Refining the evaluation of growth and the growth hormone/insulin-like growth factor-I axis in children

Abstract

Introduction: The growth hormone (GH)/Insulin-like growth factor-I (IGF) axis is a key mediator of childhood growth. Current diagnostic tests have poor specificity for disorders affecting this system, namely the growth hormone stimulation test (GHST) and IGF-I measurement. Aim: To improve the diagnostic evaluation of children with poor growth and possible GH deficiency (GHD) through 1) modifying the GHST and diagnostic fasting study; 2) utilising liquid chromatography mass spectrometry (LCMS) to measure IGF concentrations; 3) exploring genetic causes of poor growth; and 4) studying the association between body composition and infant growth. Methods: These include: additional GH measurements during the GHST and fasting study; IGF-I and –II measurement by LCMS in a well-characterised cohort; focused whole exome testing for rare clinical phenotypes; and body composition analysis using air displacement plethysmography. Results: Serial additional GH measurement after intravenous catheter placement will improve the specificity of the GHST. Similarly, serial GH measurement after a diagnostic fasting study will improve specificity for GHD. In normal infants, adiposity doubles in the first two months. Using LCMS, I have described reference data for IGF-I and –II at birth and demonstrated a relationship between these measurements and this rapid early accumulation of body fat. In our genetic studies, we have also identified a novel IGF1R mutation in a child with a phenotype consistent with IGF-I resistance. Conclusions: Diagnosing disorders of the GH/IGF-I axis remain a significant clinical challenge. I have expanded the clinical approach to evaluating the child with short stature through refining the GHST, diagnostic fasting study and body composition evaluation; describing reference data for body composition and IGFs in infancy; and exploring novel genetic causes of disordered growth. Future work will focus on studying other clinical tools in evaluating the child with short stature and predicting the clinical response to GH treatment.