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  • Review Article
  • Published:

Short and tall stature: a new paradigm emerges

Nature Reviews Endocrinology volume 11, pages 735–746 (2015)Cite this article

Subjects

Key Points

  • Linear growth (that is, gain in height) is determined by the rate of growth plate chondrogenesis

  • Short stature is caused by decreased chondrogenesis whereas tall stature is the result of increased chondrogenesis

  • The rate of growth plate chondrogenesis is regulated by many systems, including those related to intracellular, paracrine and extracellular matrix factors, as well as endocrine mechanisms

  • Findings from the past decade have identified many new genetic defects responsible for short and tall stature that occur across the systems that regulate growth plate activity

  • Similarly, genome-wide association studies have revealed that the normal variation in height seems to be due to many genes that affect the growth plate through a variety of mechanisms

  • These new findings suggest a novel conceptual framework for understanding short and tall stature, which is centred on the growth plate—the structure responsible for height gain

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.

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Figure 1: Human growth plate histology from an 11-year old boy.
Figure 2: Regulation of growth plate function.
Figure 3: The phenotypic spectrum caused by genetic variants in genes that regulate growth plate chondrogenesis.

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Authors and Affiliations

  1. Section on Growth and Development, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, 10 Center Drive, MSC-1103, Bethesda, 20892, MD, USA

    Jeffrey Baron

  2. Division of Pediatric Endocrinology, Department of Women's and Children's Health, Karolinska Institutet, SE-171 76, Stockholm, Sweden

    Lars Sävendahl & Ola Nilsson

  3. Saint Christopher's Hospital for Children, Section of Endocrinology and Diabetes, 160 East Erie Avenue, Philadelphia, 19134, PA, USA

    Francesco De Luca

  4. Division of Endocrinology, Cincinnati Center for Growth Disorders, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, 45229, OH, USA

    Andrew Dauber

  5. The Jesse Z and Sara Lea Shafer Institute for Endocrinology and Diabetes, National Center for Children's Diabetes, Schneider Children's Medical Center of Israel, 14 Kaplan Street, Petah Tikva, 49202, Israel

    Moshe Phillip

  6. Department of Pediatrics, Leiden University Medical Center, PO Box 9600, Leiden, 2300 RC, Netherlands

    Jan M. Wit

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Contributions

J.B., F.D.L., A.D., J.M.W. and O.N. researched data for the article, made substantial contributions to discussion of the content, wrote the article and reviewed/edited the manuscript before submission. L.S. made substantial contributions to discussion of the content, wrote the article and reviewed/edited the manuscript before submission. M.P. made substantial contributions to discussion of the content and reviewed/edited the manuscript before submission.

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Correspondence to Jeffrey Baron.

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Competing interests

J.B. is listed as a co-inventor on a patent application by the NIH for targeted treatment of cartilage disorders. L.S. has received speakers' honoraria and/or research support from Ferring, Merck Serono, Novo Nordisk and Pfizer, and has submitted a patent application for novel peptides to treat bone or cartilage disorders and other diseases. A.D. has been a faculty speaker at continuing medical education symposia sponsored by Ipsen, Novo Nordisk and Sandoz. M.P. has received research support from Novo Nordisk, Pfizer and Teva, personal fees from Novo Nordisk and is a director of NG Solutions. J.M.W. has served as a consultant for Ammonett, Biopartners, Merck Serono, OPKO, Pfizer, Teva and Versartis, and has received speakers' honoraria from Lilly, Merck Serono, Pfizer, Sandoz and Versartis. O.N. has received a European Society for Paediatric Endocrinology research fellowship sponsored by Novo Nordisk and speaker's honoraria from Lilly. F.D.L. has no competing interests to declare.

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Baron, J., Sävendahl, L., De Luca, F. et al. Short and tall stature: a new paradigm emerges. Nat Rev Endocrinol 11, 735–746 (2015). https://doi.org/10.1038/nrendo.2015.165

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