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Martin O Savage, Cecilia Camacho-Hübner, Alessia David, Louise A Metherell, Vivian Hwa, Ron G Rosenfeld and Adrian J L Clark

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.

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Michael Buchfelder, A J Van der Lely, Beverly M. K. Biller, Susan M Webb, Thierry Brue, Christian J Strasburger, Ezio Ghigo, Cecilia Camacho-Hubner, Kaijie Pan, Joanne Lavenberg, Peter J Jonsson and Juliana H. Hey-Hadavi

Objectives: ACROSTUDY is an international, non-interventional study of acromegaly patients treated with pegvisomant(PEGV), a growth hormone receptor antagonist and has been conducted since 2004 in 15 countries to study the long-term safety and efficacy of PEGV. This report comprises the second interim analysis of 2090 patients as of May 12, 2016.

Methods: Descriptive analyses of safety, pituitary imaging and outcomes on PEGV treatment up to 12 years were performed.

Results: Prior to starting PEGV, 96% of patients had reported surgery, radiation, medical therapy or any combinations of those. At start of PEGV, 89% of patients had IGFI levels above the ULN. The percentage of patients with normal IGFI levels increased from 53% at year 1 to 73% at year 10, and the average daily dose of PEGV increased from 12.8mg (year 1) to 18.9mg (year 10). A total of 4832 adverse events(AEs) were reported in 1137 patients (54.4%), of which 570 were considered treatment-related in 337 patients (16.1%). Serious AEs were reported in 22% of patients, of which 2.3% were considered treatment-related. Locally reported MRIs showed most patients (72.2%) had no change in tumor size relative to the prior scan; 16.8% had a decrease, 6.8% an increase, and 4.3% both. In patients with normal liver tests at PEGV start, an ALT or AST elevation of >3x ULN at any time point during their follow up was reported in 3%.

Conclusions: This second interim analysis confirms that long-term use of PEGV is an effective and safe treatment in patients with acromegaly.