ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Endocrine Abstracts (2011) 25 P207

Genetic characterisation of primary GH Insensitivity (GHI) presenting as growth failure: 10 years experience at the Centre for Endocrinology, William Harvey Research Institute, Barts and the London

Louise Metherell, Alessia David, Martin Savage, Adrian Clark & Helen Storr


William Harvey Research Institute, Barts and the London, London, UK.


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 GH–IGF1 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.

Table 1
MutationNumber of individualsCountry of origin
GHR
S40L7Turkey
V125A2Iraq, UK
R161C1Israel
G223G2Bahamas, Spain
L229P1UK
R43X7Turkey
C48X2Argentina
Q65X1Turkey
E180X1Mexico
Q216X1Turkey
IVS2 ds+1 G to A2Turkey
IVS6 ds+1 G to A1Hong Kong
Pseudoexon insertion15Pakistan
IVS7 as-6 T to A1Bangladesh
IVS8 ds-1 G to C or R274T3UK
IVS8 as-6 G to A1UK
IVS9 ds+2 T to C (heterozygous)2Spain
c.1323_1344del22 (450X)2Spain
STAT5B
c.1680delG2Saudi Arabia
IGFALS
P73L1UK
L134Q/546-548delGGCinsAG1UK
c.1490insT1Kurdish
D440N1Turkey
Total58

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.

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