GROWTH-HORMONE RECEPTOR MUTATIONS IN CHILDREN IDIOPATHIC SHORT STATURE

Homozygous or compound heterozygous mutations in the GH receptor (GHR) gene result in GH insensitivity syndrome. Previous reports have shown that some heterozygous mutations may induce a partial insensitivity t o GH, but others appear to have limited effect on growth. To investiga te further these observations, we analyzed the GHR gene in 17 subjects with idiopathic short stature (ISS). All subjects had a height 2 so o r more below the mean and/or abnormal growth velocity. In addition, se rum GH levels were 10 ng/mL or more and insulin-like growth factor I l evels were normal or low. A novel heterozygous mutation resulting in a valine to isoleucine change (V144I) in exon 6 in the extracellular do main was found in one subject. His mother and one brother had signific ant short stature and also had the identical mutation. Affected family members also had a polymorphism in exon 6 of the GHR gene, which has been present in other subjects who had short stature and heterozygous mutations of the GI-IR gene. The other subjects with ISS had normal GH R genes. However, eight subjects had neutral polymorphisms distributed throughout the GHR locus. Accumulating evidence suggests that GHR gen e mutations account for up to 5% of all ISS patients. These mutations should be considered when other causes of short stature have been elim inated.