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1. IGSF1 mutations are the most frequent genetic aetiology of thyrotropin deficiency

Author

Rachel Fourneaux, Rachel Reynaud, Gregory Mougel, Sarah Castets, Patricia Bretones, Benjamin Dauriat, Thomas Edouard, Gerald Raverot, Anne Barlier, Thierry Brue, Frederic Castinetti, Alexandru Saveanu, 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], Laboratoire de Biochimie et de Biologie Moléculaire [Hôpital de la Conception - APHM], and Hôpital de la Conception [CHU - APHM] (LA CONCEPTION)

Subjects
[SDV.GEN]Life Sciences [q-bio]/Genetics, Pituitary Diseases, Endocrinology, Diabetes and Metabolism, Thyrotropin, Immunoglobulins, Membrane Proteins, General Medicine, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], Endocrinology, Hypothyroidism, Mutation, Exome Sequencing, Humans, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

Design Thyroid-stimulating hormone deficiency (TSHD) is a rare disease. It may be isolated, secondary to abnormalities of genes involved in TSH biosynthesis, or associated with other pituitary deficits or abnormalities of genes involved in pituitary ontogenesis. Several genes are involved in thyrotroph development and function. Objective Our aim was to determine the genetic causes of TSHD, either isolated (ITSHD) or associated with somatotroph deficiency (TSHD-GHD), in the cohort of patients from the GENHYPOPIT network. Methods Next-generation sequencing (NGS) analyses were performed as a panel of genes on a cohort of patients with non-syndromic ITSHD or TSHGHD. The variants were classified according to the American College of Medical Genetics classification reviewed by the NGS-Diag network and correlated with the phenotype. Class 3, 4, and 5 single-nucleotide variants were checked by Sanger sequencing and copy number variants by multiplex ligation-dependent probe amplification (MLPA). Results A total of 64 index cases (22 ITSHD and 42 TSHD-GHD) were included in this cohort. A genetic cause was identified in 26.5% of patients, with 36.3% in the ITSHD group (variants in TSHβ and IGSF1) and 21.4% in TSHD-GHD (variants in IGSF1, TSHβ, TRHR, GH1, POU1F1, and PROP1). Among the pathogenic and likely pathogenic variants identified, 42% were in IGSF1, including six not previously reported. Conclusion Our results show that IGSF1 variants represent the most frequent aetiology of TSH deficiency. Despite a systematic NGS approach and the identification of new variants, most patients remain without a molecular diagnosis. Larger scale studies, such as exome or genome studies, should be considered in the future.

Published
2022
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2. 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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3. Uncommon nucleotide excision repair phenotypes revealed by targeted high-throughput sequencing

Author

Massimiliano Rossi, Boris Keren, François Feillet, Julien Tarabeux, Isabel Llano-Rivas, Florence Renaldo-Robin, Vincent Laugel, Patricia Bretones, Bérénice Doray, Marguerite Miguet, Géraldine Greff, Caroline Michot, Béatrice Digeon, Nadine Kempf, Nadège Calmels, Anne Cavau, Martine Doco-Fenzy, Claire Gasnier, Cathy Obringer, Jean-Louis Mandel, Pascal Sabouraud, Jesus Gardeazabal, Didier Bessis, Christel Depienne, Blanca Gener, Artur Mazur, Jean Muller, Sophie Julia, Geneviève Baujat, Laboratoire de Diagnostic Génétique, CHU Strasbourg-Hopital Civil, Laboratoire de Génétique Médicale (LGM), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Génétique Médicale [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hôpital Saint Eloi (CHRU Montpellier), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Service d'endocrinologie pédiatrique, Hôpital mère enfant, Bron, CHU Necker - Enfants Malades [AP-HP], Centre Hospitalier Universitaire de Reims (CHU Reims), Centre hospitalier Félix-Guyon [Saint-Denis, La Réunion], Nutrition-Génétique et Exposition aux Risques Environnementaux (NGERE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), BioCruces Research Institute, University of the Basque Country/Euskal Herriko Unibertsitatea (UPV/EHU)-Hospital Universitario Cruces = Cruces University Hospital, Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Rzeszow University, Unité de Neurologie, Hôpital Robert Debré, Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL), Centre de recherche en neurosciences de Lyon - Lyon Neuroscience Research Center (CRNL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-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)-Centre National de la Recherche Scientifique (CNRS), Collège de France - Chaire Génétique Humaine, Collège de France (CdF (institution)), CHU Strasbourg, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHU Saint-Eloi, University of the Basque Country [Bizkaia] (UPV/EHU)-Hospital Universitario Cruces = Cruces University Hospital, Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse], Centre de recherche en neurosciences de Lyon (CRNL), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de génétique, cytogénétique, embryologie [Pitié-Salpétrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Université Pierre et Marie Curie - Paris 6 (UPMC), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-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), Chaire Génétique Humaine, CHU Strasbourg - Hopital Civil, Laboratoire de Génétique Médicale, Université de Strasbourg - Institut National de la Santé et de la Recherche Médicale (INSERM) - Faculté de Médecine, Centre de référence maladies osseuses constitutionnelles CHU Necker, Hôpital Necker - Enfants malades, Assistance publique - Hôpitaux de Paris (AP-HP) - Université Paris Descartes - Paris 5 (UPD5), CHU Reims, CHU Félix Guyon, Université de Lorraine (UL) - Institut National de la Santé et de la Recherche Médicale (INSERM), University of the Basque Country [Bizkaia] (UPV/EHU) - Cruces University Hospital, Hôpital Purpan, Hospices Civils de Lyon / Centre hospitalier Lyon Sud (HCL), Hospices Civils de Lyon, Centre de recherche en neurosciences de Lyon, Centre National de la Recherche Scientifique (CNRS) - Institut National de la Santé et de la Recherche Médicale (INSERM) - Université Claude Bernard Lyon 1 (UCBL) - Université Jean Monnet - Saint-Etienne - PRES Université de Lyon, Université Pierre et Marie Curie - Paris 6 (UPMC) - Assistance publique - Hôpitaux de Paris (AP-HP) - CHU Pitié-Salpêtrière [APHP], Institut du Cerveau et de la Moëlle Epinière (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC) - Institut National de la Santé et de la Recherche Médicale (INSERM) - CHU Pitié-Salpêtrière [APHP] - Centre National de la Recherche Scientifique (CNRS), Service de génétique, cytogénétique, embryologie [CHU Pitié-Salpétrière], Université Pierre et Marie Curie - Paris 6 (UPMC)-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), and HAL UPMC, Gestionnaire

Subjects
0301 basic medicine, ERCC6, ERCC8, DNA Repair, DNA-Directed DNA Polymerase, Cockayne syndrome, Genetics(clinical), Pharmacology (medical), Poly-ADP-Ribose Binding Proteins, Genetics (clinical), Medicine(all), Genetics, education.field_of_study, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, High-Throughput Nucleotide Sequencing, Nuclear Proteins, General Medicine, 3. Good health, DNA-Binding Proteins, Phenotype, POLH, NGS, Xeroderma pigmentosum, Population, Single-nucleotide polymorphism, Biology, 03 medical and health sciences, medicine, Humans, education, Xeroderma Pigmentosum Group D Protein, Research, DNA Helicases, xeroderma pigmentosum, medicine.disease, Endonucleases, 030104 developmental biology, DNA Repair Enzymes, Mutation, NER, ERCC2, ERCC3, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Nucleotide excision repair, Transcription Factors, ERCC5
Abstract

Background Deficient nucleotide excision repair (NER) activity causes a variety of autosomal recessive diseases including xeroderma pigmentosum (XP) a disorder which pre-disposes to skin cancer, and the severe multisystem condition known as Cockayne syndrome (CS). In view of the clinical overlap between NER-related disorders, as well as the existence of multiple phenotypes and the numerous genes involved, we developed a new diagnostic approach based on the enrichment of 16 NER-related genes by multiplex amplification coupled with next-generation sequencing (NGS). Methods Our test cohort consisted of 11 DNA samples, all with known mutations and/or non pathogenic SNPs in two of the tested genes. We then used the same technique to analyse samples from a prospective cohort of 40 patients. Multiplex amplification and sequencing were performed using AmpliSeq protocol on the Ion Torrent PGM (Life Technologies). Results We identified causative mutations in 17 out of the 40 patients (43 %). Four patients showed biallelic mutations in the ERCC6(CSB) gene, five in the ERCC8(CSA) gene: most of them had classical CS features but some had very mild and incomplete phenotypes. A small cohort of 4 unrelated classic XP patients from the Basque country (Northern Spain) revealed a common splicing mutation in POLH (XP-variant), demonstrating a new founder effect in this population. Interestingly, our results also found ERCC2(XPD), ERCC3(XPB) or ERCC5(XPG) mutations in two cases of UV-sensitive syndrome and in two cases with mixed XP/CS phenotypes. Conclusions Our study confirms that NGS is an efficient technique for the analysis of NER-related disorders on a molecular level. It is particularly useful for phenotypes with combined features or unusually mild symptoms. Targeted NGS used in conjunction with DNA repair functional tests and precise clinical evaluation permits rapid and cost-effective diagnosis in patients with NER-defects. Electronic supplementary material The online version of this article (doi:10.1186/s13023-016-0408-0) contains supplementary material, which is available to authorized users.

Published
2016
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4. Growth curves for congenital adrenal hyperplasia from a national retrospective cohort

Author

Patricia Bretones, Benjamin Riche, Emmanuel Pichot, Michel David, Pascal Roy, Véronique Tardy, Behrouz Kassai, Ségolène Gaillard, Delphine Bernoux, Yves Morel, Pierre Chatelain, Marc Nicolino, Catherine Cornu, null for the French Collaborative CAH Gr, Biostatistiques santé, Département biostatistiques et modélisation pour la santé et l'environnement [LBBE], Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS), Evaluation et modélisation des effets thérapeutiques, Service de Biostatistiques [Lyon], and Hospices Civils de Lyon (HCL)

Subjects
Adult, Male, medicine.medical_specialty, Pediatrics, Adolescent, [SDV]Life Sciences [q-bio], Endocrinology, Diabetes and Metabolism, Population, 030209 endocrinology & metabolism, Logistic regression, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Endocrinology, 030225 pediatrics, Internal medicine, medicine, Humans, Congenital adrenal hyperplasia, Sexual Maturation, Growth Charts, Young adult, Child, education, ComputingMilieux_MISCELLANEOUS, Retrospective Studies, education.field_of_study, Bone Development, Adrenal Hyperplasia, Congenital, business.industry, Infant, Newborn, Infant, Retrospective cohort study, Bone age, medicine.disease, Body Height, Child, Preschool, Pediatrics, Perinatology and Child Health, Bone maturation, Female, business, Follow-Up Studies, Cohort study
Abstract

Background: In congenital adrenal hyperplasia (CAH), adjusting hydrocortisone dose during childhood avoids reduced adult height. However, there are currently no CAH-specific charts to monitor growth during treatment. Our objective was to elaborate growth reference charts and bone maturation data for CAH patients. Methods: We conducted a retrospective observational cohort study, in 34 French CAH centers. Patients were 496 children born 1970–1991 with genetically proven 21-hydroxylase deficiency. Their growth and bone maturation data were collected until age 18 together with adult height, puberty onset, parental height, and treatment. The mean (SD) heights were modeled from birth to adulthood. The median±1 SD and ±2 SDs model-generated curves were compared with the French references. A linear model for bone maturation and a logistic regression model for the probability of short adult height were built. Results: Growth charts were built by sex for salt wasting (SW) and simple virilizing (SV) children treated before 1 year of age. In girls and boys, growth was close to that of the general French population up to puberty onset. There was almost no pubertal spurt and the mean adult height was shorter than that of the general population in girls (−1.2 SD, 156.7 cm) and boys (−1.0 SD, 168.8 cm). Advanced bone age at 8 years had a strong impact on the risk of short adult height (OR: 4.5 per year advance). Conclusions: The 8-year bone age is a strong predictor of adult height. It will help monitoring the growth of CAH-affected children.

Published
2016
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5. Paediatric phenotype of Kallmann syndrome due to mutations of fibroblast growth factor receptor 1 (FGFR1)

Author

Patricia Bretones, Juliane Léger, Cécile Lambe, Nicolas de Roux, Delphine Zenaty, Isabelle Guemas, and Michel David

Subjects
Male, medicine.medical_specialty, Adolescent, Synkinesis, Kallmann syndrome, DNA Mutational Analysis, Anosmia, Deafness, Genitalia, Male, Biology, Biochemistry, Olfaction Disorders, Endocrinology, Hypogonadotropic hypogonadism, Internal medicine, Cryptorchidism, medicine, Humans, Testosterone, Receptor, Fibroblast Growth Factor, Type 1, Molecular Biology, Puberty, Delayed, Genetics, Genetic heterogeneity, Fibroblast growth factor receptor 1, Infant, Kallmann Syndrome, Micropenis, Luteinizing Hormone, medicine.disease, Olfactory Bulb, Hypoplasia, Pedigree, Cleft Palate, stomatognathic diseases, Phenotype, Karyotyping, Agenesis, Mutation, Dental Enamel Hypoplasia, Syndactyly, Follicle Stimulating Hormone, medicine.symptom
Abstract

Kallmann syndrome characterised by hypogonadotropic hypogonadism (HH) and anosmia is genetically heterogeneous with X-linked, autosomal dominant and autosomal recessive forms. The autosomal dominant form due to loss of function mutation in the fibroblast growth factor receptor 1 (FGFR1) accounts for about 10% of cases. We report here three paediatric cases of Kallmann syndrome with unusual phenotype in two unrelated patients with severe ear anomalies (hypoplasia or agenesis of external ear) associated with classical features, such as cleft palate, dental agenesis, syndactylia, micropenis and cryptorchidism. We found de novo mutation in these two patients (Cys178Ser and Arg622Gly, respectively), and one inherited Arg622Gln mutation with intrafamilial variable phenotype. These genotype–phenotype correlations indicate that paediatric phenotypic expression of FGFR1 loss of function mutations is highly variable, the severity of the oro-facial malformations at birth does not predict gonadotropic function at the puberty and that de novo mutations of FGFR1 are relatively frequent.

Published
2006
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6. Gonadal Dysgenesis Without Adrenal Insufficiency in a 46, XY Patient Heterozygous for the Nonsense C16X Mutation: A Case of SF1 Haploinsufficiency

Author

Yves Morel, Frédérique Dijoud, Delphine Mallet, Michel David, Patricia Bretones, and Laurence Michel-Calemard

Subjects
Male, Steroidogenic factor 1, Heterozygote, endocrine system, medicine.medical_specialty, Endocrinology, Diabetes and Metabolism, Clinical Biochemistry, Nonsense mutation, Receptors, Cytoplasmic and Nuclear, Gonadal dysgenesis, Biology, Gene mutation, Steroidogenic Factor 1, medicine.disease_cause, Biochemistry, Endocrinology, Internal medicine, Adrenal Glands, medicine, Adrenal insufficiency, Humans, Missense mutation, Gonadal Dysgenesis, 46,XY, Homeodomain Proteins, Mutation, Biochemistry (medical), medicine.disease, Pedigree, DNA-Binding Proteins, Haplotypes, Codon, Nonsense, Haploinsufficiency, Transcription Factors
Abstract

Targeted disruption of the orphan nuclear receptor SF1 results in the absence of adrenals and gonads, establishing that this transcription factor is implicated in gonadal determination and adrenal development. Four human SF1 gene mutations have been described to date: three (G35E, R92Q, R255L) were responsible for adrenal insufficiency associated with a gonadal dysgenesis in two 46, XY individuals, one (8 bp deletion in exon 6) resulted in gonadal dysgenesis without adrenal insufficiency. We identified a new heterozygous SF1 gene mutation, C16X, in a 46, XY patient showing gonadal dysgenesis with normal adrenal function: low basal levels of AMH and testosterone (T), weak T response to hCG, hypoplastic testes with abundant seminiferous tubules but rare germ cells. This mutation causes premature termination of translation and should abolish all SF1 activity. Therefore haploinsufficiency could explain the deleterious effect of this mutation in our patient suggesting that testis development is more SF1 dose-dependant than adrenal development. Although the same mechanism explains the deleterious effects of SF1 missense mutations, recent studies have demonstrated an additional dominant negative effect. These data suggest that heterozygous mutation impaired adrenal development only if the two mechanisms, gene dosage and dominant negative effects occur.

Published
2004
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7. Predictive value of maternal second-generation thyroid-binding inhibitory immunoglobulin assay for neonatal autoimmune hyperthyroidism

Author

Karim Chikh, Jacques Orgiazzi, Juliette Abeillon-du Payrat, Véronique Raverot, Pascal Gaucherand, Anne Charrié, Claire Bournaud, O Claris, Patricia Bretones, Nadine Bossard, Françoise Borson-Chazot, Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN), Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Institut National de la Recherche Agronomique (INRA), Biostatistiques santé, Département biostatistiques et modélisation pour la santé et l'environnement [LBBE], Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS), 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)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hospices Civils de Lyon (HCL), and 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)

Subjects
Male, Pediatrics, endocrine system diseases, Endocrinology, Diabetes and Metabolism, [SDV]Life Sciences [q-bio], Thyroid Gland, Disease, Infant, Newborn, Diseases, 0302 clinical medicine, Endocrinology, Prenatal Exposure Delayed Effects/*immunology, Pregnancy, Pregnancy Complications/*immunology, biology, Thyroid, General Medicine, Graves Disease, 3. Good health, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Predictive value of tests, Prenatal Exposure Delayed Effects, Female, France, Antibody, hormones, hormone substitutes, and hormone antagonists, Immunoglobulins, Thyroid-Stimulating, Diseases/*immunology, Adult, medicine.medical_specialty, endocrine system, Thyroid Gland/*immunology, Immunoglobulins, 030209 endocrinology & metabolism, Context (language use), Graves Disease/*immunology, Thyroid-Stimulating/*blood, 03 medical and health sciences, Predictive Value of Tests, Internal medicine, medicine, Humans, Retrospective Studies, Fetus, business.industry, Infant, Newborn, Infant, Retrospective cohort study, medicine.disease, Newborn, Pregnancy Complications, biology.protein, business, Biomarkers, Biomarkers/blood
Abstract

ContextHyperthyroidism occurs in 1% of neonates born to mothers with active or past Graves' disease (GD). Current guidelines for the management of GD during pregnancy were based on studies conducted with first-generation thyroid-binding inhibitory immunoglobulin (TBII) assays.ObjectiveThis retrospective study was conducted in order to specify the second-generation TBII threshold predictive of fetal and neonatal hyperthyroidism, and to identify other factors that may be helpful in predicting neonatal hyperthyroidism.MethodsWe included 47 neonates born in the Lyon area to 42 mothers harboring measurable levels of TBII during pregnancy. TBII measurements were carried out in all mothers; bioassays were carried out in 20 cases.ResultsNine neonates were born with hyperthyroidism, including five with severe hyperthyroidism requiring treatment. Three neonates were born with hypothyroidism. All hyperthyroid neonates were born to mothers with TBII levels >5 IU/l in the second trimester (sensitivity, 100% and specificity, 43%). No mother with TSH receptor-stimulating antibodies (TSAb measured by bioassay) below 400% gave birth to a hyperthyroid neonate. Among mothers of hyperthyroid neonates, who required antithyroid drugs during pregnancy, none could stop treatment before delivery. Analysis of TBII evolution showed six unexpected cases of increasing TBII values during pregnancy.ConclusionMaternal TBII value over 5 IU/l indicates a risk of neonatal hyperthyroidism. Among these mothers, a TSAb measurement contributes to identify more specifically those who require a close fetal thyroid ultrasound follow-up. These results should be confirmed in a larger series.

Published
2014
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8. Late prenatal dexamethasone and phenotype variations in 46,XX CAH: concerns about current protocols and benefits for surgical procedures

Author

Daniela Gorduza, Véronique Tardy-Guidollet, Elsa Robert, Claire-Lise Gay, Pierre Chatelain, Michel David, Patricia Bretones, Anne Lienhardt-Roussie, Aude Brac de la Perriere, Yves Morel, and Pierre Mouriquand

Subjects
Pediatrics, medicine.medical_specialty, Urology, Gestational Age, Dexamethasone, Drug Administration Schedule, Pregnancy, Medicine, Humans, Sex organ, Congenital adrenal hyperplasia, Genital tubercle, Glucocorticoids, Retrospective Studies, Fetal Therapies, Adrenal Hyperplasia, Congenital, business.industry, Infant, Surgical procedures, medicine.disease, Virilism, Large cohort, Phenotype, Pediatrics, Perinatology and Child Health, Gestation, Female, business, medicine.drug
Abstract

Objective To describe the action of prenatal dexamethasone (PreDex) on the anatomy of female congenital adrenal hyperplasia (CAH) genitalia when started at later stages of gestation. Materials and methods Our group follows a large cohort of French CAH patients who underwent PreDex therapy, of whom 258 were recently reported. Four 46,XX patients with a delayed PreDex treatment presented with a virilized genitalia and required surgical reconstruction. This is a retrospective report on genital phenotyping at the time of surgery of these four patients who began PreDex therapy at 8, 12, 20, and 28 weeks of gestation. Results Although this series is limited in number, the anatomical description of the length of the genital tubercle, the height of the urethra–vaginal confluence, and the degree of fusion of the genital folds seems to be dependent upon the starting date of PreDex. Most PreDex treatments prescribed up to now have covered the full duration of gestation. Conclusions Our findings suggest that PreDex therapy could be limited to the period of the partitioning window. It is hoped that further prospective multicentric clinical studies will obtain ethical approval in order to elucidate the place and protocols of PreDex therapy in the management of CAH.

Published
2013

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