Beckwith-Wiedemann Syndrome (BWS) Overview

Beckwith-Wiedemann Syndrome (BWS) Overview

Narrator: Beckwith-Wiedemann syndrome or BWS is a rare overgrowth disorder that is caused by a change on chromosome 11. The genetic and epigenetic causes of BWS are complex to understand and explain.

This animation provides an overview of genetics and epigenetics, the genetics and epigenetics of BWS, some physical characteristics of BWS, and how to manage BWS.

DNA, or deoxyribonucleic acid, is a substance that carries genes from parents to their children. Genes are pieces of DNA that are passed down from parents to their children and represent traits or characteristics, such as hair color or growth.

DNA is packaged into structures called chromosomes. Chromosomes carry genetic information within cells. Cells are the smallest machines in your body.

A child inherits two sets of chromosomes. One set of 23 chromosomes from their mother and one set of 23 chromosomes from their father, making a total of 46 chromosomes.

Genetics is a study of how genes are passed from a mother and father to their children. Epigenetics is a study of how the functions of a person's genes change. Some genes may or may be express certain traits. Epigenetic changes occur after conception as the embryo turns into a baby.

Here's chromosome 11 as seen through a microscope. A chromosome is made of two arms; a p-arm and a q-arm is divided into regions. BWS is a disorder that is caused by a change in one or more of the genes at a region of chromosome 11 called 11p15.

This specific chromosome region regulates growth, which is why BWS is referred to as an overgrowth disorder. In most cases, this change happens in some cells but not every cell. This situation is referred to as mosaicism, which is when some cells of the body have normal chromosome 11 and other cells of the body have a change on chromosome 11.

The features of BWS are a result of the chromosomes in some cells being different from other cells. Let's look at how normal growth occurs at a genetic level.

All children have two copies of chromosome 11; one from their mother and one from their father. Certain genes are only expressed on one of the two copies of a chromosome. This means that one chromosome 11 expresses certain genes that control growth while the other does not.

This process is called imprinting and is caused by something called methylation. Methylation is a mark on a chromosome that can be thought of as a switch. It marks the DNA to turn certain genes on or off. When the switch of methylation is on, that means the signal is on. When the switch of methylation is off, that means the signal is off.

A balance between the on and off switches promotes growth at a typical rate. Normally, the DNA is marked so that the mother’s genes make the ”don't grow” signal and the father’s genes make the ”grow” signal, creating a balance of “grow” and “don't grow” signals.

Now let's look at how changes on chromosome 11 result in BWS.

A child with BWS has an imbalance between genes that cause growth and genes that limit growth. This imbalance results in a child having too many genes turned on that cause growth or not enough that limit growth.

The changes on chromosome 11 cause the switches of methylation to be marked or unmarked in a different way.

There are several different changes on chromosome 11 that are known to cause BWS, IC2, LIT1, KvDMR. Loss of methylation occurs when the mother’s “don't grow” switch is turned off. While the change is on the mother’s chromosome, it is not something the mother carries.

IC1, H19, DMR, gain of methylation occurs when the mother’s “grow” switch is turned on in addition to the father’s “grow” switch. Paternal uniparental isodisomy (puPD11) occurs when both “grow” switches are turned on and both “don't grow” switches are turned off.

CDKN1C mutations occur when the “don't grow” switch is broken from the mother because of a change in the DNA. Other rare causes, such as duplications, deletions or chromosomal rearrangements, can lead to an increase in “grow” signal or decrease in “don't grow” signal, also resulting in BWS.

While the majority of BWS changes occur sporadically, certain deletions, duplications, or chromosomal rearrangements and mutations in CDKN1C can be inherited, meaning they may be passed from one generation to the next.

A variety of physical differences may be present in children with BWS. The cardinal features include: macroglossia meaning an enlarged tongue; omphalocele, when the intestines and other abdominal organs stick outside the body to a weak spot in the abdominal wall; hemihypertrophy/hemihyperplasia/lateralized overgrowth, when one side or part of the body is larger than the other side; hyperinsulinism or severe hypoglycemia, meaning low levels of sugar in the bloodstream; multifocal or bilateral Wilms tumors; specific tissue features seen under the microscope including mesenchymal dysplasia in the placenta.

The suggestive features include: macrosomia, meaning large birth weight; facial nevus simplex, a facial birthmark; umbilical hernia, when part of the intestine pushes through and creates a bulge or sac in the week spot of the belly button; diastasis recti, a weakening of the abdominal wall muscles; pits or creases in the earlobe or behind the ear; enlarged abdominal organs, when parts of the body such as the kidneys, liver and pancreas are larger than normal; isolated Wilms tumors; hepatoblastomas and neuroblastomas.

Management of BWS may be different for each child as it depends on their individual features. Given that children with BWS have an increased chance of developing tumors during childhood, it is recommended that they have regular screenings. Two types of tumor screenings that are recommended for children with BWS include: abdominal ultrasounds and blood tests to measure alpha-fetoprotein concentration or AFP.

Abdominal ultrasound is an imagining test that uses sound waves to display views of internal organs. Alpha-fetoprotein, AFP, is a protein that is released by the liver. Normally, AFP levels are high when a baby is first born and trend downwards toward normal range.

Increased AFP levels in a child maybe a result of hepatoblastomas, or growing liver tumor cells. It is important to follow AFP levels over time. This test should be ordered and reviewed by pediatricians, geneticists or pediatric oncologists who are familiar with BWS.

Some children with BWS may need to see other medical specialists, including: endocrinologists, doctors who treat children with hypoglycemia; geneticists, doctors who make the clinical diagnosis, order testing, interpret and review results and coordinate care; oncologists, doctors who manage the prevention, diagnosis and treatment of tumors and review the results of tests for tumors; orthodontists, doctors who treat jaw and teeth differences; orthopaedists, doctors who manage children who have a difference in the size of their legs; pediatricians, doctors who treat babies and children; plastic surgeons, doctors who treat children who have an enlarged tongue; pulmonologists, doctors who manage breathing differences.

Beckwith-Wiedemann syndrome is complex to understand, diagnose and manage. We hope you find the information provided in this animation to be informative and helpful. Understanding the diagnosis and knowing what to expect can lessen the fear of the unknown and help you and your family prepare for the future.