Publications by authors named "Madeleine Joubert"

24 Publications

  • Page 1 of 1

Structural abnormalities of chromosome 8 and fetoplacental discrepancy: A second case report and review of fetal phenotype of 8p inverted duplication deletion syndrome.

Eur J Med Genet 2021 Jan 26;64(1):104118. Epub 2020 Nov 26.

Centre Hospitalier Universitaire de Nantes, Service de Génétique Médicale, 9 quai Moncousu, 44093, Nantes, France; Université de Nantes, CNRS, INSERM, l'institut du thorax, 44000, Nantes, France.

We described a new second case of fetoplacental discrepancy involving first trimester prenatal detection of mosaic isochromosome i (8) (q10). A 32-year-old woman underwent chorionic villous sampling because of increased fetal nuchal translucency. Analysis of direct chromosome preparations was performed by R-banding and FISH using subtelomeric, centromeric and whole chromosome painting probes for chromosome 8 showing the presence of an isochromosome 8q with a complex, female mosaic karyotype: mos 46,XX,i (8) (q10)[13]/46,XX,del (8) (p23)[10]. Cytogenetic analysis of cultured CVS showed an interstitial duplication with concomitant terminal deletion of the short arm of chromosome 8: 46,XX,der (8)del (8) (p23)dup (8) (p?)[18]. Array-CGH analysis from cultured trophoblasts and fetal tissues revealed a 6.69 Mb terminal deletion in 8p23.3p23.1 associated with a 31.49 Mb duplication in 8p23.1p11.1. FISH analysis confirmed the 8p inverted duplication deletion syndrome. Moreover, polymorphic DNA marker analysis demonstrated that the derivative chromosome 8 was of maternal origin. FISH analysis of cultured peripheral blood lymphocytes showed that the mother also carried a cryptic paracentric inversion inv (8) (p23). Our report contributes to expand the fetal phenotype of 8p inverted duplication deletion syndrome and also provides further insight into the underlying mechanism of this rare genomic disorder.
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http://dx.doi.org/10.1016/j.ejmg.2020.104118DOI Listing
January 2021

12q21 deletion syndrome: Narrowing the critical region down to 1.6 Mb including SYT1 and PPP1R12A.

Am J Med Genet A 2020 09 6;182(9):2133-2138. Epub 2020 Jul 6.

Department of Medical Genetics, Centre Hospitalier Universitaire de Poitiers, Poitiers, France.

Deletions in the 12q21 region are rare and non-recurrent CNVs. To date, only 11 patients with deletions in this region have been reported in the literature. These patients most often presented with syndromic intellectual deficiency, ventriculomegaly or hydrocephalus, ectodermal abnormalities, growth retardation and renal and cardiac malformations, suggesting a recognizable microdeletion syndrome. We report three new patients with overlapping deletions of the 12q21 region, including the smallest deletion reported to date and the first case characterized by array CGH during pregnancy. We describe specific clinical findings and shared facial features as developmental delay, ectodermal abnormalities, ventriculomegaly or hydrocephalus, axial hypotonia or spastic diplegia, growth retardation, heart defect, hydronephrosis, ureteral reflux or horseshoe kidney, large thorax or pectus excavatum, syndactyly of 2-3 toes, pterygium coli or excess nuchal skin, large anterior fontanel, low set ears, prominent forehead, short-upturned nose with nostril hypoplasia, microretrognathia and hypertelorism. These new patients and a comprehensive review of the literature allow us to define a minimum critical region spanning 1.6 Mb in 12q21. By screening the critical region using prediction tools, we identified two candidate genes: SYT1and PPP1R12A.
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http://dx.doi.org/10.1002/ajmg.a.61734DOI Listing
September 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

Complex Compound Inheritance of Lethal Lung Developmental Disorders Due to Disruption of the TBX-FGF Pathway.

Am J Hum Genet 2019 02 10;104(2):213-228. Epub 2019 Jan 10.

Service de Génétique Médicale, CHU de Nantes, 44000 Nantes, France; Inserm, CNRS, Univ Nantes, l'institut du thorax, 44000 Nantes, France.

Primary defects in lung branching morphogenesis, resulting in neonatal lethal pulmonary hypoplasias, are incompletely understood. To elucidate the pathogenetics of human lung development, we studied a unique collection of samples obtained from deceased individuals with clinically and histopathologically diagnosed interstitial neonatal lung disorders: acinar dysplasia (n = 14), congenital alveolar dysplasia (n = 2), and other lethal lung hypoplasias (n = 10). We identified rare heterozygous copy-number variant deletions or single-nucleotide variants (SNVs) involving TBX4 (n = 8 and n = 2, respectively) or FGF10 (n = 2 and n = 2, respectively) in 16/26 (61%) individuals. In addition to TBX4, the overlapping ∼2 Mb recurrent and nonrecurrent deletions at 17q23.1q23.2 identified in seven individuals with lung hypoplasia also remove a lung-specific enhancer region. Individuals with coding variants involving either TBX4 or FGF10 also harbored at least one non-coding SNV in the predicted lung-specific enhancer region, which was absent in 13 control individuals with the overlapping deletions but without any structural lung anomalies. The occurrence of rare coding variants involving TBX4 or FGF10 with the putative hypomorphic non-coding SNVs implies a complex compound inheritance of these pulmonary hypoplasias. Moreover, they support the importance of TBX4-FGF10-FGFR2 epithelial-mesenchymal signaling in human lung organogenesis and help to explain the histopathological continuum observed in these rare lethal developmental disorders of the lung.
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http://dx.doi.org/10.1016/j.ajhg.2018.12.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6369446PMC
February 2019

New splicing pathogenic variant in EBP causing extreme familial variability of Conradi-Hünermann-Happle Syndrome.

Eur J Hum Genet 2018 12 22;26(12):1784-1790. Epub 2018 Aug 22.

Service de génétique, CHU de Poitiers, Poitiers, France.

X-linked dominant chondrodysplasia punctata (CDPX2 or Conradi-Hünermann-Happle syndrome, MIM #302960) is caused by mutations in the EBP gene. Affected female patients present with Blaschkolinear ichthyosis, coarse hair or alopecia, short stature, and normal psychomotor development. The disease is usually lethal in boys. Nevertheless, few male patients have been reported; they carry a somatic mosaicism in EBP or present with Klinefelter syndrome. Here, we report CDPX2 patients belonging to a three-generation family, carrying the splice variant c.301 + 5 G > C in intron 2 of EBP. The grandfather carries the variant as mosaic state and presents with short stature and mild ichthyosis. The mother also presents with short stature and mild ichthyosis and the female fetus with severe limb and vertebrae abnormalities and no skin lesions, with random X inactivation in both. This further characterizes the phenotypical spectrum of CDPX2, as well as intrafamilial variability, and raises the question of differential EBP mRNA splicing between the different target tissues.
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http://dx.doi.org/10.1038/s41431-018-0217-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6244079PMC
December 2018

Rubinstein-Taybi Syndrome in a Fetus: Contribution of 2- and 3-Dimensional Ultrasonography.

J Ultrasound Med 2018 02 16;37(2):531-534. Epub 2017 Aug 16.

Department of Gynecology and Obstetrics.

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http://dx.doi.org/10.1002/jum.14342DOI Listing
February 2018

Two novel variants in CNTNAP1 in two siblings presenting with congenital hypotonia and hypomyelinating neuropathy.

Eur J Hum Genet 2017 01 26;25(1):150-152. Epub 2016 Oct 26.

Service de Génétique Médicale, CHU Hôtel Dieu, France.

Homozygous frameshift variants in CNTNAP1 have recently been reported in patients with arthrogryposis and abnormal axon myelination. In two brothers with severe congenital hypotonia and foot deformities, we identified compound heterozygous variants in CNTNAP1, reporting the first causative missense variant, p.(Cys323Arg). Motor nerve conductions were markedly decreased. Nerve microscopical lesions confirmed a severe hypomyelinating process and showed loss of attachment sites of the myelin loops on the axons, which could be a characteristic of Caspr loss-of-function. We discuss the pathophysiology of the myelination process and we propose to consider this disorder as a congenital hypomyelinating neuropathy.
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http://dx.doi.org/10.1038/ejhg.2016.142DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5159775PMC
January 2017

Perinatal prognosis of pregnancies complicated by placental chronic villitis or intervillositis of unknown etiology and combined lesions: About a series of 178 cases.

Placenta 2016 08 15;44:104-8. Epub 2016 May 15.

Department of Obstetrics and Gynecology, Hôpital Mère-Enfant, Centre Hospitalier universitaire, Nantes, France.

Introduction: The objective of this work was to evaluate and compare perinatal outcomes of pregnancies complicated by placental chronic intervillositis (CIUE) or villitis (CVUE) of unknown etiology and combined lesions.

Methods: Retrospective study of all cases of significant CVUE and CIUE occurring during a 12-year period in a university tertiary hospital center. Multiple pregnancies, infectious and medical termination of pregnancies (TOP) without intra-uterine growth restriction (IUGR) were excluded.

Results: 178 placentas were affected (78 cases of CVUE, 24 cases of CIUE and 76 cases of combined lesions involving both villitis and intervillositis) including 12 cases of recurrence. A disorder of fetal growth was found in 73% of cases and we noted 9.5% of cases of abortion. The rate of IUGR appeared to be significantly higher in case of CIUE with a fetal death risk five times higher. These complications seems to be related to more diffuse inflammatory infiltrates (p < 0.05). CVUE was associated with a significant morbidity with 42% of severe IUGR and severe alterations of umbilical artery Doppler in nearly one third of cases. Caesarean section was important (54.8%). Sixty-one percent of newborns were hospitalized and 11.4% in neonatal reanimation. In case of combined lesions, fetal outcomes appeared relatively close to those of CVUE. CVUE could recur in more severe forms or as CIUE with an increased risk for the fetus. Clinicoanatomic correlations were noted.

Discussion: Observation of recurrence of CVUE on CIUE or combined lesions and similar phenotypic characteristics of the infiltrates suggest that they could be two different stages of a same disease. CVUE remains a disease to be considered as serious. Association of small lesions of intervillositis does not change the prognosis. The severity of histological lesions and the initial obstetrical accident could be discriminatory to identify patients at risk of serious recurrence. Harmonized classification will be required.

Conclusions: This study confirms the higher morbidity of CIUE compared to CVUE but shows the necessity of monitoring pregnancies following an episode of CVUE, which are still at risk of serious and recurrent complications.
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http://dx.doi.org/10.1016/j.placenta.2016.04.017DOI Listing
August 2016

Fetal anomalies associated with HNF1B mutations: report of 20 autopsy cases.

Prenat Diagn 2016 Aug 6;36(8):744-51. Epub 2016 Jul 6.

SOFFOET, Société Française de Fœtopathologie, Lyon, Rennes, France.

Objectives: To describe macroscopic and microscopic anomalies present in fetuses carrying hepatocyte nuclear factor-1 β mutation, their frequency, and genotype/phenotype correlations.

Methods: Clinical data, ultrasound findings, genetic studies, and autopsy reports of 20 fetal autopsies were analyzed. Histology was reviewed by two pathologists.

Results: Macroscopic findings were typically unilateral or bilateral renal enlargement and cortical cysts. Renal lesions were associated with congenital anomalies of the kidney and urinary tract in 25% of cases. Microscopic renal anomalies were dominated by glomerulocystic kidney and renal dysplasia. Extra-renal manifestations such as pancreatic hypoplasia (75%) and genital anomalies (68%) were only detected at autopsy. In 40% of cases, there was heterozygous deletion of the whole gene. There were de novo mutations in 40%.

Conclusion: This study underlines the importance of considering hepatocyte nuclear factor-1 β mutations in fetuses with congenital anomalies of the kidney and urinary tract, especially when associated with pancreatic hypoplasia. No correlation between phenotype and genotype was found, highlighting high intra-familial variability in cases with inherited mutations. © 2016 John Wiley & Sons, Ltd.
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http://dx.doi.org/10.1002/pd.4858DOI Listing
August 2016

Large Cell Neuroendocrine Carcinoma of the Nasopharynx: A Pediatric Case.

J Pediatr Hematol Oncol 2015 Aug;37(6):474-6

*Department of Pathology A, Quai Moncousu RJPT1 ‡Department of Pediatric Hematology and Oncology, Hôpital enfant-adolescent, quai Moncousu §Department of Otolaryngology-Head and Neck Surgery, Hôtel-Dieu †INSERM, UMR U957, Laboratory of Pathophysiology of Bone Resorption and Therapy of Primary Bone Tumors, Faculty of Medicine, University of Nantes, Nantes Cedex 1, France.

Neuroendocrine tumors are rare, preferentially located in the gastrointestinal tract or in the lungs. We present the case of a 9-year-old child, presenting with a tissue mass involving the nasopharynx and associated with multiple pulmonary and bone metastases. The immunohistochemical analysis showed a proliferation of large tumor cells stained with Chromogranin A and Synaptophysin. The diagnosis of multimetastatic large cell neuroendocrine carcinoma was made. This tumor is infrequent in this location and particularly in children. This case describes the pathologic aspects and immunohistochemical results and presents a discussion of the differential diagnoses.
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http://dx.doi.org/10.1097/MPH.0000000000000334DOI Listing
August 2015

Clinical spectrum of females with HCCS mutation: from no clinical signs to a neonatal lethal form of the microphthalmia with linear skin defects (MLS) syndrome.

Orphanet J Rare Dis 2014 Apr 15;9:53. Epub 2014 Apr 15.

Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Martinistraße 52, 20246 Hamburg, Germany.

Background: Segmental Xp22.2 monosomy or a heterozygous HCCS mutation is associated with the microphthalmia with linear skin defects (MLS) or MIDAS (microphthalmia, dermal aplasia, and sclerocornea) syndrome, an X-linked disorder with male lethality. HCCS encodes the holocytochrome c-type synthase involved in mitochondrial oxidative phosphorylation (OXPHOS) and programmed cell death.

Methods: We characterized the X-chromosomal abnormality encompassing HCCS or an intragenic mutation in this gene in six new female patients with an MLS phenotype by cytogenetic analysis, fluorescence in situ hybridization, sequencing, and quantitative real-time PCR. The X chromosome inactivation (XCI) pattern was determined and clinical data of the patients were reviewed.

Results: Two terminal Xp deletions of ≥ 11.2 Mb, two submicroscopic copy number losses, one of ~850 kb and one of ≥ 3 Mb, all covering HCCS, 1 nonsense, and one mosaic 2-bp deletion in HCCS are reported. All females had a completely (>98:2) or slightly skewed (82:18) XCI pattern. The most consistent clinical features were microphthalmia/anophthalmia and sclerocornea/corneal opacity in all patients and congenital linear skin defects in 4/6. Additional manifestations included various ocular anomalies, cardiac defects, brain imaging abnormalities, microcephaly, postnatal growth retardation, and facial dysmorphism. However, no obvious clinical sign was observed in three female carriers who were relatives of one patient.

Conclusion: Our findings showed a wide phenotypic spectrum ranging from asymptomatic females with an HCCS mutation to patients with a neonatal lethal MLS form. Somatic mosaicism and the different ability of embryonic cells to cope with an OXPHOS defect and/or enhanced cell death upon HCCS deficiency likely underlie the great variability in phenotypes.
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http://dx.doi.org/10.1186/1750-1172-9-53DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4021606PMC
April 2014

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

PLoS One 2014 14;9(4):e94866. Epub 2014 Apr 14.

Department of Obstetrics and Gynecology, Hôpital Antoine Béclère, APHP, Clamart, France.

Purpose: To evaluate the accuracy of ultrasonography and magnetic resonance imaging (MRI) in the diagnosis of placenta accreta and to define the most relevant specific ultrasound and MRI features that may predict placental invasion.

Material And Methods: This study was approved by the institutional review board of the French College of Obstetricians and Gynecologists. We retrospectively reviewed the medical records of all patients referred for suspected placenta accreta to two university hospitals from 01/2001 to 05/2012. Our study population included 42 pregnant women who had been investigated by both ultrasonography and MRI. Ultrasound images and MRI were blindly reassessed for each case by 2 raters in order to score features that predict abnormal placental invasion.

Results: Sensitivity in the diagnosis of placenta accreta was 100% with ultrasound and 76.9% for MRI (P = 0.03). Specificity was 37.5% with ultrasonography and 50% for MRI (P = 0.6). The features of greatest sensitivity on ultrasonography were intraplacental lacunae and loss of the normal retroplacental clear space. Increased vascularization in the uterine serosa-bladder wall interface and vascularization perpendicular to the uterine wall had the best positive predictive value (92%). At MRI, uterine bulging had the best positive predictive value (85%) and its combination with the presence of dark intraplacental bands on T2-weighted images improved the predictive value to 90%.

Conclusion: Ultrasound imaging is the mainstay of screening for placenta accreta. MRI appears to be complementary to ultrasonography, especially when there are few ultrasound signs.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0094866PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3986371PMC
May 2015

Blepharophimosis, short humeri, developmental delay and hirschsprung disease: expanding the phenotypic spectrum of MED12 mutations.

Am J Med Genet A 2014 Jul 8;164A(7):1821-5. Epub 2014 Apr 8.

Service de Génétique Médicale, CHU de Nantes, Nantes, France; INSERM, UMR-S 957, Nantes, France.

We report on two male sibs, a fetus and a newborn, with short humeri and dysmorphic facial features including blepharophimosis. The newborn also had Hirschsprung disease. Goldberg-Shprintzen syndrome and the Say-Barber-Biesecker-Young-Simpson type of Ohdo syndrome were suspected but direct sequencing of KBP and KAT6B failed to identify a mutation. Finally, direct sequencing of MED12, the gene mutated in Opitz-Kaveggia syndrome, Lujan-Fryns syndrome and X-linked Ohdo syndrome identified in the two sibs the missense mutation c.3443G>A (p.Arg1148His) inherited from the mother. This report further expands the phenotypic spectrum of MED12 mutations.
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http://dx.doi.org/10.1002/ajmg.a.36539DOI Listing
July 2014

Neuropathological review of 138 cases genetically tested for X-linked hydrocephalus: evidence for closely related clinical entities of unknown molecular bases.

Acta Neuropathol 2013 Sep 3;126(3):427-42. Epub 2013 Jul 3.

Department of Pathology, Lariboisière Hospital, APHP, 2 Rue Ambroise Paré, 75010, Paris, France.

L1 syndrome results from mutations in the L1CAM gene located at Xq28. It encompasses a wide spectrum of diseases, X-linked hydrocephalus being the most severe phenotype detected in utero, and whose pathophysiology is incompletely understood. The aim of this study was to report detailed neuropathological data from patients with mutations, to delineate the neuropathological criteria required for L1CAM gene screening in foetuses by characterizing the sensitivity, specificity and positive predictive value of the cardinal signs, and to discuss the main differential diagnoses in non-mutated foetuses in order to delineate closely related conditions without L1CAM mutations. Neuropathological data from 138 cases referred to our genetic laboratory for screening of the L1CAM gene were retrospectively reviewed. Fifty-seven cases had deleterious L1CAM mutations. Of these, 100 % had hydrocephalus, 88 % adducted thumbs, 98 % pyramidal tract agenesis/hypoplasia, 90 % stenosis of the aqueduct of Sylvius and 68 % agenesis/hypoplasia of the corpus callosum. Two foetuses had L1CAM mutations of unknown significance. Seventy-nine cases had no L1CAM mutations; these were subdivided into four groups: (1) hydrocephalus sometimes associated with corpus callosum agenesis (44 %); (2) atresia/forking of the aqueduct of Sylvius/rhombencephalosynapsis spectrum (27 %); (3) syndromic hydrocephalus (9 %), and (4) phenocopies with no mutations in the L1CAM gene (20 %) and in whom family history strongly suggested an autosomal recessive mode of transmission. These data underline the existence of closely related clinical entities whose molecular bases are currently unknown. The identification of the causative genes would greatly improve our knowledge of the defective pathways involved in these cerebral malformations.
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http://dx.doi.org/10.1007/s00401-013-1146-1DOI Listing
September 2013

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

Hepatic stem-like phenotype and interplay of Wnt/beta-catenin and Myc signaling in aggressive childhood liver cancer.

Cancer Cell 2008 Dec;14(6):471-84

Oncogenesis and Molecular Virology Unit, Institut Pasteur, Paris Cedex 15, France.

Hepatoblastoma, the most common pediatric liver cancer, is tightly linked to excessive Wnt/beta-catenin signaling. Here, we used microarray analysis to identify two tumor subclasses resembling distinct phases of liver development and a discriminating 16-gene signature. beta-catenin activated different transcriptional programs in the two tumor types, with distinctive expression of hepatic stem/progenitor markers in immature tumors. This highly proliferating subclass was typified by gains of chromosomes 8q and 2p and upregulated Myc signaling. Myc-induced hepatoblastoma-like tumors in mice strikingly resembled the human immature subtype, and Myc downregulation in hepatoblastoma cells impaired tumorigenesis in vivo. Remarkably, the 16-gene signature discriminated invasive and metastatic hepatoblastomas and predicted prognosis with high accuracy.
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http://dx.doi.org/10.1016/j.ccr.2008.11.002DOI Listing
December 2008

Inherited 18q23 duplication in a fetus with multiple congenital anomalies.

Eur J Med Genet 2008 May-Jun;51(3):231-8. Epub 2008 Jan 12.

Medical Genetic Department, Nantes University Hospital, Nantes, France.

We report on a fetus with multiple congenital anomalies including atypical lissencephaly, corpus callosum agenesis, cerebellar hypoplasia, cleft palate, ventricular septal defect, and hypoplastic aortic arch. The initial routine chromosome study failed to detect any abnormality. Subtelomeres analysis by MLPA identified an 18q23 duplication inherited from its healthy father. We describe the anomalies identified and discuss diagnosis and the causability of this telomeric duplication.
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http://dx.doi.org/10.1016/j.ejmg.2007.12.010DOI Listing
August 2008

Complete sex reversal in a WAGR syndrome patient.

Am J Med Genet A 2007 Nov;143A(22):2692-5

Service de Génétique Médicale, Centre Hospitalier Universitaire, Nantes, France.

The WAGR contiguous gene deletion syndrome is a combination of Wilms tumor, aniridia, genitourinary abnormalities, and mental retardation. Children with WAGR syndrome invariably have a constitutional chromosomal deletion at 11p13. WT1 haploinsufficiency is associated with a significant risk of Wilms tumor while PAX6 haploinsufficiency lead to aniridia, both genes located in the deleted region. The 46,XY patients with WAGR syndrome are often born with genital abnormalities such as cryptorchidism or hypospadias but more rarely ambiguous genitalia. To our knowledge, complete sex reversal has never been observed in WAGR syndrome patients. Here, we report on the clinical, cytogenetic, and molecular characterization of a child with WAGR syndrome and complete sex reversal. The young girl had female external and internal genitalia with normal uterus and fallopian tubes while the ovaries were not observed. Chromosomal analysis showed a 46,XY,del(11)(p12p14.1) karyotype. A 1-Mb resolution array CGH experiment estimated the size of the interstitial deletion at approximately 10 Mb encompassing WT1 and PAX6. The entire coding regions of WT1 and SRY have been sequenced and no mutation has been identified. Frasier syndrome (FS) and Denys-Drash syndrome (DDS) are two disorders associated with mutations in the WT1 gene. Complete sex reversal is a feature usually present in FS and sometimes in DDS, but until now never observed in WAGR syndrome. The present report suggests that these conditions may be considered as part of the spectrum of disease due to WT1 gene alterations.
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http://dx.doi.org/10.1002/ajmg.a.31997DOI Listing
November 2007

Renal tubular dysgenesis, a not uncommon autosomal recessive disorder leading to oligohydramnios: Role of the Renin-Angiotensin system.

J Am Soc Nephrol 2006 Aug 21;17(8):2253-63. Epub 2006 Jun 21.

Institut National de la Santé et de la Recherche Médicale, Unité 574, Collège de France, Paris, France.

Renal tubular dysgenesis is a clinical disorder that is observed in fetuses and characterized by the absence or poor development of proximal tubules, early onset and persistent oligohydramnios that leads to the Potter sequence, and skull ossification defects. It may be acquired during fetal development or inherited as an autosomal recessive disease. It was shown recently that autosomal recessive renal tubular dysgenesis is genetically heterogeneous and linked to mutations in the genes that encode components of the renin-angiotensin system. This study analyzed the clinical expression of the disease in 29 fetus/neonates from 18 unrelated families and evaluated changes in renal morphology and expression of the renin-angiotensin system. The disease was uniformly severe, with perinatal death in all cases as a result of persistent anuria and hypoxia related to pulmonary hypoplasia. Severe defects in proximal tubules were observed in all fetuses from 18 gestational weeks onward, and lesions also involved other tubular segments. They were associated with thickening of the renal arterial vasculature, from the arcuate to the afferent arteries. Renal renin expression was strikingly increased in 19 of 24 patients studied, from 13 families, whereas no renal renin was detected in four patients from three families. Angiotensinogen and angiotensin-converting enzyme were absent or present in only small amounts in the proximal tubule, in correlation with the severity of tubular abnormalities. No specific changes were detected in angiotensin II receptor expression. The severity and the early onset of the clinical and pathologic expression of the disease underline the major importance of this system in fetal kidney function and development in humans. The identification of the disease on the basis of precise histologic analysis and the research of the genetic defect now allow genetic counseling and early prenatal diagnosis.
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http://dx.doi.org/10.1681/ASN.2005121303DOI Listing
August 2006

Mutations in genes in the renin-angiotensin system are associated with autosomal recessive renal tubular dysgenesis.

Nat Genet 2005 Sep 14;37(9):964-8. Epub 2005 Aug 14.

Inserm U574, Hôpital Necker-Enfants Malades, Université René Descartes, 149 rue de Sèvres, 75743 Paris cedex 15, France.

Autosomal recessive renal tubular dysgenesis is a severe disorder of renal tubular development characterized by persistent fetal anuria and perinatal death, probably due to pulmonary hypoplasia from early-onset oligohydramnios (Potter phenotype). Absence or paucity of differentiated proximal tubules is the histopathological hallmark of the disease and may be associated with skull ossification defects. We studied 11 individuals with renal tubular dysgenesis, belonging to nine families, and found that they had homozygous or compound heterozygous mutations in the genes encoding renin, angiotensinogen, angiotensin converting enzyme or angiotensin II receptor type 1. We propose that renal lesions and early anuria result from chronic low perfusion pressure of the fetal kidney, a consequence of renin-angiotensin system inactivity. This is the first identification to our knowledge of a renal mendelian disorder linked to genetic defects in the renin-angiotensin system, highlighting the crucial role of the renin-angiotensin system in human kidney development.
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http://dx.doi.org/10.1038/ng1623DOI Listing
September 2005

[An unusual pediatric tumor].

Ann Pathol 2004 Dec;24(6):639-40

Service d'Anatomie et de Cytologie Pathologiques A, CHU Hôtel Dieu, 30 Bd Jean Monnet, 44093 Nantes Cedex 1, France.

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http://dx.doi.org/10.1016/s0242-6498(04)94028-xDOI Listing
December 2004

Antenatal presentation of Bardet-Biedl syndrome may mimic Meckel syndrome.

Am J Hum Genet 2005 Mar 21;76(3):493-504. Epub 2005 Jan 21.

Département de Génétique et Unité INSERM U-393, Hôpital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France.

Bardet-Biedl syndrome (BBS) is a multisystemic disorder characterized by postaxial polydactyly, progressive retinal dystrophy, obesity, hypogonadism, renal dysfunction, and learning difficulty. Other manifestations include diabetes mellitus, heart disease, hepatic fibrosis, and neurological features. The condition is genetically heterogeneous, and eight genes (BBS1-BBS8) have been identified to date. A mutation of the BBS1 gene on chromosome 11q13 is observed in 30%-40% of BBS cases. In addition, a complex triallelic inheritance has been established in this disorder--that is, in some families, three mutations at two BBS loci are necessary for the disease to be expressed. The clinical features of BBS that can be observed at birth are polydactyly, kidney anomaly, hepatic fibrosis, and genital and heart malformations. Interestingly, polydactyly, cystic kidneys, and liver anomalies (hepatic fibrosis with bile-duct proliferation) are also observed in Meckel syndrome, along with occipital encephalocele. Therefore, we decided to sequence the eight BBS genes in a series of 13 antenatal cases presenting with cystic kidneys and polydactyly and/or hepatic fibrosis but no encephalocele. These fetuses were mostly diagnosed as having Meckel or "Meckel-like" syndrome. In six cases, we identified a recessive mutation in a BBS gene (three in BBS2, two in BBS4, and one in BBS6). We found a heterozygous BBS6 mutation in three additional cases. No BBS1, BBS3, BBS5, BBS7, or BBS8 mutations were identified in our series. These results suggest that the antenatal presentation of BBS may mimic Meckel syndrome.
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http://dx.doi.org/10.1086/428679DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1196400PMC
March 2005

46,XY gonadal dysgenesis: evidence for autosomal dominant transmission in a large kindred.

Am J Med Genet A 2003 Jan;116A(1):37-43

Service de Génétique Médicale, Centre Hospitalo-Universitaire, Nantes, France.

46,XY gonadal dysgenesis is characterized by abnormal testicular determination. We describe a large kindred in which various disorders of sexual development were observed, ranging from completely female phenotype without ambiguities of the external genitalia (five cases) to men with isolated penile or perineal hypospadias (four cases), including two cases with moderate virilization and one case with ambiguity of the external genitalia. Histologic examination of gonadal tissue was performed on seven subjects. These findings were suggestive of complete gonadal dysgenesis in one patient, partial gonadal dysgenesis in three patients, and mixed gonadal dysgenesis in three patients. Four patients developed gonadal tumors (two gonadoblastoma, two dysgerminoma, and one immature teratoma, i.e., one patient had a dysgerminoma with some areas of gonadoblastoma). All affected subjects had no other congenital anomalies or dysmorphic features. Analysis of families with several affected individuals with 46,XY gonadal dysgenesis implied an X-linked mode of inheritance because of the apparent absence of male-to-male transmission. However, a sex-limited autosomal dominant mode of inheritance affecting only XY individuals could not be ruled out. Analysis of the pedigree we report indicated an autosomal dominant mode of inheritance because of male-to-male transmission. This kindred supports the involvement of at least one autosomal gene in non-syndromic 46,XY gonadal dysgenesis.
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http://dx.doi.org/10.1002/ajmg.a.10820DOI Listing
January 2003

Intraductal papillary-mucinous tumors of the pancreas: predictive criteria of malignancy according to pathological examination of 53 cases.

Arch Surg 2002 Nov;137(11):1274-8

Department of Surgery, Hospital E. Herriot, Lyon, France.

Background: One of the main problems in the management and treatment of intraductal papillary-mucinous tumors is the lack of a reliable predictive factor for malignancy.

Hypothesis: Surgical treatment could be adapted to macroscopic criteria (presence of mural nodules and diameter of the pancreatic duct and of the lesion) or to tumor location (main duct, branch duct, or combined lesions) associated with benign or malignant forms.

Design: Retrospective study.

Setting: Two university and tertiary referral centers.

Patients: Fifty-three consecutive patients who underwent pancreatic resection for intraductal papillary-mucinous tumors between January 1, 1985, and December 31, 2000.

Results: Macroscopic analyses of tumors showed 6 main duct lesions, 12 branch duct lesions, and 35 combined lesions. A carcinoma was present in 33 cases (62%): 22 (41%) were invasive and 11 (21%) were noninvasive; 9 (17%) were borderline tumors and 11 (21%) were benign. Carcinoma and invasive carcinoma forms were less frequent in branch duct lesions (P<.001 and P =.009, respectively). Mural nodules were more frequent in carcinomas (P =.006) and invasive carcinomas (P<.001), with a positive predictive value of malignancy of 81%. The diameter of lesions (branch duct lesion > or =30 mm) or main duct (main pancreatic duct > or =15 mm in combined or main pancreatic duct lesions) did not correlate with malignancy.

Conclusions: No carcinoma occurred in branch duct types smaller than 30 mm without mural nodules. Limited resection may be appropriate only in this type of tumor.
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http://dx.doi.org/10.1001/archsurg.137.11.1274DOI Listing
November 2002