Beckwith–Wiedemann syndrome: multiple molecular mechanisms

Abstract

Beckwith-Wiedemann syndrome (BWS) is a congenital overgrowth condition with an increased risk of developing embryonic tumours, such as Wilms' tumour. The cardinal features are abdominal wall defects, macroglossia and gigantism. BWS is generally sporadic; only 10-15% of cases are familial. A variety of molecular aberrations have been associated with BWS. The only mutations within a gene are loss-of-function mutations in the CDKN1C gene, which codes for an imprinted cell-cycle regulator. CDKN1C mutations appear to be particularly associated with umbilical abnormalities, but not with increased predisposition to Wilms' tumour. In the remaining BWS subgroups, a disturbance of the tight epigenetic regulation of gene expression (patUPD 11p, microdeletions or epimutations) seems to be the cause of the syndrome. Here we describe the clinical presentation of BWS and its dissociation from phenotypically overlapping overgrowth syndromes. We then review the current concepts of causative molecular genetic and epigenetic mechanisms, and discuss future directions of research.

Beckwith–Wiedemann syndrome

“…Deregulation of imprinted genes in the 11p15.5 imprinted region results in the BWS phenotype through a number of different mechanisms leading to either primary epigenetic alterations or genetic alterations that change the relative contributions of parental alleles. 24,31,32 These include parent-of-origin-specific duplications, translocations/inversions, microdeletions, DNA methylation changes at IC1 or IC2, UPD, and mutations at CDKN1C. UPD refers to the presence of two chromosomal regions from one parent and none from the other.…”

“…32,43 Positive family history. This is associated with mutations in CDKN1C or microdeletions of IC1 and very rarely IC2.…”

Frequency and Timing of Loss of Imprinting at 11p13 and 11p15 in Wilms' Tumor Development

“…The 11p15 imprinted cluster is divided into two domains, one controlled by the H19 DMR in IC1 and another by the KCNQ1OT1 DMR (Kv DMR) in IC2 (17). We therefore investigated methylation at the Kv DMR to determine whether LOI was associated with altered methylation outside of the H19 DMR.…”

“…Additional proof for a causative role for LOI has come from a mouse model of pancreatic cancer, in which Igf2 LOI was found in hyperproliferative lesions before the development of frank malignancy (16). Studies of the human overgrowth syndrome Beckwith-Wiedemann syndrome, in which patients are predisposed to pediatric malignancies including WT, have shown that germ-line LOI of IGF2 is a feature of some cases, which further implicates LOI as a major epigenetic factor in the development of WT (17). Thus, somatic epigenetic defects lead to LOI of IGF2 in sporadic WT, and similarly, germ-line epigenetic defects can lead to constitutional LOI of IGF2 in Beckwith-Wiedemann syndrome, giving WT predisposition.…”

“…The first piece of evidence implicating imprinted genes in WT development came before the discovery of LOI, when it was noted that LOH of the 11p region in WT invariably involved loss of the maternal allele (1) and that 11p15 duplications and uniparental disomy in Beckwith-Wiedemann syndrome were always of paternal origin (17). This was explained by the presence of imprinted genes on 11p, such that maternal LOH or paternal uniparental disomy led to the loss of maternally expressed growth-suppressing genes and/or the retention of paternally expressed growth-promoting genes (18).…”