Wilms tumour in Beckwith-Wiedemann Syndrome and loss of methylation at imprinting centre 2: revisiting tumour surveillance guidelines

doi:10.1038/ejhg.2017.102

Case Reports

. 2017 Sep;25(9):1031-1039.

doi: 10.1038/ejhg.2017.102. Epub 2017 Jul 12.

Wilms tumour in Beckwith-Wiedemann Syndrome and loss of methylation at imprinting centre 2: revisiting tumour surveillance guidelines

Jack Brzezinski^{1

2

3}, Cheryl Shuman^{1

4

5

6}, Sanaa Choufani¹, Peter Ray^{1

6

7}, Dmitiri J Stavropoulos^{7

8}, Raveen Basran^{7

8}, Leslie Steele^{6

7}, Nicole Parkinson^{5

6

7}, Ronald Grant^{2

9}, Paul Thorner^{7

8}, Armando Lorenzo^{10

11}, Rosanna Weksberg^{1

3

4

6

9}

Affiliations

¹ Genetics and Genome Biology Program, Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada.
² Division of Haematology and Oncology, Department of Paediatrics, The Hospital for Sick Children, Toronto, Ontario, Canada.
³ Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada.
⁴ Division of Clinical &Metabolic Genetics, Department of Paediatrics, The Hospital for Sick Children, Toronto, Ontario, Canada.
⁵ Department of Genetic Counselling, The Hospital for Sick Children, Toronto, Ontario, Canada.
⁶ Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
⁷ Cytogenetics Laboratory, Department of Paediatric Laboratory Medicine, The Hospital for Sick Children, Toronto, Ontario, Canada.
⁸ Laboratory Medicine and Pathobiology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.
⁹ Department of Paediatrics, University of Toronto, Toronto, Ontario, Canada.
¹⁰ Division of Urology, Department of Paediatrics, The Hospital for Sick Children, Toronto, Ontario, Canada.
¹¹ Department of Surgery, University of Toronto, Toronto, Ontario, Canada.

PMID: 28699632
PMCID: PMC5558170
DOI: 10.1038/ejhg.2017.102

Case Reports

Wilms tumour in Beckwith-Wiedemann Syndrome and loss of methylation at imprinting centre 2: revisiting tumour surveillance guidelines

Jack Brzezinski et al. Eur J Hum Genet. 2017 Sep.

. 2017 Sep;25(9):1031-1039.

doi: 10.1038/ejhg.2017.102. Epub 2017 Jul 12.

Authors

Affiliations

¹ Genetics and Genome Biology Program, Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada.
² Division of Haematology and Oncology, Department of Paediatrics, The Hospital for Sick Children, Toronto, Ontario, Canada.
³ Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada.
⁴ Division of Clinical &Metabolic Genetics, Department of Paediatrics, The Hospital for Sick Children, Toronto, Ontario, Canada.
⁵ Department of Genetic Counselling, The Hospital for Sick Children, Toronto, Ontario, Canada.
⁶ Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
⁷ Cytogenetics Laboratory, Department of Paediatric Laboratory Medicine, The Hospital for Sick Children, Toronto, Ontario, Canada.
⁸ Laboratory Medicine and Pathobiology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.
⁹ Department of Paediatrics, University of Toronto, Toronto, Ontario, Canada.
¹⁰ Division of Urology, Department of Paediatrics, The Hospital for Sick Children, Toronto, Ontario, Canada.
¹¹ Department of Surgery, University of Toronto, Toronto, Ontario, Canada.

PMID: 28699632
PMCID: PMC5558170
DOI: 10.1038/ejhg.2017.102

Abstract

Beckwith-Wiedemann Syndrome (BWS) is an overgrowth syndrome caused by a variety of molecular changes on chromosome 11p15.5. Children with BWS have a significant risk of developing Wilms tumours with the degree of risk being dependent on the underlying molecular mechanism. In particular, only a relatively small number of children with loss of methylation at the centromeric imprinting centre (IC2) were reported to have developed Wilms tumour. Discontinuation of tumour surveillance for children with BWS and loss of methylation at IC2 has been proposed in several recent publications. We report here three children with BWS reported to have loss of methylation at IC2 on clinical testing who developed Wilms tumour or precursor lesions. Using multiple molecular approaches and multiple tissues, we reclassified one of these cases to paternal uniparental disomy for chromosome 11p15.5. These cases highlight the current challenges in definitively assigning tumour risk based on molecular classification in BWS. The confirmed cases of loss of methylation at IC2 also suggest that the risk of Wilms tumour in this population is not as low as previously thought. Therefore, we recommend that for now, all children with a clinical or molecular diagnosis of BWS be screened for Wilms tumour by abdominal ultrasonography until the age of eight years regardless of the molecular classification.

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Conflict of interest statement

The authors disclose no conflict of interest.

Figures

**Figure 1**
Map of chromosome 11p15 region: (a) Schematic representation of imprinting regulation in the chromosome 11p15 region. Orange represents maternally derived chromosomes while green represents paternally derived chromosomes. Typically, IC1 is methylated on the paternally derived chromosome resulting in *IGF2* expression and silencing of *H19* while on the maternally derived chromosome IC2 is methylated resulting in silencing of *KCNQ1OT1* and expression of *KCNQ1* and *CDKN1C*. (b) Map of KCNQ1OT1 (DMR (IC2) indicating the coverage of pyrosequencing, MS-MLPA, and the Infinium methylation array. IC2 overlaps the CpG island indicated by a green bar. Genome maps are adapted from the UCSC Genome Browser. (c) Map of H19 (DMR (IC1) indicating coverage of pyrosequencing, methylation-specific MLPA probes (MS-MLPA), copy-number specific MLPA probes (CN-MLPA), and the Infinium methylation array. CTCF target sites are indicated.

**Figure 2**
Clinical photographs of patients reported in this case series. (a) Case 1; (b) Case 2; and (c) Case 3.

**Figure 3**
SNP Array data from the 3 cases in this series at 11p15.5 and 11p15.4. For each case the first set of data represents the B allele frequency (BAF, green) and the second set of data represents the log R ratio (LRR, blue). In the bottom panel, a red arrow marks IC1 (chr11:2019627-2024297) while a purple arrow marks IC2 (chr11:2720411-2722087).

**Figure 4**
Pathology findings from partial nephrectomy. (a–d) Treated WT. (a) Macroscopic appearance of the tumour measuring only 0.5 cm in diameter. (b) The central portion of the specimen is mainly necrotic with isolated differentiated epithelial elements. (c) The more peripheral portion consists of blastema (lower left corner) with differentiated tubules in a fibrotic stroma. (d) Intra-renal vein (vessel wall marked by arrow) containing a tumour thrombus composed of fibrous stroma and rare differentiated tubules. (e and f) perilobar nephrogenic rest showing a well circumscribed rest surrounded by normal renal parenchyma. The rest is composed of nests of tubules separated by varying amounts of fibrous stroma. (original magnifications: a × 1, b, c × 200, d × 100, e × 10, and f × 100).

See this image and copyright information in PMC

Comment in

Reply to Brioude et al.
Brzezinski J, Shuman C, Choufani S, Ray P, Stavropoulos DJ, Basran R, Steele L, Parkinson N, Grant R, Thorner P, Lorenzo A, Weksberg R. Brzezinski J, et al. Eur J Hum Genet. 2018 Apr;26(4):473-474. doi: 10.1038/s41431-017-0094-y. Epub 2018 Feb 15. Eur J Hum Genet. 2018. PMID: 29449717 Free PMC article. No abstract available.
Revisiting Wilms tumour surveillance in Beckwith-Wiedemann syndrome with IC2 methylation loss, reply.
Brioude F, Hennekam R, Bliek J, Coze C, Eggermann T, Ferrero GB, Kratz C, Bouc YL, Maas SM, Mackay DJG, Maher ER, Mussa A, Netchine I. Brioude F, et al. Eur J Hum Genet. 2018 Apr;26(4):471-472. doi: 10.1038/s41431-017-0074-2. Epub 2018 Feb 15. Eur J Hum Genet. 2018. PMID: 29449718 Free PMC article. No abstract available.

Cited by

Reply to Brioude et al.
Brzezinski J, Shuman C, Choufani S, Ray P, Stavropoulos DJ, Basran R, Steele L, Parkinson N, Grant R, Thorner P, Lorenzo A, Weksberg R. Brzezinski J, et al. Eur J Hum Genet. 2018 Apr;26(4):473-474. doi: 10.1038/s41431-017-0094-y. Epub 2018 Feb 15. Eur J Hum Genet. 2018. PMID: 29449717 Free PMC article. No abstract available.
The effectiveness of Wilms tumor screening in Beckwith-Wiedemann spectrum.
Mussa A, Duffy KA, Carli D, Griff JR, Fagiano R, Kupa J, Brodeur GM, Ferrero GB, Kalish JM. Mussa A, et al. J Cancer Res Clin Oncol. 2019 Dec;145(12):3115-3123. doi: 10.1007/s00432-019-03038-3. Epub 2019 Oct 4. J Cancer Res Clin Oncol. 2019. PMID: 31583434 Free PMC article.
[Tumor predisposition syndromes and nephroblastoma : Early diagnosis with imaging].
Welter N, Furtwängler R, Schneider G, Graf N, Schenk JP. Welter N, et al. Radiologie (Heidelb). 2022 Dec;62(12):1033-1042. doi: 10.1007/s00117-022-01056-w. Epub 2022 Aug 25. Radiologie (Heidelb). 2022. PMID: 36008692 Review. German.
Oral Health-Related Quality of Life among Children and Adolescents with Beckwith-Wiedemann Syndrome in Northern Italy.
Defabianis P, Ninivaggi R, Romano F. Defabianis P, et al. J Clin Med. 2022 Sep 26;11(19):5685. doi: 10.3390/jcm11195685. J Clin Med. 2022. PMID: 36233553 Free PMC article.
Imprinting disorders.
Eggermann T, Monk D, de Nanclares GP, Kagami M, Giabicani E, Riccio A, Tümer Z, Kalish JM, Tauber M, Duis J, Weksberg R, Maher ER, Begemann M, Elbracht M. Eggermann T, et al. Nat Rev Dis Primers. 2023 Jun 29;9(1):33. doi: 10.1038/s41572-023-00443-4. Nat Rev Dis Primers. 2023. PMID: 37386011 Review.

See all "Cited by" articles

References

1. Weksberg R, Shuman C, Beckwith JB: Beckwith-Wiedemann syndrome. Eur J Human Genet 2009; 18: 8–14. - PMC - PubMed
1. Mussa A, Russo S, De Crescenzo A et al: Prevalence of Beckwith-Wiedemann syndrome in North West of Italy. Am J Med Genet 2013; 161A: 2481–2486. - PubMed
1. Tan TY, Amor DJ: Tumour surveillance in Beckwith-Wiedemann syndrome and hemihyperplasia: a critical review of the evidence and suggested guidelines for local practice. J Paediatr Child Health 2006; 42: 486–490. - PubMed
1. Mussa A, Russo S, De Crescenzo A et al: (Epi)genotype–phenotype correlations in Beckwith–Wiedemann syndrome. Eur J Hum Genet 2016; 24: 183–190. - PMC - PubMed
1. McNeil DE, Brown M, Ching A, DeBaun MR: Screening for Wilms tumor and hepatoblastoma in children with Beckwith-Wiedemann syndromes: a cost-effective model. Med Pediatr Oncol 2001; 37: 349–356. - PubMed

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[1] Weksberg R, Shuman C, Beckwith JB: Beckwith-Wiedemann syndrome. Eur J Human Genet 2009; 18: 8–14. - PMC - PubMed

[2] Weksberg R, Shuman C, Beckwith JB: Beckwith-Wiedemann syndrome. Eur J Human Genet 2009; 18: 8–14. - PMC - PubMed

[3] Mussa A, Russo S, De Crescenzo A et al: Prevalence of Beckwith-Wiedemann syndrome in North West of Italy. Am J Med Genet 2013; 161A: 2481–2486. - PubMed

[4] Mussa A, Russo S, De Crescenzo A et al: Prevalence of Beckwith-Wiedemann syndrome in North West of Italy. Am J Med Genet 2013; 161A: 2481–2486. - PubMed

[5] Tan TY, Amor DJ: Tumour surveillance in Beckwith-Wiedemann syndrome and hemihyperplasia: a critical review of the evidence and suggested guidelines for local practice. J Paediatr Child Health 2006; 42: 486–490. - PubMed

[6] Tan TY, Amor DJ: Tumour surveillance in Beckwith-Wiedemann syndrome and hemihyperplasia: a critical review of the evidence and suggested guidelines for local practice. J Paediatr Child Health 2006; 42: 486–490. - PubMed

[7] Mussa A, Russo S, De Crescenzo A et al: (Epi)genotype–phenotype correlations in Beckwith–Wiedemann syndrome. Eur J Hum Genet 2016; 24: 183–190. - PMC - PubMed

[8] Mussa A, Russo S, De Crescenzo A et al: (Epi)genotype–phenotype correlations in Beckwith–Wiedemann syndrome. Eur J Hum Genet 2016; 24: 183–190. - PMC - PubMed

[9] McNeil DE, Brown M, Ching A, DeBaun MR: Screening for Wilms tumor and hepatoblastoma in children with Beckwith-Wiedemann syndromes: a cost-effective model. Med Pediatr Oncol 2001; 37: 349–356. - PubMed

[10] McNeil DE, Brown M, Ching A, DeBaun MR: Screening for Wilms tumor and hepatoblastoma in children with Beckwith-Wiedemann syndromes: a cost-effective model. Med Pediatr Oncol 2001; 37: 349–356. - PubMed

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Wilms tumour in Beckwith-Wiedemann Syndrome and loss of methylation at imprinting centre 2: revisiting tumour surveillance guidelines

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Wilms tumour in Beckwith-Wiedemann Syndrome and loss of methylation at imprinting centre 2: revisiting tumour surveillance guidelines

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