Beckwith-Wiedemann syndrome

What causes Beckwith-Wiedemann syndrome?

The causes of Beckwith-Wiedemann syndrome (BWS) are very complex. BWS usually results from abnormal gene regulation in a particular region of chromosome 11. Gene regulation is the process of turning genes "on" or "off" and ensures that the appropriate genes are expressed at the proper times.

Most cases of BWS are due to abnormalities involving genes on chromosome 11 that undergo genomic imprinting (imprinted genes). Normally, people inherit one copy of each chromosome from each parent, which also means that people normally inherit one copy of each gene (on the chromosomes) from each parent. Most genes on chromosome 11 have both copies activated (expressed). However, for some of these genes, only the paternal copy (inherited from a person's father) is expressed, or only the maternal copy is expressed. These parent- specific differences in gene expression are due to what is known as genomic imprinting.

The genetic imprinting results from changes produced in a process called methylation (in about 50% of the cases), a chemical reaction that occurs when egg and sperm cells are formed, and which attaches molecules called "methyl groups" to specific pieces of DNA, inactivating a specific gene, paternal or maternal. SBW is often associated with changes in regions of DNA on chromosome 11 called imprinting centers (IC1 and IC2), which control the methylation of several genes involved in normal growth. Abnormal methylation disrupts the regulation of these genes, leading to overgrowth and the other features of BWS. The genes affected include the CDKN1C __, H19 , IGF2 , and KCNQ1OT1 genes.

About 20% of cases of BWS are caused by a genetic abnormality called paternal uniparental disomy (UPD), in which both copies of chromosome 11 are inherited from the father and no copy is inherited from the mother. Paternal UPD usually occurs early in embryonic development, affecting only some of the body's cells (called mosaicism). Mosaic paternal UPD leads to an imbalance of the active genes on chromosome 11, causing the symptoms of the syndrome.

Less commonly, BWS may be caused by mutations in the CDKN1C gene, which gives instructions for making a protein that helps control growth before birth. Mutations in this gene prevent the protein from restricting growth, leading to the features of BWS.

More rarely, in about 1% of people with BWS have a chromosome abnormality, such as a translocation, duplication, or deletion of genetic material on chromosome 11 (the 11p15 region).

Because the genetic changes responsible for BWS are very complex, people with questions about the causes and inheritance of BWS should consult with a genetics professional.

Last updated on 05-01-20

Is Beckwith-Wiedemann syndrome inherited?

In about 85% percent of cases of Beckwith-Wiedemann syndrome (BWS), only one person in a family has been diagnosed. However, the parents of an affected child may be at risk of having other affected children; the risk depends on the underlying genetic cause in each case.

Most cases of Beckwith-Wiedemann syndrome are caused by abnormal regulation of imprinted genes in the BWS critical region (IC1 and IC2) on chromosome 11p15.5 caused by one of several genetic mechanisms.

About 10% to 15% of affected people are part of families with more than one affected person. In most of these families, the condition appears to be inherited in an autosomal dominant manner.[9530 This means that having only one changed (mutated) copy of the responsible gene in each cell is enough to cause symptoms of the disorder. In most of these cases, the affected person inherits the genetic change from their mother. In some cases, a person inherits the mutated gene but does not have symptoms of the disorder.

Rarely, BWS results from abnormalities of the structure of chromosome 11. Some of these chromosome abnormalities are inherited from a parent, while others occur randomly during the formation of eggs and sperm, or very early in fetal development.

The risk to the brothers and sisters of a child with BWS depends on the genetic basis for BWS in this child. The majority of families have a recurrence risk of less than 1%; however, as commented before, in some families the recurrence risk as high as 50%. In order to better assess the recurrence risk for BWS in a family, the underlying cause needs to be identified. Due to the complexity of the genetics, it is recommended that any determination of recurrence risk for the parents or adults with BWS or testing of relatives to be performed by a genetics health care professional.

Last updated on 05-01-20

Name: Beckwith-Wiedemann Children's Foundation International Email: Url:
Brioude F, Kalish JM, Mussa A, Foster AC, Bliek J et al.. Expert Consensus Document: Clinical and Molecular Diagnosis, Screening and Management of Beckwith-Wiedemann Syndrome: An International Consensus Statement Nat Rev Endocrinol. Apr 2018; 14(4). 229-249. Reference Link Wang KH, Kupa J, Duffy KA, Kalish JM. Diagnosis and Management of Beckwith-Wiedemann Syndrome. Front Pediatr. Jan 21, 2020; 7(562). 1-12. Reference Link

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