Growth hormone deficiency and combined pituitary hormone deficiency: does the genotype matter?

The past 12 years have witnessed an explosion in our understanding of the development of the anterior pituitary gland, and of mechanisms that underlie the diagnosis of growth hormone deficiency (GHD) and combined pituitary hormone deficiency (CPHD). The anterior pituitary is the end-product of a carefully orchestrated pattern of expression of signalling molecules and transcription factors that leads to the development of this complex organ secreting six hormones from five different cell types. Naturally occurring and transgenic murine models have demonstrated a role for many of these molecules in the aetiology of GHD/CPHD. These include the transcription factors HESX1, PROP1, POU1F1, LHX3, LHX4, GLI2 and SOX3. Depending upon the expression patterns of these molecules, the phenotype may consist of isolated hypopituitarism, or more complex disorders such as septo-optic dysplasia (SOD) and holoprosencephaly. The phenotype and the mode of inheritance can be highly variable. Novel mutations within the GH-1 and GHRHR genes have also shed light on the phenotype and pathogenesis of isolated GHD (IGHD). To date, genetic mutations have been identified in a modest proportion of patients with IGHD/CPHD and associated syndromes such as SOD. It is, however, clear that many genes remain to be identified, and characterization of these will further elucidate the pathogenesis of these complex conditions.