From GHRH to IGF-1 and downstream: clinical phenotypes and biological mechanisms

Genetic defects have been observed at almost all levels of the GHRH-IGF-1 axis. The first observations of GH-1 gene deletions date some 30 years ago. Whereas mutations in the GH-1 and GHRHR genes account for the majority of mutations detectable in patients with Isolated Growth Hormone Deficiency (IGHD) resulting in postnatal growth failure, the overall detection of genetic defects in these patients remains low with app. 10-15%. Similarly, at the lower end of the GHRH-IGF-1 axis the frequency of defects within the IGF-1 and IGF-1 receptor (IGF1R) genes might hardly approach 10% of all cases with intrauterine and postnatal growth retardation. In this article we examine the pathomechanisms involved in the genetic defects at both ends of the GHRH-IGF-1 axis and describe the clinical and biochemical phenotypes involved. Although it seems tempting to increase the detection rate by limiting genetic investigations to patients with phenotypic characteristics described, at present it seems more appropriate to follow a permissive approach for such investigations as we are probably have not envisioned the full spectrum of phenotypic variability.