ESPE Abstracts (2015) 84 FC-LB5

Paternally Inherited IGF2 Mutation Results in Intrauterine and Postnatal Growth Retardation

Matthias Begemannb, Birgit Zirnc,i, Gijs Santend,g, Elisa Wirthgenh, Lukas Soellnerb, Hans-Martin Büttele, Roland Schweizera, Wilbert van Workumf,g, Thomas Eggermannb & Gerhard Bindera

aPaediatric Endocrinology, University Children’s Hospital, Tübingen, Germany; bInstitute of Human Genetics, University Hospital, RWTH University Aachen, Aachen, Germany; cGeneticum, Genetic Counseling and Diagnostics, Stuttgart, Germany; dDepartment of Clinical Genetics, LUMC, Leiden, The Netherlands; eDepartment of Pediatrics and Neuropediatrics, SLK Klnikum, Heilbronn, Germany; fServiceXS B.V., Leiden, The Netherlands; gGenomeScan B.V., Leiden, The Netherlands; hLigandisGbR, Gülzow-Prüzen, Germany; iDepartment of Pediatrics and Neuropediatrics, University Medicine, Göttingen, Germany

Background: IGF1 and IGF2 are major regulators of somatic growth acting mainly through the IGF1R. Variants in IGF1 and in IGF1R were identified to cause intrauterine and postnatal growth retardation but variants in IGF2 have not yet been reported.

Method: In a multigenerational family four affected members (two siblings, one first degree cousin and the daughter of one sibling) exhibited severe growth retardation with heights between −4.2 and −5.6 SDS in childhood and dysmorphism resembling Silver–Russell syndrome. Whole exome next generation sequencing was performed to identify the genetic cause. Serum IGF1, IGFBP3, and IGF2 were assayed by RIA and clinical characterization was carried out to confirm the pathogenicity of the identified variant.

Results: We identified a heterozygote nonsense variant (c.191C>A) in the coding sequence of IGF2, resulting in a premature stop codon (p.Ser64Ter). IGF2 mRNA from the variant allele was not detectable implying nonsense mediated decay. The clinical and endocrine phenotype cosegregated with the mutation. Affected had a birth length <−4 SDS, relative macrocephaly, no skeletal asymmetry, deficient IGF2 (<5th percentile) and normal IGF1 levels. Mental retardation was present in only one of the three patients who had reached adulthood. The patients inherited the variant from their healthy fathers, and it originated from the paternal grandmother.

Conclusion: This is the first report on a functional variant in the IGF2 gene. As expected, it is associated with intrauterine growth restriction, but the severe growth retardation of variant carriers accompanied by IGF2 deficiency indicates that IGF2 is a key player in postnatal growth and development. The association of the phenotype with the sex of the parent inheriting the variant is in accordance with the imprinting status of IGF2. This observation and the additional dysmorphic features confirm the hypothesis that IGF2 is a major factor in the etiology of Silver–Russell syndrome.