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1. Identification of predictive criteria for pathogenic variants of primary bilateral macronodular adrenal hyperplasia (PBMAH) gene ARMC5 in 352 unselected patients

Author: Lucas Bouys, Anna Vaczlavik, Anne Jouinot, Patricia Vaduva, Stéphanie Espiard, Guillaume Assié, Rossella Libé, Karine Perlemoine, Bruno Ragazzon, Laurence Guignat, Lionel Groussin, Léopoldine Bricaire, Isadora Pontes Cavalcante, Fidéline Bonnet-Serrano, Hervé Lefebvre, Marie-Laure Raffin-Sanson, Nicolas Chevalier, Philippe Touraine, Christel Jublanc, Camille Vatier, Gérald Raverot, Magalie Haissaguerre, Luigi Maione, Matthias Kroiss, Martin Fassnacht, Sophie Christin-Maitre, Eric Pasmant, Françoise Borson-Chazot, Antoine Tabarin, Marie-Christine Vantyghem, Martin Reincke, Peter Kamenicky, Marie-Odile North, Jérôme Bertherat, Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Cancer et génome: Bioinformatique, biostatistiques et épidémiologie d'un système complexe, Mines Paris - PSL (École nationale supérieure des mines de Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Pontchaillou [Rennes], CHU Lille, Recherche translationnelle sur le diabète - U 1190 (RTD), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), CHU Rouen, Normandie Université (NU), Hôpital Ambroise Paré [AP-HP], Centre Hospitalier Universitaire de Nice (CHU Nice), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Sorbonne Université (SU), Centre de Recherche Saint-Antoine (CRSA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Hospices Civils de Lyon (HCL), Hôpital Haut-Lévêque - CHU de Bordeaux (Centre médico chirurgical Magellan), Physiologie et physiopathologie endocriniennes (PHYSENDO), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), University Hospital of Würzburg, Klinikum der Universität [München], CHU Saint-Antoine [AP-HP], L B is recipient of research fellowships from the Cancer Research for Personalized Medicine (CARPEM) and the Fondation ARC pour la Recherche contre le Cancer, J B laboratory is supported by the Agence Nationale pour la Recherche grant ANR-18-CE14-0008-01 and the Fondation pour la Recherche Médicale (EQU201903007854). P T, C J, M F, S C M, F B C, M R, P C and J B clinical departments are part the European Reference Network on Rare Endocrine Conditions (Endo-ERN) – Project ID No 739572, and ANR-18-CE14-0008,STEROMICS,Steroïdogénomique de l'hypersécrétion des stéroïdes surrénaliens(2018)
Subjects: Armadillo Domain Proteins, Hyperplasia, Hydrocortisone, Endocrinology, Diabetes and Metabolism, [SDV]Life Sciences [q-bio], 71 ARMC5, General Medicine, genetic screening, PBMAH, Endocrinology, Primary Bilateral Macronodular Adrenal Hyperplasia, adrenal tumors, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Adrenal Glands, Humans, Cushing syndrome, tumor suppressor gene, Retrospective Studies
Abstract: Objective Primary bilateral macronodular adrenal hyperplasia (PBMAH) is a heterogeneous disease characterized by adrenal macronodules and variable levels of cortisol excess, with not clearly established clinical diagnostic criteria. It can be caused by ARMC5 germline pathogenic variants. In this study, we aimed to identify predictive criteria for ARMC5 variants. Methods We included 352 consecutive index patients from 12 European centers, sequenced for germline ARMC5 alteration. Clinical, biological and imaging data were collected retrospectively. Results 52 patients (14.8%) carried ARMC5 germline pathogenic variants and showed a more distinct phenotype than non-mutated patients for cortisol excess (24-h urinary free cortisol 2.32 vs 1.11-fold ULN, respectively, P < 0.001) and adrenal morphology (maximal adrenal diameter 104 vs 83 mm, respectively, P < 0.001) and were more often surgically or medically treated (67.9 vs 36.8%, respectively, P < 0.001). ARMC5-mutated patients showed a constant, bilateral adrenal involvement and at least a possible autonomous cortisol secretion (defined by a plasma cortisol after 1 mg dexamethasone suppression above 50 nmol/L), while these criteria were not systematic in WT patients (78.3%). The association of these two criteria holds a 100% sensitivity and a 100% negative predictive value for ARMC5 pathogenic variant. Conclusion We report the largest series of index patients investigated for ARMC5 and confirm that ARMC5 pathogenic variants are associated with a more severe phenotype in most cases. To minimize negative ARMC5 screening, genotyping should be limited to clear bilateral adrenal involvement and autonomous cortisol secretion, with an optimum sensitivity for routine clinical practice. These findings will also help to better define PBMAH diagnostic criteria.
Published: 2023
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2. Whole exome sequencing in a cohort of familial premature ovarian insufficiency cases reveals a broad array of pathogenic or likely pathogenic variants in 50% of families

Author: Alexandre Rouen, Eli Rogers, Véronique Kerlan, Brigitte Delemer, Sophie Catteau-Jonard, Yves Reznik, Anne Gompel, Isabelle Cedrin, Anne-Marie Guedj, Virginie Grouthier, Thierry Brue, Catherine Pienkowski, Anne Bachelot, Sandra Chantot-Bastaraud, Alexandra Rousseau, Tabassome Simon, Esther Kott, Jean-Pierre Siffroi, Philippe Touraine, Sophie Christin-Maitre, Maladies génétiques d'expression pédiatrique (U933), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre Hospitalier Universitaire de Reims (CHU Reims), CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN), Hopital port Royal, Partenaires INRAE, Hôpital Jean Verdier [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hôpital Universitaire Carémeau [Nîmes] (CHU Nîmes), Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Marseille medical genetics - Centre de génétique médicale de Marseille (MMG), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Marseille Maladies Rares (MarMaRa), Aix Marseille Université (AMU), Service d'endocrinologie, diabète, maladies métaboliques [Hôpital de la Conception - APHM], CHU Saint-Antoine [AP-HP], and Programme Hospitalier de Recherche Clinique AOM08084, NI07022 FAMIOP
Subjects: premature ovarian insufficiency, Genes in POI, [SDV]Life Sciences [q-bio], Menopause, Premature, Obstetrics and Gynecology, Primary Ovarian Insufficiency, hypergonadotropic hypogonadism, whole exome sequencing, Cohort Studies, Fragile X Mental Retardation Protein, Cross-Sectional Studies, primary amenorrhea, Reproductive Medicine, Exome Sequencing, Humans, Female
Abstract: International audience; Objective: To study the diagnostic yield, including variants in genes yet to be incriminated, of whole exome sequencing (WES) in familial cases of premature ovarian insufficiency (POI). Design: Cross-sectional study. Setting: Endocrinology and reproductive medicine teaching hospital departments. Patients: Familial POI cases were recruited as part of a nationwide multicentric cohort. A total of 36 index cases in 36 different families were studied. Fifty-two relatives were available, including 25 with POI and 27 affected who were nonaffected. Karyotype analysis, FMR1 screening, single nucleotide polymorphism array analysis, and WES were performed in all subjects. Interventions: None. Main Outcome Measures: The primary outcome was a molecular etiology, as diagnosed by karyotype, FMR1 screening, single nucleotide polymorphism array, and WES. Results: A likely molecular etiology (pathogenic or likely pathogenic variant) was identified in 18 of 36 index cases (50% diagnostic yield). In 12 families, we found a pathogenic or likely pathogenic variant in a gene previously incriminated in POI, and in 6 families, we found a pathogenic or likely pathogenic variant in new candidate genes. Most of the variants identified were located in genes involved in cell division and meiosis (n = 11) or DNA repair (n = 4). Conclusions: The genetic etiologic diagnosis in POI allows for genetic familial counseling, anticipated pregnancy planning, and ovarian tissue preservation or oocyte preservation. Identifying new genes may lead to future development of therapeutics in reproduction based on disrupted molecular pathways. Clinical Trial Registration Number: NCT 01177891. ((C) 2021 by American Society for Reproductive Medicine.) El resumen esta disponible en Espanol al final del articulo.
Published: 2022
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3. Meiotic genes in premature ovarian insufficiency: variants in HROB and REC8 as likely genetic causes

Author: Solène Duros, Bénédicte Nouyou, Rajini Sreenivasan, Sultana M.H. Faradz, Jocelyn van den Bergen, Andrew H. Sinclair, Shabnam Bakhshalizadeh, Jérôme Dulon, Elena J. Tucker, Linda Akloul, Wilfrid Carré, Katrina M. Bell, Nurin Aisyiyah Listyasari, Mathilde Domin-Bernhard, Marc-Antoine Belaud-Rotureau, Sylvie Jaillard, Gorjana Robevska, Katie L. Ayers, Philippe Touraine, Murdoch Children's Research Institute (MCRI), University of Melbourne, Centre des Pathologies gynécologiques Rares [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHU Pontchaillou [Rennes], Institut de recherche en santé, environnement et travail (Irset), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Institut National de la Santé et de la Recherche Médicale (INSERM)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Université d'Angers (UA), École des Hautes Études en Santé Publique [EHESP] (EHESP), NHMRC programNational Health and Medical Research Council of Australia [1074258], NHMRC fellowshipsNational Health and Medical Research Council of Australia [1054432, 1126995, 1062854], Melbourne Research Scholarship, Victorian Government's Operational Infrastructure Support Program, CHU Rennes grant, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), and Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )
Subjects: Infertility, Cohesin complex, In silico, [SDV]Life Sciences [q-bio], Cell Cycle Proteins, Primary Ovarian Insufficiency, Biology, Premature ovarian insufficiency, Article, Chromosomes, Mice, 03 medical and health sciences, 0302 clinical medicine, Exome Sequencing, Genetics, medicine, Animals, Humans, Gene, Genetics (clinical), Exome sequencing, 030304 developmental biology, 0303 health sciences, 030219 obstetrics & reproductive medicine, MCM8, DNA Helicases, medicine.disease, Phenotype, 3. Good health, DNA-Binding Proteins, Meiosis, Female
Abstract: International audience; Premature ovarian insufficiency (POI), affecting 1 in 100 women, is characterised by loss of ovarian function associated with elevated gonadotropin, before the age of 40. In addition to infertility, patients face increased risk of comorbidities such as heart disease, osteoporosis, cancer and/or early mortality. We used whole exome sequencing to identify the genetic cause of POI in seven women. Each had biallelic candidate variants in genes with a primary role in DNA damage repair and/or meiosis. This includes two genes, REC8 and HROB, not previously associated with autosomal recessive POI. REC8 encodes a component of the cohesin complex and HROB encodes a factor that recruits MCM8/9 for DNA damage repair. In silico analyses, combined with concordant mouse model phenotypes support these as new genetic causes of POI. We also identified novel variants in MCM8, NUP107, STAG3 and HFM1 and a known variant in POF1B. Our study highlights the pivotal role of meiosis in ovarian function. We identify novel variants, consolidate the pathogenicity of variants previously considered of unknown significance, and propose HROB and REC8 variants as new genetic causes while exploring their link to pathogenesis.
Published: 2021
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4. Transition of young adults with endocrine and metabolic diseases: the TRANSEND cohort

Author: Michel Polak, Stéphane N. Hatem, Juliane Léger, Enora Le Roux, Graziella Pinto, Florence Menesguen, Philippe Touraine, Pauline Faucher, Marc Popelier, I. Tejedor, Christine Poitou, M. Halbron, Sabine Malivoir, Epidémiologie Clinique et Evaluation Economique Appliquées aux Populations Vulnérables (ECEVE (U1123 / UMR_S_1123)), Institut National de la Santé et de la Recherche Médicale (INSERM)-AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université de Paris (UP), Service d’endocrinologie et médecine de la reproduction [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre de référence des maladies endocriniennes rares de la croissance et du développement [CHU Pitié-Salpêtrière], Centre des Pathologies gynécologiques Rares [CHU Pitié-Salpêtrière], Service de Diabétologie [CHU Pitié-Salpétrière], Service de Nutrition [CHU Pitié-Salpétrière], Institut E3M [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Pitié-Salpêtrière [AP-HP], Maladies neurodéveloppementales et neurovasculaires (NeuroDiderot (UMR_S_1141 / U1141)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Cité (UPCité), Service d'Endocrinologie et Médecine de la Reproduction [CHU Pitié-Salpêtrière], Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut de Cardiométabolisme et Nutrition = Institute of Cardiometabolism and Nutrition [CHU Pitié Salpêtrière] (IHU ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Nutrition et obésités: approches systémiques (UMR-S 1269) (Nutriomics), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), HAL-SU, Gestionnaire, Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de diabétologie [CHU Pitié-Salpétrière], Service de nutrition [CHU Pitié-Salpétrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], and Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)
Subjects: Longitudinal study, Pediatrics, medicine.medical_specialty, Endocrinology, Diabetes and Metabolism, MEDLINE, 030209 endocrinology & metabolism, Disease, lcsh:Diseases of the endocrine glands. Clinical endocrinology, 03 medical and health sciences, endocrinology, 0302 clinical medicine, 030225 pediatrics, Internal Medicine, medicine, Endocrine system, case management, Young adult, Type 1 diabetes, lcsh:RC648-665, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, business.industry, Research, rare diseases, cohort, medicine.disease, Obesity, 3. Good health, transition to adult care, Cohort, business, care pathway, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: Objective The transition from paediatric to adult medicine involves risks of poor patient outcomes and of significant losses of patients to follow up. The research aimed to analyse the implementation in an initial cohort of patients of a new programme of transition to adult care based on a case management approach. Design A longitudinal study of the case management approach to transition, initiated in a university hospital in France in September 2016. Methods Patients with the endocrine or metabolic disease diagnosed during childhood and transferred to adult care were included. The transition programme includes three steps based on case management: liaising with paediatric services, personalising care pathways, and liaising with structures outside the hospital (general practitioners, agencies in the educational and social sector). Results The cohort included 500 patients, with malignant brain tumour (n = 56 (11%)), obesity (n = 55 (11%)), type 1 diabetes (n = 54 (11%)), or other disease (n = 335 (67%)). Their median age at transfer was 19, and the sex ratio was 0.5. At median 21 months of follow-up, 439 (88%) had a regular follow-up in or outside the hospital, 47 (9%) had irregular follow-up (absence at the last appointment or no appointment scheduled within the time recommended), 4 had stopped care on doctor’s advice, 4 had died, 3 had moved, and 3 had refused care. The programme involved 9615 case management actions; 7% of patients required more than 50 actions. Patients requiring most support were usually those affected by a rare genetic form of obesity. Conclusions Case managers successfully addressed the complex needs of patients. Over time, the cohort will provide unprecedented long-term outcome results for patients with various conditions who experienced this form of transition.
Published: 2020
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5. Genomic sequencing highlights the diverse molecular causes of Perrault syndrome: a peroxisomal disorder (PEX6), metabolic disorders (CLPP, GGPS1), and mtDNA maintenance/translation disorders (LARS2, TFAM)

Author: Sandra Whalen, Juliette Dupont, Sandrine Vuillaumier-Barrot, Chloe Hanna, Gorjana Robevska, Phillipa J. Lamont, Lurdes Sampaio, John Christodoulou, Rocio Rius, Elena J. Tucker, André Travessa, Jocelyn van den Bergen, Andrew H. Sinclair, Arnaud Isapof, Katrina M. Bell, Andrea Simpson, Jérôme Dulon, Sylvie Jaillard, Tanya Stojkovic, Susana Quijano-Roy, David R. Thorburn, Katie L. Ayers, Philippe Touraine, Murdoch Children's Research Institute (MCRI), University of Melbourne, CHU Pontchaillou [Rennes], Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Sorbonne Université (SU), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), AP-HP - Hôpital Bichat - Claude Bernard [Paris], Filière Neuromusculaire (FILNEMUS), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), National Health and Medical Research Council (NHMRC)National Health and Medical Research Council of Australia [1113531], NHMRCNational Health and Medical Research Council of Australia [1074258, 1054432, 1062854, 1155244], CONACYTConsejo Nacional de Ciencia y Tecnologia (CONACyT), Victorian Government's Operational Infrastructure Support Program, Université d'Angers (UA)-Université de Rennes 1 (UR1), and Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )
Subjects: Adult, Male, Candidate gene, Adolescent, Mitochondrial translation, Hearing Loss, Sensorineural, [SDV]Life Sciences [q-bio], Gene Expression, Biology, DNA, Mitochondrial, Amino Acyl-tRNA Synthetases, Mitochondrial Proteins, 03 medical and health sciences, Peroxisomal disorder, Genetics, medicine, Peroxisomes, Farnesyltranstransferase, Humans, Genetic Predisposition to Disease, Child, Genetics (clinical), 030304 developmental biology, 0303 health sciences, Base Sequence, 030305 genetics & heredity, Ovary, High-Throughput Nucleotide Sequencing, Geranyltranstransferase, Endopeptidase Clp, TFAM, medicine.disease, Dimethylallyltranstransferase, Human genetics, Premature ovarian failure, Gonadal Dysgenesis, 46,XX, Pedigree, DNA-Binding Proteins, Protein prenylation, ATPases Associated with Diverse Cellular Activities, Female, PEX6, Transcription Factors
Abstract: International audience; Perrault syndrome is a rare heterogeneous condition characterised by sensorineural hearing loss and premature ovarian insufficiency. Additional neuromuscular pathology is observed in some patients. There are six genes in which variants are known to cause Perrault syndrome; however, these explain only a minority of cases. We investigated the genetic cause of Perrault syndrome in seven affected individuals from five different families, successfully identifying the cause in four patients. This included previously reported and novel causative variants in known Perrault syndrome genes, CLPP and LARS2, involved in mitochondrial proteolysis and mitochondrial translation, respectively. For the first time, we show that pathogenic variants in PEX6 can present clinically as Perrault syndrome. PEX6 encodes a peroxisomal biogenesis factor, and we demonstrate evidence of peroxisomal dysfunction in patient serum. This study consolidates the clinical overlap between Perrault syndrome and peroxisomal disorders, and highlights the need to consider ovarian function in individuals with atypical/mild peroxisomal disorders. The remaining patients had variants in candidate genes such as TFAM, involved in mtDNA transcription, replication, and packaging, and GGPS1 involved in mevalonate/coenzyme Q(10) biosynthesis and whose enzymatic product is required for mouse folliculogenesis. This genomic study highlights the diverse molecular landscape of this poorly understood syndrome.
Published: 2020
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6. Effect of congenital adrenal hyperplasia treated by glucocorticoids on plasma metabolome: a machine-learning-based analysis

Author: Joe-Elie Salem, Edi Prifti, Monique Leban, Anne Bachelot, Lee S. Nguyen, Farid Ichou, Christian Funck-Brentano, Philippe Touraine, Centre d'investigation clinique Paris Est [CHU Pitié Salpêtrière] (CIC Paris-Est), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), CMC Ambroise Paré [Neuilly-sur-Seine], Sorbonne Université - Faculté de Médecine (SU FM), Sorbonne Université (SU), Centre d'investigation clinique Biothérapie [CHU Pitié-Salpêtrière] (CIC-BTi), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Integromics [Paris], Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut de Cardiométabolisme et Nutrition = Institute of Cardiometabolism and Nutrition [CHU Pitié Salpêtrière] (IHU ICAN), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut de Cardiométabolisme et Nutrition = Institute of Cardiometabolism and Nutrition [CHU Pitié Salpêtrière] (IHU ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Unité de modélisation mathématique et informatique des systèmes complexes [Bondy] (UMMISCO), Université de Yaoundé I-Institut de la francophonie pour l'informatique-Université Cheikh Anta Diop [Dakar, Sénégal] (UCAD)-Université Gaston Bergé (Saint-Louis, Sénégal)-Université Cadi Ayyad [Marrakech] (UCA)-Sorbonne Université (SU)-Institut de Recherche pour le Développement (IRD [France-Nord]), ICANalytics [Paris], The study sponsor was Assistance Publique – Hôpitaux de Paris (Département de la Recherche Clinique et du Développement)., CIC Paris Est, Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), CIC Pitié BT, Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Institut de Recherche pour le Développement (IRD [France-Nord])-Institut de la francophonie pour l'informatique-Université Cheikh Anta Diop [Dakar, Sénégal] (UCAD)-Université Gaston Bergé (Saint-Louis, Sénégal)-Université Cadi Ayyad [Marrakech] (UCA)-Université de Yaoundé I-Sorbonne Université (SU), Service d’endocrinologie et médecine de la reproduction [CHU Pitié-Salpêtrière], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre de référence des maladies endocriniennes rares de la croissance et du développement [CHU Pitié-Salpêtrière], Centre des Pathologies gynécologiques Rares [CHU Pitié-Salpêtrière], Centre d'investigation clinique pluridisciplinaire [CHU Pitié Salpêtrière] (CIC-P 1421), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Service d'Endocrinologie et Médecine de la Reproduction [CHU Pitié-Salpêtrière], and Bodescot, Myriam
Subjects: 0301 basic medicine, Purine, Male, Hydrocortisone, lcsh:Medicine, Machine Learning, chemistry.chemical_compound, 0302 clinical medicine, Endocrinology, Purine metabolism, lcsh:Science, [SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, Multidisciplinary, Endocrine system and metabolic diseases, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, 3. Good health, Aminosugar, Area Under Curve, Metabolome, Female, Glucocorticoid, medicine.drug, Adult, medicine.medical_specialty, Multihormonal system disorders, Article, 03 medical and health sciences, Young Adult, Metabolomics, Internal medicine, medicine, Humans, Indoleamine-Pyrrole 2,3,-Dioxygenase, Congenital adrenal hyperplasia, Glucocorticoids, Adrenal Hyperplasia, Congenital, business.industry, lcsh:R, Metabolism, medicine.disease, 030104 developmental biology, Pyrimidines, chemistry, ROC Curve, Purines, Case-Control Studies, lcsh:Q, business, 030217 neurology & neurosurgery
Abstract: Background. Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency leads to impaired cortisol biosynthesis. Treatment includes glucocorticoid supplementation. We studied the specific metabolomics signatures in CAH patients using two different algorithms. Methods. In a case-control study of CAH patients matched on sex and age with healthy control subjects, two metabolomic analyses were performed: one using MetaboDiff, a validated differential metabolomic analysis tool and the other, using Predomics, a novel machine-learning algorithm. Results. 168 participants were included (84 CAH patients). There was no correlation between plasma cortisol levels during glucocorticoid supplementation and metabolites in CAH patients. Indoleamine 2,3-dioxygenase enzyme activity was correlated with ACTH (rho coefficient = −0.25, p-value = 0.02), in CAH patients but not in controls subjects. Overall, 33 metabolites were significantly altered in CAH patients. Main changes came from: purine and pyrimidine metabolites, branched aminoacids, tricarboxylic acid cycle metabolites and associated pathways (urea, glucose, pentose phosphates). MetaboDiff identified 2 modules that were significantly different between both groups: aminosugar metabolism and purine metabolism. Predomics found several interpretable models which accurately discriminated the two groups (accuracy of 0.86 and AUROC of 0.9). Conclusion. CAH patients and healthy control subjects exhibit significant differences in plasma metabolomes, which may be explained by glucocorticoid supplementation.
Published: 2020
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7. GGPS1 Mutations Cause Muscular Dystrophy/Hearing Loss/Ovarian Insufficiency Syndrome

Author: Udo Oppermann, Richard S. Finkel, Sandra Donkervoort, Edoardo Malfatti, Mariarita Santi, Leila Qebibo, Thomas Voit, Carsten G. Bönnemann, Kamel Mamchaoui, Michio Hirano, Kate Bushby, Philippe Touraine, Isabelle Nelson, Volker Straub, Hui Xiong, Tanya Stojkovic, Jahannaz Dastgir, A. Reghan Foley, Stephanie Duguez, Thomas C. Markello, Jyoti K. Jaiswal, Jachinta Rooney, Thierry Maisonobe, Ying Hu, Imelda Hughes, Jocelyn Laporte, Norma B. Romero, Katherine G. Meilleur, Johann Böhm, Adam Horn, Yaqun Zou, James E. Dunford, Yanbin Fan, Goutam Chandra, Centre de recherche en Myologie – U974 SU-INSERM, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Handicap neuromusculaire : Physiopathologie, Biothérapie et Pharmacologies appliquées (END-ICAP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Neurophysiologie [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de Chirurgie Générale, Viscérale et Endocrinienne [CHU Pitié-Sapêtrière], Unit of Neuromuscular Morphology [CHU Pitié-Salpêtrière], Institut de Myologie, Centre National de la Recherche Scientifique (CNRS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Association française contre les myopathies (AFM-Téléthon)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Association française contre les myopathies (AFM-Téléthon)-Sorbonne Université (SU)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), ANR-10-INBS-09 Fondation Maladies Rares, FMR National Institute of Neurological Disorders and Stroke, NINDS, This study was supported by intramural funds from the NIH National Institute of Neurological Disorders and Stroke (grant to C.G.B). J.E.D. is supported by National Institute for Health Research Oxford Biomedical Research Centre, Oxford, United Kingdom. J.L. and J.B. are supported by France G?nomique (ANR-10-INBS-09) and Fondation Maladies Rares within the framework of the ?Myocapture? sequencing project. We thank the patients and their families for their generous participation in this study, Dr P. Mohassel for his help in evaluating the patients, and M. Pizzimenti for technical assistance., ANR-10-INBS-0009,France-Génomique,Organisation et montée en puissance d'une Infrastructure Nationale de Génomique(2010), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche en Myologie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Institut de Myologie, and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Male, 0301 basic medicine, Pathology, Geranylgeranyl pyrophosphate, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Primary Ovarian Insufficiency, Muscular Dystrophies, Protein Structure, Secondary, Mice, chemistry.chemical_compound, 0302 clinical medicine, Medicine, Gene Knock-In Techniques, Muscular dystrophy, Research Articles, Exome sequencing, Sanger sequencing, Geranyltranstransferase, Middle Aged, Phenotype, Pedigree, 3. Good health, Neurology, symbols, Female, Sensorineural hearing loss, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], GGPS1, medicine.symptom, Research Article, Adult, medicine.medical_specialty, Adolescent, Hearing loss, Mice, Transgenic, Young Adult, 03 medical and health sciences, symbols.namesake, Exome Sequencing, Animals, Farnesyltranstransferase, Humans, Hearing Loss, business.industry, Sequence Analysis, DNA, Dimethylallyltranstransferase, medicine.disease, 030104 developmental biology, chemistry, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Mutation, Neurology (clinical), business, 030217 neurology & neurosurgery
Abstract: International audience; Objective: A hitherto undescribed phenotype of early onset muscular dystrophy associated with sensorineural hearing loss and primary ovarian insufficiency was initially identified in 2 siblings and in subsequent patients with a similar constellation of findings. The goal of this study was to understand the genetic and molecular etiology of this condition. Methods: We applied whole exome sequencing (WES) superimposed on shared haplotype regions to identify the initial biallelic variants in GGPS1 followed by GGPS1 Sanger sequencing or WES in 5 additional families with the same phenotype. Molecular modeling, biochemical analysis, laser membrane injury assay, and the generation of a Y259C knock-in mouse were done. Results: A total of 11 patients in 6 families carrying 5 different biallelic pathogenic variants in specific domains of GGPS1 were identified. GGPS1 encodes geranylgeranyl diphosphate synthase in the mevalonate/isoprenoid pathway, which catalyzes the synthesis of geranylgeranyl pyrophosphate, the lipid precursor of geranylgeranylated proteins including small guanosine triphosphatases. In addition to proximal weakness, all but one patient presented with congenital sensorineural hearing loss, and all postpubertal females had primary ovarian insufficiency. Muscle histology was dystrophic, with ultrastructural evidence of autophagic material and large mitochondria in the most severe cases. There was delayed membrane healing after laser injury in patient-derived myogenic cells, and a knock-in mouse of one of the mutations (Y259C) resulted in prenatal lethality. Interpretation: The identification of specific GGPS1 mutations defines the cause of a unique form of muscular dystrophy with hearing loss and ovarian insufficiency and points to a novel pathway for this clinical constellation. ANN NEUROL 2020;88:332–347.
Published: 2020
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8. Illicit Upregulation of Serotonin Signaling Pathway in Adrenals of Patients With High Plasma or Intra-Adrenal ACTH Levels

Author: Olivier Chabre, Céline Duparc, Mathilde Sibony, Mari Suzuki, Philippe Touraine, Fideline Bonnet-Serrano, Estelle Louiset, Constantine A. Stratakis, Françoise Gobet, Jacques Young, Julie Le Mestre, Hervé Lefebvre, Jérôme Bertherat, Yves Reznik, Gérald Raverot, Différenciation et communication neuronale et neuroendocrine (DC2N), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Normandie Université (NU), Service Endocrinologie - Diabétologie [CHU Caen], Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Service d’endocrinologie et médecine de la reproduction [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Biologie du Cancer et de l'Infection (BCI ), Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut National de la Santé et de la Recherche Médicale (INSERM), Récepteurs stéroïdiens : physiopathologie endocrinienne et métabolique, Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR93-Université Paris-Sud - Paris 11 (UP11), Service d'anatomie pathologique [CHU Tenon], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Tenon [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service d'Anatomie et Cytologie Pathologique [CHU Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), National Institutes of Health [Bethesda] (NIH), Santé Lyon Est - Louis Léopold Ollier, Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Université Paris-Sud - Paris 11 (UP11)-IFR93-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Tenon [AP-HP], Service d'Endocrinologie et Médecine de la Reproduction [CHU Pitié-Salpêtrière], Service d'Anatomie et cytologie pathologiques [CHU Tenon], and DUPARC, Céline
Subjects: 0301 basic medicine, Male, [SDV.MHEP.PHY] Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], Endocrinology, Diabetes and Metabolism, Receptor expression, Clinical Biochemistry, Adrenal Gland Neoplasms, Stimulation, Tryptophan Hydroxylase, Biochemistry, Cushing syndrome, 0302 clinical medicine, Endocrinology, Adrenal Glands, Cyclic AMP, Cushing Syndrome, [SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, Chemistry, Adrenal cortex, Middle Aged, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, 3. Good health, Up-Regulation, medicine.anatomical_structure, Female, Signal Transduction, Cortisol secretion, Adenoma, Adult, medicine.medical_specialty, Serotonin, endocrine system, Primary Cell Culture, 030209 endocrinology & metabolism, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Serotonergic, 03 medical and health sciences, Adrenocorticotropic Hormone, Internal medicine, medicine, [SDV.MHEP.PHY]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], Humans, Pituitary ACTH Hypersecretion, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, Clinical Research Articles, Biochemistry (medical), medicine.disease, Cushing Disease, 030104 developmental biology, Receptors, Serotonin, Steroid 21-Hydroxylase, Protein Kinases
Abstract: Context In the human adrenal, serotonin (5-HT), released by mast cells stimulates corticosteroid secretion through activation of type 4 serotonin receptors (5-HT4R). In primary pigmented nodular adrenocortical disease cells, activation of the cAMP/protein kinase A (PKA) pathway by PRKAR1A mutations triggers upregulation of the 5-HT synthesizing enzyme tryptophan hydroxylase (TPH) and the 5-HT4, 5-HT6, and 5-HT7 receptors. Because ACTH stimulates cortisol secretion through activation of PKA, adrenocortical tissues exposed to sustained stimulation by ACTH may harbor increased expression of TPH and 5-HT4/6/7 receptors. Objective To investigate the effects of long-term ACTH stimulation on the serotonergic pathway in adrenals of patients with high plasma or intra-adrenal ACTH levels. Methods Adrenal tissues were obtained from patients with Cushing disease, ectopic secretion of ACTH [paraneoplastic Cushing syndrome; (paraCS)], 21-hydroxylase deficiency (21-OHD), primary bilateral macronodular adrenal hyperplasia with intra-adrenal ACTH presence, or cortisol-producing adenomas. TPH and 5-HT4/6/7 receptor expression was investigated using RT-PCR and immunochemistry in comparison with normal adrenals. Primary cultured adrenocortical cells originating from a patient with paraCS were incubated with 5-HT and 5-HTR agonists/antagonists. Results TPH and/or 5-HT4/6/7 receptors were overexpressed in the different types of tissues. In paraCS cultured cells, the cortisol response to 5-HT was exaggerated compared with normal adrenal cells and the stimulatory action of 5-HT was reduced by 5-HT4R antagonist. Conclusion Our results indicate that prolonged activation of the cAMP/PKA pathway by ACTH induces an aberrant serotonergic stimulatory loop in the adrenal cortex that likely participates in the pathogenesis of corticosteroid hypersecretion.
Published: 2019
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9. TP63-truncating variants cause isolated premature ovarian insufficiency

Author: Katrina M. Bell, Gorjana Robevska, Jérôme Dulon, Philippe Touraine, Andrew H. Sinclair, Chloe Hanna, Sylvie Jaillard, Sonia Grover, Elena J. Tucker, Simon Sadedin, Jocelyn van den Bergen, Murdoch Children's Research Institute (MCRI), Institut de recherche en santé, environnement et travail (Irset), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Institut National de la Santé et de la Recherche Médicale (INSERM)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Université d'Angers (UA), CHU Pontchaillou [Rennes], University of Melbourne, Hôpital Raymond Poincaré [AP-HP], Centre des Pathologies gynécologiques Rares [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), 1062854, National Health and Medical Research Council, 1074258, National Health and Medical Research Council, 1054432, Peter Doherty Early Career Fellowship, Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)
Subjects: premature ovarian insufficiency, media_common.quotation_subject, [SDV]Life Sciences [q-bio], Nonsense, Primary Ovarian Insufficiency, Biology, Premature ovarian insufficiency, medicine.disease_cause, 03 medical and health sciences, Exon, Protein Domains, Exome Sequencing, TP63, Genotype, Genetics, medicine, Humans, Genetic Predisposition to Disease, whole-exome sequencing, Genetics (clinical), Exome sequencing, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, media_common, 0303 health sciences, Mutation, ovarian dysgenesis, Tumor Suppressor Proteins, Serine Endopeptidases, 030305 genetics & heredity, Phenotype, PREPL, Pedigree, 3. Good health, POI cohort, Codon, Nonsense, Female, Prolyl Oligopeptidases, Transcription Factors
Abstract: Premature ovarian insufficiency involves amenorrhea and elevated follicle-stimulating hormone before age 40, and its genetic basis is poorly understood. Here, we study 13 premature ovarian insufficiency (POI) patients using whole-exome sequencing. We identify PREPL and TP63 causative variants, and variants in other potentially novel POI genes. PREPL deficiency is a known cause of syndromic POI, matching the patients' phenotype. A role for TP63 in ovarian biology has previously been proposed but variants have been described in multiorgan syndromes, and not isolated POI. One patient with isolated POI harbored a de novo nonsense TP63 variant in the terminal exon and an unrelated patient had a different nonsense variant in the same exon. These variants interfere with the repression domain while leaving the activation domain intact. We expand the phenotypic spectrum of TP63-related disorders, provide a new genotype:phenotype correlation for TP63 and identify a new genetic cause of isolated POI.
Published: 2019
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10. Post-transplant outcome of ovarian tissue cryopreserved after chemotherapy in hematological malignancies

Author: Céline Chalas, Nicolas Boissel, Yasmina Badachi, Catherine Genestie, Gérard Socié, Gilles Lefebvre, Jean-Philippe Wolf, Frédérique Capron, Jean-Paul Akakpo, Véronique Drouineaud, Pauline Brice, Catherine Poirot, Géraldine Lebègue, Jean-Marc Lacorte, Thierry Leblanc, Alain Delmer, Nathalie Dhedin, Jean Gabarre, Jean-Paul Vernant, Marc Dommergues, Sophie Egels, Anne Fortin, Philippe Touraine, CHU Saint Louis [APHP], Sorbonne Université (SU), Service de Gynécologie et Obstétrique [Groupe Hospitalier Pitié-Salpêtrière], CHU Pitié-Salpêtrière [APHP], Service d'hématologie-oncologie adultes, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris Diderot - Paris 7 (UPD7)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Service de Biochimie Endocrinienne et Oncologique [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], Service de Radiologie [CHU Pitié-Salpétrière], Service de pathologie [CHU Pitié-Salpêtrière], Service d'Hématologie Clinique [CHU Pitié-Salpêtrière], Centre Hospitalier Universitaire de Reims (CHU Reims), Service d'hématologie [Reims], Hôpital Robert Debré, Hôpital Robert Debré-Centre Hospitalier Universitaire de Reims (CHU Reims)-Hôpital Robert Debré-Centre Hospitalier Universitaire de Reims (CHU Reims), CHU Cochin [AP-HP], Institut E3M [CHU Pitié-Salpêtrière], Service d'endocrinologie et maladies métaboliques [CHU Pitié-Salpêtrière], Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de Gynécologie-Obstétrique, Maternité, Chirurgie Gynécologique [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Service de Biochimie Endocrinienne et Oncologie [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service d'Hématologie clinique [CHU Pitié-Salpêtrière], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hôpital Cochin [AP-HP], Service d’Endocrinologie, Métabolisme et Prévention des Risques Cardio-Vasculaires [CHU Pitié-Salpêtrière], and Université Paris Diderot - Paris 7 (UPD7)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris]
Subjects: Oncology, medicine.medical_specialty, Ovary transplantation, medicine.medical_treatment, [SDV]Life Sciences [q-bio], MEDLINE, [SDV.MHEP.GEO]Life Sciences [q-bio]/Human health and pathology/Gynecology and obstetrics, Cryopreservation, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Antineoplastic Combined Chemotherapy Protocols, medicine, Humans, Fertility preservation, Online Only Articles, ComputingMilieux_MISCELLANEOUS, Chemotherapy, 030219 obstetrics & reproductive medicine, Ovarian tissue transplantation, business.industry, Ovarian tissue, Ovary, Ovarian tissue cryopreservation, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, Organ Transplantation, Recovery of Function, Hematology, Post transplant, 3. Good health, Hematologic Neoplasms, 030220 oncology & carcinogenesis, Quality of Life, Female, business
Abstract: International audience
Published: 2019
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11. Endocrine manifestations in a cohort of 63 adulthood and childhood onset patients with Langerhans cell histiocytosis

Author: Philippe Touraine, Fleur Cohen, Joseph Y Drabo, Abdellatif Tazi, Carine Courtillot, Ahmed Idbaih, Jean Donadieu, Zahir Amoura, Julien Haroche, Yempabou Sagna, Gestionnaire, Hal Sorbonne Université, Centre Hospitalier Universitaire Yalgado Ouédraogo (CHUYO), Service d'Endocrinologie et Médecine de la Reproduction [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de pneumologie [Saint-Louis], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service d'hématologie-immunologie-oncologie pédiatrique [CHU Trousseau], CHU Trousseau [APHP], Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Service d'Onco-neurologie = Département de neurologie 2 [CHU Pitié Salpêtrière], Service de médecine interne [CHU Pitié-Salpétrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Service d’endocrinologie et médecine de la reproduction [CHU Pitié-Salpêtrière], Université Paris Diderot - Paris 7 (UPD7)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Sorbonne Université - Département de neurologie 2 - Mazarin, Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)
Subjects: Male, Pediatrics, Endocrinology, Diabetes and Metabolism, [SDV]Life Sciences [q-bio], Cohort Studies, 0302 clinical medicine, Endocrinology, Langerhans cell histiocytosis, Age of Onset, Child, Aged, 80 and over, [SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, General Medicine, Middle Aged, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, 3. Good health, [SDV] Life Sciences [q-bio], Histiocytosis, Child, Preschool, 030220 oncology & carcinogenesis, Cohort, Female, France, Thyroid function, Adult, Thyroid Hormones, medicine.medical_specialty, Adolescent, Endocrine System, 030209 endocrinology & metabolism, Endocrine System Diseases, Young Adult, 03 medical and health sciences, Internal medicine, medicine, Humans, Endocrine system, Aged, Retrospective Studies, business.industry, Retrospective cohort study, medicine.disease, Histiocytosis, Langerhans-Cell, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, Gonadotropins, Pituitary, Diabetes insipidus, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Age of onset, business, Follow-Up Studies
Abstract: Objective Langerhans cell histiocytosis (LCH) is a rare inflammatory myeloid neoplasm which can infiltrate any organ or tissue. Endocrine involvement has mostly been described in case reports and small retrospective studies. We aimed to describe endocrine manifestations in a large cohort of adulthood onset (AO) and childhood onset (CO) patients with LCH. Design Single-center observational study conducted between January 2002 and December 2017 at Pitié-Salpêtrière University Hospital (Paris, France), a tertiary care hospital. Method Clinical, biological and morphological evaluations of pituitary, gonadal, adrenal and thyroid function evaluations performed in 63 consecutive patients with LCH (AO patients: 40, CO patients: 23). Fifty-eight patients underwent follow-up assessments. Results Complete pituitary evaluation was performed in 38/63 patients (60.3%); at least one anterior pituitary dysfunction (APD) was found in 63.2% of them. In this subgroup of patients, the most prevalent deficiencies were diabetes insipidus (DI) and GHD (55.3% each), followed by gonadotropin deficiency (34.2%) and thyrotropin deficiency (23.7%). In the subgroup of the 25 incompletely evaluated patients, we found DI in 44%, GHD in 50%, gonadotropin deficiency in 30.4% and thyrotropin deficiency in 16%. APD was more common in CO patients (P = 0.003) but was not systematically associated with DI regardless of the age of onset. Endocrine dysfunction was most often permanent; moreover, occurrence of new deficiencies has been described during follow-up. Conclusion The spectrum of endocrine disorders appears to be large in LCH (both in AO and CO patients) and should be evaluated carefully at diagnosis and during follow-up. APD was not always associated with DI.
Published: 2019
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12. The control of diabetes and other Non-communicable Diseases is an urgent health priority in Africa: Grenoble declaration

Author: S. Wackernie, E. Giros, Philippe Touraine, Stéphane Besançon, S. Genay Diliautas, C. Mary, G. Duriez, C. Paquet, E. Aronica, I. Quick, C. Waterlot, Cynthia Fleury, C. Giron, Maryvette Balcou-Debussche, Assa Traoré Sidibé, O. Chabre, E. Comte, J. Bernasconi, Xavier Debussche, O. Toure, Joseph Drabo, A. Fontbonne, B. Burgalat, H. Du-Boullay, Naby Balde, G. Raymond, C. Debeaufort, M. de Kerdanet, L. Delisle, P. Micheletti, O. Weil, Malek Batal, P. Chancel, David Beran, J.F. Delfraissy, A.L. Coulon, D. Hacquin, P. Salignon, T. Shojaei, F. Mohadji, S. Olejas, Hôpital Donka, Laboratoire Lésions des Acides Nucléiques (LAN), Service de Chimie Inorganique et Biologique (SCIB - UMR E3), Institut Nanosciences et Cryogénie (INAC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA)-Centre National de la Recherche Scientifique (CNRS)-Institut Nanosciences et Cryogénie (INAC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA)-Centre National de la Recherche Scientifique (CNRS), Service d'Endocrinologie (GRENOBLE - Endocrino), CHU Grenoble, Institut de biologie et chimie des protéines [Lyon] (IBCP), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Département international et tropical (INVS), Institut national de veille sanitaire, Institut Pascal - Clermont Auvergne (IP), Sigma CLERMONT (Sigma CLERMONT)-Université Clermont Auvergne (UCA)-Centre National de la Recherche Scientifique (CNRS), Laboratoire Sols et Environnement (LSE), Institut National de la Recherche Agronomique (INRA)-Université de Lorraine (UL), Université Grenoble Alpes (UGA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Institut Nanosciences et Cryogénie (INAC), and Université Grenoble Alpes (UGA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Health Priorities, Public Health, Environmental and Occupational Health, Health Promotion, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, Infectious Diseases, Political science, Africa, Diabetes Mellitus, Humans, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Noncommunicable Diseases, Delivery of Health Care, Humanities, ComputingMilieux_MISCELLANEOUS
Abstract: International audience
Published: 2018
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13. Early central blood pressure elevation in adult patients with 21-hydroxylase deficiency

Author: Randa Bittar, Jérôme Dulon, Nora Dahmoune, Marie Laure Tanguy, Philippe Touraine, Gaelle Lethielleux, Joe-Elie Salem, Bernard I. Levy, Antonio Gallo, David Rosenbaum, Monique Leban, Eric Bruckert, Xavier Girerd, Anne Bachelot, Service d’Endocrinologie, Métabolisme et Prévention des Risques Cardio-Vasculaires [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Sorbonne Université (SU), Laboratoire d'Imagerie Biomédicale (LIB), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre des Pathologies gynécologiques Rares [CHU Pitié-Salpêtrière], Centre de référence des maladies endocriniennes rares de la croissance et du développement [CHU Pitié-Salpêtrière], Service d’endocrinologie et médecine de la reproduction [CHU Pitié-Salpêtrière], Institut E3M [CHU Pitié-Salpêtrière], Dyslipidémies, inflammation et athérosclérose dans les maladies métaboliques, Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Lariboisière, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Lariboisière-Fernand-Widal [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de pharmacologie médicale [CHU Pitié-Salpêtrière], Service de Biochimie Endocrinienne et Oncologie [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Université Paris Diderot - Paris 7 (UPD7)-Hôpital Lariboisière-Fernand-Widal [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de biochimie et hormonologie [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Service d'endocrinologie-métabolisme [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [APHP]-Sorbonne Université (SU), Centre de référence des maladies endocriniennes rares de la croissance [CHU Pitié-Salpêtrière], Service d'endocrinologie et de la médecine reproductive [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Lariboisière-Université Paris Diderot - Paris 7 (UPD7), and Service de pharmacologie biologique [CHU Pitié-Salpâtrière]
Subjects: Adult, medicine.medical_specialty, Physiology, [SDV]Life Sciences [q-bio], Context (language use), Blood Pressure, 030204 cardiovascular system & hematology, Pulse Wave Analysis, Carotid Intima-Media Thickness, Microcirculation, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Internal Medicine, medicine, Humans, Congenital adrenal hyperplasia, 030212 general & internal medicine, Prospective Studies, Prospective cohort study, Child, Pulse wave velocity, biology, Adrenal Hyperplasia, Congenital, business.industry, 21-Hydroxylase, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, medicine.disease, 3. Good health, Blood pressure, biology.protein, Cardiology, Female, Cardiology and Cardiovascular Medicine, business, Rare disease
Abstract: International audience; CONTEXT:Controversial data exist on cardiovascular damages in patients with congenital adrenal hyperplasia (CAH).OBJECTIVE:To assess blood pressure and early cardiovascular damages on a large cohort of adult CAH patients and control individuals.DESIGN:Case-control study.SETTING:Referral Center for Rare Disease, Pitié Salpêtrière Hospital, Paris, France.PATIENTS OR OTHER PARTICIPANTS:Fifty-eight women and 26 men with CAH diagnosed in childhood and 85 controls matched-paired for sex, age and smoking status were prospectively included.INTERVENTION:Measurement of large arteries and microcirculatory anatomical and functional indices as well as hormonal status and cardiovascular risk factors evaluation.MAIN OUTCOME MEASURE:The primary objective was to compare carotid intima-media thickness (cIMT) in CAH patients and controls. The secondary objectives were to compare blood pressure (BP), radial augmentation index (rAI), central BP, carotid-femoral pulse wave velocity (PWV), skin microcirculation indices and inflammation parameters in CAH patients and controls.RESULTS:Although PWV and cIMT were identical in patients and controls, higher rAI (64.6 ± 1.7 vs. 59.9 ± 1.6%, P = 0.02) and higher central SBP (101.8 ± 1.5 vs. 95.1 ± 1.5 mmHg, P
Published: 2018
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14. Complex Association of Sex Hormones on Left Ventricular Systolic Function: Insight into Sexual Dimorphism

Author: Philippe Touraine, Sylvie Salenave, Jean-Sébastien Hulot, Anne Bachelot, Christian Funck-Brentano, Joe-Elie Salem, N. Bourcigaux, Philippe Chanson, Monique Leban, Michel Polak, Gisèle Preud’Homme, Juliane Léger, Richard Isnard, Jérôme Dulon, Nadjib Hammoudi, Nora Dahmoune, Sophie Christin Maitre, Lee S. Nguyen, Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de pharmacologie médicale [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de Cardiologie [CHU Pitié-Salpêtrière], Centre de Référence des Maladies Endocriniennes Rares de la Croissance [APHP Robert Debré], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7), Centre des Pathologies gynécologiques Rares [CHU Pitié-Salpêtrière], Institut E3M [CHU Pitié-Salpêtrière], Service d’endocrinologie et médecine de la reproduction [CHU Pitié-Salpêtrière], Université Paris Diderot - Paris 7 (UPD7)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré, Gestionnaire, Hal Sorbonne Université, Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut de Cardiométabolisme et Nutrition = Institute of Cardiometabolism and Nutrition [CHU Pitié Salpêtrière] (IHU ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de Pharmacologie médicale [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), and Service d'Endocrinologie et Médecine de la Reproduction [CHU Pitié-Salpêtrière]
Subjects: Adult, Male, Cardiac function curve, medicine.medical_specialty, Systole, Physiology, Heart Ventricles, 030204 cardiovascular system & hematology, Ventricular Function, Left, 030218 nuclear medicine & medical imaging, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Sex hormone-binding globulin, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Interquartile range, Internal medicine, medicine, Humans, Radiology, Nuclear Medicine and imaging, Congenital adrenal hyperplasia, Sex hormones, Gonadal Steroid Hormones, [SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, Ejection fraction, biology, business.industry, Stroke Volume, Stroke volume, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, medicine.disease, Ventricular functions, Healthy Volunteers, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Echocardiography, Heart failure, Cardiology, biology.protein, Female, Cardiology and Cardiovascular Medicine, business
Abstract: International audience; BACKGROUND: Normal values of left ventricular ejection fraction (LVEF) and absolute values of global longitudinal strain (GLS) are lower in men than in women. Data concerning the association of sex hormone levels on these left ventricular systolic function surrogates are scarce. The aim of this study was to determine the association of sex hormones with systolic left ventricular function in healthy subjects and patients with congenital adrenal hyperplasia (CAH) as a model of testosterone dysregulation.METHODS: Eighty-four adult patients with CAH (58 women; median age, 27 years; interquartile range, 23-36 years) and 84 healthy subjects matched for sex and age were prospectively included. Circulating concentrations of sex hormones were measured within 48 hours of echocardiography with assessment of LVEF and left ventricular longitudinal, radial, and circumferential strain.RESULTS: LVEF and GLS were higher in healthy women than in healthy men (63.9 ± 4.2% vs 60.9 ± 5.1% [P < .05] and 20.0 ± 1.9% vs 17.9 ± 2.4% [P < .001], respectively), while there was no difference in LVEF or GLS between women and men with CAH (63.9 ± 4.5% vs 63.0 ± 4.6% [P = NS] and 19.4 ± 2.2% vs 18.3 ± 1.8% [P = NS], respectively). Bioavailable testosterone levels were higher in women with CAH than in female control subjects (0.08 ng/mL [interquartile range, 0.04-0.14 ng/mL] vs 0.16 ng/mL [interquartile range, 0.04-0.3 ng/mL], P < .001) and lower in men with CAH than in male control subjects (2.3 ng/mL [interquartile range, 1.3-3 ng/mL] vs 2.9 ng/mL [interquartile range, 2.5-3.4 ng/mL], P < .05). In men, LVEF and GLS were negatively correlated with bioavailable testosterone levels (r = -0.3, P ≤ .05, and r = -0.45, P < .01, respectively), while midventricular radial strain was positively correlated with bioavailable testosterone level (r = 0.38, P < .05). The absolute value of circumferential strain was positively correlated with follicle-stimulating hormone (r = 0.65, P < .0001).CONCLUSIONS: These data support that the existence of sex dimorphism concerning left ventricular systolic cardiac function is significantly associated with testosterone levels.
Published: 2018
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15. Impact of transition on quality of life in patients with congenital adrenal hyperplasia diagnosed during childhood

Author: Anne Bachelot, Magaly Vialon, Amandine Baptiste, Isabelle Tejedor, Caroline Elie, Michel Polak, Philippe Touraine, Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition ( ICAN ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Assistance publique - Hôpitaux de Paris (AP-HP)-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -CHU Pitié-Salpêtrière [APHP], CHU Cochin [AP-HP], CHU Necker - Enfants Malades [AP-HP], Université Paris Descartes - Paris 5 ( UPD5 ), Service d'endocrinologie, gynécologie et diabétologie pédiatriques [CHU Necker], Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Paris Descartes - Paris 5 (UPD5), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), and HAL UPMC, Gestionnaire
Subjects: Pediatrics, medicine.medical_specialty, Endocrinology, Diabetes and Metabolism, MEDLINE, 030209 endocrinology & metabolism, lcsh:Diseases of the endocrine glands. Clinical endocrinology, Psychological health, 03 medical and health sciences, 0302 clinical medicine, Endocrinology, Quality of life, Internal Medicine, medicine, Clinical endpoint, congenital adrenal hyperplasia, In patient, Congenital adrenal hyperplasia, 21OH deficiency, [SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, lcsh:RC648-665, Adult patients, business.industry, Research, transition, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, [ SDV.MHEP.EM ] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, medicine.disease, health care, humanities, 3. Good health, quality of life, 21-hydroxylase, 030220 oncology & carcinogenesis, business, Rare disease
Abstract: Background Health-related quality of life (QoL) in adult patients with congenital adrenal hyperplasia (CAH) has been variously reported. However, there is no study evaluating the impact of transition on quality of life. Methods Adult patients with classic or non-classic CAH diagnosed during childhood CAH, born between 1970 and 1990, were recruited from the registers of Pediatric departments belonging to the French reference center for endocrine rare disease. Primary end point was the QoL (WHOQOL-BREF). Results Seventy-three patients were included in the study, among them 59/73 were transferred to adult endocrinologist by their pediatricians for transition. WHOQOL-BREF scores were similar between patients with or without transition to specialist adult services, except for environment dimension score, which was slightly higher in CAH patients without transition. However, CAH patients with a regular follow-up had a better physical health, psychological health and environment score and item global QoL than the group without regular follow-up after transition. Conclusion Regular medical follow-up in adulthood is associated with the transition between pediatric and adult care and is associated with better QoL in adults with CAH.
Published: 2017
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16. Contribution of LHX4 Mutations to Pituitary Deficits in a Cohort of 417 Unrelated Patients

Author: Michel Polak, Enzo Cohen, Sophie Rose, Frédéric Brioude, Nathalie Collot, Daniela Larizza, Marie Legendre, Florence Dastot, Juliane Léger, Anne Marie Bertrand, Philippe Duquesnoy, Marie Laure Sobrier, Philippe Touraine, Mohamad Maghnie, Bruno Copin, Maïté Tauber, Irène Netchine, Serge Amselem, Isabelle Oliver-Petit, Laura González Briceño, Thomas Edouard, Physiopathologie des maladies génétiques d'expression pédiatrique, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Università degli studi di Genova = University of Genoa (UniGe), Service de génétique et embryologie médicales [CHU Trousseau], CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre de Référence des Maladies Endocriniennes Rares de la Croissance [APHP Robert Debré], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7), Service d'endocrinologie, gynécologie et diabétologie pédiatriques [CHU Necker], CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de Chirurgie Digestive et Endocrinienne [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Service de Diabétologie - Endocrinologie [CHRU Besançon], Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Service d'explorations fonctionnelles [CHU Trousseau], Fondazione IRCCS Policlinico San Matteo [Pavia], Università degli Studi di Pavia = University of Pavia (UNIPV), Couvet, Sandrine, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), CHU Pitié-Salpêtrière [AP-HP], and Societe Francaise d'Endocrinologie et Diabetologie PediatriqueFondation pour la Recherche Medicale PLP20131028838
Subjects: 0301 basic medicine, Male, Pituitary gland, MESH: Sequence Homology, Amino Acid, Endocrinology, Diabetes and Metabolism, [SDV]Life Sciences [q-bio], Clinical Biochemistry, Sequence Homology, Hypopituitarism, MESH: Amino Acid Sequence, medicine.disease_cause, MESH: Hypopituitarism, Biochemistry, Cohort Studies, 0302 clinical medicine, Endocrinology, MESH: Child, Child, MESH: Cohort Studies, Genetics, Sanger sequencing, Mutation, Blotting, MESH: Infant, Newborn, MESH: Transcription Factors, MESH: Follow-Up Studies, Prognosis, MESH: Infant, Ectopic Posterior Pituitary, Pedigree, Diabetes and Metabolism, [SDV] Life Sciences [q-bio], Amino Acid, medicine.anatomical_structure, Sella turcica, Child, Preschool, symbols, Female, Western, medicine.medical_specialty, MESH: Mutation, Adolescent, MESH: Pedigree, Blotting, Western, LIM-Homeodomain Proteins, 030209 endocrinology & metabolism, Context (language use), Biology, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, MESH: Prognosis, 03 medical and health sciences, symbols.namesake, Internal medicine, medicine, Humans, Immunoprecipitation, MESH: Blotting, Western, Amino Acid Sequence, Preschool, Biomarkers, Follow-Up Studies, Infant, Infant, Newborn, Sequence Homology, Amino Acid, Transcription Factors, Biochemistry (medical), MESH: Adolescent, MESH: LIM-Homeodomain Proteins, MESH: Humans, MESH: Immunoprecipitation, MESH: Child, Preschool, Heterozygote advantage, medicine.disease, Newborn, MESH: Male, 030104 developmental biology, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, MESH: Biomarkers, MESH: Female
Abstract: Context:LHX4 encodes a LIM-homeodomain transcription factor that is implicated in early pituitary development. In humans, only 13 heterozygous LHX4 mutations have been associated with congenital hypopituitarism.Objective:The aims of this study were to evaluate the prevalence of LHX4 mutations in patients with hypopituitarism, to define the associated phenotypes, and to characterize the functional impact of the identified variants and the respective role of the 2 LIM domains of LHX4.Design and Patients:We screened 417 unrelated patients with isolated growth hormone deficiency or combined pituitary hormone deficiency associated with ectopic posterior pituitary and/or sella turcica anomalies for LHX4 mutations (Sanger sequencing). In vitro studies were performed to assess the functional consequences of the identified variants.Results:We identified 7 heterozygous variations, including p.(Tyr131*), p.(Arg48Thrfs*104), c.606+1G>T, p.Arg65Val, p.Thr163Pro, p.Arg221Gln, and p.Arg235Gln), that were associated with variable expressivity; 5 of the 7 were also associated with incomplete penetrance. The p.(Tyr131*), p.(Arg48Thrfs*104), p.Ala65Val, p.Thr163Pro, and p.Arg221Gln LHX4 variants are unable to transactivate the POU1F1 and GH promoters. As suggested by transactivation, subcellular localization, and protein-protein interaction studies, p.Arg235Gln is probably a rare polymorphism. Coimmunoprecipitation studies identified LHX3 as a potential protein partner of LHX4. As revealed by functional studies of LIM-defective recombinant LHX4 proteins, the LIM1 and LIM2 domains are not redundant.Conclusion:This study, performed in the largest cohort of patients screened so far for LHX4 mutations, describes 6 disease-causing mutations that are responsible for congenital hypopituitarism. LHX4 mutations were found to be associated with variable expressivity, and most of them with incomplete penetrance; their contribution to pituitary deficits that are associated with an ectopic posterior pituitary and/or a sella turcica defect is ∼1.4% in the 417 probands tested.
Published: 2017
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17. French law: what about a reasoned reimbursement of serum vitamin D assays?

Author: Jean-Claude Souberbielle, Claude Laurent Benhamou, Bernard Cortet, Mickael Rousière, Christian Roux, Vered Abitbol, Cédric Annweiler, Maurice Audran, Justine Bacchetta, Pierre Bataille, Olivier Beauchet, Rémi Bardet, Alexandra Benachi, Francis Berenbaum, Hubert Blain, Françoise Borson-Chazot, Véronique Breuil, Karine Briot, Philippe Brunet, Jean-Claude Carel, Philippe Caron, Olivier Chabre, Philippe Chanson, Roland Chapurlat, Pierre Cochat, Régis Coutant, Sophie Christin-Maitre, Martine Cohen-Solal, Christian Combe, Catherine Cormier, Marie Courbebaisse, Grégory Debrus, Brigitte Delemer, Georges Deschenes, Marc Duquenne, Guillaume Duval, Patrice Fardellone, Denis Fouque, Gérard Friedlander, Jean-Bernard Gauvain, Lionel Groussin, Pascal Guggenbuhl, Pascal Houillier, Thierry Hannedouche, William Jacot, Rose-Marie Javier, Guillaume Jean, Claude Jeandel, Dominique Joly, Peter Kamenicky, Bertrand Knebelmann, Marie-Hélène Lafage-Proust, Yves LeBouc, Erick Legrand, Florence Levy-Weil, Agnès Linglart, Laurent Machet, Emmanuel Maheu, Eric Mallet, Christian Marcelli, Pierre Marès, Christophe Mariat, Gérard Maruani, Yves Maugars, France Montagnon, Bruno Moulin, Philippe Orcel, Henri Partouche, Virginie Personne, Charles Pierrot-Deseilligny, Michel Polak, Claire Pouteil-Noble, Dominique Prié, Agathe Raynaud-Simon, Yves Rolland, Jean-Louis Sadoul, Bernard Salle, Corinne Sault, Anne-Marie Schott, Isabelle Sermet-Gaudelus, Martin Soubrier, Ivan Tack, Eric Thervet, Isabelle Tostivint, Philippe Touraine, Florence Tremollières, Pablo Urena-Torres, Jean-Paul Viard, Jean-Louis Wemeau, Georges Weryha, Norbert Winer, Jacques Young, Thierry Thomas, CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Laboratoire d'Informatique de Nantes Atlantique (LINA), Mines Nantes (Mines Nantes)-Université de Nantes (UN)-Centre National de la Recherche Scientifique (CNRS), Service de rhumatologie[Lille], Hôpital Roger Salengro [Lille]-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Laboratoire d'aérologie (LAERO), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Observatoire Midi-Pyrénées (OMP), Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National d'Études Spatiales [Toulouse] (CNES)-Centre National de la Recherche Scientifique (CNRS)-Météo-France -Institut de Recherche pour le Développement (IRD)-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National d'Études Spatiales [Toulouse] (CNES)-Centre National de la Recherche Scientifique (CNRS)-Météo-France -Centre National de la Recherche Scientifique (CNRS), Laboratoire des Matériels Électriques (EDF R&D LME), EDF R&D (EDF R&D), EDF (EDF)-EDF (EDF), Centre d'Analyse et d'Intervention Sociologiques (CADIS), École des hautes études en sciences sociales (EHESS)-Centre National de la Recherche Scientifique (CNRS), Département de Médecine Interne et Gérontologie clinique, Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Service de gynécologie-obstétrique, médecine de la reproduction [Béclère], Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP - Hôpital Antoine Béclère [Clamart], Centre de Recherche Saint-Antoine (UMRS893), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Department of Geriatrics - Efficiency and Deficiency Laboratory, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de rhumatologie, Centre Hospitalier Universitaire de Nice (CHU Nice)-Hôpital l'Archet, Vascular research center of Marseille (VRCM), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Trigone-CIREL, Centre Interuniversitaire de Recherche en Education de Lille - ULR 4354 (CIREL), Université de Lille-Université de Lille, Signalisation Hormonale, Physiopathologie Endocrinienne et Métabolique, Université Paris-Sud - Paris 11 (UP11)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Service de rhumatologie [CHU Cochin], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], Biologie de l'Os et du Cartilage : Régulations et Ciblages Thérapeutiques (BIOSCAR (UMR_S_1132 / U1132)), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Rhumatologie [CHU Lariboisière], Hôpital Lariboisière-Fernand-Widal [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Unité Expérimentale Recherches Intégrées - Gotheron (UERI), Institut National de la Recherche Agronomique (INRA), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Unité de Néphrologie Pédiatrique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré, Université de Bordeaux (UB), Mécanismes physiopathologiques et conséquences des calcifications vasculaires - UR UPJV 7517 (MP3CV), Université de Picardie Jules Verne (UPJV)-CHU Amiens-Picardie, Motricité - Plasticité, Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)), Centre de recherche sur le développement territorial (CRDT), Centre de recherche sur le développement territorial, CHU Pontchaillou [Rennes], Institut de Recherche en Cancérologie de Montpellier (IRCM - U1194 Inserm - UM), CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Institut Pascal (IP), Université Blaise Pascal - Clermont-Ferrand 2 (UBP)-SIGMA Clermont (SIGMA Clermont)-Centre National de la Recherche Scientifique (CNRS), Service de rhumatologie [Nantes], Université de Nantes (UN)-Hôtel-Dieu-Centre hospitalier universitaire de Nantes (CHU Nantes), Information – Technologies – Analyse Environnementale – Procédés Agricoles (UMR ITAP), Institut national de recherche en sciences et technologies pour l'environnement et l'agriculture (IRSTEA)-Institut national d’études supérieures agronomiques de Montpellier (Montpellier SupAgro), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Lariboisière-Fernand-Widal [APHP], Centre de Physique Théorique [Palaiseau] (CPHT), École polytechnique (X)-Centre National de la Recherche Scientifique (CNRS), Département de Médecine Générale, Université Paris Descartes - Paris 5 (UPD5), CHU Pitié-Salpêtrière [AP-HP], Service de néphrologie et transplantation, Hôpital Edouard Herriot [CHU - HCL], Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Centre de recherche Croissance et signalisation (UMR_S 845), Service d'Endocrinologie (NICE - Endocrino), Centre Hospitalier Universitaire de Nice (CHU Nice), CIC Cochin Pasteur (CIC 1417), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôtel-Dieu-Université Paris Descartes - Paris 5 (UPD5)-Groupe hospitalier Broca-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Gabriel Montpied [Clermont-Ferrand], CHU Clermont-Ferrand, CPMF2 - Flemish Cluster Predictive Microbiology in Foods - www.cpmf2.be BioTeC - Chemical and Biochemical Process Technology and Control Department of Chemical Engineering, Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), Université Pierre et Marie Curie - Paris 6 (UPMC), Centre de ménopause, Centre de Diagnostic et de Thérapeutique, Hôpital de l’Hôtel-Dieu [Paris], Université Paris Descartes - Faculté de Médecine (UPD5 Médecine), Service d'Endocrinologie [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Service d'obstétrique-gynécologie [Nantes], Centre hospitalier universitaire de Nantes (CHU Nantes), Institut für Kernphysik der Universität zu Köln, Universität zu Köln = University of Cologne, Centre National de la Recherche Scientifique (CNRS)-Mines Nantes (Mines Nantes)-Université de Nantes (UN), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Observatoire Midi-Pyrénées (OMP), Météo France-Centre National d'Études Spatiales [Toulouse] (CNES)-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Météo France-Centre National d'Études Spatiales [Toulouse] (CNES)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Centre National de la Recherche Scientifique (CNRS), Service de rhumatologie [CHU Saint-Antoine], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Eq 4, Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Groupement Hospitalier Lyon-Est (GHE), Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL)-Centre de médecine nucléaire, Fédération d'endocrinologie-Groupement hospitalier Lyon-Est-Fédération d'endocrinologie-Groupement hospitalier Lyon-Est, Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro), Centre National de la Recherche Scientifique (CNRS)-École polytechnique (X), Service de neurologie 1 [CHU Pitié-Salpétrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre des Pathologies gynécologiques Rares [CHU Pitié-Salpêtrière], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut E3M [CHU Pitié-Salpêtrière], Hôpital Paule de Viguier, CHU Toulouse [Toulouse]-CHU Toulouse [Toulouse], Universität zu Köln, Hôpital Roger Salengro-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Laboratoire d'aérologie (LA), Centre National de la Recherche Scientifique (CNRS)-Observatoire Midi-Pyrénées (OMP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées, Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Antoine Béclère, Centre de Recherche Saint-Antoine (CR Saint-Antoine), Service de rhumatologie, inflammation-immunopathologie- biothérapie [CHU Saint-Antoine] (DHU i2B ), CHU Saint-Antoine [APHP]-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Centre de Recherche en Cancérologie de Lyon (CRCL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre Léon Bérard [Lyon]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre Léon Bérard [Lyon]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Groupement Hospitalier Lyon-Est (GHE), Centre Interuniversitaire de Recherche en Education de Lille (CIREL) - EA 4354 (CIREL), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Cochin [AP-HP], Hôpital Lariboisière, Unité de Recherches Intégrées - Gotheron (GOTH RI UERI), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Robert Debré, Laboratoire de génie chimique [ancien site de Basso-Cambo] (LGC), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Blaise Pascal - Clermont-Ferrand 2 (UBP)-Sigma CLERMONT (Sigma CLERMONT)-Centre National de la Recherche Scientifique (CNRS), Institut national d’études supérieures agronomiques de Montpellier (Montpellier SupAgro)-Institut national de recherche en sciences et technologies pour l'environnement et l'agriculture (IRSTEA), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Lariboisière, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Cochin [AP-HP]-Hôtel-Dieu-Université Paris Descartes - Paris 5 (UPD5)-Groupe hospitalier Broca-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Gabriel Montpied (CHU), CHU Pitié-Salpêtrière [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Institut für Kernphysik - Universität zu Köln, Institut de Recherche pour le Développement (IRD)-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National d'Études Spatiales [Toulouse] (CNES)-Centre National de la Recherche Scientifique (CNRS)-Université Fédérale Toulouse Midi-Pyrénées-Météo-France -Institut de Recherche pour le Développement (IRD)-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National d'Études Spatiales [Toulouse] (CNES)-Centre National de la Recherche Scientifique (CNRS)-Météo-France -Centre National de la Recherche Scientifique (CNRS), Service de Neurologie [CHU Pitié-Salpêtrière], IFR70-CHU Pitié-Salpêtrière [AP-HP], AP-HP - Hôpital Antoine Béclère [Clamart], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris-Sud - Paris 11 (UP11), Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU), AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Sud - Paris 11 (UP11), Laboratoire d'Informatique de Nantes Atlantique ( LINA ), Centre National de la Recherche Scientifique ( CNRS ) -Mines Nantes ( Mines Nantes ) -Université de Nantes ( UN ), Hôpital Roger Salengro-Centre Hospitalier Régional Universitaire [Lille] ( CHRU Lille ), Laboratoire d'aérologie - LA ( LA ), Université Toulouse III - Paul Sabatier ( UPS ), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut national des sciences de l'Univers ( INSU - CNRS ) -Observatoire Midi-Pyrénées ( OMP ) -Centre National de la Recherche Scientifique ( CNRS ), Laboratoire des Matériels Électriques ( EDF R&D LME ), EDF R&D ( EDF R&D ), EDF ( EDF ) -EDF ( EDF ), Centre d'Analyse et d'Intervention Sociologiques ( CADIS ), École des hautes études en sciences sociales ( EHESS ) -Centre National de la Recherche Scientifique ( CNRS ), CHU Angers, Université Paris-Sud - Paris 11 ( UP11 ) -Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Antoine Béclère, Centre de Recherche Saint-Antoine ( CR Saint-Antoine ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ), Service de rhumatologie, inflammation-immunopathologie- biothérapie [CHU Saint-Antoine] ( DHU i2B ), Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Saint-Antoine [APHP], Centre Hospitalier Régional Universitaire [Montpellier] ( CHRU Montpellier ), Centre de Recherche en Cancérologie de Lyon ( CRCL ), Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Centre Léon Bérard [Lyon]-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Centre Léon Bérard [Lyon]-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Groupement Hospitalier Lyon-Est ( GHE ), Hospices Civils de Lyon ( HCL ) -Hospices Civils de Lyon ( HCL ) -Centre de médecine nucléaire, CHU Nice-Hôpital l'Archet, Vascular research center of Marseille ( VRCM ), Aix Marseille Université ( AMU ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Centre Interuniversitaire de Recherche en Education de Lille (CIREL) - EA 4354 ( CIREL ), Université Paris-Sud - Paris 11 ( UP11 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Cochin [AP-HP], Biologie de l'Os et du Cartilage : Régulations et Ciblages Thérapeutiques ( BIOSCAR ), Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Lariboisière-Université Paris Diderot - Paris 7 ( UPD7 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Unité de Recherches Intégrées - Gotheron ( GOTH RI UERI ), Institut National de la Recherche Agronomique ( INRA ), Institut Cochin ( UM3 (UMR 8104 / U1016) ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Robert Debré, Laboratoire de génie chimique ( LGC ), Institut National Polytechnique [Toulouse] ( INP ) -Université Toulouse III - Paul Sabatier ( UPS ), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique ( CNRS ), Université de Bordeaux ( UB ), Université de Bourgogne ( UB ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Institut Necker Enfants-Malades (INEM) ( INEM - UM 111 (UMR 8253 / U1151) ), Centre de recherche sur le développement territorial ( CRDT ), Institut Pascal ( IP ), Université Blaise Pascal - Clermont-Ferrand 2 ( UBP ) -Sigma CLERMONT ( Sigma CLERMONT ) -Centre National de la Recherche Scientifique ( CNRS ), Université de Nantes ( UN ) -Hôtel-Dieu-Centre hospitalier universitaire de Nantes ( CHU Nantes ), Information – Technologies – Analyse Environnementale – Procédés Agricoles ( UMR ITAP ), Institut national de recherche en sciences et technologies pour l'environnement et l'agriculture ( IRSTEA ) -Institut national d’études supérieures agronomiques de Montpellier ( Montpellier SupAgro ), Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Lariboisière, Centre de Physique Théorique [Palaiseau] ( CPHT ), École polytechnique ( X ) -Centre National de la Recherche Scientifique ( CNRS ), Université Paris Descartes - Paris 5 ( UPD5 ), Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Pitié-Salpêtrière [APHP], Université de Lyon-Université de Lyon-Hospices Civils de Lyon ( HCL ) -Centre Hospitalier Lyon Sud [CHU - HCL] ( CHLS ), Hospices Civils de Lyon ( HCL ), Centre de recherche Croissance et signalisation ( UMR_S 845 ), Service d'Endocrinologie ( NICE - Endocrino ), CHU Nice, CIC Cochin Pasteur ( CIC 1417 ), Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Cochin [AP-HP]-Hôtel-Dieu-Université Paris Descartes - Paris 5 ( UPD5 ) -Groupe hospitalier Broca-Institut National de la Santé et de la Recherche Médicale ( INSERM ), CHU Gabriel Montpied ( CHU ), Katholieke Universiteit Leuven ( KU Leuven ), Université Pierre et Marie Curie - Paris 6 ( UPMC ), Assistance publique - Hôpitaux de Paris (AP-HP), Université Paris Descartes - Faculté de Médecine ( UPD5 Médecine ), Centre Hospitalier Régional Universitaire de Nancy ( CHRU Nancy ), Centre hospitalier universitaire de Nantes ( CHU Nantes ), and CRLCC Val d'Aurelle - Paul Lamarque-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Male, recommendation, Pediatrics, medicine.medical_specialty, Malabsorption, Legislation, Medical, [SDV]Life Sciences [q-bio], Osteoporosis, 030209 endocrinology & metabolism, Rickets, vitamin D, osteomalacia, vitamin D deficiency, 03 medical and health sciences, 0302 clinical medicine, rickets, medicine, Vitamin D and neurology, Humans, 030212 general & internal medicine, Biological Psychiatry, Reimbursement, Aged, Aged, 80 and over, Osteomalacia, Hematologic Tests, [ SDV ] Life Sciences [q-bio], business.industry, Hydroxycholecalciferols, assay, medicine.disease, Obesity, reimbursement, osteoporosis, 3. Good health, Surgery, clinical practice, Neuropsychology and Physiological Psychology, Insurance, Health, Reimbursement, Female, Neurology (clinical), France, Geriatrics and Gerontology, business, calcium phosphorus evaluation, chronic kidney disease
Abstract: International audience; The number of serum 25-hydroxyvitamin D (25OHD) assays has increased tenfold in France in less than 10 years, sometimes for invalidated reasons. In 2013, the French National Authority for Health (Haute autorité de santé, or HAS) limited the indications for serum 25OHD measurements to rickets/osteomalacia, older adults with recurrent falls, monitoring of kidney transplant in adults, and surgical treatment of obesity in adults. Our aim here was to note that other indications for serum 25OHD measurements are supported by previous literature and by a number of national and international recommendations, in particular the following: any situation of bone fragility, any chronic renal failure
Published: 2016
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18. Poor Compliance to Hormone Therapy and Decreased Bone Mineral Density in Women with Premature Ovarian Insufficiency

Author: Jérôme Dulon, Monique Leban, Carole Nicolas, Philippe Touraine, Jean Louis Golmard, Anne Bachelot, Solenne Gricourt, CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université Pierre et Marie Curie - Paris 6 (UPMC), Centre d'investigation clinique Paris Est [CHU Pitié Salpêtrière] (CIC Paris-Est), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Institut E3M [CHU Pitié-Salpêtrière], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de biochimie et hormonologie [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de recherche clinique [CHU Pitié-Salpêtrière], and Service de Biochimie Endocrinienne et Oncologie [CHU Pitié-Salpêtrière]
Subjects: Bone density, Physiology, medicine.medical_treatment, Osteopenia and Osteoporosis, Osteoporosis, Menopause, Premature, lcsh:Medicine, Turner Syndrome, Primary Ovarian Insufficiency, Chromosomal Disorders, Endocrinology, 0302 clinical medicine, Bone Density, Medicine and Health Sciences, lcsh:Science, Connective Tissue Diseases, Osteoporosis, Postmenopausal, Univariate analysis, 030219 obstetrics & reproductive medicine, Multidisciplinary, Pharmaceutics, Estrogen Replacement Therapy, Hormonal Therapy, 3. Good health, Menopause, Connective Tissue, Transgender hormone therapy, Female, Anatomy, Research Article, Adult, medicine.medical_specialty, Hormone Replacement Therapy, 030209 endocrinology & metabolism, Premature ovarian insufficiency, 03 medical and health sciences, Rheumatology, Drug Therapy, Internal medicine, medicine, Humans, Bone, Clinical Genetics, Gynecology, Endocrine Physiology, business.industry, lcsh:R, Biology and Life Sciences, medicine.disease, Osteopenia, Biological Tissue, Women's Health, lcsh:Q, Hormone therapy, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Follow-Up Studies
Abstract: International audience; Premature ovarian insufficiency leads to through infertility and estrogen deficiency. Optimal management encompasses estrogen replacement therapy. Long-term outcome of women with POI is not known. We design a study to evaluate the medical care, hormone replacement therapy compliance and bone mineral density (BMD) in POI women with at least a five-year follow-up after the first evaluation. One hundred and sixty-two patients (37.3±8.0 years) were evaluated (follow-up 7.9±2.8 years). Sixty-nine patients (42.6%) had stopped their hormone replacement therapy (HRT) for at least one year during the follow up period. BMD determination at initial evaluation and at follow-up visit was completed in 92 patients. At first evaluation, 28 patients (30%) had osteopenia and 7 (8%) had osteoporosis. At follow up, 31 women (34%) had BMD impairment with osteopenia in 61% and osteoporosis in 5%. In univariate analysis and multivariate analysis, there was a significant loss of femoral BMD in women who had stopped their HRT for over a year. In conclusion, this first study concerning long-term follow-up of POI patients shows the poor compliance to their HRT, despite its importance in the prevention of bone demineralization. This study reinforces the need for follow up and specific care for POI women.
Published: 2016
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19. Désorganisation anatomique et fonctionnelle du cortex surrénalien au cours de la maladie de Cushing et du bloc en 21-hydroxylase

Author: Céline Duparc, Estelle Louiset, Yves Reznik, Philippe Touraine, Celso E. Gomez-Sanchez, Hervé Lefebvre, Jérôme Bertherat, J. Le Mestre, Différenciation et communication neuronale et neuroendocrine (DC2N), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Normandie Université (NU), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service Endocrinologie - Diabétologie [CHU Caen], Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), Service d'hépato-gastro-entérologie [Hôpital Pitié-Salpêtrière, AP HP], CHU Pitié-Salpêtrière [APHP], University of Mississippi Medical Center (UMMC), CHU Rouen, Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'Hépato-Gastro-Entérologie [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], and Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)
Subjects: 03 medical and health sciences, 0302 clinical medicine, Endocrinology, 030220 oncology & carcinogenesis, Endocrinology, Diabetes and Metabolism, [SDV.MHEP.PHY]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], 030209 endocrinology & metabolism, General Medicine, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, ComputingMilieux_MISCELLANEOUS, 3. Good health
Abstract: Dans le cortex surrenalien, la differenciation des cellules productrices d’aldosterone dans la zone glomerulee (ZG) est sous le controle de l’activation de la voie Wnt/β-catenine alors que l’activation de la voie AMPc/PKA par l’ACTH oriente la differenciation des cellules vers la synthese de cortisol dans la zone fasciculee (ZF). La sur activation de la voie AMPc/PKA due a une hypersecretion d’ACTH pourrait perturber l’organisation anatomique et fonctionnelle du cortex surrenalien. Nous avons etudie l’histologie surrenalienne et l’expression des enzymes de la corticosteroidogenese chez des patients presentant une hypersecretion d’ACTH liee a une maladie de Cushing ou un bloc en 21-hydroxylase (21-OHD). Nos resultats revelent une organisation des cellules en faisceaux dans la zone sous-capsulaire, et non en rosettes comme dans la surrenale saine, suggerant l’absence de ZG dans ces tissus pathologiques. Toutefois, la large distribution du marquage immunohistochimique Dab2, marqueur de ZG, dans les surrenales de patients avec 21-OHD, temoigne d’une ZG etendue. Chez ces patients, la ZG est fortement immunopositive a l’aldosterone synthase (CYP11B2) mais negative pour la 11β-hydroxylase (CYP11B1), enzyme retrouvee exclusivement dans la ZF. A contrario, le marquage Dab2 est restreint a quelques groupes de cellules chez les patients avec tumeur secretrice d’ACTH. La reduction de leur ZG est associee a une faible expression de CYP11B2 au niveau de l’ARNm et de la proteine, qui contraste avec une forte expression de CYP11B1. Nos resultats indiquent que la sur activation de la voie AMPc/PKA ne s’oppose pas a la differenciation fonctionnelle des cellules de la ZG des patients avec 21-OHD.
Published: 2016

20. Hypoglycaemia revealing heterozygous insulin receptor mutations

Author: Vanessa Preumont, Olivier Lascols, Corinne Vigouroux, Christine Feincoeur, Philippe Touraine, Dominique Maiter, Carine Courtillot, Department of Endocrinology and Nutrition [Bruxelles, Belgium], Cliniques Universitaires Saint-Luc [Bruxelles], Sorbonne Université (SU), Centre de Recherche Saint-Antoine (UMRS893), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Pierre et Marie Curie - Paris 6 (UPMC), Centre des Pathologies gynécologiques Rares [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut E3M [CHU Pitié-Salpêtrière], Service d’endocrinologie et médecine de la reproduction [CHU Pitié-Salpêtrière], Vigouroux, Corinne, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service d'Endocrinologie et Médecine de la Reproduction [CHU Pitié-Salpêtrière], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)
Subjects: 0301 basic medicine, medicine.medical_specialty, endocrine system, Endocrinology, Diabetes and Metabolism, medicine.medical_treatment, 030209 endocrinology & metabolism, Hypoglycemia, medicine.disease_cause, Article, Impaired glucose tolerance, 03 medical and health sciences, 0302 clinical medicine, Endocrinology, Internal medicine, Internal Medicine, medicine, Hyperinsulinemia, Hyperinsulinemic hypoglycemia, Acanthosis nigricans, [SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, biology, business.industry, Insulin, nutritional and metabolic diseases, General Medicine, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, medicine.disease, 3. Good health, Insulin receptor, 030104 developmental biology, biology.protein, business, Tyrosine kinase
Abstract: International audience; Major hyperinsulinemia, acanthosis nigricans, impaired glucose tolerance and ovarian hyperandrogenism characterize Type A insulin resistance (IR) syndrome due to dominant-negative heterozygous mutations in the insulin receptor gene (INSR). However, two unrelated families have been described with symptomatic hypoglycemia due to heterozygous INSR p.Arg1201 substitutions in the tyrosine kinase domain. In these patients, major hyperinsulinemia together with decreased insulin clearance was suggested to rescue genetically-altered insulin signalling in vivo in liver and/or muscle. We broaden the genetic spectrum of this rare phenotype of Type A insulin resistance by reporting the observations of two patients with INSR p.Met1180Val or p.Arg1201Gln heterozygous mutations revealed by repeated symptomatic hypoglycemia. Our observations further demonstrate that hyperinsulinemic hypoglycemia in adults can reveal different heterozygous mutations in the insulin receptor tyrosine kinase domain, whether associated or not with acanthosis nigricans, impaired glucose tolerance and/or ovarian hyperandrogenism.
Published: 2016
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21. Long-term outcome of ovarian function in women with intermittent premature ovarian insufficiency

Author: Maud Bidet, Michel Polak, Anne Bachelot, Jean Louis Golmard, Philippe Touraine, Carole Nicolas, Monique Leban, Jérôme Dulon, Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service d’endocrinologie et médecine de la reproduction [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut E3M [CHU Pitié-Salpêtrière], Centre de Référence des Maladies Endocriniennes rares de la croissance et des maladies gynécologiques rares, Centre des Pathologies gynécologiques Rares [CHU Pitié-Salpêtrière], Service d'endocrinologie, gynécologie et diabétologie pédiatriques [CHU Necker], CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de biochimie et hormonologie [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Université Pierre et Marie Curie - Paris 6 (UPMC), Service de recherche clinique [CHU Pitié-Salpêtrière], Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre d'investigation clinique Paris Est [CHU Pitié Salpêtrière] (CIC Paris-Est), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Service de Biochimie Endocrinienne et Oncologie [CHU Pitié-Salpêtrière], Service d'Endocrinologie et Médecine de la Reproduction [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Unité de Recherche Clinique des hôpitaux Pitié-Salpêtrière – Charles Foix [CHU Pitié Salpêtrière] (URC PSL-CFX), CHU Charles Foix [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Direction de la Recherche Clinique et de l'Innovation [AP-HP] (DRCI), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), and HAL-UPMC, Gestionnaire
Subjects: Adult, Infertility, medicine.medical_specialty, premature ovarian insufficiency, Endocrinology, Diabetes and Metabolism, ovarian function, 030209 endocrinology & metabolism, Context (language use), Primary Ovarian Insufficiency, Premature ovarian insufficiency, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Endocrinology, Internal medicine, medicine, Humans, Cumulative incidence, Young adult, [SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, fertility, Pregnancy, Univariate analysis, 030219 obstetrics & reproductive medicine, business.industry, Ovary, Dehydroepiandrosterone, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, Prognosis, medicine.disease, 3. Good health, Cross-Sectional Studies, Cohort, Female, pregnancy, Follicle Stimulating Hormone, business, Follow-Up Studies
Abstract: Context Spontaneous resumption of ovarian function is not a rare phenomenon in patients with premature ovarian insufficiency (POI). The outcome of this resumption is not known. Objective To describe the outcome following the resumption of ovarian function in POI patients. Design Cross sectional study. Setting University medical centre. Patients and main outcome measures Cumulative incidence of ovarian function resumption and risk factors arresting this resumption during follow-up were determined in a large cohort of POI women. Results Five hundred and seven patients were included in the study, with a follow up of 3.44±4.05 years [0-29]. Of these, 117 (23%) had features of ovarian function resumption. The cumulative incidence of pregnancy was 3.5% among the whole cohort and 15.3% among patients with resumption of ovarian function. Fifty-five patients (47%) experienced an arrest of their resumption during the follow up period. In univariate analysis, high FSH and DHEA levels at initial evaluation were risk factors for the arrest of the resumption of ovarian function. In multivariate analysis, high FSH levels at the initial evaluation (1.89 [1.10-3.23], p=0.03) and older age at diagnosis (1.53 [1.01-2.33], p=0.04) were risk factors for the arrest of this resumption. Conclusion Resumption of ovarian function is not a rare or brief phenomenon in POI women. The identification of predictive factors of this resumption, as well as its duration, increases our knowledge of the natural history of POI, and will improve the medical management, especially infertility counselling of these patients.
Published: 2016
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22. The prevalence of CHD7 missense versus truncating mutations is higher in patients with Kallmann syndrome than in typical CHARGE patients

Author: Catherine Dodé, Michel Pugeat, Didier Dewailly, Patrice Rodien, O. Verier-Mine, Didier Lacombe, Chrystel Leroy, Jacques Young, Chantal Metz, Francois Kurtz, Séverine Marcos, Marion Gérard, Slawomir Wolczynski, Sophie Christin-Maitre, Trine Prescott, Philippe Touraine, F. Archambeaud, Hanne Buciek Hove, Sylvie Cabrol, Philippe Parent, Laurence Perrin, Julie Sarfati, Jean-Pierre Hardelin, Sylvie Hiéronimus, Eric Bieth, Corinne Fouveaut, Génétique, physiopathologie et approches thérapeutiques des maladies héréditaires du système nerveux (EA 7331), Université Paris Descartes - Paris 5 (UPD5), Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hôpital Morvan [Brest], University of Bialystok, Centre Hospitalier Universitaire Clémenceau (CHU Clémenceau ), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Hôpital Bel Air, CHU Valenciennes, Hôpital Robert Debré, Hôpital Trousseau, Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Copenhagen University Hospital, Rikshospitalet, Oslo, Hôpital Pellegrin, CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), CHU Pitié-Salpêtrière [AP-HP], Hôpital l'Archet, Hôpital Jeanne de Flandre [Lille], AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Hôpital neurologique et neurochirurgical Pierre Wertheimer [CHU - HCL], Hospices Civils de Lyon (HCL), Génétique et Physiologie de l'Audition, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), This work was supported by grants from Agence Nationale pour la Recherche ANR-09-GENO-017-01 (to S.M., J.Y., J.-P.H., and C.D.), Groupement d'Intérêt Scientifique Maladies Rares (Project A09051KS), and the Société Française d'Endocrinologie (Pfizer Prize 2011)., ANR-09-GENO-0017,KALGENOPATH,Syndrome de Kallmann: un paradigme pour étudier l'interaction entre récepteurs couplés aux protéines G et récepteurs à activité tyrosine kinase(2009), Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut de l'Audition [Paris] (IDA), and Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Male, Kallmann syndrome, Endocrinology, Diabetes and Metabolism, [SDV]Life Sciences [q-bio], Clinical Biochemistry, MESH: DNA Helicases, Choanal atresia, medicine.disease_cause, Biochemistry, MESH: Genotype, CHARGE syndrome, Endocrinology, MESH: Child, Prevalence, Missense mutation, Child, Frameshift Mutation, MESH: Heterozygote, Coloboma, Mutation, MESH: Middle Aged, MESH: Frameshift Mutation, Middle Aged, 3. Good health, Pedigree, DNA-Binding Proteins, Phenotype, MESH: Young Adult, Child, Preschool, MESH: Kallmann Syndrome, Female, Congenital Hypogonadotropic Hypogonadism, Adult, medicine.medical_specialty, Heterozygote, Adolescent, Genotype, MESH: Pedigree, Mutation, Missense, Context (language use), Biology, MESH: Phenotype, Young Adult, Internal medicine, medicine, Humans, MESH: Prevalence, Family Health, MESH: Adolescent, MESH: Mutation, Missense, MESH: Humans, MESH: CHARGE Syndrome, Biochemistry (medical), MESH: Child, Preschool, DNA Helicases, MESH: Adult, Kallmann Syndrome, medicine.disease, MESH: Male, MESH: Family Health, CHARGE Syndrome, MESH: Female, MESH: DNA-Binding Proteins
Abstract: International audience; CONTEXT: Mutations in CHD7, a gene previously implicated in CHARGE (coloboma, heart defect, choanal atresia, retardation of growth and/or development, genital hypoplasia, ear anomalies) syndrome, have been reported in patients presenting with Kallmann syndrome (KS) or congenital hypogonadotropic hypogonadism (CHH). Most mutations causing CHARGE syndrome result in premature stop codons and occur de novo, but the proportion of truncating vs nontruncating mutations in KS and CHH patients is still unknown. OBJECTIVE: The objective of the study was to determine the nature, prevalence, mode of transmission, and clinical spectrum of CHD7 mutations in a large series of patients. DESIGN: We studied 209 KS and 94 CHH patients. These patients had not been diagnosed with CHARGE syndrome according to the current criteria. We searched for mutations in 16 KS and CHH genes including CHD7. RESULTS: We found presumably pathogenic mutations in CHD7 in 24 KS patients but not in CHH patients. Nontruncating mutations (16 missense and a two-codon duplication) were more prevalent than truncating mutations (three nonsense, three frame shift, and a splice site), which contrasts with patients presenting with typical CHARGE syndrome. Thus, the clinical spectrum associated with CHD7 mutations may be partly explained by genotype/phenotype correlations. Eight patients also had congenital deafness and one had a cleft lip/palate, whereas six had both. For 10 patients, the presence of diverse features of the CHARGE spectrum in at least one relative argues against a de novo appearance of the missense mutation, and this was confirmed by genetic analysis in five families. CONCLUSION: Considering the large prevalence and clinical spectrum of CHD7 mutations, it will be particularly relevant to genetic counseling to search for mutations in this gene in KS patients seeking fertility treatment, especially if KS is associated with deafness and cleft lip/palate.
Published: 2014
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23. Study of anti-Müllerian hormone and its relation to the subsequent probability of pregnancy in 112 patients with systemic lupus erythematosus, exposed or not to cyclophosphamide

Author: Nathalie Morel, Du Le Thi Huong Boutin, Véronique Le Guern, Jean-Emmanuel Kahn, Zahir Amoura, Jean-Charles Piette, Zeina Chakhtoura, Marie-Laure Tanguy, Jean-Marc Lacorte, Dominique Farge, Gaëlle Guettrot-Imbert, Aurélien Delluc, Damien Sène, Anne Bachelot, Philippe Touraine, Jean-Robert Harlé, Françoise Sarrot-Reynauld, Pascale Ghillani-Dalbin, Anne Gompel, Elisabeth Vidal, Lionel Galicier, Karim Sacre, Pierre Duhaut, Olivier Lambotte, Salim Trad, Jacques Pourrat, O. Aumaître, Nathalie Costedoat-Chalumeau, Camille Francès, Centre d'études européennes de Sciences Po ( CEE ), Sciences Po, Endocrinologie moléculaire, Institut National de la Santé et de la Recherche Médicale ( INSERM ), Laboratoire d'Immunochimie ( APHP PSL Immuno ), Assistance publique - Hôpitaux de Paris (AP-HP), Service de médecine interne [CHU Pitié-Salpétrière], Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Pitié-Salpêtrière [APHP], Immunité et Infection, Université Pierre et Marie Curie - Paris 6 ( UPMC ) -IFR113-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Service d'immunologie clinique, Assistance publique - Hôpitaux de Paris (AP-HP)-Université Paris Diderot - Paris 7 ( UPD7 ) -Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Service de médecine interne, hôpital Gabriel-Montpied, CHU Clermont-Ferrand, Service de Néphrologie - Immunologie Clinique [Toulouse], CHU Toulouse [Toulouse]-Hôpital de Rangueil, CHU Toulouse [Toulouse]-PRES Université de Toulouse, Laboratoire d'Immunologie ( EA 2686 ), Université de Lille, Droit et Santé, Immunologie, dermatologie, oncologie, Oncodermatologie, immunologie et cellules souches cutanées ( DIO U976 ), Université Paris Diderot - Paris 7 ( UPD7 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Service de Dermatologie [CHU Tenon], Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Tenon [APHP], Anthropologie bio-culturelle, Droit, Ethique et Santé ( ADES ), Aix Marseille Université ( AMU ) -EFS ALPES MEDITERRANEE-Centre National de la Recherche Scientifique ( CNRS ), service de médecine interne, Hôpital de Bicêtre, Centre de Référence des microangiopathies thrombotiques ( CNR-MAT ), service d'hématologie-CHU Saint-Antoine [APHP], Service de Médecine Interne, Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Cochin [AP-HP]-Université Paris Descartes - Paris 5 ( UPD5 ), Service de Médecine interne A et polyclinique médicale [CHU Limoges], CHU Limoges, Homéostasie Cellulaire et Pathologies ( HCP ), Université de Limoges ( UNILIM ) -CHU Limoges-Génomique, Environnement, Immunité, Santé, Thérapeutique ( GEIST FR CNRS 3503 ), Clinique de médecine interne, Université Joseph Fourier - Grenoble 1 ( UJF ) -CHU Grenoble, Service d'endocrinologie gynécologique, Assistance publique - Hôpitaux de Paris (AP-HP)-Hôtel-Dieu-Université Paris Descartes - Paris 5 ( UPD5 ), Centre national de référence des angioedemes, Service de biostatistiques et information médicale [CHU Pitié-Salpêtrière], Department of Endocrinology and Reproductive Medicine, CHU Pitié-Salpêtrière [APHP]-Centre de Référence des Maladies Endocriniennes rares de la croissance et des maladies gynécologiques rares, Université Pierre et Marie Curie - Paris 6 ( UPMC ), Immunologie - Immunopathologie - Immunothérapeutique ( I3 ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Département de Médecine Interne et Pneumologie [Brest] ( DMIP - Brest ), Centre Hospitalier Régional Universitaire de Brest ( CHRU Brest ), Groupe d'Etude de la Thrombose de Bretagne Occidentale ( GETBO ), Université de Brest ( UBO ), Centre d'Investigation Clinique ( CIC - Brest ), Université de Brest ( UBO ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Centre d'études européennes et de politique comparée (Sciences Po, CNRS) (CEE), Sciences Po (Sciences Po)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR113-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de Médecine Interne [CHU Clermont-Ferrand], CHU Gabriel Montpied [Clermont-Ferrand], CHU Clermont-Ferrand-CHU Clermont-Ferrand, Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-PRES Université de Toulouse, Laboratoire d'Immunologie (EA 2686), Oncodermatologie, immunologie et cellules souches cutanées (IDO (U976 / UMR_S 976)), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Tenon [AP-HP], Anthropologie bio-culturelle, Droit, Ethique et Santé (ADES), Aix Marseille Université (AMU)-EFS ALPES MEDITERRANEE-Centre National de la Recherche Scientifique (CNRS), CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5), Homéostasie Cellulaire et Pathologies (HCP), Université de Limoges (UNILIM)-CHU Limoges-Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST FR CNRS 3503), Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôtel-Dieu-Université Paris Descartes - Paris 5 (UPD5), Université Pierre et Marie Curie - Paris 6 (UPMC), Immunologie - Immunopathologie - Immunothérapeutique (I3), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Département de Médecine Interne et Pneumologie [Brest] (DMIP - Brest), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Groupe d'Etude de la Thrombose de Bretagne Occidentale (GETBO), Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO)-Université de Brest (UBO), Centre d'Investigation Clinique (CIC - Brest), Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Service de dermatologie et allergologie [CHU Tenon], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Département de Biostatistique, Santé Publique et Information Médicale [CHU Pitié-Salpêtrière] (BIOSPIM ), Centre d'études européennes et de politique comparée (CEE), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO)-Université de Brest (UBO)-Université de Brest (UBO), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université Paris Diderot - Paris 7 (UPD7)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Université de Limoges (UNILIM)-Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST FR CNRS 3503)-CHU Limoges, and Université de Brest (UBO)-Institut Brestois Santé Agro Matière (IBSAM)
Subjects: Anti-Mullerian Hormone, Endocrinology, Diabetes and Metabolism, [SDV]Life Sciences [q-bio], Clinical Biochemistry, Biochemistry, Cohort Studies, 0302 clinical medicine, Endocrinology, MESH: Pregnancy, Pregnancy, Lupus Erythematosus, Systemic, Medicine, MESH : Lupus Erythematosus, Systemic, MESH: Double-Blind Method, MESH : Female, MESH : Immunosuppressive Agents, MESH: Cohort Studies, MESH : Cyclophosphamide, Univariate analysis, 030219 obstetrics & reproductive medicine, biology, Anti-Müllerian hormone, MESH : Adult, 3. Good health, Premature ovarian failure, MESH: Premenopause, Female, MESH: Immunosuppressive Agents, Immunosuppressive Agents, medicine.drug, Cohort study, Adult, medicine.medical_specialty, Cyclophosphamide, MESH : Cohort Studies, Context (language use), 03 medical and health sciences, Double-Blind Method, Internal medicine, Humans, MESH : Double-Blind Method, MESH: Lupus Erythematosus, Systemic, 030203 arthritis & rheumatology, Lupus erythematosus, MESH: Humans, [ SDV ] Life Sciences [q-bio], business.industry, MESH : Anti-Mullerian Hormone, Biochemistry (medical), MESH : Humans, MESH: Cyclophosphamide, MESH: Adult, medicine.disease, MESH : Pregnancy, Premenopause, biology.protein, MESH: Anti-Mullerian Hormone, business, MESH : Premenopause, MESH: Female
Abstract: Context: Cyclophosphamide is used for renal and major extrarenal involvement in systemic lupus erythematosus (SLE) and is associated with a risk of premature ovarian failure. There are no data available about the relation between anti-Müllerian hormone (AMH) serum levels and the probability of subsequent pregnancy in SLE patients. Objective: We analyzed AMH levels and the probability of pregnancy in SLE women exposed to cyclophosphamide. Design and Setting: We conducted a matched cohort study in referral centers for SLE. Patients: Fifty-six cyclophosphamide-exposed SLE women younger than 40 years of age and 56 control SLE women matched for age within 6 months participated in the study. Main Outcome Measures: AMH was measured in samples from the PLUS study (ClinicalTrials.gov no. NCT00413361). All patients were interviewed in May 2012 regarding their obstetric status. Results: The mean age ± SD of the 112 patients was 31.6 ± 5.8 years. The mean AMH level was low (1.21 ± 1.01 ng/mL) and was significantly lower in patients exposed to cyclophosphamide (P = .03) and in patients older than 30 years (P = .02). During a median follow-up (interval between sampling and the interview) period of 4.2 (range, 2.5–4.8) years, 38 patients sought to become pregnant, and 32 (84.2%) succeeded. In the univariate analysis, the risk of failure was associated with cumulative cyclophosphamide dose (P = .007) and older age (P = .02), but not with AMH. Conclusion: We confirmed that AMH levels are low in SLE patients and decrease significantly with age and cyclophosphamide exposure. Nonetheless, the risk of failure to conceive was low and was predicted by cyclophosphamide exposure and age, but not by AMH levels.
Published: 2013
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24. Cardiovascular findings and management in Turner syndrome: insights from a French cohort

Author: N. Bourcigaux, Guillaume Jondeau, Carine Courtillot, Lise Duranteau, Michel Polak, Damien Bonnet, Catherine Meuleman, Jean-Claude Carel, Yves Lebouc, Philippe Chanson, L Monnier-Cholley, Sophie Christin-Maitre, Dinane Samara-Boustani, Philippe Bouchard, Laurence Iserin, Sylvie Cabrol, Juliane Léger, Bruno Donadille, Laure Cabanes, Philippe Touraine, Alexandra Rousseau, Sylvie Salenave, Delphine Zenaty, Service d'Endocrinologie, diabétologie et endocrinologie de la reproduction [CHU Saint-Antoine], CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), CHU Trousseau [APHP], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)
Subjects: Adult, Pediatrics, medicine.medical_specialty, Adolescent, Endocrinology, Diabetes and Metabolism, [SDV]Life Sciences [q-bio], Turner Syndrome, 030209 endocrinology & metabolism, 030204 cardiovascular system & hematology, Cohort Studies, 03 medical and health sciences, Cardiovascular monitoring, Young Adult, 0302 clinical medicine, Endocrinology, Bicuspid aortic valve, Turner syndrome, Cardiac valve, medicine, Humans, Child, Aged, Body surface area, medicine.diagnostic_test, business.industry, Infant, Newborn, Infant, Magnetic resonance imaging, General Medicine, Vascular surgery, Middle Aged, medicine.disease, 3. Good health, Cardiovascular Diseases, Child, Preschool, Cohort, Female, France, business, Algorithms
Abstract: ObjectiveCongenital cardiovascular malformations and aortic dilatation are frequent in patients with Turner syndrome (TS). The objective of this study was to investigate the cardiovascular findings and management in a large cohort of patients, including children and adults.Design/methodsWe recruited 336 patients with TS from a network of tertiary centers. We reviewed their files, checking for cardiovascular events, cardiac valve abnormalities, and aortic diameters indexed to body surface area (BSA) from magnetic resonance imaging (n=110) or echocardiography (n=300).ResultsInformative cardiovascular data were available for only 233 patients. Vascular surgery was reported in 7.4% of the cohort. The first cause of surgery was aortic coarctation, detected in 6.9% at a median age of 9.5 (range: 0–60) years. Bicuspid aortic valve (BAV) was detected in 21% at a median age of 20 years (25th–75th percentiles: 15–30). At least one aortic diameter exceeded 32 mm in 12% of the cohort. This was detected at a median age of 19 (7–30) years. When indexed to BSA, at least one aortic diameter exceeded 20 mm/m2 in 39% of the cohort.ConclusionOur study shows that cardiovascular monitoring for TS patients is currently insufficient in France. BAV is present at birth, but often remains undiagnosed until later in life. Therefore, improved management in cardiovascular monitoring is required and a more systematic approach should be taken.
Published: 2012
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25. Markers of recurrence and long-term morbidity in craniopharyngioma: a systematic analysis of 171 patients

Author: Fabrice Bonnet, A. Gautier, Ariane Godbout, Mathieu Coudert, Gilles Brassier, Catherine Grosheny, Laurent Riffaud, Philippe Touraine, Christian Sainte-Rose, Marc de Kerdanet, Carine Courtillot, Christel Jublanc, Elisabeth Thibaud, Isabelle Tejedor, Jean-Yves Poirier, Remy Van Effenterre, Foie, métabolismes et cancer, Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Service d'endocrinologie diabétologie et nutrition [Rennes], Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-CHU Pontchaillou [Rennes]-Hôpital Anne-de-Bretagne, Endocrinology Division, Centre Hospitalier de l'Université de Montréal (CHUM), Université de Montréal (UdeM)-Université de Montréal (UdeM)-Department of Medicine, CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Pierre et Marie Curie - Paris 6 (UPMC), Modeling in Clinical Research, Université Pierre et Marie Curie - Paris 6 (UPMC)-EA 3974, Service de Pédiatrie, Hôpital Pontchaillou-CHU Pontchaillou [Rennes], Service de neurochirurgie [Rennes] = Neurosurgery [Rennes], CHU Pontchaillou [Rennes], Service de neurochirurgie pédiatrique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Craniopharyngioma Study Group, Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université de Rennes (UR)-CHU Pontchaillou [Rennes]-Hôpital Anne-de-Bretagne, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -CHU Pontchaillou [Rennes]-Hôpital Anne-de-Bretagne, Centre de recherche du Centre Hospitalier de l'Université de Montréal ( CRCHUM ) -Department of Medicine, Department of Endocrinology and Reproductive Medicine, CHU Pitié-Salpêtrière [APHP]-Centre de Référence des Maladies Endocriniennes rares de la croissance et des maladies gynécologiques rares, Université Pierre et Marie Curie - Paris 6 ( UPMC ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -EA 3974, Department of Biostatistics and Medical Informatics, CHU Pitié-Salpêtrière [APHP], Department of Endocrinology and Metabolism, Service de neurochirurgie [Rennes], Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -Hôpital Pontchaillou-CHU Pontchaillou [Rennes], Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Department of Neurosurgery, and Le Corre, Morgane
Subjects: Male, Pediatrics, MESH : Retrospective Studies, Endocrinology, Diabetes and Metabolism, Clinical Biochemistry, MESH : Child, Preschool, Biochemistry, MESH: Craniopharyngioma, Cohort Studies, Craniopharyngioma, 0302 clinical medicine, Endocrinology, MESH : Child, Quality of life, MESH: Child, MESH : Female, MESH : Craniotomy, [ SDV.IB ] Life Sciences [q-bio]/Bioengineering, Age of Onset, Child, MESH: Cohort Studies, [SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, MESH : Prognosis, MESH: Middle Aged, MESH : Neoplasm Recurrence, Local, MESH: Follow-Up Studies, MESH : Adult, [ SDV.MHEP.EM ] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, Middle Aged, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, Prognosis, MESH : Age of Onset, 3. Good health, 030220 oncology & carcinogenesis, Child, Preschool, MESH: Survival Analysis, MESH : Social Adjustment, Female, [SDV.IB]Life Sciences [q-bio]/Bioengineering, France, Social Adjustment, MESH: Neoplasm Recurrence, Local, Craniotomy, Cohort study, MESH: Intracranial Hypertension, Adult, medicine.medical_specialty, Adolescent, MESH : Male, MESH: Age of Onset, MESH: Craniotomy, MESH : Cohort Studies, Context (language use), MESH: Prognosis, 03 medical and health sciences, MESH : Intracranial Hypertension, MESH : Adolescent, Internal medicine, MESH : Craniopharyngioma, medicine, Humans, MESH : Middle Aged, MESH : France, Survival rate, Survival analysis, Retrospective Studies, [SDV.IB] Life Sciences [q-bio]/Bioengineering, MESH: Adolescent, MESH: Humans, business.industry, MESH : Humans, Biochemistry (medical), MESH: Child, Preschool, MESH: Quality of Life, MESH : Follow-Up Studies, Retrospective cohort study, MESH: Adult, MESH: Retrospective Studies, MESH : Quality of Life, medicine.disease, Survival Analysis, MESH: Social Adjustment, MESH: Male, Surgery, MESH: France, Quality of Life, MESH : Survival Analysis, Age of onset, Intracranial Hypertension, Neoplasm Recurrence, Local, business, MESH: Female, 030217 neurology & neurosurgery, Follow-Up Studies
Abstract: International audience; CONTEXT: Craniopharyngiomas are often associated with an unfavorable prognosis, but data on their long-term consequences are sparse. OBJECTIVE: The aim of the study was to identify markers of recurrence and factors associated with compromised social rehabilitation and altered quality of life in a large cohort of patients with either childhood-onset (CO) or adult-onset craniopharyngioma. METHODS: Retrospective analysis was performed for 171 patients treated for craniopharyngioma in two academic centers in France between 1972 and 2009. For each subject, data were collected concerning clinical presentation, imaging features, visual sequelae, endocrine and metabolic impact, treatment modalities (surgery, radiotherapy), recurrence-free survival rate, and social insertion, as well as answers to the WHO-QOL BREF questionnaire. RESULTS: A total of 65 CO and 106 adult-onset patients were reviewed. If CO was diagnosed before the age of 10 yr, this was associated with a higher incidence of obesity, blindness, and panhypopituitarism, and only 40.7% of subjects had adequate work or school attendance compared to 72.4% of patients with later disease onset. Initial symptoms of intracranial hypertension (SIHT), pterional surgery, and multiple surgery were associated with obesity and poorer social insertion. No determinant of quality of life was identified. In the subgroup of patients treated in the 1990s and later, the progression rate was 59.4% in patients with residual tumor on magnetic resonance imaging compared with a 19.8% recurrence rate in the group with apparently complete resection. Recurrence/progression correlates significantly with male gender, early onset (before 10 yr), and SIHT, but only SIHT at presentation remained a significant predictor with multivariate analysis. CONCLUSIONS: Craniopharyngioma continues to be associated with severe outcomes. Higher morbidity rates are found in patients with early-onset disease (before 10 yr), initial SIHT, or in whom pterional surgery was required. Markers of recurrence are difficult to identify, with SIHT being the most powerful predictor.
Published: 2012
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26. Novel NOBOX loss-of-function mutations account for 6.2% of cases in a large primary ovarian insufficiency cohort

Author: Justine Bouilly, Philippe Touraine, Anne Bachelot, Nadine Binart, Isabelle Broutin, Institut National de la Santé et de la Recherche Médicale (INSERM), Université Pierre et Marie Curie - Paris 6 (UPMC), Laboratoire de cristallographie et RMN biologiques (LCRB - UMR 8015), Université Paris Descartes - Paris 5 (UPD5)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Institut E3M [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Endocrinologie moléculaire, broutin, isabelle, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)
Subjects: Models, Molecular, medicine.medical_specialty, Candidate gene, Heterozygote, Protein Conformation, [SDV]Life Sciences [q-bio], Molecular Sequence Data, Biology, Growth differentiation factor-9, Primary Ovarian Insufficiency, medicine.disease_cause, Cohort Studies, 03 medical and health sciences, 0302 clinical medicine, Gene Frequency, Internal medicine, Gene Order, Genetics, medicine, Prevalence, Missense mutation, Humans, Amino Acid Sequence, Allele, Genetics (clinical), Alleles, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, Homeodomain Proteins, 0303 health sciences, Mutation, 030219 obstetrics & reproductive medicine, Base Sequence, Female infertility, Heterozygote advantage, medicine.disease, [SDV] Life Sciences [q-bio], Endocrinology, HEK293 Cells, Female, Haploinsufficiency, Sequence Alignment, Transcription Factors
Abstract: Primary ovarian insufficiency (POI) is a disorder associated with female infertility, which affects approximately 1% of women under 40 years of age. A genetic component has been suggested as one possible cause of the majority of cases of nonsyndromic forms. Newborn Ovary Homeobox (NOBOX) is an ovary-specific gene, playing a critical role in ovary in mice, as its absence leads to sterility mimicking a POI. In this study, we sequenced NOBOX in a cohort of 178 women with idiopathic POI. Among 19 identified variations, we described one nonsense (c.907C>T/p.R303X) and four missense (c.271G>T/p.G91W, c.349C>T/p.R117W, c.1025G>C/p.S342T, and c.1048G>T/p.V350L) NOBOX heterozygous mutations in 12 patients. We reproduced each of the five mutations and tested their effects on the signaling activity in transfected cells. We demonstrated that these mutations compromised the ability of the proteins to bind to and transactivate the well-known growth differentiation factor 9 (GDF9) promoter. The pattern of our findings suggests that the genetic mechanism in humans responsible for POI in women involves haploinsufficiency rather than dominant negative gene action. The identification, characterization, and the very high 6.2% prevalence of these new mutations in POI patients suggest considering NOBOX as the first autosomal candidate gene involved in this syndrome.
Published: 2011
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27. Evaluation of different markers of the ovarian reserve in patients presenting with Premature Ovarian Failure

Author: N. Massin, Geri Meduri, Micheline Misrahi, Philippe Touraine, Anne Bachelot, and Frédérique Kuttenn
Subjects: Adult, Anti-Mullerian Hormone, endocrine system, medicine.medical_specialty, endocrine system diseases, Adolescent, Biopsy, Physiology, Ovary, Biology, Primary Ovarian Insufficiency, Biochemistry, 03 medical and health sciences, 0302 clinical medicine, Endocrinology, Ovarian Follicle, Internal medicine, Follicular phase, medicine, Humans, Ovarian reserve, Molecular Biology, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, 0303 health sciences, 030219 obstetrics & reproductive medicine, medicine.diagnostic_test, Life Sciences, Histology, Vaginal ultrasonography, medicine.disease, female genital diseases and pregnancy complications, 3. Good health, Premature ovarian failure, medicine.anatomical_structure, Cross-Sectional Studies, Phenotype, Female, Immunostaining, Biomarkers
Abstract: Premature ovarian failure (POF) is a heterogeneous syndrome, possibly due to mutations of genes involved in the normal development of the ovary and/or the follicles. Based essentially on animal models, these mutations are associated with various ovarian histological phenotypes, from a complete absence of to a partial follicular maturation. The aims of our work were in one hand to determine if ovarian histology, compared to pelvic ultrasonography, would be helpful either in identifying which patients display an impaired follicular growth or in the orientation of the POF etiology; on the other hand, since developing follicles up to the antral stage are reported in POF and that Anti-Mullerian hormone (AMH) might be a good indicator of follicular presence, we decided to determine whether AMH should be a better marker to determine the presence of an ovarian reserve in POF patients. To try to answer to the first question, we studied first 166 patients suffering from POF with a normal karyotype. Vaginal ultrasonography (US) was performed in 134 patients and an ovarian biopsy was obtained in 67 women. The presence of follicles suggested at US was confirmed at histology in only 56% of the patients. Ovarian histology led to the distinction of two phenotypes (a) small-sized ovaries, deprived of follicles, and (b) normal-sized ovaries with partial follicular maturation. To confirm the value of ovarian biopsies, samples from 20 normal women have been studied, confirming that ovarian biopsy at random allow reliable assessment of follicular activity. To try to answer to the second question of our work, a cross sectional study analyzing serum AMH, ovarian histology and AMH immunoexpression in 48 POF patients, was performed. Serum AMH was significantly higher in women with more than 5 follicles at ovarian histology. Ovarian AMH immunostaining revealed a normal AMH expression in POF preantral follicles but a decrease expression at the early antral stages. In conclusion, ovarian histology appears to be a reliable tool to appreciate the follicular reserve, and helpful and complementary to clinical and hormonal phenotyping in order to orient the search for various genetic causes of POF syndrome. Finally, AMH levels in POF patients could identify women with persistent follicles.
Published: 2008
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28. Genetic investigation of four meiotic genes in women with premature ovarian failure

Author: Marc Fellous, Corinne Cotinot, Céline Derbois, Fumihiko Matsuda, Beatrice Mandon-Pepin, A. Rouxel, Alain Nicolas, Frédérique Kuttenn, Philippe Touraine, Biologie du développement et reproduction (BDR), Centre National de la Recherche Scientifique (CNRS)-École nationale vétérinaire d'Alfort (ENVA)-Institut National de la Recherche Agronomique (INRA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre National de Génotypage (CNG), Biologie Cellulaire et Cancer, Institut Curie [Paris]-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Génomique et épigénétique des pathologies placentaires (Inserm U709), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5), École nationale vétérinaire - Alfort (ENVA)-Institut National de la Recherche Agronomique (INRA)-Centre National de la Recherche Scientifique (CNRS), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), and ProdInra, Migration
Subjects: Adult, Male, medicine.medical_specialty, Spo11, Adolescent, Genotype, endocrine system diseases, Endocrinology, Diabetes and Metabolism, DNA Mutational Analysis, Cell Cycle Proteins, Primary Ovarian Insufficiency, Biology, MUTATION DES GENES, Polymerase Chain Reaction, 03 medical and health sciences, Exon, 0302 clinical medicine, Endocrinology, Internal medicine, medicine, Humans, Missense mutation, 030304 developmental biology, [SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, Genetics, 0303 health sciences, Endodeoxyribonucleases, 030219 obstetrics & reproductive medicine, Models, Genetic, fungi, Esterases, General Medicine, GENETIQUE, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, medicine.disease, female genital diseases and pregnancy complications, Pedigree, Premature ovarian failure, DNA-Binding Proteins, MSH5, Phenotype, MSH4, Mutation, biology.protein, Female, DMC1, Blood sampling
Abstract: ObjectiveThe goal of this study was to determine whether mutations of meiotic genes, such as disrupted meiotic cDNA (DMC1), MutS homolog (MSH4),MSH5, andS. cerevisiaehomolog (SPO11), were associated with premature ovarian failure (POF).DesignCase–control study.MethodsBlood sampling, karyotype, hormonal dosage, ultrasound, and ovarian biopsy were carried out on most patients. However, the main outcome measure was the sequencing of genomic DNA from peripheral blood samples of 41 women with POF and 36 fertile women (controls).ResultsA single heterozygous missense mutation, substitution of a cytosine residue with thymidine in exon 2 ofMSH5, was found in two Caucasian women in whom POF developed at 18 and 36 years of age. This mutation resulted in replacement of a non-polar amino acid (proline) with a polar amino acid (serine) at position 29 (P29S). Neither 36 control women nor 39 other patients with POF possessed this genetic perturbation. Another POF patient of African origin showed a homozygous nucleotide change in the tenth ofDMC1gene that led to an alteration of the amino acid composition of the protein (M200V).ConclusionsThe symptoms of infertility observed in theDMC1homozygote mutation carrier and in both patients with a heterozygous substitution in exon 2 of theMSH5gene provide indirect evidence of the role of genes involved in meiotic recombination in the regulation of ovarian function.MSH5andDMC1mutations may be one explanation for POF, albeit uncommon.
Published: 2008
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29. Etude observationnelle KIMS du traitement par GH des patients adultes ayant un déficit somatotrope : analyse à 12 mois des données françaises

Author: T. Brue, F. Borson-Chazot, B. Delemer, J.-L. Schlienger, Philippe Touraine, I. Pion, A. Chachuat, Gautron, Conception, Interactions cellulaires neuroendocriniennes (ICN), and Université de la Méditerranée - Aix-Marseille 2-Centre National de la Recherche Scientifique (CNRS)
Subjects: Endocrinology, Endocrinology, Diabetes and Metabolism, General Medicine
Abstract: L’etude observationnelle KIMS est une etude internationale initiee en 1994 a laquelle la France participe depuis 2003. Son objectif est de recueillir a tres large echelle, dans un contexte de routine, des donnees de long terme sur les patients adultes deficitaires hypophysaires traites ou non par hormone de croissance. Parmi les 330 patients deja inclus par 128 centres en France au moment de cette premiere analyse intermediaire, 122 patients traites avaient ete suivis au moins 12 mois. Les resultats presentes ici portent sur cette population de 122 patients. Au terme de cette premiere annee de traitement, le taux d’IGF-1 etait normalise pour l’âge et le sexe chez 77 % des patients naifs de tout traitement par hormone de croissance (GH), 71 % des patients semi-naifs et 85 % des patients non naifs. L’augmentation de la masse maigre etait de 5,1 % et la diminution de la masse grasse de 5,7 %. La qualite de vie mesuree par le questionnaire QoL-AGHDA etait amelioree avec un score median qui passait de 10 a 6. Les premiers resultats disponibles en France confortent la GH dans son indication chez les adultes ayant un deficit somatotrope severe.
Published: 2006

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29 results on '"Philippe, Touraine"'

1. Identification of predictive criteria for pathogenic variants of primary bilateral macronodular adrenal hyperplasia (PBMAH) gene ARMC5 in 352 unselected patients

2. Whole exome sequencing in a cohort of familial premature ovarian insufficiency cases reveals a broad array of pathogenic or likely pathogenic variants in 50% of families

3. Meiotic genes in premature ovarian insufficiency: variants in HROB and REC8 as likely genetic causes

4. Transition of young adults with endocrine and metabolic diseases: the TRANSEND cohort

5. Genomic sequencing highlights the diverse molecular causes of Perrault syndrome: a peroxisomal disorder (PEX6), metabolic disorders (CLPP, GGPS1), and mtDNA maintenance/translation disorders (LARS2, TFAM)

6. Effect of congenital adrenal hyperplasia treated by glucocorticoids on plasma metabolome: a machine-learning-based analysis

7. GGPS1 Mutations Cause Muscular Dystrophy/Hearing Loss/Ovarian Insufficiency Syndrome

8. Illicit Upregulation of Serotonin Signaling Pathway in Adrenals of Patients With High Plasma or Intra-Adrenal ACTH Levels

9. TP63-truncating variants cause isolated premature ovarian insufficiency

10. Post-transplant outcome of ovarian tissue cryopreserved after chemotherapy in hematological malignancies

11. Endocrine manifestations in a cohort of 63 adulthood and childhood onset patients with Langerhans cell histiocytosis

12. The control of diabetes and other Non-communicable Diseases is an urgent health priority in Africa: Grenoble declaration

13. Early central blood pressure elevation in adult patients with 21-hydroxylase deficiency

14. Complex Association of Sex Hormones on Left Ventricular Systolic Function: Insight into Sexual Dimorphism

15. Impact of transition on quality of life in patients with congenital adrenal hyperplasia diagnosed during childhood

16. Contribution of LHX4 Mutations to Pituitary Deficits in a Cohort of 417 Unrelated Patients

17. French law: what about a reasoned reimbursement of serum vitamin D assays?

18. Poor Compliance to Hormone Therapy and Decreased Bone Mineral Density in Women with Premature Ovarian Insufficiency

19. Désorganisation anatomique et fonctionnelle du cortex surrénalien au cours de la maladie de Cushing et du bloc en 21-hydroxylase

20. Hypoglycaemia revealing heterozygous insulin receptor mutations

21. Long-term outcome of ovarian function in women with intermittent premature ovarian insufficiency

22. The prevalence of CHD7 missense versus truncating mutations is higher in patients with Kallmann syndrome than in typical CHARGE patients

23. Study of anti-Müllerian hormone and its relation to the subsequent probability of pregnancy in 112 patients with systemic lupus erythematosus, exposed or not to cyclophosphamide

24. Cardiovascular findings and management in Turner syndrome: insights from a French cohort

25. Markers of recurrence and long-term morbidity in craniopharyngioma: a systematic analysis of 171 patients

26. Novel NOBOX loss-of-function mutations account for 6.2% of cases in a large primary ovarian insufficiency cohort

27. Evaluation of different markers of the ovarian reserve in patients presenting with Premature Ovarian Failure

28. Genetic investigation of four meiotic genes in women with premature ovarian failure

29. Etude observationnelle KIMS du traitement par GH des patients adultes ayant un déficit somatotrope : analyse à 12 mois des données françaises

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