Overexpression of the normally imprinted fetal insulin-like growth factor II (IGF2) has been implicated in the pathogenesis of the cancer-predisposing Beckwith-Wiedemann syndrome (BWS). We have detected constitutional 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 children showed nephromegaly and two developed Wilms' tumors. Gene methylation is known to be associated with gene silencing, and three children showed constitutional abnormalities of H19 gene methylation. Disruption of H19 methylation, and concomitant relaxation of IGF2 imprinting, provides another mechanism that can increase IGF2 expression in children 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 findings have broad implications for the characterization of idiopathic overgrowth.

Two infants with Down syndrome, one 4 weeks old and the other stillborn, at necropsy showed hepatic and pancreatic fibrosis, which was very severe in the liver of the liveborn infant and in the pancreas of the stillbirth. The liveborn infant had typical hematological features of the transient congenital leukemoid reaction of Down syndrome, and the identification of a megakaryoblastic component was consistent with recent opinion that this is a spontaneously-remitting congenital megakaryoblastic leukemia. The hydropic stillborn infant had intense extramedullary megakaryocytosis. The visceral fibrosis may have had a pathogenesis similar to that postulated for the myelofibrosis of megakaryoblastic leukemia in older children.