Beckwith-Wiedemann Syndrome

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Beckwith-Wiedemann Syndrome (BWS) was first characterized by Dr. J. Bruce Beckwith and Dr. Hans-Rudolf Wiedemann in the early 1960s. Patients were first noted to have abdominal wall defects, macrosomia, macroglossia, and enlarged adrenal glands. Since then, clinical presentation has expanded to recognize hemihypertrophy/lateralized overgrowth, hyperinsulinism, omphalocele, and organomegaly as classic features of BWS. Additionally, it is now recognized that there is a range of clinical features seen in patients with BWS. Presentation of BWS occurs on a spectrum ranging from isolated asymmetry to classic features of BWS. [1]

Beckwith-Wiedemann Syndrome (BWS) is a pediatric cancer predisposition disorder caused by changes in the imprinted gene loci on chromosome 11p15. Patients develop BWS as a result of the misregulation of key gene regions; the resulting misexpression of growth genes leads to the overgrowth that characterizes the condition.

While most autosomal genes are expressed biallelically, imprinted genes are expressed either from the maternal or paternal allele. These genes are regulated by specific regions near the genes called imprinting control regions (ICRs), which contain epigenetic marks (methylation) that coordinate gene expression. BWS is caused by genetic or epigenetic changes that disrupt the parent-of-origin specific expression of these genes. [2, 3] Most commonly, BWS is caused by epigenetic modifications to methylation at ICRs. BWS can also be caused by mutations in the genetic sequence, deletions, duplications in the region or chromosomal rearrangements.

The imprinted gene regions involved in BWS are H19/IGF2 and CDKN1C/KCNQ1OT1, all genes implicated in growth during early development. H19 encodes a long noncoding RNA that is maternally expressed; it is believed to act as a tumor suppressor. IGF2, or insulin-like growth factor 2, is a paternally expressed protein-coding gene. IGF2 is highly active during fetal development and acts as a growth promoter. CDKN1C, or cyclin-dependent kinase inhibitor 1C, is a gene that encodes a protein implicated in cell cycle regulation. KCNQ1OT1, or potassium voltage-gated channel subfamily Q member 1 opposite transcript 1 is the antisense transcript of the protein-coding gene KCNQ1. KCNQ1OT1 is implicated in regulating other growth genes. [4]

BWS can be caused by several different epigenetic or genetic changes at these loci. Causes can include changes to levels of methylation at the ICRs, paternal uniparental disomy (pUPD) of chromosome 11p15, chromosomal rearrangements involving the 11p15.5 region, point mutations in CDKN1C, or microdeletions in ICRs. [5] In cases where BWS is caused by epigenetic modifications to the genome, occurrence is sporadic and is generally not inherited. Risk of recurrence is the same as in the general population. Cases of BWS with a genetic cause may be inherited, though presentation depends on the parent of transmission.

Incidence is estimated to occur in 1 in 10,500 live births in the general population. [6] As individuals with milder phenotypes often go undiagnosed, the incidence may be higher.

The incidence of BWS in children conceived through assistive reproductive technology is about 1:1200. [6]

Based on current data, patients with BWS have an increased tumor risk during childhood, periodic screening allows early detection and intervention. Complications related to BWS features such as omphalocele, hyperinsulinism, macroglossia may arise and require additional medical attention. Lifespan is anticipated to be normal. There is currently limited data in adults.

No race predilection is observed.

No sex predilection is noted.

BWS is a congenital disorder that is commonly diagnosed in early childhood. Patients with BWS have an increased risk of developing embryonal tumors in childhood. Particularly, patients with BWS have an increased risk of developing hepatoblastoma before 4 years of age and Wilms tumor before 7 years of age. [7] Clinical features of BWS typically decrease with age.

 

Most patients with BWS have a normal life expectancy and generally do not develop serious medical problems in adulthood as a result of the condition.

About half of patients with BWS are large in height and weight for their age in early childhood, though adults with BWS may not be unusually tall. [1] Patients with BWS have increased risk of embryonal tumors, notably hepatoblastoma and Wilms tumor in childhood. Omphalocele and abdominal wall defects often either resolve or are repaired through surgery. Macroglossia may also be addressed with tongue-reduction surgery to remedy feeding, speaking, or breathing concerns, although many cases of macroglossia resolve without surgery.

Patients should be directed to either the NORD or NIH entries on Beckwith-Wiedemann syndrome. [8, 9]

Brioude F, Kalish JM, Mussa A, et al. Expert consensus document: Clinical and molecular diagnosis, screening and management of Beckwith-Wiedemann syndrome: an international consensus statement. Nat Rev Endocrinol. 2018 Apr. 14 (4):229-249. [Medline].

Weksberg R, Smith AC, Squire J, Sadowski P. Beckwith-Wiedemann syndrome demonstrates a role for epigenetic control of normal development. Hum Mol Genet. 2003 Apr 1. 12 Spec No 1:R61-8. [Medline].

Brioude F, Lacoste A, Netchine I, Vazquez MP, Auber F, Audry G, et al. Beckwith-Wiedemann syndrome: growth pattern and tumor risk according to molecular mechanism, and guidelines for tumor surveillance. Horm Res Paediatr. 2013. 80 (6):457-65. [Medline].

Cooper WN, Luharia A, Evans GA, Raza H, Haire AC, Grundy R, et al. Molecular subtypes and phenotypic expression of Beckwith-Wiedemann syndrome. Eur J Hum Genet. 2005 Sep. 13 (9):1025-32. [Medline].

Ibrahim A, Kirby G, Hardy C, Dias RP, Tee L, Lim D, et al. Methylation analysis and diagnostics of Beckwith-Wiedemann syndrome in 1,000 subjects. Clin Epigenetics. 2014. 6 (1):11. [Medline].

Mussa A, Molinatto C, Cerrato F, Palumbo O, Carella M, Baldassarre G, et al. Assisted Reproductive Techniques and Risk of Beckwith-Wiedemann Syndrome. Pediatrics. 2017 Jul. 140 (1):[Medline].

Kalish JM, Deardorff MA. Tumor screening in Beckwith-Wiedemann syndrome-To screen or not to screen?. Am J Med Genet A. 2016 Sep. 170 (9):2261-4. [Medline].

Kalish J, Duffy K, Lye C. Beckwith-Wiedemann Syndrome – NORD (National Organization for Rare Disorders). NORD (National Organization for Rare Disorders). Available at https://rarediseases.org/rare-diseases/beckwith-wiedemann-syndrome/. Accessed: March 16, 2018.

Vanderver A, Pearl PL. Beckwith-Wiedemann Syndrome. NORD Guide to Rare Disorders. Philadelphia, PA: Lippincott Williams & Wilkins; 2003. 518.

Mussa A, Russo S, De Crescenzo A, Freschi A, Calzari L, Maitz S, et al. (Epi)genotype-phenotype correlations in Beckwith-Wiedemann syndrome. Eur J Hum Genet. 2016 Feb. 24 (2):183-90. [Medline].

Elliott M, Bayly R, Cole T, Temple IK, Maher ER. Clinical features and natural history of Beckwith-Wiedemann syndrome: presentation of 74 new cases. Clin Genet. 1994 Aug. 46 (2):168-74. [Medline].

Beckwith JB. Macroglossia, omphalocele, adrenal cytomegaly, gigantism, and hyperplastic visceromegaly. Birth Defects. 1969. 5:188-96.

WIEDEMANN HR. [FAMILIAL MALFORMATION COMPLEX WITH UMBILICAL HERNIA AND MACROGLOSSIA–A “NEW SYNDROME”?]. J Genet Hum. 1964 Sep. 13:223-32. [Medline].

Maas SM, Vansenne F, Kadouch DJ, Ibrahim A, Bliek J, Hopman S, et al. Phenotype, cancer risk, and surveillance in Beckwith-Wiedemann syndrome depending on molecular genetic subgroups. Am J Med Genet A. 2016 Sep. 170 (9):2248-60. [Medline].

Kalish JM, Doros L, Helman LJ, Hennekam RC, Kuiper RP, Maas SM, et al. Surveillance Recommendations for Children with Overgrowth Syndromes and Predisposition to Wilms Tumors and Hepatoblastoma. Clin Cancer Res. 2017 Jul 1. 23 (13):e115-e122. [Medline].

DeBaun MR, Tucker MA. Risk of cancer during the first four years of life in children from The Beckwith-Wiedemann Syndrome Registry. J Pediatr. 1998 Mar. 132 (3 Pt 1):398-400. [Medline].

Mussa A, Di Candia S, Russo S, Catania S, De Pellegrin M, Di Luzio L, et al. Recommendations of the Scientific Committee of the Italian Beckwith-Wiedemann Syndrome Association on the diagnosis, management and follow-up of the syndrome. Eur J Med Genet. 2016 Jan. 59 (1):52-64. [Medline].

Genetics Home Reference. Beckwith-Wiedemann Syndrome. Genetics Home Reference. Available at https://ghr.nlm.nih.gov/condition/beckwith-wiedemann-syndrome. March 27, 2018; Accessed: March 28, 2018.

Gorlin RJ, Cohen MM, Hennekam RCM. Syndromes of the Head and Neck. 4th ed. New York, NY: Oxford University Press; 2001. 389-405.

Cohen MM, Nori G, Weksberg R. Overgrowth Syndromes. 1st ed. New York, NY: Oxford University Press; 2002. 11-31.

Jones KL. Smith’s Recognizable Patterns of Human Malformation. 5th ed. Philadelphia, PA: W. B. Saunders Co.; 1997. 174-5.

Shuman C, Smith AC, Weksberg R. Beckwith-Wiedemann Syndrome. : GeneReviews at GeneTests: Medical Genetics Information Resource (database online). Available at http://www.genetests.org. September 8, 2005;

McKusick VA. Online Mendelian Inheritance in Man (OMIM). Baltimore, MD: The Johns Hopkins University; Entry No:130650; June 4, 2007.

Jennifer M Kalish, MD, PhD Assistant Professor of Pediatrics, Assistant Professor of Genetics, Perelman School of Medicine at the University of Pennsylvania; Attending Physician, Division of Human Genetics, Research Scientist, Center for Childhood Cancer Research, Children’s Hospital of Philadelphia

Jennifer M Kalish, MD, PhD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Pediatrics, American Association for Cancer Research, American College of Medical Genetics and Genomics, American Medical Association

Disclosure: Nothing to disclose.

Alice C Yu University of Pennsylvania

Disclosure: Nothing to disclose.

Sunil Kumar Sinha, MD 

Sunil Kumar Sinha, MD is a member of the following medical societies: American Academy of Pediatrics, American Association of Clinical Endocrinologists, Endocrine Society, Pediatric Endocrine Society

Disclosure: Nothing to disclose.

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

Barry B Bercu, MD Professor, Departments of Pediatrics, Molecular Pharmacology and Physiology, University of South Florida College of Medicine, All Children’s Hospital

Barry B Bercu, MD is a member of the following medical societies: American Academy of Pediatrics, American Association of Clinical Endocrinologists, American Medical Association, American Pediatric Society, Association of Clinical Scientists, Endocrine Society, Florida Medical Association, Pediatric Endocrine Society, Society for Pediatric Research, Southern Society for Pediatric Research, Society for the Study of Reproduction, American Federation for Clinical Research, Pituitary Society

Disclosure: Nothing to disclose.

Robert P Hoffman, MD Professor and Program Director, Department of Pediatrics, Ohio State University College of Medicine; Pediatric Endocrinologist, Division of Pediatric, Endocrinology, Diabetes, and Metabolism, Nationwide Children’s Hospital

Robert P Hoffman, MD is a member of the following medical societies: American College of Pediatricians, American Diabetes Association, American Pediatric Society, Christian Medical and Dental Associations, Endocrine Society, Midwest Society for Pediatric Research, Pediatric Endocrine Society, Society for Pediatric Research

Disclosure: Nothing to disclose.

Phyllis W Speiser, MD Chief, Division of Pediatric Endocrinology, Steven and Alexandra Cohen Children’s Medical Center of New York; Professor of Pediatrics, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell

Phyllis W Speiser, MD is a member of the following medical societies: American Association of Clinical Endocrinologists, Endocrine Society, Pediatric Endocrine Society, Society for Pediatric Research

Disclosure: Nothing to disclose.

Robert J Ferry Jr, MD Le Bonheur Chair of Excellence in Endocrinology, Professor and Chief, Division of Pediatric Endocrinology and Metabolism, Department of Pediatrics, University of Tennessee Health Science Center

Robert J Ferry Jr, MD is a member of the following medical societies: American Academy of Pediatrics, American Diabetes Association, American Medical Association, Endocrine Society, Pediatric Endocrine Society, Society for Pediatric Research, and Texas Pediatric Society

Disclosure: Eli Lilly & Co Grant/research funds Investigator; MacroGenics, Inc Grant/research funds Investigator; Ipsen, SA (formerly Tercica, Inc) Grant/research funds Investigator; NovoNordisk SA Grant/research funds Investigator; Diamyd Grant/research funds Investigator; Bristol-Myers-Squibb Grant/research funds Other; Amylin Other; Pfizer Grant/research funds Other; Takeda Grant/research funds Other

Beckwith-Wiedemann Syndrome

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