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N Engl J Med. 2015 Jul 23;373(4):349-56. doi: 10.1056/NEJMoa1415227. Epub 2015 Jul 8.

Paternally Inherited IGF2 Mutation and Growth Restriction.

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From the Institute of Human Genetics, University Hospital, Rhine-Westphalia Institute of Technology (RWTH) Aachen, Aachen (M.B., L.S., T.E.), Department of Pediatrics and Neuropediatrics, University Medicine, Göttingen, and Genetikum, Genetic Counseling and Diagnostics, Stuttgart (B.Z.), Ligandis, Gülzow-Prüzen (E.W.), Department of Pediatrics and Neuropediatrics, SLK-Kliniken, Heilbronn (H.-M.B.), and Pediatric Endocrinology Section, University Children's Hospital, University of Tübingen, Tübingen (R.S., G.B.) - all in Germany; and the Department of Clinical Genetics, Leiden University Medical Center (G.S.), GenomeScan (G.S., W.W.), and ServiceXS (W.W.) - all in Leiden, the Netherlands.


In humans, mutations in IGF1 or IGF1R cause intrauterine and postnatal growth restriction; however, data on mutations in IGF2, encoding insulin-like growth factor (IGF) II, are lacking. We report an IGF2 variant (c.191C→A, p.Ser64Ter) with evidence of pathogenicity in a multigenerational family with four members who have growth restriction. The phenotype affects only family members who have inherited the variant through paternal transmission, a finding that is consistent with the maternal imprinting status of IGF2. The severe growth restriction in affected family members suggests that IGF-II affects postnatal growth in addition to prenatal growth. Furthermore, the dysmorphic features of affected family members are consistent with a role of deficient IGF-II levels in the cause of the Silver-Russell syndrome. (Funded by Bundesministerium für Bildung und Forschung and the European Union.).

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