Determinants of short stature and the response to growth hormone therapy.

Abstract

genes involved in hypothalamic-pituitary development, but this approach may be limited by fundamental differences between murine and human models of disease. In humans, microscopic chromosomal deletions, duplications and translocations identified in patients with rare developmental hypothalamic-pituitary disorders have shown the importance of other disease genes such as SOCS-2 and SOCS-3 . The application of new techniques in these patient populations, such as comparative genomic hybridization and the detection of submicroscopic chromosomal imbalances, may lead to further identification of disease genes. Professor Dattani pointed out that the recent optimization of high-density whole-genome single-nucleotide polymorphism (SNP) arrays may have the potential to identify many disease genes, thereby revolutionizing the field of human growth genetics. The discovery of gene mutations associated with defective GH secretion or GH responsiveness has been a particularly intense area of study, identifying patients with GH insensitivity due to mutations of the GH receptor and individuals with rare IGF-I gene deletions or IGFI receptor mutations. Ron Rosenfeld reviewed the ways in which analysis of these rare human mutations, combined with murine models, has helped us to clarify the GH cascade and its role in mammalian growth. He pointed out that the major regulator of post-natal growth in mammals is mediated through the stimulation of production of IGF-I, its major circulating IGF-binding protein (IGFBP3) and the acid-labile subunit. The regulation of In April 2008, experts from Europe and the USA gathered in Florence, Italy, to review recent advances in ge n etics and genomics and their potential impact on the diagnosis of growth disorders and response to growth hormone (GH) therapy. The identification of individual gene mutations affecting the GH–insulin-like growth factor (IGF)-I axis through hypothalamic-pituitary development, hypothalamic-pituitary signalling, GH production, GH responsiveness, IGF-I generation and, finally, IGF-I signalling through its receptor has accelerated over the past 20 years. These rare genetic variants have clarified and strengthened our view of the importance of the GH–IGF-I axis in regulating preand post-natal growth, but important questions remain about the overall prevalence of these rare genetic disorders and their relevance to GH therapy. The first part of the expert meeting concentrated on identifying new important gene defects that might increase our understanding and enlarge our list of indications for the GH treatment of growth disorders. The second part focused on the potential of genetics and genomics in refining therapeutic targets and assessing treatment response.