Official reprint from UpToDate®
www.uptodate.com ©2017 UpToDate, Inc. and/or its affiliates. All Rights Reserved.

Beckwith-Wiedemann syndrome

Brian Chung Hon-Yin, MD, FCCMG
Cheryl Shuman, MS, CGC
Sanaa Choufani, PhD
Rosanna Weksberg, MD, PhD, FRCPC, FCCMG, FACMG
Section Editor
Helen V Firth, DM, FRCP, DCH
Deputy Editor
Elizabeth TePas, MD, MS


Beckwith-Wiedemann syndrome (BWS, MIM #130650) is a pediatric overgrowth disorder involving a predisposition to tumor development [1]. The clinical presentation is highly variable, and some cases lack the characteristic features originally described by Beckwith and Wiedemann [2,3]. BWS exhibits etiologic molecular heterogeneity, and some molecular alterations correlate with specific phenotypic features of BWS.

The epidemiology, genetics, pathogenesis, clinical manifestations, diagnosis, management, and prognosis of BWS are reviewed in this topic.


BWS is a panethnic disorder with an estimated population prevalence of 1 in 10,300 to 13,700 [4,5]. This figure most likely represents an underestimate because milder phenotypes may not be ascertained. The prevalence is equal in males and females, with the notable exception of an increased frequency of female monozygotic twins versus male monozygotic twins [6]. BWS usually occurs sporadically (85 percent), but familial transmission occurs in approximately 15 percent of cases. Assisted reproductive technology (ART) is associated with an increased risk of imprinting disorders, with a 10-fold increased risk of BWS seen in live births from ART compared with natural conception in one Italian study [7].


Generally, both the maternally and paternally inherited alleles of each autosomal gene pair are expressed. Less than 100 genes across the genome are imprinted and expressed monoallelically in a parent of origin-specific manner (figure 1). That is, for a given imprinted gene pair, one parental allele is exclusively or preferentially expressed, whereas the other allele is silenced or weakly expressed. Genomic imprinting is regulated by epigenetic mechanisms. These include noncoding RNAs and chemical modifications extrinsic to the primary nucleotide sequence, such as DNA methylation and histone protein tail modifications. Different DNA methylation and histone modification states underpin the expression or silencing of imprinted alleles. Thus, imprinted alleles demonstrate differential DNA methylation. Imprinted genes occur in clusters referred to as imprinted domains and are regulated in cis (on the same chromosome) by imprinting centers (ICs). ICs are comprised of differentially methylated regions (DMRs) of DNA. (See "Inheritance patterns of monogenic disorders (Mendelian and non-Mendelian)", section on 'Parent-of-origin effects (imprinting)'.)

Deregulation of imprinted gene expression in the chromosome 11p15.5 region can result in the BWS phenotype [8-10]. The critical BWS genes in that region include insulin-like growth factor 2 (IGF2), H19, cyclin-dependent kinase inhibitor 1C (CDKN1C), potassium channel voltage-gated KQT-like subfamily member 1 (KCNQ1), and KCNQ1-overlapping transcript 1 (KCNQ1OT1, or long QT intronic transcript 1). A chromosome 11p15 molecular alteration is identified in only approximately 80 percent of individuals with BWS. This is due, in part, to somatic mosaicism for some of the molecular alterations.

To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information on subscription options, click below on the option that best describes you:

Subscribers log in here

Literature review current through: Nov 2017. | This topic last updated: Nov 06, 2017.
The content on the UpToDate website is not intended nor recommended as a substitute for medical advice, diagnosis, or treatment. Always seek the advice of your own physician or other qualified health care professional regarding any medical questions or conditions. The use of this website is governed by the UpToDate Terms of Use ©2017 UpToDate, Inc.
  1. Weksberg R, Shuman C, Beckwith JB. Beckwith-Wiedemann syndrome. Eur J Hum Genet 2010; 18:8.
  2. Beckwith JB. Extreme cytomegaly of the adrenal fetal cortex, omphalocele, hyperplasia of kidneys and pancreas, and Leydig-cell hyperplasia: Another syndrome? (Abstract), Western Society for Pediatric Research (Ed), Los Angeles 1963.
  4. Pettenati MJ, Haines JL, Higgins RR, et al. Wiedemann-Beckwith syndrome: presentation of clinical and cytogenetic data on 22 new cases and review of the literature. Hum Genet 1986; 74:143.
  5. Mussa A, Russo S, De Crescenzo A, et al. Prevalence of Beckwith-Wiedemann syndrome in North West of Italy. Am J Med Genet A 2013; 161A:2481.
  6. Weksberg R, Shuman C, Caluseriu O, et al. Discordant KCNQ1OT1 imprinting in sets of monozygotic twins discordant for Beckwith-Wiedemann syndrome. Hum Mol Genet 2002; 11:1317.
  7. Mussa A, Molinatto C, Cerrato F, et al. Assisted Reproductive Techniques and Risk of Beckwith-Wiedemann Syndrome. Pediatrics 2017; 140.
  8. Cooper WN, Luharia A, Evans GA, et al. Molecular subtypes and phenotypic expression of Beckwith-Wiedemann syndrome. Eur J Hum Genet 2005; 13:1025.
  9. Enklaar T, Zabel BU, Prawitt D. Beckwith-Wiedemann syndrome: multiple molecular mechanisms. Expert Rev Mol Med 2006; 8:1.
  10. Weksberg R, Shuman C, Smith AC. Beckwith-Wiedemann syndrome. Am J Med Genet C Semin Med Genet 2005; 137C:12.
  11. Bliek J, Maas S, Alders M, et al. Epigenotype, phenotype, and tumors in patients with isolated hemihyperplasia. J Pediatr 2008; 153:95.
  12. Meyer E, Lim D, Pasha S, et al. Germline mutation in NLRP2 (NALP2) in a familial imprinting disorder (Beckwith-Wiedemann Syndrome). PLoS Genet 2009; 5:e1000423.
  13. Naik S, Riordan-Eva E, Thomas NS, et al. Large de novo deletion of 7p15.1 to 7p12.1 involving the imprinted gene GRB10 associated with a complex phenotype including features of Beckwith Wiedemann syndrome. Eur J Med Genet 2011; 54:89.
  14. Lirussi F, Jonard L, Gaston V, et al. Beckwith-Wiedemann-like macroglossia and 18q23 haploinsufficiency. Am J Med Genet A 2007; 143A:2796.
  15. Hark AT, Schoenherr CJ, Katz DJ, et al. CTCF mediates methylation-sensitive enhancer-blocking activity at the H19/Igf2 locus. Nature 2000; 405:486.
  16. Abi Habib W, Azzi S, Brioude F, et al. Extensive investigation of the IGF2/H19 imprinting control region reveals novel OCT4/SOX2 binding site defects associated with specific methylation patterns in Beckwith-Wiedemann syndrome. Hum Mol Genet 2014; 23:5763.
  17. Smilinich NJ, Day CD, Fitzpatrick GV, 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.
  18. Diaz-Meyer N, Day CD, Khatod K, et al. Silencing of CDKN1C (p57KIP2) is associated with hypomethylation at KvDMR1 in Beckwith-Wiedemann syndrome. J Med Genet 2003; 40:797.
  19. Weksberg R, Smith AC, Squire J, Sadowski P. Beckwith-Wiedemann syndrome demonstrates a role for epigenetic control of normal development. Hum Mol Genet 2003; 12 Spec No 1:R61.
  20. Weksberg R, Shuman C. Beckwith-Wiedemann syndrome and hemihypertrophy. In: Management of genetic syndromes, 2nd ed, Cassidy SB, Allanson JE (Eds), John Wiley & Sons, Inc, New York 2005.
  21. Niemitz EL, DeBaun MR, Fallon J, et al. Microdeletion of LIT1 in familial Beckwith-Wiedemann syndrome. Am J Hum Genet 2004; 75:844.
  22. Prawitt D, Enklaar T, Gärtner-Rupprecht B, et al. Microdeletion of target sites for insulator protein CTCF in a chromosome 11p15 imprinting center in Beckwith-Wiedemann syndrome and Wilms' tumor. Proc Natl Acad Sci U S A 2005; 102:4085.
  23. Sparago A, Cerrato F, Vernucci M, et al. Microdeletions in the human H19 DMR result in loss of IGF2 imprinting and Beckwith-Wiedemann syndrome. Nat Genet 2004; 36:958.
  24. Baskin B, Choufani S, Chen YA, et al. High frequency of copy number variations (CNVs) in the chromosome 11p15 region in patients with Beckwith-Wiedemann syndrome. Hum Genet 2014; 133:321.
  25. Scott RH, Douglas J, Baskcomb L, et al. Constitutional 11p15 abnormalities, including heritable imprinting center mutations, cause nonsyndromic Wilms tumor. Nat Genet 2008; 40:1329.
  26. Shuman C, Smith AC, Weksberg R. Beckwith-Wiedemann Syndrome. GeneReviews [Internet] 2008.
  27. Elliott M, Bayly R, Cole T, et al. Clinical features and natural history of Beckwith-Wiedemann syndrome: presentation of 74 new cases. Clin Genet 1994; 46:168.
  28. Weng EY, Moeschler JB, Graham JM Jr. Longitudinal observations on 15 children with Wiedemann-Beckwith syndrome. Am J Med Genet 1995; 56:366.
  29. Wilson M, Peters G, Bennetts B, et al. The clinical phenotype of mosaicism for genome-wide paternal uniparental disomy: two new reports. Am J Med Genet A 2008; 146A:137.
  30. Chitayat D, Rothchild A, Ling E, et al. Apparent postnatal onset of some manifestations of the Wiedemann-Beckwith syndrome. Am J Med Genet 1990; 36:434.
  31. Weksberg R, The Hospital for Sick Children, Toronto, personal communication, 2010.
  32. Hoyme HE, Seaver LH, Jones KL, et al. Isolated hemihyperplasia (hemihypertrophy): report of a prospective multicenter study of the incidence of neoplasia and review. Am J Med Genet 1998; 79:274.
  33. Engström W, Lindham S, Schofield P. Wiedemann-Beckwith syndrome. Eur J Pediatr 1988; 147:450.
  34. Martínez y Martínez R, Ocampo-Campos R, Pérez-Arroyo R, et al. The Wiedemann-Beckwith syndrome in four sibs including one with associated congenital hypothyroidism. Eur J Pediatr 1985; 143:233.
  35. Goldman M, Shuman C, Weksberg R, Rosenblum ND. Hypercalciuria in Beckwith-Wiedemann syndrome. J Pediatr 2003; 142:206.
  36. Borer JG, Kaefer M, Barnewolt CE, et al. Renal findings on radiological followup of patients with Beckwith-Wiedemann syndrome. J Urol 1999; 161:235.
  37. Choyke PL, Siegel MJ, Oz O, et al. Nonmalignant renal disease in pediatric patients with Beckwith-Wiedemann syndrome. AJR Am J Roentgenol 1998; 171:733.
  38. Wong CA, Cuda S, Kirsch A. A review of the urologic manifestations of Beckwith-Wiedemann syndrome. J Pediatr Urol 2011; 7:140.
  39. Mussa A, Peruzzi L, Chiesa N, et al. Nephrological findings and genotype-phenotype correlation in Beckwith-Wiedemann syndrome. Pediatr Nephrol 2012; 27:397.
  40. Gardiner K, Chitayat D, Choufani S, et al. Brain abnormalities in patients with Beckwith-Wiedemann syndrome. Am J Med Genet A 2012; 158A:1388.
  41. Cohen MM Jr. Beckwith-Wiedemann syndrome: historical, clinicopathological, and etiopathogenetic perspectives. Pediatr Dev Pathol 2005; 8:287.
  42. DeBaun MR, Siegel MJ, Choyke PL. Nephromegaly in infancy and early childhood: a risk factor for Wilms tumor in Beckwith-Wiedemann syndrome. J Pediatr 1998; 132:401.
  43. Schneid H, Vazquez MP, Vacher C, et al. The Beckwith-Wiedemann syndrome phenotype and the risk of cancer. Med Pediatr Oncol 1997; 28:411.
  44. Sotelo-Avila C, Gonzalez-Crussi F, Fowler JW. Complete and incomplete forms of Beckwith-Wiedemann syndrome: their oncogenic potential. J Pediatr 1980; 96:47.
  45. 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.
  46. Wiedemann HR. Tumours and hemihypertrophy associated with Wiedemann-Beckwith syndrome (Letter to the Editor). Eur J Pediatr 1983; 141:129.
  47. Kent L, Bowdin S, Kirby GA, et al. Beckwith Weidemann syndrome: a behavioral phenotype-genotype study. Am J Med Genet B Neuropsychiatr Genet 2008; 147B:1295.
  48. Slavotinek A, Gaunt L, Donnai D. Paternally inherited duplications of 11p15.5 and Beckwith-Wiedemann syndrome. J Med Genet 1997; 34:819.
  49. Bliek J, Gicquel C, Maas S, et al. Epigenotyping as a tool for the prediction of tumor risk and tumor type in patients with Beckwith-Wiedemann syndrome (BWS). J Pediatr 2004; 145:796.
  50. Bliek J, Maas SM, Ruijter JM, et al. Increased tumour risk for BWS patients correlates with aberrant H19 and not KCNQ1OT1 methylation: occurrence of KCNQ1OT1 hypomethylation in familial cases of BWS. Hum Mol Genet 2001; 10:467.
  51. DeBaun MR, Niemitz EL, McNeil DE, et al. Epigenetic alterations of H19 and LIT1 distinguish patients with Beckwith-Wiedemann syndrome with cancer and birth defects. Am J Hum Genet 2002; 70:604.
  52. Rump P, Zeegers MP, van Essen AJ. Tumor risk in Beckwith-Wiedemann syndrome: A review and meta-analysis. Am J Med Genet A 2005; 136:95.
  53. Weksberg R, Nishikawa J, Caluseriu O, 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.
  54. Maas SM, Vansenne F, Kadouch DJ, et al. Phenotype, cancer risk, and surveillance in Beckwith-Wiedemann syndrome depending on molecular genetic subgroups. Am J Med Genet A 2016; 170:2248.
  55. Brzezinski J, Shuman C, Choufani S, et al. Wilms tumour in Beckwith-Wiedemann Syndrome and loss of methylation at imprinting centre 2: revisiting tumour surveillance guidelines. Eur J Hum Genet 2017; 25:1031.
  56. DeBaun MR, Niemitz EL, Feinberg AP. Association of in vitro fertilization with Beckwith-Wiedemann syndrome and epigenetic alterations of LIT1 and H19. Am J Hum Genet 2003; 72:156.
  57. Engel JR, Smallwood A, Harper A, et al. Epigenotype-phenotype correlations in Beckwith-Wiedemann syndrome. J Med Genet 2000; 37:921.
  58. Hatada I, Nabetani A, Morisaki H, et al. New p57KIP2 mutations in Beckwith-Wiedemann syndrome. Hum Genet 1997; 100:681.
  59. Li M, Squire J, Shuman C, et al. Imprinting status of 11p15 genes in Beckwith-Wiedemann syndrome patients with CDKN1C mutations. Genomics 2001; 74:370.
  60. Waziri M, Patil SR, Hanson JW, Bartley JA. Abnormality of chromosome 11 in patients with features of Beckwith-Wiedemann syndrome. J Pediatr 1983; 102:873.
  61. Smith AC, Rubin T, Shuman C, et al. New chromosome 11p15 epigenotypes identified in male monozygotic twins with Beckwith-Wiedemann syndrome. Cytogenet Genome Res 2006; 113:313.
  62. Smith AC, Shuman C, Chitayat D, et al. Severe presentation of Beckwith-Wiedemann syndrome associated with high levels of constitutional paternal uniparental disomy for chromosome 11p15. Am J Med Genet A 2007; 143A:3010.
  63. Scott RH, Douglas J, Baskcomb L, 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.
  64. Bliek J, Verde G, Callaway J, et al. Hypomethylation at multiple maternally methylated imprinted regions including PLAGL1 and GNAS loci in Beckwith-Wiedemann syndrome. Eur J Hum Genet 2009; 17:611.
  65. Lee MP, DeBaun M, Randhawa G, et al. Low frequency of p57KIP2 mutation in Beckwith-Wiedemann syndrome. Am J Hum Genet 1997; 61:304.
  66. Gicquel C, Gaston V, Mandelbaum J, et al. 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.
  67. Halliday J, Oke K, Breheny S, et al. Beckwith-Wiedemann syndrome and IVF: a case-control study. Am J Hum Genet 2004; 75:526.
  68. Maher ER, Afnan M, Barratt CL. Epigenetic risks related to assisted reproductive technologies: epigenetics, imprinting, ART and icebergs? Hum Reprod 2003; 18:2508.
  69. Baskin B, Molecular Genetics Specialist, Pediatric Laboratory Medicine, The Hospital for Sick Children, personal communication, 2010.
  70. Eggermann T, Brioude F, Russo S, et al. Prenatal molecular testing for Beckwith-Wiedemann and Silver-Russell syndromes: a challenge for molecular analysis and genetic counseling. Eur J Hum Genet 2016; 24:784.
  71. Storm DW, Hirselj DA, Rink B, et al. The prenatal diagnosis of Beckwith-Wiedemann syndrome using ultrasound and magnetic resonance imaging. Urology 2011; 77:208.
  72. Wilkins-Haug L, Porter A, Hawley P, Benson CB. Isolated fetal omphalocele, Beckwith-Wiedemann syndrome, and assisted reproductive technologies. Birth Defects Res A Clin Mol Teratol 2009; 85:58.
  73. Souka AP, Snijders RJ, Novakov A, et al. Defects and syndromes in chromosomally normal fetuses with increased nuchal translucency thickness at 10-14 weeks of gestation. Ultrasound Obstet Gynecol 1998; 11:391.
  74. Ballock RT, Wiesner GL, Myers MT, Thompson GH. Hemihypertrophy. Concepts and controversies. J Bone Joint Surg Am 1997; 79:1731.
  75. Leung AK, Fong JH, Leong AG. Hemihypertrophy. J R Soc Promot Health 2002; 122:24.
  76. Jones SM, Rahman RS, Bourgeois DJ 3rd, et al. Hemihyperplasia in a 4-month-old. Clin Pediatr (Phila) 2011; 50:367.
  77. Eggermann T, Schönherr N, Meyer E, et al. Epigenetic mutations in 11p15 in Silver-Russell syndrome are restricted to the telomeric imprinting domain. J Med Genet 2006; 43:615.
  78. Beckwith JB. Nephrogenic rests and the pathogenesis of Wilms tumor: developmental and clinical considerations. Am J Med Genet 1998; 79:268.
  79. Kimura Y, Kamada Y, Kimura S. Anesthetic management of two cases of Beckwith-Wiedemann syndrome. J Anesth 2008; 22:93.
  80. Tomlinson JK, Morse SA, Bernard SP, et al. Long-term outcomes of surgical tongue reduction in Beckwith-Wiedemann syndrome. Plast Reconstr Surg 2007; 119:992.
  81. Kalish JM, Doros L, Helman LJ, et al. Surveillance Recommendations for Children with Overgrowth Syndromes and Predisposition to Wilms Tumors and Hepatoblastoma. Clin Cancer Res 2017; 23:e115.
  82. Clericuzio CL, Martin RA. Diagnostic criteria and tumor screening for individuals with isolated hemihyperplasia. Genet Med 2009; 11:220.
  83. Zarate YA, Mena R, Martin LJ, et al. Experience with hemihyperplasia and Beckwith-Wiedemann syndrome surveillance protocol. Am J Med Genet A 2009; 149A:1691.
  84. MacFarland SP, Mostoufi-Moab S, Zelley K, et al. Management of adrenal masses in patients with Beckwith-Wiedemann syndrome. Pediatr Blood Cancer 2017; 64.
  85. Everman DB, Shuman C, Dzolganovski B, et al. Serum alpha-fetoprotein levels in Beckwith-Wiedemann syndrome. J Pediatr 2000; 137:123.
  86. Clericuzio CL, Chen E, McNeil DE, et al. Serum alpha-fetoprotein screening for hepatoblastoma in children with Beckwith-Wiedemann syndrome or isolated hemihyperplasia. J Pediatr 2003; 143:270.
  87. Greer KJ, Kirkpatrick SJ, Weksberg R, Pauli RM. Beckwith-Wiedemann syndrome in adults: observations from one family and recommendations for care. Am J Med Genet A 2008; 146A:1707.