Idiopathic short stature: will genetics influence the choice between GH and IGF-I therapy?
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.
Savage
Martin O
MO
Endocrinology Centre, William Harvey Research Institute, Queen Mary, University of London, London, EC1M 6BQ UK. m.o.savage@qmul.ac.uk
Camacho-Hübner
Cecilia
C
David
Alessia
A
Metherell
Louise A
LA
Hwa
Vivian
V
Rosenfeld
Ron G
RG
Clark
Adrian J L
AJ
D001827:Body Height; D002352:Carrier Proteins / Q000235:genetics; D004702:Endocrine Glands / Q000378:metabolism; D006023:Glycoproteins / Q000235:genetics; D006130:Growth Disorders / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism; D013006:Growth Hormone / Q000378:metabolism / Q000627:therapeutic use*; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000627:therapeutic use*; D009154:Mutation; D020641:Polymorphism, Single Nucleotide; D011986:Receptors, Somatotropin / Q000235:genetics; D050799:STAT5 Transcription Factor / Q000235:genetics