Idiopathic short stature: will genetics influence the choice between GH and IGF-I therapy?

Eur J Endocrinol. 2007 Aug:157 Suppl 1:S33-7. doi: 10.1530/EJE-07-0292.


Background: Idiopathic short stature (ISS) includes a range of conditions. Some are caused by defects in the GH-IGF-I axis. ISS is an approved indication for GH therapy in the USA and a similar approval in Europe may be imminent. Genetic analysis for single-gene defects has made enormous contributions to understanding the physiology of growth regulation. Can this type of investigation help in predicting growth responses to GH or IGF-I therapy?

Methods: The rationale for choice of GH or IGF-I therapy in ISS is reviewed. Many ISS patients have low IGF-I, but most can generate IGF-I levels in response to short-term GH administration. Some GH resistance seems to be present. Mutation analysis in several cohorts of GHIS and ISS patients is reviewed.

Results: Low IGF-I levels suggest either unrecognised GH deficiency or GH resistance. In classical GHIS patients, there was a positive relationship between IGFBP-3 levels and height SDS. No relationship exists between mutations and phenotype. There is a wide variability of phenotype in patients carrying identical mutations. Heterozygous GH receptor (GHR) mutations were present in <5% of ISS patients and their role in causing growth defects is questionable. Exceptions are dominant negative mutations that have been shown to disturb growth.

Conclusions: Analysis for single-gene defects does not give sensitive predictions of phenotype and cannot predict responses to GH or IGF-I therapy. Endocrine abnormalities have closer correlations with phenotype and may thus be a better guide to therapeutic responsiveness.

Publication types

  • Review

MeSH terms

  • Body Height*
  • Carrier Proteins / genetics
  • Endocrine Glands / metabolism
  • Glycoproteins / genetics
  • Growth Disorders / drug therapy*
  • Growth Disorders / genetics*
  • Growth Disorders / metabolism
  • Growth Hormone / metabolism
  • Growth Hormone / therapeutic use*
  • Humans
  • Insulin-Like Growth Factor I / therapeutic use*
  • Mutation
  • Polymorphism, Single Nucleotide
  • Receptors, Somatotropin / genetics
  • STAT5 Transcription Factor / genetics


  • Carrier Proteins
  • Glycoproteins
  • Receptors, Somatotropin
  • STAT5 Transcription Factor
  • STAT5B protein, human
  • insulin-like growth factor binding protein, acid labile subunit
  • Insulin-Like Growth Factor I
  • Growth Hormone