Background: IGF1R is a keystone of foetal growth regulation by mediating the effects of both IGF-I and IGF-II. Recently the first clinical cohort of patients carrying an IGF1R defect has been reported from which a clinical score was established for diagnosis. Since no external validation of this score is available we assessed it in a large cohort of patients with identified IGF1R defects. Furthermore we aim at setting-up a functional test to allow classification of unknown significance variants in vitro.
Methods: DNA was tested for either deletions or point mutations. By western blot and from fibroblasts of nine patients, we studied the phosphorylation of downstream pathways after stimulation with IGF-I.
Results: Twenty-one IGF1R independent defects were detected in 35 patients, including eight deletions and 10 heterozygous, one homozygous and one compound heterozygous variants. Main clinical characteristics of these patients were being born small for gestational age (90.9%), adult short stature (78.3%) and microcephaly (74.1%). Feeding difficulties and variable degrees of developmental delay were highly prevalent (54.5%). No difference in phenotypes was observed between patients with deletions or mutations of IGF1R. Functional studies showed that the six missense variants that were tested were associated with a decreased in AKT phosphorylation.
Conclusion: We report eight new pathogenic variants in IGF1R and an original case with a homozygous variant. We demonstrated that the recently proposed clinical score was accurate for the diagnosis of IGF1R defects. We developed an efficient functional test to assess pathogenicity of such variants, which is useful especially for those variants with unknown significance.
19 - 21 Sep 2019
European Society for Paediatric Endocrinology