Characterizing short stature by insulin-like growth factor axis status and genetic associations: results from the prospective, cross-sectional, epidemiogenetic EPIGROW study.

Context: Serum IGF-I levels are often low in patients with short stature (SS) without defined etiology. Hence, genetic investigations have focused on the GH–IGF-I axis. Objective: Our objectives were to characterize IGF-I axis status and search for a broader range of genetic associations in children with SS and normal GH. Design and Setting: We conducted a prospective, cross-sectional, epidemiogenetic case-control study in 9 European countries (2008–2010). Participants: Children (n = 275) aged ≥2 years with SS without defined etiology (≤−2.5 height SD score [SDS]) and ≥1 peak GH ≥7 μg/L) were recruited. Methods: Serum IGF-I, IGF-binding protein-3 (IGFBP-3), and acid-labile subunit (ALS) levels were measured in a central laboratory. Candidate gene exome sequencing was performed in this cohort and ethnicity-matched controls. Results: Serum IGF-I, IGFBP-3, and ALS levels were highly correlated, but there was a discrepancy between prevalence of IGF-I, IGFBP-3, and ALS deficiencies (53%, 30%, and 0.8%, respect...