ESPE Abstracts (2016) 86 P-P1-604

The Exon3-Deleted Growth Hormone Receptor Gene Polymorphism (d3-GHR) is Associated with Increased Spontaneous Growth and Impaired Insulin Sensitivity in Prepubertal Short SGA Children (NESGAS)

Mathilde Gersel Wegmanna, Rikke Beck Jensena, Ajay Thankamonyb, Jeremy Kirkc, Malcolm Donaldsond, Sten-A Ivarssone, Olle Söderf, Edna Rocheg, Hillary Hoeyg, David B Dungerb & Anders Juula


aDepartment of Growth and Reproduction, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark; bDepartment of Padiatrics, University of Cambridge, Cambridge, UK; cDepartment of Endocrinology, Birmingham Children’s Hospital, Birmingham, UK; dDepartment of Endocrinology, Royal Hospital for Sick Children, Glasgow, UK; eDepartment of Clinical Sciences, University of Lund, Malmö, Sweden; fPediatric Endocrinology Unit, Karolinska Institutet and University Hospital, Stockholm, Sweden; gDepartment of Pediatrics, The National Children’s Hospital, University of Dublin, Dublin, Ireland


Background: A common polymorphism in the growth hormone receptor gene (d3-GHR) was found to be associated with pre- and postnatal growth and GH-induced growth. D3-GHR was associated with glucose metabolism in adults with GHD and acromegaly, but this has not previously been explored in children.

Objective and hypotheses: We examined the impact of the GHR-exon-3 deletion on glucose metabolism and anthropometrics in short SGA children before and following 1 year of GH therapy.

Method: The North European Small for Gestational Age Study (NESGAS) is a multicentre study of GH therapy in 96 (57 males) prepubertal short SGA children receiving high-dose GH therapy (67 μg/kg per day) for 1 year. Insulin sensitivity (IS) and disposition index (DI) were estimated from IVGTT. The GHR-exon-3 locus was determined by simple multiplex PCR on isolated DNA.

Results: D3-GHR genotype frequencies were: 54.2% full-length (fl/fl), 38.5% heterozygous (fl/d3) and 7.3% homozygous (d3/d3). The d3-GHR genotype was divided into two groups: fl/fl vs. fl/d3 and d3/d3. Change in spontaneous height gain from birth to baseline was significantly higher in children carrying the d3-allele (fl/fl mean (S.D.) 0.55 SDS (1.97) vs. d3-allele 0.53 SDS (1.27), P=0.02). Baseline glucose and c-peptide levels were significantly higher in children carrying the d3-allele and there was a trend towards higher insulin levels in this group. Baseline IS was significantly lower in children carrying the d3-allele (fl/fl mean (SD) 351% (339) vs. d3-allele 248% (182), P=0.02), but there was no difference in DI. Following 1 year of GH therapy the change in IS was significantly higher in the fl/fl group compared to children carrying the d3-allele (P=0.04).

Conclusion: Short prepubertal SGA children carrying the exon3-deleted GHR allele had lower insulin sensitivity at baseline, but the change in IS was reduced compared to the fl/fl group. Furthermore, we confirmed a positive effect on postnatal spontaneous growth.