Abnormal GH receptor signaling in children with idiopathic short stature

Peripheral GH insensitivity may underlie idiopathic short stature in childr en. As the clinical and biochemical hallmarks of partial GH insensitivity h ave not yet been clearly elucidated, the identification of such patients is still difficult. We integrated functional, biochemical, and molecular stud ies to define the more reliable marker(s) of GH insensitivity. In particula r, we measured GH receptor transducing properties through GH-induced protei n tyrosine phosphorylation in patients' peripheral blood mononuclear cells and performed direct sequencing analysis of GH receptor-coding exons. Five of 14 idiopathic short stature patients with low basal IGF-I levels showed low or absent IGF-I increment after 4 d of GH administration. However, a pr olonged GH stimulation induced in 3 of them an increase in IGF-I 40% above the baseline value. The IGF-binding protein-3 behavior paralleled that of I GF-I. The 2 GH-unresponsive subjects showed an abnormal tyrosine phosphoryl ation pattern after GH challenge. Sequence analysis of the GH receptor gene revealed a heterozygous mutation resulting in an Arg to Cys change (R161C) in exon 6 in only 1 patient, who had normal GH receptor responsiveness. Ou r findings indicate that abnormal GH receptor signaling may underlie idiopa thic short stature even in the absence of GH receptor mutations. Thus, comb ining the 4-d IGF-I generation test and the analysis of GH-induced protein tyrosine phosphorylation is a useful tool to help identify idiopathic short stature patients with partial GH insensitivity.