Short and tall stature: a new paradigm emerges

Abstract

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.

Figure 1

Human growth plate histology from an 11-year old boy. The growth plate comprises three histologically and functionally distinct zones; the resting, proliferative, and hypertrophic zones. Bar represents 100 μm.

Figure 2

Schematic diagram depicting the regulation of growth plate function. Growth plate chondrocyte (grey oval) proliferation and differentiation are regulated by many factors, including nutritional, endocrine, inflammatory cytokines, extracellular fluid (e.g. oxygen, pH), paracrine, extracellular matrix, and intracellular mechanisms. Not depicted are the interactions among many of these systems; for example, nutritional intake strongly affects endocrine regulators of the growth plate.

Figure 3

Diagram depicting the phenotypic spectrum that can be caused by sequence variants in genes that regulate growth plate chondrogenesis. The spectrum shown here applies to genes that promote longitudinal bone growth, such as NPR2. For genes that inhibit longitudinal bone growth, such as FGFR3, the spectrum is reversed in that gain-of-function mutations cause short stature while loss-of-function causes tall stature.