Our study aimed to assess perinatal outcomes and recurrence rate of Chronic Intervillositis of Unknown Etiology (CIUE). We conducted an observational retrospective study in a tertiary care university ...hospital in France from January 1, 1997 to July 31, 2018. 122 pregnancies (102 women) with CIUE were included. Cases of the Department of Histopathology placenta database were re-analysed independently by three pathologists specializing in fetal pathology. Diagnosis of CIUE was confirmed according to: (1) the presence of cellular infiltrate in the intervillous space, (2) ~ 80% of the mononuclear cells in the intervillous space positive for CD68, (3) infiltration occupying at least 5% of the intervillous space, and (4) no clinical or histopathological sign of infection. Outcomes of pregnancies with CIUE (miscarriages, stillbirths, terminations of pregnancy, live birth with or without prematurity or fetal growth restriction) and proportion of CIUE recurrence were analysed. The lost pregnancies comprised 17 (13.9%) miscarriages, 17 (13.9%) stillbirths, and 18 (14.8%) terminations of pregnancy. Of the 70 (57.4%) pregnancies that led to a live birth, 38 (54.3%) new-borns were premature and 50 (72.5%) exhibited fetal growth restriction. Among the 102 women, 23 subsequently became pregnant, half of whom (n = 11) developed recurrent CIUE. CIUE was associated with high rates of adverse perinatal outcomes, including pregnancy loss, fetal growth restriction, and preterm birth with a risk of recurrence nearly 50%.
Alcohol affects multiple neurotransmitter systems, notably the GABAergic system and has been recognised for a long time as particularly damaging during critical stages of brain development. ...Nevertheless, data from the literature are most often derived from animal or in vitro models. In order to study the production, migration and cortical density disturbances of GABAergic interneurons upon prenatal alcohol exposure, we performed immunohistochemical studies by means of the proliferation marker Ki67, GABA and calretinin antibodies in the frontal cortical plate of 17 foetal and infant brains antenatally exposed to alcohol, aged 15 weeks' gestation to 22 postnatal months and in the ganglionic eminences and the subventricular zone of the dorsal telencephalon until their regression, i.e., 34 weeks' gestation. Results were compared with those obtained in 17 control brains aged 14 weeks of gestation to 35 postnatal months. We also focused on interneuron vascular migration along the cortical microvessels by confocal microscopy with double immunolabellings using Glut1, GABA and calretinin. Semi-quantitative and quantitative analyses of GABAergic and calretininergic interneuron density allowed us to identify an insufficient and delayed production of GABAergic interneurons in the ganglionic eminences during the two first trimesters of the pregnancy and a delayed incorporation into the laminar structures of the frontal cortex. Moreover, a mispositioning of GABAergic and calretininergic interneurons persisted throughout the foetal life, these cells being located in the deep layers instead of the superficial layers II and III. Moreover, vascular migration of calretininergic interneurons within the cortical plate was impaired, as reflected by low numbers of interneurons observed close to the cortical perforating vessel walls that may in part explain their abnormal intracortical distribution. Our results are globally concordant with those previously obtained in mouse models, in which alcohol has been shown to induce an interneuronopathy by affecting interneuron density and positioning within the cortical plate, and which could account for the neurological disabilities observed in children with foetal alcohol disorder spectrum.
Prenatal alcohol exposure is a major cause of neurobehavioral disabilities. MRI studies in humans have shown that alcohol is associated with white matter microstructural anomalies but these studies ...focused on myelin abnormalities only after birth. Only one of these studies evaluated oligodendrocyte lineage, but only for a short period during human foetal life. As data are lacking in humans and alcohol is known to impair oligodendrocyte differentiation in rodents, the present study aimed to compare by immunohistochemistry the oligodendrocyte precursor cells expressing PDGFR-α and immature premyelinating/mature oligodendrocytes expressing Olig2 in the ganglionic eminences and the frontal cortex of 14 human foetuses exposed to alcohol from 15 to 37 weeks' gestation with age-matched controls. The human brains used in this study were obtained at the time of foetal autopsies for medical termination of pregnancy, in utero or post-natal early death. Before birth, PDGFR-α expression was strongly increased in the ganglionic eminences and the cortex of all foetuses exposed to alcohol except at the earliest stage. No massive generation of Olig2 immunoreactive cells was identified in the ganglionic eminences until the end of pregnancy and the density of Olig2-positive cells within the cortex was consistently lower in foetuses exposed to alcohol than in controls. These antenatal data from humans provides further evidence of major oligodendrocyte lineage impairment at specific and key stages of brain development upon prenatal alcohol exposure including defective or delayed generation and maturation of oligodendrocyte precursors.
Bi-allelic pathogenic variants in genes of the EIF2B family are responsible for Childhood Ataxia with Central nervous system Hypomyelination/Vanishing White Matter disease, a progressive ...neurodegenerative disorder of the central white matter. Only seven molecularly proven cases with antenatal onset have been reported so far. We report for the first time the neuropathological findings obtained from two foetuses harbouring deleterious variants in the EIF2B5 gene who presented in utero growth retardation and microcephaly with simplified gyral pattern that led to a medical termination of the pregnancy at 27 and 32 weeks of gestation. Neuropathological examination confirmed microcephaly with delayed gyration, periventricular pseudo-cysts and severe cerebellar hypoplasia. Histologically, the cerebellar cortex was immature, the dentate nuclei were fragmented and myelin stains revealed almost no myelination of the infratentorial structures. Bergmann glia was virtually absent associated to a drastic decreased number of mature astrocytes in the cerebellar white matter, multiple nestin-positive immature astrocytes as well as increased numbers of PDGRFα-positive oligodendrocyte precursors. Whole exome sequencing performed in the two foetuses and their parents allowed the identification of two EIF2B5 compound heterozygous variants in the two foetuses: c.468C > G p.Ile156Met and c.1165G > A p.Val389Met, the parents being heterozygous carriers. These variants are absent in the genome Aggregation Database (gnomAD r2.0.2). Contrary to the variant Ile156Met already described in a patient with CACH syndrome, the variant p.Val389Met is novel and predicted to be deleterious using several softwares. Neuropathological findings further expand the phenotypic spectrum of the disease that very likely occurs during early gestation and may manifest from the second half of pregnancy by a severe impairment of cerebral and cerebellar development.
Chronic intervillositis of unknown etiology (CIUE) is a rare placental disease characterized by intervillous infiltration of maternal macrophages and associated with poor pregnancy outcomes and a ...high risk of recurrence in subsequent pregnancies. Its pathophysiology remains unclear and prognostic factors have not yet been established. In addition, clear relationships between the histologic extent of lesions and the severity of perinatal outcomes have not been demonstrated. Our objectives were to validate a CIUE classification system based on the gradation of macrophagic infiltration of the intervillous space, and to attempt to correlate these results with perinatal outcomes. For this multicenter retrospective study, 3 pathologists reviewed all cases diagnosed with “intervillositis” between 1997 and 2018. Confirmed CIUE cases were semiquantitatively graded based on the percentage of macrophagic infiltrate in the intervillous spacegrade 1 (5% to 10%), grade 2 (10% to 50%), and grade 3 (>50%). Multiple pregnancies and pregnancies with medical follow-up completed outside of the study centers were excluded. In total, 122 cases of CIUE in 102 patients were included in the study. Microscopic classification based on one criterion was easy to perform, and interobserver correlation was good. Grade 3 infiltration was strongly associated with poor perinatal outcomes and fetal growth restriction (P<0.0001). After delivery, only 16.1% of newborns from the grade 3 CIUE group were alive, compared with 59% from the grade 2 and 86.5% from the grade 1 group (P=0.0002). Recurrence risk was associated with CIUE gradation of the index case (P=0.004), with 95% of recurrent CIUE cases being from patients with grades 2 and 3 CIUE. In this study, conducted with the largest CIUE cohort to date, a classification based only on the degree of macrophagic infiltration of the intervillous space was validated, and this classification was shown to be strongly associated with poor perinatal outcomes and risk of recurrence.
Cardiomyopathies are diseases of the heart muscle with variable clinical expressivity. Most of forms are inherited as dominant trait, and with incomplete penetrance until adulthood. Severe forms of ...cardiomyopathies were observed during the antenatal period with a pejorative issue leading to fetal death or medical interruption of pregnancy. Variable phenotypes and genetic heterogeneity make etiologic diagnosis difficult. We report 11 families (16 cases) whose unborn, newborn or infant with early onset cardiomyopathies. Detailed morphological and histological examinations of hearts were implemented, as well as genetic analysis on a cardiac targeted NGS panel. This strategy allowed the identification of the genetic cause of the cardiomyopathy in 8/11 families. Compound heterozygous mutations in dominant adulthood cardiomyopathy genes were found in two, pathogenic variants in co‐dominant genes in one, de novo mutations in 5 including a germline mosaicism in one family. Parental testing was systematically performed to detect mutation carriers, and to manage cardiological surveillance and propose a genetic counseling. This study highlights the great diagnostic value of the genetic testing of severe antenatal cardiomyopathy both for genetic counseling and to detect presymptomatic parents at higher risk of developing cardiomyopathy.
Fetal cardiomyopathies are rare and could led to in utero fetal death or termination of pregnancy. Morphological analysis of 16 cases allowed to described their characteristics. Genetic analysis on a panel of cardiomyopathy genes has attested of a genetic origin of these cases and also highlighted a particular pattern (high rate of de novo mutation, compound heterozygous and co‐dominance) participating to the explanation of a severe cardiomyopathy. This work confirmed the interest of genetic testing of fetal cardiomyopathies to improve genetic counselling in the families.
Objectives
The antenatal phenotypic spectrum of Noonan Syndrome (NS) requires better characterization.
Methods
This multicenter retrospective observational included 16 fetuses with molecularly ...confirmed NS admitted for fetopathological examination between 2009 and 2016.
Results
Among 12 pathogenic variants (PV) in PTPN11 (80%), 5 (42%) fell between position c.179 and c.182. Ultrasound showed increased nuchal translucency (n = 13/16, 93%), increased nuchal fold after 15 weeks of gestation (n = 12/16, 75%), pleural effusions (n = 11/16, 69%), polyhydramnios (n = 9/16, 56%), hydrops (n = 7/16, 44%), cardiovascular (n = 6/16, 38%) and cerebral (n = 4/16, 25%) anomalies. Fetopathological examination found dysmorphic features in all cases, cardiovascular anomalies (n = 12/15, 80%), pulmonary hypoplasia (n = 10/15, 67%), effusions (n = 7/15, 47%) and neuropathological anomalies (n = 5/15, 33%). Hydrops was significantly (p = 0.02) more frequent in the four fetuses with RIT1, NRAS and RAF1 PV versus the 12 fetuses with PTPN11 PV.
Conclusions
Increased nuchal translucency and nuchal fold is common in NS. Noonan Syndrome antenatal phenotype showed high in utero fetal death, hydrops, prenatal pleural effusion and pulmonary hypoplasia, although the inclusion of only deceased fetuses will have selected more severe phenotypes. Non‐specific cardiovascular and neurological abnormalities should be added to NS antenatal phenotype. Next generation sequencing will help detect more genotypes, clarifying the prenatal phenotype and identifying genotype‐phenotype correlations.
Key points
What's already known about this topic?
Noonan Syndrome (NS) is an autosomal dominant disorder with highly variable antenatal phenotype, which sometimes does not correlate with the severity of the postnatal phenotype, making counseling challenging.
The ultrasound phenotype of NS is associated with increased nuchal translucency in first trimester and beyond the second trimester of pregnancy, polyhydramnios, pleural effusion, ascites, edema and cardiac and facial anomalies.
These signs are frequent and non‐specific.
What does this study add?
This case series better characterizes fetuses carrying NS, identifying a wider phenotypic spectrum than originally reported. The antenatal phenotype includes non‐specific cardiovascular, renal and neurological abnormalities.
This phenotype seems to be more severe than previously thought, with a high rate of hydrops, prenatal pleural effusion and pulmonary hypoplasia.
Different genotypes have specific phenotypes, for example, hydrops was more associated to mutations in non‐PTPN11 targets.
Objective
We aimed to gather fetal cases carrying a 7q11.23 copy number variation (CNV) and collect precise clinical data to broaden knowledge of antenatal features in these syndromes.
Methods
We ...retrospectively recruited unrelated cases with 7q11.23 deletion, known as Williams‐Beuren syndrome (WBS), or 7q11.23 duplication who had prenatal ultrasound findings. We collected laboratory and clinical data, fetal ultrasound, cardiac ultrasound and fetal autopsy reports from 18 prenatal diagnostic centers throughout France.
Results
40 fetuses with WBS were collected and the most common features were intra‐uterine growth retardation (IUGR) (70.0%, 28/40), cardiovascular defects (30.0%, 12/40), polyhydramnios (17.5%, 7/40) and protruding tongue (15.0%, 6/40). Fetal autopsy reports were available for 11 cases and were compared with ultrasound prenatal features. Four cases of fetuses with 7q11.23 microduplication were collected and prenatal ultrasound signs were variable and often isolated.
Conclusion
This work strengthens the fact that 7q11.23 CNVs are associated with a broad spectrum of antenatal presentations. IUGR and cardiovascular defects were the most frequent ultrasound signs. By reporting the biggest series of antenatal WBS, we aim to better delineate distinctive signs in fetuses with 7q11.23 CNVs.
Key points
What is already known on this topic?
Deletion of the 7q11.23 region causes the Williams Beuren syndrome (WBS). The reciprocal duplication is responsible for a distinctive although less severe neurodevelopmental disorder.
Diagnosis of WBS is usually suspected postnatally in infants but its prenatal presentation remains challenging.
What does this study add?
Largest series of fetuses with a 7q11.23 deletion or a 7q11.23 duplication.
Antenatal ultrasound findings of prenatal 7q11.23 copy number variations.
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