Short stature related to Growth Hormone Insensitivity (GHI) in childhood

Abstract

Linear growth during childhood is the result of the synergic contribution of different factors. The best growth determinant system during each period of life is represented by the growth hormone-insulin-like growth factor axis (GH-IGF), even if several other factors are involved in normal growth. Within the broad spectrum of growth disorders, an increased importance has been placed on growth hormone insensitivity (GHI). GHI was reported for the first time by Laron as a syndrome characterized by short stature due to GH receptor (GHR) mutation. To date, it is recognized that GHI represents a wide diagnostic category, including a broad spectrum of defects. The peculiar characteristic of GHI is the low IGF-1 levels associated with normal or elevated GH levels and the lack of IGF-1 response after GH administration. Recombinant IGF-1 preparations may be used in the treatment of these patients.

Keywords: GH insensitivity; GH receptor; GH-IGF-1 axis; childhood; growth hormone; short stature.

Figure 1

Schematic figure of GH-IGF-1 axis, its physiology, and main genetic defects related to GHI. The GH binds to a GHR, which activates JAK2 and promotes the phosphorylation of different members of the signal transducer. The final result is the IGF-1 production. IGF-1 binds to IGFBP-3 or IGFBP-5 and the acid-labile subunit (ALS) and constitutes the ternary complex. (A) Defects of the extracellular domain of the GHR; (B) defects in GHR dimerization; (C) defects of the transmembrane domain of the GHR; (D) defects of STAT5b; (E) defects of IGFBP. GH, growth hormone; GHR, growth hormone receptor; JAK2, Janus family tyrosine kinase 2; PI3K, phosphatidylinositol-3 kinase; ERK, extracellular signal-regulated kinase; STAT, signal transducer and activator of transcription; IGF, insulin-like growth factor; IGFBP, IGF-binding proteins.; ALS, acid-labile subunit.