Background

Insulin-like growth factor I (IGF-I) is the effector of growth induced by growth hormone (GH). IGF-I deficiency can be the result of GH resistance or insensitivity due to genetic disorders of the GH receptor causing GH receptor deficiency (GHRD, Laron syndrome) or postreceptor defects, including the principal transduction agent STAT5b, the IGF-I/IGFBP3 stabilizer acid labile subunit (ALS), the IGF-I gene, or the IGF-I receptor.Acquired forms of GH insensitivity include the rare GH1 mutation (in which GH inhibiting antibodies develop after a few months of replacement therapy with recombinant GH) and, far more commonly, malnutrition, hepatic disease, renal disease, and diabetes.

Pathophysiology

The GH molecule binds to its specific cell surface receptor (GHR), which dimerizes with another GHR molecule so that the single GH molecule is enveloped by 2 GHR molecules. The intact receptor lacks tyrosine kinase activity, but binding of GH and dimerization results in association with JAK2, a member of the Janus kinase family, which results in self-phosphorylation of the JAK2 and a cascade of phosphorylation of cellular proteins. The most critical of these proteins is the signal transducer and activator of transcription 5b (STAT5b), which couples GH binding to the activation of gene expression that leads to the intracellular effects of GH, including synthesis of IGF-I, insulin-like growth factor binding protein 3 (IGFBP3), and ALS.

Hepatic IGF-I circulates almost entirely bound to IGF binding proteins (IGFBPs), with less than 1% being free. The IGFBPs are a family of 6 structurally related proteins with a high affinity for binding IGF. The principal BP, IGFBP3, binds approximately 90% of circulating IGF-I in a large (150-200 kD) ternary complex consisting of IGFBP3, ALS, and the IGF molecule. The ALS stabilizes the IGF–IGFBP3 complex, reduces the passage of IGF-I to the extravascular compartment, and extends its half-life.

IGF binding involves 3 types of receptors: the structurally homologous insulin receptor and type 1 IGF receptor and the distinctive type 2 IGF-II/mannose-6-phosphate receptor. Although the insulin receptor has a low affinity for IGF-I, IGF-I is present in the circulation at molar concentrations that are 1000 times those of insulin. Thus, even a small insulin-like effect of IGF-I could be more important than that of insulin itself, were it not for the IGFBPs that control the availability and activity of IGF-I. In fact, intravenous infusion of recombinant human IGF-I (rhIGF-I) can induce hypoglycemia, especially in the IGFBP3 deficient state.

Clinical Presentation

The clinical features of GHRD are not different than those of severe GH deficiency. Postreceptor Continue reading »