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

Abstract

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.

• Authors: Martin O Savage, Cecilia Camacho-Hübner, Alessia David, Louise A Metherell, Vivian Hwa, Ron G Rosenfeld, Adrian J L Clark
• Journal: European journal of endocrinology (Eur J Endocrinol) Vol. 157 Suppl 1 Pg. S33-7 (Aug 2007) ISSN: 0804-4643 [Print] England
• PMID: 17785695 (Publication Type: Journal Article, Review)

Chemical References

• 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

Topics

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