Nicolas Jullien1, Alexandru Saveanu2,3,4,5, Julia Vergier6, Emeline Marquant6, Marie Helene Quentien2, Frederic Castinetti2,3,4, Noémie Galon-Faure7, Raja Brauner8, Zinet Marrakchi Turki9, Maité Tauber10, Mohamed El Kholy11, Agnès Linglart12, Patrice Rodien13, Nora Soumeya Fedala14, Ignacio Bergada15, Christine Cortet-Rudelli16, Michel Polak17, Marc Nicolino18, Chantal Stuckens19, Anne Barlier2,3,4,5, Thierry Brue2,3,4, Rachel Reynaud2,4,6. 1. Aix-Marseille Univ, CNRS, INP, Inst Neurophysiopathol, Marseille, France. 2. Aix-Marseille Université, Institut National de la Santé et de la Recherche Médicale (INSERM), U1251, Marseille Medical Genetics (MMG), Faculté des Sciences médicales et paramédicales, Institut Marseille Maladies Rares (MarMaRa), Marseille, France. 3. Department of Endocrinology, Centre de Référence des Maladies Rares de l'hypophyse HYPO, Hôpital de la Conception, Assistance Publique-Hôpitaux de Marseille (AP-HM), Marseille, France. 4. Centre de Référence des Maladies Rares de l'Hypophyse, CHU Conception, Assistance Publique-Hôpitaux de Marseille (APHM), Marseille, France. 5. Laboratory of Molecular Biology, CHU Conception, Assistance Publique-Hôpitaux de Marseille (APHM), Marseille, France. 6. Paediatric Endocrinology Unit, Department of Paediatrics, CHU Timone Enfants, Assistance Publique-Hôpitaux de Marseille (APHM), Marseille, France. 7. Department of Paediatrics, Centre Hospitalier du Pays d'Aix, Aix-En-Provence, France. 8. Fondation Ophtalmologique Adolphe de Rothschild and Université Paris Descartes, Paris, France. 9. National Institute of Nutrition, Tunis, Tunisia. 10. Paediatric Endocrinology Unit, Department of Paediatrics, Children Hospital, Toulouse University Hospital, Toulouse, France. 11. Department of Pediatrics, Ain Shams University, Cairo, Egypt. 12. Paediatric Endocrinology Unit, Department of Paediatrics, Assistance Publique-Hôpitaux de Paris (AP-HP), Le Kremlin-Bicêtre, France. 13. Endocrinology Department, Angers University Hospital, Angers, France. 14. Endocrinology Department, Bab El Oued University Hospital, Algiers, Algeria. 15. Children Hospital "Ricardo Gutierrez", Bueno-Aires, Argentina. 16. Department of Endocrinology and Diabetology, Lille University Hospital, Lille, France. 17. Paediatric Endocrinology Unit, Department of Paediatrics, Hôpital Universitaire Necker Enfants Malades, Assistance Publique-Hôpitaux de Paris (AP-HP), INSERM U1016, Institut IMAGINE, Paris, France. 18. Paediatric Endocrinology Unit, Department of Paediatrics, Hôpital Femme-Mère-Enfant, Hospices Civils de Lyon (HCL), Bron, France. 19. Department of Paediatrics, Hôpital Jeanne de Flandre, Lille University Hospital, Lille, France.
Abstract
CONTEXT: The international GENHYPOPIT network collects phenotypical data and screens genetic causes of non-acquired hypopituitarism. AIMS: To describe main phenotype patterns and their evolution through life. DESIGN: Patients were screened according to their phenotype for coding sequence variations in 8 genes: HESX1, LHX3, LHX4, PROP1, POU1F1, TBX19, OTX2 and PROKR2. RESULTS: Among 1213 patients (1143 index cases), the age of diagnosis of hypopituitarism was congenital (24%), in childhood (28%), at puberty (32%), in adulthood (7.2%) or not available (8.8%). Noteworthy, pituitary hormonal deficiencies kept on evolving during adulthood in 49 of patients. Growth Hormone deficiency (GHD) affected 85.8% of patients and was often the first diagnosed deficiency. AdrenoCorticoTropic Hormone deficiency rarely preceded GHD, but usually followed it by over 10 years. Pituitary Magnetic Resonance Imaging (MRI) abnormalities were common (79.7%), with 39.4% pituitary stalk interruption syndrome (PSIS). The most frequently associated extrapituitary malformations were ophthalmological abnormalities (16.1%). Prevalence of identified mutations was 7.3% of index cases (84/1143) and 29.5% in familial cases (n = 146). Genetic analysis in 449 patients without extrapituitary phenotype revealed 36 PROP1, 2 POU1F1 and 17 TBX19 mutations. CONCLUSION: This large international cohort highlights atypical phenotypic presentation of constitutional hypopituitarism, such as post pubertal presentation or adult progression of hormonal deficiencies. These results justify long-term follow-up, and the need for systematic evaluation of associated abnormalities. Genetic defects were rarely identified, mainly PROP1 mutations in pure endocrine phenotypes.
CONTEXT: The international GENHYPOPIT network collects phenotypical data and screens genetic causes of non-acquired hypopituitarism. AIMS: To describe main phenotype patterns and their evolution through life. DESIGN:Patients were screened according to their phenotype for coding sequence variations in 8 genes: HESX1, LHX3, LHX4, PROP1, POU1F1, TBX19, OTX2 and PROKR2. RESULTS: Among 1213 patients (1143 index cases), the age of diagnosis of hypopituitarism was congenital (24%), in childhood (28%), at puberty (32%), in adulthood (7.2%) or not available (8.8%). Noteworthy, pituitary hormonal deficiencies kept on evolving during adulthood in 49 of patients. Growth Hormone deficiency (GHD) affected 85.8% of patients and was often the first diagnosed deficiency. AdrenoCorticoTropic Hormone deficiency rarely preceded GHD, but usually followed it by over 10 years. Pituitary Magnetic Resonance Imaging (MRI) abnormalities were common (79.7%), with 39.4% pituitary stalk interruption syndrome (PSIS). The most frequently associated extrapituitary malformations were ophthalmological abnormalities (16.1%). Prevalence of identified mutations was 7.3% of index cases (84/1143) and 29.5% in familial cases (n = 146). Genetic analysis in 449 patients without extrapituitary phenotype revealed 36 PROP1, 2 POU1F1 and 17 TBX19 mutations. CONCLUSION: This large international cohort highlights atypical phenotypic presentation of constitutional hypopituitarism, such as post pubertal presentation or adult progression of hormonal deficiencies. These results justify long-term follow-up, and the need for systematic evaluation of associated abnormalities. Genetic defects were rarely identified, mainly PROP1 mutations in pure endocrine phenotypes.
Authors: Sebastian Alexis Vishnopolska; Maria Florencia Mercogliano; Maria Andrea Camilletti; Amanda Helen Mortensen; Debora Braslavsky; Ana Keselman; Ignacio Bergadá; Federico Olivieri; Lucas Miranda; Roxana Marino; Pablo Ramírez; Natalia Pérez Garrido; Helen Patiño Mejia; Marta Ciaccio; Maria Isabel Di Palma; Alicia Belgorosky; Marcelo Adrian Martí; Jacob Otto Kitzman; Sally Ann Camper; Maria Ines Pérez-Millán Journal: J Clin Endocrinol Metab Date: 2021-06-16 Impact factor: 6.134
Authors: Kaisa Kyöstilä; Julia E Niskanen; Meharji Arumilli; Jonas Donner; Marjo K Hytönen; Hannes Lohi Journal: Hum Genet Date: 2021-02-06 Impact factor: 4.132