Author: "Philippe, Touraine" / Topic: humans - Searchworks@Jio Institute Digital Library Search Results

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1. Pituitary function and the response to GH therapy in patients with Langerhans cell histiocytosis: analysis of the KIMS database

Author: Philippe Touraine, Yempabou Sagna, Anders F Mattsson, Pia Burman, André P Van Beek, Martin Ove Carlsson, Ferah Aydin, Ulla Feldt-Rasmussen, Cecilia Camacho-Hübner, and Center for Liver, Digestive and Metabolic Diseases (CLDM)
Subjects: Adult, Male, Hormone Replacement Therapy, Human Growth Hormone, Endocrinology, Diabetes and Metabolism, General Medicine, Hypopituitarism, Histiocytosis, Langerhans-Cell, Cross-Sectional Studies, Endocrinology, Quality of Life, Humans, Female, Child, Dwarfism, Pituitary
Abstract: Objective To analyze the effectiveness and safety of growth hormone (GH) replacement treatment in adult patients with Langerhans cell histiocytosis (LCH) and GH deficiency (GHD) enrolled in KIMS (Pfizer International Metabolic Database). Patients and methods Patients with LCH and GHD were studied at baseline and some of them after 1 year of GH treatment. The effectiveness of GH is presented as change after 1 year of treatment (mean, 95% CI). The LCH population was compared to two other groups of patients enrolled in KIMS, granulomatous and lymphocytic hypophysitis. Results At baseline, 81 adults with LCH (27 with childhood onset, 56% females), mean age at GHD onset of 29 (15) years were studied. Diabetes insipidus was diagnosed in 86% of patients. Analysis of 1 year of GH treatment was possible in 37 patients. One-year cross-sectional values for the GH dose were 0.39 (s.d.± 0.21) mg and −0.5 (−1.2 to 0.2) for insulin-like growth factor-1 s.d. Total cholesterol decreased 0.9 (−1.5 to −0.3 (mmol/L); P n = 20) was improved by 2.8 points (−5.6 to 0.0; P 2 (95% CI: −0.2 to 1.4). All these effects did not differ from the two other groups after adjusting for age, gender, and baseline values. In 20 of 77 patients included in the safety analysis, 36 serious adverse events were reported during 435 patient-years (82.8/1000); no new safety signals were reported. Conclusion After 1 year of GH treatment in patients with LCH, metabolic variables and quality of life improved, with no new safety signals.
Published: 2022
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2. Dominant TP63 missense variants lead to constitutive activation and premature ovarian insufficiency

Author: Elena J. Tucker, Niklas Gutfreund, Marc‐Antoine Belaud‐Rotureau, David Gilot, Tiffany Brun, Brianna L. Kline, Katrina M. Bell, Mathilde Domin‐Bernhard, Camille Théard, Philippe Touraine, Gorjana Robevska, Jocelyn van van den Bergen, Katie L. Ayers, Andrew H. Sinclair, Volker Dötsch, Sylvie Jaillard, University of Melbourne, Murdoch Children's Research Institute (MCRI), Institute of Biochemistry and Signal Transduction [Hamburg, Germany], Universitaetsklinikum Hamburg-Eppendorf = University Medical Center Hamburg-Eppendorf [Hamburg] (UKE), 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 ), École des Hautes Études en Santé Publique [EHESP] (EHESP), CHU Pontchaillou [Rennes], CRLCC Eugène Marquis (CRLCC), Oncogenesis, Stress, Signaling (OSS), Université de Rennes (UR)-CRLCC Eugène Marquis (CRLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de référence Maladies Rares CLAD-Ouest [Rennes], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), and This study was supported by a CHU Rennes grant (Appel à Projets Innovations 2019 to SJ), an Australian National Health and Medical Research Council (NHMRC) program grant (1074258 to AHS), NHMRC fellowships (1054432 to EJT, 1062854 to AHS), a Suzi Carp postdoctoral scholarship (to EJT) and the Deutsche Forschungsgemeinschaft (DO 545/18-1). The research conducted at the Murdoch Children's Research Institute was supported by the Victorian government's operational infrastructure support program. We thank the Bioinformatic department of Rennes University Hospital (Pr M. De Tayrac and Dr W. Carré) for technical assistance. Open access publishing facilitated by The University of Melbourne, as part of the Wiley - The University of Melbourne agreement via the Council of Australian University Librarians.
Subjects: premature ovarian insufficiency, [SDV]Life Sciences [q-bio], Tumor Suppressor Proteins, Mutation, Missense, Primary Ovarian Insufficiency, TAp63α, genomic diagnosis, Genetics, Humans, Female, TP63, infertility, p63 isoforms, Genetics (clinical), Transcription Factors
Abstract: International audience; Premature ovarian insufficiency (POI) is a leading form of female infertility, characterised by menstrual disturbance and elevated follicle-stimulating hormone before age 40. It is highly heterogeneous with variants in over 80 genes potentially causative, but the majority of cases having no known cause. One gene implicated in POI pathology is TP63. TP63 encodes multiple p63 isoforms, one of which has been shown to have a role in the surveillance of genetic quality in oocytes. TP63 C-terminal truncation variants and N-terminal duplication have been described in association with POI, however, functional validation has been lacking. Here we identify three novel TP63 missense variants in women with nonsyndromic POI, including one in the N-terminal activation domain, one in the C-terminal inhibition domain, and one affecting a unique and poorly understood p63 isoform, TA*p63. Via blue-native page and luciferase reporter assays we demonstrate that two of these variants disrupt p63 dimerization, leading to constitutively active p63 tetramer that significantly increases the transcription of downstream targets. This is the first evidence that TP63 missense variants can cause isolated POI and provides mechanistic insight that TP63 variants cause POI due to constitutive p63 activation and accelerated oocyte loss in the absence of DNA damage.
Published: 2022
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3. Long-Term Safety of Growth Hormone in Adults With Growth Hormone Deficiency

Author: Gudmundur Johannsson, Philippe Touraine, Ulla Feldt-Rasmussen, Antonio Pico, Greisa Vila, Anders F Mattsson, Martin Carlsson, Márta Korbonits, André P van Beek, Michael P Wajnrajch, Roy Gomez, Kevin C J Yuen, and Center for Liver, Digestive and Metabolic Diseases (CLDM)
Subjects: Adult, safety, Adolescent, Hormone Replacement Therapy, Pituitary Diseases, Endocrinology, Diabetes and Metabolism, Clinical Biochemistry, DIAGNOSIS, PROFILE, Biochemistry, GLUCOSE, REPLACEMENT THERAPY, Endocrinology, QUALITY-OF-LIFE, CARDIOVASCULAR RISK-FACTORS, Humans, cancer, Pituitary Neoplasms, PRIMARY CANCERS, Child, Dwarfism, Pituitary, Human Growth Hormone, MORTALITY, Biochemistry (medical), HYPOPITUITARY PATIENTS, adult growth hormone deficiency, hypopituitarism, APOLIPOPROTEIN B100 KINETICS, growth hormone, KIMS
Abstract: Context Data on long-term safety of growth hormone (GH) replacement in adults with GH deficiency (GHD) are needed. Objective We aimed to evaluate the safety of GH in the full KIMS (Pfizer International Metabolic Database) cohort. Methods The worldwide, observational KIMS study included adults and adolescents with confirmed GHD. Patients were treated with GH (Genotropin [somatropin]; Pfizer, NY) and followed through routine clinical practice. Adverse events (AEs) and clinical characteristics (eg, lipid profile, glucose) were collected. Results A cohort of 15 809 GH-treated patients were analyzed (mean follow-up of 5.3 years). AEs were reported in 51.2% of patients (treatment-related in 18.8%). Crude AE rate was higher in patients who were older, had GHD due to pituitary/hypothalamic tumors, or adult-onset GHD. AE rate analysis adjusted for age, gender, etiology, and follow-up time showed no correlation with GH dose. A total of 606 deaths (3.8%) were reported (146 by neoplasms, 71 by cardiac/vascular disorders, 48 by cerebrovascular disorders). Overall, de novo cancer incidence was comparable to that in the general population (standard incidence ratio 0.92; 95% CI, 0.83-1.01). De novo cancer risk was significantly lower in patients with idiopathic/congenital GHD (0.64; 0.43-0.91), but similar in those with pituitary/hypothalamic tumors or other etiologies versus the general population. Neither adult-onset nor childhood-onset GHD was associated with increased de novo cancer risks. Neutral effects were observed in lipids/fasting blood glucose levels. Conclusion These final KIMS cohort data support the safety of long-term GH replacement in adults with GHD as prescribed in routine clinical practice.
Published: 2022
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4. Evaluation of a new transition organization for young adults with endocrine or metabolic diseases

Author: Enora Le Roux, Agathe Turpin, Morgane Michel, Isabelle Tejedor, Florence Menesguen, Sabine Malivoir, Sandrine Bottius, Hélène Mellerio, Michel Polak, and Philippe Touraine
Subjects: Male, Adolescent, Endocrinology, Diabetes and Metabolism, Transitional Care, General Medicine, Endocrine System Diseases, Young Adult, Endocrinology, Metabolic Diseases, Patient Satisfaction, Humans, Female, Lost to Follow-Up, France, Referral and Consultation
Abstract: Objective To evaluate the effect of a new care organization on multiple outcomes of transition success and its cost-effectiveness in patients with any endocrine or metabolic disease diagnosed during childhood and transferred to adult care. Design Non-randomized controlled trial in a French university hospital. Methods Patients transferred to adult care during the control period (04/2014–08/2016) and the intervention period (09/2016–06/2018) were included. The intervention is based on case management involving liaising with pediatric services, personalizing care pathways, and liaising with structures outside hospital (general practitioner, educational and social sector). The primary endpoint was the percentage of patients lost to follow-up at 24 months post transfer. Other outcomes were collected from medical files, consultation software, and questionnaires. A cost analysis was performed. Results Two hundred two patients were included (101 per period), the most represented pathologies were congenital and non-congenital hypopituitarism (respectively n = 34 (17%) and n = 45 (22%)) and thyroid diseases (n = 21, 10%). Patients were aged 22.5 in median at 24 months post transfer where 12 were lost to follow-up in the control group vs 9 with the intervention (P = 0.49). The percentage of honored consultation among those planned during 24 months was higher with intervention (P = 0.0065). Patient satisfaction, physician trust, and transfer delay did not differ between the groups. The incremental cost-effectiveness ratio was €179 per patient not lost to follow-up. Conclusions At 24 months post transfer, the rate of lost to follow-up did not differ significantly, but indicators of a steadier follow-up were increased and the intervention appeared to be cost-effective.
Published: 2022
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5. High Prevalence of Early Endocrine Disorders After Childhood Brain Tumors in a Large Cohort

Author: Laura Gabriela González Briceño, Dulanjalee Kariyawasam, Dinane Samara-Boustani, Elisa Giani, Jacques Beltrand, Stéphanie Bolle, Brice Fresneau, Stéphanie Puget, Christian Sainte-Rose, Claire Alapetite, Graziella Pinto, Marie-Liesse Piketty, Séverine Brabant, Samuel Abbou, Isabelle Aerts, Kevin Beccaria, Marie Bourgeois, Thomas Roujeau, Thomas Blauwblomme, Federico Di Rocco, Caroline Thalassinos, Christian Pauwels, Charlotte Rigaud, Syril James, Kanetee Busiah, Albane Simon, Franck Bourdeaut, Lauriane Lemelle, Léa Guerrini-Rousseau, Daniel Orbach, Philippe Touraine, François Doz, Christelle Dufour, Jacques Grill, and Michel Polak
Subjects: Adult, Male, Brain Neoplasms, Endocrinology, Diabetes and Metabolism, Biochemistry (medical), Clinical Biochemistry, Endocrine System Diseases, Biochemistry, Endocrinology, Prevalence, Humans, Female, Pituitary Neoplasms, Cerebellar Neoplasms, Child, Retrospective Studies
Abstract: Context Endocrine complications are common in pediatric brain tumor patients. Objective We aimed to describe the endocrine follow-up of patients with primary brain tumors. Methods This is a noninterventional observational study based on data collection from medical records of 221 patients followed at a Pediatric Endocrinology Department. Results Median age at diagnosis was 6.7 years (range, 0-15.9), median follow-up 6.7 years (0.3-26.6), 48.9% female. Main tumor types were medulloblastoma (37.6%), craniopharyngioma (29.0%), and glioma (20.4%). By anatomic location, 48% were suprasellar (SS) and 52% non-suprasellar (NSS). Growth hormone deficiency (GHD) prevalence was similar in both groups (SS: 83.0%, NSS: 76.5%; P = 0.338), appearing at median 1.8 years (−0.8 to 12.4) after diagnosis; postradiotherapy GHD appeared median 1.6 years after radiotherapy (0.2-10.7). Hypothyroidism was more prevalent in SS (76.4%), than NSS (33.9%) (P < 0.001), as well as ACTH deficiency (SS: 69.8%, NSS: 6.1%; P < 0.001). Early puberty was similar in SS (16%) and NSS (12.2%). Hypogonadotropic hypogonadism was predominant in SS (63.1%) vs NSS (1.3%), P < 0.001, and postchemotherapy gonadal toxicity in NSS (29.6%) vs SS (2.8%), P < 0.001. Adult height was lower for NSS compared to target height (−1.0 SD, P < 0.0001) and to SS patients (P < 0.0001). Thyroid nodules were found in 13/45 patients (28.8%), including 4 cancers (4.8-11.5 years after radiotherapy). Last follow-up visit BMI was higher in both groups (P = 0.0001), and obesity incidence was higher for SS (46.2%) than NSS (17.4%). Conclusion We found a high incidence of early-onset endocrine disorders. An endocrine consultation and nutritional evaluation should be mandatory for all patients with a brain tumor, especially when the tumor is suprasellar or after hypothalamus/pituitary irradiation.
Published: 2021
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6. 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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7. Sperm cryopreservation in young males with congenital adrenal hyperplasia (CAH)

Author: Taous Chougar, Moussa Laanani, Lucile Ferreux, Céline Chalas, Jean‐Philippe Wolf, Jérôme Bertherat, Claire Bouvattier, Michel Polak, Anne Bachelot, Jérôme Dulon, Philippe Touraine, Catherine Patrat, and Véronique Drouineaud
Subjects: Male, Cryopreservation, Endocrinology, Adrenal Hyperplasia, Congenital, Testicular Neoplasms, Semen, Endocrinology, Diabetes and Metabolism, Humans, Adrenal Rest Tumor, Spermatozoa
Published: 2022
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8. Treatment patterns and unmet needs in adults with classic congenital adrenal hyperplasia: A modified Delphi consensus study

Author: Richard J, Auchus, Carine, Courtillot, Adrian, Dobs, Diala, El-Maouche, Henrik, Falhammar, Andre, Lacroix, Mallory, Farrar, Conor, O'Donoghue, Milena, Anatchkova, Katelyn, Cutts, Natalie, Taylor, Chuck, Yonan, Mark, Lamotte, and Philippe, Touraine
Subjects: Adult, Consensus, Adrenal Hyperplasia, Congenital, Hydrocortisone, Delphi Technique, Endocrinology, Diabetes and Metabolism, Androgens, Humans
Abstract: BackgroundClassic congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency is a rare autosomal recessive condition characterized by cortisol deficiency and excess androgen production. The current standard of care is glucocorticoid (GC) therapy, and sometimes mineralocorticoids, to replace endogenous cortisol deficiency; however, supraphysiologic GC doses are usually needed to reduce excess androgen production. Monitoring/titrating GC treatment remains a major challenge, and there is no agreement on assessment of treatment adequacy. This study surveyed expert opinions on current treatment practices and unmet needs in adults with classic CAH.MethodsA modified two-round Delphi process with adult endocrinologists was conducted via online questionnaire. Survey questions were organized into three categories: practice characteristics/CAH experience, GC management, and unmet needs/complications. Anonymized aggregate data from Round 1 were provided as feedback for Round 2. Responses from both rounds were analyzed using descriptive statistics. Consensus was defined a priori as: full consensus (100%, n=9/9); near consensus (78% to ResultsThe same nine panelists participated in both survey rounds; five (56%) were based in North America and four (44%) in Europe. Most panelists (78%) used hydrocortisone in the majority of patients, but two (22%) preferred prednisone/prednisolone. Panelists agreed (89%) that adequate control is best evaluated using a balance of clinical presentation and androgen/precursor laboratory values; no consensus was reached on optimal timing of collecting samples for androgen testing or laboratory values indicating good control. Despite lack of consensus on many aspects of CAH management, panelists agreed on the importance of many disease- and GC-related complications, and that there is a large unmet need for new treatments. With currently available treatments, panelists reported that 46% of classic CAH patients did not have optimized androgen levels, regardless of GC dose.ConclusionsThe limited areas of consensus obtained in this study reflect the variability in treatment practices for adults with classic CAH, even among clinicians with expertise in treating this population. However, all panelists agreed on the need for new treatments for classic CAH and the importance of many disease- and GC-related complications, which are difficult to manage with currently available treatments.
Published: 2022
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9. Effects of mitotane on testicular adrenal rest tumors in congenital adrenal hyperplasia due to 21-hydroxylase deficiency: a retrospective series of five patients

Author: Philippe Touraine, Raphaele Renard Penna, Monique Leban, Jérôme Dulon, Anne Bachelot, Marion Lapoirie, 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), Hospices Civils de Lyon (HCL), 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), Service d’Endocrinologie, Métabolisme et Prévention des Risques Cardio-Vasculaires [CHU Pitié-Salpêtrière], Service de Radiologie [CHU Pitié-Salpétrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Service d’endocrinologie et médecine de la reproduction [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)-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), 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, Métabolisme et Prévention des Maladies Cardio-vasculaires [CHU Pitié-Salpêtrière], 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], and Gestionnaire, HAL Sorbonne Université 5
Subjects: Adult, Male, mitotane, endocrine system, medicine.medical_specialty, Antineoplastic Agents, Hormonal, endocrine system diseases, Endocrinology, Diabetes and Metabolism, Urology, 030209 endocrinology & metabolism, Semen, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Endocrinology, Congenital adrenal hyperplasia due to 21-hydroxylase deficiency, Testicular Neoplasms, Internal medicine, medicine, Adrenal Rest Tumor, Humans, congenital adrenal hyperplasia, Endocrine system, Mitotane, Congenital adrenal hyperplasia, Young adult, Retrospective Studies, [SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, fertility, Azoospermia, Adrenal Hyperplasia, Congenital, 21-OH deficiency, business.industry, Retrospective cohort study, General Medicine, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, medicine.disease, 3. Good health, Treatment Outcome, adrenal rest tumors, sperm analysis, 030220 oncology & carcinogenesis, business, medicine.drug
Abstract: We conducted a retrospective study on the long-term effect of mitotane treatment on testicular adrenal rest tumors (TARTs) in five adult patients with classic 21-hydroxylase deficiency. After 60 months of mitotane treatment, a decrease in adrenal steroids was observed in four patients. Testicular ultrasonography showed complete disappearance of TART in two patients, stabilization in two patients and a halving of TART volume in the remaining patient. Sperm count improved notably in two patients who had normal baseline inhibin B levels and small inclusions, thus enabling cryopreservation of the subjects’ semen. Four years of follow-up of these two patients after the withdrawal of mitotane showed no recurrence of TART and persistent normal testicular function. In conclusion, mitotane could be used as a last resort in CAH patients in the cases of azoospermia associated with TARTs but normal inhibin B levels, as it can improve long-term endocrine and exocrine testicular function.
Published: 2021
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10. Safety of growth hormone replacement in survivors of cancer and intracranial and pituitary tumours: a consensus statement

Author: Margaret C S Boguszewski, Cesar L Boguszewski, Wassim Chemaitilly, Laurie E Cohen, Judith Gebauer, Claire Higham, Andrew R Hoffman, Michel Polak, Kevin C J Yuen, Nathalie Alos, Zoltan Antal, Martin Bidlingmaier, Beverley M K Biller, George Brabant, Catherine S Y Choong, Stefano Cianfarani, Peter E Clayton, Regis Coutant, Adriane A Cardoso-Demartini, Alberto Fernandez, Adda Grimberg, Kolbeinn Guðmundsson, Jaime Guevara-Aguirre, Ken K Y Ho, Reiko Horikawa, Andrea M Isidori, Jens Otto Lunde Jørgensen, Peter Kamenicky, Niki Karavitaki, John J Kopchick, Maya Lodish, Xiaoping Luo, Ann I McCormack, Lillian Meacham, Shlomo Melmed, Sogol Mostoufi Moab, Hermann L Müller, Sebastian J C M M Neggers, Manoel H Aguiar Oliveira, Keiichi Ozono, Patricia A Pennisi, Vera Popovic, Sally Radovick, Lars Savendahl, Philippe Touraine, Hanneke M van Santen, Gudmundur Johannsson, and Internal Medicine
Subjects: Adult, Human Growth Hormone, Endocrinology, Diabetes and Metabolism, General Medicine, Settore MED/38, Endocrinology, SDG 3 - Good Health and Well-being, Growth Hormone, Humans, Pituitary Neoplasms, Survivors, Insulin-Like Growth Factor I, Neoplasm Recurrence, Local, Child, General Economics, Econometrics and Finance
Abstract: Growth hormone (GH) has been used for over 35 years, and its safety and efficacy has been studied extensively. Experimental studies showing the permissive role of GH/insulin-like growth factor 1 (IGF-I) in carcinogenesis have raised concerns regarding the safety of GH replacement in children and adults who have received treatment for cancer and those with intracranial and pituitary tumours. A consensus statement was produced to guide decision-making on GH replacement in children and adult survivors of cancer, in those treated for intracranial and pituitary tumours and in patients with increased cancer risk. With the support of the European Society of Endocrinology, the Growth Hormone Research Society convened a Workshop, where 55 international key opinion leaders representing 10 professional societies were invited to participate. This consensus statement utilized: (1) a critical review paper produced before the Workshop, (2) five plenary talks, (3) evidence-based comments from four breakout groups, and (4) discussions during report-back sessions. Current evidence reviewed from the proceedings from the Workshop does not support an association between GH replacement and primary tumour or cancer recurrence. The effect of GH replacement on secondary neoplasia risk is minor compared to host- and tumour treatment-related factors. There is no evidence for an association between GH replacement and increased mortality from cancer amongst GH-deficient childhood cancer survivors. Patients with pituitary tumour or craniopharyngioma remnants receiving GH replacement do not need to be treated or monitored differently than those not receiving GH. GH replacement might be considered in GH-deficient adult cancer survivors in remission after careful individual risk/benefit analysis. In children with cancer predisposition syndromes, GH treatment is generally contraindicated but may be considered cautiously in select patients.
Published: 2022
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11. 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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12. Turner syndrome: French National Diagnosis and Care Protocol (NDCP; National Diagnosis and Care Protocol)

Author: Elodie Fiot, Bertille Alauze, Bruno Donadille, Dinane Samara-Boustani, Muriel Houang, Gianpaolo De Filippo, Anne Bachelot, Clemence Delcour, Constance Beyler, Emilie Bois, Emmanuelle Bourrat, Emmanuel Bui Quoc, Nathalie Bourcigaux, Catherine Chaussain, Ariel Cohen, Martine Cohen-Solal, Sabrina Da Costa, Claire Dossier, Stephane Ederhy, Monique Elmaleh, Laurence Iserin, Hélène Lengliné, Armelle Poujol-Robert, Dominique Roulot, Jerome Viala, Frederique Albarel, Elise Bismuth, Valérie Bernard, Claire Bouvattier, Aude Brac, Patricia Bretones, Nathalie Chabbert-Buffet, Philippe Chanson, Regis Coutant, Marguerite de Warren, Béatrice Demaret, Lise Duranteau, Florence Eustache, Lydie Gautheret, Georges Gelwane, Claire Gourbesville, Mickaël Grynberg, Karinne Gueniche, Carina Jorgensen, Veronique Kerlan, Charlotte Lebrun, Christine Lefevre, Françoise Lorenzini, Sylvie Manouvrier, Catherine Pienkowski, Rachel Reynaud, Yves Reznik, Jean-Pierre Siffroi, Anne-Claude Tabet, Maithé Tauber, Vanessa Vautier, Igor Tauveron, Sebastien Wambre, Delphine Zenaty, Irène Netchine, Michel Polak, Philippe Touraine, Jean-Claude Carel, Sophie Christin-Maitre, Juliane Léger, 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 Cité (UPCité), Maladies neurodéveloppementales et neurovasculaires (NeuroDiderot (UMR_S_1141 / U1141)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), 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), CHU Trousseau [APHP], CHU Pitié-Salpêtrière [AP-HP], Département d'obstétrique et de gynécologie [Hôpital Robert Debré], Université Paris Diderot - Paris 7 (UPD7)-AP-HP Hôpital universitaire Robert-Debré [Paris], AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHU Charles Foix [AP-HP], Service de Rhumatologie [CHU Lariboisière], Hôpital Lariboisière-Fernand-Widal [APHP], Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Hôpital Avicenne [AP-HP], Service d'endocrinologie, diabète, maladies métaboliques [Hôpital de la Conception - APHM], Aix Marseille Université (AMU), CHU de Bordeaux Pellegrin [Bordeaux], AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Hospices Civils de Lyon (HCL), CHU Tenon [AP-HP], Endocrinologie pédiatrique[CHU Angers], Université d'Angers (UA)-Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Hôpital Jean Verdier [AP-HP], 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), AP-HP - Hôpital Antoine Béclère [Clamart], Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Hôpital Jeanne de Flandre [Lille], Service de pédiatrie multidisciplinaire [Hôpital de la Timone Enfants - APHM], Hôpital de la Timone [CHU - APHM] (TIMONE), CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN), 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), Département de génétique [Robert Debré], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP Hôpital universitaire Robert-Debré [Paris], CHU Clermont-Ferrand, 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), and Ministère de la Santé
Subjects: Adult, Chromosomes, Human, X, Karyotype, Turner’s syndrome, Turner Syndrome, General Medicine, Recommendation, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, Adulthood, Childhood, Management, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Diabetes Mellitus, Type 2, Karyotyping, Diagnosis, Humans, Pharmacology (medical), Female, Genetics (clinical)
Abstract: Turner syndrome (TS; ORPHA 881) is a rare condition in which all or part of one X chromosome is absent from some or all cells. It affects approximately one in every 1/2500 liveborn girls. The most frequently observed karyotypes are 45,X (40–50%) and the 45,X/46,XX mosaic karyotype (15–25%). Karyotypes with an X isochromosome (45,X/46,isoXq or 45,X/46,isoXp), a Y chromosome, X ring chromosome or deletions of the X chromosome are less frequent. The objective of the French National Diagnosis and Care Protocol (PNDS; Protocole National de Diagnostic et de Soins) is to provide health professionals with information about the optimal management and care for patients, based on a critical literature review and multidisciplinary expert consensus. The PNDS, written by members of the French National Reference Center for Rare Growth and Developmental Endocrine disorders, is available from the French Health Authority website. Turner Syndrome is associated with several phenotypic conditions and a higher risk of comorbidity. The most frequently reported features are growth retardation with short adult stature and gonadal dysgenesis. TS may be associated with various congenital (heart and kidney) or acquired diseases (autoimmune thyroid disease, celiac disease, hearing loss, overweight/obesity, glucose intolerance/type 2 diabetes, dyslipidemia, cardiovascular complications and liver dysfunction). Most of the clinical traits of TS are due to the haploinsufficiency of various genes on the X chromosome, particularly those in the pseudoautosomal regions (PAR 1 and PAR 2), which normally escape the physiological process of X inactivation, although other regions may also be implicated. The management of patients with TS requires collaboration between several healthcare providers. The attending physician, in collaboration with the national care network, will ensure that the patient receives optimal care through regular follow-up and screening. The various elements of this PNDS are designed to provide such support.
Published: 2022
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13. Congenital adrenal hyperplasia - current insights in pathophysiology, diagnostics and management

Author: Nicole Reisch, Walter L. Miller, Wiebke Arlt, Angela Huebner, Stefan A. Wudy, Phyllis W. Speiser, Nike M. M. L. Stikkelbroeck, Richard J. Auchus, Hedi L Claahsen-van der Grinten, Anna Nordenström, Deborah P. Merke, Perrin C. White, Nils Krone, S Faisal Ahmed, Henrik Falhammar, Barbara B.M. Kortmann, Christa E. Flück, David E. Sandberg, Agustini Utari, Leonardo Guasti, and Philippe Touraine
Subjects: Hydrocortisone, medicine.drug_class, Endocrinology, Diabetes and Metabolism, Review, Disease, Steroid biosynthesis, Bioinformatics, chemistry.chemical_compound, Neonatal Screening, Endocrinology, medicine, Humans, Endocrine system, Congenital adrenal hyperplasia, Aldosterone, Adrenal Hyperplasia, Congenital, Adrenal cortex, business.industry, Infant, Newborn, Vascular damage Radboud Institute for Molecular Life Sciences [Radboudumc 16], medicine.disease, medicine.anatomical_structure, Reconstructive and regenerative medicine Radboud Institute for Molecular Life Sciences [Radboudumc 10], chemistry, Mineralocorticoid, Mutation, Steroid 21-Hydroxylase, business, Glucocorticoid, medicine.drug
Abstract: Contains fulltext : 244176.pdf (Publisher’s version ) (Closed access) Congenital adrenal hyperplasia (CAH) is a group of autosomal recessive disorders affecting cortisol biosynthesis. Reduced activity of an enzyme required for cortisol production leads to chronic overstimulation of the adrenal cortex and accumulation of precursors proximal to the blocked enzymatic step. The most common form of CAH is caused by steroid 21- hydroxylase deficiency due to mutations in CYP21A2. Since the last publication summarizing CAH in Endocrine Reviews in 2000 there have been numerous new developments. These include more detailed understanding of steroidogenic pathways, refinements in neonatal screening, improved diagnostic measurements utilizing chromatography and mass spectrometry coupled with steroid profiling, and improved genotyping methods. Clinical trials of alternative medications and modes of delivery have been recently completed or are under way. Genetic and cell-based treatments are being explored. A large body of data concerning long-term outcomes in patients affected by CAH, including psychosexual well-being, has been enhanced by the establishment of disease registries. This review provides the reader with current insights in congenital adrenal hyperplasia with special attention to these new developments.
Published: 2022

14. Hormones and fertility

Author: Agnès Linglart, Sophie Christin-Maitre, Dominique Maiter, and Philippe Touraine
Subjects: Fertility, Endocrinology, Research Design, Endocrinology, Diabetes and Metabolism, Humans, General Medicine, Hormones
Published: 2022
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15. Impact of cancer chemotherapy before ovarian cortex cryopreservation on ovarian tissue transplantation

Author: Thierry Leblanc, S Egels, Catherine Genestie, Pauline Brice, Jean Gabarre, Jean-Marc Lacorte, Céline Chalas, Sebastien Gouy, Nathalie Dhedin, Véronique Drouineaud, Gilles Lefebvre, Yasmina Badachi, Jean-Paul Akakpo, G Lebègue, Frédérique Capron, Nicolas Boissel, Catherine Poirot, Alain Delmer, Jean-Philippe Wolf, Anne Fortin, Jean-Paul Vernant, Philippe Touraine, Philippe Morice, and M Dommergues
Subjects: Adult, Oncology, medicine.medical_specialty, Time Factors, Adolescent, Ovarian Cortex, medicine.medical_treatment, Ovary, Transplantation, Autologous, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Cancer Survivors, Pregnancy, Neoplasms, Internal medicine, Follicular phase, medicine, Humans, Cumulative incidence, Ovarian tissue cryopreservation, Autografts, Birth Rate, Antineoplastic Agents, Alkylating, Cryopreservation, Chemotherapy, 030219 obstetrics & reproductive medicine, business.industry, Graft Survival, Rehabilitation, Fertility Preservation, Obstetrics and Gynecology, Recovery of Function, Chemotherapy regimen, Menstruation, Transplantation, Treatment Outcome, medicine.anatomical_structure, Reproductive Medicine, Female, business, Live Birth
Abstract: STUDY QUESTION How efficacious is transplantation of ovarian cortex previously exposed to chemotherapy? SUMMARY ANSWER Prior exposure to chemotherapy did not disrupt the function of cryopreserved ovarian tissue after transplantation. WHAT IS KNOWN ALREADY Ovarian tissue cryopreservation (OTC) followed by ovarian tissue transplantation (OTT) is an efficacious technique for restoration of female fertility. At least 130 children have been born following this procedure. To date, little is known about the efficacy of OTT in patients exposed to cancer chemotherapy prior to OTC. STUDY DESIGN, SIZE, DURATION This study evaluates the recovery of ovarian function and fertility in 31 consecutive patients who had received OTT, between 2005 and 2015. PARTICIPANTS/MATERIALS, SETTING, METHODS Thirty one patients, wanting children, were transplanted with autologous ovarian cortex, among which 22 patients (71%) had been exposed to chemotherapy before OTC. Recovery of ovarian function was considered total once menstruation occurred. Ovarian function recovery (OFR), ovarian graft survival, and incidence of pregnancy were related to previous chemotherapy exposure, type of chemotherapy and graft characteristics (number of grafted fragments and follicular density). MAIN RESULTS AND ROLE OF CHANCE The amount of ovarian tissue collected was the only parameter to show any significant change between patients with versus without previous chemotherapy. At 1 year after OTT, the cumulative incidence of OFR was 83% (93% in patients exposed to chemotherapy and 67% in others (P = 0.14)). A low follicular density (
Published: 2019
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16. Causal and Candidate Gene Variants in a Large Cohort of Women with Primary Ovarian Insufficiency

Author: Lawrence M. Nelson, Mika Moriwaki, Corrine K. Welt, Elaine R. Mardis, Clement Y. Chow, Amber R. Cooper, Elaine Taylor, Bushra Gorsi, Aleksander Rajkovic, Marvin B Moore, Philippe Touraine, Claire Lu, Edgar Javier Hernandez, Mark Yandell, Emily Coelho, and Amanda Walker
Subjects: Adult, medicine.medical_specialty, Heterozygote, Candidate gene, Adolescent, Endocrinology, Diabetes and Metabolism, Clinical Biochemistry, Primary ovarian insufficiency, DNA Mutational Analysis, Context (language use), Primary Ovarian Insufficiency, Biology, Biochemistry, Young Adult, Endocrinology, Transcription (biology), Internal medicine, Exome Sequencing, medicine, Humans, 1000 Genomes Project, Gene, Exome, Exome sequencing, Whole genome sequencing, Genetics, Clinical Research Article, Biochemistry (medical), Genetic architecture, Large cohort, WDR33, Case-Control Studies, Mutation, Female
Abstract: Context A genetic etiology likely accounts for the majority of unexplained primary ovarian insufficiency (POI). Objective We hypothesized that heterozygous rare variants and variants in enhanced categories are associated with POI. Design The study was an observational study. Setting Subjects were recruited at academic institutions. Patients Subjects from Boston (n = 98), the National Institutes of Health and Washington University (n = 98), Pittsburgh (n = 20), Italy (n = 43), and France (n = 32) were diagnosed with POI (amenorrhea with an elevated follicle-stimulating hormone level). Controls were recruited for health in old age or were from the 1000 Genomes Project (total n = 233). Intervention We performed whole exome sequencing (WES), and data were analyzed using a rare variant scoring method and a Bayes factor-based framework for identifying genes harboring pathogenic variants. We performed functional studies on identified genes that were not previously implicated in POI in a D. melanogaster model. Main Outcome Genes with rare pathogenic variants and gene sets with increased burden of deleterious variants were identified. Results Candidate heterozygous variants were identified in known genes and genes with functional evidence. Gene sets with increased burden of deleterious alleles included the categories transcription and translation, DNA damage and repair, meiosis and cell division. Variants were found in novel genes from the enhanced categories. Functional evidence supported 7 new risk genes for POI (USP36, VCP, WDR33, PIWIL3, NPM2, LLGL1, and BOD1L1). Conclusions Candidate causative variants were identified through WES in women with POI. Aggregating clinical data and genetic risk with a categorical approach may expand the genetic architecture of heterozygous rare gene variants causing risk for POI.
Published: 2021
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17. Whole exome sequencing reveals copy number variants in individuals with disorders of sex development

Author: Rajini Sreenivasan, Katrina Bell, Jocelyn van den Bergen, Gorjana Robevska, Daniele Belluoccio, Rachana Dahiya, Gary M. Leong, Jérôme Dulon, Philippe Touraine, Elena J. Tucker, Katie Ayers, and Andrew Sinclair
Subjects: Male, Comparative Genomic Hybridization, Endocrinology, DNA Copy Number Variations, Exome Sequencing, High-Throughput Nucleotide Sequencing, Humans, Exome, Female, Androgen-Insensitivity Syndrome, Molecular Biology, Biochemistry
Abstract: Complete androgen insensitivity syndrome (CAIS), where 46,XY individuals present as female, is caused by variants in the androgen receptor gene (AR). We analyzed the DNA of a patient with suspected CAIS using a targeted gene sequencing panel and whole exome sequencing (WES) but did not detect any small nucleotide variants in AR. Analysis of WES data using our bioinformatics pipeline designed to detect copy number variations (CNV) uncovered a rare duplication of exon 2 of AR. Using array comparative genomic hybridization, the duplication was found to span 43.6 kb and is predicted to cause a frameshift and loss of AR protein. We confirmed the power of our WES-CNV detection protocol by identifying pathogenic CNVs in FSHR and NR5A1 in previously undiagnosed patients with disorders of sex development. Our findings illustrate the usefulness of CNV analysis in WES data to detect pathogenic genomic changes that may go undetected using only standard analysis protocols.
Published: 2021

18. A recessive variant in TFAM causes mtDNA depletion associated with primary ovarian insufficiency, seizures, intellectual disability and hearing loss

Author: Farid, Ullah, Waqar, Rauf, Kamal, Khan, Sheraz, Khan, Katrina M, Bell, Vanessa Cristina, de Oliveira, Muhammad, Tariq, Shabnam, Bakhshalizadeh, Philippe, Touraine, Nicholas, Katsanis, Andrew, Sinclair, Sijie, He, Elena J, Tucker, Shahid M, Baig, and Erica E, Davis
Subjects: Male, Genes, Recessive, Primary Ovarian Insufficiency, DNA, Mitochondrial, Pedigree, DNA-Binding Proteins, Mitochondrial Proteins, Seizures, Intellectual Disability, Animals, Humans, Female, Gonads, Hearing Loss, Cells, Cultured, Zebrafish, Transcription Factors
Abstract: Mitochondrial disorders are collectively common, genetically heterogeneous disorders in both pediatric and adult populations. They are caused by molecular defects in oxidative phosphorylation, failure of essential bioenergetic supply to mitochondria, and apoptosis. Here, we present three affected individuals from a consanguineous family of Pakistani origin with variable seizures and intellectual disability. Both females display primary ovarian insufficiency (POI), while the male shows abnormal sex hormone levels. We performed whole exome sequencing and identified a recessive missense variant c.694C T, p.Arg232Cys in TFAM that segregates with disease. TFAM (mitochondrial transcription factor A) is a component of the mitochondrial replisome machinery that maintains mtDNA transcription and replication. In primary dermal fibroblasts, we show depletion of mtDNA and significantly altered mitochondrial function and morphology. Moreover, we observed reduced nucleoid numbers with significant changes in nucleoid size or shape in fibroblasts from an affected individual compared to controls. We also investigated the effect of tfam impairment in zebrafish; homozygous tfam mutants carrying an in-frame c.141_149 deletion recapitulate the mtDNA depletion and ovarian dysgenesis phenotypes observed in affected humans. Together, our genetic and functional data confirm that TFAM plays a pivotal role in gonad development and expands the repertoire of mitochondrial disease phenotypes.
Published: 2021

19. Genetic testing in inherited endocrine disorders: joint position paper of the European reference network on rare endocrine conditions (Endo-ERN)

Author: Eggermann T., Elbracht M., Kurth I., Juul A., Johannsen T. H., Netchine I., Mastorakos G., Johannsson G., Musholt T. J., Zenker M., Prawitt D., Pereira A. M., Hiort O., Stefan Riedl, Birgit Rami-Merhar, Greisa Vila, Sabina Baumgartner-Parzner, Walter Bonfig, Claudine Heinrichs, Dominique Maiter, Inge Gies, Martine Cools, Kristina Casteels, Albert Beckers, Sabina Zacharieva, Violeta Iotova, Tomislav Jukic, Dario Rahelic, Vassos Neocleous, Leonidas Phylactou, Michal Krsek, Jan Lebl, Claus Gravholt, Anders Juul, Vallo Tillmann, Vallo Volke, Tapani Ebeling, Thierry Brue, Patrice Rodien, Jérôme Bertherat, Christine Poitou Bernert, Philippe Touraine, Philippe Chanson, Michel Polak, Maithe Tauber, Thomas Eggermann, Joachim Spranger, Dagmar Fuhrer, Thomas Danne, Olaf Hiort, Klaus Mohnike, Dirk Prawitt, Markus Luster, Nicole Reisch, Martin Reincke, Julia Rohayem, Martin Fassnacht, Miklós Tóth, Alessandra Cassio, Sonia Toni, Csilla Krausz, Barbara Piccini, Diego Ferone, Gianni Russo, Luca Persani, Annamaria Colao, Mariacarolina Salerno, Marco Boscaro, Carla Scaroni, Ferruccio Santini, Giovanni Ceccarini, Ezio Ghigo, Iveta Dzivite-Krisane, Vita Rovite, Lauma Janozola, Rasa Verkauskiene, Michael Witsch, James Clark, Johannes Romijn, Thera Links, Nienke Biermasz, Sabine Hannema, Bas Havekes, Hedi Claahsen-van der Grinten, Henri Timmers, Robin Peeters, Gerlof Valk, A A Verrijn Stuart, Harm Haak, Eystein Husebye, Jens Bollerslev, Barbara Jarzab, Agnieszka 'Szypowska, João-Filipe Raposo, Dana Craiu, Doina Piciu, Ludmila Kostalova, Jarmila Vojtková, Tadej Battelino, Roque Cardona-Hernandez, Diego Yeste, Sonia Gaztambide, Anna Nordenström, Neil Gittoes, Trevor Cole, Elizabeth Crowne, Faisal Ahmed, Mohammed Didi, Marta Korbonits, Mehul Dattani, Peter Clayton, Justin Davies, Eggermann, T., Elbracht, M., Kurth, I., Juul, A., Johannsen, T. H., Netchine, I., Mastorakos, G., Johannsson, G., Musholt, T. J., Zenker, M., Prawitt, D., Pereira, A. M., Hiort, O, Salerno, M, Clinical sciences, Growth and Development, Pediatrics, Eggermann T., Elbracht M., Kurth I., Juul A., Johannsen T.H., Netchine I., Mastorakos G., Johannsson G., Musholt T.J., Zenker M., Prawitt D., Pereira A.M., and Hiort O., Stefan Riedl, Birgit Rami-Merhar, Greisa Vila, Sabina Baumgartner-Parzner, Walter Bonfig, Claudine Heinrichs, Dominique Maiter, Inge Gies, Martine Cools, Kristina Casteels, Albert Beckers, Sabina Zacharieva, Violeta Iotova, Tomislav Jukic, Dario Rahelic, Vassos Neocleous, Leonidas Phylactou, Michal Krsek, Jan Lebl, Claus Gravholt, Anders Juul, Vallo Tillmann, Vallo Volke, Tapani Ebeling, Thierry Brue, Patrice Rodien, Jérôme Bertherat, Christine Poitou Bernert, Philippe Touraine, Philippe Chanson, Michel Polak, Maithe Tauber, Thomas Eggermann, Joachim Spranger, Dagmar Fuhrer, Thomas Danne, Olaf Hiort, Klaus Mohnike, Dirk Prawitt, Markus Luster, Nicole Reisch, Martin Reincke, Julia Rohayem, Martin Fassnacht, Miklós Tóth, Alessandra Cassio, Sonia Toni, Csilla Krausz, Barbara Piccini, Diego Ferone, Gianni Russo, Luca Persani, Annamaria Colao, Mariacarolina Salerno, Marco Boscaro, Carla Scaroni, Ferruccio Santini, Giovanni Ceccarini, Ezio Ghigo, Iveta Dzivite-Krisane, Vita Rovite, Lauma Janozola, Rasa Verkauskiene, Michael Witsch, James Clark, Johannes Romijn, Thera Links, Nienke Biermasz, Sabine Hannema, Bas Havekes, Hedi Claahsen-van der Grinten, Henri Timmers, Robin Peeters, Gerlof Valk, A A Verrijn Stuart, Harm Haak, Eystein Husebye, Jens Bollerslev, Barbara Jarzab, Agnieszka 'Szypowska, João-Filipe Raposo, Dana Craiu, Doina Piciu, Ludmila Kostalova, Jarmila Vojtková, Tadej Battelino, Roque Cardona-Hernandez, Diego Yeste, Sonia Gaztambide, Anna Nordenström, Neil Gittoes, Trevor Cole, Elizabeth Crowne, Faisal Ahmed, Mohammed Didi, Marta Korbonits, Mehul Dattani, Peter Clayton, Justin Davies
Subjects: 0301 basic medicine, Genetic testing, disorders of sex development, PREDICTION, lcsh:Medicine, CHILDREN, Review, VARIANTS, Hypogonadotropic hypogonadism, Imprinting disorder, 0302 clinical medicine, Pharmacology (medical), Genetics (clinical), Imprinting disorders, Rare endocrine conditions, Short stature - glucose and insulin homeostasis - Hypogonadotropic hypogonadism - differences/disorders of sex development, Medicine(all), RISK, medicine.diagnostic_test, CHALLENGES, differences, High-Throughput Nucleotide Sequencing, General Medicine, genetic testing, Imprinting disorders, Rare endocrine conditions, Short stature, glucose and insulin homeostasis, Hypogonadotropic hypogonadism, disorders of sex development, Mutation (genetic algorithm), Rare endocrine condition, Identification (biology), Genetic counseling, 030209 endocrinology & metabolism, Computational biology, DIAGNOSIS, Endocrine System Diseases, differences/disorders of sex development, 03 medical and health sciences, Rare Diseases, BECKWITH-WIEDEMANN SYNDROME, medicine, MANAGEMENT, Endocrine system, Humans, business.industry, Network on, lcsh:R, glucose and insulin homeostasis, Human genetics, Short stature, 030104 developmental biology, Mutation, Position paper, business, Short stature - glucose and insulin homeostasis
Abstract: Orphanet journal of rare diseases: OJRD 15(1), 144 (2020). doi:10.1186/s13023-020-01420-w, Published by BioMed Central, London
Published: 2020
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20. Modified-Release Hydrocortisone in Congenital Adrenal Hyperplasia

Author: Alessandro Prete, F. Peter Treasure, Nicole Reisch, Wiebke Arlt, John Porter, Aude Brac de la Perriere, Colin Perry, Angelica Lindén Hirschberg, Richard J. Ross, Ashwini Mallappa, Philippe Touraine, Deborah P. Merke, Anders Juul, Nike M. M. L. Stikkelbroeck, Kerry Maltby, D. Aled Rees, John Newell-Price, National Institutes of Health [Bethesda] (NIH), Queens Elizabeth Hospital [Birmingham], University of Birmingham [Birmingham], Hospices Civils de Lyon (HCL), Karolinska University Hospital [Stockholm], Rigshospitalet [Copenhagen], Copenhagen University Hospital, University of Sheffield [Sheffield], Queen Elizabeth University Hospital (Glasgow), Cardiff University, University-Hospital Munich-Großhadern [München], Radboud University Medical Centre [Nijmegen, The Netherlands], 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), Diurnal Ltd, and University of Cambridge [UK] (CAM)
Subjects: Male, Endocrinology, Diabetes and Metabolism, Clinical Biochemistry, Anti-Inflammatory Agents, Phases of clinical research, Biochemistry, Gastroenterology, 0302 clinical medicine, Endocrinology, 030212 general & internal medicine, Vascular damage Radboud Institute for Molecular Life Sciences [Radboudumc 16], Middle Aged, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, Prognosis, 3. Good health, Tolerability, Female, adrenal insufficiency, Glucocorticoid, AcademicSubjects/MED00250, medicine.drug, Cortisol secretion, Adult, medicine.medical_specialty, 030209 endocrinology & metabolism, Context (language use), 21-hydroxylase deficiency, 03 medical and health sciences, Young Adult, All institutes and research themes of the Radboud University Medical Center, Internal medicine, Adrenal insufficiency, medicine, congenital adrenal hyperplasia, Humans, Congenital adrenal hyperplasia, hydrocortisone, Online Only Articles, Clinical Research Articles, Aged, Hydrocortisone, Adrenal Hyperplasia, Congenital, business.industry, Biochemistry (medical), medicine.disease, glucocorticoid, business, Follow-Up Studies
Abstract: Context Standard glucocorticoid therapy in congenital adrenal hyperplasia (CAH) regularly fails to control androgen excess, causing glucocorticoid overexposure and poor health outcomes. Objective We investigated whether modified-release hydrocortisone (MR-HC), which mimics physiologic cortisol secretion, could improve disease control. Methods A 6-month, randomized, phase 3 study was conducted of MR-HC vs standard glucocorticoid, followed by a single-arm MR-HC extension study. Primary outcomes were change in 24-hour SD score (SDS) of androgen precursor 17-hydroxyprogesterone (17OHP) for phase 3, and efficacy, safety and tolerability of MR-HC for the extension study. Results The phase 3 study recruited 122 adult CAH patients. Although the study failed its primary outcome at 6 months, there was evidence of better biochemical control on MR-HC, with lower 17OHP SDS at 4 (P = .007) and 12 (P = .019) weeks, and between 07:00h to 15:00h (P = .044) at 6 months. The percentage of patients with controlled 09:00h serum 17OHP ( Conclusion MR-HC improved biochemical disease control in adults with reduction in steroid dose over time and patient-reported benefit.
Published: 2021
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21. 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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22. Travelling in time and space in the heart of Paris

Author: Philippe Chanson, Olivier Chabre, Marie-Christine Vantyghem, Michel Azizi, Philippe Touraine, Patrice Rodien, and Joe-Elie Salem
Subjects: Paris, Endocrinology, History, Spacetime, Heart Diseases, Endocrinology, Diabetes and Metabolism, Calculus, MEDLINE, Humans, General Medicine, Endocrine System Diseases
Published: 2020

23. Long-term outcomes of lentiviral gene therapy for the β-hemoglobinopathies: the HGB-205 trial

Author: Elisa Magrin, Michaela Semeraro, Nicolas Hebert, Laure Joseph, Alessandra Magnani, Anne Chalumeau, Aurélie Gabrion, Cécile Roudaut, Jouda Marouene, Francois Lefrere, Jean-Sebastien Diana, Adeline Denis, Bénédicte Neven, Isabelle Funck-Brentano, Olivier Negre, Sylvain Renolleau, Valentine Brousse, Laurent Kiger, Fabien Touzot, Catherine Poirot, Philippe Bourget, Wassim El Nemer, Stéphane Blanche, Jean-Marc Tréluyer, Mohammed Asmal, Courtney Walls, Yves Beuzard, Manfred Schmidt, Salima Hacein-Bey-Abina, Vahid Asnafi, Isabelle Guichard, Maryline Poirée, Fabrice Monpoux, Philippe Touraine, Chantal Brouzes, Mariane de Montalembert, Emmanuel Payen, Emmanuelle Six, Jean-Antoine Ribeil, Annarita Miccio, Pablo Bartolucci, Philippe Leboulch, and Marina Cavazzana
Subjects: Male, Young Adult, Treatment Outcome, Adolescent, Lentivirus, beta-Thalassemia, Humans, Female, General Medicine, Anemia, Sickle Cell, Genetic Therapy, General Biochemistry, Genetics and Molecular Biology
Abstract: Sickle cell disease (SCD) and transfusion-dependent β-thalassemia (TDT) are the most prevalent monogenic disorders worldwide. Trial HGB-205 ( NCT02151526 ) aimed at evaluating gene therapy by autologous CD34
Published: 2020

24. 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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25. 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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26. Increased long QT and torsade de pointes reporting on tamoxifen compared with aromatase inhibitors

Author: Dan M. Roden, Andrew M. Glazer, Joe-Elie Salem, Anne Bachelot, Carine Courtillot, Javid Moslehi, Bénédicte Lebrun-Vignes, Antoine Pariente, Christian Funck-Brentano, Philippe Touraine, Virginie Grouthier, Centre de référence des maladies endocriniennes rares de la croissance et du développement [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 d’endocrinologie et médecine de la reproduction [CHU Pitié-Salpêtrière], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), 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), Vanderbilt University [Nashville], 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], CIC Bordeaux, Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Bordeaux [Bordeaux], Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Université Pierre et Marie Curie - Paris 6 (UPMC)
Subjects: Oncology, Databases, Factual, [SDV]Life Sciences [q-bio], Action Potentials, 030204 cardiovascular system & hematology, chemistry.chemical_compound, 0302 clinical medicine, Exemestane, Heart Rate, Risk Factors, Torsades de Pointes, Aged, 80 and over, Aromatase Inhibitors, Letrozole, Middle Aged, Prognosis, 3. Good health, Europe, Long QT Syndrome, 030220 oncology & carcinogenesis, Female, Cardiology and Cardiovascular Medicine, hormones, hormone substitutes, and hormone antagonists, medicine.drug, Adult, Selective Estrogen Receptor Modulators, medicine.medical_specialty, Adolescent, Long QT syndrome, Anastrozole, Torsades de pointes, Risk Assessment, QT interval, Article, Young Adult, 03 medical and health sciences, Heart Conduction System, Internal medicine, medicine, Adverse Drug Reaction Reporting Systems, Humans, cardiovascular diseases, Aged, business.industry, ventricular arrhythmias, medicine.disease, Cardiotoxicity, Tamoxifen, chemistry, sex steroid hormones, torsade de pointes, business, Adverse drug reaction
Abstract: ObjectiveA prolonged QTc (LQT) is a surrogate for the risk of torsade de pointes (TdP). QTc interval duration is influenced by sex hormones: oestradiol prolongs and testosterone shortens QTc. Drugs used in the treatment of breast cancer have divergent effects on hormonal status.MethodsWe performed a disproportionality analysis using the European database of suspected adverse drug reaction (ADR) reports to evaluate the reporting OR (ROR χ2) of LQT, TdP and ventricular arrhythmias associated with selective oestrogen receptor modulators (SERMs: tamoxifen and toremifene) as opposed to aromatase inhibitors (AIs: anastrozole, exemestane and letrozole). When the proportion of an ADR is greater in patients exposed to a drug (SERMs) compared with patients exposed to control drug (AIs), this suggests an association between the specific drug and the reaction and is a potential signal for safety. Clinical and demographic characterisation of patients with SERMs-induced LQT and ventricular arrhythmias was performed.ResultsSERMs were associated with higher proportion of LQT reports versus AIs (26/8318 vs 11/14851, ROR: 4.2 (2.11–8.55), pConclusionsSERMs are associated with more reports of drug-induced LQT, TdP and ventricular arrhythmias compared with AIs. This finding is consistent with oestradiol-like properties of SERMs on the heart as opposed to effects of oestrogen deprivation and testosterone increase induced by AIs.Trial registration numberNCT03259711.
Published: 2018
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27. MANAGEMENT OF ENDOCRINE DISEASE: Congenital adrenal hyperplasia due to 21-hydroxylase deficiency: update on the management of adult patients and prenatal treatment

Author: Virginie Grouthier, Anne Bachelot, Carine Courtillot, Jérôme Dulon, and Philippe Touraine
Subjects: medicine.medical_specialty, Hormone Replacement Therapy, Endocrinology, Diabetes and Metabolism, medicine.medical_treatment, 030209 endocrinology & metabolism, Disease, Androgen Excess, Dexamethasone, 03 medical and health sciences, 0302 clinical medicine, Endocrinology, Congenital adrenal hyperplasia due to 21-hydroxylase deficiency, Risk Factors, Internal medicine, medicine, Humans, Congenital adrenal hyperplasia, Glucocorticoids, Endocrine disease, Adrenal Hyperplasia, Congenital, business.industry, Disease Management, Hormone replacement therapy (menopause), General Medicine, medicine.disease, 3. Good health, 030220 oncology & carcinogenesis, business, Glucocorticoid, medicine.drug
Abstract: Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency is characterized by cortisol and in some cases aldosterone deficiency associated with androgen excess. Goals of treatment are to replace deficient hormones and control androgen excess, while avoiding the adverse effects of exogenous glucocorticoid. Over the last 5 years, cohorts of adults with CAH due to 21-hydroxylase deficiency from Europe and the United States have been described, allowing us to have a better knowledge of long-term complications of the disease and its treatment. Patients with CAH have increased mortality, morbidity and risk for infertility and metabolic disorders. These comorbidities are due in part to the drawbacks of the currently available glucocorticoid therapy. Consequently, novel therapies are being developed and studied in an attempt to improve patient outcomes. New management strategies in the care of pregnancies at risk for congenital adrenal hyperplasia using fetal sex determination and dexamethasone have also been described, but remain a subject of debate. We focused the present overview on the data published in the last 5 years, concentrating on studies dealing with cardiovascular risk, fertility, treatment and prenatal management in adults with classic CAH to provide the reader with an updated review on this rapidly evolving field of knowledge.
Published: 2017
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28. Paul Kelly, PhD (1943–2018)

Author: Philippe Touraine, Hans H. Zingg, Charlotte Sumida, Henry G. Friesen, and Vincent Goffin
Subjects: Canada, business.industry, Endocrinology, Diabetes and Metabolism, MEDLINE, Historical Article, Biography, Human physiology, History, 20th Century, History, 21st Century, Research Personnel, Prolactin, Endocrinology, Humans, Medicine, business, Classics
Published: 2019
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29. Premature ovarian insufficiency: step-by-step genetics bring new insights

Author: Philippe Touraine
Subjects: Minichromosome Maintenance Proteins, business.industry, Primary ovarian insufficiency, Menopause, Premature, Obstetrics and Gynecology, Primary Ovarian Insufficiency, medicine.disease, Premature ovarian insufficiency, Bioinformatics, Menopause, Minichromosome Maintenance Complex Component 9, Reproductive Medicine, Mutation, Mutation (genetic algorithm), medicine, Humans, Female, business
Published: 2020
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30. 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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31. 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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32. 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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33. Gain-of-function Prolactin Receptor Variants Are Not Associated With Breast Cancer and Multiple Fibroadenoma Risk

Author: Rémi Pierre, Isabelle Tejedor, Aurélie Chiche, Zeina Chakhtoura, Carine Courtillot, Florence Boutillon, P. Camparo, Fabienne Rakotozafy, Vincent Goffin, Natascha Pigat, Jacques-Emmanuel Guidotti, Marie-Laure Tanguy, Sophie Vacher, Fatima Laki, Anne Bissery, Ivan Bièche, Marc Foretz, Marie Bernadet, Jean Tichet, Virginie Grouthier, Philippe Touraine, Sophie Bernichtein, Marcio Do Cruzeiro, Brigitte Sigal-Zafrani, and Ibtissem Cherifi
Subjects: Adult, 0301 basic medicine, Genetically modified mouse, medicine.medical_specialty, Adolescent, Receptors, Prolactin, Endocrinology, Diabetes and Metabolism, Clinical Biochemistry, Breast Neoplasms, Mice, Transgenic, Context (language use), Biochemistry, Germline, Cohort Studies, Mice, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Endocrinology, Breast cancer, Breast Fibroadenoma, Internal medicine, medicine, Animals, Humans, business.industry, Prolactin receptor, Biochemistry (medical), Middle Aged, medicine.disease, Fibroadenoma, Mice, Inbred C57BL, Disease Models, Animal, 030104 developmental biology, 030220 oncology & carcinogenesis, Cohort, Female, business
Abstract: In a cohort of 95 women with multiple breast fibroadenomas (MFAs), we recently identified patients harboring germline heterozygous variants of the prolactin receptor (PRLR) exhibiting constitutive activity (PRLRThis study sought to better delineate the potential role of PRLR gain-of-function variants in benign and malignant mammary tumorigenesis.This was an observational study and transgenic mouse model analysis.The study took place at the Department of Endocrinology, Reproductive Disorders and Rare Gynecologic Diseases, Pitié Salpêtrière, Paris, and Inserm Unit 1151, Paris.We generated a second MFA cohort (n = 71) as well as a group of control subjects (n = 496) and a cohort of women with breast cancer (n = 119). We also generated two transgenic mouse models carrying the coding sequences of human PRLRWe aimed to determine the prevalence of PRLR variants in these three populations and to uncover any association of the latter with specific tumor pattern, especially in patients with breast cancer.This study did not highlight a higher prevalence of PRLR variants in the MFA group and in the breast cancer group compared with control subjects. Transgenic mice expressing PRLRPRLR
Published: 2016
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34. Deletion ofCPEB1Gene: A Rare but Recurrent Cause of Premature Ovarian Insufficiency

Author: S. Christin-Maitre, L. Mansour-Hendili, Anne Gompel, Véronique Kerlan, Philippe Touraine, Yves Reznik, Sandra Chantot-Bastaraud, Jean-Pierre Siffroi, Bruno Donadille, B. Delemer, S. Jonard, Catherine Dodé, and Capucine Hyon
Subjects: Adult, 0301 basic medicine, Endocrinology, Diabetes and Metabolism, Clinical Biochemistry, Menopause, Premature, Context (language use), Primary Ovarian Insufficiency, Biology, Premature ovarian insufficiency, medicine.disease_cause, Bioinformatics, Biochemistry, law.invention, Cohort Studies, 03 medical and health sciences, 0302 clinical medicine, Endocrinology, law, medicine, Humans, Gene, Polymerase chain reaction, mRNA Cleavage and Polyadenylation Factors, Mutation, 030219 obstetrics & reproductive medicine, Biochemistry (medical), Breakpoint, FMR1, 030104 developmental biology, Female, Gene Deletion, Transcription Factors, Cohort study
Abstract: Premature ovarian insufficiency (POI) may be secondary to chemotherapy, radiotherapy, or environmental factors. Genetic causes are identified in 20-25% of cases, but most POI cases remain idiopathic.This study aimed to identify new genes involved in POI and to characterize the implication of CPEB1 gene in POI.This was a case report and cohort study replicate conducted in academic medical centers.A deletion including CPEB1 gene was first identified in a patient with primary amenorrhea. Secondly, 191 sporadic POI cases and 68 familial POI cases were included. For each patient, karyotype was normal and FMR1 premutation was excluded. Search for CPEB1 deletions was performed by quantitative multiplex PCR of short fluorescent fragments or DNA microarray analysis. Gene sequencing of CPEB1 was performed for 95 patients.We identified three patients carrying a microdeletion in band 15q25.2. The proximal breakpoint, for the three patients, falls within a low-copy repeat region disrupting the CPEB1 gene, which represents a strong candidate gene for POI as it is known to be implicated in oocyte meiosis. No mutation was identified by sequencing CPEB1 gene. Therefore, heterozygous deletion of CPEB1 gene leading to haploinsufficiency could be responsible for POI in humans.Microdeletions of CPEB1 were identified in 1.3% of patients with POI, whereas no mutation was identified. This microdeletion is rare but recurrent as it is mediated by nonallelic homologous recombination due to the existence of low-copy repeats in the region. This result demonstrates the importance of DNA microarray analysis in etiological evaluation and counseling of patients with POI.
Published: 2016
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35. 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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36. 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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37. 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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38. Challenges of the Transition from Pediatric Care to Care of Adults: 'Say Goodbye, Say Hello'

Author: Philippe, Touraine and Michel, Polak
Subjects: Adult, Patient Transfer, Transition to Adult Care, Young Adult, Adolescent, Chronic Disease, Humans, Continuity of Patient Care, Child, Pediatrics
Abstract: Transition has been defined as "the purposeful, planned movement of adolescents and young adults with chronic physical and medical conditions from child-centered to adult-oriented health care systems." We will here describe the challenges of such a process: challenges coming from the pediatrician, from the adolescent, linked to the disease itself, and those from the parents. We will outline how to overcome those fears and challenges to provide a successful transition process. A key factor to underline that process is that a relationship based on confidence should be established between the pediatrician and the physician for adults, in order for that relationship, based on trust, to be the basis for the transfer of the adolescent from the pediatric system of care to the adult one.
Published: 2018

39. Postprandial GLP-1 Secretion After Bariatric Surgery in Three Cases of Severe Obesity Related to Craniopharyngiomas

Author: M. Bretault, Philippe Touraine, Charles Barsamian, Jean-Luc Bouillot, Marie-Laure Raffin-Sanson, Jean-Marc Lacorte, Sébastien Czernichow, Claire Carette, Michel Polak, and Suzanne Laroche
Subjects: Male, 0301 basic medicine, Sleeve gastrectomy, medicine.medical_specialty, Endocrinology, Diabetes and Metabolism, medicine.medical_treatment, Bariatric Surgery, 030209 endocrinology & metabolism, Pituitary neoplasm, Craniopharyngioma, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Insulin resistance, Glucagon-Like Peptide 1, Weight loss, medicine, Humans, Pituitary Neoplasms, Obesity, Nutrition and Dietetics, business.industry, Middle Aged, Postprandial Period, medicine.disease, Surgery, 030104 developmental biology, Postprandial, Female, medicine.symptom, business, Hyperinsulinism
Abstract: Craniopharyngiomas are rare cerebral tumors associated with severe obesity after hypothalamic surgery. A meta-analysis showed significant weight loss at 1 year after bariatric surgery in these patients even though more modest than in common causes of obesity. We hypothesized that this discrepancy could be partly explained by differences in GLP-1 secretion after surgery since patients with craniopharyngioma present a significantly higher degree of insulin resistance and hyperinsulinism than common obese control. We report three cases of bariatric surgery in patients presenting with hypothalamique obesity related to craniopharyngiomas. At 18 months, the mean weight loss was 20 kg with expected insulin resistance decrease. Before surgery, standardized test meal shows abolition of postprandial GLP-1 secretion in all patients with a progressive restoration in the patients with gastric bypass (GBP) surgery.
Published: 2016
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40. Endocrine Manifestations in a Monocentric Cohort of 64 Patients With Erdheim-Chester Disease

Author: Z. Amoura, M. Leban, J. Haroche, S. Laugier Robiolle, F. Cohen Aubart, Frédéric Charlotte, Carine Courtillot, Raphaële Renard-Penna, Philippe Touraine, and Aurélie Drier
Subjects: Adult, Male, Erdheim-Chester Disease, medicine.medical_specialty, genetic structures, Endocrinology, Diabetes and Metabolism, Pituitary Function Tests, Clinical Biochemistry, 030209 endocrinology & metabolism, Disease, Thyroid Function Tests, Biochemistry, Cohort Studies, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Endocrinology, Bone Density, Endocrine Glands, Internal medicine, Adrenal Glands, medicine, Humans, Endocrine system, Young adult, Gonads, Aged, Aged, 80 and over, business.industry, Biochemistry (medical), Middle Aged, medicine.disease, Histiocytosis, Erdheim–Chester disease, Cohort, Diabetes insipidus, Disease Progression, Female, France, business, Diabetes Insipidus, 030217 neurology & neurosurgery, Follow-Up Studies, Cohort study
Abstract: Erdheim-Chester disease (ECD) is a rare non-Langerhans cell histiocytosis, characterized by infiltration of foamy histiocytes in multiple organs. Endocrine involvement has mostly been described in case reports.We performed systematic endocrine evaluation in a large cohort of patients with ECD.This was a single-center observational study conducted between October 2007 and May 2013.The evaluation was conducted in Pitié-Salpêtrière Hospital (Paris, France), a tertiary care hospital.Sixty-four consecutive patients with ECD (sex ratio, 3.6; mean age, 57.6 years [range, 20-80 years]). Thirty-six patients had follow-up assessments.There were no interventions.Clinical, biological, and morphological evaluations of pituitary, gonadal, adrenal, and thyroid functions, as well as metabolic evaluation, were performed.Diabetes insipidus was found in 33.3% of patients, frequently as the first manifestation of ECD. Anterior pituitary dysfunction was found in 91.3% of patients with full anterior pituitary evaluation, including somatotropic deficiency (78.6%), hyperprolactinemia (44.1%), gonadotropic deficiency (22.2%), thyrotropic deficiency (9.5%), and corticotropic deficiency (3.1%). Thirty-five patients (54.7%) had ≥2 anterior pituitary dysfunctional axes, rising to 69.6% (16 of 23) when only patients with complete evaluations were considered. Two patients had panhypopituitarism. Infiltration of the pituitary and stalk was found with magnetic resonance imaging in 24.4% of patients. Testicular insufficiency was found in 53.1% of patients, with sonographic testicular infiltration in 29% of men, mostly bilateral. Computed tomography adrenal infiltration was found in 39.1% of patients, and 1 case of adrenal insufficiency was observed. No patient was free of endocrine hormonal or morphological involvement. Endocrine dysfunctions were most often permanent, and new deficits appeared during follow-up.Endocrine involvement is very frequent in ECD and should be evaluated carefully at diagnosis and during follow-up.
Published: 2016
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41. Prevalence of and Risk Factors for Anal Oncogenic Human Papillomavirus Infection Among HIV-Infected Women in France in the Combination Antiretroviral Therapy Era

Author: Valérie Potard, Isabelle Etienney, Catherine Moore, Isabelle Heard, Catherine Crenn-Hebert, Philippe Touraine, Isabelle Poizot-Martin, Dominique Costagliola, Heather Cubie, Centre National de Référence pour les Papillomavirus - Rétrovirologie moléculaire - Génétique,Papillomavirus et Cancer humain, Institut Pasteur [Paris] (IP), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Sciences Economiques et Sociales de la Santé & Traitement de l'Information Médicale (SESSTIM - U912 INSERM - Aix Marseille Univ - IRD), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'Immuno-hématologie clinique [Hôpital Sainte Marguerite - APHM], Assistance Publique - Hôpitaux de Marseille (APHM)-Hôpital Sainte-Marguerite [CHU - APHM] (Hôpitaux Sud ), Inserm-Transfert [Paris], Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Pierre Louis d'Epidémiologie et de Santé Publique (iPLESP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Dpt proctologie [CHU Croix St Simon], Groupe Hospitalier Diaconesses Croix Saint-Simon, Hôpital Louis Mourier - AP-HP [Colombes], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Scottish HPV Reference Laboratory [Edinburgh, UK], Lissalde, Claire, Institut Pasteur [Paris], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), and Institut de Recherche pour le Développement (IRD)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU)
Subjects: Adult, 0301 basic medicine, HPV, medicine.medical_specialty, Adolescent, Cross-sectional study, 030106 microbiology, HIV Infections, [SDV.CAN]Life Sciences [q-bio]/Cancer, Cervix Uteri, Young Adult, 03 medical and health sciences, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, Risk Factors, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Prevalence, medicine, Humans, Immunology and Allergy, Anal cancer, anal canal, 030212 general & internal medicine, Cervix, Gynecology, Anus Diseases, business.industry, Obstetrics, Papillomavirus Infections, cervical, HPV infection, virus diseases, Odds ratio, Middle Aged, Anal canal, medicine.disease, 3. Good health, Cross-Sectional Studies, Infectious Diseases, medicine.anatomical_structure, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, HIV-positive women, Cohort, [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Population study, Female, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, France, business
Abstract: International audience; Background. Little is known about the type-specific prevalence of anal human papillomavirus (HPV) infection and risk factors for anal high-risk (HR) HPV infection in human immunodeficiency virus (HIV)-infected women. Methods. A cross-sectional study of anal and cervical HPV infection was nested within a gynecological cohort of HIV-infected women. Specimens were tested for type-specific DNA using a polymerase chain reaction-based assay. Results. The study population consisted of 311 women with a median age of 45.3 years, of whom 42.8% originated from sub-Saharan Africa and 96.8% were receiving combination antiretroviral therapy. The median CD4 + cell count was 612/μL, and the HIV load was
Published: 2015
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42. The prolactin receptor as a therapeutic target in human diseases: browsing new potential indications

Author: Vincent Goffin and Philippe Touraine
Subjects: Male, Receptors, Prolactin, medicine.medical_treatment, Clinical Biochemistry, Antineoplastic Agents, Breast Neoplasms, Disease, Bioinformatics, Targeted therapy, Prostate, Drug Discovery, medicine, Animals, Humans, Molecular Targeted Therapy, Receptor, STAT5, Pharmacology, biology, Prolactin receptor, Prostatic Neoplasms, Cancer, medicine.disease, Prolactin, medicine.anatomical_structure, Drug Design, Immunology, biology.protein, Molecular Medicine, Female
Abstract: Prolactin (PRL) signaling has emerged as a relevant target in breast and prostate cancers. This has encouraged various laboratories to develop compounds targeting the PRL receptor (PRLR). As the latter is widely distributed, it is timely to address whether other conditions could also benefit from such inhibitors.The authors briefly overview the two classes of PRLR blockers, which involve: i) PRL-core based analogs that have been validated as competitive antagonists in various preclinical models, and ii) anti-PRLR neutralizing antibodies that are currently in clinical Phase I for advanced breast and prostate cancers. The main purpose of this review is to discuss the multiple organs/diseases that may be considered as potential targets/indications for such inhibitors. This is done in light of reports suggesting that PRLR expression/signaling is increased in disease, and/or that systemic or locally elevated PRL levels correlate with (or promote) organ pathogenesis.The two immediate challenges in the field are i) to provide the scientific community with potent anti-prolactin receptor antibodies to map prolactin receptor expression in target organs, and ii) to take advantage of the availability of functionally validated PRLR blockers to establish the relevance of these potential indications in humans.
Published: 2015
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43. Gynecologic follow up of 129 women on dialysis and after kidney transplantation: a retrospective cohort study

Author: Zeina Chakhtoura, Lucile Mercadal, Benoit Barrou, Marie Meunier, Nadia Arzouk, Jacqueline Caby, and Philippe Touraine
Subjects: Adult, medicine.medical_specialty, Metrorrhagia, medicine.medical_treatment, Population, Intrauterine device, Cohort Studies, Chlormadinone acetate, chemistry.chemical_compound, Pregnancy, Renal Dialysis, medicine, Humans, education, Menstruation Disturbances, Kidney transplantation, Dialysis, Retrospective Studies, Gynecology, education.field_of_study, business.industry, Obstetrics and Gynecology, Retrospective cohort study, Middle Aged, medicine.disease, Kidney Transplantation, Menstruation, Pregnancy Complications, Transplantation, Contraception, Reproductive Medicine, chemistry, Kidney Failure, Chronic, Female, medicine.symptom, business, Genital Diseases, Female, Follow-Up Studies
Abstract: To describe the gynecologic issues and follow-up in our referral center of women on dialysis and after kidney transplantation.This retrospective cohort study included 129 dialysed women among whom 102 had had transplants. Data on menstrual pattern, pregnancies, contraception, and cervical cytology were retrieved from patients' files.The follow-up started at age 41.6±14.2 years and lasted for 9.5±10.2 years. Of the women, 78.7% had regular menses before dialysis, decreasing to 30.6% on dialysis (p0.001), when 43.1% were amenorrheic (p0.001). After transplantation, more patients had regular menstruation and fewer were amenorrheic (respectively 57.1% and 23.1%, p0.001). On dialysis and after transplantation, 25% and 30.5% of patients suffered from metrorrhagia (compared to 17.1% before, p0.01). Concerning pregnancies, rates of spontaneous abortions (33.3%, p=0.01), intrauterine growth retardation (28.5%, p0.001) and prematurity (23.8%, p=0.008) were significantly higher after transplantation than before dialysis. Prescriptions for the combined contraceptive pill and intrauterine device decreased whereas chlormadinone acetate was widely used: it treated metrorrhagia and relieved mastodynia in 80% and 12% of the cases. Smear tests showed more inflammation (33% vs 0.8%, p0.05), condylomas (13.6% vs 3.1%, p=0.005) and intraepithelial neoplasias (12.6% vs 2.3%, p=0.003) among patients after renal graft than before dialysis.Women on dialysis and after kidney transplantation suffered more from irregular menses and metrorrhagia which was improved by chlormadinone acetate. We noted high rates of obstetrical complications and abnormal smear tests. Consequently, this population must have close follow-up to identify and treat gynecologic issues.
Published: 2015
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44. 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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45. 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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46. A common African variant of human connexin 37 is associated with Caucasian primary ovarian insufficiency and has a deleterious effect in vitro

Author: Anne, Bachelot, Jerome, Gilleron, Geri, Meduri, Mihelai, Guberto, Jerome, Dulon, Sylviane, Boucherie, Philippe, Touraine, and Micheline, Misrahi
Subjects: Heterozygote, Black People, Cell Communication, Primary Ovarian Insufficiency, Caucasian, GJA4, confocal microscopy, Connexins, White People, Mice, Animals, Humans, Granulosa Cells, Cell Membrane, African, Gap Junctions, candidate gene, Articles, connexin 37, Rats, variant, Oocytes, Gap-fluorescence recovery after photobleaching, Female, mutation, primary ovarian failure, HeLa Cells
Abstract: Folliculogenesis requires communication between granulosa cells and oocytes, mediated by connexin-based gap junctions. Connexin 37 (Cx37)-deficient female mice are infertile. The present study assessed Cx37 deficiency in patients with primary ovarian insufficiency (POI). A candidate gene study was performed in patients and controls from the National Genotyping Center (Evry, France) including 58 Caucasian patients with idiopathic isolated POI and 142 Caucasian controls. Direct genomic sequencing of the coding regions of the GJA4 gene (encoding Cx37) was performed with the aim to identify a deleterious variant associated with POI and absent in ethnically matched controls. A single Cx37 variant absent in the control population was identified, namely a c.946G>A heterozygous substitution leading to a p.Gly316Ser variant that was present in two POI patients. This variant was absent in all Caucasian controls from various databases, and has been observed exclusively in African populations. This variant was identified to have a dominant negative effect in HeLa cells in vitro to alter connexon function (by 67.2±7.17%), as determined by Gap-fluorescence recovery after photobleaching. The alteration principally resulted from a decrease of cell surface connexons due to altered trafficking (by 47.73±8.59%). In marked contrast to this observation, a p.Pro258Ser variant frequent in all ethnic populations in databases had no functional effect in vitro. In conclusion, the present study reported on a Cx37 variant in two Caucasian POI patients, which was absent in control Caucasian populations, and which had a deleterious effect in vitro. It is therefore suggested that in the genetic context of the Caucasian population, this variant may contribute to POI.
Published: 2017

47. Weakening osteopathies, chronic kidney disease, malabsorption, biological anomalies of calium/phosphorus metabolism: appropriate indications for a reasoned reimbursment of serum vitamin D measurement

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, 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, Éric 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), Centre Hospitalier Régional d'Orléans (CHRO), Service de rhumatologie[Lille], Hôpital Roger Salengro [Lille]-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Hôpital Cochin [AP-HP], Service de médecine interne et gérontologie clinique [Angers], Université d'Angers (UA)-Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Hôpital Femme Mère Enfant [CHU - HCL] (HFME), Hospices Civils de Lyon (HCL), Centre Hospitalier Boulogne-sur-mer, Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), 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), Euromov (EuroMov), Université de Montpellier (UM), 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, Hôpital de la Conception [CHU - APHM] (LA CONCEPTION), Neuroprotection du Cerveau en Développement / Promoting Research Oriented Towards Early Cns Therapies (PROTECT), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Diderot - Paris 7 (UPD7), Service Endocrinologie, maladies métaboliques et nutrition [CHU Toulouse], Pôle Cardiovasculaire et Métabolique [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Biologie du Cancer et de l'Infection (BCI ), 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), 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), Récepteurs stéroïdiens : physiopathologie endocrinienne et métabolique, Université Paris-Sud - Paris 11 (UP11)-IFR93-Institut National de la Santé et de la Recherche Médicale (INSERM), Physiopathologie, diagnostic et traitements des maladies osseuses / Pathophysiology, Diagnosis & Treatments of Bone Diseases (LYOS), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM), Endocrinologie pédiatrique[CHU Angers], Physiopathologie des maladies génétiques d'expression pédiatrique, Os et articulations, Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Fibrose hépatique et cancer du foie, Université Bordeaux Segalen - Bordeaux 2-IFR66-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Néphrologie-transplantation-dialyse [Bordeaux], CHU Bordeaux [Bordeaux], Centre de recherche Croissance et signalisation (UMR_S 845), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Nutrition [Cergy] (N - cabinet libéral ), Service d'Endocrinologie - Diabète - Nutrition [Reims], Université de Reims Champagne-Ardenne (URCA)-Hôpital Robert Debré-Centre Hospitalier Universitaire de Reims (CHU Reims), Hôpital Robert Debré, Centre Hospitalier Le Mans (CH Le Mans), Mécanismes physiologiques et conséquences des calcifications cardiovasculaires: rôle des remodelages cardiovasculaires et osseux, Université de Picardie Jules Verne (UPJV)-Institut National de la Santé et de la Recherche Médicale (INSERM), Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN), Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM), Foie, métabolismes et cancer, 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 ), Service de rhumatologie [Rennes] = Rheumatology [Rennes], CHU Pontchaillou [Rennes], Service de Physiologie [Georges-Pompidou], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Université Paris Descartes - Paris 5 (UPD5), CHU Strasbourg, Institut de recherche en cancérologie de Montpellier (IRCM - U896 Inserm - UM1), Université Montpellier 1 (UM1)-CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Centre de Rein Artificiel [Tassin la demi-lune] (CRA), Université Montpellier 1 (UM1), AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Tissu Osseux et Contraintes Mecaniques (LBTO), Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Trousseau, Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Centre Hospitalier Victor Dupouy, Immunologie et génétique du diabète de type 1, génétique multifactorielle en endocrinologie pédiatrique (U986), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Rouen, Normandie Université (NU), Service de Rhumatologie [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), Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Centre Hospitalier Universitaire de Saint-Etienne (CHU de Saint-Etienne), Service de Rhumatologie, Hôtel-Dieu, Cabinet de Rhumatologie [Saint-Etienne] (CdR), Hôpital Lariboisière-Fernand-Widal [APHP], Département de Médecine Générale, Université Paris Cité (UPCité), Service de Neurologie [CHU Pitié-Salpêtrière], IFR70-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), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Hôpital Edouard Herriot [CHU - HCL], CIC Hôpital Bichat, AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-UFR de Médecine, Gérontopôle, Epidémiologie et analyses en santé publique : risques, maladies chroniques et handicaps (LEASP), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Service d'Endocrinologie (NICE - Endocrino), Centre Hospitalier Universitaire de Nice (CHU Nice), Académie nationale de médecine, Eurofins Biomnis, CHU Gabriel Montpied [Clermont-Ferrand], CHU Clermont-Ferrand, Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Pitié-Salpêtrière [AP-HP], Université Pierre et Marie Curie - Paris 6 (UPMC), Service Obstétrique [CHU Toulouse], Pôle Femme-Mère-Couple [CHU Toulouse], Clinique du Landy [Saint-Ouen] (CL), Hôpital Hôtel-Dieu [Paris], Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Service d'Endocrinologie [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Service de Gynécologie Obstétrique (NANTES - Gynéco Obstétrique), Centre hospitalier universitaire de Nantes (CHU Nantes), Institut Gustave Roussy (IGR), Service d'endocrinologie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Bicêtre, and Jonchère, Laurent
Subjects: medicine.medical_specialty, Malabsorption, [SDV]Life Sciences [q-bio], MathematicsofComputing_GENERAL, [SDV.CAN]Life Sciences [q-bio]/Cancer, Phosphorus metabolism disorder, GeneralLiterature_MISCELLANEOUS, Phosphorus metabolism, InformationSystems_GENERAL, [SDV.CAN] Life Sciences [q-bio]/Cancer, Malabsorption Syndromes, Calcium Metabolism Disorders, Internal medicine, medicine, Serum vitamin D measurement, Vitamin D and neurology, Humans, Renal Insufficiency, Chronic, Renal Insufficiency, Chronic, Vitamin D, ComputingMilieux_MISCELLANEOUS, MESH: Bone Diseases / blood, Calcium Metabolism Disorders / blood, Malabsorption Syndromes / blood, Phosphorus Metabolism Disorders / blood, Renal Insufficiency, Chronic / blood, Vitamin D / blood, business.industry, Phosphorus Metabolism Disorders, General Medicine, medicine.disease, 3. Good health, [SDV] Life Sciences [q-bio], Endocrinology, Malabsorption syndromes, Bone Diseases, business, Kidney disease
Abstract: La mesure de la concentration serique de 25-hydroxy vitamines D (25OHD) permet d’evaluer le statut vitaminique D d’un individu. Ceci ne signifie pas qu’il faille doser ce parametre biologique chez tous les patients. Le nombre de prescriptions de dosages de 25OHD a pourtant decuple en France entre 2005 et 2013 generant un cout important de remboursement pour la Caisse nationale de l’assurance-maladie des travailleurs salaries (CNAMTS) ce qui l’a conduit, logiquement, a la saisine [...]
Published: 2014
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48. Monocentric study of 112 consecutive patients with childhood onset GH deficiency around and after transition

Author: Carine Courtillot, Roselyne Baudoin, Tatiana Du Souich, Lucile Saatdjian, Isabelle Tejedor, Graziella Pinto, Juliane Léger, Michel Polak, Jean-Louis Golmard, and Philippe Touraine
Subjects: Adult, Male, Aging, Pediatrics, medicine.medical_specialty, Adolescent, Bone density, Endocrinology, Diabetes and Metabolism, Pituitary Function Tests, Hypopituitarism, Cohort Studies, Young Adult, Absorptiometry, Photon, Endocrinology, Bone Density, Internal medicine, Humans, Medicine, Insulin-Like Growth Factor I, Young adult, Child, Retrospective Studies, Bone mineral, medicine.diagnostic_test, Human Growth Hormone, business.industry, Magnetic resonance imaging, Retrospective cohort study, General Medicine, Lipids, Recombinant Proteins, Discontinuation, Multivariate Analysis, Female, business, Lipid profile, Follow-Up Studies, Cohort study
Abstract: ObjectivesOur aim was to analyze a large cohort of childhood onset GH deficiency (CO-GHD) adults from a unique adult center, in order to analyze their clinical management and to study the metabolic and bone status in relation to GHD and to the other pituitary deficits, and to evaluate these parameters during the long-term follow-up.Design and methodsObservational retrospective cohort study on 112 consecutive CO-GHD adults transferred to our unit from 1st January 1994 to 1st March 2012. Evaluation of GHD in pediatrics and after transition was conducted following consensus guidelines. Data recorded from pediatric and adult files were GH doses, pituitary magnetic resonance imaging and function, and metabolic and bone status.ResultsMost patients presented with severe CO-GHD (64%) associated with other pituitary deficits (66%). CO-GHD was acquired in 56%, congenital in 33%, and idiopathic in 11% cases. Most patients (83%) stopped GH before transfer, at 16.3 years (median), despite persistence of GHD. Median age at transfer was 19.4 years. After transfer, GHD persisted in 101 patients and four of the 11 resolutive GHD were non idiopathic. IGF1 level was ConclusionsThis study raises concern about discontinuation of GH replacement therapy in pediatrics in severely persistent GHD patients and about the often insufficient dose of GH in the treatment of adult patients.
Published: 2013
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49. DNA Methylation Is an Independent Prognostic Marker of Survival in Adrenocortical Cancer

Author: Anne, Jouinot, Guillaume, Assie, Rossella, Libe, Martin, Fassnacht, Thomas, Papathomas, Olivia, Barreau, Bruno, de la Villeon, Simon, Faillot, Nadim, Hamzaoui, Mario, Neou, Karine, Perlemoine, Fernande, Rene-Corail, Stéphanie, Rodriguez, Mathilde, Sibony, Frédérique, Tissier, Bertrand, Dousset, Silviu, Sbiera, Cristina, Ronchi, Matthias, Kroiss, Esther, Korpershoek, Ronald, de Krijger, Jens, Waldmann, Detlef, K, Bartsch, Marcus, Quinkler, Magalie, Haissaguerre, Antoine, Tabarin, Olivier, Chabre, Nathalie, Sturm, Michaela, Luconi, Franco, Mantero, Massimo, Mannelli, Regis, Cohen, Véronique, Kerlan, Philippe, Touraine, Gaelle, Barrande, Lionel, Groussin, Xavier, Bertagna, Eric, Baudin, Laurence, Amar, Felix, Beuschlein, Eric, Clauser, Joel, Coste, Jérôme, Bertherat, Pathology, 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), Université Paris Descartes - Paris 5 (UPD5), CHU Cochin [AP-HP], Department of Psychiatry, Chirurgie digestive, hépato-biliaire et endocrinienne [CHU Cochin], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-AP-HP - Hôpital Cochin Broca Hôtel Dieu [Paris], Medizinische Klinik und Poliklinik IV, Ludwig-Maximilians-Universität München (LMU), Comprehensive Cancer Center Mainfranken, Julius-Maximilians-Universität Würzburg [Wurtzbourg, Allemagne] (JMU), Department of Pathology, Erasmus University Medical Center [Rotterdam] (Erasmus MC), Clinical Genetics, Département d'endocrinologie - Bordeaux 2, Université Bordeaux Segalen - Bordeaux 2, Groupement Hospitalier Lyon-Est (GHE), Hospices Civils de Lyon (HCL), Laboratoire de Cytologie, Département d'Anatomie et de Cytologie Pathologiques, CHU Grenoble-Hôpital Michallon, Department of Endocrinology and Diabetes Mellitus, Hôpital Delafontaine, Service d'Endocrinologie (CHRU - Endocrino), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Groupe d'Etude de la Thrombose de Bretagne Occidentale (GETBO), Université de Brest (UBO)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO), Département d'endocrinologie et Médecine Reproductive [AP-HP Hôpital Pitié-Salpétrière], AP-HP Hôpital Universitaire Pitié Salpêtrière - GHU Pitié Salpêtrière, Centre Hospitalier Régional d'Orléans (CHR), Médecine nucléaire, Département d'imagerie médicale [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Hôpital Européen Georges Pompidou [APHP] (HEGP), Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), AP-HP - Hôpital Cochin Broca Hôtel Dieu [Paris], Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP - Hôpital Cochin Broca Hôtel Dieu [Paris], Université de Brest (UBO)-Université de Brest (UBO), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre Hospitalier Régional d'Orléans (CHRO), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)
Subjects: 0301 basic medicine, Male, [SDV]Life Sciences [q-bio], Endocrinology, Diabetes and Metabolism, Clinical Biochemistry, medical, Biochemistry, 0302 clinical medicine, Endocrinology, Adrenocortical Carcinoma, Methylation, DNA, Neoplasm, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, Middle Aged, Prognosis, 3. Good health, Tumor Burden, Diabetes and Metabolism, Survival Rate, CpG site, 030220 oncology & carcinogenesis, Cohort, DNA methylation, Female, Adult, medicine.medical_specialty, Context (language use), Biology, Disease-Free Survival, 03 medical and health sciences, SDG 3 - Good Health and Well-being, Internal medicine, medicine, Journal Article, Humans, Survival rate, Aged, Neoplasm Staging, Proportional Hazards Models, Retrospective Studies, Biochemistry, medical, Proportional hazards model, Biochemistry (medical), Retrospective cohort study, DNA Methylation, Adrenal Cortex Neoplasms, 030104 developmental biology, Ki-67 Antigen, Multivariate Analysis, CpG Islands, Multiplex Polymerase Chain Reaction, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: International audience; Context:Adrenocortical cancer (ACC) is an aggressive tumor with a heterogeneous outcome. Prognostic stratification is difficult even based on tumor stage and Ki67. Recently integrated genomics studies have demonstrated that CpG islands hypermethylation is correlated with poor survival.Objective:The goal of this study was to confirm the prognostic value of CpG islands methylation on an independent cohort.Design:Methylation was measured by methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA).Setting:MS-MLPA was performed in a training cohort of 50 patients with ACC to identify the best set of probes correlating with disease-free survival (DFS) and overall survival (OS). These outcomes were validated in an independent cohort from 21 ENSAT centers.Patients:The validation cohort included 203 patients (64% women, median age 50 years, 80% localized tumors).Main Outcome Measures:DFS and OS.Results:In the training cohort, mean methylation of 4 genes (PAX5, GSTP1, PYCARD, PAX6) was the strongest methylation marker. In the validation cohort, methylation was a significant prognostic factor of DFS (P < 0.0001) and OS (P < 0.0001). Methylation, Ki67, and ENSAT stage were combined in multivariate models. For DFS, methylation (P = 0.0005) and stage (P < 0.0001) but not Ki67 (P = 0.19) remained highly significant. For OS, methylation (P = 0.0006), stage (P < 0.0001), and Ki67 (P = 0.024) were independent prognostic factors.Conclusions:Tumor DNA methylation emerges as an independent prognostic factor in ACC. MS-MLPA is readily compatible with clinical routine and should enhance our ability for prognostication and precision medicine.
Published: 2017
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50. 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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