ESPE Abstracts

Background: Heterozygous GHR gene variants were found in 5–8% of idiopathic short stature (ISS) children. Frequent polymorphisms within GHR coding regions, but not intronic SNPs, have been investigated in ISS.

Objectives: To characterize GHR gene variants in ISS children, and to test their influence on height and the peripheral GH/IGF1/IGFBPs system.

Methods: GHR gene (coding/intronic flanking regions) were PCR-amplified and sequenced in 64 unrelated ISS children (median height, range: −2.88, −4.79 to −2.00). The genotype influence on height and GH/IGF1/IGFBPs system was investigated for SNPs with a minor allele frequency (MAF) >10% (HapMap-Project). ISS children were grouped as: homozygous carriers for the major allele and carriers of one or two copies of the minor allele. IGF1 and IGFBP3 (ICMA), ALS (RIA), and GHBP (in house functional immunofluorometric-assay) were measured¹. Hardy–Weinberg equilibrium was verified. Fisher’s exact test and Mann–Whitney analysis were used as appropriate.

Results: Eight common polymorphisms were identified: exon-3 deletion (MAF: 26%), rs6179 (exon-6, 23%), rs6180 (exon-10, 42%), rs12521020 (intron-1, 32%), rs10941579 (intron-2, 32%), rs33972388 and rs34223737 (intron-7, 37 and 2%, respectively), rs6880730 (intron-8, 3%). MAF in ISS were not different to the HapMap frequencies. SNPs genotypes were not associated to height, GHBP–SDS, IGF1–SDS, IGFBP3–SDS, or ALS–SDS (P>0.10 for all analysis). Three heterozygous uncommon variants (exon-7: p.R229H, exon-10: p.R386C and p.C440F) were also identified in 3/64 children (4.7%) with normal IGF1–SDS, IGFBP3–SDS, and ALS–SDS levels, two of them with low GHBP (<−1.8 SDS). These variants were not found in 41 control children.

Conclusions: The prevalence of heterozygous uncommon GHR variants was in accordance with previous studies. These variants could be present even in children with normal GHBP and GH-dependent factors. Common SNPs genotypes are distributed as reported in the general population and do not seem to have an impact on height or components of the GH/IGF1/IGFBPs system in ISS.