About this item:

212 Views | 95 Downloads

Author Notes:

Corresponding author at: Friedrich-Stengel-Str. 14, D-61250 Usingen, Germany. wernblum@gmail.com

WFB and JK contributed to the scientific literature search.

WFB, JK, SA, CJC, CJ, AGZ, CAQ, GBC, CLD, JL, RGR, JSP and RWP contributed to the study design.

JK, SA, HMP, ML, M-LS, M-PL, RWP contributed to the genetic analyses.

SA, CLD, JL and RWP contributed to clinical data collection.

WFB, JK, CJC, AGZ, CAQ and RWP contributed to data analyses.

WFB, JK, SA, CJC and RWP drafted the manuscript and all authors provided critical revision of the manuscript.

The authors thank the patients, their families and the contributing physicians and site study coordinators for their participation and engagement in this study.

Special thanks are due to Johannes Weigel and Gunter Flemming for their assistance in targeted sequencing.

he authors thank also the Genome Aggregation Database (gnomAD) and the groups that provided exome and genome variant data to this resource.

The authors thank the NHLBI GO Exome Sequencing Project and its ongoing studies which produced and provided exome variant calls for comparison: the Lung GO Sequencing Project (HL-102923), the WHI Sequencing Project (HL-102924), the Broad GO Sequencing Project (HL-102925), the Seattle GO Sequencing Project (HL-102926) and the Heart GO Sequencing Project (HL-103010).

GeNeSIS was sponsored by Eli Lilly and Company (Lilly, Indianapolis, IN, USA).

The sponsor funded all aspects of study design, data collection, genetic analyses and statistical analyses, but did not impose any impediment, directly or indirectly, on the publication of the study results.

CJC and CJ are employees and stockholders of Lilly, while WFB, AGZ, and CAQ are former employees and stockholders of Lilly, GBC is a former employee of Lilly.

WFB also reports he is a consultant for Ammonett Pharma, Lilly Germany and Merck KGaA Darmstadt.

CLD, JL, RGR, JSP and RWP were members of the GeNeSIS International Scientific Advisory Board and received consulting and speaker fees from Lilly.

The laboratories of SA and RWP received fees and grants from Lilly for setting up and conducting the genetic analyses.

JK, HMP, ML. M-L S, and M-PL have no conflicting interests to report.


Research Funding:

GeNeSIS was sponsored by Eli Lilly and Company (Lilly, Indianapolis, IN, USA). The sponsor funded all aspects of study design, data collection, genetic analyses and statistical analyses, but did not impose any impediment, directly or indirectly, on the publication of the study results.


  • 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
  • PIT-1

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

Show all authors Show less authors


Journal Title:



Volume 36


, Pages 390-400

Type of Work:

Article | Final Publisher PDF


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.

Copyright information:

© 2018 Eli LIlly and Company

This is an Open Access work distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Creative Commons License

Export to EndNote