For decades, the dominant conceptual framework for understanding short and tall stature was centered on the GH-IGF-I axis. However, recent findings in basic molecular and cellular biology and in clinical genetics have uncovered a vast array of other regulatory systems that control skeletal growth and an accompanying vast array of genetic defects outside the GH-IGF-I axis that can cause disorders of linear growth. As a result, the traditional view of short or tall stature that is centered on the GH-IGF-I axis is now far too narrow to encompass the ever-growing number of defects that cause abnormal linear growth. A much broader conceptual framework can be based on the simple concept that linear growth disorders are necessarily due to dysfunction of the growth plate, the structure responsible for bone elongation and therefore overall body size. Consequently, short stature can more generally be conceptualized as a primary or secondary disorder of the growth plate chondrocytes. The wide array of genetic defects, many newly-discovered, that affect growth plate chondrocyte function and thereby cause childhood growth disorders will be reviewed. A novel concept that has emerged from recent findings is that sequence variants in a single gene can produce a phenotypic spectrum that ranges from a severe skeletal dysplasia to disproportionate or proportionate short stature, to normal variation in height, to tall stature. The recent advances reviewed in this paper are steadily diminishing the number of children who receive the unhelpful diagnoses of severe idiopathic short stature or tall stature.
27 - 29 Sep 2018
European Society for Paediatric Endocrinology