Background: Children with PraderWilli syndrome (PWS) attain high serum immunoreactive IGF1 levels during standard dose GH treatment, which leads to concern, but lowering the dose, deteriorates their body composition.
Objective and hypotheses: To evaluate serum IGF1, IGFBP3 and acid-labile subunit (ALS) levels, complex formation and IGF-bioactivity in GH-treated PWS children. We hypothesized that GH-treated children with PWS have a normal IGF-bioactivity, despite the high serum immunoreactive IGF1 levels.
Method: We included 40 GH-treated PWS (1.0 mg/m2 per day≈0.035 mg/kg per day) children and compared them with 41 age- and sex-matched healthy controls. Main outcome measures were serum IGF1, IGFBP3 and ALS levels, complex formation and IGF-bioactivity by IGF1 receptor kinase activation assay (KIRA).
Results: Serum IGF1, IGFBP3, ALS levels, and IGF1/IGFBP3 ratio were significantly higher in GH-treated PWS children than in healthy controls. The 150 kDa ternary complex formation was, however, also significantly higher than in controls, indicating that most of serum IGF1 is sequestered in the ternary 150 kDa complex with ALS and IGFBP3. Young GH-treated PWS children, median (IQR) age 5.2 (4.37.2) years, exhibited higher serum IGF-bioactivity than controls, but no difference was observed in IGF-bioactivity between older GH-treated PWS children, age 14.9 (13.816.2) years, and controls. The proportion of IGF-bioactivity of total serum IGF1 was, however, lower in GH-treated PWS children than in controls. Serum immunoreactive IGF1 levels did not correlate with IGF-bioactivity in GH-treated children with PWS, in contrast to a strong positive correlation in healthy controls.
Conclusion: In GH-treated PWS children, most off serum IGF1 is sequestered in the 150 kDa complex. Higher IGF-bioactivity was only found in young GH-treated PWS children and not in the older ones. IGF-bioactivity during GH showed a wide variation and there was a disrupted correlation with immunoreactive IGF1 levels, which makes immunoreactive IGF1 levels an inappropriate indicator of GH-dosing in PWS children.
Funding: This study was an investigator-initiated study, supported by an independent research grant from Pfizer.
01 - 03 Oct 2015
European Society for Paediatric Endocrinology