ESPE Abstracts (2018) 89 FC9.2

Contribution of Functionally Assessed GHRHR Mutations to Idiopathic Isolated Growth Hormone Deficiency in a Cohort of 312 Unrelated Patients

Enzo Cohena, Sabrina Belkacema, Soumeya Fedalab, Nathalie Collota, Eliane Khalloufc, Florence Dastota, Michel Polakd, Philippe Duquesnoya, Frederic Brioudee, Sophie Rosea, Géraldine Viotf, Aude Soleyana, Jean-Claude Carelg, Marie-Laure Sobriera, Philippe Chansonh,i, Frédérique Gatelaisj, Claudine Heinrichsk, Noureddine Kaffell, Regis Coutantj, Şenay Savaş Erdevem, Zehra Aycanm, Caroline Thalassinosd, Stanislas Lyonnetn, Zeynep Şıklaro, Merih Berberogluo, Cécile Brachetk, Serge Amselema & Marie Legendrea


aDépartement de Génétique, Sorbonne Université, INSERM UMR_S933, Hôpital Trousseau, AP-HP, Paris, France; bHôpital Lamine Debaghine, CHU Bab El Oued, Bab El Oued, Algeria; cHôtel Dieu de France, Endocrinologie et Diabétologie Pédiatrique, Beyrouth, Lebanon; dHôpital Necker, Service d’Endocrinologie Pédiatrique, Paris, France; eHôpital Trousseau, Explorations Fonctionnelles Endocriniennes, Paris, France; fCHU Paris Centre, Maternité Port Royal, Unité de Diagnostic Anténatal et Médecine fœtale, AP-HP, Paris, France; gHôpital Robert Debré, Service d’Endocrinologie pédiatrique, Paris, France; hHôpital de Bicêtre, Service d’Endocrinologie et des Maladies de la Reproduction et Centre des références des Maladies Rares de l’Hypophyse, Le Kremlin-Bicêtre, Paris, France; iUMR S1885, Faculté de Médecine Paris-Sud, Univ Paris Sud, Université Paris-Saclay, Le Kremlin-Bicêtre, Paris, France; jCHU d’Angers, Département d’endocrinologie, diabétologie et nutrition, Angers, France; kHôpital Universitaire des Enfants Reine Fabiola, Service d’Endocrinologie, Brussels, Belgium; lDar Attabib, Complexe Médical Multidisciplinaire, Endocrinologie, Sfax, Tunisia; mHealth Sciences University, Dr Sami Ulus Obstetrics and Gynecology, Children’s Health and Disease, Health Implementation and Research Center, Ankara, Turkey; nDépartement de Génétique et Institut Imagine, Paris Descartes-Sorbonne Paris Cité University, Hôpital Necker-Enfants Malades, APHP, Paris, France; oDepartment of Pediatric Endocrinology, Medical School of Ankara University, Ankara, Turkey


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). Genotype–phenotype 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.

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