Biallelic loss-of-function variants in <i>CACHD1 </i>cause a novel neurodevelopmental syndrome with facial dysmorphism and multisystem congenital abnormalities

Purpose We established the genetic etiology of a syndromic neurodevelopmental condition characterized by variable cognitive impairment, recognizable facial dysmorphism, and a constellation of extra-neurological manifestations. Methods We performed phenotypic characterization of 6 participants from 4 unrelated families presenting with a neurodevelopmental syndrome and used exome sequencing to investigate the underlying genetic cause. To probe relevance to the neurodevelopmental phenotype and craniofacial dysmorphism, we established two- and three-dimensional human stem cell-derived neural models and generated a stable cachd1 zebrafish mutant on a transgenic cartilage reporter line. Results Affected individuals showed mild cognitive impairment, dysmorphism featuring oculo-auriculo abnormalities, and developmental defects involving genitourinary and digestive tracts. Exome sequencing revealed biallelic putative loss-of-function variants in CACHD1 segregating with disease in all pedigrees. RNA sequencing in CACHD1-depleted neural progenitors revealed abnormal expression of genes with key roles in Wnt signaling, neurodevelopment, and organ morphogenesis. CACHD1 depletion in neural progenitors resulted in reduced percentages of post-mitotic neurons and enlargement of 3D neurospheres. Homozygous cachd1 mutant larvae showed mandibular patterning defects mimicking human facial dysmorphism. Conclusion Our findings support the role of loss-of-function variants in CACHD1 as the cause of a rare neurodevelopmental syndrome with facial dysmorphism and multisystem abnormalities

The ANTENATAL multicentre study to predict postnatal renal outcome in fetuses with posterior urethral valves: objectives and design

Abstract Background Posterior urethral valves (PUV) account for 17% of paediatric end-stage renal disease. A major issue in the management of PUV is prenatal prediction of postnatal renal function. Fetal ultrasound and fetal urine biochemistry are currently employed for this prediction, but clearly lack precision. We previously developed a fetal urine peptide signature that predicted in utero with high precision postnatal renal function in fetuses with PUV. We describe here the objectives and design of the prospective international multicentre ANTENATAL (multicentre validation of a fetal urine peptidome-based classifier to predict postnatal renal function in posterior urethral valves) study, set up to validate this fetal urine peptide signature. Methods Participants will be PUV pregnancies enrolled from 2017 to 2021 and followed up until 2023 in >30 European centres endorsed and supported by European reference networks for rare urological disorders (ERN eUROGEN) and rare kidney diseases (ERN ERKNet). The endpoint will be renal/patient survival at 2 years postnatally. Assuming α = 0.05, 1–β = 0.8 and a mean prevalence of severe renal outcome in PUV individuals of 0.35, 400 patients need to be enrolled to validate the previously reported sensitivity and specificity of the peptide signature. Results In this largest multicentre study of antenatally detected PUV, we anticipate bringing a novel tool to the clinic. Based on urinary peptides and potentially amended in the future with additional omics traits, this tool will be able to precisely quantify postnatal renal survival in PUV pregnancies. The main limitation of the employed approach is the need for specialized equipment. Conclusions Accurate risk assessment in the prenatal period should strongly improve the management of fetuses with PUV

Villites et intervillites chroniques d'étiologie indéterminée (à propos d'une série nantaise de 178 cas)

Les villites et intervillites chroniques d'étiologie indéterminée sont des lésions placentaires inflammatoires caractérisées par un infiltrat mononuclée au niveau du stroma villositaire ou de la chambre intervilleuse. Ces lésions sont associées à une morbidité fœtale sévère et sont à risque de récurrence. Cette étude rétrospective de 178 cas de villites et intervillites placentaires a permis de montrer que l'intervillite était la situation la plus à risque avec plus de 80% de RCIU et 30% de pertes fœtales anténatales. Les lésions mixtes, sans prédominance inflammatoire sur le versant fœtal ou maternel, pourraient être considérées comme équivalentes aux villites et traitées comme telles. La sévérité des complications semble reliée à l'importance de l'infiltrat inflammatoire. Un traitement par corticoïdes associé à l'aspirine pourrait être envisagé lors d'une grossesse ultérieure pour limiter les phénomènes immunologiques et inflammatoires impliqués dans la genèse des lésions. Des études complémentaires seront nécessaires pour confirmer ces hypothèses.NANTES-BU Médecine pharmacie (441092101) / SudocSudocFranceF

Diagnostic anténatal des dysgénésies du corps calleux et devenir neurologique (expérience nantaise de 2002 à 2010)

Introduction : Grâce aux progrès en matière d'imagerie anténatale, le diagnostic d'anomalies du corps calleux est de plus en plus accessible aux échographistes de dépistage. Matériel et Méthode : Cette étude nantaise a colligé 46 dossiers de dysgénésies du corps calleux isolées ou non et fait une revue de l'état des connaissances sur la malformation. L'objectif de ce travail était d'évaluer le pronostic neurologique des enfants porteurs de ce type d'anomalie et de déterminer une conduite à tenir adaptée. Résultats et Discussion : Cette série rétrospective conclut que le caractère isolé de l'anomalie est pourvoyeur de pronostic plutôt favorable concernant le développement neurologique. Cependant, il faut souligner 10% de faux diagnostics isolés (corrigés en postnatal) et un risque non négligeable de troubles du comportement et de difficultés scolaires d'apparition tardive. Conclusion : Le pronostic extrêmement difficile à évaluer en anténatal reste un problème majeur dans la prise en charge des couples pendant la grossesse qu'il sera nécessaire de mieux appréhender à l'avenir.NANTES-BU Médecine pharmacie (441092101) / SudocSudocFranceF

First Trimester Uterine Artery Doppler, sFlt-1 and PlGF to Predict Preeclampsia in a High-Risk Population

International audienceOBJECTIVE: The study aims to evaluate the accuracy of combining uterine artery Doppler (UAD), PlGF and sFlt-1 in the first trimester for preeclampsia screening. METHODS: Prospectively enrolled women at high risk of preeclampsia were included. Transabdominal UAD measurements and serum biomarkers were collected between 11 and 13 weeks of gestation in three university hospitals and in one general hospital. The main outcome was preeclampsia. UAD parameters and biomarker levels among women with preeclampsia were compared with those of women in the unaffected group in univariate and multivariate analyses. RESULTS: Out of 226 women included from May 2007 to January 2011, 27 (11.9%) women developed preeclampsia. Among women affected by preeclampsia, the lowest pulsatility index was higher (p\,=\,0.02), bilateral notching was more frequent (p\,=\,0.01), and PlGF was lower (p\,<\,0.001). No significant differences were observed for other indicators. The multivariate model, adjusted for laboratory and sonographic indicators, had an area under the curve (AUC) estimated at 0.76, which was not significantly different from the AUC of the univariate model adjusted only for PlGF (p\,=\,0.7). CONCLUSION: In a high-risk population, PlGF in the first trimester is useful for predicting preeclampsia, but neither sFlt-1 nor any UAD indices improved the prediction of preeclampsia

Accuracy of ultrasonography and magnetic resonance imaging in the diagnosis of placenta accreta.

PURPOSE: To evaluate the accuracy of ultrasonography and magnetic resonance imaging (MRI) in the diagnosis of placenta accreta and to define the most relevant specific ultrasound and MRI features that may predict placental invasion. MATERIAL AND METHODS: This study was approved by the institutional review board of the French College of Obstetricians and Gynecologists. We retrospectively reviewed the medical records of all patients referred for suspected placenta accreta to two university hospitals from 01/2001 to 05/2012. Our study population included 42 pregnant women who had been investigated by both ultrasonography and MRI. Ultrasound images and MRI were blindly reassessed for each case by 2 raters in order to score features that predict abnormal placental invasion. RESULTS: Sensitivity in the diagnosis of placenta accreta was 100% with ultrasound and 76.9% for MRI (P = 0.03). Specificity was 37.5% with ultrasonography and 50% for MRI (P = 0.6). The features of greatest sensitivity on ultrasonography were intraplacental lacunae and loss of the normal retroplacental clear space. Increased vascularization in the uterine serosa-bladder wall interface and vascularization perpendicular to the uterine wall had the best positive predictive value (92%). At MRI, uterine bulging had the best positive predictive value (85%) and its combination with the presence of dark intraplacental bands on T2-weighted images improved the predictive value to 90%. CONCLUSION: Ultrasound imaging is the mainstay of screening for placenta accreta. MRI appears to be complementary to ultrasonography, especially when there are few ultrasound signs