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Andrew Dauber

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

Andrew Dauber

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

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

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

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

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

Dr. Natasha Shur shares “Genetics and Telemedicine: Extending Our Reach” at the Future of Pediatrics CME

Virtual visits: A new house call for rare disease treatment

Dr. Natasha Shur shares “Genetics and Telemedicine: Extending Our Reach” at the Future of Pediatrics CME

Natasha Shur, M.D., an attending clinical geneticist at Children’s National Health System, shares “Genetics and Telemedicine: Extending Our Reach” at the Future of Pediatrics CME symposium in Bethesda, Maryland, on June 20.

“For the first time it wasn’t autism, autism, autism,” Shannon Chin says after learning the reason her newborn daughter, Sariyah, who turned 3 in August, couldn’t feed like normal infants was due to a tiny deletion of chromosome 22. This atypical deletion, a variation of a genetic condition known as 22q11.2 deletion syndrome, left Sariyah unable to suck and obtain nourishment as an infant. She was born premature and relied on assisted feeding tubes, inserted through her nose, to help her grow.

At 22-weeks-old, Sariyah received the diagnosis, which affects 1 in 4,000 children born each year. Sariyah’s genetic tests encouraged Chin to follow up with a nagging question: What if her two sons, Rueben and Caleb, both of whom were diagnosed with autism spectrum disorder (ASD), had something else?

Debra Regier, M.D., a medical geneticist at Children’s National Health System, encouraged Chin to follow up with a genetic test to answer these questions and to confirm 22q11.2 deletion syndrome symptoms she observed in Rueben.

A microarray analysis recently revealed Rueben, 17, has atypical  22q11.2 deletion syndrome. Caleb, 5, took the test and has developmental delay and ASD, which is more likely to occur in children with 22q11.2 deletion syndrome. He tested negative for the same deletion as his siblings. Additional tests are underway.

As Chin juggles complex care for her children, she realizes the partial deletion of chromosome 22 presents differently in every child. Sariyah and Rueben share short stature; they fit into tiny clothes. That’s where the phenotypical clues stop. They don’t have a cleft palate or dysmorphic facial features, distinctive of typical cases of 22q11.2 deletion syndrome. Sariyah has physical symptoms. Her intestines merged together, which gastrointestinal surgery fixed. Rueben experiences behavioral and neurological symptoms, including picky eating, aggression and uncontrolled body movements, which led the Chin family to Dr. Regier. Sariyah, Rueben and Caleb all have neurodevelopmental delays that impact their speech and development.

Coordinating multiple visits with geneticists, specialists, surgeons, genetic counselors and pediatricians, while navigating insurance, is a lot for any parent, but especially for those, like Chin, who have special considerations. Her children are non-verbal, so she pays close attention to their physical cues. Simplifying this process is one reason why Natasha Shur, M.D., a medical geneticist at Children’s National, introduced virtual visits to her patients, including Rueben, who had challenges with in-person visits. She thought: How can we make medical care easier for patients and families?

In January, Dr. Shur expanded virtual visits into a pilot program for 50 to 60 patients, including Sariyah and Caleb, with the support of a grant from the Health Resources and Services Administration (HRSA), the division of telemedicine at Children’s National and the Rare Disease Institute (RDI), the medical home to thousands of pediatric patients living with rare or genetic conditions. This program lets patients with concern for or already diagnosed genetic conditions in Maryland, the District of Columbia and Virginia, where Dr. Shur is licensed to practice medicine, test out virtual visits. Patients can download the HIPAA-compliant app or click through a secure link on a digital device to connect with Dr. Shur or a pediatric subspecialist.

Dr. Shur shares the preliminary findings of a new virtual visits pilot program,

Dr. Shur shares the preliminary findings of a virtual visits pilot program, which 50-60 local patients have tested in conjunction with in-person visits as a flexible way to manage medical care for genetic conditions.

On June 20, Dr. Shur shared a presentation about the program, “Genetics and Telemedicine: Extending Our Reach,” with pediatricians attending the Children’s National Future of Pediatrics continuing medical education (CME) symposium in Bethesda, Maryland.

Instead of a formal pilot program launch and end date with data, Dr. Shur mentions she conducts quality improvement assessments with each patient. She asks what they like about virtual visits. Do they feel comfortable with the software and technology? What types of visits do they prefer to do at home? What works best at the hospital? Do they want to keep using this program?

For Chin and most participants, the answer is yes. These families appreciate saving time, mileage, and being in close access to pediatric subspecialists from the comfort of home.

Parents can conference call from separate locations and share screens with the doctors, which works well if one parent is at work and another is at home – or if they live apart. Children can maintain their normal routine, such as finishing breakfast, homework, playing or staying in bed if they don’t feel well, though it is important to see the child in the virtual visit.

Families can obtain virtual assessments about urgent conditions without taking time off from work or school. Currently, only 10 to 30% of virtual visit patients with concerns about genetic conditions need an in-person, follow-up appointment. Fortunately, many conditions are less urgent than thought at the time of referral. Dr. Shur and specialists also benefit from observing children in their natural environment.

At the symposium, Dr. Shur translates this into clinical terms: reduced no-show visits, the ability to schedule shorter, more flexible visits, the ability to quickly and accurately diagnose conditions and provide care, and the ability to keep children with compromised immune function out of public areas, including waiting rooms. She discussed building rapport with patients, almost all of whom like these flexible care models.

“The idea is that we’re trying to understand what is best done using virtual technology and what is better for those in-person connections. More detailed physical exams take place in person. There are some cases where eye-to-eye contact and sitting in the exam room together is important,” says Dr. Shur. “Virtual visits should never replace in-person care. It’s just a forward way of thinking about: How do we use our time best?”

Case study 1: Saving families time and miles

Dr. Shur notes that for some patients, distance is a deciding factor for scheduling care. One mother’s five-hour round-trip commute to the children’s hospital, without traffic, is now five minutes. As an air-traffic controller, her schedule changes. She values the flexibility of the new program. To connect with Dr. Shur, she logs into the app on her computer or smart phone and brings her 2-year-old son into the video. He has cardiofaciocutaneous syndrome (CFC), a condition that affects 200 to 300 people in the world. As a result of a MAP2K1 gene variant, one of four genes – BRAF, MAP2K1, MAP2K2 and KRAS – associated with CFC, he experiences feeding problems, reflux, constipation and developmental delays.

By scheduling more frequent, but shorter check-ins, Dr. Shur assesses how he responds to treatment and makes recommendations to the mother in real time, such as trying prune juice for digestive health. They talk about rearranging feeding measurements and intervals, including his 2 a.m. dose of a peptide formula, which the mom blends at home to support her son’s growth. This modification equates to more sleep for everyone.

If follow-up tests, such as an X-ray or a blood test are needed, Dr. Shur coordinates these exams with the family at the hospital or at a nearby medical center. Depending on the condition, Dr. Shur may refer the family to an ophthalmologist, cardiologist, neurologist or learning and development specialist.

As a parent, Dr. Shur appreciates the direct approach virtual visits deliver.

“As a mom, if I’m taking my child to the doctor for two hours, I want to know why I’m there,” Dr. Shur says. “What are all the options?”

Case study 2: Observing children at home

Chin, who was also featured in Dr. Shur’s CME presentation, appreciates virtual visits for their convenience and efficiency, but her favorite feature is letting doctors observe her children at home.

“Children act differently outside the home,” says Chin.

For example, instead of describing Rueben’s rapid, rhythmic arm movements, a flinging of the arms, Chin showed neurologists at a scheduled virtual home visit. For Marc DiFazio, M.D., a pediatric neurologist, it was evident that Reuben had a movement disorder commonly seen in children with ASD, which is responsive to medication. In five minutes, her son had a diagnosis. The involuntarily movement wasn’t a behavioral issue, as previously thought, but a movement disorder.

“The regular in-person visit has a beautiful role and it’s very important, but virtual visits bring a different focus,” says Dr. Shur. “We get to see what the child’s life is like, what the home setting is like and what their schedule is like. How can we make their day-to-day life easier?”

Phenylketonuria (PKU), a rare condition that prevents the body from breaking down phenylalanine (Phe), an amino acid in protein, is another condition that pairs well with virtual visits. PKU affects 1 in 10,000 to 15,000 newborns in the U.S. People with PKU often require medication, food-based formulas and a protein-restricted diet to help their body process or regulate Phe.

If a patient with PKU connects through a virtual visit, they (or their parents) can open the refrigerator, talk about low-protein foods, discuss potential barriers to following a low-Phe diet, show the team new supplements or over-the-counter medications they are taking, discuss reactions to new therapies and, for adults, discuss an injectable drug recently approved by the FDA that has side effects but may ultimately allow them to follow a regular diet. These observations may not warrant a traditional trip to the doctor but are important for geneticists and patients to discuss. The goal of these visits is to identify and work around potential health barriers, while preventing adverse health outcomes.

To support this model, a 60-minute in-person visit scheduled every six months to a year can be broken into 15-minute video appointments at more frequent intervals. The result, based on the same amount of clinical time, is a targeted and detailed assessment to support personalized treatment and to help the patient adapt to a low-Phe meal plan.

During the video call, Dr. Shur and the team may prescribe a different medication, order a diagnostic procedure or schedule a follow-up appointment, if necessary. Depending on the situation, the patient will still likely come in for in-person annual visits.

Program assessment: Evaluating visits for each patient

Despite the popularity of virtual visits, Dr. Shur mentions this program isn’t a good fit for everyone – depending on a patient’s preferences. There are also limitations to consider. If a parent is hesitant to try this platform or if the comprehensive physical examination is the first key step, they should schedule in-person visits. The goal is to give parents who are requesting or curious about virtual visits a chance to try the platform. Having a secure area, preferably a private space at home, is important. A Wi-Fi connection and a digital device are required, which may create barriers for some patients.

However, Dr. Shur finds the program can alleviate hurdles – such as transportation challenges. One patient lives two hours away and couldn’t make it in for routine medical visits due to car problems. Now she makes every virtual appointment. For the first time in her life, she can manage medical care for herself and for her children.

Most insurance companies Dr. Shur works with cover virtual visits. The key is to have the virtual connection, or video, so Dr. Shur can still physically see the patient. Otherwise, the visit doesn’t count. A grant from CareFirst covers the costs of visits for patients who are using Medicaid or who don’t have medical insurance.

Parallel trends are happening across the country and for other conditions. Officials at the Federal Communications Commission (FCC) are reviewing a three-year pilot to expand the use of connected care services, like virtual visits, for low-income Americans living in rural areas. The Rural Health Care Program, funded by the FCC, supports hospitals that implement telehealth programs.

The American Academy of Pediatrics (AAP) released a statement in 2015 about telemedicine technologies, noting that if these technologies are applied in a synergistic model under one health care system or are guided by a family doctor, they can transform pediatric health care.

The key is to avoid a fragmented virtual health system.

The AAP applauds virtual connections that support collaborations among pediatric physicians, subspecialists and surgeons, reduce travel burdens for families, alleviate physician shortages, improve the efficiency of health care and enhance the quality of care and quality of life for children with special health care needs.

Planning for the future, investing in physician-patient partnerships

A poster at the Future of Pediatrics conference

The American Academy of Pediatrics supports telemedicine technologies that enhance the quality of care and the quality of life for children with special health care needs.

“The feedback has been phenomenal,” Dr. Shur says about the future of virtual visits for genetics. “Virtual visits will never replace in-person visits. They will be used in conjunction with in-person visits to maximize care.”

Dr. Regier and Jamie Frasier, M.D., Ph.D., medical geneticists at Children’s National, are introducing virtual visits to their patients, and many providers plan to do so as the program expands.

Sarah Viall, PPCNP, a nurse practitioner and newborn screening specialist, works with Dr. Shur and the geneticists during some visits to explain non-urgent newborn screening results to parents through virtual connections. Some parents find it’s easier to dial in during lunch or while they are together at home.

To improve education for patients and families, the education and technology committees at the RDI – led by geneticists and genetic counselors in partnership with the Clinical and Translational Science Institute at Children’s National – launched a new smartphone app called BearGenes. Families can watch 15 videos about genetics on the pin-protected app or view them online. The interactive guide serves as a gene glossary for terms patients may hear in a clinical setting. Topics range from genetics 101, describing how DNA is encrypted in the body through four letters – A, T, C and G – to different types of genetic tests, such as whole exome sequencing, to look for differences in the spelling of genes, which the genetic counselors explain are genetic mutations.

“As we unite patients with virtual health platforms and new forms of technology, we want to see what works and what doesn’t. We want their feedback,” Dr. Shur reemphasizes. “Virtual visits are a dynamic process. These visits only work through patient partnership and feedback.”

As Chin navigates atypical 22q11.2 deletion syndrome and ASD, she continues to appreciate the virtual waiting room and the ease of access virtual visits provides.

Sharing screens during virtual visits enables Chin to examine and better understand her children’s abdomen and kidney sonograms, cardiology reports and hearing exams. It forces everyone in the visit to focus on one topic or image at a time, strengthening the connection.

Chin still has questions about her children’s DNA, but she’s getting close to having more answers. She’s eager to see Caleb’s genetic test results and to work with Hillary Porter, M.S., CGC, the family’s genetic counselor, to interpret the data.

“We’re all learning together,” Dr. Shur says about the new pilot program, which applies to genomics at large.

As research about 22q11.2 deletion syndrome advances, geneticists, pediatric subspecialists and pediatricians are unifying efforts to work as one diagnostic and treatment team. Virtual visits enable faster consultations and can shorten diagnostic odysseys, some of which may take up to five years for children with rare disorders.

Attendees at the Future of Pediatrics conference

Nearly 400 pediatricians attend the Children’s National Future of Pediatrics CME symposium to learn about the future of pediatrics and about ways to work together as a diagnostic and treatment team.

For Chin, by better understanding how a tiny fragment of a missing chromosome may influence her children’s growth and development, she is already making long-term plans and coordinating multidisciplinary medical treatment for each child.

She hopes that by sharing her story and knowledge about 22q11.2 deletion syndrome, she can help other parents navigate similar situations. Heradvice to parents is to follow up on lingering questions by bringing them up with your medical team.

Chin is optimistic and happy she did. She’s grateful for the virtual visits program, which simplifies complex care for her family. And she’s still waiting, but she hopes to learn more about her middle child’s DNA, unraveling another medical mystery.

Read more about the virtual visits pilot program at Becker’s Hospital Review and listen to an interview with Dr. Shur and Shannon Chin on WTOP.

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.
  4. 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.

  5. 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.
  6. 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.
  7. 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.
  8. 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.
  9. 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 are a patient, download this patient toolkit from the National Center for Advanced Translational Sciences.

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.

DNA

International collaboration discovers new cause for dwarfism

DNA

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

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

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

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

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

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

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

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

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

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

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

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

E coli bacteria

Urinary bacteria in spinal cord injury cases may tip balance toward UTIs

E coli bacteria

Patients with spinal cord injuries nearly universally have bacteria present in their urine regardless of whether they have a urinary tract infection.

The fallout from spinal cord injury doesn’t end with loss of mobility: Patients can have a range of other issues resulting from this complex problem, including loss of bladder control that can lead to urine retention. One of the most serious implications is urinary tract infections (UTIs), the most common cause of repeat hospitalization in people with spinal cord injuries, explains Hans G. Pohl, M.D., associate chief in the division of Urology at Children’s National Health System.

Diagnosing UTIs in people with spinal cord injuries is trickier than in people who are otherwise healthy, Dr. Pohl explains. Patients with spinal cord injuries nearly universally have bacteria present in their urine regardless of whether they have a UTI. It’s unclear whether these bacteria are innocent bystanders or precursors to UTIs in patients who don’t yet show symptoms. And although antibiotics can wipe out this bacterial population, these drugs can have undesirable side effects and frequent use can promote development of antibiotic-resistant bacteria.

Although clinical dogma has long promoted the idea that “healthy” urine is sterile, Dr. Pohl and colleagues have shown that a variety of bacteria live in urine, even in people without symptoms. These microorganisms, like the intestinal microbiome, live in harmony with their hosts and may even help promote health. However, it’s unclear what this urinary microbiome might look like for patients with spinal cord injury before, during and after UTIs.

To start investigating this question, Dr. Pohl and co-authors recently reported a case study they published online Sept. 21, 2018, in Spinal Cord Series and Cases. The case report about a 55-year-old man who had injured the thoracic segment of his spinal cord—about the level of the bottom of his shoulder blades—in a skiing accident when he was 19 was selected as “Editor’s Choice” for the journal’s October 2018 issue.  The patient had a neurogenic bladder, which doesn’t function normally due to impaired communication with the spinal cord. To compensate for this loss of function, this patient needed to have urine removed every four to six hours by catheterization.

Over eight months Dr. Pohl, the study’s senior author, and colleagues collected 12 urine samples from this patient:

  • One was collected at a time the patient didn’t show any symptoms of a UTI
  • Nine were collected when the patient had UTI symptoms, such as bladder spasticity
  • Two samples were collected when the patient had finished antibiotic treatment for the UTI.

The researchers split each sample in half. One part was put through a standard urinalysis and culture, much like what patients with a suspected UTI would receive at the doctor’s office. The other part was analyzed using a technique that searched for genetic material to identify bacteria that might be present and to estimate their abundance.

The researchers found a variety of different bacteria present in these urine samples. Regardless of the patient’s health status and symptoms, the majority of these bacterial species are known to be pathogenic or potentially pathogenic. By contrast, this patient’s urine microbiome appeared to largely lack bacterial species known to be either neutral or with potentially probiotic properties, such as Lactobacillus.

All of the bacteria that grew in culture also were identified by their genetic material in the samples. However, genetic sequencing also identified a possible novel uropathogenic species called Burkholderia fungorum that didn’t grow in the lab in five of the samples. This bacterium is ubiquitous in the environment and has been identified in soil- and plant-based samples. It also has been discovered in the respiratory secretions of patients with cystic fibrosis, in patients with a heart condition called infectious endocarditis, in the vaginal microbiota of patients with bacterial vaginosis, and in the gut of patients with HIV who have low T-cell counts. Dr. Pohl says it’s unclear whether this species played an infectious role in this patient’s UTI or whether it’s just part of his normal urine flora.

“Consistent with our previous work, this case report demonstrates that rather than healthy urine being sterile, there is a diverse urine bacterial ecosystem during various states of health and disease,” Dr. Pohl says. “Rather than UTIs resulting from the growth or overgrowth of a single organism, it’s more likely that a change in the healthy balance of the urine ecosystem might cause these infections.”

By monitoring the relative abundance of different bacteria types present in the urine of patients with spinal cord injury and combining this information with a patient’s symptoms, Dr. Pohl says doctors may be able to make more accurate UTI diagnoses in this unique population.

In addition to Dr. Pohl, study co-authors include Marcos Pérez-Losada, Ljubica Caldovic, Ph.D., Bruce Sprague and Michael H. Hsieh, M.D., Children’s National; Emma Nally, Suzanne L. Groah and Inger Ljungberg, MedStar National Rehabilitation Hospital; and Neel J. Chandel, Montefiore Medical Center.

little girl in hosptial corridor

A growing list of factors that impact CKD severity for kids

little girl in hosptial corridor

Myriad biological and societal factors can impact the occurrence and accelerate progression of chronic kidney disease for children of African descent – including preterm birth, exposure to toxins during gestation and lower socioeconomic status – and can complicate these children’s access to effective treatments.

Myriad biological and societal factors can impact the occurrence and accelerate progression of chronic kidney disease (CKD) for children of African descent – including preterm birth, exposure to toxins during gestation and lower socioeconomic status – and can complicate these children’s access to effective treatments, according to an invited commentary published in the November 2018 edition of American Journal of Kidney Diseases.

Clinicians caring for “these vulnerable children should be mindful of these multiple competing and compounding issues as treatment options are being considered along the continuum from CKD to kidney failure to transplantation,” writes Marva Moxey-Mims, M.D., chief of the Division of Nephrology at Children’s National Health System.

The supplemental article was informed by lessons learned from The Chronic Kidney Disease in Children (CKiD) longitudinal study and conversations that occurred during the Frank M. Norfleet Forum for Advancement of Health, “African Americans and Kidney Disease in the 21st Century.”

African American children represent 23 percent of the overall population of kids with CKD in the CKiD study. While acquired kidney diseases can get their start during childhood when the diseases betray few symptoms, the full impact of illness may not be felt until adulthood. A number of factors can uniquely affect children of African descent, heightening risk for some kids who already are predisposed to suffering more severe symptoms. These include:

  • Preterm birth. African American children make up 36 percent of patients in CKiD with glomerular disease, which tends to have faster progression to end-stage renal disease. These diseases impair kidney function by weakening glomeruli, which impairs the kidneys’ ability to clean blood. Patients with a high-risk apolipoprotein L1 (APOL1) genotype already are at higher risk for focal segmental glomerulosclerosis (FSGS) and CKD. Researchers hypothesize that preterm birth may represent “a second hit that facilitates the development of glomerular damage resulting from the high-risk genotype.” According to the Centers for Disease Control and Prevention, 1 in 10 U.S. infants in 2016 was born preterm, e.g., prior to 37 weeks gestation.
  • APOL1 genotype. Compared with children who had a low-risk genotype and FSGS, children with a high-risk genotype had higher rates of uncontrolled hypertension, left ventricular hypertrophy, elevated C-reactive protein levels and obesity.
  • Human immunodeficiency viral (HIV) status. About 65 percent of U.S. children with HIV-1/AIDS are African American. In a recent nested case-control study of children infected with HIV in the womb, infants with high-risk APOL1 genotypes were 3.5 times more likely to develop CKD with viral infection serving as “a likely second hit.”
  • Access to kidney transplant. African American adults experience a faster transition to end-stage renal disease and are less likely to receive kidney transplants. African American children with CKD from nonglomerular diseases begin renal replacement therapy 1.6 years earlier than children of other races, after adjusting for socioeconomic status. Their wait for dialysis therapy was 37.5 percent shorter. However, these African American children waited 53.7 percent longer for transplants. Although donor blood types, genetic characteristics and other biological factors each play contributing roles, “these findings may reflect sociocultural and institutional differences not captured by socioeconomic status,” Dr. Moxey-Mims writes.

To alleviate future health care disparities, she suggests that additional research explore the impact of expanding services to pregnant women to lower their chances of giving birth prematurely; early childhood interventions to help boost children’s educational outcomes, future job prospects and income levels; expanded studies about the impact of environmental toxicities on prenatal and postnatal development; and heightened surveillance of preterm infants as they grow older to spot signs of kidney disease earlier to slow or prevent disease progression.

“Clinicians can now begin to take into account genetics, socioeconomic status and the impact of the built environment, rather than blaming people and assuming that their behavior alone brought on kidney disease,” Dr. Moxey-Mims adds. “Smoking, not eating properly and not exercising can certainly make people vulnerable to disease. However, there are so many factors that go into developing a disease that patients cannot control: You don’t control to whom you’re born, where you live or available resources where you live. These research projects will be useful to help us really get to the bottom of which factors we can impact and which things can’t we prevent but can strive to mitigate.”

The article covered in this post is part of a supplement that arose from the Frank M. Norfleet Forum for Advancement of Health: African Americans and Kidney Disease in the 21st Century, held March 24, 2017, in Memphis, Tennessee. The Forum and the publication of this supplement were funded by the Frank M. Norfleet Forum for Advancement of Health, the Community Foundation of Greater Memphis and the University of Tennessee Health Science Center.

Test tube that says IGF-1 test

PAPPA2: A genetic mystery

Test tube that says IGF-1 test

What would happen if you suddenly stopped growing at age 12 or 13?

Solving genetic growth mysteries and scheduling regular appointments with pediatric endocrinologists is atypical for most parents and pediatricians.

However, for children with growth disorders – a classification that typically describes children below the third or above the 97th percentile of growth charts for their age – receiving a diagnosis is half the battle to reaching average height. Understanding and creating treatment for a growth disorder, which could stem from an underlying medical illness, a genetic mutation or a problem with endocrine function, such as the production or action of growth hormone, is often the next step.

For Andrew Dauber, M.D., MMSc., the chief of endocrinology at Children’s National Health System, a third step is to use these clues to create larger datasets and blueprints to identify risk factors for rare growth disorders. By understanding genetic markers of growth disorders, endocrinologists can identify solutions and create plans for multidisciplinary care to help children reach developmental milestones and receive coordinated care throughout their lifespan.

A case study that Dauber and his research team continue to explore is how to correct for mutations in the PAPPA2 gene, which regulates human growth by releasing a key growth factor called insulin-like growth factor 1 (IGF-1). Dauber and his colleagues recently described a mutation in PAPPA2, observed in two families with multiple children affected with significant short stature. He found that this mutation decreased the bioavailability of IGF-1, stunting the growth and development of the children who carry this mutation.

While the PAPPA2 mutation is rare, endocrinologists, like Dauber, who understand its function and dysregulation can create solutions to support IGF-1 bioavailability, thereby supporting healthy growth and development in children.

Understanding barriers to IGF-1 function can also help researchers gain insight into the relationship between PAPPA2, levels of circulating insulin in the body, which could cause insulin resistance, and other growth hormones. For now, Dauber and his research team are exploring how to use PAPPA2 to increase IGF-1 in circulation among people with height disorders in the hopes of improving their growth.

“The population of children who have PAPPA2 mutations is small and we’re finding out that two children could respond to the same treatment in different ways,” says Dauber. “One medication could work modestly in one child and support short growth spurts, such as growing by 5 or 6 cm a year. It could also create undesirable side effects, such as headaches and migraines in another, and render it ineffective. However, the clues we walk away with enable us to test new solutions, and confirm or dissolve our hunches, about what may be preventing the bioactive release of essential growth hormones.”

To generate controls for healthy patterns of growth and development, Dauber and his research team are analyzing the relationship between PAPPA2, STC2 and IGFBP-3 concentrations among 838 relatively healthy pediatric participants, ages 3-18, with traditional growth patterns.

They are studying PAPPA2, STC2 and intact IGFBP-3 concentrations throughout childhood and the researchers are already surprised to find PAPPA2, a positive modulator of growth and IGF- bioavailability, decreased with age, while STC2, a negative modulator and traditional growth inhibitor, increased with age.

“As pediatric endocrinology researchers and clinicians, we’re looking at the pathology of traditional growth patterns and growth disorders with an open mind,” says Dr. Dauber. “These data sets are invaluable as they confirm or challenge our theories, which enable us to create and test new forms of personalized treatments. We’ll continue to share this knowledge, which informs other researchers and accelerates the field of pediatric endocrinology.”

This research was presented at the annual meeting of the European Society of Pediatric Endocrinology in Athens on Sept. 28, 2018.

Dauber and his research team will present their findings at endocrinology conferences and grand rounds throughout 2018 and 2019.

To view Dr. Dauber’s most recent research and pediatric endocrinology reviews, visit PubMed.

vitamins

Use of dietary supplements in children with Down syndrome

vitamins

There is a widespread practice of parents giving dietary supplements to children with Down syndrome in the hope of improving intelligence or function, according to new research published in The Journal of Pediatrics. The study, conducted by experts at Children’s National Rare Disease Institute (CNRDI), examined the prevalence, perceived impact, cost and other factors related to dietary supplement use in children with Down syndrome.

The survey finds nearly half of 1,167 respondents – 49 percent – have given or currently give dietary supplements to their children in an effort to improve health and development. On average, children receive three of the more than 150 supplements reported, with nearly 30 percent of users beginning supplementation before the child’s first birthday.

Amy Feldman Lewanda, M.D., a medical geneticist at CNRDI and lead author on the study, notes that the results also reveal a troubling trend – nearly 20 percent of parents who report using dietary supplements do not inform their pediatrician.

“While we know supplements are given by parents in hopes of improving developmental outcomes for children with Down syndrome, many of these supplements contain concerning ingredient profiles that can have adverse effects in infants and children that are too young to communicate their symptoms,” says Dr. Lewanda. “Additionally, these supplements have no proven safety or efficacy, so it’s important for families to consult with their pediatrician or primary care provider to help determine any risk, ill effects or conflicts with existing treatment.”

Reasons for not informing pediatricians about supplement use vary, according to the study results. The most common reason reported was that the doctor has never specifically asked about nutritional supplements. While some parents indicate they do not view supplement use as important medical information to divulge, others feel that their pediatrician may not be knowledgeable about these types of supplements or may dismiss the practice entirely, as some reportedly have done in the past.

Amy Feldman Lewanda

Amy Feldman Lewanda, M.D., a medical geneticist at CNRDI and lead author on the study.

The most popular class of products reported by 25.8 percent of respondents taking supplements are antioxidants, such as curcumin, a byproduct of turmeric, and epigallocatechin-3-gallate (ECGC), the polyphenol compound in green tea. Vitamins, both single and multivitamins, rank second, accounting for 18.9 percent of supplement use. B vitamins were the most popular among single vitamin use. The third most popular supplement category, reported by 15.8 active or previous supplement users, contains proprietary products or combination supplements, such as Nutrivene-D or HAP-CAPS (High Achievement Potential Capsules).

According to Dr. Lewanda, chemical analyses of herbal supplements find some contain anabolic steroids or pharmaceuticals that aren’t listed in the ingredients. Hepatoxicity has been cited among 60 herbs, herbal drugs and herbal supplements. The problem, she notes, is that these products aren’t regulated, like pharmaceuticals are, and similarly, they aren’t thoroughly tested for their safety and efficacy.

The study also notes potential concerns about consuming hyper-concentrated forms of fat-soluble vitamins, including vitamin E and vitamin K, which stay in the body until the vitamins are used. One particular supplement, Speak, provides 5,000 percent of the recommended daily value limits of vitamin E. Fat-soluble vitamins and/or herbal supplements pose unknown health risks – including liver damage.

Among study respondents who actively provide supplements to their children, roughly 87 percent feel they are effective. Those who stopped administering supplements to their children cite lack of efficacy and cost – approximately $90.53 per month on average – as leading reasons for discontinuing use. Approximately 17 percent of respondents note side-effects of supplement use, specifically gastrointestinal disturbance, which was the most common side effect among active and previous supplement users.

“This research gives pediatricians a bit of a wake-up call on what’s trending in the Down syndrome community and the dialogue taking place online, in parent support groups and outside of the doctor’s office,” says Marshall Summar, M.D., director of CNRDI and co-author on the study. “The goal is for pediatricians and parents to work as a team in providing the best care possible for every child, so we hope this research provides physicians greater insight and encourages more open dialogue with patient families about supplement use.  Since many of these supplements have active ingredients, it is vitally important that the primary care provider be aware of them.”

photos used for facial analysis technology

Facial analysis technology successful in identifying Williams-Beuren syndrome in diverse populations

photos used for facial analysis technology

Image Credit: Darryl Leja, NHGRI.

In an international study led by the National Human Genome Research Institute (NHGRI), researchers have successfully identified Williams-Beuren syndrome in diverse populations using clinical information and objective facial analysis technology developed by the Sheikh Zayed Institute for Pediatric Surgical Innovation at Children’s National.

The technology, which was featured by STAT as an ‘Editor’s Pick’ finalist in their recent competition to find the best innovation in science and medicine, enables users to compare the most relevant facial features characteristic of Williams-Beuren syndrome in diverse populations.

Williams-Beuren syndrome affects an estimated 1 in 7,500 to 10,000 people, with the most significant medical problems being cardiovascular, including high blood pressure. Though the syndrome is a genetic condition, most cases are not inherited. Signs and symptoms include intellectual disability and distinctive facial features including puffiness around the eyes, a short nose with a broad tip, full cheeks and a wide mouth with full lips.

Using the facial analysis technology, the researchers compared 286 African, Asian, Caucasian and Latin American children and adults with Williams-Beuren syndrome with 286 people of the same age, sex and ethnicity without the disease. They were able to correctly identify patients with the disease from each ethnic group with 95 percent or higher accuracy.

“Our algorithm found that the angle at the nose root is the most significant facial feature of the Williams-Beuren syndrome in all ethnic groups and also highlighted facial features that are relevant to diagnosing the syndrome in each group,” said Marius George Linguraru, D.Phil., developer of the facial analysis technology and an investigator in the study from Children’s National.

Linguraru and his team are working to create a simple tool that will enable doctors in clinics without state-of-the-art genetic facilities to take photos of their patients on a smartphone and receive instant results.

The technology was also highly accurate in identifying Noonan syndrome according to a study published in Sept. 2017, DiGeorge syndrome (22q11.2 deletion syndrome) in April 2017 and Down syndrome in Dec. 2016. The next study in the series will focus on Cornelia de Lange syndrome.

2nd-annual-hackathon

Genetic testing reigns triumphant at health app hackathon

2nd-annual-hackathon

The growing popularity of genetic testing has one large hurdle: There are fewer than 4,000 genetic counselors in the United States, and people who use commercial genetic testing kits may receive confusing or inaccurate information.

To combat this problem, a team of doctors from the Rare Disease Institute at Children’s National Health System created the framework for a smartphone application that would house educational videos and tools that provide reputable information about genetic disorders and genetic testing.

On April 13, 2018, Debra Regier, M.D., Natasha Shur, M.D., and their teammates presented the app “Bear Genes” at the 2nd Annual Medical & Health App Development Workshop, a competition sponsored by the Clinical and Translational Science Institute at Children’s National (CTSI-CN) and the Milken Institute School of Public Health (Milken Institute SPH) at the George Washington University. Bear Genes won first place, and the team received $10,000 to develop a working prototype of the app.

The Bear Genes team was one of 10 who presented their ideas for smartphone apps to a panel of judges at the competition. Ideas covered a variety of topics, including emergency room visits and seizures related to menstrual cycles. Sean Cleary, Ph.D., M.P.H., an associate professor of epidemiology and biostatistics at the Milken Institute SPH, and his teammates proposed an app called “MyCommunicationPal” that would assist autistic individuals in reporting their symptoms to healthcare providers.

Sean Cleary and Kevin Cleary, Ph.D., technical director of the Bioengineering Initiative at Children’s National Health System, created the hackathon to bring together professionals from various fields to create technology-based solutions for public health and medical challenges. Interested participants submit applications and app proposals in the fall, and 10 ideas are selected to be fleshed out at the half-day hackathon. Participants join teams to develop the selected ideas, and on the day of the event, create a five-minute presentation to compete for the top prize. About 90 people attended this year’s hackathon.

“The workshop provides us with the opportunity to collaborate with healthcare providers, public health professionals and community members to develop an appropriate user-friendly app for those in need,” said Sean Cleary. “The event also fosters future collaborations between important stakeholders.”

This article originally appeared in the Milken Institute SPH pressroom.

STAT Madness

Voters select Children’s National innovation as runner-up in national competition

STAT Madness

Facial recognition technology developed and tested by researchers with the Sheikh Zayed Institute for Pediatric Surgical Innovation and Rare Disease Institute at Children’s National was the runner-up in this year’s STAT Madness 2018 competition.

Facial recognition technology developed and tested by researchers with the Sheikh Zayed Institute for Pediatric Surgical Innovation and Rare Disease Institute at Children’s National was the runner up in this year’s STAT Madness 2018 competition. Garnering more than 33,000 overall votes in the bracket-style battle that highlights the best biomedical advances, the Children’s National entry survived five rounds and made it to the championship before falling short of East Carolina University’s overall vote count.

Children’s entry demonstrates the potential widespread utility of digital dysmorphology technology to diverse populations with genetic conditions. The tool enables doctors and clinicians to identify children with genetic conditions earlier by simply taking the child’s photo with a smartphone and having it entered into a global database for computer analyses.

The researchers partnered with the National Institutes of Health National Human Genome Research Institute and clinicians from 20 different countries to acquire pictures from local doctors for the study. Using the facial analysis technology, they compared groups of Caucasians, Africans, Asians and Latin Americans with Down syndrome, 22q11.2 deletion syndrome (also called DiGeorge syndrome) and Noonan syndrome to those without it. Based on more than 125 individual facial features, they were able to correctly identify patients with the condition from each ethnic group with more than a 93 percent accuracy rate. Missed diagnoses of genetic conditions can negatively impact quality of life and lead to premature death.

Children’s National also was among four “Editor’s Pick” finalists, entries that span a diverse range of scientific disciplines. Journalists at the digital publication STAT pored through published journal articles for 64 submissions in the single-elimination contest to honor a select group of entries that were the most creative, novel, and most likely to benefit the biomedical field and the general public.

Each year, 1 million children are born worldwide with a genetic condition that requires immediate attention. Because many of these children experience serious medical complications and go on to suffer from intellectual disability, it is critical that doctors accurately diagnose genetic syndromes as early as possible.

“For years, research groups have viewed facial recognition technology as a potent tool to aid genetic diagnosis. Our project is unique because it offers the expertise of a virtual geneticist to general health care providers located anywhere in the world,” says Marius George Linguraru, D.Phil., M.A., M.S., a Sheikh Zayed Institute for Pediatric Surgical Innovation principal investigator who invented the technology. “Right now, children born in under-resourced regions of the U.S. or the world can wait years to receive an accurate diagnosis due to the lack of specialized genetic expertise in that region.”

In addition to providing patient-specific benefits, Marshall Summar, M.D., director of Children’s Rare Disease Institute that partners in the facial recognition technology research, says the project offers a wider societal benefit.

“Right now, parents can endure a seemingly endless odyssey as they struggle to understand why their child is different from peers,” says Dr. Summar. “A timely genetic diagnosis can dispel that uncertainty and replace it with knowledge that can speed patient triage and deliver timely medical interventions.”

Rare Disease Institute director named to Global Commission to End the Diagnostic Odyssey for Children

Marshall Summar, M.D., director of the Children’s National Rare Disease Institute (CNRDI), has been named to the Global Commission to End the Diagnostic Odyssey for Children.

Children’s National Health System has announced that Marshall Summar, M.D., director of the Children’s National Rare Disease Institute (CNRDI), has been named to the Global Commission to End the Diagnostic Odyssey for Children (“the Global Commission”), an alliance dedicated to shortening the multi-year journey that rare disease patients and families endure on the road to diagnosis.

Established in partnership with Shire, Microsoft and EURORDIS, the Global Commission is comprised of a multi-disciplinary team of global experts that have the commitment, creativity and technological expertise required to make a substantial difference in the lives of the millions of children living with a rare disorder.

“Providing more help to children born with rare genetic diseases continues to be one of the core challenges of 21st century medicine,” says Dr. Summar, who notes that patients typically visit up to eight doctors and often receive two or three misdiagnoses along the way. “Even upon diagnosis, patients are hindered by scarce treatment options and approximately a third of patients die before their fifth birthday. We are committed to changing this trend at the CNRDI and are excited to have the opportunity to share our expertise with this alliance on a global stage.”

The Global Commission is focused on developing an actionable roadmap for the field of rare disease that offers recommendations to address core challenges that prevent timely diagnosis for rare disease patients, including improving physicians’ ability to identify and diagnose rare disorders, empowering patients to take an active role in their healthcare and providing high-level policy guidance to help rare disease patients achieve better health outcomes.

Beginning its work in 2018, the Global Commission expects to publish a roadmap that encapsulates the collective findings in early 2019. Over the course of the next year, the alliance will gather input from patients, families and other experts to gain key insights and develop solutions to shorten the diagnostic odyssey.

In the United States, it is estimated that one in 10 people has a rare disease – approximately 80 percent of which are genetically based. Additionally, the National Institutes of Health reports that more than 80 percent are childhood diseases and more than 25 percent of children admitted to pediatric hospitals have a rare disease.

Marshall Summar

Horizon Pharma gifts $3M to establish Horizon Pharma Clinical Care Endowment at Children’s National Rare Disease Institute

Marshall Summar

“Patients and families with rare conditions deserve to be treated in a place with the medical knowledge to provide quick, clear answers and the expert care they need,” says Marshall Summar, M.D., director of the CNRDI.

Children’s National Health System and Horizon Pharma plc are pleased to announce the creation of the Horizon Pharma Clinical Care Endowment, the first clinical team endowment at the Children’s National Rare Disease Institute (CNRDI). The endowment is made possible by a generous six-year, $3 million commitment from Horizon Pharma USA, Inc., a wholly owned subsidiary of Horizon Pharma plc –a biopharmaceutical company dedicated to improving the lives of people living with rare diseases.

“Patients and families with rare conditions deserve to be treated in a place with the medical knowledge to provide quick, clear answers and the expert care they need,” says Marshall Summar, M.D. , director of the CNRDI.  “We are grateful for Horizon and their support of our mission to make the Children’s National Rare Disease Institute that place. This endowment will support a dedicated team that can provide optimal, comprehensive care to more patients and ensure that families have a trusted source for all aspects of their health care.”

The Horizon Pharma Clinical Care Endowment will generate revenue annually, providing stable support for an expert care team at the CNRDI. Each team will be comprised of a clinical geneticist and support team members – such as genetic counselors, nutritionists and social workers – all specializing in the care of children with rare disease.

The long-term support provided by the Horizon Pharma Clinical Care Endowment will give the CNRDI a firm foundation for treating patients earlier, more consistently and over the course of their lifetime. Horizon’s commitment marks the first donor-funded endowment at the CNRDI.

Currently, it is estimated that one in 10 Americans has a rare disease – approximately 80 percent of which are genetically based. Additionally, the NIH reports that more than 80 percent are childhood diseases, and more than 25 percent of children admitted to pediatric hospitals have a rare disease.

The CNRDI is a first-of-its-kind center focused exclusively on advancing the care and treatment of children and adults with rare genetic diseases. It is the first National Organization for Rare Disorders (NORD) Center of Excellence and aims to provide a medical home for patients and families seeking the most advanced care and expertise for rare genetic conditions that remain largely unknown to the general medical community.

Eric Vilain

Exploring differences of sex development

Eric Vilain, M.D., Ph.D.

Eric Vilain, M.D., Ph.D., analyzes the genetic mechanisms of sex development to give families more answers that will help them make better treatment (or non treatment) decisions for a child diagnosed with DSD.

Eric Vilain, M.D., Ph.D., is well versed in the “world of uncertainty” that surrounds differences of sex development. Since joining Children’s National as the director of the Center for Genetic Medicine Research in 2017, he’s shared with our research and clinical faculty and staff his expertise about the ways that genetic analysis might help address some of the complex social, cultural and medical implications of these differences.

Over the summer, he gave a keynote address entitled “Disorders/Differences of Sex Development: A World of Uncertainty” during Children’s National’s Research and Education Week, an annual celebration of research, education, innovation and scholarship at Children’s National and around the world. In January 2018, he shared a more clinically oriented version of the talk at a special Children’s National Grand Rounds session.

The educational objective of these talks is to inform researchers and providers about the mechanisms of differences of sex development (DSD), which are defined as congenital conditions in which the development of chromosomal, gonadal or anatomical sex is atypical.

The primary goal, though, is to really shine light on the complexity of this hot topic, and share how powerful genetic tools can be used to provide vital, concrete information for care providers, patients and families to assist with difficult treatment (and non-treatment) decisions.

“A minority of DSD cases are able to receive a genetic diagnosis today,” he points out. “But geneticists know how important it is to come to a diagnosis and so we seek to increase the number of patients who receive a concrete genetic diagnosis. It impacts genetic counseling and reproductive options, and provides a better ability to predict long term outcomes.”

“These differences impact physiology and medicine. We want to better understand the biology of reproduction, with an emphasis on finding ways to preserve fertility at all costs, and how these variations may lead to additional complications, including cancer risk.”

At conception, he explains, both XX and XY embryos have bipotential gonads capable of differentiating into a testis or an ovary, though embryos are virtually indistinguishable from a gender perspective up until six weeks in utero.

Whether or not a bipotential gonad forms is largely left up to the genetic makeup of the individual. For example, a gene in the Y chromosome (SRY) triggers a cascade of genes that lead to testis development. If there is no Y chromosome, it triggers a series of pro-female genes that lead to ovarian development.

Dr. Vilain notes that a variation of enzymes or transcription factors can occur at any single step of sex development and alter all the subsequent steps. Depending on the genotype, an individual may experience normal gonadal development, but abnormal development of the genitalia, for example.

He also noted that these genes are critical to determining the differences between men and women in non-gonadal tissues, including differences in gene expression within the brain. One study in the lab of investigator Matt Bramble, Ph.D., investigates if gonadal hormones impact sex differences in the brain by modifying the genome.

This work is a prime example of research informing the care provided to patients and families. Dr. Vilain is also a member of the multidisciplinary clinical team of the PROUD Clinic at Children’s National, a program completely devoted to caring for patients with a wide array of genetic and endocrine issues, including urogenital disorders and variations of sex development.

Sarah Viall

Newborn screening leader selected to advisory committee on heritable disorders in newborns and children

Sarah Viall

Sarah Viall, PPCNP, coordinator for the Newborn Screening Program at the Children’s National Rare Disease Institute (CNRDI), has been invited to serve on the Education and Training Workgroup of the Health Resources & Services Administration’s (HRSA) Advisory Committee on Heritable Disorders in Newborns and Children (ACHDNC).

Established under the Public Health Service Act, the ACHDNC focuses on reducing morbidity and mortality in newborns and children who have, or are at risk for, genetic disorders. The Committee currently recommends that all newborn screening programs include a Uniform Screening Panel that monitors for a total of 34 core disorders and another 26 secondary disorders.

In addition to developing recommendations on national newborn screening guidelines, the ACHDNC also advises the U.S. Department of Health and Human Services Secretary on the most appropriate application of newborn screening technologies, tests, policies and standards. The Committee provides technical information that helps develop Heritable Disorders Program policies and priorities that enhance the ability of local and state health agencies to provide screening, healthcare services and counseling for newborns and children affected by genetic disease.

Viall had previously spent a year observing meetings for the ACHDNC Education and Training Workgroup.

“I am thrilled to be an official member that can contribute to the important work of educating communities about newborn screening,” says Viall.

Marshall Summar talks to a colleage in lab

$3M Retrophin gift establishes Rare Disease Network at Children’s National

Marshall Summar talks to a colleage in lab

“This is an exciting first step toward a new era of rare disease care and innovation,” says Marshall Summar, M.D., director of the CNRDI. “We are grateful for this gift from Retrophin that will help us accelerate progress for our patients and families and pursue work that will have a far-reaching impact on both children and adults across the country and around the world thanks to the support of Retrophin.”

Children’s National Health System and Retrophin, Inc. have announced the creation of the Retrophin Rare Disease Network at Children’s National. Retrophin, a biopharmaceutical company specializing in identifying, developing and delivering life-changing therapies to people living with rare diseases, has committed $3 million over the next six years to support the work of the Children’s National Rare Disease Institute (CNRDI). Retrophin’s commitment marks the first corporate gift to CNRDI.

“One of the chief challenges of 21st century pediatric medicine is our continued inability to provide more help to those born with rare genetic diseases,” says Marshall Summar, M.D., director of the CNRDI. “This is an exciting first step toward a new era of rare disease care and innovation. We are grateful for this gift from Retrophin that will help us accelerate progress for our patients and families and pursue work that will have a far-reaching impact on both children and adults across the country and around the world thanks to the support of Retrophin.”

As a dedicated source of funding, the Retrophin Rare Disease Network will advance the CNRDI’s efforts to create a global “hub and spoke” model for disseminating and streamlining patient access to optimal care methods and among national and international peer institutions. The network will enhance the field of rare disease medicine by standardizing care models and establishing world-wide best practices in diagnosis and treatment.

The Retrophin Rare Disease Network will also provide funding for new dedicated positions at the CNRDI and build on the Institute’s existing digital and telemedicine programs, to extend the reach of its researchers and caregivers in areas where there is currently limited care available for children and adults living with rare diseases.

CNRDI is a first-of-its-kind center focused exclusively on advancing the care and treatment of children and adults with rare genetic diseases. The first National Organization for Rare Disorders (NORD) Center of Excellence, it aims to provide a medical home for patients and families seeking the most advanced care and expertise for rare genetic conditions that remain largely unknown to the general medical community.

Children’s National leaders join with Governor Martin O'Malley

Facial analysis technology successfully used to identify Noonan syndrome in diverse populations

facial recognition of noonan syndrome

According to an international study led by the National Human Genome Research Institute (NHGRI), researchers have successfully used facial analysis software, developed by the Sheikh Zayed Institute for Pediatric Surgical Innovation at Children’s National, to identify Noonan syndrome in diverse populations.

Noonan syndrome is relatively common, affecting between 1 in 1,000 to 1 in 2,500 children, however few studies have been conducted in non-Europeans. For this study, the researchers evaluated children (average age of eight) with Noonan syndrome from 20 countries. Using the facial analysis software and clinical criteria, the researchers compared 161 white, African, Asian and Latin American children with Noonan syndrome with 161 people of the same age and gender without the disease. Using the software to analyze facial features, they were able to correctly diagnose patients with the disease from each ethnic group with 94 percent or higher accuracy.

“Our algorithm found widely spaced eyes as a significant facial feature in all ethnic groups and also highlighted facial features that are relevant to diagnosing the syndrome in each group,” said

Marius George Linguraru, D.Phil., developer of the facial analysis technology and an investigator in the study from Children’s National.

Linguraru and his team are working to create a simple tool that will enable doctors in clinics without state-of-the-art genetic facilities to take photos of their patients on a smartphone and receive instant results.

Sarah B. Mulkey

Researchers tackle Zika’s unanswered questions

Youssef A. Kousa

Youssef A. Kousa, D.O., Ph.D., M.S., is examining whether interplays between certain genes make some women more vulnerable to symptomatic Zika infections.

A Maryland woman traveled to the Dominican Republic early in her pregnancy, spending three weeks with family. She felt dizzy and tired and, at first, attributed the lethargy to jet lag. Then, she experienced a rash that lasted about four days. She never saw a bite or slapped a mosquito while in the Dominican Republic but, having heard about the Zika virus, asked to be tested.

Her blood tested positive for Zika.

Why was this pregnant woman infected by Zika while others who live year-round in Zika hot zones remain free of the infectious disease? And why was she among the slim minority of Zika-positive people to show symptoms?

Youssef A. Kousa, D.O., Ph.D., M.S., a pediatric resident in the child neurology track at Children’s National Health System, is working on a research study that will examine whether interplays between certain genes make some women more vulnerable to symptomatic Zika infections during pregnancy, leaving  some fetuses at higher risk of developing microcephaly.

Dr. Kousa will present preliminary findings during Research and Education Week 2017 at Children’s National.

At sites in Puerto Rico, Colombia and Washington D.C., Dr. Kousa and his research collaborators are actively recruiting study participants and drawing blood from women whose Zika infections were confirmed in the first or second trimester of pregnancy. The blood is stored in test tubes with purple caps, a visual cue that the tube contains an additive that binds DNA, preventing it from being cut up. Additional research sites are currently being developed.

When the blood arrives at Children’s National, Dr. Kousa will use a centrifuge located in a sample preparation room to spin the samples at high speed for 11 minutes. The sample emerges from the centrifuge in three discrete layers, separated by weight. The rose-colored section that rises to the top is plasma. Plasma contains tell-tale signs of the immune system’s past battles with viruses and will be analyzed by Roberta L. DeBiasi, M.D., M.S., Chief of the Division of Pediatric Infectious Diseases at Children’s National, and Dr. Kousa’s mentor.

A slender line at the middle indicates white blood cells. The dark red layer is heavier red blood cells that sink to the bottom. This bottom half of the test tube, where the DNA resides, is where Dr. Kousa will perform his genetic research.

For years, Dr. Kousa has worked to identify genetic risk factors that influence which fetuses develop cleft lip and palate. In addition to genetic variances that drive disease, he looks at environmental overlays that can trigger genes to respond in ways that cause pediatric disease. When Zika infections raced across the globe, he says it was important to apply the same genetic analyses to the emerging disease. Genes make proteins that carry out instructions, but viral infection disrupts how genes interact, he says. Cells die. Other cells do not fully mature.

While certain poverty-stricken regions of Brazil have recorded the highest spikes in rates of microcephaly, more is at play than socioeconomics, he says. “It didn’t feel like all of the answers lie in the neighborhood. One woman with a Zika-affected child can live just down the street from a child who is more or less severely affected by Zika.”

As a father, Dr. Kousa is particularly concerned about how Zika stunts growth of the fetal brain at a time when it should expand exponentially. “I have three kids. You see them as they achieve milestones over time. It makes you happy and proud as a parent,” he says.

Sarah B. Mulkey

Sarah B. Mulkey, M.D., Ph.D., is studying whether infants exposed to Zika in utero achieve the same developmental milestones as uninfected infants.

While Dr. Kousa concentrates on Zika’s most devastating side effects, his colleague Sarah B. Mulkey, M.D., Ph.D., is exploring more subtle damage Zika can cause to fetuses exposed in utero. In the cohort of Colombian patients that Dr. Mulkey is researching, just 8 percent had abnormal fetal brain magnetic resonance images (MRIs). At first glance, the uncomplicated MRIs appear to be reassuring news for the vast majority of pregnant women.

Dr. Mulkey also will present preliminary findings during Research and Education Week 2017 at Children’s National.

In the fetus, the Zika virus makes a beeline to the developing brain where it replicates with ease and can linger after birth. “We need to be cautious about saying the fetal MRI is ‘normal’ and the infant is going to be ‘normal,’ ” Dr. Mulkey says. “We know with congenital cytomegalovirus that infected infants may not show symptoms at birth yet suffer long-term consequences, such as hearing deficits and vision loss.”

Among Zika-affected pregnancies in Colombia in which late-gestational age fetal MRIs were normal, Dr. Mulkey will use two different evaluation tools at 6 months and 1 year of age to gauge whether the babies accomplish the same milestones as peers. One evaluation tool is a questionnaire that has been validated in Spanish.

At 6 months and 1 year of age, the infants’ motor skills will be assessed, such as their ability to roll over in both directions, sit up, draw their feet toward their waist, stand, take steps independently and purposefully move their hands. Videotapes of the infants performing the motor skills will be scored by Dr. Mulkey and her mentor, Adre du Plessis, M.B.Ch.B., Chief of the Division of Fetal and Transitional Medicine at Children’s National. The Thrasher Research Fund is funding the project, “Neurologic outcomes of apparently normal newborns from Zika virus-positive pregnancies,” as part of its Early Career Award Program.

Both research projects are extensions of a larger multinational study co-led by Drs. du Plessis and DeBiasi that explores the impact of prolonged Zika viremia in pregnant women, fetuses and infants; the feasibility of using fetal MRI to describe the continuum of neurological impacts in Zika-affected pregnancies; and long-term developmental issues experienced by Zika-affected infants.

Teen Girl drawing a heart on an iPad

Illuminating cardiometabolic risk in Down syndrome

Teen Girl drawing a heart on an iPad

A leading researcher at Children’s National says researchers should look closely at the increased risks of obesity and thyroid disease common in patients with Down Syndrome, and determine how these long term comorbidities relate to cardiovascular and metabolic (cardiometabolic) risk, body image, and quality of life.

Over the last several decades, physicians’ improved ability to treat the common comorbidities of Down syndrome, such as congenital heart disease, has dramatically prolonged survival. Today, more than 400,000 people across the country are living with Down syndrome, and life expectancy has increased to 60 years.

New strategies to manage care for patients with Down syndrome must include preventive, evidence-based approaches to address the unique needs of these patients, according to Sheela N. Magge, M.D., M.S.C.E., Director of Research in the Division of Endocrinology and Diabetes at Children’s. She says that these efforts should include looking more closely at the increased risks of obesity and thyroid disease common in this population, and determining how these long term comorbidities relate to cardiovascular and metabolic (cardiometabolic) risk, body image, and quality of life.

An NIH-funded study from Children’s National and the Children’s Hospital of Philadelphia (CHOP), led by Dr. Magge and her colleague from CHOP, Dr. Andrea Kelly, seeks to better understand how the body composition of patients with Down syndrome impacts their likelihood for developing diabetes and obesity-related cardiovascular risks long term.

“We know that individuals with Down syndrome are at increased risk for obesity, but what hasn’t been clear is whether or not they also have the same cardiometabolic risk associated with obesity that we know holds true for other populations,” says Dr. Magge. “In this previously under-studied population, the common assumption based on very limited studies from the 1970’s was that individuals with Down syndrome were protected from the diabetes and cardiovascular risks that can develop in other overweight people. However, more recent epidemiologic studies contradict those early findings.”

The study has enrolled 150 Down syndrome patients and almost 100 controls to date, and the team is currently beginning to analyze the data. Dr. Magge believes that the findings from this study will help to provide new, research-driven evidence to inform the long term clinical management of obesity and cardiometabolic risk in adolescents with Down syndrome.

She concludes, “The goal is for our research to provide the foundation that will advance prevention and treatment strategies for this understudied group, so that individuals with Down syndrome not only have a longer life expectancy, but also a healthier and better quality of life.”

Sarah B. Mulkey

Puzzling symptoms lead to collaboration

Sarah B. Mulkey, explaining the research

Sarah B. Mulkey, M.D., Ph.D., is lead author of a study that describes a brand-new syndrome that stems from mutations to KCNQ2, a genetic discovery that began with one patient’s unusual symptoms.

Unraveling one of the greatest mysteries of Sarah B. Mulkey’s research career started with a single child.

At the time, Mulkey, M.D., Ph.D., a fetal-neonatal neurologist in the Division of Fetal and Transitional Medicine at Children’s National Health System, was working at the University of Arkansas for Medical Sciences. Rounding one morning at the neonatal intensive care unit (NICU), she met a new patient: A newborn girl with an unusual set of symptoms. The baby was difficult to wake and rarely opened her eyes. Results from her electroencephalogram (EEG), a test of brain waves, showed a pattern typical of a severe brain disorder. She had an extreme startle response, jumping and twitching any time she was disturbed or touched, that was not related to seizures. She also had trouble breathing and required respiratory support.

Dr. Mulkey did not know what to make of her new patient: She was unlike any baby she had ever cared for before. “She didn’t fit anything I knew,” Dr. Mulkey remembers, “so I had to get to the bottom of what made this one child so different.”

Suspecting that her young patient’s symptoms stemmed from a genetic abnormality, Dr. Mulkey ran a targeted gene panel, a blood test that looks for known genetic mutations that might cause seizures or abnormal movements. The test had a hit: One of the baby’s genes, called KCNQ2, had a glitch. But the finding deepened the mystery even further. Other babies with a mutation in this specific gene have a distinctly different set of symptoms, including characteristic seizures that many patients eventually outgrow.

Dr. Mulkey knew that she needed to dig deeper, but she also knew that she could not do it alone. So, she reached out first to Boston Children’s Hospital Neurologist Philip Pearl, M.D., an expert on rare neurometabolic diseases, who in turn put her in touch with Maria Roberto Cilio, M.D., Ph.D., of the University of California, San Francisco and Edward Cooper, M.D., Ph.D., of Baylor College of Medicine. Drs. Cilio, Cooper and Pearl study KCNQ2 gene variants, which are responsible for causing seizures in newborns.

Typically, mutations in this gene cause a “loss of function,” causing the potassium channel to remain too closed to do its essential job properly. But the exact mutation that affected KCNQ2 in Dr. Mulkey’s patient was distinct from others reported in the literature. It must be doing something different, the doctors reasoned.

Indeed, a research colleague of Drs. Cooper, Cilio and Pearl in Italy — Maurizio Taglialatela, M.D., Ph.D., of the University of Naples Federico II and the University of Molise — had recently discovered in cell-based work that this particular mutation appeared to cause a “gain of function,” leaving the potassium channel in the brain too open.

Wondering whether other patients with this same type of mutation had the same unusual constellation of symptoms as hers, Dr. Mulkey and colleagues took advantage of a database that Dr. Cooper had started years earlier in which doctors who cared for patients with KCNQ2 mutations could record information about symptoms, lab tests and other clinical findings. They selected only those patients with the rare genetic mutation shared by her patient and a second rare KCNQ2 mutation also found to cause gain of function — a total of 10 patients out of the hundreds entered into the database. The researchers began contacting the doctors who had cared for these patients and, in some cases, the patients’ parents. They were scattered across the world, including Europe, Australia and the Middle East.

Dr. Mulkey and colleagues sent the doctors and families surveys, asking whether these patients had similar symptoms to her patient when they were newborns: What were their EEG results? How was their respiratory function? Did they have the same unusual startle response?

She is lead author of the study, published online Jan. 31, 2017 in Epilepsia, that revealed a brand-new syndrome that stems from specific mutations to KCNQ2. Unlike the vast majority of others with mutations in this gene, Dr. Mulkey and her international collaborators say, these gain-of-function mutations cause a distinctly different set of problems for patients.

Dr. Mulkey notes that with a growing focus on precision medicine, scientists and doctors are becoming increasingly aware that knowing about the specific mutation matters as much as identifying the defective gene. With the ability to test for more and more mutations, she says, researchers likely will discover more cases like this one: Symptoms that differ from those that usually strike when a gene is mutated because the particular mutation differs from the norm.

Such cases offer important opportunities for researchers to come together to share their collective expertise, she adds. “With such a rare diagnosis,” Dr. Mulkey says, “it’s important for physicians to reach out to others with knowledge in these areas around the world. We can learn much more collectively than by ourselves.”