Genetic characterization of growth hormone deficiency and resistance: implications for treatment with recombinant growth hormone.

Growth failure can be caused by deficient growth hormone production or action. The genes involved in pituitary development, somatotrope function, as well as growth hormone synthesis, secretion, and action have recently been characterized in considerable detail. Familial growth failure has played an important role in identifying these genes, and a large number of mutations adversely affecting the development and function of the growth hormone/insulin-like growth factor axis have been discovered. Inactivating mutations leading to growth retardation in humans have been identified in several pituitary transcription factor genes (HESX1, PITX2, LHX3, PROP1, POU1F1) as well as in genes encoding the growth hormone-releasing hormone receptor (GHRH-R), the G(s) protein alpha subunit (GNAS1), growth hormone itself (GH-1), the growth hormone receptor (GHR), and in a single case each, the insulin-like growth factor I (IGF-I) and the IGF-I receptor. Mutations in pituitary transcription factors cause developmental abnormalities of the pituitary and deficiency of multiple pituitary hormones [growth hormone (GH), prolactin (Prl), thyrotropin (TSH) and lutropin/follitropin (LH/FSH)]. Most of the syndromes respond well to therapy with recombinant GH; exceptions are antibody-mediated resistance in GHD type IA (not all patients) and cases of Laron syndrome (GHR deficiency). Such patients respond to IGF-I therapy. This review summarizes the molecular genetics, functional defects, phenotypes, diagnostic considerations and therapeutic aspects of syndromes associated with mutations in the relevant genes.