Five Fascinating Facets of Beckwith-Wiedemann Syndrome

Beckwith-Wiedemann Syndrome (BWS) is a condition that occurs when parts of the body grow too large, too fast. Not surprisingly, the full story of BWS was too big to be fully contained in a recent article in Bench to Bedside, the monthly newsletter of The Children’s Hospital of Philadelphia Research Institute. Here are five fascinating things to know about BWS that delve deeper into the science of the condition, the experiences of families of children with BWS, and the research at CHOP led by Jennifer M. Kalish, MD, PhD, and funded by the St. Baldrick’s Foundation, the Alex’s Lemonade Stand Foundation, and the National Cancer Institute.

1. BWS is a mosaic condition.

Some cells and organs or limbs grow unusually large in children with BWS, and some do not. Patterns of this overgrowth vary from child to child. This mosaicism happens because the changes in gene expression that cause BWS arise early when the developing human embryo has relatively few cells — and the changes occur in only some of them. Cells and organs descended from those dysregulated cells have unusual growth patterns, while cells and organs descended from normally developing cells continue to grow at normal rates. This results in a widely varying presentation of the syndrome in different children.

The mosaic nature of the condition makes it challenging to manage the elevated cancer risk that goes along with BWS. As Dr. Kalish noted, “I can see if a child’s arms are bigger. I cannot see what is going on in the liver or kidney.” Each child’s areas of overgrowth are variable, so all young children with BWS must undergo regular cancer screenings.

2. In BWS, it matters which copy of certain genes came from a child’s mother and which copy came from his or her father. During normal development, the body precisely controls which parent’s copy of BWS-associated genes is expressed and when. This parent-specific expression is very unusual. Only a small number of specific genes, including those involved in BWS, are expressed in a parent-specific basis, which the body keeps track of through a process called genomic imprinting. Most of the body’s genes are expressed from the copies inherited from both parents.

The imprinting process begins when these few specific genes are tagged in the DNA of sperm and egg cells with epigenetic marks. Epigenetic marks are extra chemical groups added to the DNA that do not change its sequence, but do affect which genes are expressed and when. They are a common way of regulating the expression of all genes, not just imprinted ones.

BWS occurs when one or more of several different errors arise on imprinted genes on chromosome 11 that control growth. These errors can include mutations in the gene sequence, mistakes in epigenetic marking of the genes, or making an extra copy of a section of one parent’s chromosome. BWS is the syndrome that occurs when growth-gene errors of these types cause partial overgrowth. It has a mirror syndrome, Russell-Silver syndrome, frequently caused by the same growth-gene regions being expressed in ways that result in undergrowth.

It gets even more complex: “You can have cells that all have the genetic changes but do not necessarily show the epigenetic changes,” Dr. Kalish said. “Even the patients who have the epigenetic changes do not all have the same clinical features. There’s clearly something going on that makes them mosaic in a way that we do not quite understand yet.”

To learn at a more technical level about the science of genomic imprinting and imprinting disorders, read a review article by Dr. Kalish and colleagues.

3. Many pediatricians and pediatric specialists know very little about BWS — which poses challenges for families getting children diagnosed and treated for its symptoms.

Two years ago, Becky Feldman was initially scared when her 16-week fetal scan at her local hospital for twins Julian and Isabelle showed Julian had an omphalocele, a common occurrence with BWS. Becky and her husband soon came to CHOP’s Center for Fetal Diagnosis and Treatment for further testing, and, eventually, her delivery.

“When they told us the test was positive for BWS, it wasn’t a devastating blow,” Becky said. “Because at CHOP I had all these doctors who were so familiar with BWS, they brought me hope and comfort and the feeling that this was going to be okay.”

Since the twins’ birth, Julian has needed to see a lot of specialists for complications related to BWS and prematurity — and the contrast between doctors who know about BWS and those who do not, is striking.

“At other doctors it’s, ‘I’m sorry, can you please tell me what that is? I’ve never heard of it,’” Becky said.

That is a common experience.

“It’s so strange to be the parent who knows more than the doctors,’” said Alisha Devlin, mother of Ary, who is nearly two years old and was diagnosed with BWS at CHOP at the age of two months.

Alisha and Becky both want more members of the medical community, especially obstetricians and pediatricians, to know about BWS so they can more readily spot young children with symptoms such as macroglossia, (enlarged tongue) and hemihypertrophy (asymmetry in growth), and recognize that such children may have a syndrome that requires monitoring for cancer risk.

“I just want medical professionals to be aware that this is a possibility, and that if it is the case, it really is manageable,” Becky said. “All the kids with BWS I’ve seen seem to be so happy and very strong. They’re extremely resilient. And it’s really not a horrible diagnosis.”

Becky and Alisha used in-vitro fertilization (IVF) to conceive their babies and suspect that the procedure may raise the risk of BWS, a possibility supported by a few small studies. They want obstetricians and pediatricians to take extra care with IVF-conceived babies to ensure they are monitoring for BWS-related warning signs and complications such as low blood sugar.

“There have been a number of cases of BWS, especially in the past few years, in families that had IVF,” Dr. Kalish said. “The heightened risk has not been studied as extensively as we hope, but we can look into this further with the BWS registry.”

As discussed in the Bench to Bedside story, the BWS registry is a database Dr. Kalish and colleagues at CHOP have developed to track development and outcomes of children and adults with BWS and other overgrowth disorders, even if not treated at CHOP.

4. Connecting with other parents is a meaningful part of the experience for many families of children with BWS. Alisha and Becky first met each other in a waiting room at CHOP.

“I noticed her son looked like he had BWS,” Alisha recalled. “My husband said not to go ask a stranger, but I asked, and she said yes.”

The two moms befriended each other on Facebook, where they are now also active in a large and vibrant community of families of children and adults with BWS.

Forging connections on social media was particularly comforting for Becky during the uncertain time in her pregnancy after discovering Julian’s omphalocele.

“BWS moms started chiming in saying this was a possibility,” she recalled. “It really brought a lot of comfort seeing actual kids of different ages and even some adults. They all looked like normal, healthy, happy kids.”

Still, while the social connections online were comforting, they were not scientific.

“It’s a beautiful thing with social media to connect with other families going through the same thing, but it’s so ‘wild west’ that you don’t get an objective view of what’s going on,” Alisha said. She added that parents ask each other about their children’s treatment outcomes and medical complications, but the answers are only anecdotal, and the parents who participate are self-selected — meaning parents of children with fewer problems may abstain. “The registry is a place that we’re going to be able to send parents who’ve just received a BWS diagnosis and be able to say, ‘Look, here’s the data, you need to be looking out for this,’” Alisha said.

5. Children generally outgrow the risks associated with BWS as they grow up, but a lot of unknowns about long-term development remain. The growth genes that cause problems in BWS are active during fetal development and early childhood and then typically are turned off in most tissues from later childhood on. Still, Dr. Kalish noted that there are some issues that can affect people with BWS later in life, and there is even less data about this older group than about young children.

Most information about adults with BWS is anecdotal, including the cases of two NFL football players who have been reported to have the syndrome in press accounts: Mike Pennel, a defensive end for the Green Bay Packers, and Jerry Ostrosky, a retired Buffalo Bills player, although it is unclear how much BWS contributed to their size.

“It is important to know what is going on with patients when they are first diagnosed, but it would be nice to know what is happening when they are 25,” Dr. Kalish said. “That is a question that families ask all the time.”

Because the BWS registry tracks participants over time, it will be possible to answer some of these questions as the current cohort grows up — or sooner if more adults with BWS opt to enroll. “I especially encourage adults to participate in the registry because there’s really no information as to what the future holds,” Becky said.

Individuals and parents interested in more information about the BWS clinical registry should email bws [at] chop.edu (bws[at]chop[dot]edu).