Study of GH Sensitivity in Chilean Patients with Idiopathic Short Stature

Abstract

We hypothesized that some children with idiopathic short stature in Chile might bear heterozygous mutations of the GH receptor. We selected 26 patients (3 females, 23 males) from 112 patients who consulted for idiopathic short 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 protein, 0.4 +/- 0.8 SDS. Patients were admitted, and blood samples were obtained 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 analysis. Mean serum GH concentration, over 12-h, was 0.20 +/- 0.08 nM; pulse amplitude, 0.40 +/- 0.15 nM; number of peaks, 5.8 +/-1.5 peaks/12 h; peak value 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 for exon 6 in 9 patients and for exon 10 in 9 patients, which (by sequence analysis) 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 transversion 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 change (Arg to Cys) in an heterozygous form in the patient and his father. In conclusion, the results of our study suggest that, in Chilean patients with idiopathic short stature, GH receptor gene mutations are uncommon, although we cannot exclude mutations that were missed by single-strand conformational analysis or mutations within introns or in the promoter regions of the GH receptor gene.

Growth Hormone (GH) Dose, But Not Exon 3-Deleted/Full-Length GH Receptor Polymorphism Genotypes, Influences Growth Response to Two-Year GH Therapy in Short Small-for-Gestational-Age Children

“…In short SGA patients, responsiveness to GH therapy varies from patient to patient, and genetic differences in the GH-IGF-I axis cascade, which leads to biological effects, have been suggested (11)(12)(13)(14)(15)(16)(17)(18)(19)(20). In two cohorts of short SGA patients, Dos Santos et al…”

Association of serum components of the GH-IGFs-IGFBPs system with GHR-exon 3 polymorphism in normal and idiopathic short stature children

“…Our present work also demonstrated low ALS SDS (27%) and IGFBP-3 (22%) SDS values in ISS children. GHBP, IGF-I, IGFBP-3 and ALS production may be disturbed in states of GH insensitivity due to heterozygosity for specific mutations affecting the GH-IGF axis in some children with ISS [9][10][11][12][13][14]. Therefore, our results may reflect potential defects in GH receptor action that may result in partial GH insensitivity.…”

“…Abnormalities of the growth hormone-insulin-like growth factors system has been reported in ISS children [9][10][11][12][13][14][15], some of them reported in the GHR gene [9][10][11][12][13][14]. Nevertheless, the possible association of basal serum GHBP, IGF-I, IGFBP-3, and ALS with GHR-exon 3 genotype in ISS children as compared to normal children has not been investigated.…”

Spontaneous Prolactin Secretion in Growth Hormone-deficient Children

“…Currently, all the ISS children studied have achieved a final height within their individual target height, thus confirming our biochemical diagnosis. Sjoberg et al reported an elevated GH peak frequency in 26 children (f = 3, m = 23) with ISS, whereas mean GH levels and peak amplitude were normal [16]. In 50 children with ISS, Achermann et al found an inverse relationship between GH and height velocity in 24-hour GH profiles [17].…”