Tag Archive for: rare disease

Marius George Linguraru giving a lecture on AI

Artificial – and accelerated – intelligence: endless applications to expand health equity

In the complex world of pediatric diseases, researchers need access to data to develop clinical trials and the participation of vulnerable patients to develop new devices and therapies. Both are in short supply, given that most children are born healthy, and most severe pediatric diseases are rare.

That creates a dilemma: how do researchers build a foundation to advance new treatments? Enter artificial intelligence (AI).

“AI is the equalizer: accelerated intelligence for sick kids. No other advance on the horizon holds more promise for improving equity and access to pediatric healthcare when diseases are rare and resources are limited,” says Marius George Linguraru, D.Phil., M.A., M.Sc., the Connor Family Professor in Research and Innovation and principal investigator in the Sheikh Zayed Institute for Pediatric Surgical Innovation (SZI). “AI will shrink the distance between patient and provider, allowing our physicians and scientists to provide targeted healthcare for children more efficiently. The possibilities are endless.”

Why we’re excited

By pioneering AI innovation programs at Children’s National Hospital, Dr. Linguraru and the AI experts he leads are ensuring patients and families benefit from a coming wave of technological advances. The team is teaching AI to interpret complex data that could otherwise overwhelm clinicians. Their work will create systems to identify at-risk patients, forecast disease and treatment patterns, and support complex clinical decisions to optimize patient care and hospital resources. Already, the AI team at SZI has developed data-driven tools touching nearly every corner of the hospital:

  • AI for rheumatic heart disease (RHD): In partnership with Children’s National cardiology leaders, including Craig Sable, M.D., the Uganda Heart Institute and Cincinnati Children’s Hospital, the AI team has developed an algorithm that can use low-cost, portable ultrasound imaging to detect RHD in children and young adults, a disease that takes nearly 400,000 lives annually in limited-resource countries. Early testing shows the AI platform has the same accuracy as a cardiologist in detecting RHD, paving the way for earlier treatment with life-saving antibiotics. This year, Children’s National physicians will be in Uganda, screening 200,000 children with local cardiology experts and AI technology.
  • Newborn screening for genetic conditions with mGene: Working with Rare Disease Institute clinicians and Chief of Genetics and Metabolism Debra Regier, M.D., the AI team has built technology to detect rare genetic disorders, using an algorithm and a smartphone camera to identify subtle changes in facial features. Tested on patients from over 30 countries and published in The Lancet Digital Health, the application helps screen children for advanced care when a geneticist may not be within reach. With funding from the National Institutes of Health, Children’s National and its research partners are piloting a newborn screening program in the Democratic Republic of the Congo.
  • Pediatric brain tumors: To improve and personalize the treatment decisions for children with brain tumors, Dr. Linguraru’s team is working with Brain Tumor Institute Director Roger Packer, M.D., the Gilbert Family Distinguished Professor of Neurofibromatosis, on algorithms that can characterize and measure brain tumors with unprecedented precision. The team recently won the International Pediatric Brain Tumor Segmentation Challenge, distinguishing the Children’s National algorithm as among the best in the world.
  • Ultra-low field magnetic resonance imaging (MRI): With a grant from the Bill & Melinda Gates Foundation, the AI team is working alongside Children’s Hospital Los Angeles, King’s College London and the UNITY Consortium to expand global brain imaging capacity. The consortium is helping clinicians in limited-resource countries improve the treatment of neonatal neurological conditions, using AI to boost the quality of ultra-low field MRI and expand access to this portable and more affordable imaging option.
  • Federated learning: Children’s National has collaborated with NVIDIA and other industry leaders to accelerate AI advances through federated learning. Under this approach, institutions share AI models rather than data, allowing them to collaborate without exposing patient information or being constrained by essential data-sharing restrictions. The SZI team was the only pediatric partner invited to join the largest federated learning project of its kind, studying the lungs of COVID-19 patients. Details were published in Nature Medicine.

Children’s National leads the way

Looking ahead, the Children’s National AI team is pursuing a wide range of advances in clinical care. To support patients treated at multiple clinics, they are developing systems to harmonize images from different scanners and protocols, such as MRI machines made by different manufacturers. Similar work is underway to analyze pathology samples from different institutions consistently.

Automation is also making care more efficient. For example, using data from 1 million chest X-rays, the team is collaborating with NVIDIA to develop a conversational digital assistant that will allow physicians to think through 14 possible diagnoses.

Dr. Linguraru says he and his colleagues are galvanized by the jarring statistic that one in three children with a rare disease dies before age 5. While well-implemented AI initiatives can change outcomes, he says the work must be done thoughtfully.

“In the future, patients will be evaluated by human clinicians and machines with extraordinary powers to diagnose illness and determine treatments,” Dr. Linguraru said. “Our team at Children’s National is leading conversations about the future of pediatric healthcare with a focus on safety, resource allocation and basic equity.”

Learn more about our AI initiatives

Innovation leaders at Children’s National Hospital are building a community of AI caregivers through educational and community-building events. At the inaugural Symposium on Artificial Intelligence in 2023 at the Children’s National Research & Innovation Campus, experts from Virginia Tech, JLABS, Food and Drug Administration, Pfizer, Oracle Health, NVIDIA, AWS Health and elsewhere laid out a vision for using data to advance pediatric medicine. The symposium will return on Sept. 6.

Dr. Linguraru is the program chair of MICCAI 2024, the top international meeting on medical image computing and computer-assisted intervention and the preeminent forum for disseminating AI developments in healthcare. The conference is an educational platform for scientists and clinicians dedicated to AI in medical imaging, with a focus on global health equity. It will take place for the first time in Africa on Oct. 6-10.

 

 

Patient and doctor demoing Rare-CAP technology

M.D. in your pocket: New platform allows rare disease patients to carry medical advice everywhere

When someone has a rare disease, a trip to the emergency room can be a daunting experience: Patients and their caregivers must share the particulars of their illness or injury, with the added burden of downloading a non-specialist on the details of a rare diagnosis that may change treatment decisions.

Innovators at Children’s National Hospital and Vanderbilt University Medical Center, supported by Takeda, are trying to simplify that experience using a new web-based platform called the Rare Disease Clinical Activity Protocols, or Rare-CAP. This revolutionary collection of medical information allows patients to carry the latest research-based guidance about their rare disorders in their phones, providing a simple QR code that can open a trove of considerations for any medical provider to evaluate as they work through treatment options for someone with an underlying rare disease.

“No one should worry about what happens when they need medical help, especially patients with rare diseases,” said Debra Regier, M.D., division chief of Genetics and Metabolism at Children’s National and Rare-CAP’s lead medical advisor. “We built this new tool because I have watched as my patient-families have wound up in an emergency room — after all, kids get sprains or fractures — but they don’t have the expertise of a rare disease specialist with them. My hope is that they’re going to pull out their phones and access Rare-CAP, which will explain their rare disease to a new provider who can provide more thoughtful and meaningful care.”

The big picture

A rare disease is defined as any disorder that affects less than 200,000 people in the United States. Some 30 million Americans are believed to be living with one of the 7,000 known rare disorders tracked by the National Organization of Rare Diseases (NORD). Led by Dr. Regier, the Rare Disease Institute at Children’s National is one of 40 NORD centers for excellence in the country that provide care, guidance and leadership for the wide array of disorders that make up the rare disease community.

While a key goal of Rare-CAP is to bolster patient self-advocacy, the platform will also allow medical providers to proactively search for protocols on rare diseases when they know they need specialized advice from experts at Children’s National, a network of tertiary care centers and patient organizations.

As a leading values-based, R&D-driven biopharmaceutical company, Takeda has committed $3.85 million to the project to help activate meaningful change and empower a brighter future for rare disease communities, providing a unique understanding of the struggle that patients and caregivers face when they need care.

“Our team, alongside the medical and rare disease community, saw the need for a single portal to collect standardized care protocols, and we are thrilled to see this innovative tool come to life,” said Tom Koutsavlis, M.D., head of U.S. Medical Affairs at Takeda. “People with rare diseases and their caregivers need faster access to authoritative medical information that providers anywhere can act on, this will lead to improving the standard of care, accelerating time to diagnosis and breaking down barriers to increase equitable access.”

The patient benefit

The creators of Rare-CAP imagined its use in a wide range of settings, including emergency rooms, surgical suites, dental offices, urgent care offices and school clinics. The platform will eventually profile thousands of rare diseases and lay out the implications for care, while also creating a dynamic conversation among users who can offer updates based on real-world experience and changes in medical guidance.

“Our patients are unique, and so is this tool,” Dr. Regier said. “As we roll out Rare-CAP, we believe it is just the beginning of the conversation to expand the platform and see its power for the patient and provider grow, with each entry and each new rare disease that’s added to the conversation.”

newborn baby with bandaid on heel

JAMA Pediatrics editorial: A better approach for newborn screening

The medical community has an opportunity to update its approach to newborn screening (NBS) to be prepared for emerging technological advancements that will help diagnose children with rare diseases from their first weeks of life, according to an editorial from a leading Children’s National Hospital researcher published in JAMA Pediatrics.

“In health care, we are seeing ways in which we can identify more children who have rare diseases even earlier, in the newborn period, rather than waiting for children to develop symptoms or experience irreversible changes,” said Beth Tarini, M.D., M.S., M.B.A., associate director of the Center for Translational Research. “We have continued innovations in screening technology – with more on the way – that can be added to the screening programs overseen by all 50 states. Updating how we approach newborn screening presents an incredible opportunity for doctors and their patient-families.”

Why it matters

Newborn screening happens before the baby leaves the hospital, generally with a prick of the heel to take a small sample of blood to look for several dozen rare, debilitating disorders such as sickle cell disease, congenital hypothyroidism and cystic fibrosis. The current screening system has grown successfully for roughly 60 years and creates a network of state programs. Along the way, researchers have had extensive debates about which disorders to include, based on whether there are treatments and options for patients.

Dr. Tarini, a pediatrician who has done extensive research on NBS and related policies, said that the existing screening programs across all 50 states should be modernized, with federal research support and funding, to create a unified “learning newborn screening system” that derives information from the 4 million babies born each year and provides feedback to the medical community about best practices for babies who are diagnosed with a rare disease or at risk for developing one.

“A new approach will require resources and infrastructure, but as the technology advances, we should change our system to leverage the experience of doctors, patients, and NBS programs across the country,” Dr. Tarini said. “We have the will, the experience and the ability to transform the care for children with rare disease.”

Read the full editorial in JAMA Pediatrics.

Germ cell tumor of testicle under microscopy

New research: Genes that drive testicular cancer identified

In the largest sequencing study to date on testicular cancer, researchers at Children’s National Hospital have identified genes that contribute to testicular germ cell tumors (TGCT), the most common cancer among young, white men.

The findings, published in European Urology, provide direction for future screening and treatment of this disease, which can strike during the teen years and often runs in families. While treatable when identified early, testicular cancer leads to infertility, mental health issues and sometimes death, making its identification crucial for young adults.

“Testicular cancer is really a young person’s disease,” said Louisa Pyle, M.D., Ph.D. , a pediatrician, medical geneticist and research geneticist at the Children’s National Rare Disease Institute. “Most folks who have testicular cancer are between the ages of 15 and 45. Even though testicular cancer is relatively rare in the cancer world, it results in the greatest number of years lost among all adult cancers.”

What we hope to discover

Dr. Pyle led a research team that included experts at the National Cancer Institute and the University of Pennsylvania to study families with multiple members diagnosed with testicular cancer. They used whole exome sequencing to identify variants in many genes that predisposed patients to TGCT. Their work suggests that multiple variants – inherited together – increased the risk for the disease and provides potential routes for drugs that could be used for prevention and treatment.

“We found many genes that help us understand how testicular cancer happens,” Dr. Pyle said. “Our hope is that we can use that to try to come up with better treatments or better ways to preserve fertility for people with testicular cancer or gonadal differences.”

The patient benefit

Testicular cancer most often strikes men of European ancestry. It is also more common among intersex patients and those with differences in sex development, which is a clinical and research focus for Dr. Pyle. Medically, these are children who have a change in the biological characteristics of sex, including their chromosomes, hormones, gonads or physical body parts.

By studying a more common version of testicular cancer, the team learned about the underlying genetics in a way that will benefit intersex patients.

“One of the things we do in medicine is study a common version of the rare thing,” Dr. Pyle said.  “Through this research, we learned that the same genes that cause intersex traits in some patients are also changed in subtle ways for people with testicular cancer. This is a way to study something that could improve care for those kids, by studying a group that has greater numbers.”

family with child in wheelchair

The psychosocial needs of children with rare diseases

family with child in wheelchairA special issue of the journal Children, guest-edited by Maureen Lyon, Ph.D., clinical health psychologist at Children’s National Hospital, features a compilation of articles from a diverse group of professionals. The authors share their expertise on topics related to psychosocial considerations for children and adolescents living with rare diseases.

Co-edited by Lori Wiener, Ph.D., of the National Cancer Institute, the special issue contains articles addressing the psychosocial, neuropsychological and educational needs these children face as well as the impact on their family, friends and community.

According to Lyon and Wiener, “Living with a long-term medical condition, particularly if it is a rare disease, can have a profound impact on the lives of children and their caregivers. Our goal is to update readers on evolving research in the field and familiarize them with useful clinical knowledge and interventions.”

The issue contains 13 peer-reviewed manuscripts from around the globe, including Asia (Taiwan), Australia, Europe (Germany, Italy, Sweden, and Netherlands) and the United States. The following were authored by experts from Children’s National:

Read the full issue of Psychosocial Considerations for Children and Adolescents Living with Rare Diseases.

Marshall and Karen Summar

Marshall Summar, M.D., receives Lifetime Achievement Award for rare disease work

Marshall Summar

For making strides to improve the lives of the rare disease community, the National Organization for Rare Disorders (NORD®) recognized Marshall Summar, M.D., with a Lifetime Achievement Award.

For making strides to improve the lives of the rare disease community, the National Organization for Rare Disorders (NORD®) recognized Marshall Summar, M.D., chief of the Division of Genetics and Metabolism and the director of the Rare Disease Institute at Children’s National Hospital, with a Lifetime Achievement Award.

This award honors individuals for outstanding career-long achievement on behalf of the rare disease community and commitment to improving the lives of those affected by rare diseases. It has been presented only a few times over NORD’s nearly 40-year history, most recently to former NIH Director Francis Collins, M.D., Ph.D., in 2015 and to clinician and researcher Robert Campbell, M.D., of Children’s Hospital of Philadelphia in 2018.

“I am honored to receive this award from NORD. It is so special to be recognized by the leading rare disease organization. This award comes from the work of so many people over the years, particularly our great team at Children’s National,” said Dr. Summar. “This acknowledgement of what we have done to date just gets me more excited about the future!”

Dr. Summar developed and launched the world’s first Rare Disease Institute at Children’s National in 2017, which is now located on the Children’s National Research & Innovation Campus, a first-of-its-kind pediatric research and innovation hub in Washington, D.C.

The institute, which includes the largest clinical group of pediatric geneticists in the nation, focuses on developing the clinical care field of the more than 8,000 rare diseases currently recognized and advancing the best possible treatments for children with these diseases.

Marshall and Karen Summar

Marshall and Karen Summar.

“Dr. Summar’s passion for serving patients is at the core of everything he does,” said Debra Regier, M.D., medical director of the Rare Disease Institute. “His mentorship for the next generation of medical and biochemical geneticists has become his legacy.”

The work Dr. Summar has done over the course of his career has resulted in new drugs in FDA trials for patients with congenital heart disease and premature birth. He also holds more than 60 patents and has published more than 160 peer-reviewed research studies.

“Beginning with his work as a clinician in the 1980s, Dr. Marshall Summar has spent a career forging partnerships, advocating at the highest level and developing new ways to treat rare disease patients,” said Peter L. Saltonstall, president and CEO of NORD.

“Dr. Summar served on the NORD Board of Directors for nine years, including six years as Chairman, and so we at NORD have been lucky enough to have years of firsthand experience with his leadership, community-building and innovation efforts in the rare disease field. This award is a recognition and appreciation for sustained excellence, including critical work with organizations such as the American College of Medical Genetics, the National Institutes of Health, NORD, and the Rare Disease Institute at Children’s National. For decades of commitment to families and organizations combating rare diseases, NORD is thrilled to present the Lifetime Achievement Award to Dr. Marshall Summar at the 2022 Rare Impact Awards,” Saltonstall added.

Learn more about the Rare Disease Institute at Children’s National.

Midsection of a handicapped man and woman

Increasing the patient’s voice in osteogenesis imperfecta research and care

Midsection of a handicapped man and woman

The Osteogenesis Imperfecta Foundation Patient-Centered Outcomes Research Project brought patient voices into efforts to improve patient-centered outcomes research and education in osteogenesis imperfecta.

Rare bone diseases constitute about 5% of all known rare diseases. Osteogenesis imperfecta (OI) is a group of genetic disorders causing connective tissue dysfunction and bone fragility, affecting an estimated 25,000 to 50,000 people in the U.S. Many patients with rare diseases, including those with conditions like OI, suffer from delays in diagnosis and lack of access to the complex multidisciplinary care they require.

Children’s orthopaedic surgeon Laura Tosi, M.D., is the co-lead of a two-year program, Osteogenesis Imperfecta Foundation Patient-Centered Outcomes Research Project. The now completed program brought patient voices into efforts to improve patient-centered outcomes research and education in osteogenesis imperfecta.

Increasingly, the OI community has become more vocal about its need for information and options for evidence-based care. Research about this condition often lacks the patient’s voice. Collecting the patient’s perspective about natural history, clinical best practices, quality of life and research priorities is challenging because, like so many rare diseases, the affected population is relatively small and geographically dispersed.

“We were excited that so many members of the OI community (patients, caregivers, clinicians, and researchers) stepped up to help us with this work for the last two years,” said Dr. Tosi. “They served on committees, completed surveys, and attended training sessions to learn more about patient-centered outcomes research.”

The program accomplished many goals, including creating a community of stakeholders who are trained in patient-centered outcomes research, with specific attention to priority topics identified by the OI community.

“We believe that attention to the broad impact of OI on patients’ lives, from patients’ perspectives, is urgently needed to better inform assessment, care and comparative effectiveness recommendations across the life span,” said Dr. Tosi.

The program considered the patients’ perspective and encouraged a collaborative effort among Children’s National Bone Health Program staff, geneticists, endocrinologists and other specialists to achieve rapid, accurate diagnosis that facilitates individualized care.

“Advances in knowledge can and will happen faster when more people participate in research from the outset,” said Dr. Tosi. “This means not just shaping the questions but also gaining the ability to understand and interpret the impact of such investigations.”

The program also expanded the communications and education strategies related to patient-centered outcomes, even during COVID-19.

The pandemic positively influenced the program’s educational efforts, Dr. Tosi added. The difficulties that emerged in the early months of the pandemic helped capture the community’s attention as they discussed the importance of the program. Through a COVID-19 supplemental award, the program gained more resources to expand the scope of the original education efforts.

With the new challenges and the possible physical and mental health threats that the pandemic posed to people with OI, including isolation and social distancing, the team used engagement strategies to raise awareness of the COVID-19 hazards, disseminated best practices for responses, and enhanced communications between stakeholders. The researchers were able to:

  1. Expand virtual meetings, which allowed them to reach a wider range of patients.
  2. Create and disseminate COVID-19 content (e.g., prophylactic care, symptoms, diagnosis, treatment, outcomes).
  3. Use their existing OI Registry to document and track evolving issues such as more difficult access to medical care (or other necessary services), “daily living” concerns or burdens, and options for safe “return to work” and American Disabilities Act “work accommodations.”
  4. Gather information on therapeutic options (e.g., pros and cons of medicines, counseling, telemedicine) and their potential to mitigate the health problems that isolation and social distancing create.
  5. Develop tools to prepare the community for telemedicine, with emphasis on educating health professionals about patients’ higher vulnerability to coronavirus.

While the outcomes of this initiative were overwhelmingly positive, the researchers are also considering some changes, such as implementing “hybrid” models of in-person and remote meetings in the future.

Dr. Tosi served as project co-lead alongside colleagues Tracy Hart, project lead, from the Osteogenesis Imperfecta Foundation (OIF) and Bryce Reeve, Ph.D., co-project lead, director of the Center for Health Measurement at Duke University.

Bear Institute PACK logo

Winners of the first annual Bear Institute PACK Event

Bear Institute PACK logo

On August 26, 2021, the Bear Institute, along with Children’s National Hospital and Cerner Corporation, hosted the first annual Bear Institute PACK (Pediatric Accelerator Challenge for Kids). Bear Institute PACK is a start-up competition aimed to address the gap in digital health innovation funding dedicated to children.

“Children are a unique population that requires different health solutions than those designed for adults, which address their unique needs,” says Dr. Lu de Souza, Vice President and Chief Medical Officer, Cerner Corporation. “With Bear Institute PACK, we hope to increase focus and delivery of digital health innovations for kids. Bear Institute PACK brings together the pediatric health care community, including pediatric health care providers and hospital administrators from across the country to identify top start-up digital applications that best serve children.”

This year’s start-up participants competed across four innovation tracks, including rare disease, telemedicine, remote patient monitoring and patient education. Student teams competed in a separate student track. Bear Institute PACK consists of three rounds of judging: an initial review of applications from the Bear Institute PACK team, judging from participating pediatric healthcare providers and administrators and review from an expert panel of judges during finalist start-ups’ live pitches.

The start-ups competed for a rich prize pool, including cash prizes totaling over $100,000, on-site pilots and software development support. Winners were selected in each of the event’s four innovation tracks, as well as an additional two student team winners. This year winners are:

  • In the rare disease track, first place winner, Bloom Standard, Inc., with its solution Automated Ultrasound Wrap that screen infants and children for serious lung and cardiac conditions, and second place winner, Mira Medical LLC, with its solution Bear Growth: A Three-Dimensional Pediatric Growth Modeling App.
  • In the telehealth track, Keriton, Inc., with its solution Keriton Kare, a healthcare SaaS platform built to improve outcomes for neonatal and pediatric patients.
  • In the remote patient monitoring track, Sonavi Labs, with its solution Feelix, a platform that features proprietary hardware embedded with clinically validated diagnostic software capable of detecting respiratory diseases.
  • In the patient education track, Smileyscope, with its comprehensive virtual reality (VR) platform to help support patients with procedural pain management, drug-free anxiety care, education, and guided relaxation.
  • Student team first place winner, CASP Technologies, with its solution Operation Serenity, which allows pediatric patients to prepare for and understand their simulated surgery to reduce anxiety and second place winner, Ankle Rehab, with its solution Foot Joystick for Children with Cerebral Palsy meant to improve mobility.

More information on this year’s winners can be found on the Bear Institute PACK website.

“This year’s Bear Institute PACK had a lot of start-ups and student team participants with very impressive innovation solutions for kids. Selecting a single winner in each innovation track was a tough decision, and it was encouraging to see all the work being done to bring these solutions to market,” says Matt MacVey, Vice President and Chief Information Officer, Children’s National Hospital. “Thank you to everyone who participated and helped make the inaugural Bear Institute PACK a success! We hope to make next year even bigger as we continue to strive to close the gap in funding for children’s digital health innovation.”

More information on next year’s event will be forthcoming on the Bear Institute PACK website.

facial recognition of noonan syndrome

Commercialization of novel facial analysis technology can improve diagnosis of rare disorders in pediatric patients

facial recognition of noonan syndrome

Children’s National Hospital has entered into a licensing agreement with MGeneRx Inc. for its patented pediatric medical device technology using objective digital biometric analysis software for the early and non-invasive screening of dysmorphic genetic diseases such as Noonan syndrome.

Children’s National Hospital has entered into a licensing agreement with life sciences technology company MGeneRx Inc. for its patented pediatric medical device technology using objective digital biometric analysis software for the early and non-invasive screening of dysmorphic genetic diseases. The technology, developed by a multidisciplinary Children’s National team led by Marius George Linguraru, D.Phil, M.A., M.Sc., of the Sheikh Zayed Institute for Pediatric Surgical Innovation and Marshall Summar, M.D., director of the Children’s National Rare Disease Institute (CNRDI), can provide a more advanced diagnostic tool for regions of the world with limited access to geneticists or genetic testing.

The application utilizes artificial intelligence (AI) and machine learning to analyze biometric data and identify facial markers that are indicative of genetic disorders. Physicians can capture biometric data points of a child’s face in real time within the platform, where it scans facial biometric features to determine the potential presence of a genetic disease, which can often be life-threatening without early intervention. Research studies conducted in conjunction with the National Human Genome Research Institute at the National Institutes of Health further enhanced the development of the application in recent years, showing the potential to detect, with a 90 percent accuracy, early diagnosis of 128 genetic diseases across pediatric subjects in 28 countries. These diseases include DiGeorge syndrome (22q11.2 deletion syndrome), Down syndrome, Noonan syndrome and Williams-Beuren syndrome.

“We are delighted to enter into this licensing agreement through Innovation Ventures, the commercialization arm of Children’s National Hospital, which seeks to move inventions and discoveries from Children’s National to the marketplace to benefit the health and well-being of children. Our mission is to add the ‘D’ in development to the ‘R’ in research to accelerate the commercialization of our intellectual property,” says Kolaleh Eskandanian, Ph.D., M.B.A., P.M.P., vice president and chief innovation officer at Children’s National and managing director of Innovation Ventures. “It is through partnerships with startups and the industry that we can achieve this goal and thus we highly value this new partnership with MGeneRx Inc. The acceleration and commercialization of this objective digital biometric analysis technology will not only help diagnose rare genetic disorders – it will also allow for earlier interventions that improve the quality of life for the children living with these conditions.”

Eskandanian adds that the social impact of this technology is especially profound in lower income nations around the world, where there is a high prevalence of rare genetic conditions but a severe lack in the specialty care required to diagnose and treat them. Additional data collected through the expanded use of the technology will help to further develop the application and expand its capabilities to identify and diagnose additional rare genetic conditions.

The licensing agreement was arranged by the Children’s National Office of Innovation Ventures, which is focused on the commercialization of impactful new pediatric medical device technologies and therapies to advance children’s health care. Created to catalyze the ongoing translational research of the Children’s National Research Institute (CNRI) as well as inventions by hospital’s clinicians, Innovation Ventures focuses on four core pillars to advance pediatric medical technologies including a Biodesign program, partnerships and alliances to augment internal capacity, seed funding to de-risk technologies and validate market and clinical relevance, and back-office operations to manage intellectual property and licensing activities. Since 2017, Children’s National intellectual property has served as the basis for over 15 licensing or option agreements with commercial partners.

Providing access to an array of experts and resources for pediatric innovators is one of the aims of the Children’s National Research & Innovation Campus, a first-of-its-kind focused on pediatric health care innovation, with the first phase currently open on the former Walter Reed Army Medical Center campus in Washington, D.C. With its proximity to federal research institutions and agencies, universities, academic research centers, as well as on-site incubator Johnson and Johnson Innovation – JLABS, the campus provides a rich ecosystem of public and private partners, which will help bolster pediatric innovation and commercialization.

x-ray of a fracture

Genetic disorders, including osteogenesis imperfecta, rarely mimic child abuse

x-rays of fractures

In suspected child abuse cases, pediatric specialists are often called for clinical consultations or subpoenaed to courtrooms to discuss unexplained fractures and hemorrhage. During routine clinical practice, Children’s National Hospital (CNH) geneticists, child abuse pediatricians, orthopedists and radiologists use a multidisciplinary, stepwise approach that differentiates genetic disorders from cases of suspected child abuse. These teams provide a clear process for when clinical and radiological review suffices versus cases when judicious use of genetic testing and biochemical testing should be considered.

Every year, approximately 675,000 children suffer abuse or neglect, and at least 1,700 die from abuse — one of the leading causes of childhood morbidity and mortality nationwide.

Ill-intended arguments regarding genetic disorders often reach the court. Out of the 7,000 known rare diseases, rare bone diseases constitute about 5% of the cases. When there are true genetic disorders like osteogenesis imperfecta (OI), a group of genetic disorders that cause fractures, orthopedic specialists help tremendously with diagnosis and treatment.  The Children’s National Bone Health Program specializes in caring for healthy children, children with genetic bone conditions, and children whose bones have been damaged from illness or poor nutrition. Their team of experts enhances treatment to meet the needs of each child help us provide the best possible care for children with a broad range of bone health conditions  When a rare condition that causes bone fragility is suspected, these teams work together to provide proper diagnosis and management.

“OI is a diagnosis that can be made clinically with the help of geneticists, radiologists and orthopedists,” said Tanya Hinds, M.D., a child abuse pediatrician at Children’s National. “Outside of the newborn period, multiple unexplained fractures in infants with radiologically normal bones is suspicious for child physical abuse, not OI.”

When these regional cases reach the courtroom, Children’s National pediatricians often serve as clinician-educators and expert witnesses. According to Children’s National experts, clinicians must share the best available medical practices in both the hospital and courtroom.  Unfortunately, in some cases around the country, a handful of expert medical witnesses provide unique and unsubstantiated opinions, sometimes claiming the presence of a rare genetic disorder as a cause of fracture or hemorrhage, when this has not been diagnosed by mainstream genetics specialists.

“On the part of expert witnesses, scientifically sound explanations versus unfounded hypotheses can influence outcomes in civil proceedings, which determine a child’s placement and criminal proceedings, which determine judgment on the perpetrators,” said Natasha Shur, M.D., medical geneticist at Children’s National, and Nathaniel Robin, M.D., professor and clinical genetics director at the University of Alabama in an editorial published in Current Opinion in Pediatrics.

Dr. Hinds works on behalf of children to provide the best and most comprehensive work-up in cases of unexplained fractures or hemorrhage. As a board-certified child abuse pediatrician, she is responsible for implementing the evidence-based practice guidelines of the American Academy of Pediatrics and other similar societies.  Dr. Hinds mentioned that it is possible to use medical history, physical examination and diagnostic testing to differentiate traumatic causes of fractures and subdural hematomas from genetic causes, a belief she states is held by the vast majority of child serving clinicians.

“In cases of suspected child abuse, a multidisciplinary group of clinicians at Children’s National routinely provide comprehensive and top-rate care and consider alternative explanations for fractures,” said Eglal Shalaby-Rana, M.D., a radiologist at Children’s National who has partnered with the hospital’s Child and Adolescent Protection Center team on these challenging cases since 1991. “A multidisciplinary team is crucial to the evaluation and often includes additional specialists such as pediatric radiology, trauma surgery, hematology and in some cases genetics.”

Further, these clinician-educators and researchers at Children’s National call for increased publication and use of consensus guidelines such as the consensus statement on abusive head trauma published in Pediatric Radiology in 2018.  “Consensus guidelines synthesize the best available medical evidence and should be the basis for both clinical practice and education offered in the courtroom,” said Drs. Shur, Hinds and Shalaby-Rana.

 Distinguishing child abuse from genetic disorders

Drs. Hinds, Shalaby-Rana and Shur have served as expert witnesses and in turn wanted to come together to help develop frameworks that share scientifically sound information with peers who might encounter spurious arguments in courtrooms regarding genetic disorders as an explanation for physical abuse and inflicted fractures. Their 2021 literature review, published in Current Opinion in Pediatrics, addresses some of these issues.

To help distinguish child physical abuse from a genetic disorder, Drs. Shur, Hinds and Shalaby-Rana  worked as a multidisciplinary team to highlight best practices in six instances when genetic disorders were raised as explanations for inflicted fractures or hemorrhage, including Elhers-Danlos syndrome (EDS), osteogenesis imperfecta (OI), Menkes Disease and Glutaric Acidemia type I. In some cases, these explanations could be reasonable but should be diagnosed using routine clinical and radiological review, and when indicated, genetic and biochemical testing.

For instance, EDS is a diagnosis that is sometimes erroneously used to explain multiple fractures in cases of suspected physical abuse and can be misused in courtrooms. The most common EDS type is hypermobile EDS, often found in late adolescence or early adulthood. In some cases, babies erroneously receive hypermobility exams, or clinicians perform hypermobility assessments on parents of children with unexplained fractures — neither practice is indicated. Instead, the Children’s National team points out that children should receive a medical evaluation using the standard guidelines set by the American Academic of Pediatrics, American College of Radiology and other professional societies.

Dr. Shur also collaborated with radiologists at Boston Children’s Hospital in a related review published in Pediatric Radiology. There, George et al. addressed the clinical and molecular diagnosis criteria for EDS to help radiologists prevent misdiagnosis and support clinicians when seeing patients with multiple fractures.

“It is disturbing that the unsubstantiated EDS infant bone fragility hypothesis continues to be advanced in civil and criminal child abuse proceedings when fractures are not part of the diagnosis criteria for EDS,” said George et al.

The clinicians noted that the Beighton score, which helps diagnose hypermobile EDS, is not intended for children younger than 8 years old. Additionally, since the score provides insufficient data, other EDS features must be present, such as skin findings and connective tissue abnormalities.

OI, known as ‘‘brittle bone disease,’’ is a group of disorders that rarely present only with unexplained fractures. The researchers emphasize that infants and children with mild OI do not present exclusively with multiple fractures, which are specific to physical abuse such as multiple, bilateral rib fractures and classic metaphyseal lesions. Drs. Shur, Hinds and Shalaby-Rana share that pediatric specialists could overcome the diagnostic challenges between OI and child abuse through the inclusion of a genetic team in some cases, during the medical evaluation while also considering various criteria, such as family history, physical examination and laboratory findings. Molecular testing may be required in some instances, but it cannot substitute traditional clinical and radiology evaluations, according to these clinician-researchers.

Similarly, while Menkes disease can present with intracranial hemorrhage and fractures like child physical abuse, there are other distinguishing characteristics unique to Menkes disease, such as hair and facial dysmorphism. In a third related case-review published in Pediatric Radiology, Shur, Hinds and Shalaby-Rana et al. emphasize that diagnostic difficulties may arises when a multidisciplinary evaluation is omitted. They call upon all clinicians to provide ethical testimony in civil or criminal proceedings and to continue to utilize a multidisciplinary approach during daily clinical practice.

Irresponsible testimony and predatory journals

According to George et al., in collaboration with Dr. Shur, there are flawed publications on EDS associated with infant bone fragility that do not follow the gold standard of the scientific community. They believe this hypothesis must be rejected by experts in the field of pediatric imaging to safeguard the scientific integrity of the discipline. The lack of scientific design, peer review process and transparency causes negative consequences in the courtroom and threatens the proper adjudication of cases of suspected child physical abuse.

“Irresponsible testimony increasingly enters medico-legal proceedings dealing with allegations of child abuse, and so-called expert witnesses regularly cite these deeply flawed publications — in addition to misquoting the medical literature, loosely interpreting medical findings, presenting fictitious findings, and excluding salient and widely accepted facts from consideration,” said George et al.

In these pieces of literature, our Children’s National multidisciplinary team members reviewed the best available evidence and their collective decades of patient experience to highlight standard processes, which differentiate child physical abuse as a cause of fractures and hemorrhage from rare disorders.  Rare does not mean mysterious, and with education and a multidisciplinary approach, every child can receive the best possible medical work-up and care, according to Drs. Shur, Hinds and Shalaby-Rana. They urge all physicians to share only mainstream clinical medicine in the courtroom to help ensure the best possible social outcomes for children and their families.

red flags for irresponsible testimony

Andrea Hahn

Pediatric Research names Andrea Hahn, M.D., M.S., early career investigator

Andrea Hahn

“I am honored to be recognized by Pediatric Research and the Society of Pediatric Research (SPR) at large,” said Dr. Hahn. “SPR is an amazing organization filled with excellent scientists, and to be highlighted by them for my work is truly affirming.”

For her work on the impact of bacterial functional and metabolic activity on acute episodes of cystic fibrosis, the journal Pediatric Research recognized Andrea Hahn, M.D., M.S., as Pediatric Research’s Early Career Investigator.

Cystic fibrosis is an autosomal recessive genetic disease, affecting more than 70,000 people worldwide. The condition’s morbidity and mortality are recurrent and result in a progressive decline of lung function.

“I am honored to be recognized by Pediatric Research and the Society of Pediatric Research (SPR) at large,” said Dr. Hahn. “SPR is an amazing organization filled with excellent scientists, and to be highlighted by them for my work is truly affirming.”

The exact mechanisms of the bacteria that chronically infect the airway triggering acute cystic fibrosis episodes, also known as pulmonary exacerbations, remain unclear. Dr. Hahn’s research is one of the few to explore this gap and found an association with long-chain fatty acid production in cystic fibrosis inflammation.

“As a physician-scientist, there are many competing priorities between developing and executing good science — including writing manuscripts and grants — and providing excellent patient care both directly and through hospital-wide quality improvement initiatives,” said Dr. Hahn. “It is often easier to have successes and feel both effective and appreciated on the clinical side. This recognition of my scientific contributions to the medical community is motivating me to continue pushing forward despite the setbacks that often come up on the research side.”

The exposure to many programs and institutions gave Dr. Hahn the foundation to create a research program at Children’s National that helps decipher the complexities of antibiotic treatment and how it changes the airway microbiome of people with cystic fibrosis. The program also explores the impacts of antibiotic resistance and beta-lactam pharmacokinetics/pharmacodynamics (PK/PD) — the oldest class of antibiotics used to treat infections.

Dr. Hahn believes that the people and environment at Children’s National Hospital allowed her to grow and thrive as a physician-scientist.

“I was initially funded through an internal K12 mechanism, which was followed up by Foundation support, which was only possible because of the strong mentorship teams I have been able to build here at Children’s National,” said Dr. Hahn. “My division chief has also been very supportive, providing me with both protected time as well as additional resources to build my research lab.”

She is particularly appreciative of Robert Freishtat, M.D., M.P.H, senior investigator at the Center for Genetic Medicine Research, and Mary Callaghan Rose (1943-2016).

“Robert Freishtat has been a great advocate for me, and I am indebted to him for my success thus far in my career,” said Dr. Hahn. “Likewise, I want to specifically recognize Mary Rose. She was a great scientist at Children’s National until her death in 2016. She gave me the initial opportunity and support to begin a career studying cystic fibrosis, and she is missed dearly.”

You can learn more about Dr. Hahn’s research in this Pediatric Research article.

Natasha Shur

NORD names Natasha Shur, M.D., as hero of rare disease

Natasha Shur

Dr. Shur has a career working as a clinical geneticist for over a decade. She has been a part of the Children’s National community for more than two years. Dr. Shur as well serves as the lead for the Telemedicine Genetics Program under the Rare Disease Institute.

For her advancements in telemedicine genetics and rare diseases, Medical Geneticist Natasha Shur, M.D., received the 2021 Rare Impact Award from the National Organization for Rare Disorders (NORD). The recognition is the highest honor given to individuals that developed exceptional work benefiting the rare disease community.

“Despite the pandemic and the challenges we have faced, there are still heroes to be found among us from whom we can draw inspiration and motivation to keep moving forward,” said Peter L. Saltonstall, NORD president and CEO.

Given her involvement with several innovative projects at Children’s National Hospital, Dr. Shur built an active in-home telemedicine program where patients are being seen for first visits and follow-ups. Her work is helping families, including those with autistic children.

“Recently, in our division, we have been talking a lot about the concept of ‘failing forward.’ The idea is to try new approaches. These methods may not work, but the status quo does not always work either,” said Dr. Shur. “Since we have such a supportive and wonderful group, we can try new ways of working and new models of care.”

During the pandemic, the division led by Marshall Summar,.M.D., also created a telehealth first model of care and augmented educational apps and opportunities. The goal was to ensure that patients with rare disease would not lose access to care. The medical geneticists, genetic counselors, dieticians and administrative team met daily and cohesively to explore and improve new clinical approaches in order to put patients and families first.

Dr. Shur has a career working as a clinical geneticist for over a decade. She has been a part of the Children’s National community for more than two years. Dr. Shur as well serves as the lead for the Telemedicine Genetics Program under the Rare Disease Institute.

The Rare Disease Institute recently opened its new location on the Children’s National Research & Innovation Campus, a first-of-its-kind pediatric research and innovation hub located in Washington, D.C. The campus will provide a unique, state-of-the-art home for clinical genetic and specialty services.

Gracie Popielarcheck

Raising awareness about Turner Syndrome

Gracie Popielarcheck

Gracie Popielarcheck was diagnosed at age one with Turner Syndrome.

By Roopa Kanakatti Shankar, M.D., M.S., Director of the Turner Syndrome Program at Children’s National Hospital.

The Children’s National  Turner Syndrome Clinic is part of the Division of Endocrinology and Diabetes which is ranked by U.S. News & World Report as one of the top 10 programs in the nation. The clinic opened in January 2019 and is the first of its kind in the Washington, D.C., region. A multidisciplinary clinic is held once a month with a team experts in cardiology, endocrinology, psychology, gynecology and genetics to help care for the needs of patients with Turner Syndrome all in one day. The referral network of specialties includes neuropsychology, otolaryngology, audiology, orthopedics, urology and dentistry.

Turner syndrome (TS) is a rare disease affecting girls, with a prevalence of around 25-50 out of every 100,000 females. It is caused by partial or complete loss of the second sex chromosome. This affects multiple organs and can cause heart defects, skeletal abnormalities, hearing loss and learning difficulties. It also affects growth and puberty and can cause infertility. Although the condition was first described in 1938 by Henry Turner, an endocrinologist from Oklahoma, and is well characterized, there is a significant delay in diagnosis and recognition of the condition, especially in milder forms that can still significantly impact the well-being of the individual.

Gracie Popielarcheck with a pet bird

“Having a Turner Syndrome clinic near our city has made life so much easier,” says Gracie’s mom, Leslie Popielarcheck. “We can see all of Gracie’s specialists all in one day and under one roof.”

Families often ask why it took so long to recognize this condition. Many findings can be subtle, the presentation can vary greatly and often short stature may be overlooked in some girls. We now recognize that the classic form (monosomy X) impacts less than half of the girls and the rest have mosaicism (45,X/ 46XX) or other structural abnormalities in the X-chromosome. Recognizing features beyond the classic “short stature, neck webbing, lymphedema and cardiac defects” is indeed important to get timely care for these girls and women across the lifespan. Many have recurrent ear infections and hearing loss. Most have a normal intelligence, and even superior verbal skills but face challenges in visual spatial perception, executive function, working memory and social cognition that impact academic achievement.

13-year-old Gracie Popielarcheck was diagnosed with TS at the age of one after her parents noticed a delay in her speech and development. “We had never heard of Turner Syndrome when Gracie was diagnosed,” says Leslie Popielarcheck, Gracie’s mom. “Gracie didn’t have the classic physical features that girls with Turner Syndrome are known to have.”

With support, most of these girls and women can manage the medical and psychosocial challenges and rise to their full potential. Advances in the field and multidisciplinary care models have helped in the establishment of TS clinics across the country that strive to improve the standard care for these girls.

However, several challenges remain:

  • Improving awareness among primary care physicians in regard to the extended spectrum and variability of presentation at a wide variety of ages
  • Decreasing health disparities and making multidisciplinary clinics and comprehensive care available and accessible even to disadvantaged communities
  • Ensuring adequate medical and social support for transition of young adults and care of adults with Turner syndrome
Gracie P., Kyra Dorfman with Dr. Shankar

Kyra Dorfman, Dr. Shankar and Gracie.

Our TS program, initiated 2 years ago, aims to overcome these challenges and provide care to families impacted by TS in our community. We strive to serve as a Regional Resource for the community as well as physicians in our community and have been recognized by the TSGA (Turner syndrome Global Alliance) as one of only nine clinics nationwide with a Level 4 designation.

“Having a Turner Syndrome clinic near our city has made life so much easier,” Popielarcheck says. “We can see all of Gracie’s specialists all in one day and under one roof.”

As we highlight these resources for the Turner Syndrome Awareness Month this February 2021, and celebrate the strength and tenacity of our beautiful girls, we hope our efforts will improve recognition of the condition and delivery of comprehensive medical care and support to the community we serve.

sick child in palliative care hospital bed

Children’s National Research Institute receives NIH grant for palliative care study

sick child in palliative care hospital bed

A new NIH grant will support the first study that examines palliative care needs in pediatric rare disease community.

The National Institute of Health (NIH) has awarded $500,875 to the Children’s National Research Institute (CNRI), the academic arm of Children’s National Hospital, to support a new study examining the palliative care needs of children living with rare genetic diseases.

This is the first study of families of children with genetic and metabolic conditions, termed collectively as rare diseases, that is designed to intervene to support the well-being of family caregivers and create advance care plans for future medical decision making. In the United States, a rare disease is defined as a particular condition affecting fewer than 200,000 people. Pediatric patients with rare diseases experience high mortality rates, with 30 percent not living to see their fifth birthday.

“Children with ultra-rare or complex rare disorders are routinely excluded from research studies because of their conditions, creating a significant health disparity. Surveys show that families of children with rare diseases are adversely impacted by lack of easy access to peer and psychological support,” says Maureen Lyon, Ph.D., Clinical Health Psychologist and Professor of Pediatrics at the CNRI and principal investigator on the project. “This study will examine the palliative care needs of family caregivers of children with rare genetic disorders and advance care planning intervention, which will ultimately help facilitate discussions about future medical care choices that families are likely to be asked to make for their child.”

Although greatly needed, there are few empirically validated interventions to address these issues Currently, there is only one intervention described for families of children with rare diseases — a Swedish residential, competence program — which focuses on active coping. However, this intervention does not address pediatric advance care planning, a critical aspect of palliative care.

Lyon adds that the major benefit of this proposed project will be filling the gap in knowledge about what family caregivers of medically fragile children with rare diseases want with respect to palliative care. In the United States, these families are expected to provide a level of care that, until a few decades ago, was reserved for hospitals.

Maureen E Lyon

Maureen Lyon, Ph.D., Clinical Health Psychologist and Professor of Pediatrics at the CNRI and principal investigator on the project.

“Our hope is that this study will provide a structured model for facilitating family decisions about end-of-life care, for those families who do not have the good fortune to have children who have the capacity to share in decision-making,” Lyon says.

In addition to bridging the knowledge gap regarding palliative care in rare disease patients, the study will also help inform current clinical, ethical and policy discussions, as well as the legal issues in a variety of areas, such as the debate surrounding advocacy, particularly for those children with impairments in physical function.

“We look forward to the results of this study,” said Marshall Summar, M.D., director of the Rare Disease Institute and division chief, Genetics and Metabolism at Children’s National Hospital. “As a leader in rare disease care, we continually examine how we can improve care and support for our patient families at our clinic and want to share our findings with others engaged in caring for rare disease patients. Because rare diseases can be life limiting in some cases, we need to learn all we can about how best to care and support a patient and family as they prepare for a potential transition to palliative care.”

All research at Children’s National Hospital is conducted through the CNRI, including translational, clinical and community studies. The CNRI also oversees the educational activities and academic affairs of the hospital and the Department of Pediatrics at the George Washington University School of Medicine and Health Sciences, frequently partnering with many other research institutions regionally and nationally. CNRI conducts and promotes translational and clinical medical research and education programs within Children’s National Hospital that lead to improved understanding, prevention, treatment and care of childhood diseases.

Laura Tosi

Technology bridges knowledge gaps in rare bone disease care

Laura Tosi

Dr. Tosi and colleagues presented on the NIH Rare Disease Day 2020 panel, Nontraditional Approaches to Improving Access for Rare Diseases.

As part of the global observance of Rare Disease Day in February, the NCATS and NIH Clinical Center hosted a special event to raise awareness about rare diseases, the people they affect and NIH research collaborations under way to address scientific challenges and advance new treatments.

This year, Children’s National Hospital orthopaedic surgeon Laura Tosi, M.D., took part in an afternoon panel, Nontraditional Approaches to Improving Access for Rare Diseases, where she outlined her work as the faculty chair of the Rare Bone Disease TeleECHO, a virtual meeting that allows care providers and experts to come together via the Zoom platform, discuss diagnosis of specific disorders and present cases for group input.

Dr. Tosi and the Rare Bone Disease Alliance have called Project ECHO Rare Bone Disease a game changer for care of these complex conditions. Rare bone disorders are only about 5% of all birth defects but include 461 skeletal disorders caused by 437 genes – making it difficult for any physician to see enough cases of any one disorder to correctly diagnose and treat it.

“Most doctors are like me, a pediatric orthopaedic surgeon. I need to know a lot of different rare diseases and it’s hard to keep everybody on the cutting edge,” Dr. Tosi says. “Even though we have found the genes for most of the disorders, the phenotypic overlaps, shortage of specialists and the multi-disciplinary needs of so many of the patients add to the challenges.”

So 7 months ago, Dr. Tosi joined together with colleagues at the Rare Bone Disease Alliance and the Osteogenesis Imperfecta Foundation to launch Project ECHO Rare Bone Disease. The now monthly telehealth meeting engages a distinguished faculty of experts from around the world and from across the spectrum of care for these rare bone disorders, including specialists in genetics, endocrinology, orthopaedics and others.

Project ECHO is a specific model for bridging distance and creating a network of professionals, with the goal of leveling the playing field for all by making vital information accessible to everyone, regardless of their location. In healthcare the model transcends traditional “telemedicine,” however. The program, launched from the University of New Mexico, self-describes itself as “telementoring, a guided practice where the participating clinician retains responsibility for the patient” but is able to discuss diagnosis and therapeutic recommendations with a set of esteemed faculty via a regular virtual meeting series.

In the case of the Rare Bone Disease TeleECHO, the ECHO’s faculty decided on two major foci for the curriculum. Half of the content is about how to make the right diagnosis and the other half shares the latest information about specific diseases. The sessions also offer free CME to attendees.

Dr. Tosi says that while finding cases to discuss can sometimes be challenging when it comes to rare bone diseases, she takes responsibility on herself to make sure the content is robust each month. So far the meetings have attracted between 40 and 90 participants per session – a great engagement rate for such a young teleECHO program.

“I believe ECHO advances knowledge of healthcare and democratizes it by offering universal accessibility across the globe,” Tosi notes.

The Rare Bone Disease Alliance, which consists of 12 organizations, experts and patient families working together, is now deciding what’s next for the Rare Bone Disease TeleECHO. They may develop disorder-specific ECHOs, are studying the frequency of the sessions and how best to improve participation for all sessions. The idea is to increase access to this expertise even further, as it could have critical impacts on patients worldwide living with these rare diseases.

In terms of key take-aways from the panel of experts at Rare Disease Day, the hope is that more disease groups might leverage this type of technology to connect people in nontraditional ways. Doing so has the potential to ensure that everyone with a rare disease receives the best support and care possible because their doctors have the knowledge they need when they need it.

Watch more sessions from the NIH’s Rare Disease Day 2020.

mitochondria

Molecular gatekeepers that regulate calcium ions key to muscle function

mitochondria

Controlled entry of calcium ions into the mitochondria, the cell’s energy powerhouses, makes the difference between whether muscles grow strong or easily tire and perish from injury, according to research published in Cell Reports.

Calcium ions are essential to how muscles work effectively, playing a starring role in how and when muscles contract, tap energy stores to keep working and self-repair damage. Not only are calcium ions vital for the repair of injured muscle fibers, their controlled entry into the mitochondria, the cell’s energy powerhouses, spells the difference between whether muscles will be healthy or if they will easily tire and perish following an injury, according to research published Oct. 29, 2019, in Cell Reports.

“Lack of the protein mitochondrial calcium uptake1 (MICU1) lowers the activation threshold for calcium uptake mediated by the mitochondrial calcium uniporter in both, muscle fibers from an experimental model and fibroblast of  a patient lacking MICU1,” says Jyoti K. Jaiswal, MSc, Ph.D., a principal investigator in the Center for Genetic Medicine Research at Children’s National Hospital and one of the paper’s corresponding authors. “Missing MICU1 also tips the calcium ion balance in the mitochondria when muscles contract or are injured, leading to more pronounced muscle weakness and myofiber death.”

Five years ago, patients with a very rare disease linked to mutations in the mitochondrial gene MICU1 were described to suffer from a neuromuscular disease with signs of muscle weakness and damage that could not be fully explained.

To determine what was going awry, the multi-institutional research team used a comprehensive approach that included fibroblasts donated by a patient lacking MICU1 and an experimental model whose MICU1 gene was deleted in the muscles.

Loss of MICU1 in skeletal muscle fibers leads to less contractile force, increased fatigue and diminished capacity to repair damage to their cell membrane, called the sarcolemma. Just like human patients, the experimental model suffers more pronounced muscle weakness, increased numbers of dead myofibers, with greater loss of muscle mass in certain muscles, like the quadriceps and triceps, the research team writes.

“What was happening to the patient’s muscles was a big riddle that our research addressed,” Jaiswal adds. “Lacking this protein is not supposed to make the muscle fiber die, like we see in patients with this rare disease. The missing protein is just supposed to cause atrophy and weakness.”

Patients with this rare disease show early muscle weakness, fluctuating levels of fatigue and lethargy, muscle aches after exercise, and elevated creatine kinase in their bloodstream, an indication of cell damage due to physical stress.

“One by one, we investigated these specific features in experimental models that look normal and have normal body weight, but also show lost muscle mass in the quadriceps and triceps,” explains Adam Horn, Ph.D., the lead researcher in Jaiswal’s lab who conducted this study. “Our experimental model lacking MICU1 only in skeletal muscles responded to muscle deficits so similar to humans that it suggests that some of the symptoms we see in patients can be attributed to MICU1 loss in skeletal muscles.”

Future research will aim to explore the details of how the impact of MICU1 deficit in muscles may be addressed therapeutically and possible implications of lacking MICU1 or its paralog in other organs.

In addition to Jaiswal and Horn, Children’s National Hospital Center for Genetic Medicine Research co-authors include Marshall W. Hogarth and Davi A. Mazala. Additional co-authors include Lead Author Valentina Debattisti, Raghavendra Singh, Erin L. Seifert, Kai Ting Huang, and Senior Author György Hajnóczky, all from Thomas Jefferson University; and Rita Horvath, from Newcastle University.

Financial support for research described in this post was provided by the National Institutes of Health under award numbers R01AR55686, U54HD090257 and RO1 GM102724; National Institute of Arthritis and Musculoskeletal and Skin Diseases under award number T32AR056993; and Foundation Leducq.

The Rare Disease Institute staff on Rare Disease Day

Genetics 101: Rare diseases aren’t rare

The Rare Disease Institute staff on Rare Disease Day

Children’s National Health System is home to the Rare Disease Institute, the National Organization for Rare Disease’s first Center of Excellence, the largest clinical genetics program in the United States.

With the advent of DNA databanks, informatics, new technology, pediatric consortiums and global partnerships, clinical researchers have never been in a better position to diagnose and treat rare diseases. A rare disease is categorically defined as a condition that affects less than 200,000 people. However, 25 to 30 million Americans, about one in 10, have a rare disease.

Accelerations in genetic research and diagnostic criteria remain one of the most significant accomplishments in medicine, but these breakthroughs invite new challenges: How will researchers provide ongoing care and treatment for patients navigating a rare disease? How can doctors and researchers multiply themselves to ensure everyone has the latest information and resources they need? How can researchers use existing trials to augment other fields? How can we diagnose, catalogue and treat hundreds of new rare diseases each year, while accelerating the research and care of 7,000 existing rare conditions?

If these questions intrigue you, excite you and make you want to collaborate with scientific peers, welcome to the field of genetics. A common theme researchers and families talk about is that rare diseases affect a small proportion of the population, but have a huge impact.

On April 10, 1,200 international researchers, lawmakers, scientists and drug developers from 50 countries will meet in Oxon Hill, Md., 10 miles south of Washington, for a three-day summit, the World Orphan Drug Congress USA, to discuss how to unify efforts to enhance and maximize care for rare disease patients.

Here are eight themes to keep in mind:

    1. Rare diseases are chronic diseases. The human genome project has enabled the molecular mapping of 8,000 diseases with genetic underpinnings. Of these diseases, 600 diseases have therapies. A child born with a urea cycle disorder had a 5% chance of surviving the disease 40 years ago. Now the survival rate is 95%. Helping children survive is essential, but we need to think about the best treatments and standards for long-term care.
    2. Rare diseases are expensive. In Western Australia, according to the 2010 Western Australia Population Cohort, rare diseases account for less than 5% of hospital visits but for 10% of hospital costs. Similar data from Cleveland finds one-third of pediatric hospital visits have a genetic link but account for half of hospital costs.
    3. Rare diseases share common links. We’ve diagnosed 7,000 rare diseases but there are more to unravel. For example, breast cancer has over 30 molecular subtypes – some of which turn into rare diseases. By better understanding these molecular pathways, we may be able to inform common fields of medicine.
Marshall Summar's Rare Disease 101 presentation

Dr. Marshall Summar, a medical geneticist, speaks about the future of rare disease research and treatment at a Rare Disease 101 lecture hosted by the Rare Disease Congressional Caucus on Capitol Hill on Feb. 27. To sustain discoveries, Dr. Summar mentions a digital-first, flexible mindset is essential. Standard language and scalable, universal reference structures are required.

  1. Global partnerships create research repositories. Gold-standard research models – double blind, controlled studies with numerous participants – aren’t possible if five people in the world share the same disease. To increase the number of study participants, global partnerships and longitudinal registries are essential.
  2. Standard language helps. To avoid replicating existing research and to help teams quickly reference findings, we need to adopt standardized language to quantify measurements. Researchers from Berlin and Brazil may help inform the etiology of and future treatments for PKU, but they need to manage, store, access and share their collective findings, while remaining flexible.
  3. The science is here. The FDA is approving more drugs for rare diseases than ever before including gene therapy and micro organs, or Rare Diseases-on-chip models. The challenge with treating so many rare diseases isn’t developing new research, but creating therapies and studies to accommodate this patient volume. About 250 rare disease discoveries happen each year. At the current rate, it will take 2,000 years to treat them all.
  4. Progress is here. The Orphan Drug Act fast-tracked approval for rare disease treatments and therapies, and nearly half of all drugs coming in for FDA approval are for rare diseases. However, only 5% of rare diseases have FDA-approved drugs.
  5. We need to replicate geneticists. To provide optimal care, doctors need to standardize education models and use new forms of technology, such as artificial intelligence and deep learning, to share resources faster via patient education portals, resources for families, CME courses and virtual connections with pediatricians or families.

If you would like to learn more or get involved, watch this international summit, the Rare Disease Day Policy Event, which took place at the United Nations Headquarters in New York on Feb. 21. (Some of these issues are covered in video 4.)

If you live in Washington, D.C., follow the genetics team and consider working with us as we move into a new home, the Children’s National Research and Innovation Campus, in 2020.

Kwitkin-family-photo

A rare diet: Could you survive on six grams of protein a day?

Clara Barton

Clara Rose Kwitkin was born at a healthy 7 pounds, 14 ounces on Nov. 12, 2018.

 

Children’s National Health System introduces clinic to help adults with phenylketonuria, a rare inherited disorder, experiment with Palynziq, an FDA-approved drug that helps the body process phenylalanine.

“What can you eat?” is a common question for picky eaters, particularly individuals with phenylketonuria (PKU), a rare inherited metabolic condition that prevents an enzyme in the body from processing the amino acid phenylalanine (Phe), a building block of protein.

About one in 10,000 or 15,000 people in the U.S. with PKU, approximately 50,000 people worldwide, understand this line of questioning. 

“It’s emotional,” says 27-year-old Ashley Kwitkin, a Northern Va. resident and new mom, about the complexities of following a low-Phe diet.

When Kwitkin previously went “off diet,” meaning eating more than six grams of protein a day, the equivalent of a handful of almonds, she felt the consequences: irritability, moodiness and poor concentration. Her body couldn’t process Phe.

The National Institutes of Health mentions excessive levels of Phe can lead to toxic levels in the blood and tissues, and even cause brain damage.

Kwitkin’s motivation during pregnancy quickly changed. “It’s not just me anymore,” notes Kwitkin, who gave birth to Clara Rose Kwitkin on Nov. 12. “It’s me and my child. The moment we met her, our lives changed forever.”  

If Kwitkin went off her PKU-approved diet while pregnant, she may have increased the chance that her baby would have been born with intellectual disabilities, heart problems, delayed growth, microcephaly or behavioral problems.

Fortunately, Kwitkin received medical clearance from her doctors to move forward with a safe and healthy pregnancy. While she is a carrier for PKU, her husband is not – which meant their child had less than a 1 percent change of being born with this rare disease.

Like many adults with PKU, Kwitkin is grateful for advancements with early disease detection and treatment. If she had been born six decades earlier, she may have been hospitalized for neurological impairments, before PKU was recognized, screened for and treated with a low-Phe diet to support cognitive development.

Kwitkin is grateful for the popularity of gluten-free, PKU-friendly products and specialty food stores – compared to when she was growing up and had to order medical bread, which cost $13 a loaf and came out of a can. This trend makes it easy to find PKU-friendly meals to eat.

Expanding her palate is one of the reasons Kwitkin is following the results of a new clinic at Children’s National to help people with PKU experiment with Palynziq, an enzyme substitution therapy that helps people with PKU digest Phe.

Palynziq was approved by the Food and Drug administration on May 24, 2018 and a team of metabolic dietitians and geneticists at Children’s National have been helping a handful of adult PKU patients test out the treatment, slowly, over a preliminary period.

To prescribe the drug in a medically-supervised setting, the doctors introduced the injectable enzyme treatment to participants in small .25-mg doses, which started on Aug. 20, 2018, and monitored their progress as they worked up to the standard 20-mg treatment, a milestone many in the group reached in November 2018.

If the treatment continues to go well, based on the results of the FDA’s recommended titration schedule, the medical team will enroll additional participants in its clinic and share the results with other medical centers.

The timing of the new Palynziq clinic is also perfect for Kwitkin. If the drug works for her in the future, she won’t have to make three dinners: one for her, one for her husband and one for Clara Rose. While Kwitkin is currently off the low-Phe diet, she looks forward to resuming a PKU-friendly diet in the future – especially as she and her husband consider having a second child.

Kwitkin’s PKU-friendly diet consists of “safe” foods, such as unlimited amounts of peaches, apples, cabbage and green beans, which contain zero traces of Phe, and portioned amounts of low-Phe foods: pasta, bread, baked potatoes and specialty-ordered, low-protein items.

While planning for pregnancy, Kwitkin adjusted her protein intake to eight grams of protein a day. During pregnancy, she ate up to 19 grams of daily protein – to satiate her body’s needs and the needs of her baby – and regularly checked in with Erin MacLeod, Ph.D., a metabolic dietitian at Children’s National who is guiding the Palynziq clinic.

Kwitkin-family-photo

Ashley Kwitkin and her husband look forward to expanding their family in the future.

While the new Palynziq therapy carries potential benefits, such as the ability to join a family potluck without counting grams of protein, have second servings of broccoli, a carefully-portioned vegetable on the PKU diet, or thinking clearly while eating a low-Phe diet, a motivating factor for many of MacLeod’s patients, the treatment also carries risks. 

Potential side effects of Palynziq include severe allergic reactions – swelling of the face, lips, eyes and tongue – as well as shortness of breath, a faster heart rate, rashes, confusion, lightheadedness, nausea and vomiting.

So far, minor side effects, such as rashes and injection-site soreness, are noted among participants in the Palynziq trial at Children’s National. The full 20-mg prescription could be increased or decreased, based on how a person’s immune system responds to the foreign agent. If all continues to go well for the participants, they will take the recommended dose, equivalent to about 20 injections a week, and check in with the medical team every three months during the first year. Based on their benefit-risk assessment of the new drug, they can then segue into bi-annual visits if they want to continue with the treatment.  

“Our goal is to help participants decide if this therapy is a good fit for them, based on their lifestyle and health preferences,” notes MacLeod. For some people, MacLeod explains, such as those entering college or who form strong social connections around food, and who may experience the impact of going ‘off diet,’ this treatment could change their lives. Others, such as those who are in the process of moving to a new city or are in a busy period of their lives, may prefer following a strict low-protein diet compared to taking daily enzyme injections.

Another factor Kwitkin and MacLeod will keep in mind as the Palynziq clinics advance is the treatment’s variability. For example, Kuvan, the first drug of its kind is an enzyme therapy developed to help the body break down Phe. The drug was approved by the FDA in 2007, but only works in a small portion of the PKU population – about 10 percent of patients with a mild form of the condition. Instead of eating high-Phe foods, Kuvan users follow a mild-protein diet.

MacLeod views this type of individualized meal planning and how her patients react to food as a science, which drew her to the field. She works with 70 to 100 PKU patients each year from infancy to adulthood, including patients in their 60s, to help them meet their unique metabolic needs.

MacLeod is also tracking the use of gene therapy in metabolic disorders in addition to how the gut flora, or gut bacteria, helps PKU patients modulate and break down Phe.

“A lot of research is happening right now,” adds MacLeod about accelerations with PKU therapy. “I’ve seen how patients respond to new treatments, including a carefully-measured, low-Phe diet, and how their lives start to change once they can think clearly and feel better, which is a motivating factor and goal for many of our patients. I’ve also seen others pursue their dreams, which in Kwitkin’s case was to become a parent and history teacher.”

Like Kwitkin and others impacted by PKU, MacLeod looks forward to ongoing developments and research for this rare disease.

 

Maureen E Lyon

Maureen E. Lyon, Ph.D., ABPP, lauded for outstanding excellence in patient-centered advance care planning

Maureen E Lyon

Maureen E. Lyon, Ph.D., a principal investigator at Children’s Center for Translational Science, will be honored with a “Recognition Award for Excellence and Innovation in Research” by Respecting Choices for outstanding excellence in patient-centered advance care planning and shared decision-making.

Respecting Choices will present the award on Oct. 26, 2018, during its “National Share the Experience Conference” in Bloomington, Minnesota.

Lyon’s expertise is in advance care planning and shared decision-making for children and adolescents with life-threatening illnesses and their families, a field that has transformed in recent decades in order to pave better paths forward for difficult but necessary conversations.

“It came from my clinical experience,” Lyon says. “In the early days of the human immunodeficiency virus (HIV) epidemic in the U.S., everything, absolutely everything, was done to keep the kids alive in the hopes that some new drug would come around the corner, and we could bring them back from the brink. I remember one of the young boys saying to his case manager that he didn’t want all of these interventions. But he hadn’t told his family.”

That young man’s eye-opening comments – and learning that Children’s National Health System had a policy that teenagers were to be included in conversations about their own advance care planning – inspired Lyon to conduct a series of surveys involving adolescents, families and clinicians.

“I remember sitting down with friends and saying ‘There must be a better way to do this. Everyone is afraid to broach the subject,’ ” Lyon recalls. So, she conducted surveys of all healthy kids coming through Children’s adolescent clinic and kids diagnosed with HIV, cancer and sickle cell disease.

“It turned out the kids did want to talk about it. That was the first thing. Families told us they wanted help breaking the ice. Physicians felt it wasn’t their role – many doctors felt their role was to save people – or, they didn’t have the training,” she says.

Through a series of focus groups with youths living with HIV, families and community members, Lyon adapted the adult-centric Respecting Choices model to create a three-session intervention to better meet the advance care planning needs of youths and adolescents living with HIV.

Lyon’s recent work includes a single-blinded, randomized study published Oct. 19, 2018, in Pediatrics that finds the more families understand the end-of-life treatment preferences expressed by adolescents living with HIV, the less likely these youth are to suffer HIV-related symptoms, compared with youths whose families do not understand their end-of-life care goals.

She also has adapted the Respecting Choices intervention to facilitate its use with children diagnosed with cancer. More recently, she has adapted the model for use by parents of children with rare diseases who cannot communicate on their own.

“For the other life-threatening health conditions, we worked to support adolescents in expressing their advance care planning choices in their own voices. With rare diseases, we’re shifting gears,” she adds.

Published research indicates a sizable proportion of pediatric patients who die in hospitals now have confirmed or suspected rare diseases, she says. During a pilot involving seven families, many parents multitasked during the conversations, taking pauses to attend to various alarms as they sounded, to complete regular feedings and to contend with their child’s petit mal seizures.

“The level of burden of taking care of these children with terminal illnesses was pretty overwhelming,” she says. “Still, families were not too burdened to participate in advance care planning, but first wanted to identify their priority palliative care needs and to develop a support plan to meet those needs. We also had more fathers involved.”

Telemedicine

A rare prescription: Providing children with palliative care

Telemedicine

A pilot program at Children’s National enabled parents of children with extremely rare diseases to receive in-person or virtual health consultations with a trained provider.

Pediatric advance care planning (pACP) and making complex  medical decisions is especially difficult for parents of children with extremely rare diseases. Imagine if your child is the only person in the world with a rare disease that may limit basic functions: eating, breathing, walking and talking. Now, imagine you are presented with two scenarios: Experiment with a new drug to see if it improves your child’s conditions or plan for near-future, end-of-life care.

While these types of difficult decisions for parents of children with rare diseases are common, a new counseling model, based on a four-session pilot program conducted at Children’s National, aims to ease this process by providing parents with a comprehensive support plan.

On Oct. 15 and 16, Maureen Lyon, Ph.D., a clinical psychologist at Children’s National and a professor of pediatrics at the George Washington University School of Medicine and Health Sciences, will present “Living on the Precipice: The Journey of Children with Rare Diseases and Their Families” at a poster session at the National Organization for Rare Disorders’ Rare Disease and Orphan Products Breakthrough Summit at the Marriott Wardman Park in Washington.

Dr. Lyon will highlight key take-home points she observed during the pilot program:

  • Background: Eight families were recruited for the pilot program and seven enrolled. Six completed the four-session program, which was spread out over two months.
    • All parents were mothers, but two fathers joined for the goal-planning care conversation sessions. Some families brought their children to visits.
    • Five parents were married and two were single.
    • Four families identified as Caucasian, three families identified as African American, and one family identified as American Indian or Alaska Native.
  • Visits: About half of the families – three – attended the sessions at Children’s National. Four used the telemedicine option. A research nurse, clinical psychologist and advanced practice nurse participated in the 60- to 90-minute sessions.
  • Plans: The families discussed basic palliative care needs, such as comprehensive care coordination, which is highly individualized, before discussing their goals of care. After their needs and goals were discussed, the families created advance care plans to guide them during a medical crisis.
  • Results: Out of the six parents who completed the study, the mean positive caregiver appraisal score increased from 4.5. To 4.7, mean family well-being increased from 3.9 to 4.1, and the mean score for meaning and peace increased from 21.4 to 23.3. The scores were calculated by using the Carer Support Needs Assessment Tool (CSNAT) during the assessment and with modified protocols to assess quality of life and caregiver appraisal after the intervention.

Maureen Lyon

“The goal of palliative care is to optimize quality of life for children with life-threatening illnesses and their families by anticipating, preventing and treating suffering in all its forms,” explains Maureen Lyon, Ph.D. “This is delivered throughout illness and addresses physical, intellectual, emotional, social and spiritual needs.”

“These sessions increased a family’s sense of overall well-being,” says Jessica Thompkins, B.S.N., R.N., C.P.N., a research nurse coordinator with the FAmily CEntered Advanced Care Planning Team (FACE) and a co-author of the poster. “The families felt better just by knowing that they had time scheduled each week to connect with a trained medical provider to discuss a range for options they need as a caregiver, from everyday care at home to long-term health care planning at the hospital.”

The top-rated support need identified by all parents, according to the survey: “Knowing what to expect in the future when caring for their children.”

“The goal of palliative care is to optimize quality of life for children with life-threatening illnesses and their families by anticipating, preventing and treating suffering in all its forms,” says Dr. Lyon. “This is delivered throughout illness and addresses physical, intellectual, emotional, social and spiritual needs.”

The researchers would like to use this pilot to partner with other medical centers to create an evidence-based template to support the palliative care needs of family caregivers who have children with life-limiting rare diseases. Their goal is to improve a family caregiver’s quality of life, over time, and increase the completion and documentation of advance care plans for children of all ethnic and racial groups.

Rare diseases are defined as a disease that affects fewer than 200,000 people in the U.S. Extremely rare diseases, including those observed in this pilot, may affect just one or a few people in the world.

The rare disease pilot program is based on previous pACP models with adolescent HIV and pediatric cancer populations.

Additional poster authors include Jichuan Wang, Ph.D., Karen Fratantoni, M.D., M.P.H., Kate Detwiler, Ph.D., Yao Cheng, M.S., and Marshall Summar, M.D.