An endocrine and molecular study of idiopathic short stature
This project investigated possible mechanisms of impaired growth in 23 children with ISS by analysing the activity of the GH-IGF-I axis by assessment of spontaneous GH secretion, and IGF-I and IGFBP-3 responses in standard and low dose IGF-I generation tests. The GH receptor (GHR) gene was analysed in a subgroup of children with evidence of impaired GH responsesiveness. The role of the short stature homeobox containing gene (SHOX) in the regulation growth was studied by gene analysis in 50 children with ISS, and investigation of the effect of SHOX gene expression n osteoblast differentiation in vitro. Endocrine evaluation demonstrated low basal serum IGF-I, more likely to reflect GH insufficiency than GH insensitivity. Impaired GH responsiveness was observed in 6/23 subjects, 1 of whom had a missense (S375C) and a nonsense mutation (Q431X) in exon 10, and 4 a previously reported polymorphism (A780G) in exon 6. Analysis of the SHOX gene identified a missense mutation in exon 2 (Q92K) in a subject with impaired GH responsiveness and disordered GH secretion. Another subject was either homozygous for a polymorphism in intron 3, or was haploinsufficeint for SHOX. Murine multipotential cells (C3H10T½) were transfected with SHOX and stimulated to undergo osteoblast differentiation. In this model, SHOX gene expression inhibited osteoblast differentiation and proliferation. By clarifying the role of partial GH insensitivity in the aetiology of ISS, and identifying the primary role of SHOX, it may be possible to explore new, more accurately directed interventions for the treatment of impaired growth.