ESPE Abstracts (2016) 86 RFC14.1

Important Contribution of GH, GHRHR and GHSR Mutations in Isolated Growth Hormone Deficiency with a Normal Location of the Posterior Pituitary -Functional Characterization of New Variants

Enzo Cohena, Marie-Laure Sobriera, Florence Dastotb, Nathalie Collotb, Sophie Roseb, Aude Soleyanb, Marie-Pierre Vie-Lutona,b, Philippe Duquesnoya, Bruno Copina,b, Serge Amselema,b & Marie Legendrea,b

aInserm UMR_S933 and UPMC Univ Paris 06, Hôpital Trousseau, Paris, F-75012, France; bU.F. de Génétique clinique et moléculaire, AP-HP, Hôpital Trousseau, Paris, F-75012, France

Background: Although growth hormone (GH) and the GH releasing hormone receptor (GHRHR) are known as etiologic factors in non-syndromic isolated growth hormone deficiency (IGHD), very few mutations have been identified in this rare condition (accounting for only 6–12.5% and 0–6.7% of IGHD cases depending on studies). The functional consequences of the identified variants have rarely been assessed.

Objective and hypotheses: To assess the contribution of mutations in GH, GHRHR and GHSR in IGHD pathogenesis in a large cohort of patients with a non-syndromic IGHD and normal posterior pituitary.

Method: The GH gene was analyzed in 360 independent patients; the GHRHR gene was subsequently analyzed in the remaining 320 patients (those with no identified GH defect and available DNA); the GHSR gene was analyzed in a subset of 226 patients with partial IGHD. The GHRHR variants were assessed through a GHRH-induced CRE-dependent luciferase assay.

Results: GH mutations were identified in 40 independent patients (40/360, 12%), 17 of them (42.5%) representing familial forms of IGHD. These include 6 novel mutations (1 nonsense, 1 splice, 4 missense). We identified GHRHR mutations in 22 patients (22/320, 7%), 8 of them (36%) representing familial cases. The GHRHR mutation spectrum (6 truncating, 2 splice, 9 missense) comprises 11 novel mutations. Functional studies showed that 6 of the GHRHR missense variations are loss-of-function mutations. GHSR mutations were identified in 7 independent probands (7/233, 3%).

Conclusion: This study, which was performed in a large cohort of independent patients, identified unambiguous molecular defects in GH, GHRHR or GHSR in almost 20% of the patients (69/360). Such high rate of mutation detection underlines the need to screen these genes in non-syndromic forms of IGHD with a normal location of the posterior pituitary. Noteworthy, 58% (41/69) of the patients with a GH, GHRHR or GHSR defect represent sporadic cases.