Mammalian growth is an extraordinarily complex phenomenon, regulated by a panoply of genetic and environmental factors. In light of this, it is all the more extraordinary that the combination of targeted gene knock-out studies and human mutational analysis has convincingly demonstrated that the Insulin-like growth factor (IGF) system is responsible for a significant portion of both intrauterine and postnatal growth. IGF production in utero is essentially growth hormone (GH) independent, whilst postnatally it is profoundly growth GH-dependent. Accordingly, GH deficiency or insensitivity is characterized by near-normal prenatal growth, but severe postnatal growth failure; prenatal IGF deficiency or resistance, on the other hand, results in combined intrauterine and postnatal growth retardation.
Over the last two years, our IGF Deficiency Research Centre has collected serum, DNA, or cells from approximately 200 individuals presenting with various degrees of growth failure and/or GH resistance. Molecular diagnoses have been established, and confirmed, where possible, by functional studies, in patients with mutations of the extracellular, transmembrane or intracellular domains of the GH receptor (n=20), the gene for signal transducer and activator of transcription (STAT5b; n=6), the gene for the acid labile subunit (ALS; n=3), and the gene for the IGF-I receptor (n=3). These cases serve to underscore the critical role of the IGF system in human growth and provide a framework for speculating on factors that have regulated growth in hominids.