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Growth Hormone Receptor Exon-3 and Response to Growth Hormone Treatment« Back to Volume 22, Issue 2, June 2006 - Table of Contents A polymorphism in the growth hormone receptor (GHR) gene, the presence or absence of exon -3, has recently been shown to influence the one 1- and 2-year growth response to human growth hormone (hGH) therapy in children without GH deficiency (GHD). To study the influence of GHR-exon-3 genotype on the short- and long-term response to hGH therapy in children with GHD, Jorge et al genotyped and followed the first year growth velocity following hGH treatment in 58 children (36 boys, 22 girls) who remained prepubertal and the adult height of 44 patients (included 27 patients analyzed for the firs t-year response) after 7.5 ± 3.0 years of treatment. Clinical and laboratory data at the start of treatment were indistinguishable among patients carrying GHR-exon-3 genotypes. Patients carrying at least one exon-3 deleted GHR (GHRd3) allele had a significantly better growth velocity in the first year of treatment (12.3 ± 2.6 vs . 10.6 ± 2.3 cm/year, p<0.05) and achieved a taller adult height (final height SDS of –0.8 ± 1.1 vs . –1.7 ± 1.2, p<0.05) when compared with patients homozygous for GHR full-length alleles (GHRfl). They conclude that patients with GHD who are homozygous for GHR exon 3fl were less responsive to short- and long-term hGH therapy. Approximately half of the population is homozygous for GHRfl , ; thus , future studies adjusting hGH therapy to genotype may improve outcome to therapy. Editor’s Comment: Different variables can influence the growth velocity and the final height of children treated with hGH, but so far there is no way of accurately predicting response to therapy. Duration of treatment, height SDS at the start of treatment, bone age delay, midparental height, and growth velocity during the first year of treatment, are some of the variables which could influence final height after therapy. However, as suggested by Jorge and colleagues, these variables only partially explain the inter-individual variab ility response to hGH treatment in children with GHD. The GHR gene is an obvious candidate to influence the response to hGH. The GHR gene is located in the short arm of chromosome 5; two of the most common isoforms of GHR in humans are generated by retention of GHRfl or exclusion of GHRd3. The frequency of each allele in humans ranges from 68 % - to 75% for GHRfl and from 25 % - to 32% for GHRd3. Patients reported in this paper, with GHD who were homozygous for GHR exon 3fl were less responsive to short-and long-term hGH therapy. However, Pilotta et al1, very recently evaluated 54 GHD children treated for at least one year with hGH; they found no significant differences in growth velocities between groups of subjects defined by polymorphic genotypes , and concluded that the most common polymorphisms, alone or in association, did not appear to affect the growth response to hGH in GHD children. On the other hand, studies by Dos Santos et al2 and Binder et al3 support the theory that there is increased responsiveness to high dose hGH in association with GHRd3 genotype in patients with Turner syndrome, small for gestational age (SGA), and idiopathic short stature (ISS); the magnitude of this effect may depend on the primary cause of the short stature. The Binder group demonstrated that girls with Turner syndrome who were homocygote homo z ygote for the GHRd3 variant showed the highest increment in height velocity and exceeded their growth prediction, whereas short children born SGA demonstrated only a mildly increased response to high-dose hGH in the presence of the GHRd3 variant. G enotyping of the GHRd3 protein polymorphism may prove to be a tool for a more precise understanding of hGH effects on growth and for the individualization of hGH dosing in both GHD and non non -GHD children; however, its effectiveness is still in doubt. Roberto Lanes, MD References - (linked to
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Volume 26 Number 1
September 2010
www.GGHjournal.com
ISSN 1932-9032
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