Abstract
Beckwith–Wiedemann Spectrum (BWSp) is the most common epigenetic childhood cancer predisposition disorder. BWSp is caused by (epi)genetic changes affecting the BWS critical region on chromosome 11p15. Clinically, BWSp represents complex molecular and phenotypic heterogeneity resulting in a range of presentations from Classic BWS to milder features. The previously reported tumor risk based on Classic BWS cohorts is 8–10% and routine tumor screening has been recommended. This work investigated the tumor risk and correlation with phenotype within a cohort of patients from Classic BWS to BWSp using a mixed-methods approach to explore phenotype and epigenotype profiles associated with tumor development through statistical analyses with post-hoc retrospective case series review. We demonstrated that tumor risk across BWSp differs from Classic BWS and that certain phenotypic features are associated with specific epigenetic causes; nephromegaly and/or hyperinsulinism appear associated with cancer in some patients. We also demonstrated that prenatal and perinatal factors that are not currently part of the BWSp classification may factor into tumor risk. Additionally, blood testing results are not necessarily synonymous with tissue testing results. Together, it appears that the current understanding from Classic BWS of (epi)genetics and phenotype correlations with tumors is not represented in the BWSp. Further study is needed in this complex population.
Highlights
LOM (n = 118), IC1 GOM (n = 32), or pUPD11 (n = 78) and eligible for the study. From these 228 patients, there were 10 excluded for lack of data available for phenotype profiling and/or tumor development history required for the objectives of the current study and three patients from two unrelated families with IC2 LOM were found to have maternal microdeletion leading to the methylation abnormality
The Beckwith–Wiedemann syndrome (BWS) from a syndrome to a spectrum (BWSp) Study Population included for analysis consisted of a total of 215 patients with a molecular diagnosis of BWSp due to a methylation abnormality detected in the IC1 and/or IC2 regions
Our results suggest that some phenotypes may be associated with tumor development; the heterogeneity of the BWSp population presents a challenge to understanding the full spectrum of
Summary
Beckwith–Wiedemann syndrome (BWS; OMIM #130650) is the most common epigenetic overgrowth disorder in children, affecting approximately 1 in 10,000 live births and is caused by (epi)genetic mechanisms involving chromosome 11p15.5 [1]. The disorder leads to a variety of clinical manifestations with heterogeneous individual phenotypes, which prompted the reclassification of BWS from a syndrome to a spectrum (BWSp) by a recent international consensus group (ICG-BWSp) [1]. Within BWSp, patients can be affected by isolated lateralized overgrowth (ILO; previously hemihypertrophy/hemihyperplasia) in addition to atypical and classic BWS phenotypes [1]. To aide in clinical and molecular diagnosis, the BWSp-ICG introduced a diagnostic scoring system for patients and stratified common clinical features into cardinal and suggestive features, based on the likelihood of the feature leading to a BWSp diagnosis. Identification of patients who may experience a higher risk for tumor development within the BWSp population represents an important goal in guiding clinical care
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