Overgrowth syndromes (OGS) comprise different disorders with overlapping phenotypes. They demonstrate a variety of features, including pre- and post-natal overgrowth, macroglossia, organomegaly, abdominal wall defects, and hypoglycaemia. They also predispose to the development of embryonic tumours (most commonly Wilms’ tumour).¹ The pathogenesis of two different OGS is well established. Beckwith-Wiedemann syndrome (BWS; OMIM #130650) is related to genetic or epigenetic changes in the imprinted 11p15 region resulting in an increased level of IGF2 (reviewed by Maher & Reik²). Simpson-Golabi-Behmel syndrome (SGBS; OMIM #312870) is an X linked disease attributed to mutations in the glypican-3 gene (GPC3), which encodes an extracellular proteoglycan believed to interact with insulin-like growth factor II (IGF2) ^3,4 and/or other growth factors.^5,6

The proliferative effects of IGF2 are mediated by the type 1 IGF receptor. In contrast, the mannose-6-phosphate/IGF2 receptor (IGF2R) has an anti-proliferative function, by ensuring the clearance and inactivation of IGF2.⁷ This function of IGF2R is well supported by knockout mouse models; mice lacking functional IGF2R (KO-IGF2R) are up to 30% larger than their wild type littermates.^8–10 The increased growth of KO-IGF2R mice can be attributed to higher IGF2 levels because this phenotype is corrected in KO-IGF2R mice that also lack functional IGF2 or IGF1R.^9,10

IGF2R is developmentally regulated and its expression is maximal during fetal development and organogenesis.¹¹ Its expression pattern correlates with that of the IGF2 and GPC3 genes.^12–14 In the mouse, IGF2R is subject to parental imprinting with a maternal specific expression, and this pattern is maintained throughout development and in all somatic tissues in the adult.^15,16 In humans, the imprinting status of IGF2R is controversial. Some data are supportive of a polymorphic imprinting that occurs in the pre-term post-implantation embryo in 25–50% of individuals^17–19 …