GH responsiveness in a large multinational cohort of SGA children with short stature (NESTEGG) is related to the exon 3 GHR polymorphism

Clin Endocrinol (Oxf). 2007 Sep;67(3):457-61. doi: 10.1111/j.1365-2265.2007.02911.x. Epub 2007 Jun 7.


Objective: The polymorphic deletion of exon 3 of the GH receptor (d3-GHR) has recently been linked to the magnitude of growth response to recombinant human GH (rhGH) therapy in short children with or without GH deficiency. We investigated this association in a large multinational cohort from the Network of European Studies of Genes in Growth (NESTEGG), comprising short children born small for gestational age (SGA).

Design: The study included short prepubertal SGA children treated with rhGH for 1 or 2 years.

Population: Two hundred and forty white Caucasian SGA children (138 male, 102 female) aged 6.6 +/- 2.3 years with a height at -3.0 +/- 0.7 SDS at start of rhGH treatment; 193 ethnically matched controls.

Methods: The GHR polymorphism (fl/fl, fl/d3 or d3/d3) was genotyped by polymerase chain reaction (PCR) multiplex assay. Growth velocity (G/V) in cm/year and changes in GV during the first and second year of rhGH treatment were evaluated.

Results: The change in GV was significantly greater in SGA children carrying one or two copies of the d3-GHR allele (P = 0.038 for the first year and P = 0.041 for the second year of GH treatment), but the change in height was not significantly different. Birthweight was significantly lower in SGA children with the d3/d3 genotype than in SGA children with the fl/fl genotype (P = 0.034) and in those with the fl/d3 genotype (P = 0.016).

Conclusion: Our data, based on a large cohort, showed that the exon 3 GHR polymorphism is associated with responsiveness to rhGH treatment in SGA children with short stature.

MeSH terms

  • Body Height / drug effects*
  • Body Height / genetics*
  • Carrier Proteins / genetics*
  • Child
  • Child, Preschool
  • Cohort Studies
  • Drug Resistance / genetics
  • Exons / genetics
  • Female
  • Genotype
  • Growth Disorders / drug therapy*
  • Growth Disorders / genetics*
  • Human Growth Hormone / administration & dosage*
  • Humans
  • Infant, Newborn
  • Infant, Small for Gestational Age / growth & development
  • Internationality
  • Male
  • Phenotype
  • Polymorphism, Genetic / genetics
  • Treatment Outcome


  • Carrier Proteins
  • Human Growth Hormone
  • somatotropin-binding protein