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Original research
Increasing knowledge in IGF1R defects: lessons from 35 new patients
  1. Eloïse Giabicani1,2,3,
  2. Marjolaine Willems4,
  3. Virginie Steunou3,
  4. Sandra Chantot-Bastaraud5,
  5. Nathalie Thibaud2,
  6. Walid Abi Habib3,
  7. Salah Azzi3,
  8. Bich Lam3,
  9. Laurence Bérard2,
  10. Hélène Bony-Trifunovic6,
  11. Cécile Brachet7,
  12. Elise Brischoux-Boucher8,
  13. Emmanuelle Caldagues9,
  14. Regis Coutant10,
  15. Marie-Laure Cuvelier11,
  16. Georges Gelwane12,13,
  17. Isabelle Guemas9,
  18. Muriel Houang1,2,3,
  19. Bertrand Isidor14,
  20. Claire Jeandel15,
  21. James Lespinasse16,
  22. Catherine Naud-Saudreau17,
  23. Monique Jesuran-Perelroizen18,19,
  24. Laurence Perrin13,20,
  25. Juliette Piard8,
  26. Claire Sechter21,
  27. Pierre-François Souchon22,
  28. Caroline Storey12,13,
  29. Domitille Thomas3,
  30. Yves Le Bouc1,3,
  31. Sylvie Rossignol23,24,
  32. Irène Netchine1,2,3,
  33. Frédéric Brioude1,2,3
  1. 1 Sorbonne Université, UFR Médecine, Paris, France
  2. 2 AP-HP, Hôpital Armand Trousseau—Explorations Fonctionnelles Endocriniennes, Paris, France
  3. 3 INSERM, Centre de Recherche Saint-Antoine, Paris, France
  4. 4 CHU Montpellier, Génétique Médicale, Montpellier, France
  5. 5 AP-HP, Hôpital Armand Trousseau—Génétique Chromosomique, Paris, France
  6. 6 CHU Amiens-Picardie, Médecine Pédiatrique et Médecine de l'Adolescent, Amiens, France
  7. 7 U.L.B., Pediatric Endocrinology, Reine Fabiola Children's Hospital, Brussels, Belgium
  8. 8 Université de Franche-Comté, CHU Besançon, Centre de Génétique Humaine, Besançon, France
  9. 9 CHU Nantes, Médecine Pédiatrique, Nantes, France
  10. 10 CHU Angers, Endocrinologie et Diabétologie Pédiatriques, Angers, France
  11. 11 CH de Calais, Pédiatrie, Calais, France
  12. 12 AP-HP, Hôpital Robert Debré, Endocrinologie et Diabétologie Pédiatriques, Paris, France
  13. 13 Université Paris Diderot, Hôpital Robert Debré, Paris, France
  14. 14 CHU Nantes, Génétique Médicale, Nantes, France
  15. 15 CHRU Montpellier Pôle Mère et enfant, Pédiatrie Spécialisée Endocrinologie Gynécologie de l’Enfant et de l’Adolescent, Montpellier, France
  16. 16 CH-Chambéry, Génétique Chromosomique, Chambéry, France
  17. 17 CH Bretagne Sud, Endocrinologie et Diabétologie Pédiatriques, Lorient, France
  18. 18 Endocrinologie-pédiatrique, Cabinet libéral, Toulouse, France
  19. 19 AFPEL, Association Française des Pédiatres Endocrinologues Libéraux, Lille, France
  20. 20 AP-HP, Hôpital Robert Debré, Génétique Clinique, Paris, France
  21. 21 Université de Franche-Comté, CHU Jean Minjoz, Unité d’Endocrinologie et Diabétologie Pédiatriques, Besançon, France
  22. 22 American Memorial Hospital, Diabétologie et Endocrinologie Pédiatriques, CHU Reims, Reims, France
  23. 23 Hopitaux universitaires de Strasbourg, Service de Pédiatrie 1, Strasbourg, France
  24. 24 INSERM U1112, Institut de Génétique Médicale d’Alsace, Laboratoire de Génétique Médicale, Strasbourg, France
  1. Correspondence to Dr Eloïse Giabicani, Centre de Recherche Saint-Antoine, Sorbonne Université, Paris 75000, France; eloise.giabicani{at}


Background The type 1 insulin-like growth factor receptor (IGF1R) is a keystone of fetal growth regulation by mediating the effects of IGF-I and IGF-II. Recently, a cohort of patients carrying an IGF1R defect was described, from which a clinical score was established for diagnosis. We assessed this score in a large cohort of patients with identified IGF1R defects, as no external validation was available. Furthermore, we aimed to develop a functional test to allow the classification of variants of unknown significance (VUS) in vitro.

Methods DNA was tested for either deletions or single nucleotide variant (SNV) and the phosphorylation of downstream pathways studied after stimulation with IGF-I by western blot analysis of fibroblast of nine patients.

Results We detected 21 IGF1R defects in 35 patients, including 8 deletions and 10 heterozygous, 1 homozygous and 1 compound-heterozygous SNVs. The main clinical characteristics of these patients were being born small for gestational age (90.9%), short stature (88.2%) and microcephaly (74.1%). Feeding difficulties and varying degrees of developmental delay were highly prevalent (54.5%). There were no differences in phenotypes between patients with deletions and SNVs of IGF1R. Functional studies showed that the SNVs tested were associated with decreased AKT phosphorylation.

Conclusion We report eight new pathogenic variants of IGF1R and an original case with a homozygous SNV. We found the recently proposed clinical score to be accurate for the diagnosis of IGF1R defects with a sensitivity of 95.2%. We developed an efficient functional test to assess the pathogenicity of SNVs, which is useful, especially for VUS.

  • IGF1R
  • IGF-I
  • fetal growth restriction
  • homozygous variant
  • small for gestational age

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  • Contributors EG: wrote the manuscript, performed the experiments, collected and analysed the data and revised the manuscript. MW: collected and analysed the data and revised the manuscript. VS: performed the experiments. SC-B, SA, BL: performed the experiments, analysed the data and helped in revising the manuscript. NT: performed the experiments. WAH: analysed the data and helped in revising the manuscript. LB, HB-T, CB, EB-B, EC, RC, M-LC, GG, IG, MH, BI, CJ, JL, CN-S, MJ-P, LPS, JP, P-FS, CS, YLB and SR: collected data and helped to revise the manuscript. DT: performed the experiments, collected data and helped to revise the manuscript. IN: analysed the data and revised the manuscript. FB: analysed the data, wrote and revised the manuscript.

  • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

  • Competing interests None declared.

  • Patient consent for publication Not required.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data availability statement Data are available on reasonable request.