Publications by authors named "Fanny Pelluard"

31 Publications

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

Chronic Intervillositis of Unknown Etiology: Development of a Grading and Scoring System That Is Strongly Associated With Poor Perinatal Outcomes.

Am J Surg Pathol 2020 10;44(10):1367-1373

CNRS-UMR 5164 ImmunoConcEpT.

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 space: grade 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.
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http://dx.doi.org/10.1097/PAS.0000000000001549DOI Listing
October 2020

Adverse perinatal outcomes of chronic intervillositis of unknown etiology: an observational retrospective study of 122 cases.

Sci Rep 2020 07 28;10(1):12611. Epub 2020 Jul 28.

Department of Internal Medicine, Bordeaux University Hospital, Bordeaux, France.

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%.
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http://dx.doi.org/10.1038/s41598-020-69191-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7387519PMC
July 2020

p57-discordant villi in hydropic products of conception: a clinicopathological study of 70 cases.

Hum Pathol 2020 07 6;101:18-30. Epub 2020 May 6.

Department of Pathology, Lyon Sud University Hospital, Hospices Civils de Lyon, Pierre Bénite, Lyon, 69495, France; French Reference Center for Gestational Trophoblastic Diseases, Lyon Sud University Hospital, Hospices Civils de Lyon, Pierre-Bénite, 69495, France. Electronic address:

p57 immunostaining is performed on hydropic products of conception to diagnose hydatidiform moles (HMs), which can progress to gestational trophoblastic neoplasia. Partial hydatidiform mole (PHM) and hydropic abortion (HA) display positive staining in stromal and cytotrophoblastic cells, whereas complete hydatidiform mole (CHM) is characterized by loss of p57 expression in both cell types. In some cases, an aberrant pattern is observed, called discordant p57 expression, with positive cytotrophoblast staining and negative stromal staining, or vice versa. The aim of this study was to describe the clinical, biological, and pathological characteristics of p57-discordant villi (p57DV) and other associated populations in cases of divergent p57 expression and to compare the evolutions of p57DV-associated and classic CHMs. Seventy cases of p57DV diagnosed by referent pathologists were divided into two groups, G1: p57DV ± non-CHM component (n = 22) and G2: p57DV + CHM component (n = 48). p57DV morphology was similar in the two groups. Observation of more than two populations and hybrid villi on p57 immunostaining were significantly more frequent in G2. The clinical, ultrasound, and biological presentations of p57DV-associated and classic CHMs were similar. The initial pathological diagnosis was more frequently incorrect, missing the CHM component, for the p57DV-associated CHMs. Molecular genotyping was informative in seven cases and identified as androgenetic/biparental mosaicism in four cases. These results show that p57DV are a diagnostic challenge for pathologists and that most are associated with a CHM component. However, the clinical management of p57DV-associated CHMs should be the same as that of classic CHMs.
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http://dx.doi.org/10.1016/j.humpath.2020.04.011DOI Listing
July 2020

Foetal onset of EIF2B related disorder in two siblings: cerebellar hypoplasia with absent Bergmann glia and severe hypomyelination.

Acta Neuropathol Commun 2020 04 15;8(1):48. Epub 2020 Apr 15.

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

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.
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http://dx.doi.org/10.1186/s40478-020-00929-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7161274PMC
April 2020

TAR syndrome: Clinical and molecular characterization of a cohort of 26 patients and description of novel noncoding variants of RBM8A.

Hum Mutat 2020 07 6;41(7):1220-1225. Epub 2020 Apr 6.

Clinical Genetics Department, Reference Center for Developmental Anomalies, CHU Lille, Lille, France.

Thrombocytopenia-absent radius (TAR) syndrome is characterized by radial defect and neonatal thrombocytopenia. It is caused by biallelic variants of RBM8A gene (1q21.1) with the association of a null allele and a hypomorphic noncoding variant. RBM8A encodes Y14, a core protein of the exon junction complex involved in messenger RNA maturation. To date, only two hypomorphic variants have been identified. We report on a cohort of 26 patients affected with TAR syndrome and carrying biallelic variants in RBM8A. Half patients carried a 1q21.1 deletion and one of the two known hypomorphic variants. Four novel noncoding variants of RBM8A were identified in the remaining patients. We developed experimental models enabling their functional characterization in vitro. Two variants, located respectively in the 5'-untranslated region (5'-UTR) and 3'-UTR regions, are responsible for a diminished expression whereas two intronic variants alter splicing. Our results bring new insights into the molecular knowledge of TAR syndrome and enabled us to propose genetic counseling for patients' families.
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http://dx.doi.org/10.1002/humu.24021DOI Listing
July 2020

Exome sequencing identifies the first genetic determinants of sirenomelia in humans.

Hum Mutat 2020 05 1;41(5):926-933. Epub 2020 Mar 1.

Department of Genetics and Reference Center for Developmental Disorders, Normandy Center for Genomic and Personalized Medicine, Normandie Univ, UNIROUEN, Inserm U1245 and Rouen University Hospital, Rouen, France.

Sirenomelia is a rare severe malformation sequence of unknown cause characterized by fused legs and severe visceral abnormalities. We present a series of nine families including two rare familial aggregations of sirenomelia investigated by a trio-based exome sequencing strategy. This approach identified CDX2 variants in the two familial aggregations, both fitting an autosomal dominant pattern of inheritance with variable expressivity. CDX2 is a major regulator of caudal development in vertebrate and mouse heterozygotes are a previously described model of sirenomelia. Remarkably, the p.(Arg237His) variant has already been reported in a patient with persistent cloaca. Analysis of the sporadic cases revealed six additional candidate variants including a de novo frameshift variant in the genetically constrained NKD1 gene, encoding a known interactor of CDX2. We provide the first insights for a genetic contribution in human sirenomelia and highlight the role of Cdx and Wnt signaling pathways in the development of this disorder.
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http://dx.doi.org/10.1002/humu.23998DOI Listing
May 2020

Human interleukin-2 receptor β mutations associated with defects in immunity and peripheral tolerance.

J Exp Med 2019 06 30;216(6):1311-1327. Epub 2019 Apr 30.

Molecular Development of the Immune System Section, Laboratory of Immune System Biology and Clinical Genomics Program, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD

Interleukin-2, which conveys essential signals for immunity, operates through a heterotrimeric receptor. Here we identify human interleukin-2 receptor (IL-2R) β chain () gene defects as a cause of life-threatening immune dysregulation. We report three homozygous mutations in the gene of eight individuals from four consanguineous families that cause disease by distinct mechanisms. Nearly all patients presented with autoantibodies, hypergammaglobulinemia, bowel inflammation, dermatological abnormalities, lymphadenopathy, and cytomegalovirus disease. Patient T lymphocytes lacked surface expression of IL-2Rβ and were unable to respond to IL-2 stimulation. By contrast, natural killer cells retained partial IL-2Rβ expression and function. IL-2Rβ loss of function was recapitulated in a recombinant system in which mutations caused reduced surface expression and IL-2 binding. Stem cell transplant ameliorated clinical symptoms in one patient; forced expression of wild-type IL-2Rβ also increased the IL-2 responsiveness of patient T lymphocytes in vitro. Insights from these patients can inform the development of IL-2-based therapeutics for immunological diseases and cancer.
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http://dx.doi.org/10.1084/jem.20182304DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6547869PMC
June 2019

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

: report of three cases and review of literature.

Afr Health Sci 2018 Mar;18(1):147-156

Department of Fetopathology, CHU Pellegrin, place Amélie Raba, 33076 Bordeaux cedex France.

Background: (TAC) is a congenital heart defect in which the physiologic arterial common trunk was not divided into aorta and pulmonary artery trunk.

Objectives: In this paper, we report on three observed cases from which we looked for (in conjunction with literature review) the different causes of TAC many of which have genetic origins.

Methods: We collected three clinical files of fetuses having a TAC. Two of them were examinated after a medical termination of pregnancy motivated by severe cardiopathy. The malformation had been diagnosed based on different techniques: echocardiography, skeletal radiography, arteriography, fetal autopsy, karyotype and fluorescence in situ hybridization (FISH).

Results: Imaging and fetopathological examination revealed the presence of TAC type 3 and 4 in the Van Praaghs classification. FISH analysis showed a 22q11.2 deletion in one fetus in favour of Digeorge syndrome. The karyotype analysis performed in two cases was normal.

Conclusion: Truncus arteriosus is a rare pathology caused by numerous etiologies from which many of them have genetic origin. This malformation can be diagnosed early during prenatal period. Postmortem fetopathological examination allows a better diagnosis approach and eventually a genetic counseling in recurrent cases such as case of consanguinity.
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http://dx.doi.org/10.4314/ahs.v18i1.19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6016971PMC
March 2018

Monoallelic BMP2 Variants Predicted to Result in Haploinsufficiency Cause Craniofacial, Skeletal, and Cardiac Features Overlapping Those of 20p12 Deletions.

Am J Hum Genet 2017 Dec 30;101(6):985-994. Epub 2017 Nov 30.

Institute of Medical Genetics, University of Zurich, 8952 Schlieren-Zurich, Switzerland.

Bone morphogenetic protein 2 (BMP2) in chromosomal region 20p12 belongs to a gene superfamily encoding TGF-β-signaling proteins involved in bone and cartilage biology. Monoallelic deletions of 20p12 are variably associated with cleft palate, short stature, and developmental delay. Here, we report a cranioskeletal phenotype due to monoallelic truncating and frameshift BMP2 variants and deletions in 12 individuals from eight unrelated families that share features of short stature, a recognizable craniofacial gestalt, skeletal anomalies, and congenital heart disease. De novo occurrence and autosomal-dominant inheritance of variants, including paternal mosaicism in two affected sisters who inherited a BMP2 splice-altering variant, were observed across all reported families. Additionally, we observed similarity to the human phenotype of short stature and skeletal anomalies in a heterozygous Bmp2-knockout mouse model, suggesting that haploinsufficiency of BMP2 could be the primary phenotypic determinant in individuals with predicted truncating variants and deletions encompassing BMP2. These findings demonstrate the important role of BMP2 in human craniofacial, skeletal, and cardiac development and confirm that individuals heterozygous for BMP2 truncating sequence variants or deletions display a consistent distinct phenotype characterized by short stature and skeletal and cardiac anomalies without neurological deficits.
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http://dx.doi.org/10.1016/j.ajhg.2017.10.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5812889PMC
December 2017

Early fetal presentation of Koolen-de Vries: Case report with literature review.

Eur J Med Genet 2017 Nov 12;60(11):605-609. Epub 2017 Aug 12.

Department of Pathology, Bordeaux University Hospital, Pellegrin Hospital, Bordeaux, France.

Koolen-de Vries syndrome (MIM#610443) is a rare microdeletion syndrome involving the 17q21.31 region, which was first described by Koolen in 2006. Clinical and behavioral characteristics have been extensively reported from more than 100 postnatal cases including infants, children and young adults. The syndrome is highly clinically heterogeneous, but the main features associate characteristic cranio-facial dysmorphism, heart defects, limb, skeletal, genito-urinary anomalies, along with intellectual disability with early childhood epilepsy and behavioral disturbances. Central nervous system malformations usually consist in hydrocephalus and thin corpus callosum. We report herein an early fetal case with an apparently isolated abnormal corpus callosum diagnosed by ultrasonography, for which a medical termination of the pregnancy was achieved at 22 weeks of gestation. Postmortem examination displayed facial dysmorphism consisting of hypertelorism, short philtrum and flat and broad nose, cleft palate and left duplex ureter. Neuropathological examination revealed a mega corpus callosum that has never been reported so far in this syndrome. Array-CGH performed on thymic DNA tissue revealed a 17q21.31 microdeletion, which allowed for the confirmation of early occurring Koolen-de Vries syndrome.
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http://dx.doi.org/10.1016/j.ejmg.2017.08.012DOI Listing
November 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

Prenatal Testicular Torsion: Not Always in the Late Third Trimester.

Urology 2016 Mar 4;89:132-3. Epub 2015 Dec 4.

Department of Fœtopathology, CHU de Bordeaux, Bordeaux, France.

Prenatal testicular torsion is a very rare morbid entity, described in the literature to occur when the testicle is intrascrotal, around the 34th week of gestation. Here we report a case of early testicular necrosis. This male fetus was the product of a medical abortion at 27 weeks. During evisceration, a left testicular nubbin free in the peritoneal cavity was found. Histologically, it was extensively necrotic. Because of the location, the size, and the histological features of this necrotic testicle, we conclude that it was the result of torsion of the pedicle that occurred around the 20th week of pregnancy.
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http://dx.doi.org/10.1016/j.urology.2015.11.024DOI Listing
March 2016

Mutations in KIAA0586 Cause Lethal Ciliopathies Ranging from a Hydrolethalus Phenotype to Short-Rib Polydactyly Syndrome.

Am J Hum Genet 2015 Aug 9;97(2):311-8. Epub 2015 Jul 9.

INSERM U1163, Laboratory of Embryology and Genetics of Congenital Malformations, Paris Descartes University, Sorbonne Paris Cité and Imagine Institute, 75015 Paris, France. Electronic address:

KIAA0586, the human ortholog of chicken TALPID3, is a centrosomal protein that is essential for primary ciliogenesis. Its disruption in animal models causes defects attributed to abnormal hedgehog signaling; these defects include polydactyly and abnormal dorsoventral patterning of the neural tube. Here, we report homozygous mutations of KIAA0586 in four families affected by lethal ciliopathies ranging from a hydrolethalus phenotype to short-rib polydactyly. We show defective ciliogenesis, as well as abnormal response to SHH-signaling activation in cells derived from affected individuals, consistent with a role of KIAA0586 in primary cilia biogenesis. Whereas centriolar maturation seemed unaffected in mutant cells, we observed an abnormal extended pattern of CEP290, a centriolar satellite protein previously associated with ciliopathies. Our data show the crucial role of KIAA0586 in human primary ciliogenesis and subsequent abnormal hedgehog signaling through abnormal GLI3 processing. Our results thus establish that KIAA0586 mutations cause lethal ciliopathies.
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http://dx.doi.org/10.1016/j.ajhg.2015.06.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4573270PMC
August 2015

Incidence of obstetrical thrombotic thrombocytopenic purpura in a retrospective study within thrombocytopenic pregnant women. A difficult diagnosis and a treatable disease.

BMC Pregnancy Childbirth 2015 Jun 17;15:137. Epub 2015 Jun 17.

Service de Néphrologie Transplantation Dialyse, Centre Hospitalier Universitaire de Bordeaux, Bordeaux, France.

Background: Thrombotic thrombocytopenic Purpura (TTP) defined as ADAMTS-13 (A Disintegrin And Metalloprotease with ThromboSpondin type 1 domain 13) activity <10 % is a rare aetiology of thrombocytopenia during pregnancy, although the precise incidence is unknown. During pregnancy, the diagnosis of TTP is crucial as it has high feto-maternal morbidity-mortality and requires urgent plasma exchange. The purpose of this study was to assess the incidence of TTP retrospectively and to describe case presentations and follow-up.

Methods: A monocentric retrospective study (2008-2009) was conducted among pregnant women followed in a tertiary care obstetrical unit who experienced at least one episode of severe thrombocytopenia (platelets ≤75 G/L) during 2008 and 2009. In cases of uncertain aetiology of thrombocytopenia, ADAMTS-13 activity was assessed by the full length technique.

Results: Among 8,908 deliveries over the 2 year period, 79 women had a platelet count nadir ≤75 G/L. Eighteen had a known aetiology of thrombocytopenia and 11 were lost to follow-up. Among 50 remaining patients, ADAMTS-13 activity was undetectable (<5 %) in 4, consistent with the diagnosis of TTP. Platelet count spontaneously normalized in 3 patients after delivery. None presented focal cerebral involvement. Three of the four, who were primipara patients, had a sustained severe deficiency in the absence of anti-ADAMTS-13 antibodies, and ADAMTS-13 gene sequencing indicated a constitutive deficiency. The fourth, a multipara patient, had an acquired, auto-immune TTP. Placental pathology in the three primipara patients showed severe and non-specific ischemic lesions. Two patients lost their babies shortly after birth. In subsequent pregnancies in these two patients, prophylactic plasma infusion initiated early with increasing volume throughout pregnancy prevented TTP relapse, improved placental pathology, and led to normal delivery.

Conclusions: The prevalence of TTP among thrombocytopenic pregnant women is high, up to 5 % in a tertiary unit. Platelet count normalization after delivery does not eliminate TTP. Clinicians should be aware of TTP during pregnancy, and, even if assessed retrospectively, ADAMTS-13 assessment is of particular importance for identifying patients with congenital TTP. In these patients, preventive plasma infusion and/or exchange can dramatically improve foetal prognosis, resulting in successful childbirth.
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http://dx.doi.org/10.1186/s12884-015-0557-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4469004PMC
June 2015

Severe X-linked chondrodysplasia punctata in nine new female fetuses.

Prenat Diagn 2015 Jul 30;35(7):675-84. Epub 2015 Mar 30.

Service de Gynécologie, Centre Hospitalo-Universitaire Tours, Tours, France.

Objectives: Conradi-Hünermann-Happle [X-linked dominant chondrodysplasia punctata 2 (CDPX2)] syndrome is a rare X-linked dominant skeletal dysplasia usually lethal in men while affected women show wide clinical heterogeneity. Different EBP mutations have been reported. Severe female cases have rarely been reported, with only six antenatal presentations.

Methods: To better characterize the phenotype in female fetuses, we included nine antenatally diagnosed cases of women with EBP mutations. All cases were de novo except for two fetuses with an affected mother and one case of germinal mosaicism.

Results: The mean age at diagnosis was 22 weeks of gestation. The ultrasound features mainly included bone abnormalities: shortening (8/9 cases) and bowing of the long bones (5/9), punctuate epiphysis (7/9) and an irregular aspect of the spine (5/9). Postnatal X-rays and examination showed ichthyosis (8/9) and epiphyseal stippling (9/9), with frequent asymmetric short and bowed long bones. The X-inactivation pattern of the familial case revealed skewed X-inactivation in the mildly symptomatic mother and random X-inactivation in the severe fetal case. Differently affected skin samples of the same fetus revealed different patterns of X-inactivation.

Conclusion: Prenatal detection of asymmetric shortening and bowing of the long bones and cartilage stippling should raise the possibility of CPDX2 in female fetuses, especially because the majority of such cases involve de novo mutations.
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http://dx.doi.org/10.1002/pd.4591DOI Listing
July 2015

Fetal phenotype associated with the 22q11 deletion.

Am J Med Genet A 2014 Nov 8;164A(11):2724-31. Epub 2014 Aug 8.

Service de Génétique et Biologie de la Reproduction, Hôpital Maison Blanche, Centre Hospitalier Universitaire, Reims, France.

The 22q11 deletion syndrome is one of the most common human microdeletion syndromes, with a wide spectrum of abnormalities. The fetal phenotype associated with the 22q11 deletion is poorly described in the literature. A national retrospective study was performed from 74 feto-pathological examinations. The objectives were to evaluate the circumstances of the 22q11 deletion diagnosis and to describe fetal anomalies. Post mortem examinations were performed after 66 terminations of pregnancy and eight fetal deaths. The series included nine fetuses from the first trimester, 55 from the second trimester, and ten from the third trimester. A 22q11 FISH analysis was recommended for 57 fetuses after multidisciplinary prenatal diagnostic counseling and for 17 fetuses by a fetal pathologist. Conotruncal heart defects were the most common anomalies (65 fetuses), followed by thymus defects (62 fetuses), and malformations of the urinary tract (25 fetuses). This study identified several unusual and severe features rarely described in the literature. Neurological abnormalities were described in ten fetuses, with seven neural tube defects and five arhinencephalies. This series also included lethal malformations: two hypoplastic left heart syndromes, two bilateral renal agenesis, and one tracheal agenesis. Genetic analysis for a 22q11 deletion is usually indicated when a congenital conotruncal heart and/or thymus defect is detected, but might also be useful in case of other lethal or severe malformations that initially led to the termination of pregnancy.
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http://dx.doi.org/10.1002/ajmg.a.36720DOI Listing
November 2014

[Incidental intraplacental gestational choriocarcinoma on a full-term placenta].

Ann Pathol 2014 Apr 16;34(2):119-23. Epub 2014 Mar 16.

Unité de pathologie fœtoplacentaire, université Bordeaux-Segalen, 146, rue Léo-Saignat, 33076 Bordeaux cedex, France.

Of all the gestational trophoblastic tumors, the gestational choriocarcinomas have the worst prognosis and the most uncommon. We report a case diagnosed on a full-term placenta, discovered incidentally. The patient, gravida 2, para 1, delivered a hypotrophic infant at 38 weeks gestation. The placenta was examined in the laboratory to perform anatomo-pathological examination in order to explain the growth retardation. This study revealed the presence of an intraplacental choriocarcinoma. Disease staging was negative for both mother and child, and beta-HCG levels remained at zero. These two factors are rather good prognosis for choriocarcinoma. With this observation, we highlight the added-value of placental examination, which seems essential for any fetal pathology, pathological pregnancy and intrapartum complications. Anatomo-pathological examination must be meticulous and systematized in order to not overlook an intraplacental tumor.
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http://dx.doi.org/10.1016/j.annpat.2014.02.009DOI Listing
April 2014

Pathological Findings in Feto-maternal Hemorrhage.

Pediatr Dev Pathol 2014 Mar-Apr;17(2):102-6. Epub 2014 Feb 27.

Department of Pathology, Centre Hospitalier Universitaire de Bordeaux, Bordeaux, France.

Feto-maternal hemorrhage (FMH) is the cause of late fetal death in 1.6%-11% of cases. In spite of this high frequency, its pathological features have received little attention. The definitive diagnosis of lethal FMH requires confirmation of sufficient fetal blood volume loss. This is determined by tests such as the Kleihauer-Betke test, which may not have been obtained or not have been available before the autopsy. The pathologist may offer a tentative diagnosis of FMH from the autopsy findings. The objective of this study was to better characterize the placental and fetal autopsy findings in lethal FMH. This was a retrospective study of 17 cases of FMH proven by a positive Kleihauer-Betke test. The cases were selected from the autopsy files of the Department of Pathology, Centre Hospitalier Universitaire de Bordeaux. The pathological reports as well as the placental and fetal photographs and the microscopic slides of each case were systematically reviewed. The fetal autopsy findings in FMH are characterized by a eutrophic pale macerated fetus, low liver weight, absent intrathoracic petechiae, increased extramedullary hematopoiesis in the liver and kidney, and increased circulating nucleated red blood cells. The placenta shows an increased frequency of intervillous thrombi. Although nonpathognomonic, some of the pathological features are strongly suggestive of FMH. When the latter is present, a Kleihauer-Betke test should be performed, even some days after the delivery.
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http://dx.doi.org/10.2350/13-12-1419-OA.1DOI Listing
August 2014

[Placental pathology of uteroplacental vascular deficiency].

Ann Pathol 2013 Aug 31;33(4):230-6. Epub 2013 Jul 31.

Université Bordeaux-Segalen, hôpital Pellegrin, Bordeaux cedex, France.

The indications of the pathological examination of the placenta are mainly represented by uteroplacental vascular deficiency. The clinical context is often evocative, but it can sometimes be solely an intra-uterine growth retardation or an unexplained in utero fetal death. So, the pathological lesions of this uteroplacental vascular deficiency must be well-known to be correctly interpreted, for none of these lesions is truly specific. The pathological diagnosis is based on a group of macroscopic and microscopic arguments. Various physiopathological mechanisms, often imperfectly known, can be at the origin of an uteroplacental vascular insufficiency, but in the current position, the pathological examination does not allow etiopathogenic orientation. The development of the trophoblastic biopsies gives us access to a new material which, in parallel with the cytogenetic analysis, often allows us, in front of an unexplained intra-uterine growth retardation, to direct the diagnosis towards uteroplacental vascular insufficiency. The histological analysis of the chorionic villous sampling taken precociously during pathological pregnancies is thus a major diagnostic contribution. But especially, this analysis gives access to new information which, in the near future, will enable us to better define the pathological evolution of the lesions of hypoxic chorionic villous and to contribute to a better knowledge of this pathology which, under many aspects, still conceals many mysteries.
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http://dx.doi.org/10.1016/j.annpat.2013.04.018DOI Listing
August 2013

Reduced placental telomere length during pregnancies complicated by intrauterine growth restriction.

PLoS One 2013 11;8(1):e54013. Epub 2013 Jan 11.

EA 2406 Histologie et pathologie moléculaire des tumeurs, Université Bordeaux Segalen, Bordeaux, France.

Objectives: Recent studies have shown that telomere length was significantly reduced in placentas collected at delivery from pregnancies complicated by intrauterine growth restriction secondary to placental insufficiency. Placental telomere length measurement during ongoing pregnancies complicated by intrauterine growth restriction has never been reported. This was the main objective of our study.

Methods: In our center, late chorionic villus samplings were performed between 18 and 37 weeks of amenorrhea in 24 subjects with severe intrauterine growth restriction (cases) and in 28 subjects with other indications for prenatal diagnosis (controls). Placental insufficiency was assessed by histo-pathological examination. Relative measurement of telomere length was carried out prospectively by quantitative Fluorescent In Situ Hybridization using fluorescent Peptide Nucleic Acid probes on interphase nuclei obtained from long-term cultured villi and with an automated epifluorescent microscope. A quantitative Polymerase Chain Reaction technique was performed to confirm the quantitative Fluorescent In Situ Hybridization results. The number of copies of gene loci encoding the RNA template (hTERC) and the catalytic subunit (hTERT) of the enzyme complex telomerase were also estimated in these placentas by Fluorescent In Situ Hybridization.

Results: Mean fluorescence intensity of telomere probes estimated by quantitative Fluorescent In Situ Hybridization was significantly less for cases compared to controls (p<0.001). This result indicated that mean telomere length was significantly reduced in placentas during pregnancies complicated by intrauterine growth restriction. Reduced telomere length was confirmed by the quantitative Polymerase Chain Reaction technique. No copy number variation of the hTERC and hTERT loci was noticed for cases, or for controls.

Conclusion: This study clearly demonstrates a reduction of placental telomere length in ongoing pregnancies (from 18 to 37 weeks of amenorrhea) complicated by severe intrauterine growth restriction secondary to placental insufficiency.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0054013PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3543434PMC
July 2013

[Cardiac tamponade with anterior interventricular vein thrombosis complicating central venous catheter insertion in a neonate].

Ann Pathol 2012 Jun 30;32(3):217-9. Epub 2012 Apr 30.

Unité de pathologie fœtoplacentaire, université Bordeaux-Segalen, 146 rue Léo-Saignat, Bordeaux cedex, France.

Tamponade is a rare but particularly serious complication of central venous catheters in the newborn. Tamponade can be due to the endocardic aggression caused by the continuous flow of a hyperosmotic solution or by a mechanical injury that can result in perforation of the atrial wall. The risk of tamponade is present whatever is the position of the tip of the catheter, although it has been shown that this risk is increased when this tip is in the right auricle. The originality of our observation is the discovery at the post-mortem examination of an anterior interventricular vein thrombosis, without any lesion of the atrial wall. In the event of the diagnosis of tamponade in living newborn, this etiology must be required because of its therapeutic implications.
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http://dx.doi.org/10.1016/j.annpat.2011.10.014DOI Listing
June 2012

Cobblestone lissencephaly: neuropathological subtypes and correlations with genes of dystroglycanopathies.

Brain 2012 Feb 9;135(Pt 2):469-82. Epub 2012 Feb 9.

Institut de Pathologie, Centre de Biologie-Pathologie, CHU Lille, 33.3.20446983, France.

Cobblestone lissencephaly represents a peculiar brain malformation with characteristic radiological anomalies, defined as cortical dysplasia combined with dysmyelination, dysplastic cerebellum with cysts and brainstem hypoplasia. Cortical dysplasia results from neuroglial overmigration into the arachnoid space, forming an extracortical layer, responsible for agyria and/or 'cobblestone' brain surface and ventricular enlargement. The underlying mechanism is a disruption of the glia limitans, the outermost layer of the brain. Cobblestone lissencephaly is pathognomonic of a continuum of autosomal recessive diseases with cerebral, ocular and muscular deficits, Walker-Warburg syndrome, muscle-eye-brain and Fukuyama muscular dystrophy. Mutations in POMT1, POMT2, POMGNT1, LARGE, FKTN and FKRP genes attributed these diseases to α-dystroglycanopathies. However, studies have not been able to identify causal mutations in the majority of patients and to establish a clear phenotype/genotype correlation. Therefore, we decided to perform a detailed neuropathological survey and molecular screenings in 65 foetal cases selected on the basis of histopathological criteria. After sequencing the six genes of α-dystroglycanopathies, a causal mutation was observed in 66% of cases. On the basis of a ratio of severity, three subtypes clearly emerged. The most severe, which we called cobblestone lissencephaly A, was linked to mutations in POMT1 (34%), POMT2 (8%) and FKRP (1.5%). The least severe, cobblestone lissencephaly C, was linked to POMGNT1 mutations (18%). An intermediary type, cobblestone lissencephaly B, was linked to LARGE mutations (4.5%) identified for the first time in foetuses. We conclude that cobblestone lissencephaly encompasses three distinct subtypes of cortical malformations with different degrees of neuroglial ectopia into the arachnoid space and cortical plate disorganization regardless of gestational age. In the cerebellum, histopathological changes support the novel hypothesis that abnormal lamination arises from a deficiency in granule cells. Our studies demonstrate the positive impact of histoneuropathology on the identification of α-dystroglycanopathies found in 66% of cases, while with neuroimaging criteria and biological values, mutations are found in 32-50% of patients. Interestingly, our morphological classification was central in the orientation of genetic screening of POMT1, POMT2, POMGNT1, LARGE and FKRP. Despite intensive research, one-third of our cases remained unexplained; suggesting that other genes and/or pathways may be involved. This material offers a rich resource for studies on the affected neurodevelopmental processes of cobblestone lissencephaly and on the identification of other responsible gene(s)/pathway(s).
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http://dx.doi.org/10.1093/brain/awr357DOI Listing
February 2012

Contribution of referent pathologists to the quality of trophoblastic diseases diagnosis.

Hum Reprod 2011 Oct 12;26(10):2651-7. Epub 2011 Aug 12.

Department of Obstetrics and Gynecology, Lyon 1 University, Lyon Hospital, Lyon Sud University Hospital, Lyon, France.

Objective: To evaluate the contribution of referent pathologists (RPs) to the quality of diagnosis of trophoblastic diseases and to study the level of diagnostic agreement between the initial pathologists and the RPs.

Methods: This observational retrospective study was carried between 1 November 1999 and 11 January 2011 using the database of the French Trophoblastic Disease Reference Centre in Lyon. All files for hydatiform moles (HMs), trophoblastic tumours and non-molar pregnancies for which there was an initial suspicion of trophoblastic disease were included, whenever there was rereading of the slides by an RP. A total of 1851 HMs and 150 gestational trophoblastic tumours were analysed.

Results: When the initial pathologist diagnosed a complete mole, the RP confirmed the diagnosis in 96% of cases. When the initial pathologist diagnosed a partial mole, the RP confirmed the diagnosis in only 64% of cases. For trophoblastic tumours, when the initial pathologist diagnosed a choriocarcinoma, the RP confirmed the diagnosis in 86% of cases. When the initial anatomopathology suggested an invasive mole, the diagnosis was confirmed in 96% of cases. Finally, when the initial diagnosis was a placental site trophoblastic tumour or an epithelioid trophoblastic tumour, the RP confirmed the diagnosis in 60 and 100% of cases, respectively.

Conclusion: A systematic policy of rereading of slides for all suspicious moles improves the quality of management of trophoblastic diseases at a national level.
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http://dx.doi.org/10.1093/humrep/der265DOI Listing
October 2011

[Pathology of the placenta. Case 7. Massive perivillous fibrin deposits (maternal floor infarct)].

Authors:
Fanny Pelluard

Ann Pathol 2010 Aug 5;30(4):306-9. Epub 2010 Aug 5.

Service d'anatomie pathologique, groupe hospitalier Pellegrin, place Amélie-Raba-Léon, 33076 Bordeaux, France.

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http://dx.doi.org/10.1016/j.annpat.2010.05.008DOI Listing
August 2010

[Pathology of the placenta. Case 6. Placental mesenchymal dysplasia].

Authors:
Fanny Pelluard

Ann Pathol 2010 Aug 5;30(4):301-5. Epub 2010 Aug 5.

Service d'anatomie pathologique, groupe hospitalier Pellegrin, place Amélie-Raba-Léon, 33076 Bordeaux, France.

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http://dx.doi.org/10.1016/j.annpat.2010.05.007DOI Listing
August 2010

[Maze-like vascular anomaly in partial mole. Interest for the pathological diagnosis of partial mole on chorionic villous sampling].

Ann Pathol 2009 Oct;29(5):424-7

Université Victor-Segalen Bordeaux-2, CHU de Bordeaux, Bordeaux cedex, France.

A case of maze-like angiomatoid anomaly in villi obtained by chorionic villous sampling (CVS) is described. This feature is pathognomonic of partial mole (triploid syndrome) and it was later confirmed by chromosomal analysis. Maze-like angiomatoid anomaly was previously described on specimen submitted after spontaneous or induced abortions, but it was never reported on CVS. This report emphasized that microscopic investigation of CVS cannot be conclusive for cytogenetic anomaly in almost all cases excepted for partial mole where diagnosis criteria are usually characteristic.
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http://dx.doi.org/10.1016/j.annpat.2009.10.005DOI Listing
October 2009

[Advantages and limitations of chorionic villous sampling].

Bull Acad Natl Med 2009 Mar;193(3):675-89; discussion 689-90

Unité de Pathologie Foetoplacentaire, Service d'Anatomie Pathologique, Hôpital Pellegrin, 33076 Bordeaux.

Chorionic villous sampling (CVS) has been available for more than twenty years. Together with amniocentesis, it helps the cytogenetician to determine the fetal karyotype for prenatal diagnosis. The choice between these two methods depends on the team and the indication. CVS can now provide sufficient material for both histopathologic and cytogenetic analyses. We evaluated the accuracy of microscopic examination of CVS for detecting primary ovular, uteroplacental vascular (preeclampsia) and inflammatory disorders. Four hundred CVS were examined in the pathology laboratory of Pellegrin Hospital, Bordeaux, France, from January 1995 to February 2008. The results were analyzed according to the indication, the karyotype, the results of placental examination, pregnancy outcome and, when available (following spontaneous or medical termination), fetoplacental findings. The sample was representative of patients requiring CVS for prenatal diagnosis, with respect to maternal age, the stage of pregnancy, and the indications. When used to screen for preeclamsia (prevalence 29.6% in the sample), the sensitivity and specificity of placental biopsy were respectively 56.8% and 87.2% (76.9% in case of intra-uterine growth retardation). When used to screen for chromosomal aberrations (prevalence 7.4%), the specificity was 14.3% and the sensitivity 93.2%. The prevalence of other disorders, and particularly chronic intervillitis, was too low for meaningful analysis. This study shows that histopathologic analysis of chorionic villous samples is useful for detecting the utero-placental vascular origin of intrauterine growth retardation in the absence of other clinical, biological or ultrasound signs, and that it is complementary to cytogenetic analysis. Being a simple and inexpensive examination, histopathologic analysis of CVS could be performed systematically in this indication. Its value and diagnostic signs in other settings need to be determined in larger series.
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March 2009

Rhombencephalosynapsis and related anomalies: a neuropathological study of 40 fetal cases.

Acta Neuropathol 2009 Feb 5;117(2):185-200. Epub 2008 Dec 5.

Medical Genetics Unit, Rennes University Hospital, Rennes, France.

Rhombencephalosynapsis is an uncommon cerebellar malformation defined by vermian agenesis with fusion of the hemispheres and of the dentate nuclei. Embryologic and genetic mechanisms are still unknown, and to date, no animal models are available. Ultrasound diagnosis is generally suspected after 22 weeks of gestation, and usually the abnormality is suggested by ventriculomegaly. Morphological analysis of 40 fetuses after medical termination of pregnancy allowed us to confirm that rhombencephalosynapsis was always associated with other brain abnormalities or malformations: Purkinje cell heterotopias, fusion of colliculi, forking and/or atresia of the aqueduct and of the third ventricle resulting in a fusion of the thalami, agenesis of the corpus callosum, lobar holoprosencephaly and neural tube defects. Pons and medulla were very infrequently abnormal. Furthermore, complete autopsy made it possible to separate either pure neurologic phenotypes, or associated with extraneural anomalies from syndromic forms: Gomez-Lopez-Hernandez syndrome (1 case) and VACTERL-H syndrome (6 cases). The number of our fetal cases strongly suggests that VACTERL-H association related with rhombencephalosynapsis emerges as a non-random association. Furthermore, recurrence and consanguinity were noted in two different families, which argue for a sporadic or inherited cause. From our results, it could be suggested that rhombencephalosynapsis may be due to defective genes regulating formation of the roof plate and the development of midline cerebellar primordium at the junction of the mesencephalon and of the first rhombomere.
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http://dx.doi.org/10.1007/s00401-008-0469-9DOI Listing
February 2009