Expert consensus document: Clinical and molecular diagnosis, screening and management of Beckwith-Wiedemann syndrome: an international consensus statement

Abstract

Beckwith-Wiedemann syndrome (BWS), a human genomic imprinting disorder, is characterized by phenotypic variability that might include overgrowth, macroglossia, abdominal wall defects, neonatal hypoglycaemia, lateralized overgrowth and predisposition to embryonal tumours. Delineation of the molecular defects within the imprinted 11p15.5 region can predict familial recurrence risks and the risk (and type) of embryonal tumour. Despite recent advances in knowledge, there is marked heterogeneity in clinical diagnostic criteria and care. As detailed in this Consensus Statement, an international consensus group agreed upon 72 recommendations for the clinical and molecular diagnosis and management of BWS, including comprehensive protocols for the molecular investigation, care and treatment of patients from the prenatal period to adulthood. The consensus recommendations apply to patients with Beckwith-Wiedemann spectrum (BWSp), covering classical BWS without a molecular diagnosis and BWS-related phenotypes with an 11p15.5 molecular anomaly. Although the consensus group recommends a tumour surveillance programme targeted by molecular subgroups, surveillance might differ according to the local health-care system (for example, in the United States), and the results of targeted and universal surveillance should be evaluated prospectively. International collaboration, including a prospective audit of the results of implementing these consensus recommendations, is required to expand the evidence base for the design of optimum care pathways.

Figure 1. The Beckwith–Wiedemann spectrum

The Consensus group introduced the concept of Beckwith-Wiedemann Spectrum (BWSp) that includes patients with a clinical diagnosis of Beckwith–Wiedemann syndrome (BWS) with or without an (epi)genetic change at the BWS locus on chromosome 11p15; patients with ‘atypical BWS’ (defined as fewer cardinal and suggestive features than those needed for a clinical diagnosis of BWS) and an (epi)genetic change at the BWS locus; and patients with ‘isolated lateralised overgrowth’ and an (epi)genetic change at the BWS locus. The dotted arrowed line indicates that some patients with apparent isolated lateralised overgrowth and no 11p15 abnormality might subsequently be found to have an 11p15 abnormality on testing of additional tissues or with a more sensitive assay. Patients with clinical BWS and no detectable 11p15 abnormality might be further investigated with additional clinical evaluation and consideration of other syndromes which may have features overlapping with BWSp and appropriate testing for those syndromes may be warranted.

Figure 2. The Beckwith–Wiedemann syndromelocus at chromosome 11p15.5

The figure depicts the chromosome 11p15. –11p15.4 region with the imprinted genes and control regions that are implicated in the pathophysiology of BWSp. The BWSp locus can be divided in two functionally independent domains, the telomeric and centromeric domains. Each domain harbours its own imprinting control region that is differentially methylated on the maternal and paternal chromosomes. The insulin-like growth factor 2 encoding gene IGF2 and the gene encoding the non-translated long non-coding RNA (lncRNA) H19 are located in the telomeric domain and are controlled by the H19/IGF2:IG DMR (Imprinting Centre 1, IC1) that is methylated on the paternal chromosome. The cell cycle inhibitor gene CDKN1C and the gene encoding the regulatory long non-coding RNA KCNQ1OT1 are located in the centromeric domain and are controlled by the KCNQ1OT1:TSS DMR (Imprinting Centre 2, IC2) that is methylated on the maternal chromosome. Genes expressed from the maternal chromosome are depicted as red boxes and genes expressed from the paternal chromosome as blue boxes. Grey boxes indicate non-expressed alleles. Filled lollipops indicate methylated ICs and open lollipops indicate unmethylated ICs. Bent arrows indicate the orientation of transcription.

Figure 3. Flowchart for investigation and diagnosis of Beckwith–Wiedemann syndrome

The figure summarises the molecular diagnostic pathway for investigation of suspected BWSp. Patients with clinical features reaching a score of ≥2 should be genetically tested. H19/IGF2:IG DMR (IC1) and KCNQ1OT1:TSS DMR (IC2) methylation are recommended as first-line molecular testing. If not estimated simultaneously with DNA methylation, DMR copy number should then be determined in all cases with IC1 and/or IC2 methylation abnormalities. If positive, these assays lead to the molecular diagnosis of BWSp with IC2 LOM, IC1 GOM, segmental upd(11)pat or CNV (most commonly dup(11)(p15.5)pat). Further molecular tests can be considered to determine underlying mechanism of methylation abnormality, UPD or CNV. If DNA methylation testing is negative, further molecular tests can be considered to identify mosaic methylation abnormalities, pathogenic CDKN1C variants or rare balanced chromosomal rearrangements. If all molecular tests are negative, differential diagnosis should be considered. However, a diagnosis of classical BWS is made in presence of a clinical score of ≥4 even in absence of the molecular confirmation of an 11p15 anomaly. Clinical questions are in blue boxes, recommended molecular tests in yellow boxes, molecular diagnoses in pink boxes, molecular testing to be considered in green boxes. CMA, chromosome microarray analysis, which can be oligonucleotide- and/or SNP-based platforms. CNV, copy number variation; SNV, single nucleotide variation; SNP, Single nucleotide polymorphism; LOM, loss of methylation; GOM, gain of methylation. ¹ICNV status may be determined simultaneously with methylation testing ²refer to text for indications for testing ³del(11)(p15.5)mat may be detected with lower frequency