IGF2 Mutations: Report of Five Cases, Review of the Literature, and Comparison with H19/IGF2:IG-DMR Epimutations.

Abstract

OBJECTIVE\nIGF2 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.\n\n\nRESULTS\nWe recruited five cases with IGF2 mutations, i.e., 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 non-mosaic 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.\n\n\nCONCLUSIONS\nThis 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.