Synchronous B-cell precursor acute lymphoblastic leukaemia and Wilms tumour in a patient with lateralised overgrowth: causation or coincidence?

Synchronous B-cell precursor acute lymphoblastic leukaemia and Wilms tumour in a patient with lateralised overgrowth: causation or coincidence? | Authorea try { document.documentElement.classList.add('js'); } catch (e) { } var _gaq = _gaq || []; _gaq.push(['_setAccount', 'G-8VDV14Y67G']); _gaq.push(['_trackPageview']); (function() { var ga = document.createElement('script'); ga.type = 'text/javascript'; ga.async = true; ga.src = ('https:' == document.location.protocol ? 'https://ssl' : 'http://www') + '.google-analytics.com/ga.js'; var s = document.getElementsByTagName('script')[0]; s.parentNode.insertBefore(ga, s); })(); Skip to main content Preprints Collections Wiley Open Research IET Open Research Ecological Society of Japan All Collections About About Authorea FAQs Contact Us Quick Search anywhere Search for preprint articles, keywords, etc. Search Search ADVANCED SEARCH SCROLL Pediatric Blood & Cancer This is a preprint and has not been peer reviewed. Data may be preliminary. 3 October 2025 V1 Latest version Share on Synchronous B-cell precursor acute lymphoblastic leukaemia and Wilms tumour in a patient with lateralised overgrowth: causation or coincidence? Authors : Karolina Miarka-Walczyk 0000-0001-6038-8842 , Aleksandra Filipiuk , Kamila Wypyszczak 0000-0001-5951-0177 , Zuzanna Urbanska , Marta Kozłowska , Wojciech Mlynarski , Ninela Irga-Jaworska , and Agata Pastorczak [email protected] Authors Info & Affiliations https://doi.org/10.22541/au.175952090.09290533/v1 Published Pediatric Blood & Cancer Version of record Peer review timeline 236 views 144 downloads Contents Abstract Information & Authors Metrics & Citations View Options References Figures Tables Media Share Abstract Synchronous primary malignancies are rare in paediatric patients and usually develop based on inherited cancer predisposition. We report the case of a 4-year-old girl with lateralised overgrowth who was diagnosed with concomitant B-cell precursor acute lymphoblastic leukaemia and Wilms tumour. Methylation analysis at chromosome 11p15.5 revealed a mosaic gain of methylation at IC1 on the maternal allele in kidney tissue, which was absent in leukemic and remission blood cells, confirming the diagnosis of Beckwith-Wiedemann syndrome. We discuss the cause-and-effect relationship for both malignancies and point out diagnostic and therapeutic difficulties that were encountered in this patient. Title: Synchronous B-cell precursor acute lymphoblastic leukaemia and Wilms tumour in a patient with lateralised overgrowth: causation or coincidence? Karolina Miarka-Walczyk 1 , Aleksandra Filipiuk 2 , Kamila Wypyszczak 1 , Zuzanna Urbańska 1 , Marta Kozłowska 2 , Wojciech Młynarski 3 , Ninela Irga-Jaworska 2* , Agata Pastorczak 1* 1 Department of Genetic Predisposition to Cancer, Medical University of Lodz, Lodz, Poland 2 Department of Pediatrics Hematology and Oncology, Medical University, Gdansk, Poland 3 Department of Pediatrics, Oncology and Hematology, Medical University of Lodz, Lodz, Poland * equally contributed as senior authors Corresponding author: Agata Pastorczak, MD, PhD Department of Genetic Predisposition to Cancer, Medical University of Lodz, Czechosłowacka Street 4, 92-216 Lodz, Poland Tel.:+48 42 272 53 33, Email: [email protected] Word count main text: 1194 Word count abstract: 96 Short running title: Synchronous B-ALL and Wilms tumour in a patient with BWS. Key words: Wilms tumour, Beckwith-Wiedemann syndrome, acute lymphoblastic leukaemia, children, synchronous malignancies Tables: 0 Figures: 2 Supplementary Information File: 1 BCP-ALL B-cell precursor acute lymphoblastic leukaemia WT Wilms tumour IC1 Imprinting Control Region 1 CMMRD Constitutional mismatch repair deficiency RTPS Rhabdoid tumour predisposition syndromes BWS Beckwith-Wiedemann syndrome WBC White blood cells BM Bone marrow ALL Acute lymphoblastic leukaemia CNS2 Central Nervous System status 2 SNP Single-nucleotide polymorphism NGS Next-generation sequencing MRI Magnetic Resonance Imaging NSS Nephron-sparing surgery MRD Minimal residual disease PCR-MRD Polymerase chain reaction – minimal residual disease MS-MLPA Methylation-specific multiplex ligation-dependent probe amplification IG DMR Imprinted gene differentially methylated region CNV Copy number variation allo-HSCT-MUD Allogeneic hematopoietic stem cell transplant from a matched unrelated donor Abstract: Synchronous primary malignancies are rare in paediatric patients and usually develop based on inherited cancer predisposition. We report the case of a 4-year-old girl with lateralised overgrowth who was diagnosed with concomitant B-cell precursor acute lymphoblastic leukaemia and Wilms tumour. Methylation analysis at chromosome 11p15.5 revealed a mosaic gain of methylation at IC1 on the maternal allele in kidney tissue, which was absent in leukemic and remission blood cells, confirming the diagnosis of Beckwith-Wiedemann syndrome. We discuss the cause-and-effect relationship for both malignancies and point out diagnostic and therapeutic difficulties that were encountered in this patient. Introduction Synchronous primary malignancies of different tissue origin are exceedingly rare in children and usually arise from underlying genetic cancer predisposition syndromes 1,2 . Patients with DNA repair disorders, including constitutional mismatch repair deficiency (CMMRD), Bloom syndrome, or Fanconi anaemia, are particularly prone to develop multiple synchronous or metachronous tumours 3–5 . Co-occurrence of malignancies has also been reported in children with Li-Fraumeni syndrome, rhabdoid tumour predisposition syndromes (RTPS), and Beckwith-Wiedemann syndrome (BWS) 4,6–9 . The management of individuals with synchronous malignancies usually requires several modifications resulting from specific types of coexisting tumours and is associated with individual clinical context of the constitutional defect. When co-occurring neoplasms fall within the phenotypic spectrum of the defined cancer predisposing entity, their pathogenetic background can be relatively easily identified. However, some atypical constellation of synchronous malignancies may pose greater diagnostic difficulties in terms of common genetic basis promoting their development. Therefore, the possible coincidence should be considered in every case. Such example can be illustrated by concomitant acute lymphoblastic leukaemia (ALL) and Wilms tumour (WT), which have been reported in three paediatric patients yet and only in one of them, a genetic diagnosis associated with Fanconi anaemia group D1 was revealed 4,10 . Here, we describe a 4-year-old girl diagnosed with synchronous B-ALL and WT. Although the inherited cancer predisposition syndrome was eventually recognized, the cause-and-effect relationship for both cancers remains an open question. Case description A 4-year-old girl with mild lateral overgrowth (hypertrophy of the left lower limb and foot) was admitted with respiratory infection and rapidly progressing pancytopenia (WBC: 4100/µl; neutrophils: 300/µl; haemoglobin: 5.8g/dl; platelets: 24,000/µl). Bone marrow (BM) biopsy revealed 96% infiltration by pathological B-cell precursor lymphoblasts. Cytogenetic analysis showed dic(9;20) in 12 of 20 metaphases; single-nucleotide polymorphism (SNP) array revealed deletions of the p arms of chromosomes 9 and 20 (Fig. 1A). Targeted RNA next-generation sequencing (NGS) identified a PAX5::ZCCHC7 fusion and a somatic NF1 variant (NM_001042492.3:c.5359=/G>T, p.Glu1787=/*) present in 33% of reads. As part of standard diagnostics (AEIOP-BFM 2017), abdominal ultrasound was performed and revealed a left kidney mass (61×59×71 mm) suggestive of WT, with no pulmonary involvement. Magnetic resonance imaging (MRI) showed possible bilateral nephroblastomatosis. The patient received induction chemotherapy (vincristine, daunorubicin, prednisone, PEG-asparaginase, methotrexate ith), achieving remission by day 33 with MRD (minimal residual disease) below <1x10-4 and was assigned to the standard risk group. The dimension of the kidney tumour decreased during the ALL induction treatment to 34ml (45mmx33mmx41mm), and the foci of possible nephroblastomatosis disappeared. The patient underwent nephron-sparing surgery (NSS) of the left kidney, which confirmed stage III blastemal-predominant nephroblastoma according to the SIOP UMBRELLA 2016 protocol. Six cycles of chemotherapy (cyclophosphamide, doxorubicin, etoposide, carboplatin) were administered, with one episode of severe myelosuppression requiring G-CSF. Following the first course (CPM/DOX and VP16/CARBO), the left kidney was irradiated (25 Gy in 14 fractions). Four doses of intrathecal methotrexate (12 mg each) were given before the fourth chemotherapy cycle (VP16+CARBO) and at that time, PCR-MRD remained negative. After 11 months from the diagnosis of malignancies, the patient developed B-ALL relapse and, after achieving complete remission, was treated with allo-HSCT-MUD (Fig. 2B). The patient underwent testing for cancer predisposition using a custom NGS panel (Methods in Supporting Information and S1 Table). Sequencing revealed a heterozygous missense variant of unknown significance in MBD4 (NM_001276270.2): c.1366G>A, p.(Ala456Thr), inherited from the mother, without copy number alterations in the second allele (Fig. 2A). Interestingly, Dadi et al. recently showed that germline heterozygous loss-of-function variant in DNA Glycosylase (MBD4) affects base excision repair and increases genomic instability, possibly contributing to leukaemia development 11. Since no causative variant was identified based on NGS testing and the patient had mild lateralised overgrowth, BWS was suspected. According to the international consensus criteria dedicated to the clinical diagnosis of BWS 12, the patient scored 3 points (1 for unilateral Wilms tumour, 2 for lateralised overgrowth), warranting molecular testing. Given the tissue-specific and mosaic nature of methylation defects in BWS, methylation analysis of the 11p15.5 imprinted region was performed using MS-MLPA (ME030-C3 BWS/RSS, MRC Holland, Amsterdam, Netherlands) in normal kidney, Wilms tumour, BCP-ALL cells, and remission blood13. Gain of methylation in the IC1 (H19/IGF2:IG DMR) region on the maternal allele was detected in both kidney-derived samples (Figs. 1B, D), without coexisting deletion involving chromosome 11p15.5 (Figs. 1A, C). Epigenetic alterations and copy number abnormalities of the 11p15.5 region were absent either in leukemic cells-derived DNA or in the remission blood sample. The results confirmed the diagnosis of BWS. Considering four previously reported cases of childhood ALL in the context of BWS 4,10, we analysed CNVs and copy-neutral LOH affecting chromosome 11p in n=446 paediatric B-ALL samples from non-syndromic patients treated according to the AIEOP-BFM 2017 protocol (Fig. 1G). We did not identify any deletions involving the BWS imprinting region. Copy-neutral LOH of 11p was observed in 10 cases (2.24%), while duplication of 11p15.5 and trisomy 11 were found in 4 and 21 cases, respectively (Fig. 1G). Discussion Outside of the context of highly penetrant paediatric cancer variants affecting TP53 or DNA repair genes, synchronous malignancies occur in children very rarely 3,14,15. Although overall risk for all types of malignancies in patients with BWS varies between 2% to 28% depending on the specific molecular background of the syndrome, ALL does not represent a cancer in the phenotypic spectrum of the disorder 16. Hypermethylation of IC1 on maternal allele, seen in 5–10% of BWS cases, is strongly associated with increased risk of WT 17–19. Our observations confirm the notion presented by Hol JA. et al. that patients diagnosed with WT who have at least one additional feature of BWS may carry methylation changes of 11p15.5 region below the detection threshold of MS-MLPA in blood, but gain of methylation can still be identified in other tissues 15. In addition, mosaicism occurs frequently in children who have mild or atypical BWS phenotypes (e.g., ear pits and umbilical hernia) but they are at increased risk of developing multifocal or bilateral WT and nephroblastomatosis. 12. Although our patient showed only a few cardinal features of classical BWS, the possible foci of nephroblastomosis coexisting with the kidney tumour were initially observed on MRI scans and disappeared after chemotherapy. Although secondary malignancies occur in BWS, cancers that are outside of the tumour spectrum have been noted very rarely. Two such cases, including fibroadenoma and glioblastoma diagnosed in teenager and adult individuals, have been reported 20,21. Since in our patient epigenetic 11p15.5 alterations were absent in both blood and leukemic DNA and they were found in non-syndromic BCP-ALL very infrequently, leukaemia development in our patient is unlikely to be related to BWS. The optimal management of synchronous tumours requires considering the risk of recurrence of both diseases and the potential toxicities resulting from inherited cancer predisposition. In our patient, rapid exclusion of DNA repair disorders was essential before starting intensive induction chemotherapy of ALL. After achieving remission, tumour resection with preservation of unaffected kidney tissue was possible. Patients with BWS typically do not experience excessive complications of antineoplasmatic therapy, which was also observed in case of our patient, who easily achieved remission of both cancers. However, probably due to alleviated treatment of ALL harbouring dic(9;20) the leukaemia relapse evolved. Authors’ contributions: ZU, KM-W and KW - wet lab & data analysis, Patients’ treatment and clinical data collection: AF, MK, Original draft writing: KM-W, AP, Review and editing: AP, WM, NIJ, Conceptualization: AP. All authors have read and agreed to the published version of the manuscript and agreed to the published version of the manuscript. Acknowledgements: The illustrations were created with BioRender.com. Funding: The study was supported by projects funded by the Saving Kids with Cancer Foundation (Poland) (grant no. 01/2024/BN/PK) and the Medical Research Agency (Poland) (grant no. 2024/ABM/03/KPO/KPOD.07.07-IW.07-00156/24-00). Conflict of interest statement: No conflicts of interest declared. Disclosure and competing interests statement: The authors have no competing interests. Data availability statement: Data related to this study’s findings will be made available upon request from the corresponding author Ethics approval statement: The work described in this article has been carried out following The Code of Ethics of the World Medical Association (Declaration of Helsinki) for experiments involving humans; EU Directive 2010/63/EU for animal experiments; and uniform requirements for manuscripts submitted to biomedical journals. This study was approved by the Local Ethical Committee at the Medical University of Lodz (decision No. RNN/213/22/KE, dated September 13, 2022). The patient’s guardian has provided informed consent for the publication of this case report. References 1. Torina TB, Hudspeth EL, Chun JM, Zaloga W, Alderink C, Abdeen Y. An Unusual Occurrence of Multiple Metachronous and Synchronous Primary Cancers in a Female Patient. Case Rep Oncol Med . 2020;2020:1-5. doi:10.1155/2020/5691732 2. Zhang B, He L, Zhou C, et al. A pancancer analysis of the clinical and genomic characteristics of multiple primary cancers. Scientific Reports 2024 14:1 . 2024;14(1):1-13. doi:10.1038/s41598-024-52659-3 3. Cruz O, Caloretti V, Salvador H, et al. Synchronous choroid plexus papilloma and Wilms tumor in a girl, disclosing a Li-Fraumeni syndrome. Hered Cancer Clin Pract . 2021;19(1). doi:10.1186/S13053-020-00158-7 4. Yi JS, Kamihara J, Kesselheim JC, et al. Synchronous occurrence of acute lymphoblastic leukemia and wilms tumor in two patients: underlying etiology and combined treatment plan. Pediatr Blood Cancer . 2017;64(5):e26345. doi:10.1002/PBC.26345 5. Dembowska A, Dubaj M, Bigosiński K, Raniewicz M, Mitura-Lesiuk M. Synchronous neoplasms in a paediatric patient. Pediatria Polska - Polish Journal of Paediatrics . 2024;99(1):66-70. doi:10.5114/POLP.2024.135857 6. Cavalier ME, Davis MM, Croop JM. Germline p53 mutation presenting as synchronous tumors. J Pediatr Hematol Oncol . 2005;27(8):441-443. doi:10.1097/01.MPH.0000176732.68090.C8 7. Roque L, Lacerda A, Rodrigues R, Almeida O, Salgueiro J, Pinto C. CGH evaluation of two de novo synchronous tumors in a child with a germline p53 mutation. Pediatr Blood Cancer . 2006;47(7):949-954. doi:10.1002/PBC.20603 8. Moke DJ, Thomas SM, Hiemenz MC, et al. Three synchronous malignancies in a patient with DICER1 syndrome. Eur J Cancer . 2018;93:140. doi:10.1016/J.EJCA.2017.12.021 9. Orbach D, Brecht IB, Corradini N, et al. The role of cancer predisposition syndrome in children and adolescents with very rare tumours. EJC Paediatric Oncology . 2023;2:100023. doi:10.1016/J.EJCPED.2023.100023 10. Esfahani H, Abdolkarimi B, Dehghan A. A case report of simultaneous occurrence of wilms tumor and acute lymphoblastic leukemia. J Pediatr Hematol Oncol . 2012;34(7). doi:10.1097/MPH.0B013E31824C8DC6 11. Dadi G, Rosen S, Naor H, et al. 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Acta Neurochir (Wien) . 2022;164(2):419-422. doi:10.1007/S00701-021-05105-6 Figure Legend Figure 1 A-F The results of molecular karyotyping performed using single-nucleotide polymorphism array and methylation profiling of 11p15.5 imprinted region assessed with MS-MLPA in leukaemic cells ( A, B) , Wilms tumour ( C, D ) and healthy kidney ( E, F ); G) Schematic representation of genetic aberrations affecting chromosome 11p, which were detected at diagnosis of paediatric B-ALL among non-syndromic 446 patients. (red boxes represent deletions, blue boxes represent duplications and copy - neutral losses of heterozygosity are depicted as violet boxes). Figure 2 A) Pedigree of the proband (indicated by an arrow; IV:3) and her family. Circles represent females; squares represent males. B) The clinical history of the B-ALL and Wilms tumour treatment in a patient with BWS. Figures Figure 1 Figure 2 Information & Authors Information Version history V1 Version 1 03 October 2025 Peer review timeline Published Pediatric Blood & Cancer Version of Record 6 Nov 2025 Published Copyright This work is licensed under a Non Exclusive No Reuse License. Collection Pediatric Blood & Cancer Keywords all cancer genetics wilms tumor Authors Affiliations Karolina Miarka-Walczyk 0000-0001-6038-8842 Medical University of Lodz View all articles by this author Aleksandra Filipiuk Medical University View all articles by this author Kamila Wypyszczak 0000-0001-5951-0177 Medical University of Lodz View all articles by this author Zuzanna Urbanska Medical University of Lodz View all articles by this author Marta Kozłowska Medical University View all articles by this author Wojciech Mlynarski Medical University of Lodz View all articles by this author Ninela Irga-Jaworska Medical University View all articles by this author Agata Pastorczak [email protected] Medical University of Lodz View all articles by this author Metrics & Citations Metrics Article Usage 236 views 144 downloads .FvxKWukQNSOunydq8rnd { width: 100px; } Citations Download citation Karolina Miarka-Walczyk, Aleksandra Filipiuk, Kamila Wypyszczak, et al. Synchronous B-cell precursor acute lymphoblastic leukaemia and Wilms tumour in a patient with lateralised overgrowth: causation or coincidence?. Authorea . 03 October 2025. DOI: https://doi.org/10.22541/au.175952090.09290533/v1 If you have the appropriate software installed, you can download article citation data to the citation manager of your choice. Simply select your manager software from the list below and click Download. For more information or tips please see 'Downloading to a citation manager' in the Help menu . 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