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Nat Rev Endocrinol. 2015 Dec;11(12):735-46. doi: 10.1038/nrendo.2015.165. Epub 2015 Oct 6.

Short and tall stature: a new paradigm emerges.

Author information

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, MD 20892, USA.
Division of Pediatric Endocrinology, Department of Women's and Children's Health, Karolinska Institutet, SE-171 76, Stockholm, Sweden.
Saint Christopher's Hospital for Children, Section of Endocrinology and Diabetes, 160 East Erie Avenue, Philadelphia, PA 19134, USA.
Cincinnati Center for Growth Disorders, Cincinnati Children's Hospital Medical Center, Division of Endocrinology, 3333 Burnet Avenue, Cincinnati, OH 45229, USA.
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.
Department of Pediatrics, Leiden University Medical Center, PO Box 9600, Leiden, 2300 RC, Netherlands.


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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Conflict of interest statement

Declaration of interests FDL, and JMW have no interests to declare. JB is listed as a co-inventor on a patent application by the National Institutes of Health for targeted treatment of cartilage disorders. LS has received speakers’ honoraria and/or research support from Novo Nordisk, Pfizer, Ferring, and Merck Serono and has submitted a patent application for novel peptides to treat bone or cartilage disorders and other diseases. AD has been a faculty speaker at continuing medical education symposia sponsored by Novo Nordisk, Sandoz, and Ipsen. MP has received research support from Novo Nordisk, Pfizer, Teva, personal fees from Novo Nordisk, and is a director of NG Solutions Ltd. ON has received an ESPE research fellowship sponsored by Novo Nordisk and speaker’s honorarium from Lilly.

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