Loss-of-function variants in ZEB1 cause dominant anomalies of the corpus callosum with favourable cognitive prognosis.

BACKGROUND: The neurodevelopmental prognosis of anomalies of the corpus callosum (ACC), one of the most frequent brain malformations, varies extremely, ranging from normal development to profound intellectual disability (ID). Numerous genes are known to cause syndromic ACC with ID, whereas the genetics of ACC without ID remains poorly deciphered. METHODS: Through a collaborative work, we describe here ZEB1, a gene previously involved in an ophthalmological condition called type 3 posterior polymorphous corneal dystrophy, as a new dominant gene of ACC. We report a series of nine individuals with ACC (including three fetuses terminated due to ACC) carrying a ZEB1 heterozygous loss-of-function (LoF) variant, identified by exome sequencing. RESULTS: In five cases, the variant was inherited from a parent with a normal corpus callosum, which illustrates the incomplete penetrance of ACC in individuals with an LoF in ZEB1. All patients reported normal schooling and none of them had ID. Neuropsychological assessment in six patients showed either normal functioning or heterogeneous cognition. Moreover, two patients had a bicornuate uterus, three had a cardiovascular anomaly and four had macrocephaly at birth, which suggests a larger spectrum of malformations related to ZEB1. CONCLUSION: This study shows ZEB1 LoF variants cause dominantly inherited ACC without ID and extends the extraocular phenotype related to this gene.

Artificial intelligence-based diagnosis in fetal pathology using external ear shapes.

OBJECTIVE: Here we trained an automatic phenotype assessment tool to recognize syndromic ears in two syndromes in fetuses-=CHARGE and Mandibulo-Facial Dysostosis Guion Almeida type (MFDGA)-versus controls. METHOD: We trained an automatic model on all profile pictures of children diagnosed with genetically confirmed MFDGA and CHARGE syndromes, and a cohort of control patients, collected from 1981 to 2023 in Necker Hospital (Paris) with a visible external ear. The model consisted in extracting landmarks from photographs of external ears, in applying geometric morphometry methods, and in a classification step using machine learning. The approach was then tested on photographs of two groups of fetuses: controls and fetuses with CHARGE and MFDGA syndromes. RESULTS: The training set contained a total of 1489 ear photographs from 526 children. The validation set contained a total of 51 ear photographs from 51 fetuses. The overall accuracy was 72.6% (58.3%-84.1%, p < 0.001), and 76.4%, 74.9%, and 86.2% respectively for CHARGE, control and MFDGA fetuses. The area under the curves were 86.8%, 87.5%, and 90.3% respectively for CHARGE, controls, and MFDGA fetuses. CONCLUSION: We report the first automatic fetal ear phenotyping model, with satisfactory classification performances. Further validations are required before using this approach as a diagnostic tool.

Evidence of disrupted rhombic lip development in the pathogenesis of Dandy-Walker malformation.

Dandy-Walker malformation (DWM) and Cerebellar vermis hypoplasia (CVH) are commonly recognized human cerebellar malformations diagnosed following ultrasound and antenatal or postnatal MRI. Specific radiological criteria are used to distinguish them, yet little is known about their differential developmental disease mechanisms. We acquired prenatal cases diagnosed as DWM and CVH and studied cerebellar morphobiometry followed by histological and immunohistochemical analyses. This was supplemented by laser capture microdissection and RNA-sequencing of the cerebellar rhombic lip, a transient progenitor zone, to assess the altered transcriptome of DWM vs control samples. Our radiological findings confirm that the cases studied fall within the accepted biometric range of DWM. Our histopathological analysis points to reduced foliation and inferior vermian hypoplasia as common features in all examined DWM cases. We also find that the rhombic lip, a dorsal stem cell zone that drives the growth and maintenance of the posterior vermis is specifically disrupted in DWM, with reduced proliferation and self-renewal of the progenitor pool, and altered vasculature, all confirmed by transcriptomics analysis. We propose a unified model for the developmental pathogenesis of DWM. We hypothesize that rhombic lip development is disrupted through either aberrant vascularization and/or direct insult which causes reduced proliferation and failed expansion of the rhombic lip progenitor pool leading to disproportionate hypoplasia and dysplasia of the inferior vermis. Timing of insult to the developing rhombic lip (before or after 14 PCW) dictates the extent of hypoplasia and distinguishes DWM from CVH.

Two-Port Fetoscopic Repair of Myelomeningocele in Fetal Lambs.

OBJECTIVE: The aim of this study was to assess the feasibility and the effectiveness of a fetoscopic myelomeningocele (MMC) repair with a running single suture using a 2-port access in the sheep model. METHODS: Eighteen fetuses underwent surgical creation of a MMC defect at day 75. Fetuses were then randomized into 3 groups. Four fetuses remained untreated (control group). In the other 14 fetuses, a prenatal repair was performed at day 90: 7 fetuses had an open repair (oMMC), and 7 fetuses had a fetoscopic repair (fMMC) using a single-layer running suture through a 2-port access. Lambs were sacrificed at term, and histological examinations were performed. RESULTS: Hindbrain herniation was observed in all live lambs in the control group. A complete closure of the defect was achieved in all the lambs of the fMMC group. A complete healing of the defect and no hindbrain herniation were observed in all live lambs of the oMMC and fMMC groups. The durations of surgeries were not statistically different between the oMMC and the fMMC groups (60 vs. 53 min, p = 0.40), as was the risk of fetal loss (fMMC: 1/7, oMMC: 3/7, p = 0.56). DISCUSSION: Fetoscopic repair of MMC can be performed using a single-layer running suture through a 2-port access and may be promising to reduce the risk of premature rupture of membranes.

Therapeutic Patient Education in Cancer Pain Management: from Practice to Research: Proposals and Strategy of the French EFFADOL Program.

In the field of cancer pain, therapeutic patient education (TPE) allows patients to develop skills to better manage their pain. In the Lower Normandy region of France, the management of pain is based on networking, thus allowing proximity and accessibility for all concerned. We have thus designed and initiated a broad five-stage research program that includes the following: (1) training for caregivers in TPE; (2) identifying the educational expectations of patients and their relatives with regard to cancer pain; (3) the design of a TPE program; (4) the evaluation of its quality; and (5) the evaluation of its effectiveness by comparative randomization. This article presents this approach and more particularly the research phases (stages 2, 4, 5) for which the objectives, the methodology, and the expected results are justified. Among the key points, particular attention is paid to the evaluation of the educational dimension that provides patients with self-efficacy to participate actively in the management of their pain, their perception of changes in relation to it and its impact. The choice of a specific assessment criterion (subscale 9 of the Brief Pain Inventory) and of the step-wedge design are thus argued. This approach, which is based on a partnership between health care professionals and researchers, aims to demonstrate the benefits provided by TPE to patients in order to enable them to better manage their pain on a daily basis.

Fetoscopic patch coverage of experimental myelomenigocele using a two-port access in fetal sheep.

PURPOSE: This study aims to assess the feasibility and the effectiveness of a fetoscopic myelomeningocele (MMC) coverage using a sealed inert patch through a two-port access, in the sheep model. METHODS: Forty-four fetuses underwent surgical creation of a MMC defect at day 75 and were divided into four groups according to the MMC repair technique, performed at day 90. Group 1 remained untreated. Group 2 had an open surgery using suture of the defect. Groups 3 and 4 underwent defect coverage using a Gore®-polytetrafluoroethylene patch secured with surgical adhesive (Bioglue®), with an open approach (group 3) and a fetoscopic one (group 4). Lambs were killed at term, and histological examinations were performed. RESULTS: Fetoscopic patch coverage was achieved in all the lambs of group 4. All the fetuses of group 2 had a complete closure of the defect whereas only 38% in group 3 and 14% in group 4. Fetal loss rate seems to be lower in group 4 than in groups 2 and 3. CONCLUSION: Fetoscopic coverage of MMC defect can be performed using a sealed patch through a two-port access, but the patch and glue correction may not be the ideal technique to repair fetal MMC.

Prenatal diagnosis of SLC25A24 Fontaine progeroid syndrome: description of the fetal phenotype, genotype and detection of parental mosaicism.

BACKGROUND: Fontaine progeroid syndrome (FPS, OMIM 612289) is a recently identified genetic disorder stemming from pathogenic variants in the SLC25A24 gene, encoding a mitochondrial carrier protein. It encompasses Gorlin-Chaudry-Moss syndrome and Fontaine-Farriaux syndrome, primarily manifesting as craniosynostosis with brachycephaly, distinctive dysmorphic facial features, hypertrichosis, severe prenatal and postnatal growth restriction, limb shortening, and early aging with characteristic skin changes, phalangeal anomalies, and genital malformations. CASES: All known occurrences of FPS have been postnatally observed until now. Here, we present the first two prenatal cases identified during the second trimester of pregnancy. While affirming the presence of most postnatal abnormalities in prenatal cases, we note the absence of a progeroid appearance in young fetuses. Notably, our reports introduce new phenotypic features like encephalocele and nephromegaly, which were previously unseen postnatally. Moreover, paternal SLC25A24 mosaicism was detected in one case. CONCLUSIONS: We present the initial two fetal instances of FPS, complemented by thorough phenotypic and genetic assessments. Our findings expand the phenotypical spectrum of FPS, unveiling new fetal phenotypic characteristics. Furthermore, one case underscores a potential novel inheritance pattern in this disorder. Lastly, our observations emphasize the efficacy of exome/genome sequencing in both prenatal and postmortem diagnosis of rare polymalformative syndromes with a normal karyotype and array-based comparative genomic hybridization (CGH).

Bi-allelic variations in CRB2, encoding the crumbs cell polarity complex component 2, lead to non-communicating hydrocephalus due to atresia of the aqueduct of sylvius and central canal of the medulla.

Congenital hydrocephalus is a common condition caused by the accumulation of cerebrospinal fluid in the ventricular system. Four major genes are currently known to be causally involved in hydrocephalus, either isolated or as a common clinical feature: L1CAM, AP1S2, MPDZ and CCDC88C. Here, we report 3 cases from 2 families with congenital hydrocephalus due to bi-allelic variations in CRB2, a gene previously reported to cause nephrotic syndrome, variably associated with hydrocephalus. While 2 cases presented with renal cysts, one case presented with isolated hydrocephalus. Neurohistopathological analysis allowed us to demonstrate that, contrary to what was previously proposed, the pathological mechanisms underlying hydrocephalus secondary to CRB2 variations are not due to stenosis but to atresia of both Sylvius Aqueduct and central medullar canal. While CRB2 has been largely shown crucial for apico-basal polarity, immunolabelling experiments in our fetal cases showed normal localization and level of PAR complex components (PKCι and PKCζ) as well as of tight (ZO-1) and adherens (ß-catenin and N-Cadherin) junction molecules indicating a priori normal apicobasal polarity and cell-cell adhesion of the ventricular epithelium suggesting another pathological mechanism. Interestingly, atresia but not stenosis of Sylvius aqueduct was also described in cases with variations in MPDZ and CCDC88C encoding proteins previously linked functionally to the Crumbs (CRB) polarity complex, and all 3 being more recently involved in apical constriction, a process crucial for the formation of the central medullar canal. Overall, our findings argue for a common mechanism of CRB2, MPDZ and CCDC88C variations that might lead to abnormal apical constriction of the ventricular cells of the neural tube that will form the ependymal cells lining the definitive central canal of the medulla. Our study thus highlights that hydrocephalus related to CRB2, MPDZ and CCDC88C constitutes a separate pathogenic group of congenital non-communicating hydrocephalus with atresia of both Sylvius aqueduct and central canal of the medulla.

Two novel variations p.(Ser1275Thr) and p.(Ser1275Arg) in FLT4 causing prenatal hereditary lymphedema type 1.

BACKGROUND: Hereditary lymphedema 1 is a rare congenital condition, characterized by the development of chronic swelling in body parts. It is highly variable in expression and age of onset with different presentations: from feet edema to hydrops fetalis. This affection is genetically heterogeneous with autosomal dominant inheritance and incomplete penetrance due to a mutation in the FLT4 gene in most cases. CASES: In our study, we report on two fetuses harboring congenital lymphedema with FLT4 variation and review the prenatal confirmed ones of the literatures. Our cases were selected within fetuses explored by exome sequencing in a diagnosis setting. Prenatal ultrasonography showed hydrops fetalis in one case and an increased nuchal translucency with hydrothorax in the other. Comparative genomic hybridization array on amniocentesis was normal in both cases. Exome sequencing identified a variation p.(Ser1275Thr) and p.(Ser1275Arg) in fetus 1 and fetus 2 in the FLT4 gene, respectively. A de novo mutation at the same codon was reported in prenatal literature suggesting possible genotype phenotype correlation. CONCLUSION: Cystic hygroma/hydrops fetalis are possible manifestations of several disorders. This study illustrates how the integration of exome sequencing in prenatal clinical practice can facilitate the diagnosis and genetic counseling of heterogeneous developmental affections.

Diagnostic value of fetal autopsy after early termination of pregnancy for fetal anomalies.

BACKGROUND: In early terminations of pregnancy for fetal anomaly (TOPFA) without identified cytogenetic abnormality, a fetal autopsy is recommended for diagnostic purposes, to guide genetic counseling. Medical induction, which allows analysis of a complete fetus, is generally preferred over surgical vacuum aspiration. Our objective was to assess the diagnostic value of fetal autopsies in these early terminations, relative to the first-trimester ultrasound, overall and by termination method. MATERIALS: For this retrospective study at the Port Royal Maternity Hospital, we identified all TOPFA performed from 11 weeks to 16 weeks diagnosed at the first-trimester ultrasound in cases with a normal karyotype. The principal endpoint was the additional value of the autopsy over /compared to the ultrasound and its impact on genetic counseling, globally and by termination method. The secondary objective was to compare the complication rate by method of termination. RESULTS: The study included 79 women during period of 2013-2017: 42 with terminations by medical induction and 37 by aspiration. Fetal autopsy found additional abnormalities in 54.4% of cases, more frequently after medical induction (77.5%) than after aspiration (21.4%, p < .01). Genetic counseling was modified in 20.6% of cases, more often after induction (32.5% vs 3.6%, p < .01). The length of stay was significantly longer and a secondary aspiration was required in 16,7% of case in the medical induction group (p < .01). CONCLUSION: Medically induced vaginal expulsion appears preferable and can change genetic counseling for subsequent pregnancies.

Biallelic THOC6 pathogenic variants: Prenatal phenotype and review of the literature.

BACKGROUND: The THOC6 protein is a component of the THO complex. It is involved in mRNA transcription, processing and nuclear export. Interestingly molecular biallelic loss-of-function variants of the THOC6 gene were identified in the Beaulieu-Boycott-Innes syndrome (BBIS- OMIM # 613680). This condition was described in 17 patients and is characterized by a moderate to severe intellectual disability, facial dysmorphic features and severe birth defects such as heart, skeletal, ano-genital and renal congenital malformations. METHODS: In the present study, we report on a new family with two affected sibs. The 6-year-old female had severe intellectual disability with autistic features, feeding difficulties, growth delay, facial dysmorphic, and congenital malformations (hand, skeletal and cardiac anomalies). The male fetus presented antenatally with a cystic hygroma associated with severe aortic and left ventricular hypoplasia. Autopsy, after termination of pregnancy at 15 weeks of gestation, showed facial dysmorphic, short right thumb and hypospadias. RESULTS: Exome sequencing detected in both sibs compound heterozygous variants of the THOC6 gene (NM_024339.3, GRCh37): the already reported c.[298T>A;700G>T;824G>A] haplotype and a novel variant c.977T>G, p.(Val326Gly). DISCUSSION: We made a review of the literature of 17 BBIS reported patients including our two siblings. Severe to moderate ID and congenital malformations were constant. Prenatal and postnatal failure to thrive were frequent. Brain MRI were not specific. Prenatal findings were reported in 40% of cases but we described the first case of cystic hygroma. The present study reports extends the prenatal delineation of the phenotypic features observed in association with the presence of THOC6 variants. In addition, it underscores the intrafamilial phenotypic variability observed in BBIS.

[Delicate transition: Building-up an adult life for young people with developmental chromosomal anomalies]. / Délicates transitions - Construction d'une place d'adulte pour des jeunes vivant avec une anomalie chromosomique du développement.

A qualitative study was performed in the South of France among young people (16-25 years) affected by chromosomal anomalies: Down, velo-cardio-facial, or Williams-Beuren syndromes. We conducted interviews with them and with their parents to understand the obstacles to social participation that they most frequently face when becoming adults. Once their education comes to an end, young adults with developmental anomalies face several difficulties to develop and keep diversified social ties and to find their place in society, be it with a stable job - either in the ordinary working environment or in sheltered employment - or by attending occupational workshops. While parents are mostly concerned with finding a professional place for their children, the latter seem to especially value opportunities for satisfactory relational dynamics outside of the protective frame of the family. Nevertheless, a wish for familial protection keeps coexisting with their wish for independence.

TITLE: Délicates transitions - Construction d'une place d'adulte pour des jeunes vivant avec une anomalie chromosomique du développement. ABSTRACT: Nous avons mené une étude qualitative par entretiens individuels et collectifs (focus groups) auprès de jeunes (de 16 à 25 ans) touchés par une anomalie chromosomique (trisomie 21, microdélétion 22q11.2 associée au syndrome vélo-cardio-facial, ou microdélétion 7q11.23 associée au syndrome de Williams-Beuren) et de leurs familles, afin de comprendre les obstacles à la participation sociale qu'ils rencontrent lors du passage à l'âge adulte. Confrontés à de nombreuses contraintes pour développer des liens sociaux diversifiés et pour trouver une place sociale, professionnelle ou non, après la scolarité, ces jeunes semblent attribuer la plus grande importance à une dynamique relationnelle positive en dehors de l'espace familial, dont ils continuent toutefois de souhaiter la protection.

Trial of labor after cesarean and contribution of pelvimetry in the prognosis of neonatal morbidity.

INTRODUCTION: To estimate the association between an abnormal pelvic dimension at pelvimetry and the occurrence of severe neonatal morbidity after trial of labor after cesarean (TOLAC). MATERIALS AND METHODS: Retrospective observational cases-controls study conducted at a level 3 maternity units between 2006 and 2016. Included women were patient with trial of labor after one previous cesarean section, alive singleton fetus in cephalic presentation ≥ 37WG. Two groups were compared according to pelvic mesures at pelvimetry: pelvic dimension considered as abnormal, defined by Conjugate Diameter <10.5cm and/or Transverse Diameter <12cm and pelvic dimension considered as normal for other women. The primary outcome was a composite criterion of neonatal morbidity and mortality. A logistic multivariate regression model was use to estimate the association between an abnormal pelvic dimension at pelvimetry and the occurrence of severe neonatal morbidity. RESULTS: 2474 women were included. 863 (34.8 %) have a normal pelvic dimension and 1611 (65.2 %) an abnormal. Characteristics of labor were similar in two groups. Success of TOLAC was 84.7 % in normal pelvic group and 64.6 % in abnormal dimension of pelvic group. Neonatal morbidity was similar between two groups (1.7 % in normal pelvic dimension group versus 2.3 % in abnormal pelvic dimension group, p=0.26; crude OR: 1.39 (0.77-2.49) ; adjusted OR : 0.93 (0.51-1.68)). DISCUSSION: There were no association between pelvic dimension at pelvimetry and neonatal morbidity. In case of abnormal pelvic dimension, a combination of more prudence, and stringent user practices, achieve a high rate of vaginal delivery and a neonatal morbidity comparable to the normal pelvic dimension group.

Early surgical management for giant omphalocele: Results and prognostic factors.

OBJECTIVES: Giant omphalocele often represents a major surgical challenge and is reported with high mortality and morbidity rates. The aim of this study was to assess the outcome of neonates with giant omphalocele managed with early operative surgical treatment, and subsequently to identify possible factors that could alter the prognosis. METHODS: We reviewed the medical records of 29 consecutive newborns with prenatally diagnosed giant omphalocele. In these cases one of two procedures had been performed: either staged closure after silo, or immediate closure with a synthetic patch. The cases were separated into 2 groups: Isolated giant omphalocele (IO group) and giant omphalocele associated with malformation (NIO group). RESULTS: Infants in the IO group had a lower size of the omphalocele (p<0,001), a shorter hospital stay (95 days [45-915] vs. 41.5 days [10-110] p= 0, 02), and a shorter median ventilation length (10 days [1-33] vs. 27, 5 [6-65] p = 0, 05). In the NIO group, 5 cases displayed a significantly more difficult course than the others. They were compared to the remaining cases for prenatal and anatomic features. Four factors associated with greater morbidity were identified: CONCLUSIONS: Isolated omphalocele, even containing the whole liver, has a very good prognosis with early surgical treatment. Without associated anomalies, 95% of giant omphaloceles can be discharged with a median of 41.5 days in hospital. However, associated anomalies (especially cardiopathies) may burden the prognosis and should be both carefully assessed during pregnancy and taken into account in parental information. TYPE OF STUDY: Retrospective Study LEVEL OF EVIDENCE: Level I.

[Elaboration and evaluation of a therapeutic education program in cancer pain management]. / Construction et évaluation d'un programme d'éducation thérapeutique du patient dans le domaine de la douleur liée au cancer.

Pain, one of the most feared symptoms for patients with cancer, remains insufficiently alleviated and impairs quality of life. Therapeutic patient education (TPE) is a relevant approach to this problem while allowing patients to develop skills to better manage their pain. In the "Basse-Normandie" French region, the management of pain relies on two organized networks, thus allowing proximity and accessibility for all concerned. In this context, our team has begun a broad five-step research program that is part of a regional health policy: (1) training in TPE of 10 doctor/nurse pairs; (2) identification of educational expectations of patients and their relatives in the field of cancer pain; (3) design and optimization of a TPE program dedicated to cancer pain; (4) regional pilot study aiming to assess the feasibility, quality and transferability of the program; (5) evaluation of the TPE program by interventional comparative randomization at the national level. This article aims to present the program which originality and strengths are based on collaborative work between health stakeholders. Objectives, methodology and expected results of the research phase (stages 2, 4, 5) are notably developed. The main expected outcomes are to prove the effectiveness of the program in improving the knowledge and skills of patients in the field of pain cancer in order to promote their adherence to treatment and, consequently, to enable them to better manage it. The long-term objective is to disseminate the educational approach by modifying practices that provide a mutual benefit for caregivers and patients.

Relation between the quality of the ultrasound image acquisition and the precision of the measurement of the crown-rump length in the late first trimester: what are the consequences?

OBJECTIVE: To assess the extent to which the distribution of crown-rump length (CRL) values may be correlated with different criteria for the quality of the CRL images. STUDY DESIGN: This is a retrospective analysis of a series of 977 CRL images, by two independent observers, for the presence or the absence of 14 quality hallmarks. Inter-observer agreement for the hallmarks was assessed by the proportion of agreement and Cohen's kappa. The association between the quantiles of the CRL distribution and the presence or absence of the 14 quality hallmarks was modeled using quantile regression. RESULTS: The overall inter-observer agreement across the 14 hallmarks was 91.7%, kappa=0.81, 95% CI [0.80-0.82]. Distribution of CRL measurements varied considerably as a function of image quality: when the fetus was in extension, the mean CRL was +5.7mm (vs. not in extension, p<0.001), when the fetus was in flexion (vs. not), the mean CRL was -4.7mm (p<0.001) and when the image magnification was <65% (vs. >65%), the mean CRL was -4.2mm (p<0.001). There was a global trend to over-estimate the CRL for the higher deciles and to under-estimate the CRL for the lower deciles when the sagittal quality hallmarks were absent. No significant impact on CRL distribution was observed in association with the precise placement of the calipers nor with the horizontal orientation of the fetus. CONCLUSION: Distribution of CRL measurements was influenced by the quality of CRL images. In particular, inadequate position of the fetus (flexion/extension) and insufficient image magnification were associated with systematic changes in the values of CRL. Our results show that as the quality of CRL images decreases, the associated variations in the distribution of CRL can have an impact on the chromosomal risk assessment and may lead to inappropriate obstetrical decisions.