beckwith wiedemann syndrome


Summary: A syndrome of multiple defects characterized primarily by umbilical hernia (HERNIA, UMBILICAL); MACROGLOSSIA; and GIGANTISM; and secondarily by visceromegaly; HYPOGLYCEMIA; and ear abnormalities.

Top Publications

  1. Weksberg R, Shuman C, Smith A. Beckwith-Wiedemann syndrome. Am J Med Genet C Semin Med Genet. 2005;137C:12-23 pubmed
    ..In the future, such molecular studies in BWS will permit enhanced medical management and targeted genetic counseling. ..
  2. Engemann S, Strödicke M, Paulsen M, Franck O, Reinhardt R, Lane N, et al. Sequence and functional comparison in the Beckwith-Wiedemann region: implications for a novel imprinting centre and extended imprinting. Hum Mol Genet. 2000;9:2691-706 pubmed
    ..One of the genes outside the cluster, Obph1, is imprinted in mouse placenta indicating that at least in extra-embryonic tissues the imprinting cluster extends into a larger domain. ..
  3. Fitzpatrick G, Soloway P, Higgins M. Regional loss of imprinting and growth deficiency in mice with a targeted deletion of KvDMR1. Nat Genet. 2002;32:426-31 pubmed
    ..These findings support the hypothesis that loss of methylation in BWS patients activates the repressive function of KvDMR1 on the maternal chromosome, resulting in abnormal silencing of CDKN1C and the development of BWS. ..
  4. Hertel N, Carlsen N, Kerndrup G, Pedersen I, Clausen N, Hahnemann J, et al. Late relapse of adrenocortical carcinoma in Beckwith-Wiedemann syndrome. Clinical, endocrinological and genetic aspects. Acta Paediatr. 2003;92:439-43 pubmed
    ..Adrenocortical carcinoma in childhood may recur years after onset and at rare sites and hormonal levels may be an insufficient indicator of small metastases. ..
  5. Sun F, Dean W, Kelsey G, Allen N, Reik W. Transactivation of Igf2 in a mouse model of Beckwith-Wiedemann syndrome. Nature. 1997;389:809-15 pubmed
    ..These phenotypes establish Igf2 overexpression as a key determinant of Beckwith-Wiedemann syndrome. ..
  6. Niemitz E, Feinberg A, Brandenburg S, Grundy P, Debaun M. Children with idiopathic hemihypertrophy and beckwith-wiedemann syndrome have different constitutional epigenotypes associated with wilms tumor. Am J Hum Genet. 2005;77:887-91 pubmed
    ..0028). These results indicate that children with IH and Wilms tumor have different constitutional epigenotypes from those of children with BWS and Wilms tumor. ..
  7. Niemitz E, Debaun M, Fallon J, Murakami K, Kugoh H, Oshimura M, et al. Microdeletion of LIT1 in familial Beckwith-Wiedemann syndrome. Am J Hum Genet. 2004;75:844-9 pubmed
    ..When inherited paternally, there is no phenotype, suggesting that the LIT1 RNA itself is not necessary for normal development in humans. ..
  8. Paulsen M, Davies K, Bowden L, Villar A, Franck O, Fuermann M, et al. Syntenic organization of the mouse distal chromosome 7 imprinting cluster and the Beckwith-Wiedemann syndrome region in chromosome 11p15.5. Hum Mol Genet. 1998;7:1149-59 pubmed
    ..Our study opens the way for a systematic analysis of the cluster by genetic manipulation in the mouse which will lead to animal models of Beckwith-Wiedemann syndrome and childhood tumours. ..
  9. Reish O, Lerer I, Amiel A, Heyman E, Herman A, Dolfin T, et al. Wiedemann-Beckwith syndrome: further prenatal characterization of the condition. Am J Med Genet. 2002;107:209-13 pubmed

More Information


  1. Smilinich N, Day C, Fitzpatrick G, Caldwell G, Lossie A, Cooper P, et al. A maternally methylated CpG island in KvLQT1 is associated with an antisense paternal transcript and loss of imprinting in Beckwith-Wiedemann syndrome. Proc Natl Acad Sci U S A. 1999;96:8064-9 pubmed
    ..We propose that KvDMR1 and/or its associated antisense RNA (KvLQT1-AS) represents an additional imprinting control element or center in the human 11p15.5 and mouse distal 7 imprinted domains. ..
  2. Scott R, Douglas J, Baskcomb L, Nygren A, Birch J, Cole T, et al. Methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) robustly detects and distinguishes 11p15 abnormalities associated with overgrowth and growth retardation. J Med Genet. 2008;45:106-13 pubmed publisher
    ..MS-MLPA robustly and sensitively detects and distinguishes epigenetic and copy number abnormalities at 11p15 and is an effective first line investigation of 11p15 in individuals with overgrowth or growth retardation. ..
  3. H mida D, Gribaa M, Yacoubi T, Chaieb A, Adala L, Elghezal H, et al. Placental mesenchymal dysplasia with beckwith-wiedemann syndrome fetus in the context of biparental and androgenic cell lines. Placenta. 2008;29:454-60 pubmed publisher
    ..This represents a well-documented case of androgenic and biparental mixture of cell types in both fetal and placental tissues. ..
  4. Diaz Meyer N, Day C, Khatod K, Maher E, Cooper W, Reik W, et al. Silencing of CDKN1C (p57KIP2) is associated with hypomethylation at KvDMR1 in Beckwith-Wiedemann syndrome. J Med Genet. 2003;40:797-801 pubmed
    ..An epimutation at KvDMR1, the absence of maternal methylation, causes the aberrant silencing of CDKN1C, some 180 kb away on the maternal chromosome. Similar to mutations at this locus, this silencing may give rise to BWS. ..
  5. Mitsuya K, Meguro M, Lee M, Katoh M, Schulz T, Kugoh H, et al. LIT1, an imprinted antisense RNA in the human KvLQT1 locus identified by screening for differentially expressed transcripts using monochromosomal hybrids. Hum Mol Genet. 1999;8:1209-17 pubmed
    ..Thus, this positional approach using human monochromosomal hybrids could contribute to the efficient identification of imprinted loci in humans. ..
  6. Rossignol S, Steunou V, Chalas C, Kerjean A, Rigolet M, Viegas Pequignot E, et al. The epigenetic imprinting defect of patients with Beckwith-Wiedemann syndrome born after assisted reproductive technology is not restricted to the 11p15 region. J Med Genet. 2006;43:902-7 pubmed
    ..Moreover, the mosaic distribution of epimutations suggests that imprinting is lost after fertilisation owing to a failure to maintain methylation marks during pre-implantation development. ..
  7. Clericuzio C, Chen E, McNeil D, O CONNOR T, Zackai E, Medne L, et al. Serum alpha-fetoprotein screening for hepatoblastoma in children with Beckwith-Wiedemann syndrome or isolated hemihyperplasia. J Pediatr. 2003;143:270-2 pubmed
    ..We describe five children with Beckwith-Wiedemann syndrome or isolated hemihyperplasia for whom serial serum alpha-fetoprotein screening, usually in combination with abdominal ultrasound, led to early detection of hepatoblastoma. ..
  8. Brown K, Villar A, Bickmore W, Clayton Smith J, Catchpoole D, Maher E, et al. Imprinting mutation in the Beckwith-Wiedemann syndrome leads to biallelic IGF2 expression through an H19-independent pathway. Hum Mol Genet. 1996;5:2027-32 pubmed
    ..DNA methylation in IGF2 remained monoallelic, suggesting that the mutation in this family had uncoupled allele-specific methylation from expression. ..
  9. Hatada I, Ohashi H, Fukushima Y, Kaneko Y, Inoue M, Komoto Y, et al. An imprinted gene p57KIP2 is mutated in Beckwith-Wiedemann syndrome. Nat Genet. 1996;14:171-3 pubmed
    ..Consequently, little or no active p57KIP2 should exist and this probably causes the overgrowth in this BWS patient. ..
  10. Gicquel C, Gaston V, Mandelbaum J, Siffroi J, Flahault A, Le Bouc Y. In vitro fertilization may increase the risk of Beckwith-Wiedemann syndrome related to the abnormal imprinting of the KCN1OT gene. Am J Hum Genet. 2003;72:1338-41 pubmed
  11. Debaun M, Niemitz E, Feinberg A. Association of in vitro fertilization with Beckwith-Wiedemann syndrome and epigenetic alterations of LIT1 and H19. Am J Hum Genet. 2003;72:156-60 pubmed
    ..We discuss the implications of our finding that ART is associated with human overgrowth, similar to the large offspring syndrome reported in ruminants. ..
  12. John R, Ainscough J, Barton S, Surani M. Distant cis-elements regulate imprinted expression of the mouse p57( Kip2) (Cdkn1c) gene: implications for the human disorder, Beckwith--Wiedemann syndrome. Hum Mol Genet. 2001;10:1601-9 pubmed
    ..Therefore, BWS in humans may result from disruption of appropriate expression of the p57(KIP2) (CDKN1C) gene through mutations that occur at a substantial distance from the gene. ..
  13. Paulsen M, El Maarri O, Engemann S, Strödicke M, Franck O, Davies K, et al. Sequence conservation and variability of imprinting in the Beckwith-Wiedemann syndrome gene cluster in human and mouse. Hum Mol Genet. 2000;9:1829-41 pubmed
    ..This and additional comparisons with other imprinted and non-imprinted regions suggest that CpG islands are key features of imprinted domains. ..
  14. Tan T, Amor D. 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;42:486-90 pubmed
    ..We critically review the evidence for tumour surveillance in Beckwith-Wiedemann syndrome and isolated hemihyperplasia and suggest local practice guidelines. ..
  15. Shuman C, Smith A, Steele L, Ray P, Clericuzio C, Zackai E, et al. Constitutional UPD for chromosome 11p15 in individuals with isolated hemihyperplasia is associated with high tumor risk and occurs following assisted reproductive technologies. Am J Med Genet A. 2006;140:1497-503 pubmed
    ..Of note, two of the eight patients with UPD and IH were conceived using assisted reproductive technologies (ART), thus raising the question whether ART might impact the rate of somatic recombination during embryonic development. ..
  16. Martin R, Grange D, Zehnbauer B, Debaun M. LIT1 and H19 methylation defects in isolated hemihyperplasia. Am J Med Genet A. 2005;134A:129-31 pubmed
    ..Eight children (29.6%) had a defect in methylation of one or both of these alleles, supporting our hypothesis that these epigenetic changes can result in a phenotype distinct from typical Beckwith-Wiedemann syndrome. ..
  17. Cerrato F, Sparago A, Di Matteo I, Zou X, Dean W, Sasaki H, et al. The two-domain hypothesis in Beckwith-Wiedemann syndrome: autonomous imprinting of the telomeric domain of the distal chromosome 7 cluster. Hum Mol Genet. 2005;14:503-11 pubmed
  18. Weksberg R, Nishikawa J, Caluseriu O, Fei Y, Shuman C, Wei C, et al. Tumor development in the Beckwith-Wiedemann syndrome is associated with a variety of constitutional molecular 11p15 alterations including imprinting defects of KCNQ1OT1. Hum Mol Genet. 2001;10:2989-3000 pubmed
    ..This suggests that distinct tumor predisposition profiles result from dysregulation of the telomeric domain versus the centromeric domain and that these imprinting defects activate distinct genetic pathways for embryonal tumorigenesis. ..
  19. Zhang P, Liegeois N, Wong C, Finegold M, Hou H, Thompson J, et al. Altered cell differentiation and proliferation in mice lacking p57KIP2 indicates a role in Beckwith-Wiedemann syndrome. Nature. 1997;387:151-8 pubmed
  20. Cooper W, Luharia A, Evans G, Raza H, Haire A, Grundy R, et al. Molecular subtypes and phenotypic expression of Beckwith-Wiedemann syndrome. Eur J Hum Genet. 2005;13:1025-32 pubmed
  21. Maher E, Brueton L, Bowdin S, Luharia A, Cooper W, Cole T, et al. Beckwith-Wiedemann syndrome and assisted reproduction technology (ART). J Med Genet. 2003;40:62-4 pubmed
  22. Eggenschwiler J, Ludwig T, Fisher P, Leighton P, Tilghman S, Efstratiadis A. Mouse mutant embryos overexpressing IGF-II exhibit phenotypic features of the Beckwith-Wiedemann and Simpson-Golabi-Behmel syndromes. Genes Dev. 1997;11:3128-42 pubmed
  23. Grandjean V, Smith J, Schofield P, Ferguson Smith A. Increased IGF-II protein affects p57kip2 expression in vivo and in vitro: implications for Beckwith-Wiedemann syndrome. Proc Natl Acad Sci U S A. 2000;97:5279-84 pubmed
    ..In addition, p57(kip2) expression is down-regulated in mice with high serum levels of IGF-II. These data suggest that the effects of increased IGF-II in BWS may, in part, be mediated through a decrease in p57(kip2) gene expression. ..
  24. Lee M, DeBaun M, Mitsuya K, Galonek H, Brandenburg S, Oshimura M, et al. Loss of imprinting of a paternally expressed transcript, with antisense orientation to KVLQT1, occurs frequently in Beckwith-Wiedemann syndrome and is independent of insulin-like growth factor II imprinting. Proc Natl Acad Sci U S A. 1999;96:5203-8 pubmed
  25. Hatada I, Mukai T. Genomic imprinting of p57KIP2, a cyclin-dependent kinase inhibitor, in mouse. Nat Genet. 1995;11:204-6 pubmed
    ..This murine gene maps to the distal region of chromosome 7, within a cluster of imprinted genes, including insulin-2, insulin-like growth factor-2, H19 and Mash2 (refs 14-18). ..
  26. Viljoen D, Jaquire Z, Woods D. Prenatal diagnosis in autosomal dominant Beckwith-Wiedemann syndrome. Prenat Diagn. 1991;11:167-75 pubmed
    ..Early ultrasound diagnosis enabled appropriate genetic counselling to be given; neonatal complications, such as hypoglycaemic episodes, were prevented. ..
  27. Paulsen M, Khare T, Burgard C, Tierling S, Walter J. Evolution of the Beckwith-Wiedemann syndrome region in vertebrates. Genome Res. 2005;15:146-53 pubmed
    ..To address this question we compared the organization of the Beckwith Wiedemann syndrome (BWS) gene cluster in mammals, chicken, Fugu (pufferfish), and zebrafish...
  28. Kotoku R, Kinouchi K, Fukumitsu K, Taniguchi A. [A neonate with Beckwith-Wiedemann syndrome who developed upper airway obstruction after glossopexy]. Masui. 2002;51:46-8 pubmed
    ..At 69 days of life she died of sepsis complicated with disseminated intravascular coagulation and renal failure. A needle biopsy at autopsy revealed nephroblastomatosis. ..
  29. Jones V, Shun A. Is the inferior vena cava dispensable?. Pediatr Surg Int. 2007;23:885-8 pubmed
    ..We suggest that during surgery, when other options are absent, the IVC can be safely ligated in children, providing a therapeutic benefit to the patient. ..
  30. Kalish J, Boodhansingh K, Bhatti T, Ganguly A, Conlin L, Becker S, et al. Congenital hyperinsulinism in children with paternal 11p uniparental isodisomy and Beckwith-Wiedemann syndrome. J Med Genet. 2016;53:53-61 pubmed publisher
    ..Testing for pUPD11p should be considered in all patients with persistent congenital HI, especially for those without an identified HI gene mutation. ..
  31. Goldman M, Shuman C, Weksberg R, Rosenblum N. Hypercalciuria in Beckwith-Wiedemann syndrome. J Pediatr. 2003;142:206-8 pubmed
    ..Serum calcium was normal in all patients with HC. Because we found that an increased prevalence in the occurrence of HC and its complications in a group of children with BWS, any child with BWS should be evaluated for HC. ..
  32. Palsson G, Finnsdóttir V, Jóhannsson J, Ingvarsson S. [Uniparental disomy of chromosome 11 in a patient with Beckwith-Wiedemann syndrome. First reported case in Iceland]. Laeknabladid. 2005;91:837-40 pubmed
    ..The diagnosis of Beckwith-Wiedemann syndrome is important as the risk of malignant tumors makes it mandatory that the children are followed for several years with regular investigations to detect the tumors as early as possible. ..
  33. Hamada H, Fujiki Y, Obata Yasuoka M, Watanabe H, Yamada N, Kubo T. Prenatal sonographic diagnosis of Beckwith-Wiedemann syndrome in association with a single umbilical artery. J Clin Ultrasound. 2001;29:535-8 pubmed
    ..The possibility of this syndrome should be considered when performing a detailed sonographic examination of a fetus with a single umbilical artery. ..
  34. Thavaraj V, Sethi A, Arya L. Incomplete Beckwith-Wiedemann syndrome in a child with orbital rhabdomyosarcoma. Indian Pediatr. 2002;39:299-304 pubmed
  35. Bliek J, Alders M, Maas S, Oostra R, Mackay D, van der Lip K, et al. Lessons from BWS twins: complex maternal and paternal hypomethylation and a common source of haematopoietic stem cells. Eur J Hum Genet. 2009;17:1625-34 pubmed publisher
    ..This finding supports the theory that a methylation error proceeds and possibly triggers the twinning process. ..
  36. Muguerza R, Rodriguez A, Formigo E, Montero M, Vazquez J, Páramo C, et al. Pancreatoblastoma associated with incomplete Beckwith-Wiedemann syndrome: case report and review of the literature. J Pediatr Surg. 2005;40:1341-4 pubmed
    ..Beckwith-Wiedemann syndrome was suggested to be a favorable biological marker for survival in children who have intraabdominal tumors. ..
  37. Colianni S, Ping J, Fischer P, Freese D, Chan K, Alkuraya F. Index of suspicion. Pediatr Rev. 2004;25:289-94 pubmed
  38. Vincent M, Benbrik N, Romefort B, Colombel A, Bezieau S, Isidor B. Three patients presenting with severe macrosomia and congenital hypertrophic cardiomyopathy: a case series. J Med Case Rep. 2017;11:78 pubmed publisher
    ..These three original observations indicate that gynecologists and neonatologists should pay attention to neonates from mothers with a high body mass index and when maternal diabetes is not documented. ..
  39. DeBaun M, King A, White N. Hypoglycemia in Beckwith-Wiedemann syndrome. Semin Perinatol. 2000;24:164-71 pubmed
    ..Detailed genotype phenotype evaluations are needed and should provide an insight as to why patients with BWS have hypoglycemia. ..
  40. MacFarland S, Mostoufi Moab S, Zelley K, Mattei P, States L, Bhatti T, et al. Management of adrenal masses in patients with Beckwith-Wiedemann syndrome. Pediatr Blood Cancer. 2017;64: pubmed publisher
  41. Enklaar T, Zabel B, Prawitt D. Beckwith-Wiedemann syndrome: multiple molecular mechanisms. Expert Rev Mol Med. 2006;8:1-19 pubmed
    ..We then review the current concepts of causative molecular genetic and epigenetic mechanisms, and discuss future directions of research. ..
  42. Lew J, Fei Y, Aleck K, Blencowe B, Weksberg R, Sadowski P. CDKN1C mutation in Wiedemann-Beckwith syndrome patients reduces RNA splicing efficiency and identifies a splicing enhancer. Am J Med Genet A. 2004;127A:268-76 pubmed
    ..However, the total amount of spliced message was not reduced by the mutation in spite of the reduced efficiency of splicing. We discuss the possible role of the splicing defect in the pathogenesis of WBS in this pedigree. ..
  43. Uchigata Y. [Neonatal hypoglycemia]. Nihon Rinsho. 2006;Suppl 3:181-5 pubmed
  44. Bedeschi M, Calvello M, Paganini L, Pezzani L, Baccarin M, Fontana L, et al. Sequence variants identification at the KCNQ1OT1:TSS differentially Methylated region in isolated omphalocele cases. BMC Med Genet. 2017;18:115 pubmed publisher
    ..624-629delGGCCCC at exon 1 of CDKN1C, with unknown clinical significance, in two unrelated cases. Taken together, these findings suggest that KCNQ1OT1:TSS-DMR could be a susceptibility locus for the isolated omphalocele. ..
  45. Gripp K, Baker L, Kandula V, Conard K, Scavina M, Napoli J, et al. Nephroblastomatosis or Wilms tumor in a fourth patient with a somatic PIK3CA mutation. Am J Med Genet A. 2016;170:2559-69 pubmed publisher
    ..It is not known if the specific PIK3CA mutation, the mosaic distribution, or the clinical presentation affect the Wilms tumor or nephroblastomatosis risk in individuals with PROS. © 2016 Wiley Periodicals, Inc. ..
  46. Best L, Gilbert Barness E, Gerrard D, Gendron Fitzpatrick A, Opitz J. "Double-muscle" trait in cattle: a possible model for Wiedemann-Beckwith syndrome. Fetal Pediatr Pathol. 2006;25:9-20 pubmed
    ..Other dysplastic changes of a cystic nature are seen in the adrenal. The renal histology of DM fetuses did not appear significantly different than controls. ..
  47. Hussain K, Cosgrove K, Shepherd R, Luharia A, Smith V, Kassem S, et al. Hyperinsulinemic hypoglycemia in Beckwith-Wiedemann syndrome due to defects in the function of pancreatic beta-cell adenosine triphosphate-sensitive potassium channels. J Clin Endocrinol Metab. 2005;90:4376-82 pubmed
    ..However, in a small group of patients the hypoglycemia can be persistent and may require pancreatectomy. The mechanism of persistent hyperinsulinemic hypoglycemia in this group of patients is unclear...
  48. Chen L, Li Y, Lin J. Intraneural perineurioma in a child with Beckwith-Wiedemann syndrome. J Pediatr Surg. 2005;40:E12-4 pubmed
    ..This report adds a new entity in the spectrum of tumor formation in Beckwith-Wiedemann syndrome. ..
  49. Schwienbacher C, Sabbioni S, Campi M, Veronese A, Bernardi G, Menegatti A, et al. Transcriptional map of 170-kb region at chromosome 11p15.5: identification and mutational analysis of the BWR1A gene reveals the presence of mutations in tumor samples. Proc Natl Acad Sci U S A. 1998;95:3873-8 pubmed
    ..These results indicate that BWR1A may play a role in tumorigenesis. ..
  50. Redeker E, Hoovers J, Alders M, van Moorsel C, Ivens A, Gregory S, et al. An integrated physical map of 210 markers assigned to the short arm of human chromosome 11. Genomics. 1994;21:538-50 pubmed
    ..A detailed 10-Mb pulsed-field physical map of the region 11p15.3-pter was constructed. These three different approaches enabled the high-resolution mapping of 210 markers, including 22 known genes. ..
  51. Zollino M, Orteschi D, Marangi G, De Crescenzo A, Pecile V, Riccio A, et al. A case of Beckwith-Wiedemann syndrome caused by a cryptic 11p15 deletion encompassing the centromeric imprinted domain of the BWS locus. J Med Genet. 2010;47:429-32 pubmed publisher
    ..It also supports the model of two independent domains within the BWS locus. ..
  52. Anichini C, Lotti F, Longini M, Felici C, Proietti F, Buonocore G. Antioxidant strategies in genetic syndromes with high neoplastic risk in infant age. Tumori. 2014;100:590-9 pubmed publisher
    ..The aim of this review is to focus on the oxidative mechanisms intervening in carcinogenesis in cancer-prone genetic disorders and to analyze the current status and future prospects of antioxidants. ..
  53. Niemitz E, Feinberg A. Epigenetics and assisted reproductive technology: a call for investigation. Am J Hum Genet. 2004;74:599-609 pubmed