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Clinical Significance of a 6 Hr Exon 3-deletion Polymorphism« Back to Volume 23, Issue 1, March 2007 - Table of Contents Audi and colleagues from the Spanish SGA Study Group reported the relative frequencies of the deleted and full-length exon 3 growth hormone receptor (GHR) polymorphisms in 247 short stature children and adolescents with birth weight small for gestational age (SGA) and 289 normal stature adult control subjects. The homozygous or heterozygous inheritance of the exon 3 deleted isoform has been reported to enhance GH action, although the significance of this genotype on GHR function is unknown. There was a 2-fold increase of the biologically less active homozygous full-length exon 3 isoform genotype in the SGA subjects. In the control population, there was no relationship between the height phenotypes and genotypes of the subjects. Therefore, it is suggested that in short stature SGA subjects, the presence of the full-length isoform may have impeded post-natal catch-up growth. Carrascosa et al, also from the Spanish SGA Hormone Study Group, reported the results of GH therapy in patients from the same cohort of SGA subjects as described by Audi and colleagues. Previous reports have demonstrated an increased growth response to GH therapy in SGA subjects who have the deleted exon 3 isoform, compared to those with the full-length receptor.1 In contrast, this paper reported no differences in first- or second-year growth velocity and height gain between the different genotypes of 86 GH-treated SGA subjects. These patients were treated with a GH dose of 66 µg/kg/day, an amount that is at the upper end of the recommended dose and higher than in other reported series. It was suggested that these high GH doses might over-ride a more subtle effect reported with lower GH regimens. Jorge and colleagues from São Paulo, Brazil performed a retrospective genetic analysis for the retained or deleted exon 3 GHR genotypes in 75 patients with severe isolated or combined GH deficiency. Clinical and laboratory data were similar at baseline in patients with different genotypes. However, patients on GH therapy who were carrying at least one GHRd3 allele demonstrated a higher first-year height velocity (P<0.05), compared to those with the full-length isoform. Final height was also greater in the GHRd3 subjects. No parental height data were given. Jorge et al hypothesized that manipulation of GH dose following genotype characterization might become a reality in the future. Blum and colleagues from Eli Lilly in Germany studied 107 patients with severe idiopathic GH deficiency. In contrast to the Jorge group, they found no difference in growth responses to GH therapy between the subjects with the d3-GHR allele and those with the full-length receptor. Editor’s CommentSeveral large studies that look at the possible influence on responses to GH therapy of homozygous or heterozygous inheritance of the deleted exon 3 GHR isoform have now been performed. The results are conflicting in SGA subjects as no difference in growth response was found in the Spanish study, contrasting with the original description of an apparent growth-enhancing effect shown in the French study. However, Binder et al2 reported significantly increased responses in both SGA and Turner syndrome patients carrying the exon 3-deleted isoform. Now, Jorge and Blum have reported different outcomes and conclusions in patients with GH deficiency. With such differing conclusions, it is hard to imagine that an effect of real clinical relevance exists from the inheritance of the deleted isoform. No doubt further studies will be published with probably differing conclusions. At this stage, the prospective genotyping of short patients in order to optimize their responses to GH therapy seems premature. Martin O. Savage, MD References - (linked to
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Volume 24 Number 1
May 2008
www.GGHjournal.com
ISSN 1932-9032
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