Purpose: Isolated growth hormone deficiency (IGHD) is a rare condition mainly caused by mutations in GH1. The aim of this study was to assess the contribution of GHRHR mutations to IGHD in a very large cohort of patients.
Methods: All GHRHR coding exons and flanking intronic regions were sequenced in 312 unrelated patients with non-syndromic IGHD. Functional consequences of all newly identified missense variants were assessed in vitro (i.e. study of subcellular localization of recombinant GHRHRs and their ability to activate the cAMP pathway). Genotypephenotype correlation analyses were performed according to the nature of the identified mutation.
Results: We identified 20 different disease-causing GHRHR mutations, among which 15 are novel, in 24 unrelated patients. Of note, 54% of those patients represent sporadic cases. The clinical phenotype of patients with at least one missense GHRHR mutation was found to be indistinguishable from that of patients with bi-allelic truncating mutations.
Conclusion: This study, which unveils disease-causing GHRHR mutations in 8% (24/312) of IGHD cases, identifies GHRHR as the second IGHD gene after GH1. This finding, together with the high proportion of sporadic cases among patients with GHRHR mutations and the documented phenotypic impact of missense mutations, represents key data for genetic counselling and future GHRHR testing.
27 - 29 Sep 2018
European Society for Paediatric Endocrinology