Genetics Explained

My child has BWS, so what does all this chromosome stuff mean? If you’re like me, you want to know the reason behind the overgrowth disorder. How did this happen and what caused this? These were just a few of the questions I was asking myself, especially with the thought of what can be expected  if we want to have more children. Most of the articles you read online or in medical journals are wordy and overwhelming to the average reader. So here it is…my collection of genetics explained for the every day Mom and Dad.

 I didn’t realize there were so many different factors that could contribute to BWS. Each  different type of BWS is associated with different characteristics, which helps explain why our children have such a wide variety of features, such as macroglossia (enlarged tongue), omphalocele (abdominal wall defects), cleft palate, and excessive over growth.

Note: The documents were provided by the Emily Center Medical Library at Phoenix Children's Hospital. This information was gathered from a collection of resources (please see below for references). 

Was Beckwith-Wiedemann inherited?

In most cases, BWS randomly occurred from a change that happened on chromosome 11 where two gene factors that control growth are found. In some cases, the syndrome can be passed down from a parent.

What causes Beckwith-Wiedemann Syndrome?

There are 4 most common causes of BWS and a few causes that remain unknown.

I received the following chart from the Emily Center Health Library at Phoenix Children's Hospital. It is by far my favorite chart explaining the causes of BWS and makes the most sense to me by referring to the ON/OFF switches within the chromosome. 

The 4 main types of BWS and characteristics associated with each type

1. Loss of methylation (KvDMR at IC2)

-occurs in 50% of cases

-CDKN1C (slows cell growth) was turned OFF, when it should have been turned ON. This results in overgrowth associated with BWS because the body is not being told to slow growth down.

-Individuals with a loss of methylation usually have:

            a. omphalocele (abdominal wall defects)

            b. hemihyperplasia (where one side of the body or parts grow faster)

            c. lower tumor risk     

2. Paternal UPD (uniparental disomy)

-occurs in about 20% of cases

-refers to the presence of two chromosomal regions from one parent and none from the other. The CDKN1C (slows cell growth) is missing or turned OFF and an extra IGF2 (increases cell growth) is turned ON. The body is not being told to slow down growth AND the genes are being told to increase cell growth since have an extra IGF2. 

-Individuals with UPD usually have;

            a. hemihyperplasia (where one side of the body or parts grow faster)

            b. higher risk for Wilms tumor and hepatoblastoma due to increased cell growth

3. CDKN1C Mutations (CDKN1C is responsible for slowing cell growth)

-occurs in less than 10% of cases

-refers to the mutated functioning of CDKN1C (slows cell growth) either turned OFF or not present. The body is not being told to slow growth down.

-usually associated with a positive family history, but can occur sporadically.

-Individuals with CDKN1C mutations have increased risk for:

            a. omphalocele (abdominal wall defects)

            b. cleft palate

            c. carry lower risk for developing tumors

4. Gain of methylation (H19 DMR at IC1)

-occurs in less than 5% of BWS cases

-refers to an overexpression of IGF2 (increases cell growth), which is turned ON when it should be turned OFF. The body is being told to increase growth due to an extra IGF2. 

-Inviduals with IC1 gain of methylation usually have:

            a. higher risk for developing Wilms tumor and hepatoblastoma due to increased cell growth

            b. hemihyperplasia (where one side of the body or parts grow faster)

BWS Diagrams

**Reminder: All children with BWS should follow the recommended screening protocol for tumor checks. Please read below for AFP blood draws and ultrasound testing.

What are genes and chromosomes?

Our genetic information can be pictured as the ‘Book of Life’ and made up of 2 volumes, one from each parent.

-One volume was inherited from your mother and one from your father

-Both volumes contain 23 chapters which represent the 23 chromosomes.

-The 23 chapters (chromosomes) are made of a different number of pages (genes)

When thinking of Beckwith-Wiedemann Syndrome the words on the pages (genes) is how the book is put together or made. If the genes read something different, then the number of pages change, which in turn changes the entire book. 

BWS Genetics Testing Approach

AFP Testing and Ultrasound Scans

1 in 10 children with Beckwith-Wiedemann will develop cancer. Even though most children with BWS do not develop cancer, due to the higher risk, a routine testing protocol has been developed in order to screen for the two most common types of cancer: Wilms tumor and hepatoblastoma. Both of these cancers are fast growing so early detection is key. 

Michael DeBaun, M.D., MPH, is the Principal Investigator of the BWS Registry and Associate Professor of Pediatrics and Biostatistics. He recommends the following protocol:

1. Alpha-fetoprotein (AFP) blood draw every 6 weeks until the age of 4 years.

The AFP is a protein that is found in the liver at birth. Doctor's use it as a tumor marker because most infants AFP levels gradually decline to adult levels by 10 months. If the AFP level increases dramatically and/or does not continue to drop in level, then this would be a cause for concern. When this occurs, they recommend the patient repeat the AFP test in 2 weeks and follow up with an imaging exam (ultrasound, CT scan, or MRI). 

2. Abdomen ultrasound every 3 months to scan the kidneys and liver until the age of 8 years.

Dr. Choyke, a radiologist, suggests what to look for in each ultrasound.  You can read his note to BWS families on the following webpage: http://www.beckwith-wiedemann.info/drchoyke.html

For more information on Dr. Michael DeBaun's screening protocol

http://www.beckwith-wiedemann.info/protocol.html

Predicted AFP Levels Chart

What AFP level is considered too high?

According to the Washington University School of Medicine, "in healthy children AFP levels are higher at birth and they decline to normal levels by 9 to 12 months of age. Children with BWS also exhibit a decline in AFP levels during the first year of life; however, this decrease appears to be slower when compared to children without BWS (Everman et al 2000, Serum a-fetoprotein levels in Beckwith-Wiedemann syndrome). Given the variability in AFP, one AFP measurement typically can not be used to determine if the child is at risk for having hepatoblastoma. Several measurements of AFP are commonly needed to determine a trend of either decreasing or increasing AFP levels."

From what I gather reading this, as well as speaking with my son's oncologist,each child with BWS will have a range of AFP levels, but as long as the AFP levels continue to decrease, there is no reason for concern. Even a slight increase, does not necessarily mean there is a tumor present, because the average healthy child may also have an increase in AFP if they are sick or not feeling well, but no one realizes this because their levels are not being checked on a regular basis.

What if the AFP level increases?

The Washington University School of Medicine states "A small increase (<20ng/ml) of an AFP level likely reflects a measuring error associated with the AFP test and not a true increase. In cases of hepatoblastoma we observe AFP increases of a greater magnitude."

If the AFP level increases greatly, your doctor or oncologist will most likely order an AFP blood draw in 2 weeks. If the results continue to show an increase, an ultrasound, CT-Scan or MRI will be done in order to rule out a possible tumor. It is always better safe than sorry. 

Our AFP Experience

Our son's AFP was quite high as a newborn. We do not know his exact AFP level at birth because his first AFP blood draw was done incorrectly. The doctor noticed that he had 2 blood draws in a row that both read 60,500. She researched the issue by contacting the lab to discover that 60,500 is the initial cap, and if a child's AFP blood draw reaches that cap, they need to continue to thin the blood to get a true testing for the AFP level. When they retested his AFP levels he was at 124,000 at 1 month and his second AFP blood draw was 394,000. They suspected a tumor so they sent us to the Children's Hospital for a CT-scan. No tumor was found and since then his AFP levels have started to drop. His oncologist explained that AFP usually has a half-life every 2 weeks, but they are simply looking for the AFP levels to continue to decrease every 6 weeks. 

References

1. Center for Genetics Education  www.genetics.edu.au

2. Washington University School of Medicine www.wustl.edu

3. National Center for Biotechnology Information, US National Library of Medicine

        http://www.ncbi.nlm.nih.gov/books/NBK1394/

4. European Journal of Human Genetics (2010)