Beckwith-Wiedemann Syndrome (BWS) is a well-known syndrome of overgrowth.  Macrosomia, neonatal hypoglycemia, midline abdominal defects, macroglossia, ear pits and the predisposition to embryonic cancers in infants and young children, including Wilms tumor, hepatoblastoma and neuroblastoma are the important clinical features of BWS.  It is now possible to correlate the phenotypic features with specific genetic disturbances.  Most recently, alterations in the imprinting and methylation of several genes in the 11p15 region have been implicated in its etiology. Different patients have different involvement phenotypically and genetically.

De Baun et al have correlated anomalies of DNA methylation of one of the relevant genes, H19, in patients with cancer, as compared to those without. Those with cancer are less likely to have abnormalities of the methylation of another gene in the area, LIT1. Conversely, abnormalities of methylation of LIT1 are more likely to be associated with abnormal wall defects and macrosomia.  Affected individuals with paternal uniparental disomy of 11p15 are more likely to have associated hemihypertrophy, cancer, and hypoglycemia than those without uniparental disomy.

These findings suggest that all individuals with BWS deserve a precise molecular evaluation in order to be able to appropriately screen for expected complications. The cluster of genes related to BWS has been studied extensively because of its involvement in the epigenetic phenomenon of imprinting. Abnormal and loss of imprinting of the IGF2 gene found in this region is present in a number of tumors. H19 plays a role in the methylation of IGF2 and so its abnormal methylation or expression may increase the risk of cancer by its relation to IGF2.

In the evaluation of BWS, one would expect that cancerous tissue might have different imprinting or methylation than other easier to study tissues. This is particularly frustrating when hemihypertrophy is present. It is interesting to note that any hypertrophy observed in patients with BWS is suggestive of mosaicism. To date, all of the reported patients with paternal UPD of 11p15 are in fact, mosaic.  Thus, the two sides of the body probably have different manifestations of the Beckwith-Wiedemann gene cluster.

The hypoglycemia that can be seen in Beckwith-Wiedemann Syndrome also is associated with uniparental paternal disomy. Since hypoglycemia can result in secondary mental retardation, both screening and watching for hypoglycemia in patients with BWS is extremely important during infancy. 

DeBaun, et al.  Am J Hum Genet 2002;70:604-611.

Editor’s Comment:  Most of the conditions recognized to be involved in genomic imprinting are associated with abnormalities of growth. Thus, the possibility of genomic imprinting must be considered in any syndrome of abnormal growth. Further evaluation can obviously lead to unique insights about pathogenesis as are being developed in the BWS. This work is allowing recognition of the heterogeneity existing in BWS that may predispose to severe complications.

Judith G. Hall, OC, MD