ESPE Abstracts (2015) 84 WG1.1

Short Stature: Blame the Chondrocyte

Jeffrey Baron

NICHD, National Institutes of Health, Bethesda, Maryland, USA

Background: In the past, the GH–IGF1 axis was thought to be the central system regulating childhood growth and therefore responsible for short stature and tall stature.

Objective and hypotheses: The objective of this talk is to conceptualize disorders of linear growth in terms of the underlying growth plate biology.

Method: Powerful, new, unbiased tools have recently been developed to investigate the genetic control of childhood growth. These approaches include genome-wide association studies and exome sequencing. Concomitantly, cell culture, organ culture, and animal studies have helped elucidate the mechanisms regulating growth plate chondrogenesis.

Results: Recent findings have revealed that the GH–IGF1 axis is just one of many regulatory systems that control chondrogenesis in the growth plate, the biological process that drives height gain. Consequently, normal growth in children depends not only on GH and IGF1 but on multiple hormones, paracrine factors, extracellular matrix molecules, and intracellular proteins that regulate growth plate chondrocytes. Mutations in genes encoding many of these local proteins cause short stature or tall stature. Similarly, genome-wide association studies have revealed that the normal variation in height appears to be due largely to genes outside the GH–IGF1 axis that affect growth at the growth plate through a wide variety of mechanisms.

Conclusion: Growth plate chondrogenesis is the final common pathway through which many systems regulate childhood linear growth. Consequently, the primary genetic defects responsible for short and tall stature lie scattered throughout these many regulatory systems at multiple different levels.

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