title: Novel deletion in 11p15.5 imprinting center region 1 in a patient with Beckwith-Wiedemann syndrome provides insight into distal enhancer regulation and tumorigenesis.
abstract: Beckwith-Wiedemann syndrome (BWS) is an early-onset overgrowth disorder with a high risk for embryonal tumors. It is mainly caused by dysregulation of imprinted genes on chromosome 11p15.5; however, the driving forces in the development of tumors are not fully understood.
  
  
  
  We report on a female patient presenting with macrosomia, macroglossia, organomegaly and extensive bilateral nephroblastomatosis. Adjuvant chemotherapy was initiated; however, the patient developed hepatoblastoma and Wilms tumor at 5 and 12 months of age, respectively. Subsequent radiofrequency ablation of the liver tumor and partial nephrectomy followed by consolidation therapy achieved complete remission.
  
  
  
  Molecular genetic analysis revealed a maternally derived large deletion of the complete H19-differentially methylated region (H19-DMR; imprinting control region-1 [ICR1]), the whole H19 gene itself as well as large parts of the distal enhancer region within the imprinting cluster-1 (IC1). Extended analysis showed highly elevated insulin-like growth factor 2 (IGF2) expression, possibly explaining at least in part the distinct BWS features and tumor manifestations.
  
  
  
  This study of a large maternal deletion encompassing the H19 gene and complete ICR1 is the first to demonstrate transcriptional consequences on IGF2 in addition to methylation effects resulting in severe overgrowth and occurrence of multiple tumors in a BWS patient. Studying this deletion helps to clarify the complex molecular processes involved in BWS and provides further insight into tumorigenesis.
authors.affiliation: Center for Human Genetics, Bioscientia, Ingelheim, Germany.
authors.forename: Nadine
authors.initials: N
authors.lastname: Bachmann
authors.affiliation: Department for Pediatrics, Medical University Innsbruck, Innsbruck, Austria.|Tyrolean Cancer Research Institute, Innsbruck, Austria.
authors.forename: Roman
authors.initials: R
authors.lastname: Crazzolara
authors.affiliation: Center for Pediatrics and Adolescent Medicine, Johannes Gutenberg University Medical Center, Mainz, Germany.
authors.forename: Florian
authors.initials: F
authors.lastname: Bohne
authors.affiliation: Division of Human Genetics, Medical University of Innsbruck, Innsbruck, Austria.
authors.forename: Dieter
authors.initials: D
authors.lastname: Kotzot
authors.affiliation: Department for Pediatrics, Medical University Innsbruck, Innsbruck, Austria.
authors.forename: Kathrin
authors.initials: K
authors.lastname: Maurer
authors.affiliation: Center for Pediatrics and Adolescent Medicine, Johannes Gutenberg University Medical Center, Mainz, Germany.
authors.forename: Thorsten
authors.initials: T
authors.lastname: Enklaar
authors.affiliation: Center for Pediatrics and Adolescent Medicine, Johannes Gutenberg University Medical Center, Mainz, Germany.
authors.forename: Dirk
authors.initials: D
authors.lastname: Prawitt
authors.affiliation: Center for Human Genetics, Bioscientia, Ingelheim, Germany.|Department of Medicine, University Hospital Freiburg, Freiburg, Germany.
authors.forename: Carsten
authors.initials: C
authors.lastname: Bergmann
mesh_terms: D001506:Beckwith-Wiedemann Syndrome / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D002880:Chromosomes, Human, Pair 11 / Q000235:genetics*; D019175:DNA Methylation; D005260:Female; D018392:Genomic Imprinting / Q000235:genetics*; D006801:Humans; D007231:Infant, Newborn; D007335:Insulin-Like Growth Factor II / Q000378:metabolism; D010641:Phenotype; D011379:Prognosis; D017384:Sequence Deletion
chemical_list: C035170:IGF2 protein, human; D007335:Insulin-Like Growth Factor II
keywords: Beckwith-Wiedemann syndrome; embryonal tumors, imprinting and allele-specific expression; insulin-like growth factor 2, pediatric cancers