Relationship between phenotype and genotype in growth hormone insensitivity syndrome

Growth hormone insensitivity syndrome (GHIS) of genetic origin Is associate d with many different mutations of the growth hormone receptor (GHR) gene a nd 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-bindin g protein-3 (IGFBP-3) SDS was -8.5. In total. 19 of the 82 patients (23%) w ere growth hormone-binding protein (GHBP)-positive (> 10%). The mean height s 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 identi fied in 27 patients with GHIS, All of these patients had homozygous mutatio ns, except one who had a compound heterozygous mutation. There was no relat ionship between the type or site within the GHR gene of the mutation and th e 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 var iation cannot clearly be accounted for by defects in the GHR gene alone. Ot her genes or environmental factors must contribute to the control of growth in patients with GHIS.