Screening a Large Pediatric Cohort with GH Deficiency for Mutations in Genes Regulating Pituitary Development and GH Secretion: Frequencies, Phenotypes and Growth Outcomes

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 b .001) and in patients with non-GHD short stature.

Clinical lessons learned in constitutional hypopituitarism from two decades of experience in a large international cohort

“…Genetic analysis revealed an overall incidence of 7.3% of mutations in index cases of this cohort and 5.7% in the subgroup of patients with adult diagnosis of hypopituitarism. Most cases thus remain unsolved 33,34 . Massive parallel sequencing including 8 candidate genes did not identify more mutations than targeted Sanger sequencing based on a phenotypic decisional tree.…”

“…According to Blum et al, significant indicators of a mutation were combined pituitary hormone deficiency, greater patient‐parent height difference (SDS), low GH peak and young age 34 …”

“…Most cases thus remain unsolved. 33,34 In case of negative results in patients with CPHD, genetic analysis must be extended using whole exome or whole genome sequencing in further studies. 25 Further NGS approaches recently led to gene discovery and emergence of guidelines for variants assigning causality.…”

“…We describe for the first time PROP1 or POU1F1 mutations (in 12 and 1 cases, respectively) in patients harbouring extrapituitary features, most of them born from consanguineous unions, which increases the risk of abnormalities linked to other unrelated autosomal recessive disorders. Therefore, PROP1 and POU1F1 analysis should not be excluded in consanguineous CPHD patients with syndromic forms and extrapituitary phenotypes.According to Blum et al, significant indicators of a mutation were combined pituitary hormone deficiency, greater patient-parent height difference (SDS), low GH peak and young age 34.…”