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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;  PInterpretation  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 .

ebiomedicine

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