Molecular subtypes and phenotypic expression of Beckwith–Wiedemann syndrome

Abstract

Beckwith -Wiedemann Syndrome (BWS) results from mutations or epigenetic events involving imprinted genes at 11p15.5. Most BWS cases are sporadic and uniparental disomy (UPD) or putative imprinting errors predominate in this group. Sporadic cases with putative imprinting defects may be subdivided into (a) those with loss of imprinting (LOI) of IGF2 and H19 hypermethylation and silencing due to a defect in a distal 11p15.5 imprinting control element (IC1) and (b) those with loss of methylation at KvDMR1, LOI of KCNQ1OT1 (LIT1) and variable LOI of IGF2 in whom there is a defect at a more proximal imprinting control element (IC2). We investigated genotype/epigenotype-phenotype correlations in 200 cases with a confirmed molecular genetic diagnosis of BWS (16 with CDKN1C mutations, 116 with imprinting centre 2 defects, 14 with imprinting centre 1 defects and 54 with UPD). Hemihypertrophy was strongly associated with UPD (Po0.0001) and exomphalos was associated with an IC2 defect or CDKN1C mutation but not UPD or IC1 defect (Po0.0001). When comparing birth weight centile, IC1 defect cases were significantly heavier than the patients with CDKN1C mutations or IC2 defect (P ¼ 0.018). The risk of neoplasia was significantly higher in UPD and IC1 defect cases than in IC2 defect and CDKN1C mutation cases. KaplanMeier analysis revealed a risk of neoplasia for all patients of 9% at age 5 years, but 24% in the UPD subgroup. The risk of Wilms' tumour in the IC2 defect subgroup appears to be minimal and intensive screening for Wilms' tumour appears not to be indicated. In UPD patients, UPD extending to WT1 was associated with renal neoplasia (P ¼ 0.054). These findings demonstrate that BWS represents a spectrum of disorders. Identification of the molecular subtype allows more accurate prognostic predictions and enhances the management and surveillance of BWS children such that screening for Wilms' tumour and hepatoblastoma can be focused on those at highest risk.

(Epi)genotype–phenotype correlations in Beckwith–Wiedemann syndrome

“…10 It is well established that patients with telomeric defects (IC1-GoM/UPD) have a major risk of tumors, especially Wilms' tumor, whereas patients with defects of the centromeric domain (IC2-LoM/CDKN1C variant) have a lower risk. 4,9,10,40 Our data also point to a gradient of oncogenic risk between the three main molecular subgroups. At one end of the spectrum, patients with IC2-LoM have a very low risk of tumors and can develop histotypes seen in both IC1-GoM and IC2-LoM cases; furthermore, UPD cases show a previously unreported predisposition to hepatoblastoma, the second more common histotype of BWS, occurring in 1.6% of BWS patients, that is, 6% of UPD cases.…”

“…4,[9][10][11]13,[27][28][29] In this study we further investigated these correlations providing data on a large cohort of fully characterized BWS patients with 11p15 region molecular defects. Our analysis evidences in the four BWS molecular subtypes differences in the incidence of many phenotypic traits, such as growth pattern, prevalence and severity of abdominal wall defects, macrosomia, nevus flammeus, ear signs, renal malformations, ureteral anomalies, organ enlargement, polyhydramnios, cancer incidence, and histotypes.…”

Epigenetic deregulation of imprinting in congenital diseases of aberrant growth

“…Most frequently, however, BWS is sporadic and results from epigenetic alterations at 11p15, altering the expression of several imprinted genes including IGF2 and CDKN1C. (23,24) BWS can arise not only from epigenetic perturbations at the H19 ICR, as mentioned before, but also by altered imprinting at the KvDMR1 ICR (Fig. 1D).…”

“…(23,24) It is characterized by pre-and postnatal overgrowth, macroglossia, abdominal wall defects, organomegaly, hemihyperplasia, neonatal hypoglycaemia, ear abnormalities and increased risk of Wilms' tumour of the kidney. Similarly to SRS, this syndrome can arise from genetic alterations, which affect imprinted expression in the 11p15 region.…”

“…(30) How can overexpression of IGF2 or loss of CDKN1C expression separately lead to BWS? Detailed analyses of genotype/epigenotype-phenotype correlations (24,31,32) indicate that in the case of alteration at the KvDMR1 the phenotype is milder, with a minimal risk of Wilms' tumour (as compared to cases with epigenetic deregulation at H19). This stresses that BWS, like SRS, is a heterogeneous disease, where more than one regulatory pathway might be involved.…”