Deficiency of the Circulating Insulin-like Growth Factor System Associated with Inactivation of the Acid-Labile Subunit Gene

Abstract

he 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 autocrineparacrine 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 acidlabile 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.No data regarding gestation and the perinatal period were available, because the boy had been adopted at one week of age, at which time his length and weight were recorded as 47 cm and 2500 g, respectively.His childhood medical history was unremarkable.Psychomotor and neurologic development was normal.At 14.6 years of age, he was referred for evaluation of growth and pubertal delay, at which time his height was 145.2 cm (2.05 SD below the mean), 12 near the third percentile by Argentinean standards (2.37 SD below the mean 13 according to a Tanner growth chart).His weight was 35.9 kg (2.34 SD below the mean), his head circumference 55.2 cm (1.78 SD below the mean), 13 and his body-mass index (the weight in kilograms divided by the square of the height in meters) 17, with Tanner stage 1 for both sexual development and pubic hair; both testes were 3 ml in volume.14 The clinical examination showed no abnormalities, except for mild micrognathia and truncal obesity.The bone age was 12.5 years.15 Routine laboratory analyses ruled out hematologic, liver, and renal diseases.Magnetic resonance imaging of the brain was normal.The growth hormone responses to provocative tests with the use of arginine and clonidine were normal, but there was a marked reduction of both IGF-I (31 ng per milliliter [4.0 nmol per liter]; 5.3 SD below the mean for his chronologic age) and IGF-binding protein 3 (0.22 µg per milliliter [7.7 nmol per t case report