Genetic Disorders of the Hypothalamic-Pituitary-GH/IGF-I Axis

Abstract

Insulin-like growth factor I (IGF-I) is the effector of the growth effects of growth hormone (GH). Genetic disorders resulting in deficiency of IGF-I or resistance to its effects encompass a wide range of abnormalities, beginning with structural malformations of the central nervous system affecting pituitary development. Mutations of critical factors in the differentiation or function of GH-producing cells of the pituitary and mutations of the GH molecule also result in GH deficiency that can be effectively treated with recombinant human (rh) GH injection. These genetic defects account for perhaps 10–15% of all GH deficiency. Peripheral unresponsiveness to GH due to mutation of the cell surface GH receptor (GHR), failure of the GH–GHR interaction to effect IGF-I synthesis because of mutation of transcription factors, and the extremely rare (three cases) mutations of the IGF-I gene result in severe growth failure that cannot be corrected with rhGH therapy. In addition to severe postnatal growth failure, as is seen with mutations resulting in GH deficiency and GHR mutations, the patients with IGF-I gene mutation had intrauterine growth retardation and severe mental retardation, indicative of intrauterine somatic and brain growth dependency on GH-independent IGF-I. Mutations of the signal transducer and activator of transcription 5b (STAT5b) are associated with problems of immuno-incompetence, as well as growth. Mutations of the GH-dependent acid labile subunit (ALS), which stabilizes the binary complex of IGF-I and IGF binding protein 3 in the circulation, result in severe IGF-I deficiency but only modest, at worst, growth impairment, emphasizing the importance of GH stimulation of autocrine/paracrine IGF-I synthesis in growing bone. Heterozygous defects in the IGF-I receptor result in growth failure that is not as severe as with GHR deficiency and is partly responsive to rhGH. These receptor and postreceptor genetic abnormalities account for a tiny fraction of growth failure, not more than about 200 children worldwide.