IGF2 Mutations

J Clin Endocrinol Metab. 2020 Jan 1;105(1):dgz034. doi: 10.1210/clinem/dgz034.


Objective: IGF2 is a paternally expressed growth-promoting gene. Here, we report five cases with IGF2 mutations and review IGF2 mutation-positive patients described in the literature. We also compare clinical features between patients with IGF2 mutations and those with H19/IGF2:IG-DMR epimutations.

Results: We recruited five cases with IGF2 mutations: case 1 with a splice site mutation (c.-6-1G>C) leading to skipping of exon 2 and cases 2-5 with different missense mutations (p.(Cys70Tyr), p.(Cys71Arg), p.(Cys33Ser), and p.(Cys45Ser)) affecting cysteine residues involved in the S-S bindings. All the mutations resided on the paternally inherited allele, and the mutation of case 5 was present in a mosaic condition. Clinical assessment revealed Silver-Russell syndrome (SRS) phenotype with Netchine-Harbison scores of ≥5/6 in all the apparently nonmosaic 14 patients with IGF2 mutations (cases 1-4 described in this study and 10 patients reported in the literature). Furthermore, compared with H19/IGF2:IG-DMR epimutations, IGF2 mutations were associated with low frequency of hemihypoplasia, high frequency of feeding difficulty and/or reduced body mass index, and mild degree of relative macrocephaly, together with occasional development of severe limb malformations, high frequency of cardiovascular anomalies and developmental delay, and low serum IGF-II values.

Conclusions: This study indicates that IGF2 mutations constitute a rare but important cause of SRS. Furthermore, while both IGF2 mutations and H19/IGF2:IG-DMR epimutations lead to SRS, a certain degree of phenotypic difference is observed between the two groups, probably due to the different IGF2 expression pattern in target tissues.

Publication types

  • Case Reports
  • Comparative Study
  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Abnormalities, Multiple / genetics*
  • Abnormalities, Multiple / pathology*
  • Adolescent
  • Adult
  • Child
  • Child, Preschool
  • DNA Methylation*
  • Female
  • Follow-Up Studies
  • Genomic Imprinting*
  • Humans
  • Infant
  • Insulin-Like Growth Factor II / genetics*
  • Limb Deformities, Congenital / genetics
  • Limb Deformities, Congenital / pathology
  • Male
  • Mutation*
  • Paternal Inheritance
  • Prognosis
  • RNA, Long Noncoding / genetics
  • Silver-Russell Syndrome / genetics
  • Silver-Russell Syndrome / pathology
  • Young Adult


  • H19 long non-coding RNA
  • IGF2 protein, human
  • RNA, Long Noncoding
  • Insulin-Like Growth Factor II