Beckwith-Wiedemann Syndrome

Updated: Apr 03, 2018
  • Author: Jennifer M Kalish, MD, PhD; Chief Editor: Robert P Hoffman, MD  more...
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Overview

Practice Essentials

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]

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Pathophysiology

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.

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Epidemiology

Frequency

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]

Mortality/Morbidity

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.

Race

No race predilection is observed.

Sex

No sex predilection is noted.

Age

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.

 

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Prognosis

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.

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Patient Education

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

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