Screening a large pediatric cohort with GH deficiency for mutations in genes regulating pituitary development and GH secretion: Frequencies, phenotypes and growth outcomes

• Authors: Werner F. Blum, University of Leipzig; Jurgen Klammt, University of Leipzig; Serge Amselem, Sorbonne Universite; Heike M. Pfaeffle, University of Leipzig; Marie Legendre, Sorbonne Universite; Marie-Laure Sobrier, Sorbonne Universite; Marie-Pierre Luton, Sorbonne Universite; Christopher J. Child, Eli Lilly & Company; Christine Jones, Eli Lilly & Company; Alan G. Zimmermann, Eli Lilly & Company; Charmian A. Quigley, Sydney Children's Hospital; Gordon B. Cutler, Gordon Cutler Consultancy LLC; Cheri L. Deal, University of Montreal; Jan Lebl, Charles University Prague; Ron G. Rosenfeld, Oregon Health & Science University; John Parks, Emory University; Roland W. Pfaeffle, University of Leipzig
• Journal Title: EBioMedicine
• Volume: Volume 36
• Publisher: Elsevier: Creative Commons | 2018-10-01, Pages 390-400
• Type of Work: Article | Final Publisher PDF
• Publisher DOI: http://doi.org/10.1016/j.ebiom.2018.09.026
• Subjects: Health Sciences, General
• Keywords: Science & Technology; Life Sciences & Biomedicine; Medicine, General & Internal; Medicine, Research & Experimental; General & Internal Medicine; Research & Experimental Medicine; Pituitary; Growth hormone deficiency; Hypopituitarism; Genetics; Short stature; SEPTO-OPTIC DYSPLASIA; HORMONE DEFICIENCY; SHORT STATURE; TRANSCRIPTION FACTORS; MIDLINE DEFECTS; CHILDREN; DELETIONS; RECEPTOR; PIT-1; HYPOPITUITARISM

Abstract

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; Clinical Trial Registry Number: NCT01088412) 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 (3-6 μg/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 <.001) and in patients with non-GHD short stature. Interpretation: DNA testing for mutations in children with severe GHD shows a positive finding in approximately 10%. Phenotypes of mutation carriers can be variable. The benefit for clinical practice justifies DNA testing as an important component in the diagnostic work-up of patients with severe GHD. Fund: Eli Lilly and Company, Indianapolis, IN, USA. ClinicalTrials.com registration: NCT01088412.