GHI is a genetic condition in which patients present with growth failure due to primary IGF1 deficiency caused by a defect in the GH-IGF1 axis. In the last 10 years in the Centre for Endocrinology of WHRI at Barts and the London, 24 causative mutations in genes of the GHIGF1 axis have been determined in 58 patients (Table 1). STAT5B mutations were responsible in 2 cases, IGFALS in 4 but the majority of defects identified were in GHR. Most mutations identified were autosomal recessive, missense or nonsense changes in extracellular domain coding exons of GHR, but we also described pseudoexon activation as a cause and reported the first polypyrimidine tract mutation. Other unusual cases included a homozygous deletion of 22 bp in the intracellular domain and a dominant negative mode of inheritance in a child with a mild short stature phenotype.
|Mutation||Number of individuals||Country of origin|
|IVS2 ds+1 G to A||2||Turkey|
|IVS6 ds+1 G to A||1||Hong Kong|
|IVS7 as-6 T to A||1||Bangladesh|
|IVS8 ds-1 G to C or R274T||3||UK|
|IVS8 as-6 G to A||1||UK|
|IVS9 ds+2 T to C (heterozygous)||2||Spain|
In conclusion, genotyping of candidate genes was informative in the investigation of a significant proportion of patients with GHI. Most cases were caused by defects in GHR but mutations in other genes of the GH-IGF1 axis such as STAT5B and IGFALS are being increasingly recognised as causal.