Publications by authors named "Fabien Guimiot"

75 Publications

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

Acta Neuropathol 2021 10 4;142(4):761-776. Epub 2021 Aug 4.

Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, USA.

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.
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http://dx.doi.org/10.1007/s00401-021-02355-7DOI Listing
October 2021

Human neuropathology confirms projection neuron and interneuron defects and delayed oligodendrocyte production and maturation in FOXG1 syndrome.

Eur J Med Genet 2021 Sep 17;64(9):104282. Epub 2021 Jul 17.

Institut Imagine-Inserm UMR-1163, Genetics and Development of the Cerebral Cortex, 75015, Paris, France; Paris Descartes - Sorbonne Paris Cite University, 75006, Paris, France; Hôpital Necker-Enfants Malades, Pediatric Neurology, 75015, Paris, France. Electronic address:

The Forkhead transcription factor FOXG1 is a prerequisite for telencephalon development in mammals and is an essential factor controlling expansion of the dorsal telencephalon by promoting neuron and interneuron production. Heterozygous FOXG1 gene mutations cause FOXG1 syndrome characterized by severe intellectual disability, motor delay, dyskinetic movements and epilepsy. Neuroimaging studies in patients disclose constant features including microcephaly, corpus callosum dysgenesis and delayed myelination. Currently, investigative research on the underlying pathophysiology relies on mouse models only and indicates that de-repression of FOXG1 target genes may cause premature neuronal differentiation at the expense of the progenitor pool, patterning and migration defects with impaired formation of cortico-cortical projections. It remains an open question to which extent this recapitulates the neurodevelopmental pathophysiology in FOXG1-haploinsufficient patients. To close this gap, we performed neuropathological analyses in two foetal cases with FOXG1 premature stop codon mutations interrupted during the third trimester of the pregnancy for microcephaly and corpus callosum dysgenesis. In these foetuses, we observed cortical lamination defects and decreased neuronal density mainly affecting layers II, III and V that normally give rise to cortico-cortical and inter-hemispheric axonal projections. GABAergic interneurons were also reduced in number in the cortical plate and persisting germinative zones. Additionally, we observed more numerous PDGFRα-positive oligodendrocyte precursor cells and fewer Olig2-positive pre-oligodendrocytes compared to age-matched control brains, arguing for delayed production and differentiation of oligodendrocyte lineage leading to delayed myelination. These findings provide key insights into the human pathophysiology of FOXG1 syndrome.
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http://dx.doi.org/10.1016/j.ejmg.2021.104282DOI Listing
September 2021

CAMSAPs organize an acentrosomal microtubule network from basal varicosities in radial glial cells.

J Cell Biol 2021 Aug 21;220(8). Epub 2021 May 21.

Institut Curie, Paris Sciences et Lettres Research University, Centre national de la recherche scientifique UMR144, Paris, France.

Neurons of the neocortex are generated by stem cells called radial glial cells. These polarized cells extend a short apical process toward the ventricular surface and a long basal fiber that acts as a scaffold for neuronal migration. How the microtubule cytoskeleton is organized in these cells to support long-range transport is unknown. Using subcellular live imaging within brain tissue, we show that microtubules in the apical process uniformly emanate for the pericentrosomal region, while microtubules in the basal fiber display a mixed polarity, reminiscent of the mammalian dendrite. We identify acentrosomal microtubule organizing centers localized in varicosities of the basal fiber. CAMSAP family members accumulate in these varicosities, where they control microtubule growth. Double knockdown of CAMSAP1 and 2 leads to a destabilization of the entire basal process. Finally, using live imaging of human fetal cortex, we reveal that this organization is conserved in basal radial glial cells, a related progenitor cell population associated with human brain size expansion.
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http://dx.doi.org/10.1083/jcb.202003151DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8144914PMC
August 2021

Phenotypic spectrum and genomics of undiagnosed arthrogryposis multiplex congenita.

J Med Genet 2021 Apr 5. Epub 2021 Apr 5.

Department of Pediatric Neurology, APHP-Bicêtre Hospital, Le Kremlin-Bicêtre, France.

Background: Arthrogryposis multiplex congenita (AMC) is characterised by congenital joint contractures in two or more body areas. AMC exhibits wide phenotypic and genetic heterogeneity. Our goals were to improve the genetic diagnosis rates of AMC, to evaluate the added value of whole exome sequencing (WES) compared with targeted exome sequencing (TES) and to identify new genes in 315 unrelated undiagnosed AMC families.

Methods: Several genomic approaches were used including genetic mapping of disease loci in multiplex or consanguineous families, TES then WES. Sanger sequencing was performed to identify or validate variants.

Results: We achieved disease gene identification in 52.7% of AMC index patients including nine recently identified genes (, , , , , , , and ). Moreover, we identified pathogenic variants in and expanding the phenotypes associated with these genes. The most frequent cause of AMC was a primary involvement of skeletal muscle (40%) followed by brain (22%). The most frequent mode of inheritance is autosomal recessive (66.3% of patients). In sporadic patients born to non-consanguineous parents (n=60), de novo dominant autosomal or X linked variants were observed in 30 of them (50%).

Conclusion: New genes recently identified in AMC represent 21% of causing genes in our cohort. A high proportion of de novo variants were observed indicating that this mechanism plays a prominent part in this developmental disease. Our data showed the added value of WES when compared with TES due to the larger clinical spectrum of some disease genes than initially described and the identification of novel genes.
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http://dx.doi.org/10.1136/jmedgenet-2020-107595DOI Listing
April 2021

Dysregulation of the NRG1/ERBB pathway causes a developmental disorder with gastrointestinal dysmotility in humans.

J Clin Invest 2021 03;131(6)

Department of Genetics, La Pitié-Salpêtrière Hospital, AP-HP, Paris, France.

Hirschsprung disease (HSCR) is the most frequent developmental anomaly of the enteric nervous system, with an incidence of 1 in 5000 live births. Chronic intestinal pseudo-obstruction (CIPO) is less frequent and classified as neurogenic or myogenic. Isolated HSCR has an oligogenic inheritance with RET as the major disease-causing gene, while CIPO is genetically heterogeneous, caused by mutations in smooth muscle-specific genes. Here, we describe a series of patients with developmental disorders including gastrointestinal dysmotility, and investigate the underlying molecular bases. Trio-exome sequencing led to the identification of biallelic variants in ERBB3 and ERBB2 in 8 individuals variably associating HSCR, CIPO, peripheral neuropathy, and arthrogryposis. Thorough gut histology revealed aganglionosis, hypoganglionosis, and intestinal smooth muscle abnormalities. The cell type-specific ErbB3 and ErbB2 function was further analyzed in mouse single-cell RNA sequencing data and in a conditional ErbB3-deficient mouse model, revealing a primary role for ERBB3 in enteric progenitors. The consequences of the identified variants were evaluated using quantitative real-time PCR (RT-qPCR) on patient-derived fibroblasts or immunoblot assays on Neuro-2a cells overexpressing WT or mutant proteins, revealing either decreased expression or altered phosphorylation of the mutant receptors. Our results demonstrate that dysregulation of ERBB3 or ERBB2 leads to a broad spectrum of developmental anomalies, including intestinal dysmotility.
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http://dx.doi.org/10.1172/JCI145837DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7954599PMC
March 2021

CD4CD8 T-Lymphocytes in Xenogeneic and Human Graft-versus-Host Disease.

Front Immunol 2020 24;11:579776. Epub 2020 Nov 24.

INSERM U976, Université de Paris, École Pratique des Hautes Études/PSL Research University, Institut de Recherche Saint Louis, Paris, France.

Mechanisms driving acute graft-versus-host disease (aGVHD) onset in patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT) are still poorly understood. To provide a detailed characterization of tissue-infiltrating T lymphocytes (TL) and search for eventual site-specific specificities, we developed a xenogeneic model of aGVHD in immunodeficient mice. Phenotypic characterization of xenoreactive T lymphocytes (TL) in diseased mice disclosed a massive infiltration of GVHD target organs by an original CD4CD8 TL subset. Immunophenotypic and transcriptional profiling shows that CD4CD8 TL comprise a major PD1CD62L transitional memory subset (>60%) characterized by low level expression of cytotoxicity-related transcripts. CD4CD8 TL produce high IL-10 and IL-13 levels, and low IL-2 and IFN-γ, suggestive of regulatory function. In vivo tracking of genetically labeled CD4 or CD8 TL subsequently found that CD4CD8 TL mainly originate from chronically activated cytotoxic TL (CTL). On the other hand, phenotypic profiling of CD3 TL from blood, duodenum or rectal mucosa in a cohort of allo-HSCT patients failed to disclose abnormal expansion of CD4CD8 TL independent of aGVHD development. Collectively, our results show that acquisition of surface CD4 by xenoreactive CD8 CTL is associated with functional diversion toward a regulatory phenotype, but rule out a central role of this subset in the pathogenesis of aGVHD in allo-HSCT patients.
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http://dx.doi.org/10.3389/fimmu.2020.579776DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7732609PMC
June 2021

Feasibility of a fetal anatomy 3D atlas by computer-assisted anatomic dissection.

J Gynecol Obstet Hum Reprod 2020 Nov 2;49(9):101880. Epub 2020 Aug 2.

Paris University, Faculty of Medicine, Paris, France.

Objective: To assess the feasibility of 3D modelisation of fetal anatomy by using the Computer-assisted anatomic dissection (CAAD) based on immunolabeled histologic slices and MRI slices with a specific 3D software.

Study Design: For pelvis and lower limbs, subjects came from legal abortion, medical pregnancy termination, or late miscarriage. Specimens were fixed in 10 % formalin, then embedded in paraffin wax and serially sectioned. The histological slices were stained using HES and Masson Trichrome. Protein S-100 and D2-40 markers were used for immuno-labelling. Serial transverse sections were digitalized and manually aligned. Fetal brain slices were obtained from in utero or post-mortem MRI.

Results: CAAD was performed on 10 fetuses: pelvis was modelised with 3 fetuses of 13, 15 and 24 W G, lower limbs with 2 fetuses of 14 and 15 W G and brain with 5 fetuses aged between 19 and 37 W G. Fetal pelvis innervation was analysed after immunolabelling and nerves appeared proportionally bigger than in adults with the same topography. Lower limbs analysis revealed that nerve development was guided by vascular development: the sciatic nerve along the big axial vein, the saphen nerve along the big saphen vein and the sural nerve along the small saphen vein. Fetal brain study allowed to describe the gyration process and the lateral ventricle development.

Conclusion: CAAD technique provides an accurate 3D reconstruction of fetal anatomy for lower limbs and pelvis but has to be improved for brain model since midline structures were not amendable for analysis. These results need to be confirmed with larger series of specimens at different stages of development.
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http://dx.doi.org/10.1016/j.jogoh.2020.101880DOI Listing
November 2020

Single-Cell Transcriptomic Analyses of the Developing Meninges Reveal Meningeal Fibroblast Diversity and Function.

Dev Cell 2020 07;54(1):43-59.e4

Department of Pediatrics Section of Developmental Biology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA; Cell Biology, Stem Cells and Development Graduate Program, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA. Electronic address:

The meninges are a multilayered structure composed of fibroblasts, blood and lymphatic vessels, and immune cells. Meningeal fibroblasts secrete a variety of factors that control CNS development, yet strikingly little is known about their heterogeneity or development. Using single-cell sequencing, we report distinct transcriptional signatures for fibroblasts in the embryonic dura, arachnoid, and pia. We define new markers for meningeal layers and show conservation in human meninges. We find that embryonic meningeal fibroblasts are transcriptionally distinct between brain regions and identify a regionally localized pial subpopulation marked by the expression of μ-crystallin. Developmental analysis reveals a progressive, ventral-to-dorsal maturation of telencephalic meninges. Our studies have generated an unparalleled view of meningeal fibroblasts, providing molecular profiles of embryonic meningeal fibroblasts by layer and yielding insights into the mechanisms of meninges development and function.
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http://dx.doi.org/10.1016/j.devcel.2020.06.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7769050PMC
July 2020

PHOX2B Immunostaining: A Simple and Helpful Tool for the Recognition of Ganglionic Cells and Diagnosis of Hirschsprung Disease.

Am J Surg Pathol 2020 10;44(10):1389-1397

Departments of Pathology.

Hirschsprung disease (HD) is a congenital disorder of the enteric nervous system that occurs in ∼1 in 5000 live births. It is characterized by the absence of ganglionic cells (GCs) in the distal intestine. The diagnosis relies on the thorough analysis of a rectal suction biopsy (RSB), which must show a complete absence of GCs after careful examination of at least 100 serial sections. Such a negative characteristic explains the difficulty of this diagnosis. Moreover, GCs may be immature in very young or preterm born children, making them hard to recognize. Therefore, ancillary techniques have been developed as diagnostic help, such as acetylcholinesterase histochemistry and calretinin immunostaining. These techniques reveal only indirect clues, focusing mainly on the changes in nerve fibers, but not on GCs themselves. As PHOX2B has been shown to be a very specific transcription factor in GCs and in progenitor enteric nerve cells, we have assessed (i) PHOX2B immunostaining in immature enteric ganglia and (ii) the use of PHOX2B immunostaining for the recognition of GCs on RSBs for suspicion of HD. We have observed PHOX2B expression in all GCs, both mature and immature, and its complete absence in Hirschsprung cases. We suggest that the use of PHOX2B immunostaining is of great help (i) in the recognition of GCs on RSBs regardless of their differentiation and therefore (ii) in the diagnosis of HD.
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http://dx.doi.org/10.1097/PAS.0000000000001528DOI Listing
October 2020

primary microcephaly is associated with hypothalamic, retinal and cochlear developmental defects.

J Med Genet 2020 06 3;57(6):389-399. Epub 2020 Feb 3.

Département de Génétique, APHP, Hopital Robert Debré, 75019 Paris, France

Background: Primary hereditary microcephaly (MCPH) comprises a large group of autosomal recessive disorders mainly affecting cortical development and resulting in a congenital impairment of brain growth. Despite the identification of >25 causal genes so far, it remains a challenge to distinguish between different MCPH forms at the clinical level.

Methods: 7 patients with newly identified mutations in (MCPH3) were investigated by performing prospective, extensive and systematic clinical, MRI, psychomotor, neurosensory and cognitive examinations under similar conditions.

Results: All patients displayed neurosensory defects in addition to microcephaly. Small cochlea with incomplete partition type II was found in all cases and was associated with progressive deafness in 4 of them. Furthermore, the CDK5RAP2 protein was specifically identified in the developing cochlea from human fetal tissues. Microphthalmia was also present in all patients along with retinal pigmentation changes and lipofuscin deposits. Finally, hypothalamic anomalies consisting of interhypothalamic adhesions, a congenital midline defect usually associated with holoprosencephaly, was detected in 5 cases.

Conclusion: This is the first report indicating that not only governs brain size but also plays a role in ocular and cochlear development and is necessary for hypothalamic nuclear separation at the midline. Our data indicate that CDK5RAP2 should be considered as a potential gene associated with deafness and forme fruste of holoprosencephaly. These children should be given neurosensory follow-up to prevent additional comorbidities and allow them reaching their full educational potential.

Trial Registration Number: NCT01565005.
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http://dx.doi.org/10.1136/jmedgenet-2019-106474DOI Listing
June 2020

Finding vacuolated lymphocytes in fetal effusions improves the prenatal diagnosis of lysosomal storage diseases.

Prenat Diagn 2020 04 11;40(5):605-611. Epub 2020 Feb 11.

Fœtopathologie, Hôpital Robert-Debré Paris, APHP, Paris, France.

Objectives: There are many causes of fetal effusions, including the rare lysosomal storage diseases (LSDs). Vacuolated lymphocytes (VLs) are found in the blood of infants with LSDs, and their presence in fetal effusion could increase the risk of underlying LSD.

Methods: Between 2006 and 2018, all fetal effusions samples from 43 fetal multidisciplinary centers were referred to a single laboratory. Cells were counted, and, if observed, VLs were categorized and counted. Screening for LSDs was performed by metabolite analyses on amniotic fluid supernatant. The diagnosis of an LSD was confirmed by measuring the activity of the corresponding enzyme and/or mutation analysis.

Results: Our laboratory received 614 ascitic fluids and 280 pleural fluids sampled between 22 and 33 weeks of gestation. The final diagnosis was LSD in 16 cases (1.8%). VLs were reported in all these 16 cases, in a mix of lymphocytes with and without vacuoles. Vacuoles in VLs varied in size and number. In most cases, VLs were easy to recognize, with numerous, large, round, well-defined vacuoles, but in three cases of LSDs, VLs were atypical.

Conclusion: The finding of VLs in fetal effusions is an inexpensive first-line test that may help to prioritize biochemical and genetic tests for LSDs.
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http://dx.doi.org/10.1002/pd.5657DOI Listing
April 2020

Spatiotemporal expansion of primary progenitor zones in the developing human cerebellum.

Science 2019 10 17;366(6464):454-460. Epub 2019 Oct 17.

Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, WA, USA.

We present histological and molecular analyses of the developing human cerebellum from 30 days after conception to 9 months after birth. Differences in developmental patterns between humans and mice include spatiotemporal expansion of both ventricular and rhombic lip primary progenitor zones to include subventricular zones containing basal progenitors. The human rhombic lip persists longer through cerebellar development than in the mouse and undergoes morphological changes to form a progenitor pool in the posterior lobule, which is not seen in other organisms, not even in the nonhuman primate the macaque. Disruptions in human rhombic lip development are associated with posterior cerebellar vermis hypoplasia and Dandy-Walker malformation. The presence of these species-specific neural progenitor populations refines our insight into human cerebellar developmental disorders.
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http://dx.doi.org/10.1126/science.aax7526DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6897295PMC
October 2019

Sostdc1 is expressed in all major compartments of developing and adult mammalian eyes.

Graefes Arch Clin Exp Ophthalmol 2019 Nov 16;257(11):2401-2427. Epub 2019 Sep 16.

Centre de Recherches des Cordeliers, UMR_S INSERM 1138, Equipe 17, Université Paris Descartes, 15 rue de l'école de médecine, 75006, Paris, France.

Purpose: This study was conducted in order to study Sostdc1 expression in rat and human developing and adult eyes.

Methods: Using the yeast signal sequence trap screening method, we identified the Sostdc1 cDNA encoding a protein secreted by the adult rat retinal pigment epithelium. We determined by in situ hybridization, RT-PCR, immunohistochemistry, and western blot analysis Sostdc1 gene and protein expression in developing and postnatal rat ocular tissue sections. We also investigated Sostdc1 immunohistolocalization in developing and adult human ocular tissues.

Results: We demonstrated a prominent Sostdc1 gene expression in the developing rat central nervous system (CNS) and eyes at early developmental stages from E10.5 days postconception (dpc) to E13 dpc. Specific Sostdc1 immunostaining was also detected in most adult cells of rat ocular tissue sections. We also identified the rat ocular embryonic compartments characterized by a specific Sostdc1 immunohistostaining and specific Pax6, Sox2, Otx2, and Vsx2 immunohistostaining from embryonic stages E10.5 to E13 dpc. Furthermore, we determined the localization of SOSTDC1 immunoreactivity in ocular tissue sections of developing and adult human eyes. Indeed, we detected SOSTDC1 immunostaining in developing and adult human retinal pigment epithelium (RPE) and neural retina (NR) as well as in several developing and adult human ocular compartments, including the walls of choroidal and scleral vessels. Of utmost importance, we observed a strong SOSTDC1 expression in a pathological ocular specimen of type 2 Peters' anomaly complicated by retinal neovascularization as well in the walls ofother pathological extra-ocular vessels.  CONCLUSION: As rat Sostdc1 and human SOSTDC1 are dual antagonists of the Wnt/β-catenin and BMP signaling pathways, these results underscore the potential crucial roles of these pathways and their antagonists, such as Sostdc1 and SOSTDC1, in developing and adult mammalian normal eyes as well as in syndromic and nonsyndromic congenital eye diseases.
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http://dx.doi.org/10.1007/s00417-019-04462-4DOI Listing
November 2019

Study of Human T21 Placenta Suggests a Potential Role of Mesenchymal Spondin-2 in Placental Vascular Development.

Endocrinology 2019 03;160(3):684-698

INSERM, UMR-S 1139, Paris, France.

Placental development is particularly altered in trisomy of chromosome 21 (T21)-affected pregnancies. We previously described in T21-affected placentae an abnormal paracrine crosstalk between the villus mesenchymal core and villus trophoblasts. T21-affected placentae are known to be characterized by their hypovascularity. However, the causes of this anomaly remain not fully elucidated. Therefore, the hypothesis of an abnormal paracrine crosstalk between fetal mesenchymal core and placental endothelial cells (PLECs) was evocated. Villus mesenchymal cells from control (CMCs) and T21 placentae (T21MCs) were isolated and grown in culture to allow their characterization and collection of conditioned media for functional analyses (CMC-CM and T21MC-CM, respectively). Interestingly, PLEC proliferation and branching ability were less stimulated by T21MC-CM than by CMC-CM. Protein array analysis identified secreted proangiogenic growth factors in CMC-CM, which were reduced in T21MC-CM. Combined mass spectrometry and biochemical analysis identified spondin-2 as a factor decreased in T21MC-CM compared with CMC-CM. We found that exogenous spondin-2 stimulated PLEC proliferation and established that T21MC-CM supplemented with spondin-2 recovered conditioned media ability to induce PLEC proliferation and angiogenesis. Hence, this study demonstrates a crosstalk between villus mesenchymal and fetal endothelial cells, in which spondin-2 secreted from mesenchymal cells plays a central role in placental vascular functions. Furthermore, our results also suggest that a reduction in spondin-2 secretion may contribute to the pathogenesis of T21 placental hypovascularity.
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http://dx.doi.org/10.1210/en.2018-00826DOI Listing
March 2019

TRAP Sequence in Monochorionic/Monoamniotic (MC/MA) Discordant Twins: Two Cases Treated with Fetoscopic Laser Surgery.

Fetal Pediatr Pathol 2018 12 12;37(6):433-447. Epub 2019 Jan 12.

h Paulista School of Medicine - Federal University of São Paulo, Obstetrics , São Paulo , Brazil.

Introduction: Ablation of the acardiac twin umbilical cord in the TRAP protects the normal donor twin.

Materials And Methods: Two case descriptions, one of interstitial laser photocoagulation and one of laser umbilical cord occlusion (L-UCO) of the acardiac twin in monochorionic monoamniotic pregnancies are reported.

Results: L-UCO in two pregnancies with TRAP syndrome in the second trimester resulted in intrauterine fetal death in both cases after 1 month. Case 1 had no detectable cause of fetal death. Case 2 had rupture of the amniotic sac causing anhydramnios and acute chorioamnionitis. A groove on the umbilical cord of the normal twin indicated a cord stricture due to cord entanglement.

Conclusion: Our experience confirms that the best timing and optimal treatment of MC/MA twins complicated by TRAP sequence still remains a controversial clinical issue. Cord entanglement may continue be a potential clinical risk factor for adverse perinatal outcome even after ablation therapy.
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http://dx.doi.org/10.1080/15513815.2018.1526240DOI Listing
December 2018

Bardet-Biedl syndrome: Antenatal presentation of forty-five fetuses with biallelic pathogenic variants in known Bardet-Biedl syndrome genes.

Clin Genet 2019 03;95(3):384-397

Laboratoire de Diagnostic Génétique, Hôpitaux Universitaires de Strasbourg, Strasbourg, France.

Bardet-Biedl syndrome (BBS) is an emblematic ciliopathy associated with retinal dystrophy, obesity, postaxial polydactyly, learning disabilities, hypogonadism and renal dysfunction. Before birth, enlarged/cystic kidneys as well as polydactyly are the hallmark signs of BBS to consider in absence of familial history. However, these findings are not specific to BBS, raising the problem of differential diagnoses and prognosis. Molecular diagnosis during pregnancies remains a timely challenge for this heterogeneous disease (22 known genes). We report here the largest cohort of BBS fetuses to better characterize the antenatal presentation. Prenatal ultrasound (US) and/or autopsy data from 74 fetuses with putative BBS diagnosis were collected out of which molecular diagnosis was established in 51 cases, mainly in BBS genes (45 cases) following the classical gene distribution, but also in other ciliopathy genes (6 cases). Based on this, an updated diagnostic decision tree is proposed. No genotype/phenotype correlation could be established but postaxial polydactyly (82%) and renal cysts (78%) were the most prevalent symptoms. However, autopsy revealed polydactyly that was missed by prenatal US in 55% of the cases. Polydactyly must be carefully looked for in pregnancies with apparently isolated renal anomalies in fetuses.
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http://dx.doi.org/10.1111/cge.13500DOI Listing
March 2019

Studies in an Early Development Window Unveils a Severe HSC Defect in both Murine and Human Fanconi Anemia.

Stem Cell Reports 2018 11 25;11(5):1075-1091. Epub 2018 Oct 25.

CNRS UMR7622/IBPS, Paris, France; Université Pierre et Marie Curie, Sorbonne Universités, Paris, France; INSERM UMR_S1131, Hôpital Saint Louis, Paris, France; IUH, Université Paris Diderot, Sorbonne Paris Cité, Paris, France. Electronic address:

Fanconi anemia (FA) causes bone marrow failure early during childhood, and recent studies indicate that a hematopoietic defect could begin in utero. We performed a unique kinetics study of hematopoiesis in Fancg mouse embryos, between the early embryonic day 11.5 (E11.5) to E12.5 developmental window (when the highest level of hematopoietic stem cells [HSC] amplification takes place) and E14.5. This study reveals a deep HSC defect with exhaustion of proliferative and self-renewal capacities very early during development, together with severe FA clinical and biological manifestations, which are mitigated at E14.5 due to compensatory mechanisms that help to ensure survival of Fancg embryos. It also reports that a deep HSC defect is also observed during human FA development, and that human FA fetal liver (FL) HSCs present a transcriptome profile similar to that of mouse E12.5 Fancg FL HSCs. Altogether, our results highlight that early mouse FL could represent a good alternative model for studying Fanconi pathology.
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http://dx.doi.org/10.1016/j.stemcr.2018.10.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6234961PMC
November 2018

Three-Dimensional Modelization of the Female Human Inferior Hypogastric Plexus: Implications for Nerve-Sparing Radical Hysterectomy.

Gynecol Obstet Invest 2019 31;84(2):196-203. Epub 2018 Oct 31.

Department of Gynecologic and Breast Oncologic Surgery, Georges Pompidou European Hospital, Paris, France.

Background/aims: This study aims to describe the autonomic nervous network of the female pelvis with a 3D model and to provide a safe plane of dissection during radical hysterectomy for cervical cancer.

Methods: Pelvises of 3 human female fetuses were studied by using the computer-assisted anatomic dissection.

Results: The superior hypogastric plexus (SHP) was located at the level of the aortic bifurcation in front of the sacral promontory and divided inferiorly and laterally into 2 hypogastric nerves (HN). HN ran postero-medially to the ureter and in the lateral part of the uterosacral ligament until the superior angle of the inferior hypogastric plexus (IHP). IHP extended from the anterolateral face of the rectum, laterally to the cervix and attempted to the base of the bladder. Vesical efferences merged from the crossing point of the ureter and the uterine artery and ran through the posterior layer of the vesico-uterine ligament.

Conclusions: The SHP could be injured during paraaortic lymphadenectomy. Following the ureter and resecting the medial fibrous part of the uterosacral ligament may spare the HN. No dissection should be performed under the crossing point of the ureter and the uterine artery.
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http://dx.doi.org/10.1159/000494255DOI Listing
May 2019

Duplicated distal phalanx of thumb or hallux in trisomy 13: A recurrent feature in a series of 42 fetuses.

Am J Med Genet A 2018 11 17;176(11):2325-2330. Epub 2018 Oct 17.

Unité fonctionnelle de fœtopathologie, Département de génétique, CHU Robert Debré, Assistance Publique - Hôpitaux de Paris, Paris, France.

Trisomy 13 or Patau syndrome (PS) is a well-known aneuploidy characterized by a polymalformative syndrome. We described a large series of fetuses with PS and compared them with cases described in the literature, most of which were live-born. In all, 42 fetuses, aged from 14 to 41 gestational weeks (GW), were examined. The main defects observed were similar to those described in live-born patients: congenital heart defects (76%), holoprosencephaly spectrum anomalies including arhinencephaly and hypotelorism (74%), urinary tract anomalies (71%), ear anomalies (69%), postaxial polydactyly (67%), anogenital anomalies (60%), anophthalmos, and/or microphthalmos (53%), brachycephaly (45%), and oro-facial clefts (45%). A duplication or triplication of at least one distal phalanx of the thumb or hallux was present in 38% of fetuses. This sign has only been reported previously in one patient in the literature. Fetal examination in trisomy 13, is thus, useful to complete the phenotype or to orient diagnosis toward trisomy 13 in the absence of cytogenetic analysis.
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http://dx.doi.org/10.1002/ajmg.a.40505DOI Listing
November 2018

Severe Phenotype of Cutis Laxa Type 1B with Antenatal Signs due to a Novel Homozygous Nonsense Mutation in .

Mol Syndromol 2018 Jul 8;9(4):190-196. Epub 2018 Jun 8.

Unités Fonctionnelles de Fœtopathologie.

mutations are known to be responsible for autosomal recessive cutis laxa type 1B (ARCL1B), a rare multisystem disease affecting skin, skeleton, and vascular structures. We report 2 additional related cases of ARCL1B of particular severity leading to termination of pregnancy. Cardinal signs of this connective tissue disease were already seen during the second trimester of pregnancy, then confirmed and clarified at autopsy. Anomalies included cutis laxa, arachnodactyly, clubfoot, wormian bones, moderate bowing of long bones with slender bone trabeculae, rib fractures, undermuscularized diaphragm, hiatal hernia, and arterial tortuosity with thick vascular walls and disorganized elastic fibers. Sequencing of the gene revealed a novel homozygous nonsense mutation: c.639C>A (p.Cys213*). We performed a thorough histological analysis and discuss differential diagnoses, genotype-phenotype correlations, and the challenge of prenatal diagnosis of this disease.
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http://dx.doi.org/10.1159/000489838DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6103346PMC
July 2018

How to Explore Fetal Sacral Agenesis Without Open Dysraphism: Key Prenatal Imaging and Clinical Implications.

J Ultrasound Med 2018 Jul 27;37(7):1807-1820. Epub 2018 Jan 27.

Department of Obstetrics and Gynecology, Hospital Antoine Béclère, Assistance Publique-Hôpitaux de Paris, Université Paris Sud, Paris, France.

The estimated prevalence of fetal caudal dysgenesis is 1 per 100,000 births. The functional prognosis of sacral agenesis is dominated by the large spectrum of associated caudal malformations. Except for cases associated with hydrocephalus secondary to open spinal dysraphism or chromosomal anomalies, association with mental deficiency is rare. We propose a systematic prenatal approach to cases of fetal sacral agenesis based on 9 etiologic items: clinical context, type of sacral dysgenesis, associated spinal cord malformations, mobility of lower limbs, investigation of the presacral region, analysis of the gastrointestinal tract, analysis of the genitourinary tract, associated vertebral defects, and cytogenetic analysis.
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http://dx.doi.org/10.1002/jum.14522DOI Listing
July 2018

Placental Findings and Effect of Prophylactic Hydrocortisone in Extremely Preterm Infants.

Pediatrics 2018 02 18;141(2). Epub 2018 Jan 18.

NICU,

Objectives: To investigate the relationship between histologic findings of the placenta and response to early postnatal hydrocortisone treatment used to prevent bronchopulmonary dysplasia (BPD) in extremely preterm infants.

Methods: In an exploratory analysis of the Early Low-Dose Hydrocortisone to Improve Survival Without Bronchopulmonary Dysplasia in Extremely Preterm Infants (PREMILOC) trial, detailed placental analyses were performed on the basis of standardized macroscopic and histologic examinations. Placental histology, categorized into 3 groups, was correlated to neonatal outcomes and response to hydrocortisone treatment.

Results: Of 523 randomly assigned patients, 457 placentas were analyzed. In total, 125 out of 457 (27%) placentas were classified as normal, 236 out of 457 (52%) placentas were classified as inflammatory, and 96 out of 457 (21%) placentas were classified as vascular. Placental inflammation was associated with a significant, increased rate of BPD-free survival at 36 weeks' postmenstrual age, independent of gestational age, treatment group, and sex (adjusted odds ratio: 1.72, 95% confidence interval [CI]: 1.05 to 2.82, = .03). Regarding the response to treatment, the strongest benefit of hydrocortisone compared with placebo was found in infants born after placental vascular disease, with significantly more patients extubated at day 10 (risk difference: 0.32, 95% CI: 0.08 to 0.56, = .004) and similar positive direction on survival without BPD (risk difference: 0.23, 95% CI: 0.00 to 0.46, = .06). Adjusted to gestational age and treatment groups, placental inflammation was associated with significantly fewer patent ductus arteriosus ligation (adjusted hazard ratio: 0.58, 95% CI: 0.36 to 0.95, = .03). Placental histology was not found to be associated with other adverse events related to preterm birth.

Conclusions: With these findings, we confirm that early low-dose hydrocortisone confers benefits in extremely preterm infants overall and we suggest there is a higher treatment effect in those born after placental vascular disease.
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http://dx.doi.org/10.1542/peds.2017-1788DOI Listing
February 2018

Molecular and Functional Characterization of Lymphoid Progenitor Subsets Reveals a Bipartite Architecture of Human Lymphopoiesis.

Immunity 2017 10;47(4):680-696.e8

INSERM U1126, Université Paris-Diderot, École Pratique des Hautes Etudes/PSL Research University, Institut Universitaire d'Hématologie, Hôpital Saint-Louis, Paris, France. Electronic address:

The classical model of hematopoiesis established in the mouse postulates that lymphoid cells originate from a founder population of common lymphoid progenitors. Here, using a modeling approach in humanized mice, we showed that human lymphoid development stemmed from distinct populations of CD127 and CD127 early lymphoid progenitors (ELPs). Combining molecular analyses with in vitro and in vivo functional assays, we demonstrated that CD127 and CD127 ELPs emerged independently from lympho-mono-dendritic progenitors, responded differently to Notch1 signals, underwent divergent modes of lineage restriction, and displayed both common and specific differentiation potentials. Whereas CD127 ELPs comprised precursors of T cells, marginal zone B cells, and natural killer (NK) and innate lymphoid cells (ILCs), CD127 ELPs supported production of all NK cell, ILC, and B cell populations but lacked T potential. On the basis of these results, we propose a "two-family" model of human lymphoid development that differs from the prevailing model of hematopoiesis.
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http://dx.doi.org/10.1016/j.immuni.2017.09.009DOI Listing
October 2017

Molecular and clinical delineation of 2p15p16.1 microdeletion syndrome.

Am J Med Genet A 2017 Aug 1;173(8):2081-2087. Epub 2017 Jun 1.

Genetics Department, AP-HP, Robert-Debré University Hospital, Paris, France.

Interstitial 2p15p16.1 microdeletion is a rare chromosomal syndrome previously reported in 33 patients. It is characterized by intellectual disability, developmental delay, autism spectrum disorders, microcephaly, short stature, dysmorphic features, and multiple congenital organ defects. It is defined as a contiguous gene syndrome and two critical regions have been proposed at 2p15 and 2p16.1 loci. Nevertheless, patients with deletion of both critical regions shared similar features of the phenotype and the correlation genotype-phenotype is still unclear. We review all published cases and describe three additional patients, to define the phenotype-genotype correlation more precisely. We reported on two patients including the first prenatal case described so far, carrying a 2p15 deletion affecting two genes: XPO1 and part of USP34. Both patients shared similar features including facial dysmorphism and cerebral abnormalities. We considered the genes involved in the deleted segment to further understand the abnormal phenotype. The third case we described here was a 4-year-old boy with a heterozygous de novo 427 kb deletion encompassing BCL11A and PAPOLG at 2p16.1. He displayed speech delay, autistic traits, and motor stereotypies associated with brain structure abnormalities. We discuss the contribution of the genes included in the deletion to the abnormal phenotype. Our three new patients compared to previous cases, highlighted that despite two critical regions, both distal deletion at 2p16.1 and proximal deletion at 2p15 are associated with phenotypes that are very close to each other. Finally, we also discuss the genetic counseling of this microdeletion syndrome particularly in the course of prenatal diagnosis.
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http://dx.doi.org/10.1002/ajmg.a.38302DOI Listing
August 2017

Hydrocephalus due to multiple ependymal malformations is caused by mutations in the MPDZ gene.

Acta Neuropathol Commun 2017 05 1;5(1):36. Epub 2017 May 1.

Department of Pathology, Normandie Univ, UNIROUEN, INSERM U1245, Rouen University Hospital, F76000, Rouen, France.

Congenital hydrocephalus is considered as either acquired due to haemorrhage, infection or neoplasia or as of developmental nature and is divided into two subgroups, communicating and obstructive. Congenital hydrocephalus is either syndromic or non-syndromic, and in the latter no cause is found in more than half of the patients. In patients with isolated hydrocephalus, L1CAM mutations represent the most common aetiology. More recently, a founder mutation has also been reported in the MPDZ gene in foetuses presenting massive hydrocephalus, but the neuropathology remains unknown. We describe here three novel homozygous null mutations in the MPDZ gene in foetuses whose post-mortem examination has revealed a homogeneous phenotype characterized by multiple ependymal malformations along the aqueduct of Sylvius, the third and fourth ventricles as well as the central canal of the medulla, consisting in multifocal rosettes with immature cell accumulation in the vicinity of ependymal lining early detached from the ventricular zone. MPDZ also named MUPP1 is an essential component of tight junctions which are expressed from early brain development in the choroid plexuses and ependyma. Alterations in the formation of tight junctions within the ependyma very likely account for the lesions observed and highlight for the first time that primary multifocal ependymal malformations of the ventricular system is genetically determined in humans. Therefore, MPDZ sequencing should be performed when neuropathological examination reveals multifocal ependymal rosette formation within the aqueduct of Sylvius, of the third and fourth ventricles and of the central canal of the medulla.
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http://dx.doi.org/10.1186/s40478-017-0438-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5412059PMC
May 2017

Phenotypic outcomes in Mouse and Human dependent Dandy-Walker cerebellar malformation suggest shared mechanisms.

Elife 2017 01 16;6. Epub 2017 Jan 16.

Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, United States.

loss contributes to Dandy-Walker malformation (DWM), a common human cerebellar malformation. Previously, we found that complete loss leads to aberrations in proliferation, neuronal differentiation and migration in the embryonic mouse cerebellum (Haldipur et al., 2014). We now demonstrate that hypomorphic mutant mice have granule and Purkinje cell abnormalities causing subsequent disruptions in postnatal cerebellar foliation and lamination. Particularly striking is the presence of a partially formed posterior lobule which echoes the posterior vermis DW 'tail sign' observed in human imaging studies. Lineage tracing experiments in mutant mouse cerebella indicate that aberrant migration of granule cell progenitors destined to form the posterior-most lobule causes this unique phenotype. Analyses of rare human del chr 6p25 fetal cerebella demonstrate extensive phenotypic overlap with our mutant mouse models, validating our DWM models and demonstrating that many key mechanisms controlling cerebellar development are likely conserved between mouse and human.
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http://dx.doi.org/10.7554/eLife.20898DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5271606PMC
January 2017

Fraser syndrome: features suggestive of prenatal diagnosis in a review of 38 cases.

Prenat Diagn 2016 Dec 9;36(13):1270-1275. Epub 2016 Dec 9.

Department of Genetics, Rouen University Hospital and Inserm U1079, Faculty of Medicine, Normandy Centre for Genomic and Personalized Medicine, Rouen, France.

Objective: Fraser syndrome (FS) is a rare malformation recessive disorder. Major criteria are cryptophtalmos, syndactyly, respiratory, genital and urinary tract anomalies. Few prenatal presentations have been reported.

Method: We analyzed the prenatal and postnatal fetal phenotype in 38 cases of FS, including 25 pregnancy termination cases, 8 intra-uterine death cases and 4 cases that died after birth.

Results: Including both prenatal and postnatal fetal phenotypic evaluation, all cases presented dysmorphic features with nose and ear dysplasia. Renal anomalies and syndactyly were present in 37/38 cases, cryptophtalmos in 36/38, airways anomalies in 30/37 and genital anomalies in 30/35 cases. Anomalies of the abdominal wall such as low set umbilicus and omphalocele were found in 31 cases. Among the 26 cases for which ultrasound data were available, detectable anomalies included oligohydramnios (22), ascites/hydrops (9), renal anomalies (20), evidence for high airways obstruction (11), ophthalmologic anomalies (4), ear dysplasia (2) and syndactyly (2).

Conclusion: This study shows that the postnatal phenotype of FS is very specific, whereas oligohydramnios hampers the prenatal recognition of the cardinal FS diagnosis criteria. Association of oligohydramnios, kidney agenesis and CHAOS should lead to consider this diagnosis. © 2016 John Wiley & Sons, Ltd.
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http://dx.doi.org/10.1002/pd.4971DOI Listing
December 2016

Think of the Conus Medullaris at the Time of Diagnosis of Fetal Sacral Agenesis.

Fetal Diagn Ther 2017 29;42(2):137-143. Epub 2016 Oct 29.

Department of Obstetrics, Gynecology and Reproductive Medicine, Hospital Antoine Béclère, AP-HP, Université Paris-Sud, Paris, France.

Background: There is no precise prenatal indicator to refine an accurate prognosis in case of sacral agenesis and to define the diagnostic approach and outcome criteria in case of fetal sacral agenesis using 3 characteristics of the conus medullaris (CM): its position, its appearance, and associated spinal abnormalities.

Methods: Ten cases of prenatally diagnosed sacral agenesis were included between 1995 and 2014 after collating ultrasound findings and prenatal computed tomography data.

Results: Two cases of total sacral agenesis and 8 of partial agenesis were included. There were 1 or more spinal abnormalities in 8/10 cases: 6 lipomas, 4 low-lying tethered cords, 2 diastematomyelias, and 1 syringomyelia. Three situations were distinguished: sacral agenesis with low-lying tethered cord, sacral agenesis with a truncated CM, and sacral agenesis with CM in place. If the sacral agenesis is isolated, a lipoma should be sought. Lipomas of the filum have a good prognosis, whereas lipomas of the CM cause neurological deficits in 1/3 of cases. When there is a low-lying tethered cord, a diastematomyelia or a syringomyelia may be associated. In truncated CM, there may be a severe form suggestive of caudal regression syndrome. Serious ultrasound signs are immobility of the lower limbs, talipes equinovarus, impaired bladder emptying, and dilatation of the upper urinary tract.

Conclusion: A precise description of the morphology of the CM, its position, and associated spinal malformations are important in defining the neurological, urinary, gastrointestinal, and motor functions prognosis in cases of fetal sacral agenesis.
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http://dx.doi.org/10.1159/000451080DOI Listing
May 2018
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