It was weekend of firsts on many fronts, as physicians, genetic counselors, nurses, researchers, and families gathered July 21–23 at Children’s Hospital of Philadelphia Research Institute for the inaugural Deciphering Beckwith-Wiedemann syndrome (BWS) conference. BWS is a rare overgrowth disorder involving genetic and epigenetic changes that occur approximately every one in 10,500 births.
Attendees were among the first to hear the exciting news that the Orphan Disease Center of the Perelman School of Medicine at the University of Pennsylvania is creating a new Program of Excellence to support BWS research within the CHOP and Penn communities. CHOP’s cohort of BWS pediatric patients is the largest in the country, and many participate in a clinical registry and biorepository begun by CHOP three years ago that has become a vital resource to filling critical gaps in research data and clinical knowledge about BWS.
“The Beckwith-Wiedemann Syndrome Program of Excellence brings together experts from across CHOP and Penn to improve the clinical care of BWS patients through translational and basic science research with an eye towards improved diagnostics and therapeutic development,” said Jennifer M. Kalish, MD, PhD, attending physician and geneticist at CHOP and an assistant professor of pediatrics at Penn, who has championed a team of specialists from the two institutions with unique expertise in BWS. Several of those team members gave talks at the conference, including geneticists, endocrinologists, plastic surgeons, pediatric oncologists, dental specialists, researchers and others.
Mosaicism in Beckwith-Wiedemann Syndrome
Diagnosing, treating, and studying children with BWS is a challenge not only because it’s so uncommon, but also because it’s a mosaic disorder. That means some cells in the body may be affected and others may not. For example, some body parts may grow larger than others, such as an arm or leg that is bigger than the other and is not symmetric. Experts call this lateralized overgrowth.
Mosaicism also explains why some patients with BWS may have a negative genetic testing result, depending on the tissue tested. Testing for this mosaicism is available through the Genetic Diagnostic Laboratory at Penn, under the guidance of Arupa Ganguly, PhD, using the most sensitive clinical testing for BWS currently available.
Approximately 85 percent of people with BWS have genetic changes that appear to occur randomly; more rarely, the disorder appears to be inherited. Researchers have learned that these errors occur during cell division at the earliest stages of embryonic development on imprinted genes found on a growth-regulating region of chromosome 11p15.
In a Saturday morning session, Matthew Deardorff, MD, PhD, an attending physician at CHOP and associate professor of pediatrics at Penn, explained to families the concept that BWS involves a spectrum of symptoms and physical features. How these characteristics are manifested usually depends on the underlying molecular mechanism of an individual’s subtype of BWS. One child with BWS may have subtle manifestations, while another may have more prominent growth differences including lateralized overgrowth, macroglossia (enlarged tongue), and enlarged organs.
“As kids come into clinic, not everybody shows up looking like Beckwith-Wiedemann syndrome,” Dr. Deardorff said. “Some kids do, but other kids are much harder to sort out.”
New Diagnostic Criteria and Tumor Screening Recommendations
In light of these diagnostic difficulties, an international group of 35 experts, including Dr. Kalish, met in Paris this spring and created a list of cardinal features and suggestive features of BWS and a new scoring system to guide the diagnostic process. That group is continuing to work on an international consensus statement for overall management of BWS.
Early and accurate diagnosis is crucial because all patients with BWS have an increased risk for the development of tumors — hepatoblastoma (liver cancer) and Wilms tumor (kidney cancer) — that requires surveillance during infancy and childhood. At the BWS conference, Dr. Kalish presented new tumor screening recommendations for North America published in the July issue of Clinical Cancer Research. Dr. Kalish is lead author of the article that calls for performing full abdominal ultrasounds every three months until age 4, renal ultrasounds every three months from age 4 to age 7, and alpha-fetoprotein measurements every three months until age 4.
BWS Registry Celebrates Three-year Anniversary
Many families who attended the conference also are participants in the BWS Registry that Dr. Kalish’s team coordinates. The registry collects longitudinal clinical data on development and outcomes for patients with BWS. Individuals of all ages with BWS or other forms of growth differences are welcome to participate in the registry, even if not treated at CHOP. Participants share their clinical data and biological samples remaining from clinical testing.
Kelly Duffy, MPH, who is the registry’s coordinator, told the audience Sunday morning about the registry’s growth and success. So far, the registry represents hundreds of patients with BWS and family members from 16 countries and 37 states in the U.S.
“From partnering with these families over the past three years, we know what their research interests are and how to best help them,” Duffy said. “There’s not a lot of information out there about the clinical management of these patients, and most of how we’ve figured it out has come from research. For instance, our registry data helped inform development of the new tumor screening guidelines.”
BWS Families Share Experiences, Give Support
Just as important as hearing about the latest science and gaining a deeper understanding of their most common BWS concerns, families also had the valuable opportunity to make connections and friendships. The Lavallee family traveled from Massachusetts for an appointment at CHOP for their one-year-old son, Ezra, and then stayed for the weekend. They met face to face for the first time many of the BWS parents who support each other by sharing their experiences on social media channels.
“It was amazing getting to know other families with BWS,” Jaclyn Lavallee said. “When Ezra was first diagnosed, it felt as if we were the only ones out there dealing with this rare disease.”
Magicians, princesses, and face-painting filled the kids’ time at the conference, along with crayons and a special “BWS and You” coloring book created just for them. Rachel Ottman, 19, from New Jersey is a young adult with BWS who collaborated with Dr. Kalish to author and illustrate the book as an educational resource to improve knowledge about BWS. Ottman also contributed to the conference’s planning.
“As an adult with Beckwith, I now feel it’s my role to help families with younger children who may be scared of what the outcomes will be,” Ottman said. “I want to show them how it’s going to get better, and they’ll grow up normal — with a few extra doctors’ visits, of course. There is definitely hope.”
The Deciphering Beckwith-Wiedemann syndrome conference was sponsored by CHOP, Penn’s Orphan Disease Center, and Alex’s Lemonade Stand Foundation. For more information about the BWS Registry, email firstname.lastname@example.org.
See more pictures from the conference on our new Instagram page.