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Genetic causes and treatment of isolated growth hormone deficiency—an update

Nature Reviews Endocrinology volume 6, pages 562–576 (2010)Cite this article

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Abstract

Isolated growth hormone deficiency is the most common pituitary hormone deficiency and can result from congenital or acquired causes, although the majority of cases are idiopathic with no identifiable etiology. Known genes involved in the genetic etiology of isolated growth hormone deficiency include those that encode growth hormone (GH1), growth-hormone-releasing hormone receptor (GHRHR) and transcription factor SOX3. However, mutations are identified in a relatively small percentage of patients, which suggests that other, yet unidentified, genetic factors are involved. Among the known factors, heterozygous mutations in GH1 remain the most frequent cause of isolated growth hormone deficiency. The identification of mutations has clinical implications for the management of patients with this condition, as individuals with heterozygous GH1 mutations vary in phenotype and can, in some cases, develop additional pituitary hormone deficiencies. Lifelong follow-up of these patients is, therefore, recommended. Further studies in the genetic etiology of isolated growth hormone deficiency will help to elucidate mechanisms implicated in the control of growth and may influence future treatment options. Advances in pharmacogenomics will also optimize the treatment of isolated growth hormone deficiency and other conditions associated with short stature, for which recombinant human growth hormone is a licensed therapy.

Key Points

  • Mutations have been identified in up to 11% of cases of isolated growth hormone deficiency, with a higher percentage found in familial cases

  • Known genes involved in the genetic etiology of isolated growth hormone deficiency include GH1 (which encodes growth hormone), GHRHR (which encodes growth-hormone-releasing hormone receptor) and SOX3 (which encodes transcription factor SOX3)

  • Unidentified genetic factors may also be involved in the etiology of isolated growth hormone deficiency and their identification could lead to reclassification of the types of isolated growth hormone deficiency in the future

  • Patients with autosomal dominant GH1 mutations have variable phenotypes and, in some cases, can develop additional pituitary hormone deficiencies; lifelong follow-up is, therefore, recommended

  • Genetic variations in growth hormone, its receptor, insulin-like growth factor (IGF) 1, IGF-binding protein 3, or other factors may explain the variability in the therapeutic response to recombinant human growth hormone

  • Further studies are required to elucidate the pharmacogenomics of growth hormone activity, as results so far have not proved conclusive

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Figure 1: Schematic presentation of GH1.
Figure 2: The 13 exons of GHRHR.

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  1. Clinical and Molecular Genetics Unit, UCL Institute of Child Health, 30 Guilford Street, London, WC1N 1EH, UK

    Kyriaki S. Alatzoglou & Mehul T. Dattani

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K. S. Alatzoglou and M. T. Dattani researched the data for the article and both provided a substantial contribution to discussions of the content. K. S. Alatzoglou and M. T. Dattani contributed equally to writing the article and M. T. Dattani reviewed and/or edited the manuscript before submission.

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Alatzoglou, K., Dattani, M. Genetic causes and treatment of isolated growth hormone deficiency—an update. Nat Rev Endocrinol 6, 562–576 (2010). https://doi.org/10.1038/nrendo.2010.147

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