Beckwith-Wiedemann spectrum (BWSp): an update on diagnosis, management, and follow-up from the scientific committee of the Italian BWSp association.
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Beckwith-Wiedemann spectrum (BWSp) is a congenital imprinting disorder characterized by overgrowth, cancer predisposition, and diverse clinical manifestations, resulting from epigenetic and genetic alterations at chromosome 11p15.5. BWSp represents the most common imprinting disorder, with a prevalence exceeding 1:10,000. The disorder is primarily associated with loss or gain of methylation at imprinting control regions IC2 and IC1, paternal uniparental disomy of 11p15, or pathogenic variants in CDKN1C. Advances in molecular diagnostics have refined genotype-phenotype correlations, improving both clinical management and tumor screening protocols. This review, produced by the Scientific Committee of the Italian BWSp Association (AIBWS), builds upon the 2018 international consensus, incorporating updated scientific evidence up to 2024. The committee critically assessed post-2017 literature using PRISMA and Delphi methodologies to revise ten key topics, including diagnosis and criteria, prenatal testing, molecular testing strategies, tumor surveillance, macroglossia surgery, growth monitoring, limb-length discrepancy, cognitive and psychosocial outcomes, and MLID (multi-locus imprinting disturbances). A major focus is optimizing diagnosis in cases with negative methylation tests on DNA from blood, where somatic mosaicism often necessitates alternative tissue testing. The review emphasizes prenatal diagnosis challenges, recommends including ART-related pregnancies in diagnostic criteria, and proposes a prenatal scoring system. Updated tumor surveillance strategies are presented, including universal α-fetoprotein screening for hepatoblastoma up to 3 years and genotype-based protocols for Wilms tumor. CDKN1C-related neuroblastoma surveillance is also addressed. MLID, often co-occurring with IC2-LoM, is discussed regarding clinical relevance, testing strategies, and implications for recurrence risk, particularly involving maternal-effect gene variants. Orthopedic and surgical management of limb-length discrepancy (LLD) and macroglossia is reviewed, alongside growth chart development and their role in personalized interventions. New findings on cognitive, behavioral, and psychosocial aspects highlight the need for routine screening and supportive care. The transition to adult care remains underexplored, though recommendations include attention to residual pediatric complications, fertility, and potential long-term risks. This review reinforces the importance of a multidisciplinary and personalized approach to BWSp across the lifespan, calling for further research to refine diagnostics, long-term outcomes, and transition models.