Relationship between phenotype and genotype in growth hormone insensitivity syndrome

Growth hormone insensitivity syndrome (GHIS) of genetic origin is associated with many different mutations of the growth hormone receptor (GHR) gene and a recently described genetic defect of the insulin-like growth factor I (IGF-I) gene. Phenotypic and biochemical features were examined in a cohort of 82 patients with GHIS from 23 countries. The mean age of these patients was 8.3 years, their mean height SDS was -6.09 and their median IGF-binding protein-3 (IGFBP-3) SDS was -8.5. In total, 19 of the 82 patients (23%) were growth hormone-binding protein (GHBP)-positive (> 10%). The mean heights in GHBP-negative and GHBP-positive patients were -6.45 SDS and -4.89 SDS, respectively (p < 0.001). Sixteen different GHR gene mutations were identified in 27 patients with GHIS. All of these patients had homozygous mutations, except one who had a compound heterozygous mutation. There was no relationship between the type or site within the GHR gene of the mutation and the height SDS or IGFBP-3 SDS of the patients. GHIS is associated with a wide variation in the severity of clinical and biochemical phenotypes. This variation cannot clearly be accounted for by defects in the GHR gene alone. Other genes or environmental factors must contribute to the control of growth in patients with GHIS.