Background/ Aim: Over the past 6 years, the IGF1/ IGFBP3 generation test (IGFGT) has been used in Belgium in a standardized form to identify children with severe primary IGF1 deficiency (SPIGFD). In this study, the discordance of the IGF1 and IGFBP3 responses during an IGFGT and the prevalence of SPIGFD were analyzed in a cohort of children with short stature (height SDS < - 2) and presenting with low (below lower reference limit) serum IGF1 level and normal stimulated GH peak (> 7 µg/L).
Methods: In total, 56 (35 male) children aged between 1.3 and 14.8 years (median 7.5) underwent an IGFGT. Only 34 IGFGT were analyzed, because of non-persisting low serum IGF1 values and/or an underlying chronic disease in 22 children. Morning serum IGF1 and IGFBP3 concentrations were measured by the IDS-iSYS assay before and after 7 daily injections of GH (0.05 mg/kg bodyweight somatotropin) in the evening. An abnormal IGF1/ IGFBP3 response was defined by a stimulated value remaining below gender and age specific basal reference limits. SPIGFD was defined by a low basal IGF1 together with a IGF1 response < 15 µg/l and a IGFBP3 response < 400 µg/l during the IGFGT.
Results: In 16/34 (47%) children, a normal basal serum IGF1 by the IDS-iSYS assay was measured and paralleled with a normal serum IGFBP3 in 13 cases. Twelve (67 %) of the 18 children with a confirmed low basal IGF1 had a low serum IGFBP3, 6 (33 %) had an abnormal IGF1 response and the same 6 cases had an abnormal IGFBP3 response, whereas 6 had a IGF1 response < 15 µg/l, 5 had a IGFBP3 response < 400 µg/l and 4 had both responses below the defined limits. Genetic studies in 3 of these 4 cases confirmed a pathogenic heterogenous GHR gene mutation (c.899 dup p. and c.876G>T) in 2 cases and a pathogenic PTPN11 mutation in another case.
Conclusion: In short children with persistent low IGF1 values and a normal stimulated GH peak, a low IGF1 status could be confirmed in only half of the cases using the IDS-iSYS assay. In those children, a 100 % concordance between low stimulated IGF1 and low stimulated IGFBP3 levels was observed during a standardized (high dose and prolonged up to 7 days) IGF1/ IGFBP3 generation test, permitting finally the biochemical diagnosis of a severe primary IGF1 deficiency in 12 %.
15 Sep 2022 - 17 Sep 2022