The Silver-Russel syndrome (SRS) is characterized by an intrauterine growth retardation accompanied by postnatal growth deficiency. Affected individuals typically have proportionately short statue, finger deformities as well as typical facial features. About 10% of individuals with SRS have maternal uniparental disomy for chromosome 7 (UPD7) and 35%50% showed hypomethylation of the parental imprinting center region 1 (ICR1) of chromosome 11p15.5. In the recent past also paternally inherited IGF2 mutations have been identified in patients with a SRS-like phenotype with evidence of pathogenicity. Here, we identify a novel de novo c.195delC IGF2 genevariant [NM_000612, p.(Ile66Serfs*93)] in a patient with a SRS like phenotype using NGS sequencing. The patient exhibited severe pre- and postnatal growth retardation in combination with dystrophy, facial dimorphism, finger deformities as well as a patent ductus. Cloning and sequencing of a long-range PCR product harboring the deletion and a SNP informative site chr11:2153634 (rs680, NC_000011.9:g.2153634T>C) demonstrated that the variant resided on the paternal allele. This finding is consistent with the known maternal imprinting of IGF2. 3D protein structure prediction and overexpression studies demonstrated that the p.(Ile66Serfs*93) variation resulted in an altered protein structure that impaired ligand/receptor binding and thus prevents IGF1R activation. In summary, our patient has an IGF2 deficiency due to a biologically inactive IGF2 protein that associated with pre- and postnatal growth retardations. The severity of the phenotype and dominant mode of transmission indicates that the p.(Ile66Serfs*93) variation might be responsible for the clinical picture of the patient, which argues for the inclusion of IGF2 in gene panels designed for routine diagnostics of intrauterine growth failure. The identification of such new mutations in combination with a detailed description of the phenotype could increase the awareness of physicians on the pathophysiological relevance of IGF2 which will facilitate early diagnosis and the initiation of an adequate treatment in order to avoid serious long-term effects.
27 - 29 Sep 2018
European Society for Paediatric Endocrinology