Genetic Analysis of Short Children with Apparent Growth Hormone Insensitivity

Abstract

<b><i>Background/Aims:</i></b> In short children, a low IGF-I and normal GH secretion may be associated with various monogenic causes, but their prevalence is unknown. We aimed at testing <i>GH1</i>, <i>GHR</i>, <i>STAT5B</i>, <i>IGF1</i>, and <i>IGFALS</i> in children with GH insensitivity. <b><i>Subjects and Methods:</i></b> Patients were divided into three groups: group 1 (height SDS <–2.5, IGF-I <–2 SDS, n = 9), group 2 (height SDS –2.5 to –1.9, IGF-I <–2 SDS, n = 6) and group 3 (height SDS <–1.9, IGF-I –2 to 0 SDS, n = 21). An IGF-I generation test was performed in 11 patients. Genomic DNA was used for direct sequencing, multiplex ligation-dependent probe amplification and whole-genome SNP array analysis. <b><i>Results:</i></b> Three patients in group 1 had two novel heterozygous <i>STAT5B</i> mutations, in two combined with novel <i>IGFALS</i> variants. In groups 2 and 3 the association between genetic variants and short stature was uncertain. The IGF-I generation test was not predictive for the growth response to GH treatment. <b><i>Conclusion:</i></b> In severely short children with IGF-I deficiency, genetic assessment is advised. Heterozygous <i>STAT5B</i> mutations, with or without heterozygous <i>IGFALS</i> defects, may be associated with GH insensitivity. In children with less severe short stature or IGF-I deficiency, functional variants are rare.