Short and tall stature: a new paradigm emerges

In this Review, Jeffrey Baron and colleagues explore the latest discoveries in the molecular and cell biology of childhood growth and in the clinical genetics of childhood growth disorders. These findings challenge the established theory that childhood growth is primarily controlled by growth hormone and insulin-like growth factor 1, leading the authors to suggest a broader framework for understanding linear growth disorders. In the past, the growth hormone (GH)–insulin-like growth factor 1 (IGF-1) axis was often considered to be the main system that regulated childhood growth and, therefore, determined short stature and tall stature. However, findings have now revealed that the GH–IGF-1 axis is just one of many regulatory systems that control chondrogenesis in the growth plate, which is the biological process that drives height gain. Consequently, normal growth in children depends not only on GH and IGF-1 but also on multiple hormones, paracrine factors, extracellular matrix molecules and intracellular proteins that regulate the activity of growth plate chondrocytes. Mutations in the genes that encode many of these local proteins cause short stature or tall stature. Similarly, genome-wide association studies have revealed that the normal variation in height seems to be largely due to genes outside the GH–IGF-1 axis that affect growth at the growth plate through a wide variety of mechanisms. These findings point to a new conceptual framework for understanding short and tall stature that is centred not on two particular hormones but rather on the growth plate, which is the structure responsible for height gain.