Abstract
Beckwith–Wiedemann syndrome (BWS) is characterized by cancer predisposition, overgrowth and highly variable association of macroglossia, abdominal wall defects, nephrourological anomalies, nevus flammeus, ear malformations, hypoglycemia, hemihyperplasia, and organomegaly. BWS molecular defects, causing alteration of expression or activity of the genes regulated by two imprinting centres (IC) in the 11p15 chromosomal region, are also heterogeneous. In this paper we define (epi)genotype–phenotype correlations in molecularly confirmed BWS patients. The characteristics of 318 BWS patients with proven molecular defect were compared among the main four molecular subclasses: IC2 loss of methylation (IC2-LoM, n=190), IC1 gain of methylation (IC1-GoM, n=31), chromosome 11p15 paternal uniparental disomy (UPD, n=87), and cyclin-dependent kinase inhibitor 1C gene (CDKN1C) variants (n=10). A characteristic growth pattern was found in each group; neonatal macrosomia was almost constant in IC1-GoM, postnatal overgrowth in IC2-LoM, and hemihyperplasia more common in UPD (P<0.001). Exomphalos was more common in IC2/CDKN1C patients (P<0.001). Renal defects were typical of UPD/IC1 patients, uretheral malformations of IC1-GoM cases (P<0.001). Ear anomalies and nevus flammeus were associated with IC2/CDKN1C genotype (P<0.001). Macroglossia was less common among UPD patients (P<0.001). Wilms’ tumor was associated with IC1-GoM or UPD and never observed in IC2-LoM patients (P<0.001). Hepatoblastoma occurred only in UPD cases. Cancer risk was lower in IC2/CDKN1C, intermediate in UPD, and very high in IC1 cases (P=0.009). In conclusion, (epi)genotype–phenotype correlations define four different phenotypic BWS profiles with some degree of clinical overlap. These observations impact clinical care allowing to move toward (epi) genotype-based follow-up and cancer screening.
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Acknowledgements
We thank all of the family members who participated in this study and the colleagues who referred patients. This research was supported by grants from MIUR PRIN 2009 (to AR, LL, and GBF), and Telethon-Italia grant no. GGP11122, EU-FP7-ITN INGENIUM no. 290123, Progetto Bandiera MIUR-CNR Epigenomica and Associazione Italiana Ricerca sul Cancro (to AR). LL and AR are members of the COST Action BM1208. We thank the Italian Onco-Hematological Association (Associazione Italiana Ematologia Oncologia Pediatrica, AIEOP) for providing access to cancer registry data. This research was supported by grants from MIUR PRIN 2009 (to AR, LL, and GBF), and Telethon-Italia grant no. GGP11122, EU-FP7-ITN INGENIUM no. 290123, Progetto Bandiera MIUR-CNR Epigenomica and Associazione Italiana Ricerca sul Cancro (to AR).
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Appendix
Here are the members of the Italian BWS collaborative group: C Anichini, MD, Department of Pediatrics, Obstetrics, and Reproductive Medicine, University of Siena, Siena, Italy; L Boccone, MD, Ospedale Regionale Microcitemie, Cagliari, Italy; A Bonfante, MD, Medical Genetics, Bassano del Grappa Hospital, Bassano del Grappa, Italy; D Concolino, MD, Department of Pediatrics, University of Catanzaro, Catanzaro, Italy; M Della Monica, MD, Medical Genetics Department, Gaetano Rummo Hospital, Benevento, Italy; R Fischetto, MD, Department of Metabolic and Genetic Disease, PO Giovanni XXIII, AOU Policlinico Consorziale, Bari, Italy; L Garavelli, MD, Clinical Genetics Unit, Obstetric and Paediatric Department, Arcispedale S Maria Nuova, Reggio Emilia, Italy; F Gurrieri, MD, PhD, Medical Genetics, School of Medicine, Catholic University, Roma, Italy; E Lapi, MD, Human Genetic Unit, Anna Meyer Children's University Hospital, Firenze, Italy; C Magnani, MD, Mather and Child Department, University of Parma, Parma, Italy; MG Patricelli, MD, Biologia Molecolare e Citogenetica, Diagnostica e Ricerca, Ospedale San Raffaele, Milano, Italy; M Piccione, MD, Dipartimento Materno Infantile, Università di Palermo, Palermo, Italy; GB Pozzan, MD, UO, Pediatria Mestre-Venezia, Italy; L Zelante, MD, Medical Genetics Unit, IRCCS Casa Sollievo Della Sofferenza Hospital, San Giovanni Rotondo, Italy.
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Mussa, A., Russo, S., De Crescenzo, A. et al. (Epi)genotype–phenotype correlations in Beckwith–Wiedemann syndrome. Eur J Hum Genet 24, 183–190 (2016). https://doi.org/10.1038/ejhg.2015.88
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DOI: https://doi.org/10.1038/ejhg.2015.88
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