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Impact of the Exon 3-Deleted Growth Hormone (GH) Receptor Polymorphism on Baseline Height and the Growth Response to Recombinant Human GH Therapy in GH-Deficient (GHD) and Non-GHD Children with Short Stature: A Systematic Review and Meta-Analysis

Departments of Endocrinology and Metabolism (M.J.E.W., O.M.D., A.M.P., J.W.S., N.R.B., J.A.R.) Pediatrics (J.M.W.), and Clinical Epidemiology (O.M.D.), Leiden University Medical Center, 2300 RC Leiden, The Netherlands

Address all correspondence and requests for reprints to: N. R. Biermasz, M.D., Ph.D., Department of Endocrinology and Metabolic Diseases C4-R, Leiden University Medical Center, P.O. Box 9600, 2300 RC Leiden, The Netherlands. E-mail: n.r.biermasz{at}lumc.nl.

Context: The exon-3 deleted GH receptor (GHR_d3) polymorphism is associated with an increased growth response to recombinant human GH (rhGH) therapy in some, but not all, studies in GH-deficient (GHD) and non-GHD children with short stature.

Objective: The aim of the study was to assess the effects of GHR_d3 on baseline height and the first year’s growth response to rhGH treatment in prepubertal GHD and non-GHD children with short stature.

Design: We conducted a systematic review and meta-analysis.

Methods: Fifteen studies reporting the effect of GHR_d3 on growth parameters were included. Principal outcomes were baseline height SD score (SDS) and the weighted average of change in growth velocity ( cm/yr) and height gain ( height SDS) after 1 yr of rhGH.

Results: In GHD, not in non-GHD, baseline height SDS was 0.159 SD higher [95% confidence interval (CI), 0.020, 0.298] in GHR_d3 compared with GHR_wt-wt. In GHR_d3, rhGH therapy resulted in a higher increase in growth velocity (0.521 cm/yr; 95% CI, 0.196, 1.015) and height gain (0.075 SD; 95% CI, 0.007, 0.143) compared with GHR_wt-wt. Meta-regression demonstrated a larger difference between GHR_d3 and GHR_wt-wt in studies using lower rhGH doses and carried out at a higher age, independently of the cause of short stature.

Conclusions: This meta-analysis in prepubertal children with short stature indicates that GHR_d3 is associated with increased baseline height in GHD, but not in non-GHD. Furthermore, GHR_d3 stimulates growth velocity by an additional effect of approximately 0.5 cm during the first year of rhGH treatment, and this effect is more pronounced at lower doses of rhGH and higher age.