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

Peter Clayton, Mireille Bonnemaire, Pascale Dutailly, Pascal Maisonobe, Laurent Naudin, Emmanuel Pham, Zhidong Zhang, Andrew Grupe, Arunthathi Thiagalingam, Patrice Denèfle, Klaus Kapelari, Martin Borkenstein, Robert Payer, Jean De Schepper, Sylvie Tenoutasse, Raoul Rooman, Margarita Craen, Yves Le Bouc, Michel Colle, Michel PolakEric Mallet, Marc Petrus, Mohamad Maghnie, Stefano Zucchini, Sandro Loche, Malgorzata Wasniewska, Giovanni Battista Pozzan, Gianni Bona, Nella Greggio, Piernicola Garofalo, Marco Cappa, Silivia Vannelli, Boudewijn Bakker, Jurrian Hoekx, Edgar G A H Van Mil, Evelyn Van Pinxteren-Nagler, Dorota Birkholz, Leszek Szewczyk, Corina Galesanu, José Ignacio Labarta, Itxaso Rica Echevarria, Jesús Argente, Gabriel Á Martos-Moren, Maria Caimari, Carlos Pavia Sesma, Elena Gallego Gomez, Charles Buchanan, Helen Storr, Assunta Albanese

Research output: Contribution to journalArticlepeer-review


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%, 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.

Original languageEnglish
JournalJournal of Clinical Endocrinology and Metabolism
Issue number6
Publication statusPublished - Jun 2013

ASJC Scopus subject areas

  • Biochemistry
  • Clinical Biochemistry
  • Endocrinology
  • Biochemistry, medical
  • Endocrinology, Diabetes and Metabolism

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