Screening a large pediatric cohort with GH deficiency for mutations in genes regulating pituitary development and GH secretion: Frequencies, phenotypes and growth outcomes
| Autor: | Marie-Laure Sobrier, Serge Amselem, Heike Pfäffle, Cheri Deal, Charmian A. Quigley, Jurgen Klammt, John S. Parks, Ron G. Rosenfeld, Alan Zimmerman, Roland Pfäffle, Gordon B. Cutler, Marie Legendre, Marie-Pierre Luton, Christine Jones, Werner F. Blum, Christopher J. Child, Jan Lebl |
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| Přispěvatelé: | Universität Leipzig [Leipzig], Justus-Liebig-Universität Gießen = Justus Liebig University (JLU), Maladies génétiques d'expression pédiatrique [CHU Trousseau] (Inserm 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), UF de Génétique moléculaire [CHU Trousseau], Eli Lilly and Company Limited [Windlesham], Eli Lilly and Company [Bad Homburg] (ELC), Eli Lilly and Company [Indianapolis], Sydney Children's hospital, Gordon Cutler Consultancy LLC [Deltaville, VA, USA] (G2C), Université du Québec à Montréal = University of Québec in Montréal (UQAM), University Hospital Motol [Prague], Charles University [Prague] (CU), Oregon Health and Science University [Portland] (OHSU), Emory University School of Medicine, Emory University [Atlanta, GA], Couvet, Sandrine |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Male Receptors Neuropeptide Research paper DNA Mutational Analysis Physiology Hypopituitarism medicine.disease_cause 0302 clinical medicine Receptors Pituitary Hormone-Regulating Hormone Prospective Studies Mutation frequency Child Mutation Human Growth Hormone Nuclear Proteins General Medicine Growth hormone secretion Phenotype Child Preschool Pituitary Gland Cohort Medical genetics Female medicine.symptom Transcription Factor Pit-1 medicine.medical_specialty Adolescent LIM-Homeodomain Proteins 030209 endocrinology & metabolism [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics Neuroendocrinology Zinc Finger Protein Gli2 Short stature General Biochemistry Genetics and Molecular Biology Growth hormone deficiency 03 medical and health sciences Young Adult Internal medicine medicine Genetics Humans Dwarfism Pituitary Genotyping Homeodomain Proteins business.industry SOXB1 Transcription Factors medicine.disease Clinical trial 030104 developmental biology [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics Pituitary business Transcription Factors |
| Zdroj: | EBioMedicine EBioMedicine, 2018, 36, pp.390-400. ⟨10.1016/j.ebiom.2018.09.026⟩ |
| ISSN: | 2352-3964 |
| Popis: | Background: Pituitary development and GH secretion are orchestrated by multiple genes including GH1, GHRHR, GLI2, HESX1, LHX3, LHX4, PROP1, POU1F1, and SOX3. We aimed to assess their mutation frequency and clinical relevance in children with severe GH deficiency (GHD). Methods:The Genetics and Neuroendocrinology of Short Stature International Study (GeNeSIS) was a prospective, open-label, observational research program for pediatric patients receiving GH treatment, conducted in 30 countries between 1999 and 2015. The study included a sub-study to investigate mutations in the genes listed above. PCR products from genomic blood cell DNA were analyzed by Sanger sequencing. DNA variants were classified as pathogenic according to the recommendations of the American College of Medical Genetics and Genomics. Demographic, auxologic, and endocrine data at baseline and during GH treatment were documented and related to the genotyping results. Findings: The analysis comprised 917 patients. In 92 patients (10%) 33 mutations were found, 16 previously described and 17 novel (52%). Mutation carriers were significantly younger, shorter, and more slowly growing than non-carriers. In general, their peak values in GH stimulation tests were very low; however, in 15/77 (20%) patients with GH1, PROP1, and SOX3 mutations they were only moderately diminished (3- 6µg/L). Two patients with a GH1 mutation developed TSH deficiency and one ADH deficiency. Using logistic multi-regression analysis, significant indicators of a mutation were combined pituitary hormone deficiency, greater patient-parent height difference (SDS), low GH peak, and young age. Final height SDS gain in mutation carriers (mean±SD 3.4±1.4) was greater than in non-carriers (2.0±1.4; P |
| Databáze: | OpenAIRE |
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