ESPE Abstracts (2016) 86 RFC14.2

Contribution of GHR and IGFALS Mutations to Growth Hormone Resistance - Identification of New Variants and Impact on the Inheritance Pattern

Marie Legendrea,b, Florence Dastotb, Nathalie Collotb, Philippe Duquesnoya, Enzo Cohena, Marie-Laure Sobriera, Paola Adiceamc, Donald Andersond, Sabine Barone, Sylvie Cabrolf, Bert Callewaertg, Maryse Cartignyh, Margarita Craeni, Patricia Crockd, Asmahane Ladjouzej, Cecilia Lazeak, Michel Polakl, Lars Savendahlm, Asmae Touzanin & Serge Amselema,b

aInserm UMR_S933 and UPMC Université Paris 06, Hôpital Trousseau, Paris, F-75012, France; bU.F. de Génétique moléculaire, Hôpital Trousseau, AP-HP, Paris, F-75012, France; cService de Pédiatrie, CH du Pays d’Aix, Aix en Provence 13616, France; dPaediatric Diabetes and Endocrine Service, John Hunter Children’s Hospital, New Lambton Heights NSW 2305, Australia; eClinique Médicale Pédiatrique, CHU de Nantes, Nantes 44093, France; fExplorations fonctionnelles endocriniennes, Hôpital Trousseau, AP-HP, Paris, F-75012, France; gCenter of Medical Genetics, Ghent University Hospital, Ghent B-900, Belgium; hService d’endocrinologie diabétologie, Hôpital Jeanne de Flandres, Lille, F-59000, France; iPediatrie, UZ Gent, Ghent B-900, Belgium; jEndocrinologie Pédiatrique, Hôpital de Bab El Oued, Alger, Algeria; kClinica Pediatrie I, Cluj 400370, Romania; lService d’Endocrinologie pédiatrique, Hôpital Necker, AP-HP, Paris, F-75015, France; mPediatrics Endocrinology, Karolinska Hospital, Stockholm, Sweden; nEndocrinologie Diabétologie Pédiatrique, Rabat 10000, Morocco

Background: Bi-allelic GHR mutations are classically responsible for Laron syndrome, a severe growth hormone (GH) resistance syndrome. A few GHR missense mutations have also been implicated in mild GH resistance or idiopathic short stature. IGFALS mutations are responsible for recessive or semi-dominant short stature with normal GH provocative test contrasting with extremely low IGF-I levels.

Objective and hypotheses: To assess the contribution of GHR and IGFALS mutations to severe and mild non-syndromic GH resistance, and study the correlation between the genotype and resistance severity.

Method: All GHR and IGFALS coding regions were analyzed by Sanger sequencing in 92 independent patients with normal or high GH secretion test (>20 mUI/l) associated with low IGF-I levels (<−2SD) and/or short stature.

Results: GHR mutations were identified in 16% of the patients (15/92) and IGFALS mutations in 5% of them (5/92). Among the patients with GHR mutations, a recessive transmission was found for 11 probands with a severe growth delay (<−4SD). A less severe dominant phenotype was observed in 4 families. Among the recessive cases, 4 carried a bi-allelic truncating mutation, 1 was a compound heterozygote (splice, missense mutation), 4 had bi-allelic missense mutations in the GHR extracellular domain. A dominant GH resistance was associated with a GHR mutation in 4 families (1 splice, 3 missense mutations). Interestingly, 2 neighboring mutations c.876-2_876-1delAG and c.876G>T were respectively responsible for a recessive and a dominant form of GH resistance, underlining the impact of a complex alternative splicing pattern on nonsense-mediated mRNA decay. IGFALS mutations were identified in 5 independent patients: 2 homozygotes for truncating mutations, 1 compound heterozygote (whole gene deletion, missense mutation), and 2 heterozygotes (1 deletion, 1 missense).

Conclusion: Overall, this study, performed in a large cohort of patients with GH resistance (n=92), identifies molecular defects in GHR and IGFALS in 20% of the patients.

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