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Influence of Growth Hormone (GH) Receptor Deletion of Exon 3 and Full-Length Isoforms on GH Response and Final Height in Patients with Severe GH Deficiency

University Children’s Hospital (B.R., M.J., V.P., D.L., A.E., C.E.F., P.E.M.), Pediatric Endocrinology, Diabetology & Metabolism, University Bern, CH-3010 Bern, Switzerland; and Developmental Endocrinology Research Group (M.T.D., P.C.H., P.E.M.), Clinical and Molecular Genetics Unit, Institute of Child Health, London WC1N 1EH, United Kingdom

Address all correspondence and requests for reprints to: Professor Dr. Primus E. Mullis, University Children’s Hospital, Pediatric Endocrinology, Diabetology, Metabolism, University of Bern, CH-3010 Bern, Switzerland. E-mail: primus.mullis{at}insel.ch.

Context: A polymorphism of the GH receptor (GHR) gene resulting in genomic deletion of exon 3 (GHR-d3) has been associated with responsiveness to GH therapy. However, the data reported so far do vary according to the underlying condition, replacement dose, and duration of the treatment.

Objective, Design: The aim of this study was to analyze the impact of the GHR genotypes in terms of the initial height velocity (HV) resulting from treatment and the impact upon adult height in patients suffering from severe isolated GH deficiency.

Controls, Patients, Setting: A total of 181 subjects (peak stimulated GH 2 ng/ml) were studied. In addition, GHR genotype frequency was compared with a healthy adult control group.

Interventions: Based on the various GHR genotypes, HV, effect of recombinant human GH dose used, and final height were analyzed.

Main Outcome Measures, Results: In the 181 subjects after the first two yr on recombinant human GH treatment, HV SD score (SDS) as well as height gain were significantly greater in subjects with the GHR-d3/d3 genotype when compared with the subjects presenting with the GHR-full-length/full-length genotype (P < 0.05). A GHR-d3 allele dose-dependent effect was found for both HV SDS (r = 0.72) and height gain (r = 0.77). However, there was no significant difference in final adult height and height SDS according to the exon-3 genotypes.

Conclusions: Our results indicate that in patients with severe isolated GH deficiency, although the GHR genotype might play a role in GH responsiveness, at least at the beginning of treatment, there is no effect on final height.