Lessons from the genetics of Laron syndrome

In the decade since the cloning and sequencing of the growth hormone receptor (GHR) and the recognition that the circulating GH-binding protein (GHBP) is structurally identical to the extracellular domain of the GHR, 34 mutations have been described. These include one deletion, eight nonsense mutations, eleven missense mutations, four frameshift mutations and ten splice mutations. More than half of the 131 patients with Laron syndrome whose molecular defects have been identified comprise the Ecuadorian cohort who share a single splice mutation. Variable expression of different homozygous or compound heterozygous defects of the GHR is no greater than the variation within a genetically homogeneous population. Some features, such as birth size and intelligence, are unlikely to be affected by GHRD. Greater understanding of the genetics, physiology, and clinical expression of abnormalities in the GH-GHR-IGF-I (insulin-like growth factor I) axis necessitates a reconsideration of the classification of GH insensitivity (GHI).