Deficiency of the circulating insulin-like growth factor system associated with inactivation of the acid-labile subunit gene

The growth-promoting actions of growth hormone were originally hypothesized to be mediated through a circulating liver-generated sulfation factor that later came to be known as insulin-like growth factor I (IGF-I).(1) This growth factor is produced in almost every tissue in the body.(2) In the cartilage growth plate, growth hormone-induced IGF-I-3 acts locally through autocrine paracrine mechanisms.(4) Some 80 to 85 percent of IGF-I circulates as a 150-kD ternary complex that includes the ligand itself, IGF-binding protein 3, and an acid-labile subunit.(5) The acid- labile subunit is a glycoprotein found almost exclusively in the circulation and produced in the liver under growth hormone stimulation.(6,7) This subunit stabilizes the IGF-IGF-binding protein 3 complex, reduces the passage of IGF-I to the extravascular compartment, and extends its half-life.(8) Recently, the role of circulating IGF-I in growth has been challenged by the finding that specific disruption of the hepatic igf1 gene in mice, the main source of circulating IGF-I,(9,10) or the inactivation of the gene encoding the acid-labile subunit protein (igfals) in mice(11) has a minor effect on growth, despite causing a profound reduction in the serum IGF-I level. In this report, we describe a 17-year-old boy who had a delayed onset of puberty, slow pubertal progress, and yet minimal slowing of his linear growth in association with an inactivation of the IGFALS gene.