Genetic Analysis of Short Children with Apparent Growth Hormone Insensitivity

Abstract

Background/Aims: 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 GH1, GHR, STAT5B, IGF1, and IGFALS in children with GH insensitivity. Subjects and Methods: 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. Results: Three patients in group 1 had two novel heterozygous STAT5B mutations, in two combined with novel IGFALS 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. Conclusion: In severely short children with IGF-I deficiency, genetic assessment is advised. Heterozygous STAT5B mutations, with or without heterozygous IGFALS defects, may be associated with GH insensitivity. In children with less severe short stature or IGF-I deficiency, functional variants are rare.

Genetic characterisation of a cohort of children clinically labelled as GH or IGF1 insensitive: diagnostic value of serum IGF1 and height at presentation

“…A higher prevalence of genetic variants, identified by single gene sequencing, has been reported in children with heights !K2.5 SDS compared with less severely affected subjects (24). However, although this is a logical hypothesis, these results need confirmation.…”

Copy number variants in patients with short stature

“…Case II.14 carries a duplication of TBL1X (alias TBL1), encoding for transducin beta-like protein 1 (TBL1), which is required for Wnt-beta-catenin-mediated transcription. 39 Case II.17, described previously, 12 carries a duplication of 3p12.3 containing part of ROBO2, encoding a receptor for SLIT2 and probably SLIT1, thought to function in axon guidance and cell migration. 40 Case II.21, born SGA, length À3.7 SDS and head circumference À3.1 SDS presented with clinodactily, a protruded [30][31][32][33] Associated with fibrillin-1 function.…”

“…In two previous papers from our group, 11,12 we have described the results of a candidate gene approach in children with short stature, either associated with a low birth size (small for gestational age, SGA) 13 or with a normal birth size (idiopathic short stature). 14 In this article, we describe the results of a genome-wide analysis for CNVs using SNP arrays in short children, in an effort to identify novel gene variants associated with short stature.…”

Next generation sequencing-based mutation screening of 86 patients with idiopathic short stature

“…Moreover, mutations in GHR, IGFALS, and IGF1R have been detected in patients with normal blood levels of GH and IGF1 [10][11][12]. In fact, although IGF1R mutations usually underlie short stature with small for gestational age (SGA), such mutations have also been linked to ISS without SGA [12][13][14].…”