title: Characterizing short stature by insulin-like growth factor axis status and genetic associations: results from the prospective, cross-sectional, epidemiogenetic EPIGROW study.
abstract: BACKGROUND
  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.
  
  
  METHODS
  We conducted a prospective, cross-sectional, epidemiogenetic case-control study in 9 European countries (2008-2010).
  
  
  METHODS
  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%, respectively). An insertion-deletion (Indel) on the IGF1 gene (P = 1.2 × 10(-5), Bonferroni-corrected; case vs control frequency: 0.04 vs 0.112), an Indel on NFKB1 (P = 1.36 × 10(-10); case vs control frequency: 0.464 vs 0.272), and 2 single-nucleotide polymorphisms on ZBTB38 (P < 2.3 × 10(-6)) were associated with SS. At P < 10(-4), single-nucleotide polymorphisms on genes related to protein kinase regulation, MAPK, and Fanconi pathways were also associated with SS.
  
  
  CONCLUSIONS
  IGF-I deficiency is a common feature in SS without defined etiology; an Indel in the IGF1 gene was associated with SS. However, genes involved in transcriptional regulation (NFKB1 and ZBTB38) and growth factor signaling were also associated, providing further candidates for genetic investigations on individual patients.
authors.affiliation: University of Manchester, Manchester Academic Health Sciences Centre, Pediatric Endocrinology, Fifth Floor (Research), Royal Manchester Children's Hospital, Oxford Road, Manchester M13 9WL, United Kingdom. peter.clayton@manchester.ac.uk
authors.forename: Peter
authors.initials: P
authors.lastname: Clayton
authors.forename: Mireille
authors.initials: M
authors.lastname: Bonnemaire
authors.forename: Pascale
authors.initials: P
authors.lastname: Dutailly
authors.forename: Pascal
authors.initials: P
authors.lastname: Maisonobe
authors.forename: Laurent
authors.initials: L
authors.lastname: Naudin
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Pham
authors.forename: Zhidong
authors.initials: Z
authors.lastname: Zhang
authors.forename: Andrew
authors.initials: A
authors.lastname: Grupe
authors.forename: Arunthathi
authors.initials: A
authors.lastname: Thiagalingam
authors.forename: Patrice
authors.initials: P
authors.lastname: Denèfle
mesh_terms: D001827:Body Height; D002648:Child; D002675:Child, Preschool; D003430:Cross-Sectional Studies; D005260:Female; D006130:Growth Disorders / Q000097:blood / Q000209:etiology* / Q000235:genetics; D019382:Human Growth Hormone / Q000097:blood; D006801:Humans; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000097:blood / Q000172:deficiency; D007334:Insulin-Like Growth Factor I / Q000032:analysis / Q000172:deficiency* / Q000235:genetics; D020935:MAP Kinase Signaling System; D008297:Male; D052002:NF-kappa B p50 Subunit / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D011446:Prospective Studies
chemical_list: C515497:IGFBP3 protein, human; D018972:Insulin-Like Growth Factor Binding Protein 3; D052002:NF-kappa B p50 Subunit; C489548:NFKB1 protein, human; D019382:Human Growth Hormone; D007334:Insulin-Like Growth Factor I