The spectrum of growth-hormone insensitivity

To summarize the steps that led to the recognition of the Laron syndrome of growth-hormone (GH) insensitivity as a recessive disorder that is caused by mutations in the growth hormone receptor (GHR) gene, to discuss the different types of mutations that have been found in the GHR gene, and to examine whether the degree of growth impairment in affected homozygotes depends on the specific type of GHR mutation.

A broad spectrum of abnormalities in the GHR gene have been reported. These abnormalities range from deletions of multiple exons, through deletions of a small number of base pairs, nonsense mutations, missense mutations that alter GH-binding affinity or impair receptor processing, to mutations that exert their deleterious effects by altering messenger RNA splicing and result in the loss of portions of the GHR.

Different abnormalities in the GHR gene have different effects on the concentrations of circulating GH-binding protein that represents the extracellular portion of the GHR. Homozygosity or compound heterozygosity for the different mutations produces a fairly uniform phenotype of severe postnatal growth retardation. The differences in height standard deviation scores between persons appear to depend more on age, sex, and nutritional status than on the specific type of GHR mutation.