Diabetes & Endocrinology

Mihailo Kaplarevic

Extracting actionable research data faster, with fewer hassles

Mihailo Kaplarevic

Mihailo Kaplarevic, Ph.D., the newly minted Chief Research Information Officer at Children’s National Hospital and Bioinformatics Division Chief at Children’s National Research Institute, will provide computational support, advice, informational guidance, expertise in big data and data analyses for researchers and clinicians.

Kaplarevic’s new job is much like the role he played most recently at the National Heart, Lung and Blood Institute (NHLBI), assembling a team of researchers and scientists skilled in computing and statistical analyses to assist as in-house experts for other researchers and scientists.

NHLBI was the first institute within the National Institutes of Health (NIH) family to set up a scientific information office. During his tenure, a half-dozen other NIH institutions followed, setting up the same entity to help bridge the enormous gap between basic and clinical science and everything related to IT.

“There is a difference compared with traditional IT support at Children’s National – which will remain in place and still do the same sort of things they have been doing so far,” he says of The Bear Institute for Health Innovation. “The difference is this office has experience in research because every single one of us was a researcher at a certain point in our career: We are published. We applied for grants. We lived the life of a typical scientist. On top of that, we’re coming from the computational world. That helps us bridge the gaps between research and clinical worlds and IT.”

Ultimately, he aims to foster groundbreaking science by recognizing the potential to enhance research projects by bringing expertise acquired over his career and powerful computing tools to help teams achieve their goals in a less expensive and more efficient way.

“I have lived the life of a typical scientist. I know exactly how painful and frustrating it can be to want to do something quickly and efficiently but be slowed by technological barriers,” he adds.

As just one example, his office will design the high-performance computing cluster for the hospital to help teams extract more useful clinical and research data with fewer headaches.

Right now, the hospital has three independent clinical systems storing patient data; all serve a different purpose. (And there are also a couple of research information systems, also used for different purposes.) Since databases are his expertise, he will be involved in consolidating data resources, finding the best way to infuse the project with the bigger-picture mission – especially for translational science – and creating meaningful, actionable reports.

“It’s not only about running fewer queries,” he explains. “One needs to know how to design the right question. One needs to know how to design that question in a way that the systems could understand. And, once you get the data back, it’s a big set of things that you need to further filter and carefully shape. Only then will you get the essence that has clinical or scientific value. It’s a long process.”

As he was introduced during a Children’s National Research Institute faculty meeting in late-September 2019, Kaplarevic joked that his move away from pure computer science into a health care and clinical research domain was triggered by his parents: “When my mom would introduce me, she would say ‘My son is a doctor, but not the kind of doctor who helps other people.’ ”

Some of that know-how will play out by applying tools and methodology to analyze big data to pluck out the wheat (useful data) from the chaff in an efficient and useful way. On projects that involve leveraging cloud computing for storing massive amounts of data, it could entail analyzing the data wisely to reduce its size when it comes back from the cloud – when the real storage costs come in. “You can save a lot of money by being smart about how you analyze data,” he says.

While he expects his first few months will be spent getting the lay of the land, understanding research project portfolios, key principal investigators and the pediatric hospital’s biggest users in the computational domain, he has ambitious longer-term goals.

“Three years from now, I would like this institution to say that the researchers are feeling confident that their research is not affected by limitations related to computer science in general. I would like this place to become a very attractive environment for up-and-coming researchers as well as for established researchers because we are offering cutting-edge technological efficiencies; we are following the trends; we are a secure place; and we foster science in the best possible way by making computational services accessible, affordable and reliable.”

Andrew Dauber

Andrew Dauber, M.D., MMSc, awarded prestigious laureate award

Andrew Dauber

Unfortunately, we’ve been notified that the ENDO2020 conference has been canceled due to concerns of COVID-19. Because of this, we will not be hosting our reception in honor of Andrew Dauber, M.D., on Sunday, March 29.

We hope to see you at a future Endocrinology or Pediatric Endocrinology event.

Children’s National Hospital is incredibly proud of the work Dr. Dauber has done in the endocrinology community.

Andrew Dauber, M.D., MMSc, division chief of Endocrinology at Children’s National Hospital, will receive the 2020 Richard E. Weitzman Outstanding Early Career Investigator Award from The Endocrine Society. Given annually, the award was established in 1982 and honors the memory of the late Richard E. Weitzman, who had a brief but outstanding career studying neurohypophyseal hormone and cardiovascular-endocrine physiology – two seminal areas of modern endocrinology.

Dr. Dauber was selected as a recipient for the prestigious award for his contributions to understanding the regulation of growth and puberty, and his success at applying innovative genetic technologies to studying pediatric endocrinology.

“I feel extremely honored and humbled to be the recipient of the Richard E. Weitzman Outstanding Early Career Investigator Award from the Endocrine Society,” says Dr. Dauber. “I am so grateful to my many collaborators throughout the world as well as to my entire research team whose hard work and friendship are the basis for this award. I am excited to continue our work at Children’s National, an institution dedicated to innovation and team science.”

Dr. Dauber joined Children’s National in 2018 and specializes in studying and treating growth disorders. He has published over 75 studies examining genetic clues to endocrine disorders, with a focus on short stature and growth disorders.

The award will be presented at ENDO 2020, The Endocrine Society’s annual meeting, March 28-31, 2020, in San Francisco, California.

Lee Beers

Getting to know Lee Beers, M.D., FAAP, future president-elect of AAP

Lee Beers

Lee Savio Beers, M.D., FAAP, Medical Director of Community Health and Advocacy at the Child Health Advocacy Institute (CHAI) at Children’s National Hospital carved out a Monday morning in late-September 2019, as she knew the American Academy of Pediatrics (AAP) would announce the results of its presidential election, first by telephone call, then by an email to all of its members.  Her husband blocked off the morning as well to wait with her for the results.  She soon got the call that she was elected by her peers to become AAP president-elect, beginning Jan. 1, 2020. Dr. Beers will then serve as AAP president in 2021 for a one-year term.

That day swept by in a rush, and then the next day she was back in clinic, caring for her patients, some of them teenagers whom she had taken care of since birth. Seeing children and families she had known for such a long time, some of whom had complex medical needs, was a perfect reminder of what originally motivated Dr. Beers to be considered as a candidate in the election.

“When we all work together – with our colleagues, other professionals, communities and families – we can make a real difference in the lives of children.  So many people have reached out to share their congratulations, and offer their support or help. There is a real sense of collaboration and commitment to child health,” Dr. Beers says.

That sense of excitement ripples through Children’s National.

“Dr. Beers has devoted her career to helping children. She has developed a national advocacy platform for children. I can think of no better selection for the president-elect role of the AAP. She will be of tremendous service to children within AAP national leadership,” says Kurt Newman, M.D., Children’s National Hospital President and CEO.

AAP comprises 67​,000 pediatricians, and its mission is to promote and safeguard the health and well-being of all children – from infancy to adulthood.

The daughter of a nuclear engineer and a schoolteacher, Dr. Beers knew by age 5 that she would become a doctor. Trained as a chemist, she entered the Emory University School of Medicine after graduation. After completing residency at the Naval Medical Center, she became the only pediatrician assigned to the Guantanamo Bay Naval Station.

That assignment to Cuba, occurring so early in her career, turned out to be a defining moment that shapes how she partners with families and other members of the team to provide comprehensive care.

“I was a brand-new physician, straight out of residency, and was the only pediatrician there so I was responsible for the health of all of the kids on the base. I didn’t know it would be this way at the time, but it was formative. It taught me to take a comprehensive public health approach to taking care of kids and their families,” she recalls.

On the isolated base, where she also ran the immunization clinic and the nursery, she quickly learned she had to judiciously use resources and work together as a team.

“It meant that I had to learn how to lead a multi-disciplinary team and think about how our health care systems support or get in the way of good care,” she says.

One common thread that unites her past and present is helping families build resiliency to shrug off adversity and stress.

“The base was a difficult and isolated place for some families and individuals, so I thought a lot about how to support them. One way is finding strong relationships where you are, which was important for patients and families miles away from their support systems. Another way is to find things you could do that were meaningful to you.”

Cuba sits where the Atlantic Ocean, Caribbean Sea and Gulf of Mexico meet. Dr. Beers learned how to scuba dive there – something she never would have done otherwise – finding it restful and restorative to appreciate the underwater beauty.

“I do think these lessons about resilience are universal. There are actually a lot of similarities between the families I take care of now, many of whom are in socioeconomically vulnerable situations, and military families when you think about the level of stress they are exposed to,” she adds.

Back stateside in 2001, Dr. Beers worked as a staff pediatrician at the National Naval Medical Center in Bethesda, Maryland, and Walter Reed Army Medical Center in Washington, D.C. In 2003, Dr. Beers joined Children’s National Hospital as a general pediatrician in the Goldberg Center for Community Pediatric Health. Currently, she oversees the DC Collaborative for Mental Health in Pediatric Primary Care, a public-private coalition that elevates the standards of mental health care for all children, and is Co-Director of the Early Childhood Innovation Network. She received the Academic Pediatric Association’s 2019 Public Policy and Advocacy Award.

As a candidate, Dr. Beers pledged to continue AAP’s advocacy and public policy efforts and to further enhance membership diversity and inclusion. Among her signature issues:

  • Partnering with patients, families, communities, mental health providers and pediatricians to co-design systems to bolster children’s resiliency and to alleviate growing pediatric mental health concerns
  • Tackling physician burnout by supporting pediatricians through office-based education and systems reforms
  • Expanding community-based prevention and treatment

“I am humbled and honored to have the support of my peers in taking on this newest leadership role,” says Dr. Beers. “AAP has been a part of my life since I first became a pediatrician, and my many leadership roles in the DC chapter and national AAP have given me a glimpse of the collective good that pediatricians can accomplish by working together toward common strategic goals.”

AAP isn’t just an integral part of her life, it’s where she met her future husband, Nathaniel Beers, M.D., MPA, FAAP, President of The HSC Health Care System. The couple’s children regularly attended AAP meetings with them when they were young.

Just take a glimpse at Lee Beers’ Twitter news feed. There’s a steady stream of images of her jogging before AAP meetings to amazing sunrises, jogging after AAP meetings to stellar sunsets and always, always, images of the entire family, once collectively costumed as The Incredibles.

“I really do believe that we have to set an example: If we are talking about supporting children and families in our work, we have to set that example in our own lives. That looks different for everyone, but as pediatricians and health professionals, we can model prioritizing our families while still being committed to our work,” she explains.

“Being together in the midst of the craziness is just part of what we do as a family. We travel a lot, and our kids have gone with us to AAP meetings since they were infants. My husband even brought our infant son to a meeting at the mayor’s office when he was on paternity leave. Recognizing that not everyone is in a position to be able to do things like that, it’s important for us to do it – to continue to change the conversation and make it normal to have your family to be part of your whole life, not have a separate work life and a separate family life.”

Julia Finkel

Two Children’s National spin-outs join Johnson & Johnson–JLABS

Julia Finkel

AlgometRx, which joins JPOD @ Philadelphia, was founded by Julia Finkel, M.D., pediatric anesthesiologist and director of Pain Medicine and Research at Children’s Sheikh Zayed Institute.

AlgometRx and Adipomics, two companies that spun out of innovations discovered at Children’s National Health System, have been selected by Johnson & Johnson Innovation – JLABS to join JPOD @ Philadelphia and JPOD @ Boston, respectively.

JLABS is a global network of no-strings-attached incubators for innovative companies from across the pharmaceutical, medical device, consumer and health technology sectors. Start-up companies are free to pursue their own research priorities independently, with access to state-of-the-art facilities to develop new drugs, medical devices, precision diagnostics and health technologies for people around the world.

Both companies got their start at the Sheikh Zayed Institute for Pediatric Surgical Innovation at Children’s National. The Institute focuses on research and innovation that can improve health for children everywhere.

AlgometRx, which joins JPOD @ Philadelphia, was founded by Julia Finkel, M.D., pediatric anesthesiologist and director of Pain Medicine and Research at Children’s Sheikh Zayed Institute. The AlgometRx device is a first-of-its-kind platform technology that aims to objectively measure pain intensity, type and drug effects in real time by capturing a digital image of a patient’s pupillary light response and applying a series of proprietary algorithms to various characteristics.

AlgometRx is designed to provide an objective pain measurement that aims to help physicians select the correct analgesic class of drug and dosage. By optimizing pain assessment, drug selection and drug management, AlgometRx aims to impact the opioid epidemic and the monitoring and management of Opioid Use Disorder.

Robert Freishtat and Evan Nadler

Adipomics, which joins JPOD @ Boston, was co-founded by Robert Freishtat, M.D., M.P.H., senior investigator in the Center for Genetic Medicine of the Children’s Research Institute and chief of the Division of Emergency Medicine at Children’s National, and pediatric surgeon Evan P. Nadler, M.D., co-director of the Obesity Program and director of the Bariatric Surgery Program at Children’s National.

Adipomics, which joins JPOD @ Boston, was co-founded by pediatric surgeon Evan P. Nadler, M.D., co-director of the Obesity Program and director of the Bariatric Surgery Program at Children’s National, and Robert Freishtat, M.D., M.P.H., senior investigator in the Center for Genetic Medicine of the Children’s Research Institute and chief of the Division of Emergency Medicine at Children’s National. Adipomics was founded with the aim to address the global epidemic of obesity-related diseases including Type 2 diabetes and cardiovascular diseases. World health experts predict that one billion people worldwide will be obese by 2030.

Drs. Nadler and Freishtat discovered that exosomes released from fat cells (adipocytes) carry genetic material that can mediate various diseases related to obesity. Through their research, they developed a proprietary method that aims to detect how obesity affects an individual patient’s metabolism before the onset of overt disease. Adipomics aims to create the first non-invasive, “anticipatory medicine” diagnostic that detects risk for obesity-related diseases prior to the onset of clinical signs or even biochemical abnormalities. If successful, this predictive methodology would enable treatment much earlier in the disease process, which is likely to improve effectiveness.

A recent news release from Children’s National provides more details on these innovations.

As organizations that share a commitment to improving the pace of healthcare innovation, Children’s National and Johnson & Johnson Innovation – JLABS also recently announced their collaboration to launch JLABS @ Washington, DC,  a 32,000-square foot facility to be located at the new Children’s National Research & Innovation Campus in Washington, D.C. The JLABS @ Washington, DC will have the capacity to house up to 50 pharmaceutical, medical device, consumer and health technology companies that are aiming to advance the development of new drugs, medical devices, precision diagnostics and health technologies, including applications in pediatrics. The campus is located on a 12-acre portion of the former Walter Reed Army Medical Center campus in the nation’s capital and is slated to open in 2020, coinciding with the 150th Anniversary of Children’s National Health System.

Cholesterol plaque in artery

Looking for atherosclerosis’ root cause

Cholesterol plaque in artery

A multi-institutional team led by research faculty at Children’s National in Washington, D.C., finds that extracellular vesicles derived from kids’ fat can play a pivotal role in ratcheting up risk for atherosclerotic cardiovascular disease well before any worrisome symptoms become visible.

According to the Centers for Disease Control and Prevention, about one in five U.S. kids aged 6 to 19 is obese, boosting their risk for a variety of other health problems now and later in life.

One of these is atherosclerosis, a term that translates literally as hardening of the arteries. Atherosclerosis causes blood vessels that carry oxygen-rich blood throughout the body to become inflamed. White blood cells called macrophages settle in the vessel wall, which becomes overloaded with cholesterol. A plaque forms that restricts blood flow. But it remains a mystery how fat cells residing in one place in the body can trigger mayhem in cells and tissues located far away.

Small, lipid-lined sacs called extracellular vesicles (EVs), released by cells into the bloodstream, are likely troublemakers since they enable intercellular communication. Now, a multi-institutional team led by research faculty at Children’s National in Washington, D.C., finds that EVs derived from kids’ fat can play a pivotal role in ratcheting up risk for atherosclerotic cardiovascular disease well before any worrisome symptoms become visible. What’s more, the team showed that EVs found in the body’s fat stores can disrupt disposal of cholesterol in a variety of kids, from lean to obese, the team reports online July 22, 2019, in the Journal of Translational Medicine.

“We found that seven specific small sequences of RNA (microRNA) carried within the extracellular vesicles from human fat tissue impaired the ability of white blood cells called macrophages to eliminate cholesterol,” says Robert J. Freishtat, M.D., MPH, senior scientist at the Center for Genetic Medicine Research at Children’s National and the study’s senior author. “Fat isn’t just tissue. It can be thought of as a metabolic organ capable of communicating with types of cells that predispose someone to develop atherosclerotic cardiovascular disease, the leading cause of death around the world.”

Research scientists and clinicians from Children’s National, the George Washington University, NYU Winthrop Hospital and the National Heart, Lung and Blood Institute collaborated to examine the relationship between the content of EVs and their effect on macrophage behavior. Their collaborative effort builds on previous research that found microRNA derived from fat cells becomes pathologically altered by obesity, a phenomenon reversed by weight-loss surgery.

Because heart disease can have its roots in adolescence, they enrolled 93 kids aged 12 to 19 with a range of body mass indices (BMIs), including the “lean” group, 15 youth whose BMI was lower than 22 and the “obese” group, 78 youths whose BMI was in the 99th percentile for their age. Their median age was 17. Seventy-one were young women. They collected visceral adipose tissue during abdominal surgeries and visited each other’s respective labs to perform the experiments.

“We were surprised to find that EVs could hobble the macrophage cholesterol outflow system in adolescents of any weight,” says Matthew D. Barberio, Ph.D., the study’s lead author, a former Children’s National scientist who now is an assistant professor at the George Washington University’s Milken Institute School of Public Health. “It’s still an open question whether young people who are healthy can tolerate obesity—or whether there are specific differences in fat tissue composition that up kids’ risk for heart disease.”

The team plans to build on the current findings to safeguard kids and adults against future cardiovascular risk.

“This study was a huge multi-disciplinary undertaking,” adds Allison B. Reiss, M.D., of NYU Winthrop Hospital and the study’s corresponding author. “Ultimately, we hope to learn which properties belonging to adipose tissue EVs make them friendly or unfriendly to the heart, and we hope that gaining that knowledge will help us decrease morbidity and mortality from heart disease across the lifespan.”

In addition to Dr. Freishtat, additional study co-authors include Samuel B. Epstein, Madeleine Goldberg, Sarah C. Ferrante, and Evan P. Nadler, M.D., director of the Bariatric Surgery Program, all of Children’s National’s Center for Genetic Medicine Research; Lead Author, Matthew D. Barberio, of Millken Institute School of Public Health at the George Washington University; Lora J. Kasselman, Heather A. Renna, Joshua DeLeon, Iryna Voloshyna, Ashley Barlev, Michael Salama and Allison B. Reiss, all of NYU Winthrop Hospital; and Martin P. Playford and Nehal Mehta, of the National Heart, Lung and Blood Institute.

Financial support for research described in this post was provided by the National Institutes of Health National Center for Advancing Translational Sciences under award number UL1TR000075, the National Heart, Lung and Blood Institute under award number Z1AHL-06193-4, the American Heart Association under award number 17POST33670787, the Clark Charitable Foundation, the Elizabeth Daniel Research Fund, and Robert Buescher.

Children’s National ranked No. 6 overall and No. 1 for newborn care by U.S. News

Children’s National in Washington, D.C., is the nation’s No. 6 children’s hospital and, for the third year in a row, its neonatology program is No.1 among all children’s hospitals providing newborn intensive care, according to the U.S. News Best Children’s Hospitals annual rankings for 2019-20.

This is also the third year in a row that Children’s National has been in the top 10 of these national rankings. It is the ninth straight year it has ranked in all 10 specialty services, with five specialty service areas ranked among the top 10.

“I’m proud that our rankings continue to cement our standing as among the best children’s hospitals in the nation,” says Kurt Newman, M.D., President and CEO for Children’s National. “In addition to these service lines, today’s recognition honors countless specialists and support staff who provide unparalleled, multidisciplinary patient care. Quality care is a function of every team member performing their role well, so I credit every member of the Children’s National team for this continued high performance.”

The annual rankings recognize the nation’s top 50 pediatric facilities based on a scoring system developed by U.S. News. The top 10 scorers are awarded a distinction called the Honor Roll.

“The top 10 pediatric centers on this year’s Best Children’s Hospitals Honor Roll deliver outstanding care across a range of specialties and deserve to be nationally recognized,” says Ben Harder, chief of health analysis at U.S. News. “According to our analysis, these Honor Roll hospitals provide state-of-the-art medical expertise to children with rare or complex conditions. Their rankings reflect U.S. News’ assessment of their commitment to providing high-quality, compassionate care to young patients and their families day in and day out.”

The bulk of the score for each specialty is based on quality and outcomes data. The process also includes a survey of relevant specialists across the country, who are asked to list hospitals they believe provide the best care for patients with challenging conditions.

Below are links to the five specialty services that U.S. News ranked in the top 10 nationally:

The other five specialties ranked among the top 50 were cardiology and heart surgery, diabetes and endocrinology, gastroenterology and gastro-intestinal surgery, orthopedics, and urology.

Vittorio Gallo Alpha Omega Alpha Award

Vittorio Gallo, Ph.D., inducted into Alpha Omega Alpha

Vittorio Gallo Alpha Omega Alpha Award

Vittorio Gallo, Ph.D., Chief Research Officer at Children’s National, was inducted into Alpha Omega Alpha (AΩA), a national medical honor society that since 1902 has recognized excellence, leadership and research in the medical profession.

“I think it’s great to receive this recognition. I was very excited and surprised,” Gallo says of being nominated to join the honor society.

“Traditionally AΩA membership is based on professionalism, academic and clinical excellence, research, and community service – all in the name of ‘being worthy to serve the suffering,’ which is what the Greek letters AΩA stand for,” says Panagiotis Kratimenos, M.D., Ph.D., an ΑΩΑ member and attending neonatologist at Children’s National who conducts neuroscience research under Gallo’s mentorship. Dr. Kratimenos nominated his mentor for induction.

“Being his mentee, I thought Gallo was an excellent choice for AΩΑ faculty member,” Dr. Kratimenos says. “He is an outstanding scientist, an excellent mentor and his research is focused on improving the quality of life of children with brain injury and developmental disabilities – so he serves the suffering. He also has mentored numerous physicians over the course of his career.”

Gallo’s formal induction occurred in late May 2019, just prior to the medical school graduation at the George Washington University School of Medicine & Health Sciences (GWSMHS) and was strongly supported by Jeffrey S. Akman, Vice President for Health Affairs and Dean of the university’s medical school.

“I’ve been part of Children’s National and in the medical field for almost 18 years. That’s what I’m passionate about: being able to enhance translational research in a clinical environment,” Gallo says. “In a way, this recognition from the medical field is a perfect match for what I do. As Chief Research Officer at Children’s National, I am charged with continuing to expand our research program in one of the top U.S. children’s hospitals. And, as Associate Dean for Child Health Research at GWSMHS, I enhance research collaboration between the two institutions.”

nurse checking boy's blood sugar levels

Improving glycemic control in diabetic children

nurse checking boy's blood sugar levels

A 10-week pilot study at Children’s National Health System integrated weekly caregiver coaching, personalized glucose monitoring and incentives into standard treatment for 25 pediatric patients with type 1 diabetes, lowering A1c by .5%

The life of a type 1 diabetes patient – taking daily insulin shots or wearing an insulin pump, monitoring blood sugar, prioritizing healthful food choices and fitting in daily exercise – can be challenging at age 5 or 15, especially as holidays, field trips and sleepovers can disrupt diabetes care routines, creating challenges with compliance. This is why endocrinologists from Children’s National Health System experimented with using health coaches over a 10-week period to help families navigate care for children with type 1 diabetes.

By assembling a team of diabetes educators, dietitians, social workers, psychologists and health care providers, Fran Cogen, M.D., C.D.E., director of diabetes care at Children’s National, helped pediatric patients with type 1 diabetes manage their glycemic status, or blood-sugar control.

On Saturday, June 8, 2019, Dr. Cogen will share results of the pilot program as poster 1260-P, entitled “A Clinical Care Improvement Pilot Program: Individualized Health Coaching and Use of Incentives for Youth with Type 1 Diabetes and their Caregivers,” at the American Diabetes Association’s 79th Scientific Sessions, which takes place June 7-11 at the Moscone Center in San Francisco.

Dr. Cogen’s study was offered at no cost to caregivers of 179 patients at Children’s National seeking treatment for type 1 diabetes. The pilot program included two components: 1) Weekly phone calls or emails from a health coach to a caregiver with personalized insulin adjustments, based on patient blood sugars submitted through continuous glucose monitoring apps; and 2) Incentives for patients to participate in the program and reach health targets.

Twenty-five participants, ages 4-18, with a mean age of 11.6 and A1c ranges between 8.6 – 10% joined the study. The average A1c was 9.4% at the beginning of the program and dropped by an average of .5% at the end of the trial. Twenty of the 25 participants, 80%, improved A1c levels by .5%. Seventeen participants, 68%, improved A1c levels by more than .5%, while seven participants, 28%, improved A1c levels by more than 1%.

“Chronic disease is like a marathon,” says Dr. Cogen. “You need to have constant reinforcement and coaching to get people to do their best. Sometimes what drives people is to have people on the other end say, ‘Keep it up, you’re doing a good job, keep sending us information so that we can make changes to improve your child’s blood sugar management,’ which gives these new apps and continuous glucose monitoring devices a human touch.”

Instead of waiting three months between appointments to talk about ways a family can make changes to support a child’s insulin control and function, caregivers received feedback from coaches each week. Health coaches benefitted, too: They reported feeling greater empathy for patients, while becoming more engaged in personalizing care plans.

Families who participated received a gift card to a local grocery store, supporting a child’s dietary goals. Children who participated were also entered into an iPad raffle. Improvements in A1c levels generated extra raffle tickets per child, which motivated participants, especially teens.

“These incentives are helpful in order to get kids engaged in their health and in an immediate way,” says Dr. Cogen. “Teenagers aren’t always interested in long-term health outcomes, but they are interested in what’s happening right now. Fluctuating blood sugars can cause depression and problems with learning, while increasing risk for future complications, including eye problems, kidney problems and circulation problems. As health care providers, we know the choices children make today can influence their future health outcomes, which is why we designed this study.”

Moving forward, Dr. Cogen and the endocrinologists at Children’s National would like to study the impact of using this model over several months, especially for high-risk patients, while  asynchronously targeting information to drive behavior change – accommodating the needs of families, while delivering dose-specific recommendations from health care providers.

Dr. Cogen adds, “We’re moving away from office-centric research models and creating interventions where they matter: at home and with families in real time.”

Read more about the study at Healio.com and dLife.

Additional study authors, all of whom work within the division of diabetes and endocrinology at Children’s National, include Lauren Clary, Ph.D., Sue-Ann Airborne, C.D.E., Andrew Dauber, M.D., Meredith Dillon, R.D., L.D.N., C.D.E., Beakel Eshete, B.S.N., R.N., C.D.E., Shaina Hatchell, B.S.N., R.N., Shari Jones, R.N., C.D.E., and Priya Vaidyanathan, M.D.

Robert J. Freishtat working in the lab

Detecting early signs of type 2 diabetes through microRNA

Robert J. Freishtat working in the lab

Obesity is a major risk factor for insulin resistance and type 2 diabetes. Now researchers understand the pathogenesis better among teens with mid-level obesity, thanks to clues released from circulating adipocyte-derived exosomes.

Researchers know that exosomes, tiny nanoparticles released from fat cells, travel through the bloodstream and body, regulating a variety of processes, from growth and development to metabolism. The exosomes are important in lean, healthy individuals in maintaining homeostasis, but when fat gets ‘sick’ – the most common reason for this is too much weight gain – it can change its phenotype, becoming inflammatory, and disrupts how our organs function, from how our skeletal muscle and liver metabolize sugar to how our blood vessels process cholesterol.

Robert J. Freishtat, M.D., M.P.H., the chief of emergency medicine at Children’s National Health System and a professor of precision medicine and genomics at the George Washington University School of Medicine and Health Sciences, and Sheela N. Magge M.D., M.S.C.E., who is now the director of pediatric endocrinology and an associate professor of medicine at the Johns Hopkins School of Medicine, were curious about what this process looked like in teens who fell in the mid-range of obesity.

Obesity is a major risk factor for insulin resistance and type 2 diabetes, but Dr. Freishtat and Dr. Magge wanted to know: Why do some teens with obesity develop type 2 diabetes over others? Why are some teens in this mid-range of obesity metabolically healthy while others have metabolic syndrome? Can fat in obese people become sick and drive disease?

To test this, Dr. Freishtat and Dr. Magge worked with 55 obese adolescents, ages 12 to 17, as part of a study at Children’s National. The participants – 32 obese normoglycemic youth and 23 obese hyperglycemic youth – were similar in age, sex, race, pubertal stage, body mass index and overall fat mass. The distinguishing factor: The hyperglycemic study participants, the teens with elevated blood sugar, differed in where they stored fat. They had extra visceral fat (or adipose tissue) storage, the type of fat that surrounds the liver, pancreas and intestines, a known risk factor for type 2 diabetes.

Dr. Magge and Dr. Freishtat predicted that circulating exosomes from the teens with elevated blood sugar are enriched for microRNAs targeting carbohydrate metabolism.

They used three tests to examine study participants’ metabolism, body composition and circulating exosomes. The first test, an oral glucose tolerance test, measures how efficiently the body metabolizes sugar; the second test is the whole body DXA, or dual-energy x-ray absorptiometry, which analyzes body composition, including lean tissue, fat mass and bone mineral density; and the third test, the serum adipocyte-derived exosomal microRNA assays, is an analysis of circulating fat signals in the bloodstream.

They found that teens with elevated blood sugar and increased visceral fat had different circulating adipocyte-derived exosomes. These study participants’ exosomes were enriched for 14 microRNAs, targeting 1,304 mRNAs and corresponding to 179 canonical pathways – many of which are directly associated with carbohydrate metabolism and visceral fat.

Dr. Magge will present this research, entitled “Changes in Adipocyte-Derived Exosomal MicroRNAs May Play a Role in the Progression from Obese Normoglycemia to Hyperglycemia/Diabetes,” as an oral abstract at the American Diabetes Association’s 79th Scientific Sessions on Saturday, June 8.

Dr. Freishtat envisions having this information will be especially helpful for a patient in a mid-range of obesity. Exosomes primarily consist of small non-coding RNAs. In the current study, the altered RNAs affect P13K/AKT and STAT3 signaling, vital pathways for metabolic and immune function.

“Instead of waiting until someone has the biochemical changes associated with type 2 diabetes, such as hyperglycemia, hyperlipidemia and insulin resistance, we’re hoping physicians will use this information to work with patients earlier,” says Dr. Freishtat. “Through earlier detection, clinicians can intervene when fat shows sign of illness, as opposed to when the overt disease has occurred. This could be intervening with diet and lifestyle for an obese individual or intervening with medication earlier. The goal is to work with children and teens when their system is more plastic and responds better to intervention.”

As this research evolves, Dr. Freishtat continues to look at the intergenerational effects of circulating adipocyte-derived exosomes. Through ongoing NIH-funded research in India, he finds these exosomes, similar in size to lipoproteins, can travel across the placenta, affecting development of the fetus in utero.

“What we’re finding in our initial work is that these exosomes, or ‘sick’ fat, cross the placenta and affect fetal development,” Dr. Freishtat says. “Some of the things that we’re seeing are a change in body composition of the fetus to a more adipose phenotype. Some of our work in cell cultures shows changes in stem cell function and differentiation, but what’s even more interesting to us is that if the fetus is a female sex that means her ovaries are developing while she’s in utero, which means a mother’s adipocyte-derived exosomes could theoretically be affecting her grandchild’s phenotype – influencing the health of three generations.”

While this research is underway, Dr. Freishtat is working with JPOD @ Boston, co-located with the Cambridge Innovation Center in Cambridge, Massachusetts, to develop a test to provide analyses of adipocyte-derived exosomal microRNAs.

“It’s important for families to know that these studies are designed to help researchers and doctors better understand the development of disease in its earliest stages, but there’s no need for patients to wait for the completion of our studies,” says Dr. Freishtat. “Reaching and maintaining a healthy body weight and exercising are important things teens and families can do today to reduce their risk for obesity and diabetes.”

child measuring his stomach

Cognitive function does not predict weight-loss outcome for adolescents

child measuring his stomach

Though young people with intellectual disabilities or cognitive impairment have greater rates of obesity and other comorbidities that impact their health and well-being, primary care providers are often reluctant to discuss or refer these patients for weight-loss surgery due to concerns about their ability to assent to both the surgery and the ongoing diet and lifestyle changes after surgery.

However, a study in Pediatrics authored by psychologists at Children’s National Health System finds that these young people, including those with Down syndrome, have similar weight-loss trajectories to those with typical cognitive function after bariatric surgery. The study is the first to look at post-surgical outcomes for this subgroup of adolescent bariatric surgery patients.

“It’s challenging to ensure that an adolescent who is cognitively impaired understands what it means to undergo a surgical procedure like bariatric surgery, but we do find ways to ensure assent whenever possible, and make sure the patient also has a guardian capable of consent,” says Sarah Hornack, Ph.D., a clinical psychologist at Children’s National and the study’s first author. “A very important determinant of post-surgical success for any young candidate, however, is a support structure to help them with weight-loss surgery requirements. Often, we see that adolescents with lower cognitive function already have a well-established support system in place to assist them with other care needs, that can easily adapt to providing structure and follow through after weight-loss surgery, too.”

The study reviewed outcomes for 63 adolescents ranging in age from 13 to 24 years old with an average body mass index of 51.2, all of whom were part of the bariatric surgery program at Children’s National Health System. The participants were diagnosed with cognitive impairment or intellectual disability via standardized cognitive assessments as part of a preoperative psychological evaluation or through a previous diagnosis. This study adds to the body of research that is helping to create standard criteria for bariatric surgery in adolescents and teenagers.

Children’s National is one of only a few children’s hospitals with accreditation from the Metabolic and Bariatric Surgery Accreditation and Quality Improvement Program of the American College of Surgeons and the American Society for Metabolic and Bariatric Surgery to offer bariatric surgery for adolescents with severe obesity. The extraordinary diversity of the patient population in Washington, D.C., including high rates of young people with obesity, allows the team to collect more comprehensive information about successful interventions across subgroups, including cognitive impairment or developmental disabilities, than nearly every other center in the United States.

“We’re happy to contribute evidence that can help families and care providers make informed health decisions for young people with intellectual disabilities or cognitive impairments. So many families are hoping to make sure that their children, despite disabilities, can be as healthy as possible in the long term,” says Eleanor Mackey, Ph.D., who is also a clinical psychologist at Children’s National and served as the study’s senior author. “Though the sample size is small, it does give credence to the idea that for many adolescents and teenagers, weight loss surgery may be a really viable option regardless of pre-existing conditions such as intellectual ability or cognitive function.”

M and her daughter

Tracing the history of aggrecan gene mutations

M and her daughter

M takes a photo with her daughter in Washington, where they learned they have an ACAN gene mutation that causes short stature.

On Sunday, April 28, 2019 a team of researchers received the 2019 Human Growth Award at the Pediatric Endocrine Society’s Annual Meeting for their abstract, entitled “Clinical Characterization and Trial of Growth Hormone in Patients with Aggrecan Deficiency: 6 Month Data,” and presented this at the PES Presidential Poster Session.

Eirene Alexadrou, M.D., a fellow at Cincinnati Children’s Hospital Medical Center, accepted the award and honorarium, while ongoing research is underway. This study started in 2017, with the objective of characterizing the phenotypic spectrum and response to a standardized regimen of growth hormone in a small cohort of 10 patients and their families.

In 2017, Andrew Dauber, M.D., MMSc., the division chief of endocrinology at Children’s National Health System, led an international consortium of researchers in publishing a manuscript describing the phenotypic spectrum of 103 individuals – 70 adults and 33 children, including 57 females and 46 males – from 20 families with aggrecan gene (ACAN) mutations.

Dr. Dauber and his colleagues have established that short stature and accelerated bone age is common among people with ACAN mutations. In a review of retrospective data, including patients treated with a variety of growth-promoting therapies at varying doses, the research team found that over the first one, two and three years of treatment, the standard deviation scores (SDS) for height increased by .4, .7 and 1, respectively. The current abstract now describes seven children enrolled in a prospective standardized trial of growth hormone therapy. After six months of treatment, the children have increased their height SDS by an average of 0.46.

Additionally, the researchers are performing an in-depth look at the joint effects, including special MRIs of the knees. They found that two of the children had a problem with their knee cartilage called osteochondritis dissecans. They had not yet presented with clinical symptoms. The researchers hope that early intervention with physical therapy can help prevent significant joint disease in the future.

M and her mother and daughter in Cincinnati

M, her daughter, and M’s mother take a photo in Cincinnati, where they are participating in a clinical trial for aggrecan deficiency.

“Providing growth hormone therapy to children with ACAN gene mutations is relatively new in the field of pediatric endocrinology,” notes Dr. Dauber. “Previously, the assumption was that this was just short stature. We’ll continue to diagnose ACAN mutations in a clinical setting and work with families to reduce the risk of complications, such as joint problems or early-onset arthritis, which may co-occur with this gene mutation.”

As an example, Dr. Dauber met an 8-year-old patient several months ago who presented with symptoms of short stature. The patient is healthy, confident and still growing so her mother wasn’t worried about her but she made the appointment to see if there was an underlying cause to her daughter’s short stature. Her family history revealed clues to an ACAN mutation, which was later confirmed through genetic tests. Her mom, M, stands 4’8; her grandmother is 4’9. Her great grandmother was short and her great, great grandfather was 5’1. Short stature and joint problems run in the family. Once M mentioned she had osteochondritis dissecans and a hip replacement, she provided a textbook case study for carrying the ACAN mutation.

After the appointment, M shared the news with her mother about the possibility of having aggrecan deficiency. After taking genetic tests, M, her mother and M’s daughter learned they all have the ACAN mutation, and enrolled in the study that Dr. Dauber is guiding. Suddenly, it all made sense. After examining family photos, they traced the ACAN mutation back through four generations.

They could tell what relatives had an altered copy of the ACAN gene. M had it, while her two sisters did not. M’s mother was an only child, so she didn’t have aunts or uncles to compare her mother’s height to, but M’s grandmother was short, while her grandmother’s brother was average height. Although her mother’s family was from Germany, she learned that there is no specific ancestry associated with this mutation. It happens by chance and is passed down from a single parent to, on average, half of their children, a form of genetic inheritance called autosomal dominant transmission.

Ms great grandmother and grandfather

M’s great grandfather was noticeably shorter than her great grandmother, who was 5’4.

Through further research, M learned that the ACAN gene provides instructions for producing aggrecan protein, which is essential for bone growth, as well as for the stability of cartilage that lines bones and joints, explaining her recurring joint problems.

She also looked into the future, examining potential risk factors for her daughter: joint pain and bone conditions, which could contribute to arthritis, hip dysplasia and back problems.

The diagnosis now makes it easier for M and her daughter to favor bone-building activities that are easy on the joints, like swimming or water aerobics, instead of gymnastics and weight lifting. After having a hip replacement, M was careful to supplement with calcium and vitamin D. Now, she’ll take the same steps to ensure optimal bone health for her daughter. She’ll work with orthopedic specialists as her daughter grows into her pre-teen and adolescent years, carefully monitoring joint pain – altering activities that are tough on the joints, as necessary.

M let her daughter make a decision about growth hormone therapy, which she decided to try. The benefits of the treatment, increased height, carry inconveniences, such as taking daily shots, but they are sticking with it.

“We’re at the tip of the iceberg with research that explores this gene mutation,” says Dr. Dauber. “We’ll continue to study these families, and more, over time to assess growth patterns and  gene expression, which may reveal other mutations associated with short stature or joint problems, and guide future treatment options. It was a coincidence that this family had the ACAN mutation and scheduled an appointment, while we’re conducting this study. Otherwise, they may not have had an answer since this is fairly new research.”

M and her daughter are happy to be part of this study, which they will participate in for the next few years. M’s mother is also glad to participate. She made a different choice, decades ago, to reject hormone treatment when it was offered to her for undiagnosed short stature, but she’s sharing genetic clues, which may influence treatment options for her granddaughter and for her family’s next generation.

The original study, “Clinical Characterization of Patients with Autosomal Dominant Short Stature due to Aggrecan Mutations,” appeared in the Feb. 2017 issue of the Journal of Clinical Endocrinology and Metabolism, and published as an online advance on Nov. 21, 2016.

Thirty-six researchers collaborated on this original paper, which was funded by 16 international health institutes and foundations, including the Eunice Kennedy Shriver National Institute of Child Health and Human Development at the National Institutes of Health, the Swedish Research Council, the Swedish Governmental Agency for Innovation Systems, the Marianne and Marcus Wallenberg Foundation, the Stockholm County Council, the Swedish Society of Medicine, Byggmastare Olle Engkvist’s Foundation, the Sao Paulo Research Foundation, the Spanish Ministry of Education and Science, the Czech Health Research Council and the Ministry of Health, Czech Republic.

DNA Molecule

Using genomics to solve a 20-year case study

DNA Molecule

“The advent of different technologies and techniques over the years allowed pieces of her diagnosis to be made – and then brought all together,” says Andrew Dauber, M.D., MMSc.

After 20 years, a patient’s family received an answer to a decades-long genetic mystery. Their daughter had two rare disorders, Angelman syndrome and P450scc deficiency, which was detected after researchers found out she had uniparental disomy, two copies of chromosome 15 from one parent and none from another.

The research paper, entitled “Adrenal Insufficiency, Sex Reversal and Angelman Syndrome due to Uniparental Disomy Unmasking a Mutation in CYP11A1,” was published on March 22, 2018, and recognized as the best novel insight paper published by Hormone Research in Paediatrics in 2018, announced at the Pediatric Endocrine Society’s Annual Meeting in Baltimore on Saturday, April 27, 2019.

By using a variety of genetic tools, including whole-exome sequencing, microarray analyses and in-vitro modeling for gene splicing, the researchers were able to confirm this patient had uniparental disomy, a recessive genetic condition. They learned that after she received two impaired copies of chromosome 15 from her father, this woman developed a hormonal problem that led to adrenal insufficiency and sex reversal. This explained why she physically presented as a female, despite having testes and a Y-chromosome. It also explained other symptoms, including developmental delays and seizures.

“It’s a unique conglomeration of symptoms, manifested by the combination of these two very rare disorders,” says Andrew Dauber, M.D., MMSc., the division chief of endocrinology at Children’s National Health System and a guiding research author of this study. “The advent of different technologies and techniques over the years allowed pieces of her diagnosis to be made – and then brought together, commencing a 20-year diagnostic odyssey.”

For example, each of the conditions this patient has is known and rare: Angelman syndrome affects about one in 10 to 20,000 people in the U.S. Typical symptoms include those observed in this patient: delayed development, intellectual disability, speech impairment and seizures. Side-chain cleavage disorder, which leads to adrenal disorders and sex reversal, is also very rare. In 2005 the chances of survival with a P450scc defect were slim, but since then more than 28 infants have been diagnosed with this gene deficiency, which is required to convert cholesterol to pregnenolone, a hormone in the adrenal gland.

Dr. Dauber notes the chances of this occurring again are highly unlikely. The odds here are one in a gazillion. In this case, one disorder unmasked another, leaving researchers with new insights into the methodology for unraveling ultra-rare genetic disorders or for more common rare conditions.

“Knowing about the gene that caused the adrenal insufficiency and understanding this etiology won’t change medical care for this patient, but it will change the way researchers think about genetic detective work and about combining different technologies,” says Dr. Dauber. “We know that genetic disorders can be complex presentations of different disorders combined. This patient didn’t have one disorder, but three.”

When asked about the significance of the award, Dr. Dauber notes that, “It’s not that other people haven’t recognized this concept before, but this case is a striking example of it. Different technologies will unveil different types of genetic changes, which is why you have to use the right technology or the right technologies in the right combination to piece together the whole picture.”

Ahlee Kim, M.D., the lead study author and a clinical research fellow at Cincinnati Children’s Hospital Medical Center, will receive the award and the honorarium.

Additional study authors include Masanobu Fujimoto, Ph.D., Vivian Hwa, Ph.D., and Philippe Backeljauw, M.D., from Cincinnati Children’s Hospital.

The research was supported by grant K23HD07335, awarded to Dr. Dauber, from the Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health (NIH). Additional funding included grant 1UL1TR001425 from the NIH’s National Center for Advancing Translational Sciences.

Billie Lou Short and Kurt Newman at Research and Education Week

Research and Education Week honors innovative science

Billie Lou Short and Kurt Newman at Research and Education Week

Billie Lou Short, M.D., received the Ninth Annual Mentorship Award in Clinical Science.

People joke that Billie Lou Short, M.D., chief of Children’s Division of Neonatology, invented extracorporeal membrane oxygenation, known as ECMO for short. While Dr. Short did not invent ECMO, under her leadership Children’s National was the first pediatric hospital to use it. And over decades Children’s staff have perfected its use to save the lives of tiny, vulnerable newborns by temporarily taking over for their struggling hearts and lungs. For two consecutive years, Children’s neonatal intensive care unit has been named the nation’s No. 1 for newborns by U.S. News & World Report. “Despite all of these accomplishments, Dr. Short’s best legacy is what she has done as a mentor to countless trainees, nurses and faculty she’s touched during their careers. She touches every type of clinical staff member who has come through our neonatal intensive care unit,” says An Massaro, M.D., director of residency research.

For these achievements, Dr. Short received the Ninth Annual Mentorship Award in Clinical Science.

Anna Penn, M.D., Ph.D., has provided new insights into the central role that the placental hormone allopregnanolone plays in orderly fetal brain development, and her research team has created novel experimental models that mimic some of the brain injuries often seen in very preterm babies – an essential step that informs future neuroprotective strategies. Dr. Penn, a clinical neonatologist and developmental neuroscientist, “has been a primary adviser for 40 mentees throughout their careers and embodies Children’s core values of Compassion, Commitment and Connection,” says Claire-Marie Vacher, Ph.D.

For these achievements, Dr. Penn was selected to receive the Ninth Annual Mentorship Award in Basic and Translational Science.

The mentorship awards for Drs. Short and Penn were among dozens of honors given in conjunction with “Frontiers in Innovation,” the Ninth Annual Research and Education Week (REW) at Children’s National. In addition to seven keynote lectures, more than 350 posters were submitted from researchers – from high-school students to full-time faculty – about basic and translational science, clinical research, community-based research, education, training and quality improvement; five poster presenters were showcased via Facebook Live events hosted by Children’s Hospital Foundation.

Two faculty members won twice: Vicki Freedenberg, Ph.D., APRN, for research about mindfulness-based stress reduction and Adeline (Wei Li) Koay, MBBS, MSc, for research related to HIV. So many women at every stage of their research careers took to the stage to accept honors that Naomi L.C. Luban, M.D., Vice Chair of Academic Affairs, quipped that “this day is power to women.”

Here are the 2019 REW award winners:

2019 Elda Y. Arce Teaching Scholars Award
Barbara Jantausch, M.D.
Lowell Frank, M.D.

Suzanne Feetham, Ph.D., FAA, Nursing Research Support Award
Vicki Freedenberg, Ph.D., APRN, for “Psychosocial and biological effects of mindfulness-based stress reduction intervention in adolescents with CHD/CIEDs: a randomized control trial”
Renee’ Roberts Turner for “Peak and nadir experiences of mid-level nurse leaders”

2019-2020 Global Health Initiative Exploration in Global Health Awards
Nathalie Quion, M.D., for “Latino youth and families need assessment,” conducted in Washington
Sonia Voleti for “Handheld ultrasound machine task shifting,” conducted in Micronesia
Tania Ahluwalia, M.D., for “Simulation curriculum for emergency medicine,” conducted in India
Yvonne Yui for “Designated resuscitation teams in NICUs,” conducted in Ghana
Xiaoyan Song, Ph.D., MBBS, MSc, “Prevention of hospital-onset infections in PICUs,” conducted in China

Ninth Annual Research and Education Week Poster Session Awards

Basic and Translational Science
Faculty: Adeline (Wei Li) Koay, MBBS, MSc, for “Differences in the gut microbiome of HIV-infected versus HIV-exposed, uninfected infants”
Faculty: Hayk Barseghyan, Ph.D., for “Composite de novo Armenian human genome assembly and haplotyping via optical mapping and ultra-long read sequencing”
Staff: Damon K. McCullough, BS, for “Brain slicer: 3D-printed tissue processing tool for pediatric neuroscience research”
Staff: Antonio R. Porras, Ph.D., for “Integrated deep-learning method for genetic syndrome screening using facial photographs”
Post docs/fellows/residents: Lung Lau, M.D., for “A novel, sprayable and bio-absorbable sealant for wound dressings”
Post docs/fellows/residents: Kelsey F. Sugrue, Ph.D., for “HECTD1 is required for growth of the myocardium secondary to placental insufficiency”
Graduate students: Erin R. Bonner, BA, for “Comprehensive mutation profiling of pediatric diffuse midline gliomas using liquid biopsy”
High school/undergraduate students: Ali Sarhan for “Parental somato-gonadal mosaic genetic variants are a source of recurrent risk for de novo disorders and parental health concerns: a systematic review of the literature and meta-analysis”

Clinical Research
Faculty: Amy Hont, M.D., for “Ex vivo expanded multi-tumor antigen specific T-cells for the treatment of solid tumors”
Faculty: Lauren McLaughlin, M.D., for “EBV/LMP-specific T-cells maintain remissions of T- and B-cell EBV lymphomas after allogeneic bone marrow transplantation”

Staff: Iman A. Abdikarim, BA, for “Timing of allergenic food introduction among African American and Caucasian children with food allergy in the FORWARD study”
Staff: Gelina M. Sani, BS, for “Quantifying hematopoietic stem cells towards in utero gene therapy for treatment of sickle cell disease in fetal cord blood”
Post docs/fellows/residents: Amy H. Jones, M.D., for “To trach or not trach: exploration of parental conflict, regret and impacts on quality of life in tracheostomy decision-making”
Graduate students: Alyssa Dewyer, BS, for “Telemedicine support of cardiac care in Northern Uganda: leveraging hand-held echocardiography and task-shifting”
Graduate students: Natalie Pudalov, BA, “Cortical thickness asymmetries in MRI-abnormal pediatric epilepsy patients: a potential metric for surgery outcome”
High school/undergraduate students: Kia Yoshinaga for “Time to rhythm detection during pediatric cardiac arrest in a pediatric emergency department”

Community-Based Research
Faculty: Adeline (Wei Li) Koay, MBBS, MSc, for “Recent trends in the prevention of mother-to-child transmission (PMTCT) of HIV in the Washington, D.C., metropolitan area”
Staff: Gia M. Badolato, MPH, for “STI screening in an urban ED based on chief complaint”
Post docs/fellows/residents: Christina P. Ho, M.D., for “Pediatric urinary tract infection resistance patterns in the Washington, D.C., metropolitan area”
Graduate students: Noushine Sadeghi, BS, “Racial/ethnic disparities in receipt of sexual health services among adolescent females”

Education, Training and Program Development
Faculty: Cara Lichtenstein, M.D., MPH, for “Using a community bus trip to increase knowledge of health disparities”
Staff: Iana Y. Clarence, MPH, for “TEACHing residents to address child poverty: an innovative multimodal curriculum”
Post docs/fellows/residents: Johanna Kaufman, M.D., for “Inpatient consultation in pediatrics: a learning tool to improve communication”
High school/undergraduate students: Brett E. Pearson for “Analysis of unanticipated problems in CNMC human subjects research studies and implications for process improvement”

Quality and Performance Improvement
Faculty: Vicki Freedenberg, Ph.D., APRN, for “Implementing a mindfulness-based stress reduction curriculum in a congenital heart disease program”
Staff: Caleb Griffith, MPH, for “Assessing the sustainability of point-of-care HIV screening of adolescents in pediatric emergency departments”
Post docs/fellows/residents: Rebecca S. Zee, M.D., Ph.D., for “Implementation of the Accelerated Care of Torsion (ACT) pathway: a quality improvement initiative for testicular torsion”
Graduate students: Alysia Wiener, BS, for “Latency period in image-guided needle bone biopsy in children: a single center experience”

View images from the REW2019 award ceremony.

Beth Tarini

Getting to know SPR’s future President, Beth Tarini, M.D., MS

Beth Tarini

Quick. Name four pillar pediatric organizations on the vanguard of advancing pediatric research.

Most researchers and clinicians can rattle off the names of the Academic Pediatric Association, the American Academy of Pediatrics and the American Pediatric Society. But that fourth one, the Society for Pediatric Research (SPR), is a little trickier. While many know SPR, a lot of research-clinicians simply do not.

Over the next few years, Beth A. Tarini, M.D., MS, will make it her personal mission to ensure that more pediatric researchers get to know SPR and are so excited about the organization that they become active members. In May 2019 Dr. Tarini becomes Vice President of the society that aims to stitch together an international network of interdisciplinary researchers to improve kids’ health. Four-year SPR leadership terms begin with Vice President before transitioning to President-Elect, President and Past-President, each for one year.

Dr. Tarini says she looks forward to working with other SPR leaders to find ways to build more productive, collaborative professional networks among faculty, especially emerging junior faculty. “Facilitating ways to network for research and professional reasons across pediatric research is vital – albeit easier said than done. I have been told I’m a connector, so I hope to leverage that skill in this new role,” says Dr. Tarini, associate director for Children’s Center for Translational Research.

“I’m delighted that Dr. Tarini was elected to this leadership position, and I am impressed by her vision of improving SPR’s outreach efforts,” says Mark Batshaw, M.D., Executive Vice President, Chief Academic Officer and Physician-in-Chief at Children’s National. “Her goal of engaging potential members in networking through a variety of ways – face-to-face as well as leveraging digital platforms like Twitter, Facebook and LinkedIn – and her focus on engaging junior faculty will help strengthen SPR membership in the near term and long term.”

Dr. Tarini adds: “Success to me would be leaving after four years with more faculty – especially junior faculty – approaching membership in SPR with the knowledge and enthusiasm that they bring to membership in other pediatric societies.”

SPR requires that its members not simply conduct research, but move the needle in their chosen discipline. In her research, Dr. Tarini has focused on ensuring that population-based newborn screening programs function efficiently and effectively with fewer hiccups at any place along the process.

Thanks to a heel stick to draw blood, an oxygen measurement, and a hearing test, U.S. babies are screened for select inherited health conditions, expediting treatment for infants and reducing the chances they’ll experience long-term health consequences.

“The complexity of this program that is able to test nearly all 4 million babies in the U.S. each year is nothing short of astounding. You have to know the child is born – anywhere in the state – and then between 24 and 48 hours of birth you have to do testing onsite, obtain a specific type of blood sample, send the blood sample to an off-site lab quickly, test the sample, find the child if the test is out of range, get the child evaluated and tested for the condition, then send them for treatment. Given the time pressures as well as the coordination of numerous people and organizations, the fact that this happens routinely is amazing. And like any complex process, there is always room for improvement,” she says.

Dr. Tarini’s research efforts have focused on those process improvements.

As just one example, the Advisory Committee on Heritable Disorders in Newborns and Children, a federal advisory committee on which she serves, was discussing how to eliminate delays in specimen processing to provide speedier results to families. One possible solution floated was to open labs all seven days, rather than just five days a week. Dr. Tarini advocated for partnering with health care engineers who could help model ways to make the specimen transport process more efficient, just like airlines and mail delivery services. A more efficient and effective solution was to match the specimen pick-up and delivery times more closely with the lab’s operational times – which maximizes lab resources and shortens wait times for parents.

Conceptual modeling comes so easily for her that she often leaps out of her seat mid-sentence, underscoring a point by jotting thoughts on a white board, doing it so often that her pens have run dry.

“It’s like a bus schedule: You want to find a bus that not only takes you to your destination but gets you there on time,” she says.

Dr. Tarini’s current observational study looks for opportunities to improve how parents in Minnesota and Iowa are given out-of-range newborn screening test results – especially false positives – and how that experience might shake their confidence in their child’s health as well as heighten their own stress level.

“After a false positive test result, are there parents who walk away from newborn screening with lingering stress about their child’s health? Can we predict who those parents might be and help them?” she asks.

Among the challenges is the newborn screening occurs so quickly after delivery that some emotionally and physically exhausted parents may not remember it was done. Then they get a call from the state with ominous results. Another challenge is standardizing communication approaches across dozens of birthing centers and hospitals.

“We know parents are concerned after receiving a false positive result, and some worry their infant remains vulnerable,” she says. “Can we change how we communicate – not just what we say, but how we say it – to alleviate those concerns?”

Elizabeth Estrada

A new type 2 diabetes program leader in a time of change

Elizabeth Estrada

Elizabeth Estrada, M.D., was struck by the increasing number of children with obesity and type 2 diabetes when she finished her fellowship in 1996. That fascination, along with increasingly alarming statistics about the rise in type 2 diabetes in youth over the past 20 years, steered her to a career focused on pediatric diabetes and metabolism that eventually led her to Children’s National Health System, where she will become the director of the type 2 diabetes program this spring.

Coming most recently from the University of North Carolina, where she served as Chief of the Division of Pediatric Endocrinology and Diabetes, Dr. Estrada will work closely with Children’s National Endocrinology Division Chief Andrew Dauber, M.D., and Diabetes Services Director Fran Cogen, M.D., to create a multidisciplinary type 2 diabetes care structure that she has seen success with throughout her career.

“Children with type 2 diabetes have very different needs than children with type 1,” Dr. Estrada explains. “They need more nutrition, more social work, and psychological support.”

Children’s National presents Dr. Estrada with a unique opportunity at a time when the field of care and treatment options for children with type 2 diabetes is expanding. She aims to develop a comprehensive, multidisciplinary program integrating the established Children’s National obesity program with the nationally-ranked endocrinology and diabetes team, which has a strong foundation in providing psychological support to families, which is part of a larger toolkit at Children’s National to help families manage a diabetes diagnosis.

The obesity program at Children’s National emphasizes personalized clinical care and education to prevent and reduce the prevalence of obesity, incorporating multiple aspects of medical and surgical care for obese children and adolescents through the Improving Diet, Energy and Activity for Life (IDEAL) clinic and the bariatric surgery program. The IDEAL clinic helps children with dietary counseling, health education classes, physical activity and weight-management techniques, as well as psychosocial support to help children reach and maintain a healthy weight.

One of the first children’s hospitals to be accredited by the Metabolic and Bariatric Surgery Accreditation and Quality Improvement Program (MBSAQIP®) and the only hospital in the area to be accredited to perform bariatric surgery on adolescents, the bariatric surgery program at Children’s National is directed by Evan Nadler, M.D., who has been safely performing surgeries for nearly 15 years.

The American Diabetes Association (ADA) recently published updates to the “Standards of Medical Care in Diabetes,” which provides research-based practice recommendations for children and adolescents with type 2 diabetes, including metabolic surgery as a treatment recommendation, stating:

The results of weight-loss and lifestyle interventions for obesity in children and adolescents have been disappointing, and no effective and safe pharmacologic intervention is available or approved by the U.S. Food and Drug Administration in youth. Over the last decade, weight-loss surgery has been increasingly performed in adolescents with obesity. Small retrospective analyses and a recent prospective multicenter nonrandomized study suggest that bariatric or metabolic surgery may have benefits in obese adolescents with type 2 diabetes similar to those observed in adults.

The recommendations further stipulate that metabolic surgery should only be considered under certain circumstances, including for those adolescents with T2D who are markedly obsess (BMI > 35 kg/m2) and who have uncontrolled glycemia and/or serious comorbidities despite lifestyle and pharmacologic intervention, and it should only be performed by an experienced surgeon working as part of a well-organized and engaged multidisciplinary team.

Working closely with Dr. Nadler and the obesity team will be a hallmark of Dr. Estrada’s role.

Her goal is to organize a clinic that not only provides clinical care and surgical options, but also includes research and provides medical education and training to medical students, residents and fellows. Dr. Estrada’s own research has focused on insulin resistance, one of the underlying problems in type 2 diabetes.

“There are several clinical trials currently exploring the efficacy and safety of medications for type 2 diabetes in children, something that is incredibly important since Metformin and insulin are the only approved options at this point,” Estrada says. “It is imperative that we bring research to Children’s National as a complement to the existing programs and to continue providing the highest level of care for these patients.”

The Division of Diabetes and Endocrinology works with the National Institutes of Health, conducts independent research and received support from the Washington Nationals Dream Foundation for its diabetes program, the largest pediatric diabetes program in the region, which provides community education and counsels 1,800 pediatric patients each year.

Test tube that says IGF-1 test

A new algorithm: Using genomics and EHR to detect severe growth disorders

Test tube that says IGF-1 test

Andrew Dauber, M.D., MMSc., a pediatric endocrinologist and the chief of endocrinology at Children’s National, guided research presented at ENDO 2019, the Endocrine Society’s annual meeting, enabling clinicians and researchers to understand the genetic underpinnings of certain pediatric growth disorders, while using electronic health record (EHR) algorithms to screen for presenting symptoms in the exam room. In some cases, this prompts further genetic testing and shortens the diagnostic odyssey for pediatric growth disorders – such as Turner syndrome.

Here is a summary of the research findings, delivered as two oral abstracts and a poster session.

ABSTRACT 1: Presented on Saturday, March 23, at 12:30 p.m. CST

Healthy childhood growth cohort provides insight into PAPPA2 and IGF-1 relationship, revealing a new level of complexity to the biology of growth with implications for the study and treatment of severe growth disorders

Program: Growth, puberty, and insulin action and resistance

Session OR07-5: A Cross-Sectional Study of IGF-I Bioavailability through Childhood: Associations with PAPP-A2 and Anthropometric Data

Background: Insulin-like growth factor 1 (IGF-1) is a hormone essential for human growth and is often bound to IGFBP-3, an IGF binding protein. Pregnancy Associated Plasma Protein-A2 (PAPP-A2) cleaves intact IGFBP-3, freeing IGF-1 to support normal growth functions. This is the first study, led by Dr. Andrew Dauber with collaborators from Cincinnati Children’s Hospital Medical Center, to track PAPP-A2 and intact IGFBP-3 concentrations throughout childhood. The research team studied 838 healthy children, ages 3-18, in the Cincinnati Genomic Control Cohort, to better understand patterns of growth and development by examining the relationship between PAPPA2 and IGF-1 bioavailability.

Study results: Free IGF-1 increased with age. PAPP-A2, a positive modulator of IGF-1 bioavailability, decreased with age, which surprised the researchers, and is not positively associated with absolute levels of free IGF-1. However, higher levels of PAPP-A2 cleave IGFBP-3 resulting in lower levels of intact IGFBP-3, and consequently, increasing the percentage of free to total IGF-1. This demonstrates that PAPP-A2 is a key regulator of IGF-1 bioavailability on a population-wide scale.

Impact: This research may help endocrinologists create unique, targeted treatment for children with PAPPA2 mutations and could help stratify patients with potential risk factors, such as IGF-1 resistance due to increased binding of IGF-1, associated with severe growth and height disorders. See adjoining study below.

Watch: Video interview with Dr. Dauber

ABSTRACT 2: Presented on Saturday, March 23, at 12:45 p.m. CST

Electronic health records can alert physicians to patients who could benefit from genetic testing to identify severe growth disorders

Program: Growth, puberty, and insulin action and resistance

Session OR07-6: Integrating Targeted Bioinformatic Searches of the Electronic Health Records and Genomic Testing Identifies a Molecular Diagnosis in Three Patients with Undiagnosed Short Stature

Background: Despite referrals to pediatric endocrinologists and extensive hormonal analysis, children with short stature due to a genetic cause, may not receive a diagnosis. Electronic health records may help identify patients – based on associated phenotypes and clinical parameters – who could benefit from genetic testing.

Study results: Researchers from three children’s hospitals – Boston Children’s Hospital, Children’s Hospital of Philadelphia and Cincinnati Children’s Hospital Medical Center – gathered data, starting small, with a known variable, or phenotype, associated with severe growth disorders: insulin-like growth factor 1 (IGF-1) resistance. A targeted bioinformatics search of electronic health records led the team to identify 39 eligible patients out of 234 candidates who met the criteria for a possible genetic-linked growth disorder. Participants were included if their height fell below two standard deviations for age and sex and if their IGF-1 levels rose above the 90th percentile. Patients who had a chronic illness, an underlying genetic condition or precocious puberty were excluded. Whole-exome sequencing (WES) was performed on DNA extracted from willing participants, including 10 patients and their immediate family members. The research team identified new genetic causes in three out of 10 patients with severe growth disorders, who were previously missed as having a genetic-linked growth disorder.

Note: Two patients had two novel IGF1R gene variants; a third had a novel CHD2 variant (p. Val540Phe). The two patients with IGF1R variants had a maternally inherited single amino acid deletion (p.Thr28del) and a novel missense variant (p. Val1013Phe).

Impact: Similar EHR algorithms can be replicated to identify pediatric patients at risk for or thought to have other genetic disorders, while expanding genetic research and improving patient care.

Watch: Video interview with Dr. Dauber

POSTER: Presented on Monday, March 25, at 1 p.m. CST

Electronic health record alerts could help detect Turner syndrome, shorten diagnostic odyssey for girls born with a missing or partially-deleted X chromosome

Program: Session P54. Pediatric puberty, ovarian function, transgender medicine and obesity

Poster Board #MON-249: Algorithm-Driven Electronic Health Record Notification Enhances the Detection of Turner Syndrome

Background: Turner syndrome (TS) results from a complete or partial loss of the second X chromosome and affects about one in every 2,500 female births. TS is common in females with unexplained short stature, but the diagnosis is often not made until late childhood (8-9 years), leading to delays in treatment and screening for comorbidities, such as heart conditions, chronic ear infections, vision problems and challenges with non-verbal learning. Using electronic health record (EHR) alarms can help clinicians screen for and diagnose TS patients earlier in life.

Study results: Researchers from Cincinnati Children’s Hospital Medical Center searched EHRs for female patients with idiopathic short stature who met the team’s selection criteria: Their height fell below two standard deviations from the mean for age as well as one standard deviation below the mid-parental height, had a BMI greater than 5 percent and did not have a chronic illness. The search produced 189 patients who met the diagnostic criteria, 72 of whom had not received prior genetic testing. Out of genetic samples available, 37 were compatible for a microarray analysis – which helped the team identify two cases of TS and a third chromosomal abnormality, all of which were missed by routine clinical evaluation.

Impact: DNA samples may not be available for all patients, but clinicians and researchers can identify and integrate tools into EHR’s – creating their own algorithms. An example includes setting up alerts for specific growth parameters, which helps identify and screen patients for TS.

The abstracts Dr. Dauber and his team discuss at ENDO 2019 support ongoing research, including a partnership among four leading children’s hospitals – Children’s National Health System, Boston Children’s Hospital, Children’s Hospital of Philadelphia and Cincinnati Children’s Medical Center – funded by an R01 grant to study how electronic health records can detect and identify novel markers of severe growth disorders.

The researchers hope their findings will also identify and help screen for comorbidities associated with atypical growth patterns, supporting multidisciplinary treatment throughout a child’s life. The study started in August 2018 and includes three sets of unique diagnostic criteria and will analyze WES from dozens of patients over five years.

Read more about Dr. Dauber’s research presented at ENDO 2019 in Endocrine Today and watch his video commentary with Medscape.

Dr. Kurt Newman in front of the capitol building

Kurt Newman, M.D., shares journey as a pediatric surgeon in TEDx Talk

Kurt Newman, M.D., president and chief executive officer of Children’s National, shares his poignant journey as a pediatric surgeon, offering a new perspective for approaching the most chronic and debilitating health conditions. In this independently-organized TEDx event, Dr. Newman also shares his passion for Children’s National and the need to increase pediatric innovations in medicine.

Stat Madness 2019

Vote for Children’s National in STAT Madness

Stat Madness 2019

Children’s National Health System has been selected to compete in STAT Madness for the second consecutive year. Our entry for the bracket-style competition is “Sensitive liquid biopsy platform to detect tumor-released mutated DNA using patient blood and CSF,” a new technique that will allow kids to get better treatment for an aggressive type of pediatric brain tumor.

In 2018, Children’s first-ever STAT Madness entry advanced through five brackets in the national competition and, in the championship round, finished second. That innovation, which enables more timely diagnoses of rare diseases and common genetic disorders, helping to improve kids’ health outcomes around the world, also was among four “Editor’s Pick” finalists, entries that spanned a diverse range of scientific disciplines.

“Children’s National researchers collaboratively work across divisions and departments to ensure that innovations discovered in our laboratories reach clinicians in order to improve patient care,” says Mark Batshaw, M.D., Children’s Executive Vice President, Chief Academic Officer and Physician-in-Chief. “It’s gratifying that Children’s multidisciplinary approach to improving the lives of children with brain tumors has been included in this year’s STAT Madness competition.”

Pediatric brain cancers are the leading cause of cancer-related death in children younger than 14. Children with tumors in their midline brain structures have the worst outcomes, and kids diagnosed with diffuse midline gliomas, including diffuse intrinsic pontine glioma, have a median survival of just 12 months.

“We heard from our clinician colleagues that many kids were coming in and their magnetic resonance imaging (MRI) suggested a particular type of tumor. But it was always problematic to identify the tumor’s molecular subtype,” says Javad Nazarian, Ph.D., MSC, a principal investigator in Children’s Center for Genetic Medicine Research. “Our colleagues wanted a more accurate measure than MRI to find the molecular subtype. That raised the question of whether we could actually look at their blood to determine the tumor subtype.”

Children’s liquid biopsy, which remains at the research phase, starts with a simple blood draw using the same type of needle as is used when people donate blood. When patients with brain tumors provide blood for other laboratory testing, a portion of it is used for the DNA detective work. Just as a criminal leaves behind fingerprints, tumors shed telltale clues in the blood. The Children’s team searches for the histone 3.3K27M (H3K27M), a mutation associated with worse clinical outcomes.

“With liquid biopsy, we were able to detect a few copies of tumor DNA that were hiding behind a million copies of healthy DNA,” Nazarian says. “The blood draw and liquid biopsy complement the MRI. The MRI gives the brain tumor’s ZIP code. Liquid biopsy gives you the demographics within that ZIP code.”

Working with collaborators around the nation, Children’s National continues to refine the technology to improve its accuracy. The multi-institutional team published findings online Oct. 15, 2018, in Clinical Cancer Research.

Even though this research technique is in its infancy, the rapid, cheap and sensitive technology already is being used by people around the globe.

“People around the world are sending blood to us, looking for this particular mutation, H3K27M, ” says Lindsay B. Kilburn, M.D., a Children’s neuro–oncologist, principal investigator at Children’s National for the Pacific Pediatric Neuro-Oncology Consortium, and study co-author. “In many countries or centers, children do not have access to teams experienced in taking a biopsy of tumors in the brainstem, they can perform a simple blood draw and have that blood processed and analyzed by us. In only a few days, we can provide important molecular information on the tumor subtype previously only available to patients that had undergone a tumor biopsy.”

“With that DNA finding, physicians can make more educated therapeutic decisions, including prescribing medications that could not have been given previously,” Nazarian adds.

The STAT Madness round of 64 brackets opened March 4, 2019, and the championship round voting concludes April 5 at 5 p.m. (EST).

In addition to Nazarian and Dr. Kilburn, study co-authors include Eshini Panditharatna, Madhuri Kambhampati, Heather Gordish-Dressman, Ph.D., Suresh N. Magge, M.D., John S. Myseros, M.D., Eugene I. Hwang, M.D. and Roger J. Packer, M.D., all of Children’s National; Mariam S. Aboian, Nalin Gupta, Soonmee Cha, Michael Prados and Co-Senior Author Sabine Mueller, all of University of California, San Francisco; Cassie Kline, UCSF Benioff Children’s Hospital; John R. Crawford, UC San Diego; Katherine E. Warren, National Cancer Institute; Winnie S. Liang and Michael E. Berens, Translational Genomics Research Institute; and Adam C. Resnick, Children’s Hospital of Philadelphia.

Financial support for the research described in the report was provided by the V Foundation for Cancer Research, Goldwin Foundation, Pediatric Brain Tumor Foundation, Smashing Walnuts Foundation, The Gabriella Miller Kids First Data Resource Center, Zickler Family Foundation, Clinical and Translational Science Institute at Children’s National under award 5UL1TR001876-03, Piedmont Community Foundation, Musella Foundation for Brain Tumor Research, Matthew Larson Foundation, The Lilabean Foundation for Pediatric Brain Cancer Research, The Childhood Brain Tumor Foundation, the National Institutes of Health and American Society of Neuroradiology.

DNA

International collaboration discovers new cause for dwarfism

DNA

An international collaboration resulted in the identification of a new cause of dwarfism: mutations in a gene known as DNMT3A.

Beyond diabetes, short stature is the most common reason for children in the U.S. to visit an endocrinologist. For the vast majority of children with short stature, the cause remains unknown – even though many of these conditions stem from an as-yet unidentified genetic cause, says Andrew Dauber, M.D., M.M.Sc., division chief of Endocrinology at Children’s National Health System.

“Parents are concerned about why their child isn’t growing and if there are other complications or health problems they’ll need to watch out for,” he says. “Without a diagnosis, it’s very hard to answer those questions.”

Dauber’s research focuses on using cutting-edge genetic techniques to unravel the minute differences in DNA that limit growth. This research recently led him and his colleagues to identify a new cause of dwarfism: mutations in a gene known as DNMT3A. The discovery, which the team published in the January 2019 Nature Genetics, didn’t happen in isolation – it required a rich collaboration of labs spread across the world in Scotland, Spain, France and New Zealand, in addition to Dauber’s lab in the U.S.

The journey that brought Dauber into this group effort got its start with a young patient in Spain. The boy, then four years old, was at less than 0.1 percentile on the growth curve for height with a very small head circumference and severe developmental delays. This condition, known as microcephalic dwarfism, is incredibly rare and could stem from one of several different genetic causes. But his doctors didn’t know the reason for this child’s specific syndrome.

To better understand this condition, Dauber used a technique known as whole exome sequencing, a method that sequences all the protein-coding regions in an individual’s entire genome. He found a mutation in DNMT3A – a change known as a de novo missense mutation, meaning that the mutation happened in a single letter of the boy’s genetic code in a way that hadn’t been inherited from his parents. But although this mutation was clear, its meaning wasn’t. The only clue that Dauber had as to DNMT3A’s function was that he’d read about overgrowth syndromes in which the function of this gene is lost, leading to large individuals with large heads, the exact opposite of this patient’s condition.

To gather more information, Dauber reached out to Andrew Jackson, Ph.D., a researcher who studies human genes for growth at the University of Edinburgh in Scotland. Coincidentally, Jackson had already started studying this gene after two patients with a shared mutation in a neighboring letter in the genetic code – who also had short stature and other related problems – were referred to him.

Dauber and his colleagues sent the results from their genetic analysis back across the Atlantic to Jackson’s Edinburgh lab, and the doctors from Spain sent more information to Jackson’s lab, including the patient’s clinical information, blood samples and skin biopsy samples. Then the whole team of collaborators from around the globe set to work to discover the processes influencing short stature in each of these three patients.

Their results showed that these mutations appear to cause a gain of function in DNMT3A. This gene codes for a type of enzyme known as a methyltransferase, which places methyl groups on other genes and on the protein spools called histones that DNA wraps around. Each of these functions changes how cells read the instructions encoded in DNA. While the mutations that cause the overgrowth syndromes appear to allow stem cells to keep dividing long past when they should taper off and differentiate into different cell types – both normal processes in development – the gain of function that appears to be happening in these three patients prompts the opposite situation: Stem cells that should be dividing for a long time during development stop dividing and differentiate earlier, leading to smaller individuals with far fewer cells overall.

The researchers confirmed their findings by inserting one of the gain-of-function human DNMT3A mutations into a mouse, leading to short animals with small heads.

Eventually, says Dauber, these findings could help lead to new treatments for this and other types of dwarfism that act on these genetic pathways and steer them toward normal growth. These and other scientific discoveries hinge on the type of international collaboration that he and his colleagues engaged in here, he adds – particularly for the types of rare genetic syndromes that affect the patients that he and his colleagues study. With only a handful of individuals carrying mutations in certain genes, it’s increasingly necessary to combine the power of many labs to better understand the effects of these differences and how doctors might eventually intervene.

“The expertise for all aspects of any single research project is rarely centered in one institution, one city, or even one country,” Dauber says. “Often, you really need to reach out to people with different areas of expertise around the world to make these types of new discoveries that can have pivotal impacts on human health.”

little girl being examined by doctor

First Washington-based Turner syndrome clinic opens Jan. 28

little girl being examined by doctor

Endocrinologists at Children’s National work with a team of cardiologists, gynecologists, geneticists, psychologists and other clinicians to provide comprehensive and personalized care for girls with Turner syndrome.

Starting Monday, Jan. 28, 2018 girls with Turner syndrome will be able to receive comprehensive and personalized treatment at Children’s National Health System for the rare chromosomal condition that affects about one in 2,500 female births.

Many girls with Turner syndrome often work with a pediatric endocrinologist to address poor growth and delayed puberty, which may be treated with human growth hormone and estrogen replacement therapy. They may also need specialty care to screen for and treat heart defects, frequent ear infections, hearing loss, vision problems and challenges with non-verbal learning.

Roopa Kanakatti Shankar, M.D., M.S., a pediatric endocrinologist at Children’s National, aims to consolidate this treatment with a comprehensive Turner syndrome clinic.

“We’re creating a place that girls with Turner syndrome can come to receive specialized and personalized treatment, while feeling supported,” says Dr. Shankar.

Patients can now schedule visits and meet with multiple specialists in one clinic location:

The multispecialty referral team includes neuropsychologists, otolaryngologists (ear, nose and throat doctors), orthopedics, urology and dentistry to address unique medical needs. Families can also schedule appointments with audiology and get labs and other studies on the same day.

As girls with Turner syndrome age, they are at increased risk for diabetes, an underactive thyroid and osteoporosis, which is one reason Dr. Shankar wants to educate and increase awareness early on.

“There is something special about girls with Turner syndrome,” says Dr. Shankar. “They are very inspiring and endearing to work with,” she adds, reflecting on her past research and future goals with the clinic. “Their perseverance in the face of challenges is one of the things that inspires me to work in this field.”

The Turner syndrome clinic at Children’s National meets the criteria for a level 2 clinic designation by the Turner Syndrome Global Alliance by providing coordinated medical care, same-day visits with multiple specialists and connecting patients with advocacy groups.

Within the next two years, Dr. Shankar looks forward to meeting level 4 criteria, the designation for a regional resource center, by adding multi-institutional research partners, mentoring programs and organizing a patient-family advisory council.

“As we start out, we aim to provide excellent clinical care and create a database while forming these partnerships, and over time, we hope this information will influence future research studies and foster a greater depth of tailored care,” says Dr. Shankar. “Our ultimate goal is to treat, support and empower girls with Turner syndrome to achieve their full potential.”

To learn more about the Turner syndrome clinic, available on the fourth Monday of every month, visit ChildrensNational.org/endocrinology.