Performance Metrics of the Scoring System for the Diagnosis of the Beckwith–Wiedemann Spectrum (BWSp) and Its Correlation with Cancer Development

SIMPLE SUMMARY: Beckwith-Wiedemann syndrome (BWSp) has recently been renamed to spectrum to reflect its diverse presentation and clinical features. In 2018, an international consensus developed a diagnostic approach and redefined clinical criteria, establishing a score above which a diagnosis can be made in case of a negative genetic test. We described a cohort of 831 patients to validate the efficacy of the 2018 consensus score for BWSp diagnosis, and to gather data on the performance of previous and current scoring systems, as well as the relationship between BWSp features, molecular tests, and the risk of cancer development. ABSTRACT: Different scoring systems for the clinical diagnosis of the Beckwith–Wiedemann spectrum (BWSp) have been developed over time, the most recent being the international consensus score. Here we try to validate and provide data on the performance metrics of these scoring systems of the 2018 international consensus and the previous ones, relating them to BWSp features, molecular tests, and the probability of cancer development in a cohort of 831 patients. The consensus scoring system had the best performance (sensitivity 0.85 and specificity 0.43). In our cohort, the diagnostic yield of tests on blood-extracted DNA was low in patients with a low consensus score (~20% with a score = 2), and the score did not correlate with cancer development. We observed hepatoblastoma (HB) in 4.3% of patients with UPD(11)pat and Wilms tumor in 1.9% of patients with isolated lateralized overgrowth (ILO). We validated the efficacy of the currently used consensus score for BWSp clinical diagnosis. Based on our observation, a first-tier analysis of tissue-extracted DNA in patients with <4 points may be considered. We discourage the use of the consensus score value as an indicator of the probability of cancer development. Moreover, we suggest considering cancer screening for negative patients with ILO (risk ~2%) and HB screening for patients with UPD(11)pat (risk ~4%).