Nov 27 2015

Five Fascinating Facets of Beckwith-Wiedemann Syndrome

Beckwith-Wiedemann SyndromeBeckwith-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.

  1. 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.

  1. Many pediatricians and pediatric specialists know very little about BWS — which poses challenges for families getting children diagnosed and treated for its symptoms.
Beckwith-Wiedemann Syndrome

Isabelle (left) and Julian (right) Petty

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.

Beckwith-Wiedemann Syndrome

Ary Devlin

“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.

  1. 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.

  1. 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

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Nov 25 2015

CChIPS Grateful for a Decade of Innovation in Child Safety


The Center for Child Injury Prevention Studies (CChIPS) 10 year anniversary report cover.

In the 10 years that the Center for Child Injury Prevention Studies (CChIPS) has been on the road to improving child safety, the unique collaboration between industry members, academia, and government has reached many milestones, which are being celebrated with a special anniversary report and timeline.

Flaura Winston, MD, PhD, CChIPS founder and director, wrote a blog post that took a look at how far CChIPS has come over the past decade and the program’s future path to child injury prevention. She recalled a pivotal moment – Jan. 8, 2003—that paved the way for the creation of CChIPS. On that date, Dr. Winston and her CChIPS co-director Kristy Arbogast, PhD met with Alexander Schwarzkopf at the National Science Foundation (NSF) Industry/University Cooperative Research Center (I/UCRC) Directors Meeting.

“A force of nature, Alex was the mastermind behind the very successful NSF I/UCRC program which succeeded in ushering in a new era of government-industry-academia partnership that features high-quality, industrially relevant fundamental research with direct transfer of needed scientific foundation to foster innovation,” Dr. Winston wrote.

Dr. Schwarzkopf believed in CChIPS’ vision to bring competitors, manufacturers, advocates, policymakers, and scientists around the same table to find ways to make children and young adults safer. Since it launched in 2005 with NSF funding, CChIPS has facilitated more than 100 projects to date that are informing advances in product design and policy for child occupant protection, biomechanics, and young driver safety.

“The high rates of traffic injury and mortality among children have created a public health crisis that requires immediate research solutions,” said Dr. Winston, who also serves as the scientific director of the Center for Injury Research and Prevention (CIRP) at The Children’s Hospital of Philadelphia and is a professor of Pediatrics at the Perelman School of Medicine at the University of Pennsylvania.

The CChIPS research team, which includes investigators at CHOP and The Ohio State University, has responded to these real-world challenges by developing a research portfolio in conjunction with an Industry Advisory Board (IAB). Representatives from IAB member companies include auto manufacturers, child restraint manufacturers, an anthropomorphic test device (ATD) manufacturer, insurance companies, advocacy organizations, and others.

For example, since its inception, CChIPS has been committed to improving pediatric ATDs, or crash test dummies. To be an effective tool, pediatric ATDs must accurately mimic how child occupants move and respond to the forces of a vehicle crash. The research being conducted through CChIPS is delivering the fundamental data needed to improve the design of pediatric ATDs and to develop innovative restraint products to make vehicles safer for children in the future.

In 2006, CChIPS researchers, led by Dr. Arbogast, co-scientific director and director of Engineering for CIRP, with founding CChIPS IAB member TK Holdings Inc. (Takata Corp.), Rowan University, and University of Virginia researchers developed a low-speed human volunteer sled to mimic the crash experienced by children and adults when they ride an amusement park bumper car. This allowed CChIPS to collect the only known data on the kinematics and kinetics of restrained 6- to 14-year-old pediatric human volunteers in low speed impacts. The crash sled has been used in several CChIPS studies to compare child and adult volunteers’ heads, necks, and spines during a bumper car’s safe crash, as well as the same body regions on pediatric ATDs.

The CChIPS IAB has expanded from six founding members in 2005 (all remain active) to 22 members in 2015. By pooling its annual $50,000 membership fees for the 2014-2015 project year, the IAB leveraged those member investments into a sizeable $850,000 fund to support the center’s mission.

CChIPS also invests in the next generation of scientists and engineers. Every CChIPS research project includes at least one student, which demonstrates the program’s commitment to creating a diverse, internationally competitive, and globally engaged science and engineering workforce focused on injury prevention.

While traffic safety will continue to be a primary focus of the CChIPS research portfolio, the Center is looking forward to pursuing other safety topics that affect children, including bicycle and pedestrian safety, aviation safety, sports injury prevention, and trauma care and treatment.

“We will continue to utilize the model established during our first decade — conducting rigorous, impactful research that’s responsive to what’s happening in the real world, all with a goal to save children’s lives,” Dr. Winston said.

Download a report that highlights 10 years of advancing the science around child injury prevention.
Download and share the accompanying timeline infographic of the past decade of CChIPS research.
Read a press release announcing CChIPS’ 10th anniversary.

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Nov 23 2015

Girls in Families With Breast Cancer Risk Well-Adjusted

breast cancer

Norma Roth, a breast cancer survivor, has had conversations with her children to reassure them that recent breast cancer advances have made it more curable than ever before. Her daughter, Marlena, is involved with the LEGACY Girls Study.

The thought of getting breast cancer can be a worrisome one, and it may be on the minds of young girls more than ever before, as knowledge about family and genetic risk has increased in the recent decade. The LEGACY Girls Study, a study taking place across five sites in North America, is the first to focus on preadolescent girls growing up in families with breast cancer risk. One of its many aims is to understand if they have poorer psychosocial adjustment and breast-cancer specific stress.

“We know that whether or not there is full disclosure about family breast cancer risk, that children pick up on things,” said Lisa Schwartz, PhD, a psychologist in the Division of Oncology at The Children’s Hospital of Pennsylvania and assistant professor at the Perelman School of Medicine at the University of Pennsylvania, who is a co-investigator for the LEGACY Girls Study. “We also know that it heightens anxiety of mothers, so we suspected that it could impact the family environment in some way, whether that be positive or negative.”

The study team, led by Angela Bradbury, MD, assistant professor in the Department of Medicine, Division of Hematology/Oncology, and the Department of Medical Ethics and Health Policy at the Perelman School of Medicine at the University of Pennsylvania, between August 2011 and July 2013 enrolled 1,040 girls at ages 6 to 13. They analyzed behavioral surveys submitted by about 800 mother-daughter pairs. Half of the participants had a first or second-degree relative with breast cancer or a known BRCA1/2 mutation in the family, and the other half did not.

It is estimated that 5 to 10 percent of breast cancer cases result directly from high risk genes like BRCA1/2. As more women get access to genetic testing, it is important for clinicians to be aware of how this information could possibly influence daughters’ risk-taking or health-promoting behaviors, Dr. Schwartz said.

The study results, which were published in Pediatrics, did not reveal any stark differences in the general emotional well-being between the two groups. Girls from families with a history of breast cancer or risk seem to cope as well psychosocially as girls without that known risk. However, girls ages 10 to 13 did report higher breast-cancer specific distress if they came from a family at risk for breast cancer, and 12 percent had a distress level that would be considered clinically significant.

“This shows that these girls are aware that they are at higher risk for breast cancer than their peers, but it is not impacting them in a global way or permeating their whole psychological functioning,” Dr. Schwartz said. “Also, maternal anxiety was related to child anxiety, which is a very common finding. We can help mothers and daughters communicate with one another about the risk in a healthy way. We don’t want daughters to have a heightened sense of risk. We want them to have an accurate sense of risk and know that they have control over managing that risk and over their health.”

To that end, the LEGACY investigators are working on an internet-based intervention to educate adolescent girls about breast cancer risk and to create a platform for mothers to talk with daughters and relay accurate information in a developmentally sensitive way. The next step for the researchers is to test the intervention in a randomized trial with the same cohort of LEGACY Girls Study participants.

One of the messages the intervention will convey to girls is that it is highly unlikely for breast cancer to occur in the teenage years. It also will inform girls about how healthy choices during adolescence can minimize risk of adult cancer. And it will provide tips on how to handle everyday stressors that can make coping with an ambiguous health situation that has unknown outcomes difficult.

These are the types of important conversations that Norma Roth, a breast cancer survivor, has had with her children to reassure them that recent breast cancer advances have made it more curable than ever before. Her daughter, Marlena, is involved with the LEGACY Girls Study.

“Way before the BRCA genes were discovered, the women in my family truly thought something in their DNA was killing them, and they felt helpless,” Norma said in an interview that appeared in the Research Institute’s 2014 Annual Report. “Today we have better mammograms, we have MRIs, and we have genetic testing. All of these tools are very empowering for my generation. I think the more you know, the better you can control things and change the history in your life. That’s why I really wanted Marlena to be part of the LEGACY study.”

Teaching young girls how to prevent breast-cancer specific distress will become especially important, Dr. Schwartz pointed out, if there comes a time when experts determine that it makes sense to test for the genes for breast cancer in adolescence. Currently, professional societies do not recommend that children, even those with a family history of BRCA1/2 mutation, undergo genetic testing because no strategies are in place for how to respond to positive findings. Surveillance and imaging usually begins at age 25 for women who have a family history that suggests the presence of a harmful mutation.

The LEGACY Girls Study team is finishing up final assessments of data that they have gathered during the study period and plan to look at any changes in girls’ psychosocial adjustment over time. The project has been funded by the National Cancer Institute, and the investigators have submitted additional research grants with hopes of continuing to follow this unique cohort into young adulthood.

Read more about the latest study results in this CBS News report.

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Nov 19 2015

Dancing Eyes Brought a Research Team Together

T-cells attacking cancer cell illustration of microscopic photos

It started at the end of a long day. Jessica Panzer, MD, PhD, then just a few weeks into her pediatric neurology residency at The Children’s Hospital of Philadelphia, was about to go home. Instead, she was called to the emergency room to consult on a 3-year-old girl who could barely walk. What happened then opened up new questions in her budding research career.

Not long after that, Miriam Rosenberg, PhD, started on a convergent path when her own 19-month-old daughter got sick. The toddler first developed problems with excessive drooling and stumbling while she walked. Within a few months, she had a sudden onset of more severe symptoms — unable to walk, severe tremor, unable to feed herself. Dr. Rosenberg and her husband brought their child to the nearest hospital.

Several months and multiple hospitalizations later, after Dr. Rosenberg and her family moved to Israel for her current position as a scientist at the Weizmann Institute of Science, doctors identified her daughter’s condition as an autoimmune disease called Opsoclonus Myoclonus Ataxia Syndrome (OMAS). OMAS is so rare that many clinicians can go their entire careers without ever seeing a case.

On the other side of the world, Dr. Panzer fortunately recognized her own patient’s strange, jerky eye movements, known as “opsoclonus” and sometimes colloquially called “dancing eyes.” Once she diagnosed OMAS, she prescribed immune drugs to diminish the body’s attack on its healthy neurons, and the child’s symptoms improved.

Each scientist found herself with more questions than answers. OMAS is so little understood that its treatment remains tricky. The pair has now teamed up to lead a research project seeking the underlying cause of OMAS, with a recent grant from the Pablove Foundation. A recent article in CHOP’s Bench to Bedside research newsletter goes into further details about their study.

No Standard Treatment, No Test

When Dr. Panzer’s OMAS patient started having problems in rehab, she realized she had little clear advice from other medical professionals on what to do.

“There was no test I could do to see if she was really flaring up or not, and there were no studies to say what treatment we should give at this point if she was flaring up,” Dr. Panzer said. “How can we not know what to do with this disease? That’s how I got interested in doing research in this area.”

Dr. Panzer first teamed up with Angela Waanders, MD, MPH, then an oncology fellow at CHOP and now an attending physician specializing in neuro-oncology. The pair focused on improving clinical treatment plans for patients with OMAS, about half of whom also have the nerve-cell tumor neuroblastoma. (The cancer is believed to trigger the autoimmune response.) The two young doctors started treating OMAS patients in a standardized manner and writing protocols based on the best-available information so that other clinicians could follow or refine their methods.

Then, as the end of her pediatric neurology residency neared, Dr. Panzer sought the advice of Josep Dalmau, MD, PhD, a neurologist and autoimmune disease expert then at the University of Pennsylvania, to develop a residency research project focused on OMAS. Dr. Dalmau encouraged her to try to find the antigen that triggers the immune response in OMAS. Scientists need to fundamentally understand how the disease works to have the best hope of interrupting the process with targeted treatments, or monitoring its status with a lab test.

The results of that residency research project were published this summer in the Journal of Immunology and provide a promising hint that the antigen that triggers OMAS may be detectable. Dr. Panzer is about to carry this research into the next phase.

She will not be doing it alone.

A Daughter’s Dancing Eyes Inspire New Scientific Approaches

While Dr. Panzer was getting familiar with OMAS from treating patients and doing preliminary lab research, Dr. Rosenberg was seeking answers about her own daughter’s disease. She used her scientific training to ask deeper questions than most parents could.

In February 2014, Dr. Rosenberg attended a conference of OMAS researchers in the United Kingdom, the biannual Dancing Eye Syndrome Support Trust symposium. She learned about the state of the OMAS research from presenters who were mostly focused on clinical questions and approaches.

“At the conference, I had the realization that people weren’t answering the molecular and biochemical questions that my training would lead me to ask,” Dr. Rosenberg said.

She went home and wrote her first grant to study OMAS.

At the same time, she and her husband were focused on their daughter’s treatment. As a result of their persistence, doctors eventually found that the child had a neuroblastoma that was missed on her original scans. She had surgery just after her third birthday and is now doing well — cancer-free with only some mild OMAS symptoms.

Dr. Rosenberg’s scientific curiosity about the disease persisted. Her first grants were not funded. Before she tried again this year, she contacted John Maris, MD at CHOP, to discuss a potential collaboration. She knew him as a leader in the field who had an outstanding track record with neuroblastoma therapeutics and a deep knowledge of genomics. Dr. Maris, an attending physician and Giulio D’Angio Chair in Neuroblastoma Research at CHOP, and a professor of pediatrics at the Perelman School of Medicine at Penn, knew exactly which CHOP doctor she should talk to about an OMAS study.

Dr. Rosenberg’s collaboration with Dr. Panzer was born.

Different Disciplines, Different Insights

As the pair gets started on their research together, they are drawing on the insights of their different scientific backgrounds and those of their collaborators: Dr. Waanders’ neuro-oncology, Dr. Maris’ neuroblastoma and molecular genetics, Dr. Dalmau’s neuroimmune expertise, and clinical trial insights from Pedro de Alarcon, MD, of the University of Illinois.

“Both of the experiments I proposed are basically things where you get back a long list of molecules and make sense of them,” Dr. Rosenberg said. “Different people recognize different things based on their background and training in different areas of biology.

“It’s an all-star team. I hope this will be a really truly interdisciplinary collaboration success story.”

To learn more about the research this team will do, read the story in Bench to Bedside.

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Nov 17 2015

Why Kids Need Bug Squashers: An Infectious Disease Q&A

Infectious_DiseasesPediatric infectious disease specialists, the doctors who specialize in wiping out microbial and other infections in children, are a dedicated bunch. These physicians work at the front lines of diseases new and old, as well as protecting against complications from other medical interventions.

Last month, members of this profession honored Theoklis E. Zaoutis, MD, MSCE, chief of the Division of Infectious Diseases at The Children’s Hospital of Philadelphia, as an exemplary leader in their midst with the Distinguished Service Award from the Pediatric Infectious Diseases Society (PIDS). This award, presented at the Society’s annual IDWeek meeting, recognizes a member who has made an outstanding contribution to the specialty of pediatric infectious diseases.

On the occasion of this recognition, Cornerstone sat down with Dr. Zaoutis, who is also director of the Center for Pediatric Clinical Effectiveness Research at CHOP and Thomas Frederick McNair Scott Professor of pediatrics and professor of epidemiology at the Perelman School of Medicine at the University of Pennsylvania. We wanted to know what is hot in the field of pediatric infectious disease research and what lies ahead. Read on for the edited conversation.

What is exciting and important in the world of infectious diseases today?

Everything. Infectious diseases are at the forefront of public health issues right now. If we look back at what’s happened in this past year alone, Ebola comes to mind. The world was taken aback by Ebola, by the magnitude of the outbreak, by the magnitude of the mortality associated with the outbreak, and by all the preparedness we had to do to build capacity to tackle it.

I would put Ebola under the larger umbrella of emerging infectious threats to the world. Ebola may be today, but there may be other ones that are out there. I think what’s exciting in the field now is thinking about ways to prepare for these diseases. That includes surveillance — how do we catch it before it gets out of control? How do we stop it? That means rapid capability to respond with treatments, development of vaccines, and infection control methodology. What do we need to wear when we take care of these patients? Emerging infectious diseases are a huge area right now.

What else is really hot right now in infectious diseases is antibiotic resistance. The World Health Organization (WHO) has listed antibiotic resistance — germs that are resistant to antibiotics — as one of the three greatest threats to human health. Antibiotic resistance is clearly an infectious-disease-related issue. For the first time in United States history, a U.S. president used the words “antibiotic resistance” in the State of the Union address. That’s how important infectious disease is right now. The Obama administration has a national strategic plan to combat antibiotic resistance called CARB, Combatting Antibiotic Resistant Bacteria. Again, this is the first time the United States government administration has declared war on infectious disease like this. It’s not a specific infectious disease like Ebola, but it’s more broadly a threat of having germs we can’t treat with antibiotics. Those are two big areas in infectious diseases that are at the forefront right now.

What are some of the biggest concerns or challenges in the pediatric infectious disease realm?

I think a lot of the concerns are very similar in pediatrics as in the general population. Kids were affected by Ebola. Kids will be affected by emerging infectious diseases. Kids are affected by antibiotic resistance. I think, in many ways, infectious disease does not necessarily know bounds in terms of adult versus pediatric patients. I can’t think of one infectious disease that affects just adults and doesn’t affect children. The magnitude of effect may be different depending on which infectious disease we’re talking about, but they’re very similar concerns in pediatrics.

One of the challenges for the field of pediatric infectious disease is it’s very hard in this healthcare climate to show value in what we do. Those of us in cognitive specialties in general in pediatrics — the ones who bring the know-how in aid of other specialties — don’t make a lot of money because we aren’t doing a procedure that we can list as a billable item for insurance companies. For example, we had three people on our faculty working on Ebola. They didn’t get paid for that. The current way the system is structured there is no way to pay for that.

This challenge has led to a significant decline in pediatric residents going into pediatric infectious diseases in the last two years. There was a report put out several years ago showing it was the pediatric subspecialty with the lowest return on investment if you just looked at it in terms of dollars. Infectious diseases are at the forefront, and yet we have people not going into the specialty because the return on investment is not there, and there’s no way to quantify the financial impact of the specialty.

What can be done about this decline in pediatric infectious disease specialists?

I have been working on an initiative that I think is one of the reasons for the PIDS Distinguished Service recognition. The initiative is an effort to both qualitatively and quantitatively assess the value of the subspecialty of pediatric infectious disease specialists.

We’re partnering with a medical sociologist, Julia Szymcak, who’s been involved in other studies here in the institution, to talk to all the stakeholders, from administrators to our customers, who are the other physicians who consult with infectious disease specialists, to say: Where’s the value added with the infectious disease folks?

There’s a lot of value added. It’s just hard to measure it. That’s the upshot of the study, that it’s hard to measure. Bean counters can’t value it. They know it’s there, they know it’s valuable, but when they get to their line items in the budget they can’t quantify it. People talked about improving antibiotic use in the hospital, that infectious disease is involved in quality. The results of this qualitative study so far have been presented at a national meeting.

Also as part of this initiative, we’re in the process of looking at data that’s more quantitative, trying to see other differences in patient outcomes when an infectious disease physician is consulted versus not consulted for similar kinds of patients and conditions. Both of these assessments are ongoing.

Were there other factors that you think contributed to your recognition by PIDS for distinguished service?

A few years ago the Pediatric Infectious Disease Society decided to launch its own journal, the Journal of the Pediatric Infectious Disease Society (JPIDS). I was fortunate enough to be named the inaugural editor-in-chief of that journal. I was given the task of taking a journal from zero to success. One of the milestones for a journal is to be listed in the National Library of Medicine and be searchable. We just made that milestone in June. The journal has been very successful, the quality of the papers has been very good, and it has increased revenue for the Society, and now it’s listed in PubMed. I think that part of the award was acknowledging that success.

Tell us about your current projects here at CHOP.

A lot of my current research work is focusing on addressing the problem of antibiotic resistance and improving antibiotic use. I’m involved in several national, NIH-funded studies now to determine what is the least amount of antibiotics we can use to effectively treat infections. The less antibiotics you use, the less likely you are to develop a resistant bug or bacteria. A lot of my research work is focused on using antibiotics more appropriately so that we do not develop antibiotic resistance.

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Nov 12 2015

Targeted Gene Therapy Aimed at Devastating Childhood Disease

active nerve cell illustration

When something important is missing, we often search for a replacement. After many years of looking, a team of researchers at The Children’s Hospital of Philadelphia and the University of Missouri have found a way to substitute for a missing gene linked to a relentless childhood neurodegenerative disease.

Late Infantile Neuronal Ceroid Lipofuscinosis (LINCL-Batten Disease) is a rare, inherited condition that erodes toddlers’ abilities to walk, talk, think, and see. Their development appears normal until debilitating symptoms and seizures arise between ages 2 to 4 and then gradually worsen until the children succumb to disease, generally by age 10.

LINCL-Batten is caused by mutations in the TPP1 gene, which encodes the lysosomal enzyme TPP1 that every brain cell needs in order to get rid of waste. When TPP1 is deficient, scientists using fluorescent microscopes can see glowing accumulations of storage material in cells, which is a hallmark of LINCL-Batten.

Beverly Davidson, PhD, director of the Raymond G. Perelman Center for Cellular and Molecular Therapeutics at CHOP and her research team have been trying to understand what is going wrong in the absence of these proteins and how they can develop therapies to treat children with LINCL-Batten.

In a new paper published in the journal Science Translational Medicine, they describe a novel approach using canine TPP1 gene transfer to treat dogs who have TPP1 deficiency and manifest the disease in ways comparable to humans. The lead co-authors included Luis Tecedor, PhD, and Yong Hong Chen, PhD, both from CHOP, and Martin Katz, PhD, of the University of Missouri.

During a 30-minute surgical procedure, a surgeon infuses the gene vector into the dog’s brain. The vector delivers its genetic material to a subset of cells that can then secrete the protein into the cerebral spinal fluid bathing the brain. Subsequent long-term and widespread distribution of TPP1 helps to correct the disease in the dog model.

A one-time infusion resulted in a “remarkable clinical benefit,” the study authors wrote. The treated dogs showed delays in onset of clinical signs and disease progression, protection from cognitive decline, and extension of lifespan.

“With gene therapy, we not only change when those symptoms occur, but we also spread them out,” Dr. Davidson said. “We give the dogs a profound improvement in their quality of life. It is really remarkable.”

Dr. Davidson envisions a similar short procedure could be used to target gene therapy in the brains of children with LINCL-Batten. Early diagnosis will be crucial so that the intervention could preserve as much of their functions as possible and prolong the onset of declines. It is unknown if TPP1 replacement could potentially alleviate any brain damage that already has occurred.

A “one and done” infusion would be a valuable alternative to another experimental therapy that is available called TPP1 enzyme replacement therapy (ERT). While the two approaches share the same basic concept, ERT does not rely on delivery of the TPP1 gene. Instead, it requires children to make biweekly visits to the intensive care unit to receive infusions of TPP1 through an indwelling device.

Dr. Davidson anticipates her lab’s gene therapy research will be ready to translate to a human clinical trial soon. “If the outcome in children with TPP1 deficiency is as profound as in the canine model, we would expect an enormous benefit to the quality of life of the affected children, and also their families,” Dr. Davidson said.

The National Institutes of Health, the Batten Disease Support and Research Association, Blake’s Purpose Foundation, the Roy J. Carver Trust, and the Children’s Hospital of Philadelphia Research Institute supported the canine investigations. The research team at the University of Missouri contributed to the study as well and provided exemplary collaboration in providing for the care and health of the dog colony.

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Nov 11 2015

New Growth Charts for Down Syndrome a Tall Order

Portrait of beautiful girl

Pediatricians have long known that children with Down syndrome grow differently than typical children, but the last growth charts for children with Down syndrome were developed almost 30 years ago. Since that time, clinical care for children with Down syndrome, especially early in life, has changed enormously, and their life expectancy has increased from 35 years in 1985 to 53 years in 2007.

It was clear to researchers at The Children’s Hospital of Philadelphia and the Centers for Disease Control (CDC) that the growth charts available for children with Down syndrome no longer measured up.

In 2009, they launched the Down Syndrome Growing Up Study (DSGS), funded by a four-year, $1.2 million grant from the CDC. The goal was to gather information about contemporary growth patterns of children with Down syndrome so that pediatricians and parents could see where a child’s height and weight stood relative to their genetic potential.

Using highly trained people to do the growth measurements, the study team led by Babette Zemel, PhD, director of the Nutrition and Growth Laboratory at CHOP, followed 637 participants, up to age 20, from January 2010 to July 2013. About 80 percent of the participants were recruited from the Trisomy 21 Program at CHOP and from community locations in the greater Philadelphia area.

“The families and the kids were so enthusiastic and appreciative that we were doing this project,” Dr. Zemel said. “They knew that there was a problem with the growth charts for children with Down Syndrome, and they really wanted to be a part of fixing it. The Trisomy 21 Program, led by Mary Pipan, MD, was superb to work with. ”

While checking a child’s height and weight may seem like an ordinary task, asking hundreds of children with Down syndrome to take their shoes off is far from routine. Down syndrome, a multisystem genetic disorder resulting from an extra copy of chromosome 21, occurs in about one in 700 U.S. births. Medical complications that accompany the condition affect every aspect of children’s daily lives, including eating, sleeping, hearing, talking, moving, and learning.

“Rather than using growth measurements that were acquired in the clinic, which are sometimes done under hurried circumstances, we were able to do it in a research setting so that we could take our time and make sure the children were comfortable and got used to the idea,” Dr. Zemel said. “We had a picture book to show and explain to them how we would take growth measurements so that they could anticipate what we were going to do. We had good participation and very accurate measurements.”

Results from the study appeared online Oct. 26 in Pediatrics. Dr. Zemel’s co-authors were Dr. Pipan, Virginia A. Stallings, MD; Waynitra Hall, MS; Kim Schadt, MSN; all from CHOP; and David S. Freedman, PhD, and Phoebe Thorpe, MD, MPH, both of the CDC.

One of the major study findings is that infants with Down syndrome are growing much better than they were several decades ago. Children under age 3 showed marked improvements in weight gain compared to the 1988 U.S. growth charts for children with Down syndrome. Improvements in height, reflecting taller stature, occurred mainly in males aged 2 to 20, relative to the earlier charts. In general, the DSGS charts were consistent with charts from children with Down syndrome in the United Kingdome, published in 2002.

The DSGS team also created the first-ever body mass index (BMI) charts for children with Down syndrome. The researchers noted that the charts do not represent an ideal distribution of BMI, but only describe BMI distribution among their study participants. They added that further investigations should determine how to use the BMI charts to screen patients for excess body fat and associated health symptoms.

While clinicians and researchers realize that obesity is a problem for children with Down syndrome, especially as they move into their teenage years and beyond, an interesting finding from the study that Dr. Zemel pointed out is that the weight charts for children with Down syndrome did not change much over the past few decades.

“This is quite surprising, given that for the rest of the U.S. population, there has been an increase in the prevalence of obesity,” said Dr. Zemel, who also is on the faculty of the Perelman School of Medicine at the University of Pennsylvania.

Another research project led by Andrea Kelly, MD, at CHOP and Sheela Magge, MD, MSCE, at Children’s National Medical Center is focusing on any health consequences of excess weight in teens with Down syndrome. They will determine if being overweight or obese carries the same cardiometabolic risks as it does for typical children, and they also will assess study participants’ body image and quality of life.

For more information on the DSGS study, visit here.

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Nov 10 2015

CHOP Leads Patient-Reported Outcomes in Chronic Diseases Consortium

Meeting with the doctor office

“How tired do you feel?” a doctor asks a child with a chronic disease. Or, “How well are you managing stress?”

The answers to questions like these are even more important, from many patients’ and families’ perspectives, than the particular numerical result of their lab test results.

But the answers are less useful to doctors than they could be. Doctors do not have validated tools to use such patient-reported outcomes to track progress managing a condition over time in the same way they can compare results of blood tests over time. In clinical research, they are unable to compare the answers across patients to ultimately show an experimental drug meaningfully improves fatigue or other patient-reported measures.

“Our vision is that patient-reported outcomes become like lab tests,” said Christopher Forrest, MD, PhD, a pediatrician and researcher at The Children’s Hospital of Philadelphia and professor of pediatrics at the Perelman School of Medicine at the University of Pennsylvania. “Soon doctors will use patient-reported outcomes to monitor patients’ clinical care in the same way they use lab tests or X-rays.”

Dr. Forrest and colleagues at CHOP and partner institutions received a new grant from the National Institutes of Health to advance the science of patient-reported outcome measures to one day achieve that vision.

The grant establishes CHOP as the administrative leader and one of four centers awarded as part of the Validation of Pediatric Patient-Reported Outcomes in Chronic Diseases (PEPR) Consortium. The PEPR Consortium will work to improve pediatric health and well-being by capturing the voice and experience of children and their families living with a variety of chronic diseases and conditions.

“There are a lot of outcomes that we can’t get except by child report,” said Katherine Bevans, PhD, who is co-leading the PEPR Consortium research at CHOP with Dr. Forrest. “There’s a long line of research, going back 20 years, that kids are in fact accurate and reliable reporters of their own health.”

Dr. Bevans noted that considering patient-reported outcomes is essential to ensure that clinicians and clinical researchers are achieving their goals of delivering patient- and family-centered care.

The group will test several tools for collecting children’s self-reported outcomes that were previously developed under the Pediatric PROMIS initiative. Under PROMIS, NIH-funded researchers at multiple sites, including a group led by Dr. Forrest at CHOP, developed survey tools for collecting and scoring a variety of patient-reported outcome measures in both pediatric and adult populations.

Development of new tools under PROMIS has ended, and the PEPR consortium will now continue to collect evidence to validate the tools’ effectiveness at measuring clinically meaningful outcomes specifically in populations of children with chronic diseases. They intend to connect children’s scores on PROMIS surveys to clinically meaningful outcomes so doctors and clinical researchers can know when a fluctuation in a survey score represents a meaningful improvement or worsening.

In addition, PEPR Consortium centers will include a focus on improving understanding of environmental influences on pediatric diseases, in keeping with the goals of the National Children’s Study (NCS). PEPR is one of the NIH programs receiving funds diverted from the now-cancelled NCS and tasked with answering some of the study’s important questions about children’s environment and health.

The group led by Dr. Bevans and Dr. Forrest at CHOP will integrate PROMIS survey tools into several existing studies, including a long-term study of chronic kidney disease led at CHOP by nephrology division chief Susan Furth, MD, PhD; a clinical trial for pediatric Crohn’s disease, led at CHOP by Andrew Grossman, MD; and, a clinical study of survivors of cancer treatment at St. Jude Children’s Research Hospital.

“The opportunity with the PEPR grant is to get a much more in-depth view from the patient’s perspective on how concerns that go along with chronic kidney disease including pain, mobility issues, and social functioning, affect their lives,” said Dr. Furth. “Ultimately, when we can target our interventions and include the perspectives of kids and their families, we will focus on the key areas that really make their lives better.”

Dr. Grossman noted, “The PEPR grant will afford the opportunity for us to develop and refine the tools that will allow the patient and parent voice to be inculcated into our assessment of disease activity. In turn, we will better be able to determine the effectiveness of our interventions going forward.”

As the administrative leader of the PEPR Consortium, CHOP also will support resources and technical expertise for projects undertaken by PEPR investigators at the other three centers receiving NIH PEPR awards. These centers will benefit from Dr. Forrest’s work as principal investigator of PEDSnet, a major clinical data research network that includes data from electronic health records and patient-reported data. The infrastructure developed under PEDSnet will offer a data management platform and standardized data formats and sharing for PEPR research data.

At CHOP, Dr. Forrest and Dr. Bevans are further working to build both PEPR and PEDSnet into a new center of emphasis focused on research that informs doctors’ routine treatment decisions. They aim to build a community of clinicians and researchers interested in effectiveness research and patient-reported outcomes. They encourage CHOP researchers and clinicians to contact them to discuss collaborations.

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Nov 09 2015

Teens Receive Inconsistent Emergency Care After Sexual Assault

TeenAssaultAbout 10 percent of high school girls and half as many high school boys report that they have been sexually assaulted in Centers for Disease Control and Prevention (CDC) surveys. But when these young victims come to pediatric emergency rooms,, they are not consistently getting recommended tests and treatment, according to new research from The Children’s Hospital of Philadelphia.

“Our study was remarkable in that there was so much variation in the care adolescents received after sexual assault,” said Samantha Schilling, MD, MSHP, an assistant clinical professor at the University of North Carolina School of Medicine who is first author of the study, conducted when she was a fellow at CHOP and at the Leonard Davis Institute of Health Economics at the University of Pennsylvania (LDI). “While overall performance wasn’t ideal, there were also wide ranges in testing and treatment for infections and pregnancy.”

Dr. Schilling worked with CHOP and Penn colleagues including senior author Joanne N. Wood, MD, MSHP, a CHOP PolicyLab faculty member, assistant professor at Penn’s Perelman School of Medicine, and Penn LDI senior fellow, to conduct a retrospective analysis of health data from adolescents seen in 38 pediatric emergency rooms over a 10-year period, 2004 to 2013. The demographic data of patients, combined with data on the tests and treatments they received, provided a picture of care adolescents received in this treatment setting when seen for sexual assault. The study results appeared online Oct. 28 in the journal Pediatrics.

Guidelines from the CDC and American Academy of Pediatrics (AAP) recommend testing youth for sexually transmitted infections chlamydia and gonorrhea when they report sexual assault, as well as testing for pregnancy in female victims past the age of puberty. These guidelines also call for physicians to provide prophylactic treatment for these infections and emergency contraception, even before the testing outcome is known.

Yet the rates at which teens received these tests and treatments were low overall and highly varied between hospitals, Dr. Schilling and colleagues found. On average, 44 percent of victims received the recommended testing, with rates between 6 and 89 percent. On average, 35 percent of victims received recommended prophylaxis, ranging from zero to 57 percent among different hospitals.

One key finding offers a potential means of improving the consistency and quality of care for these teens:

“The presence of a specialized pathway did show a modest improvement in care,” Dr. Schilling said.

A specialized pathway is a standard set of steps for evaluation and care for patients seen with a given chief complaint. For example, pathways of care exist for children with asthma, and for infants under 56 days of age who come to the hospital with a fever. Some hospitals have adopted specialized pathways for sexual assault.

In a survey of specialized physicians from each of the participating hospitals about their routine practices for sexual assault evaluations, researchers asked about whether and when the hospital had established specialized sexual assault pathways and teams in the emergency department. Overall, 30 percent of the sexual assault cases in the study were seen at hospitals that had a specialized care pathway. These cases had higher rates of receiving recommended prophylaxis treatments even when adjusted for other hospital characteristics.

The presence of a specialized team of clinicians to address sexual assault was not associated with any difference in the quality of care. Dr. Schilling said that may be because the nature of teams was too variable.

“Future research that would be helpful in understanding solutions and the nature of the problem would include more detailed studies looking at the specific structure, training, and peer-review process for specialized teams, as well as studies to understand more about the content and the methods of delivery of specialized pathways,” Dr. Schilling said. “Understanding the structure of teams and pathways that work well, and disseminating and implementing more models like them, will ultimately help improve the care that adolescents who have been sexually assaulted receive in emergency settings.”

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Nov 05 2015

Research Tech Raises Awareness About Bone Marrow Donation

Bone marrow stem cells

It only took 10 minutes during Harold “Reed” Salmons’ lunch break to sign up and save a man’s life. A Be The Match recruiter performed a quick cheek swab to collect Salmons’ cells and sent them for testing as a potential match for future bone marrow transplant recipients. Salmons hoped that his molecular match was out there somewhere.

“It’s so rare to match that you don’t even think at the time that it could be a possibility six months later to be needed,” said Salmons, 23, as he sat at an outdoor café sipping his breakfast blend coffee and telling his remarkable story.

According to Be the Match, a marrow registry operated by the National Marrow Donor Program, about one in 540 U.S. Be The Match registry members will go on to donate bone marrow or peripheral blood stem cells to a patient. Currently, there are 11 million registry members.

“I think a lot more people would do it if they knew about it,” Salmons said. “It’s not a heroic thing; I think it is knowledge that you have to vibe with sentiment, and just know enough about it to go for it.”

A 2014 biology graduate of Dickinson College in Carlisle, Pa., Salmons is working as a research technician in the lab of Beverly Emanuel, PhD, at The Children’s Hospital of Philadelphia. He discovered that CHOP was a good career fit during a prior internship with the CHOP Research Institute’s Summer Scholars program.

“It is an honor to work at CHOP,” Salmons said. “I knew I was going to come back before I even donated. I just love the environment here.”

During his senior year in college, Salmons learned about the Be The Match registry, an organization that works to pair patients with bone marrow donors. Currently, Salmons is trying to partner Be The Match with colleges and universities to encourage students to register. He mostly is focused on running drives in the Greater Philadelphia region, and his first drive will be held Nov. 19 at 10 a.m. in Penn Medicine’s Abramson Cancer Center.

“I was a college athlete in my final year and was hoping to get some time on the field,” Salmons recalled. “I thought, ‘Why not show that it doesn’t matter about that stuff when someone else is in this much need?’”

Across the country in Everett, Wash., that “someone” was 60-year-old Mark Tose, once a senior manager in Boeing’s commercial airplanes division who had endured five rigorous rounds of chemotherapy in seven months to treat his acute myeloid leukemia. A cancer of the blood, leukemia occurs most often in adults older than 55 years, and it is the most common cancer in children younger than 15 years old, according to the National Cancer Institute. Tose’s survival depended on having a successful bone marrow transplant, and Salmons was his best chance as a compatible donor.

Five days before donating, Salmons came back from West Virginia where was doing work for Habitat for Humanity and began receiving injections of a growth factor drug that would help mobilize his marrow stem cells into his bloodstream rather than in his bones. He felt flu-like side effects, including weakness and bone aches. On his donation day, Jan. 21, 2014, he received his last injection at 5 a.m. and then spent the next five to six hours undergoing leukapheresis, a procedure that collects the part of the blood containing the stem cells and returns the remaining blood to Salmons.

“It was the most powerful thing I will ever do,” Salmons said. “It has been a privilege and a blessing to go through the process.”

It was critical for the bone marrow specimen to arrive in Seattle within 24 hours, in order to be processed and transplanted. Despite weather obstacles, it arrived in time for Tose to have the transplant procedure Jan. 22. It took until Feb. 10 for Tose to regain consciousness, but the transplant had worked. He had a slow recovery and was told that his risk of dying within the first 100 days after the transplant was 20 to 30 percent.

A year later, Salmons received an email while visiting his brother in upstate New York, with the subject line: “How do you thank someone for saving your life?”

The two medical compatriots arranged to meet for the first time at the Bloodworks Center in Seattle, and Salmons and Tose became quick friends who stay in touch regularly. Both have a genuine concern for others, and together they decided to share their Be The Match story to encourage others to register.

“I think a lot of people are scared of the bone marrow process,” Salmons said. “The big thing for me is trying to demystify it and show people how even though you are a college athlete and you are supposed to do well in the classroom and the sports field, you can step out of your own schedule and cycle and do this for someone else.”

Being an integral part of a Be The Match success story has motivated Salmons to attend medical school and become a physician. When his days get tough, he hopes to model Tose’s sense of determination.

“His attitude throughout the whole process was, ‘It’s all good,’” Salmons said. “Other than my parents, I think he’s up there as the most inspirational person in my life because of his attitude.”

November is National Marrow Awareness Month. To read more about how you can join the registry, visit Be The Match here, or come to the drive Nov. 19 from 10 a.m. until 2 p.m., at the Abramson Cancer Center, 3400 Civic Center Blvd., Philadelphia, 19104.

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