. 38%; p < 0.005) pre-eclampsia (8% vs. 21%; p < 0.005) and prematurity <35 weeks (15% vs 38%; p < 0.0001) were lower. CONCLUSIONS: The implementation of guidelines has allowed the standardization of TS pregnancy care and improved perinatal indicators for both mothers and children. However, an effort must be done, in a postpartum survey.

Prenatal diagnosis of primary anophthalmia with a 3q27 interstitial deletion involving SOX2.

We report an interstitial deletion of chromosome 3q26-q28 in a fetus in which anophthalmia had been detected prenatally. FISH analysis, using BAC clones encompassing the SOX2 locus, showed that SOX2 gene was involved in the chromosomal breakpoint of the deletion. This case confirms that haploinsufficiency for SOX2 plays a crucial role in human eye development and emphasizes the necessity of careful chromosomal analysis, including FISH analysis of the 3q region, in case of prenatal discovery of anophthalmia.