Study of GH sensitivity in Chilean patients with idiopathic short stature

We hypothesized that some children with idiopathic short stature in Chile m ight bear heterozygous mutations of the GH receptor. We selected 26 patient s (3 females, 23 males) from 112 patients who consulted for idiopathic shor t stature at the University of Chile. Their chronological age was 8.3 +/-1. 9, and bone age was 6.1 +/-1.0 yr. Their height was -3.0 +/-0.7 SDS; IGF-I, -1.2 +/-1.1 SD; IGF binding protein 3, -0.7 +/-2.0 SDS; and GH binding pro tein, 0.4 +/-0.8 SDS. Patients were admitted, and blood samples were obtain ed every 20 min to determine GH concentrations overnight. Coding sequences and intron-exon boundaries of exons 2-10 of GH receptor gene were amplified by PCR and subsequently analyzed through single-strand conformational anal ysis. Mean serum GH concentration, over 12-h, was 0.20 +/-0.08 nm; pulse am plitude, 0.40 +/-0.15 nM; number of peaks, 5.8 +/-1.5 peaks/12 h; peak valu e of GH during the 12-h sampling, 1.03 +/-0.53 nm; and area under the curve , 151.4 +/- 56.1 nM/12 h. There were positive correlations between mean GH vs. area under the curve (P<0.001) and GH peak (P<0.01). The single-strand conformational analysis of the GH receptor gene showed abnormal migration f or exon 6 in 9 patients and for exon 10 in 9 patients, which (by sequence a nalysis) corresponded to 2 polymorphisms of the GH receptor gene: an A-to-G transition in third position of codon 168 in exon 6 and a C-to-A transvers ion in the first position of codon 526 in exon 10. We further sequenced all coding exons and intron-exon boundaries in the most affected patients (nos . 6, 9, 11, 14, 15, 16, and 23). This analysis revealed a C-to-T transition in codon 161 of exon 6 in patient 23, which results in an amino acid chang e (Arg to Cys) in an heterozygous form in the patient and his father. In co nclusion, the results of our study suggest that, in Chilean patients with i diopathic short stature, GH receptor gene mutations are uncommon, although we cannot exclude mutations that were missed by single-strand conformationa l analysis or mutations within introns or in the promoter regions of the GH receptor gene.