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.

• Keywords
• Genetics, Growth hormone deficiency, Hypopituitarism, Pituitary, Short stature,
• MeSH
• Child MeSH
• Phenotype MeSH
• Homeodomain Proteins genetics   MeSH
• Pituitary Gland growth & development   metabolism   MeSH
• Dwarfism, Pituitary genetics   metabolism   physiopathology   MeSH
• Nuclear Proteins genetics   MeSH
• Humans MeSH
• Human Growth Hormone genetics   MeSH
• Adolescent MeSH
• Young Adult MeSH
• Mutation * MeSH
• DNA Mutational Analysis MeSH
• Child, Preschool MeSH
• Prospective Studies MeSH
• Zinc Finger Protein Gli2 genetics   MeSH
• LIM-Homeodomain Proteins genetics   MeSH
• Receptors, Pituitary Hormone-Regulating Hormone MeSH
• Receptors, Neuropeptide MeSH
• Transcription Factor Pit-1 genetics   MeSH
• SOXB1 Transcription Factors genetics   MeSH
• Transcription Factors genetics   MeSH
• Check Tag
• Child MeSH
• Humans MeSH
• Adolescent MeSH
• Young Adult MeSH
• Male MeSH
• Child, Preschool MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Multicenter Study MeSH
• Observational Study MeSH
• Names of Substances
• GHRHR protein, human MeSH Browser
• GLI2 protein, human MeSH Browser
• HESX1 protein, human MeSH Browser
• Homeodomain Proteins MeSH
• Nuclear Proteins MeSH
• Lhx3 protein MeSH Browser
• LHX4 protein, human MeSH Browser
• Human Growth Hormone MeSH
• POU1F1 protein, human MeSH Browser
• Prophet of Pit-1 protein MeSH Browser
• Zinc Finger Protein Gli2 MeSH
• LIM-Homeodomain Proteins MeSH
• Receptors, Pituitary Hormone-Regulating Hormone MeSH
• Receptors, Neuropeptide MeSH
• SOX3 protein, human MeSH Browser
• Transcription Factor Pit-1 MeSH
• SOXB1 Transcription Factors MeSH
• Transcription Factors MeSH

Pituitary development depends on a complex cascade of interacting transcription factors and signaling molecules. Lesions in this cascade lead to isolated or combined pituitary hormone deficiency (CPHD). The aim of this study was to identify copy number variants (CNVs) in genes known to cause CPHD and to determine their structure. We analyzed 70 CPHD patients from 64 families. Deletions were found in three Turkish families and one family from northern Iraq. In one family we identified a 4.96 kb deletion that comprises the first two exons of POU1F1. In three families a homozygous 15.9 kb deletion including complete PROP1 was discovered. Breakpoints map within highly homologous AluY sequences. Haplotype analysis revealed a shared haplotype of 350 kb among PROP1 deletion carriers. For the first time we were able to assign the boundaries of a previously reported PROP1 deletion. This gross deletion shows strong evidence to originate from a common ancestor in patients with Kurdish descent. No CNVs within LHX3, LHX4, HESX1, GH1 and GHRHR were found. Our data prove multiplex ligation-dependent probe amplification to be a valuable tool for the detection of CNVs as cause of pituitary insufficiencies and should be considered as an analytical method particularly in Kurdish patients.

• MeSH
• Child MeSH
• Adult MeSH
• Haplotypes * MeSH
• Homeodomain Proteins genetics   MeSH
• Hypopituitarism genetics   MeSH
• Humans MeSH
• Adolescent MeSH
• Child, Preschool MeSH
• Pedigree MeSH
• Sequence Deletion * MeSH
• Transcription Factor Pit-1 genetics   MeSH
• Check Tag
• Child MeSH
• Adult MeSH
• Humans MeSH
• Adolescent MeSH
• Male MeSH
• Child, Preschool MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Case Reports MeSH
• Names of Substances
• Homeodomain Proteins MeSH
• POU1F1 protein, human MeSH Browser
• Prophet of Pit-1 protein MeSH Browser
• Transcription Factor Pit-1 MeSH