SOMATIC OVERGROWTH ASSOCIATED WITH OVEREXPRESSION OF INSULIN-LIKE GROWTH-FACTOR-II

Overexpression of the normally imprinted fetal insulin-like growth fac tor II (IGF2) has been implicated in the pathogenesis of the cancer-pr edisposing Beckwith-Wiedemann syndrome (BWS). We have detected constit utional relaxation of imprinting of IGF2 in four children with somatic overgrowth who do not show diagnostic features of BWS. Three children showed constitutional abnormalities of H19 methylation. All four chil dren showed nephromegaly and two developed Wilms' tumors. Gene methyla tion is known to be associated with gene silencing, and three children showed constitutional abnormalities of H19 gene methylation. Disrupti on of H19 methylation, and concomitant relaxation of IGF2 imprinting, provides another mechanism that can increase IGF2 expression in childr en with overgrowth. The accumulated data on normal and pathologic IGF2 expression are now sufficient to define an entity, ''IGF2 overgrowth disorder,'' of which BWS may be one extreme manifestation. These findi ngs have broad implications for the characterization of idiopathic ove rgrowth.