Exon 3-deleted genotype of growth hormone receptor (GHRd3) positively influences IGF-1 increase at generation test in children with idiopathic short stature

CONTEXT: A GHR-exon 3 polymorphism has been reported to influence the growth response to hGH therapy in short stature children. None of these studies provided data on IGF-1 generation test. OBJECTIVE: To evaluate the influence of the GHR-exon 3 polymorphism on the generation test in children with idiopathic short stature (ISS). DESIGN AND PATIENTS: A total of 45 prepubertal ISS children were submitted to IGF-1 and IGFBP-3 generation test (4 days of hGH 33 microg/kg/day). Children were genotyped for GHR-exon 3: full-length (fl) and exon 3-deleted (d3) alleles. MEASUREMENTS: IGF-1 and IGFBP-3 increment as absolute values and standard deviation scores (SDS). RESULTS: Basal clinical and laboratory data were similar among patients with different genotypes (fl/fl vs. fl/d3 or d3/d3). All patients presented IGF-1 increase >or= 15 microg/l at generation test. Children with GHRd3 allele, as a group, presented a statistically significant higher IGF-1 SDS increase at generation test than children homozygous for GHRfl allele (1.0 ranging from 0.1 to 3.7 for fl/fl vs. 1.2 ranging from 0.3 to 4.4 for fl/d3 and d3/d3; P = 0.037). Multiple linear regression found a positive association between increase in IGF-1 SDS with chronological age (P = 0.007) and GHR genotype (P = 0.027), which together explain 24% of the variability of IGF-1 SDS increment at generation test. There was no difference in IGFBP-3 generation test between the two genotype groups. Conclusion: This study demonstrates that ISS children carrying the GHRd3 allele, as a group, present a slightly higher GH sensitivity regarding short-term IGF-1 generation during hGH stimulus than children homozygous for GHRfl allele.