Growth is considered as one of the best indicators of a child's health and deviations from the normal range both for height and for rate of growth may indicate an underlying problem (1). The disorders of growth hormone (GH) in childhood comprise a spectrum of clinical conditions characterized by short stature of varying degrees of severity and slow growth caused by either abnormalities in GH itself, the GH-releasing hormone receptor (GHRHR) and the GH receptor (GHR). Abnormalities in GH itself include alterations in the production, regulation, secretion or bioactivity of GH and will be described in this chapter under GH deficiency (GHD). Abnormalities in the GHR may be due to genetic or acquired defects that cause a state of GH resistance or insensitivity and such conditions will be referred in this chapter as GH insensitivity syndromes (GHIS) (2).

The mature pituitary gland contains a functionally diverse population of specialized cell types that produce six hormones: GH, luteinizing hormone (LH), follicle stimulating hormone (FSH), thyroid stimulating hormone (TSH), prolactin (Prl) and adrenocorticotropin (ACTH). This differentiated structure is the result of a complex process that involves activation and repression of numerous genes encoding homeodomain transcription factors (3).

GH is a small protein hormone of 191 amino acids that causes growth of almost all tissues of the body by increasing cell number and cell size and by promoting differentiation of specific cells i.e., muscle cells. GH is secreted in a pulsatile fashion and is under the regulation of the hypothalamic hormones GHRH and somatostatin, (review in Chapter 1). In plasma the majority of GH circulates in the free form but ~40% of GH circulates bound to GH binding protein (GHBP) which in man corresponds to the extracellular domain of the GHR (4). GH signaling requires dimerization of two GHR molecules to exert its full biological action (5). It is well established that one of the most important biological actions of GH is to induce the synthesis of insulin-like growth factor (IGF)-I in the liver and in other extra-hepatic tissues. Most of the circulating IGF-I is derived primarily from hepatic production (6), and it is believed that one of the main functions of circulating IGF-I is to mediate GH negative feedback (7).

The IGF system is composed of IGF-I and IGF-II, a family of six distinct IGF-binding proteins (IGFBP), acid labile subunit (ALS), specific IGF receptors and IGFBP proteases (6). IGF-I, IGFBP-3, IGFBP-5 and ALS are all GH-dependent proteins and reflect integrated GH secretion in post-natal life (6). Most of the IGF-I circulates bound to IGFBP-3 and to ALS, forming the 150-kDa ternary complex and IGF-I bound to these two proteins has a significantly extended half-life (8). It is worth noting that IGF-I is regulated by a number of other factors besides GH. Under physiological conditions circulating IGF-I, IGFBP-3 and ALS concentrations depend on age, gender and nutritional status (6).

The aim of this chapter is to briefly examine the different pathogenesis, clinical presentations, current investigations and treatment of GHD and GHIS in childhood and present the recent biochemical and molecular developments that have led to increasing understanding of the underlying defects in the GH axis