Diabetes and Endocrinology

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.”

little girl being examined by doctor

First Washington-based Turner syndrome clinic opens Jan. 28

little girl being examined by doctor

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

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

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

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

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

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

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

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

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

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

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

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

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

AlgometRX

Breakthrough device objectively measures pain type, intensity and drug effects

AlgometRX

Clinical Research Assistant Kevin Jackson uses AlgometRx Platform Technology on Sarah Taylor’s eyes to measure her degree of pain. Children’s National Medical Center is testing an experimental device that aims to measure pain according to how pupils react to certain stimuli. (AP Photo/Manuel Balce Ceneta)

Pediatric anesthesiologist Julia C. Finkel, M.D., of Children’s National Health System, gazed into the eyes of a newborn patient determined to find a better way to measure the effectiveness of pain treatment on one so tiny and unable to verbalize. Then she realized the answer was staring back at her.

Armed with the knowledge that pain and analgesic drugs produce an involuntary response from the pupil, Dr. Finkel developed AlgometRx, a first-of-its-kind handheld device that measures a patient’s pupillary response and, using proprietary algorithms, provides a diagnostic measurement of pain intensity, pain type and, after treatment is administered, monitors efficacy. Her initial goal was to improve the care of premature infants. She now has a device that can be used with children of any age and adults.

“Pain is very complex and it is currently the only vital sign that is not objectively measured,” says Dr. Finkel, who has more than 25 years of experience as a pain specialist. “The systematic problem we are facing today is that healthcare providers prescribe pain medicine based on subjective self-reporting, which can often be inaccurate, rather than based on an objective measure of pain type and intensity.” To illustrate her point, Dr. Finkel continues, “A clinician would never prescribe blood pressure medicine without first taking a patient’s blood pressure.”

The current standard of care for measuring pain is the 0-to-10 pain scale, which is based on subjective, observational and self-reporting techniques. Patients indicate their level of pain, with zero being no pain and ten being highest or most severe pain. This subjective system increases the likelihood of inaccuracy, with the problem being most acute with pediatric and non-verbal patients. Moreover, Dr. Finkel points out that subjective pain scores cannot be standardized, heightening the potential for misdiagnosis, over-treatment or under-treatment.

Dr. Finkel, who serves as director of Research and Development for Pain Medicine at the Sheikh Zayed Institute for Pediatric Surgical Innovation at Children’s National, says that a key step in addressing the opioid crisis is providing physicians with objective, real-time data on a patient’s pain level and type, to safely prescribe the right drug and dosage or an alternate treatment.,

She notes that opioids are prescribed for patients who report high pain scores and are sometimes prescribed in cases where they are not appropriate. Dr. Finkel points to the example of sciatica, a neuropathic pain sensation felt in the lower back, legs and buttocks. Sciatica pain is carried by touch fibers that do not have opioid receptors, which makes opioids an inappropriate choice for treating that type of pain.

A pain biomarker could rapidly advance both clinical practice and pain research, Dr. Finkel adds. For clinicians, the power to identify the type and magnitude of a patient’s nociception (detection of pain stimuli) would provide a much-needed scientific foundation for approaching pain treatment. Nociception could be monitored through the course of treatment so that dosing is targeted and personalized to ensure patients receive adequate pain relief while reducing side effects.

“A validated measure to show whether or not an opioid is indicated for a given patient could ease the health care system’s transition from overreliance on opioids to a more comprehensive and less harmful approach to pain management,” says Dr. Finkel.

She also notes that objective pain measurement can provide much needed help in validating complementary approaches to pain management, such as acupuncture, physical therapy, virtual reality and other non-pharmacological interventions.

Dr. Finkel’s technology, called AlgometRx, has been selected by the U.S. Food and Drug Administration (FDA) to participate in its “Innovation Challenge: Devices to Prevent and Treat Opioid Use Disorder.” She is also the recipient of Small Business Innovation Research (SBIR) grant from the National Institute on Drug Abuse.

Andrew Dauber at his computer doing a Reddit AMA

Thirteen questions for a pediatric endocrinologist

Andrew Dauber at his computer doing a Reddit AMA

Andrew Dauber, M.D., hosts an AMA chat with Reddit’s science community and offers feedback about height, growth disorders and pediatric endocrinology.

Andrew Dauber, M.D., MMSc., the division chief of endocrinology at Children’s National, spoke about epigenetics – how genes are expressed – and about all things related to pediatric endocrinology in a recent Ask Me Anything (AMA) chat with Reddit’s science community.

We’ve selected highlights from several questions Dr. Dauber received. You can view the full AMA discussion on Reddit.

Q1: What will the future of type 1 diabetes treatment look like?

As a pediatric endocrinologist, Dr. Dauber sees a lot of patients with type 1 diabetes. He predicts technology will pave the way for advancements with continuous glucose monitoring and encourage a ‘real-time’ interaction between patients and providers:

“I anticipate that within a few years, everyone will have access to continuous glucose monitoring technology and that these will be seamlessly connected to insulin pumps or artificial pancreas technologies,” types Dr. Dauber in response to the first AMA question. “I also think there will be more virtual interaction between medical providers and patients with doctors and nurses reviewing blood sugar data in the cloud.”

Q2: What height range is considered normal for a growing child? What is the difference between short stature and a height problem?

The Centers for Disease Control and Prevention has a growth chart, which shows ‘normal’ ranges, based on statistical definitions of height in the general population.

“The truth is that I know plenty of people who have heights below the ‘normal’ population, and they don’t think they have a problem at all,” says Dr. Dauber. “From a genetics point of view, the question can be reframed: When do we call a genetic variant a ‘mutation’ versus a rare variant in the population? For example: If there is a genetic change that 1 in a 1,000 people have that causes you to be 2 inches shorter – is that a problem? Is that a disease?”

“From a clinical perspective, I tend to have a discussion with my patients and their families and ask them how their stature is affecting their lives and whether changing that would really make a meaningful difference,” adds Dr. Dauber. “I believe that this is a very personal decision but people need to be realistic about expected outcomes.”

Q3: What are your favorite case studies about atypical growth or height patterns?

Dr. Dauber references two case studies about growth and puberty:

The growth case study refers to the PAPPA2 gene, which was particularly meaningful for Dr. Dauber since he got to know the family and was able to provide answers to a previously undiagnosed medical mystery about short stature. This research is also opening future studies and analysis about the regulation of IGF-1 bioavailability.

The puberty case study looks at the opposite end of growth and development: precocious puberty. In this case an inherited MKRN3 gene mutation resulted in new insight about the regulation of pubertal timing: Deficiency of MKRN3 caused central precocious puberty in humans. Girls who had inherited the mutated genes from their father (an imprint gene) started to develop breasts before age 6. The results were published in The New England Journal of Medicine.

Q4: What are the differences with consistent and inconsistent growth disorders? Could one arm or leg experience accelerated or stunted growth?

“Most genetic disorders that affect growth will have a uniform effect throughout the body as they are likely to affect all aspects of the skeleton,” says Dr. Dauber. “That being said, there are some notable exceptions such as Russell-Silver syndrome which presents with body asymmetry. There are also somatic mutations (mutations which are just present in some cells in the body) that can lead to segmental areas of overgrowth leading to asymmetry.”

Q5: Can you predict height and growth by looking at genetic factors? What are your thoughts about polygenic risk scores?

“Polygenic risk scores will probably play more of a role in the future to help determine risk of a certain disease,” says Dr. Dauber. “Right now, for most conditions, the risk score does not explain a substantial enough fraction of the variation to help with prediction.”

Dr. Dauber discusses how this works for height, a highly hereditable trait, in The Journal for Clinical Endocrinology and Metabolism. In the review, Dr. Dauber and the study co-authors note that individuals with extreme heights are more likely to have abnormal stature as a result of a severe mutation that causes a growth disorder. For these individuals, whole exome sequencing may reveal gene mutations.

However, the study authors note that for now, the role of these technologies in individuals with extreme stature but without any syndromic features has not been rigorously and systematically explored. (Dr. Dauber and a team of endocrinologists from leading children’s hospitals are currently using electronic health records to study and track these types of genetic clues over time.)

Q6: The general public is excited about genetics and ongoing research, especially with consumer applications – such as genetic tests, including 23andMe. What misconceptions about genetics do people have? What ethical concerns do geneticists share right now?

“Many people think that genetics is completely deterministic,” says Dr. Dauber. “In reality, most genetic variants influence a person’s predisposition toward a trait or disease but don’t actually determine the outcome. Also, the genetic sequence itself is just the first step. Epigenetics, gene regulation, and gene-environment interactions are all important and we are just scratching the surface of understanding these areas.”

“I think that people engaged in genetics research are very interested in the ethical questions,” adds Dr. Dauber. “The problem is that technology is advancing at such a rapid pace, that often consumers are using technologies in ways that we haven’t yet had time to figure out the ethics for. The medical community is often playing catch up.”

Q7: Aside from using gene modifications to cure diseases, where or when should we draw the line in terms of enhancement?

“I think genetic modification for enhancement is a very dangerous slippery slope that we should avoid,” says Dr. Dauber. “We really don’t know the full effect of many genes and by enhancing them, we could be causing lots of problems that we can’t anticipate. There is a reason that evolution is a slow process that happens over millions of years. I think we need to start with the most devastating diseases and try to cure those first.”

Q8: Would it be ethical to use CRISPR on the genes for short stature to produce tall offspring if the risks are sufficiently small? This would be similar to what Dr. He did, but without the ethical violations.

This is a fascinating question and it will become more of an issue over time,” says Dr. Dauber. “Where do we draw the line between fixing, preventing disease and enhancing physical function? Personally, I think using genome editing to promote height is a terrible idea. Our current perception that taller height is more desirable is a social construct and varies by culture. This idea also changes over time.”

Q9: Overall, how does this fit into meeting unmet medical needs?

I would be very wary about trying to design our children’s physical features,” Dr. Dauber notes. “We need to figure out as a society what diseases are sufficiently problematic that we feel comfortable trying to eliminate them via genome editing.”

Q10: How many genes control acromegaly? Is it possible (in theory) to Top of Formselect them just to gain the positive effects of gigantism without the health risks?

Dr. Dauber explains that acromegaly, a condition often referred to as gigantism, is caused by a growth hormone-producing tumor. There are a few genes known to cause these tumors, including the AIP, and there was recently a genetic cause of X-linked gigantism, which was published in The New England Journal of Medicine.

“This basic idea is a good one,” notes Dr. Dauber. “We can find genes that when mutated can cause tall stature – and then try to manipulate those pathways. A great example is the NPR2 gene, which when mutated can cause short or tall stature. This pathway is being targeted for therapeutics related to achondroplasia.”

The National Institutes of Health (NIH) refers to achondroplasia as ‘short-limbed dwarfism,’ which results in an average-sized trunk with short limbs, especially arms and legs, due to a lack of cartilage turning into bone. The average height of an adult male with achondroplasia is 4 feet, 4 inches, while the average height of adult females with achondroplasia is less than 4 feet, 1 inch. In this case, manipulating growth pathways may help alleviate health problems associated with achondroplasia: lack of mobility or range of motion, an enlarged head, apnea, ear infections and spinal stenosis, or a compression or pinching of the spinal cord.

Q11: Give us a history lesson. Why are there variations of height within populations, such as Asia and Latin America?

“The average height in a population is due to the influence of literally thousands of common genetic variants,” says Dr. Dauber. “These population differences have evolved over thousands of years due to a combination of migration and selection. There is a well-known difference in the genetic makeup of various populations which likely underlies the differences across the globe. There are even differences within Europe.”

Q12: Are there examples of pseudoscience or theories about growth, such as recommendations to eat a certain food instead of taking growth hormones to correct for a growth disorder, which runs contrary to scientific evidence, that drive you crazy?

“I don’t really get bothered by crazy theories, but it is upsetting when patients and their families get swindled into spending their money on therapies that aren’t truly effective,” says Dr. Dauber. “People ask me all the time if a certain food or exercise can make their child taller. The bottom line is that in a well-nourished (and healthy) child, there is no magical food that is going to make them tall.”

Q13: According to almost every theory of how life evolved on Earth, from religion to evolution, we all have one common ancestor. In theory doesn’t that make us all cousins?

“Yes, just very distant ones,” says Dr. Dauber. “People always point out the vast number of differences between races but in fact we are all more than 99.9 percent identical on a genetic level.”

Stay on top of the latest pediatric endocrinology news by following @EndoDocDauber and @ChildrensHealth on Twitter: #GrowUpStronger.

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.

Andrew Dauber

Growth disorder study starts by analyzing DNA

The National Institutes of Health has awarded Andrew Dauber, M.D., MMSc, the chief of endocrinology at Children’s National Health System, a five-year grant that will allow four pediatric health systems to compile and study clinical and genetic markers of severe pediatric growth disorders.

The study will use the electronic health records of large health systems combined with DNA samples from dozens of children, with the goal of enabling endocrinologists to detect children with previously undiagnosed severe genetic growth disorders.

“If you’re a pediatrician treating an 8-year-old patient who has stopped growing, the first thing you’ll want to do is determine the underlying cause, which could be due to many factors including a genetic mutation,” says Dr. Dauber. “There are many reasons why children grow poorly and it is often very difficult to figure out what is causing the problem. However, the various causes may be treated quite differently and may alert us to other medical issues that we need to watch out for. We need to be able to identify clues from the patient’s clinical presentation that may point us to the right diagnosis.”

Dr. Dauber and endocrinology researchers from Children’s National Health System, Cincinnati Children’s Hospital Medical Center, Boston Children’s Hospital and The Children’s Hospital of Philadelphia will use electronic health records to identify children who likely have rare genetic growth disorders. They will then use cutting-edge DNA sequencing technologies, whole exome sequences, to identify novel genetic causes of severe growth disorders. Patients with growth hormone resistance, resistance to insulin-like growth factor 1 (IGF-I) and severe short stature inherited from a single parent will be recruited for the initial phases of the study.

“It’s rare to find patients meeting criteria for each of these subgroups, which is why it’s critical to work collaboratively across institutions,” says Dr. Dauber. “This type of genetic sorting and sharing brings us closer to identifying new markers for severe or treatment-resistant growth disorders, which will help alert pediatricians and parents to potential risks earlier on in a child’s life.”

In addition to assessing genetic markers for short stature, the endocrinologists will conduct pilot studies of targeted interventions, such as IGF-I therapy in patients with mutations in the growth hormone pathway, based on these genetic underpinnings.

“Ideally, by identifying markers of severe growth disorders first, we’ll be able to provide targeted treatments and therapies later on to help patients throughout their lifespan,” adds Dr. Dauber.

Typical treatments for atypical growth patterns include growth hormone or less commonly insulin-like growth factor, or IGF-1, for short stature and hormone-inhibiting treatments for precocious puberty.

The multicenter clinical trial is funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), under grant Ro1HD093622, and runs through June 30, 2023.

Marva Moxey Mims

Making the case for a comprehensive national registry for pediatric CKD

Marva Moxey Mims

“It’s of utmost importance that we develop more sensitive ways to identify children who are at heightened risk for developing CKD.,” says Marva Moxey-Mims, M.D. “A growing body of evidence suggests that this includes children treated in pediatric intensive care units who sustained acute kidney injury, infants born preterm and low birth weight, and obese children.”

Even though chronic kidney disease (CKD) is a global epidemic that imperils cardiovascular health, impairs quality of life and heightens mortality, very little is known about how CKD uniquely impacts children and how kids may be spared from its more devastating effects.

That makes a study published in the November 2018 issue of the American Journal of Kidney Diseases all the more notable because it represents the largest population-based study of CKD prevalence in a nationally representative cohort of adolescents aged 12 to 18, Sun-Young Ahn, M.D., and Marva Moxey-Mims, M.D., of Children’s National Health System, write in a companion editorial published online Oct. 18, 2018.

In their invited commentary, “Chronic kidney disease in children: the importance of a national epidemiological study,” Drs. Ahn and Moxey-Mims point out that pediatric CKD can contribute to growth failure, developmental and neurocognitive defects and impaired cardiovascular health.

“Children who require renal-replacement therapy suffer mortality rates that are 30 times higher than children who don’t have end-stage renal disease,” adds Dr. Moxey-Mims, chief of the Division of Nephrology at Children’s National. “It’s of utmost importance that we develop more sensitive ways to identify children who are at heightened risk for developing CKD. A growing body of evidence suggests that this includes children treated in pediatric intensive care units who sustained acute kidney injury, infants born preterm and low birth weight, and obese children.”

At its early stages, pediatric CKD usually has few symptoms, and clinicians around the world lack validated biomarkers to spot the disease early, before it may become irreversible.

While national mass urine screening programs in Japan, Taiwan and Korea have demonstrated success in early detection of CKD, which enabled successful interventions, such an approach is not cost-effective for the U.S., Drs. Ahn and Moxey-Mims write.

According to the Centers for Disease Control and Prevention, 1 in 10 U.S. infants in 2016 was born preterm, prior to 37 weeks gestation. Because of that trend, the commentators advocate for “a concerted national effort” to track preterm and low birth weight newborns. (These infants are presumed to have lower nephron endowment, which increases their risk for developing end-stage kidney disease.)

“We need a comprehensive, national registry just for pediatric CKD, a database that represents the entire U.S. population that we could query to glean new insights about what improves kids’ lifespan and quality of life. With a large database of anonymized pediatric patient records we could, for example, assess the effectiveness of specific therapeutic interventions, such as angiotensin-converting enzyme inhibitors, in improving care and slowing CKD progression in kids,” Dr. Moxey-Mims adds.

Stephen Teach does an asthma exam

Stephen J. Teach, M.D., MPH, inaugural holder of new endowed chair

Stephen Teach does an asthma exam

Stephen J. Teach, M.D., M.P.H., has been named the inaugural Wendy Goldberg Professor in Translational Research in Child Health and Community Partnerships. This professorship comes with an endowed chair at Children’s National Health System.

The prestigious honor is given for the duration of Dr. Teach’s (and future chair holders’) employment at Children’s National. The award’s namesake, Wendy Goldberg, and her husband, Fred T. Goldberg Jr., are among the brightest stars in the constellation of Children’s National supporters, says Dr. Teach, Associate Dean for Pediatric Academic Affairs and Chair of the Department of Pediatrics at The George Washington University School of Medicine & Health Sciences.

In addition to serving on many Children’s boards, in the mid-2000s the Goldbergs made a $250,000 gift that benefited Improving Pediatric Asthma Care in the District of Columbia (IMPACT DC), Dr. Teach’s award-winning program to improve clinical care, empower patients and families, and conduct new research to improve patients’ outcomes.

“In recognition of the anchor aims of Children’s new strategic plan, the Goldbergs wanted this new gift to focus on the intersection of community health and research,” Dr. Teach says. “Thanks to their generosity, my team will work with community partners to use data to drive improvements in population health.”

With the dedicated funding Dr. Teach was able to hire a new staffer, Caitlin Munoz, to help mine electronic health records to create disease-specific registries that include 15,000 children and adolescents – the lion’s share of kids younger than 17 who live in Washington and have asthma.

“For the first time, we will be able to describe in granular detail the near-universe of local children who have this chronic respiratory disease,” he says. “We will be able to describe many of the most clinically meaningful aspects of nearly every child with asthma who lives in D.C., including mean age, gender, ethnicity and mean number visits to the emergency department.”

Such a richly textured database will help identify children who should be prescribed daily controller medications to help them avoid missing school days due to asthma exacerbations, he says. The next pediatric chronic disease they will track via registry will be pediatric obesity via elevated body mass index.

“That, in and of itself, is insightful data. But the enduring impact of this applied research is it will inform our continuous quality-improvement efforts,” he adds.

By querying the registries the team will be able to tell, for example, how Children’s primary care centers rank comparatively by asking such questions as which percentage of kids with asthma actually take the medicines they had been prescribed the year prior.

“Increasingly, clinical research falls into one of two buckets. You can either do better things: That’s discovering new drugs or processes, like our ongoing clinical trial to desensitize kids to asthma allergens. Or, you can do things better. We often know what to do already. We know that guideline-based asthma care works well. We don’t need to prove that again. We just need to do things better by getting this care to the kids who need it. That’s where this line of research/quality improvement comes in: It’s getting people to do things better.”

boy on a treadmil

Therapeutic targets in African-American youth with type 2 diabetes

boy on a treadmil

Ongoing research is helping to define the broad spectrum and multi-faceted nature of type 2 diabetes in terms of its presentation, its rapidity of progression and its underlying genetic susceptibilities. In a recent study of 8,980 adults published in The Lancet, diabetes was further classified into five clusters, ranging from insulin-deficient, typically referred to as type 1, to groups of patients with primary insulin-resistance, traditionally classified as type 2 diabetes, with the caveat that each cluster had a distinct risk profile for disease progression and risk for diabetes complications.

Moreover, investigators have recently demonstrated, through the Restoring Insulin Secretion (RISE) Consortium, that youth compared to adults with early type 2 diabetes have greater insulin resistance relative to insulin secretion. Understanding variances on the diabetes spectrum, especially as it relates to risk for disease progression in youth, helps researchers develop targeted therapies that may help reduce complications and the burden of this chronic disease.

Ongoing research

Stephanie Chung, M.B.B.S., a pediatric endocrinologist at the National Institutes of Health and an adjunct assistant professor of pediatrics at Children’s National, is one researcher who hopes to use this knowledge to transform public health outcomes. Dr. Chung is studying how teens and young adults with severe insulin-resistant diabetes (SIRD) respond to new treatment, paired with lifestyle-based interventions.

Here is a Q&A with Dr. Chung about her latest research:

Tell Innovation District readers more about your diabetes research. How has your previous research influenced this study?

My research and publications are focused on understanding how genes, environment and lifestyle factors contribute to the pathology of diabetes, obesity and insulin resistance in populations of African descent and on identifying more effective screening and treatment options.

We know that African-American youth with type 2 diabetes have the highest complication and treatment failure rates among minority youth. However, the reasons underlying this health disparity are still not fully understood. Metformin, the only approved oral diabetes treatment for youth with type 2 diabetes, works less than half of the time in African-American youth. Although new evidence suggests that gut bacteria and genetics may influence the efficacy of metformin, this data is insufficient in African-American youth.

What is your goal with this diabetes clinical study?

The primary objective of this new study, entitled Therapeutic Targets in African-American Youth with Type 2 Diabetes, is to compare the combination of metformin and liraglutide versus metformin alone to reduce excess glucose produced by the liver in African-American youth with type 2 diabetes.

Additional objectives will evaluate the mechanism of action in the liver of these two agents and the influence of genetics and gut bacteria. This project brings together the research expertise of the National Institute of Diabetes and Digestive and Kidney Diseases, the National Human Genome Research Institute and the Children’s National Medical Center.

Do you envision this type of dual therapy, a combination of drugs and lifestyle interventions, will serve as a bridge to optimal insulin function?

While metformin, diet and lifestyle changes remain the mainstay of diabetes treatment, our study will evaluate whether this combination regimen could help to slow the progression of type 2 diabetes in African American youth. Our ultimate goal is the development of new precision medicine treatment options that can address the disparities in outcomes for African-American youth with type 2 diabetes.

What lessons do you see participants learning as they progress through the trial?

Our patients and their families are equal partners in care. Our comprehensive team of doctors, nurses, dietitians and counselors work closely with the patients and their families to help empower them to take charge of managing their diabetes. We teach them skills that include regularly monitoring their blood glucose levels and understanding how their activity and foods affect these levels. They are coached on making healthy food choices and incorporating exercise into their daily lives.

How do you teach children and teens about how their body responds to different foods?

This education starts as soon as participants enter the study. While patients are at the NIH for the inpatient study, we provide them with meals containing different ratios of carbohydrates, proteins, and fats and help them to analyze how their blood sugar responds to these levels, both before and after they take the medication. This type of education is important since participants will also have to monitor their blood sugar twice a day at home during the study. Most of the time, we use real-life situations as teaching moments. For example, if a participant had pizza for dinner, we will discuss with them why their blood sugar spiked and suggest alternative food choices. We provide this type of coaching every week. I often joke that after three months they become tired of hearing from us. But one of the strengths of this study is that participants receive personalized feedback that enables them to make healthy food choices for the rest of their life.

Can you tell us more about targeted food choices for teens?

A very enlightening procedure that we conduct on all of our study participants is measuring their basal metabolic rate (energy expenditure at rest). We show them how many calories they need to consume each day to maintain their body’s normal functions and compare that number with an estimate of how many calories they usually consume in a day. For many participants this is the first time that they have insight into the reasons for their weight gain.

How does this lab work help with meal planning?

After we create a participant’s metabolic chart we make food plans that support their lifestyle and caloric needs and are realistic to follow. For example, a 2,000 calorie per day diet can be separated into 400 calories for breakfast, 600 calories for lunch, 200 calories for snack and 800 calories for dinner.

How do you envision personalizing the field of diabetes research and treatment?

A precision medicine approach to type 2 diabetes will help us to better explore if and how factors like genes, environment and lifestyle impact insulin and glucose metabolism in populations with significant treatment outcomes disparities. With this approach we hope to uncover novel targeted treatment and prevention strategies that demonstrate more efficacy and cost-efficiency than current treatment approaches for high-risk populations.

Where can people learn more about the trial?

Learn more about the study by watching this informational video. If you’re interested in joining the study, please contact the NIH Office of Clinical Trial Recruitment at 866-999-1116.

Andrew Dauber

Andrew Dauber, M.D., joins Children’s National as Chief of Endocrinology

Andrew Dauber

“Researchers, clinicians and medical trainees are pressed for time,” says Andrew Dauber, M.D. “Merging these three arenas into a joint infrastructure powers institutional collaboration and fuels transformative, cutting-edge care.”

Imagine an endocrinology division staffed with endowed researchers, clinicians and specialists, that serves as an engine of innovation, making it easy for pediatricians to make the right referrals, based on the best research, to endocrinologists who can provide families with cutting-edge care.

Andrew Dauber, M.D., MMSc, the new chief of endocrinology at Children’s National, is turning this dream into a reality. Over the next few years, Dr. Dauber will work with a nationally-ranked endocrinology and diabetes center to build a clinical endocrinology research program, housing specialty clinics for Turner’s syndrome, thyroid care and growth disorders, amongst others.

“Researchers, clinicians and medical trainees are pressed for time,” notes Dr. Dauber. “Merging these three arenas into a joint infrastructure powers institutional collaboration and fuels transformative, cutting-edge care.”

To put his real-life hypothesis of providing an engine for innovation into practice, Dr. Dauber led the interdisciplinary growth center at Cincinnati Children’s Hospital Medical Center and organized a Genomics First for Undiagnosed Diseases Program to study genetic clues for undiagnosed diseases. At Boston Children’s Hospital, he was the assistant medical director for the clinical research unit and held academic appointments with Harvard Medical School.

Dr. Dauber finds it’s critically important to merge clinical practice with research and education. He received his medical degree and a Master’s of Medical Sciences in Clinical Investigation from Harvard Medical School. He has published more than 65 studies examining genetic clues to endocrine disorders, with a focus on short stature and growth disorders.

Dr. Dauber conducted the majority of his research – ranging from studying genetic clues for rare growth disorders and causes of precocious puberty to genes that regulate the bioavailability of IGF1, insulin-like growth factor – while counseling patients, advising students and fellows, managing grants, reviewing studies and speaking at international pediatric endocrinology conferences.

He’s harnessing this data by combining genomic insights with electronic health records and patient registries. While some of this information can be used immediately to identify a high-risk patient, other conditions may take years to understand. Dr. Dauber views this as an investment in the future of pediatric endocrinology.

“I’m excited to join Children’s National and to work in Washington, where we can power our city and the nation with premier partnerships and collaboration,” adds Dr. Dauber. “In addition to using genetic clues to investigate growth disorders, we’re just as enthusiastic about investing in and expanding access to youth-focused diabetes education and care.”

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

Nikki Gillum Posnack

Do plastic chemicals contribute to the sudden death of patients on dialysis?

Nikki Gillum Posnack

Nikki Posnack, Ph.D., assistant professor with the Children’s National Heart Institute, continues to explore how repeat chemical exposure from medical devices influences cardiovascular function.

In a review published in HeartRhythmNikki Posnack, Ph.D., an assistant professor at the Children’s National Heart Institute, and Larisa Tereshchenko, M.D., Ph.D., FHRS, a researcher with the Knight Cardiovascular Institute at Oregon Health and Science University, establish a strong foundation for a running hypothesis: Replacing BPA- and DEHP- leaching plastics for alternative materials used to create medical devices may help patients on dialysis, and others with impaired immune function, live longer.

While Drs. Tereshchenko and Posnack note clinical studies and randomized controlled trials are needed to test this theory, they gather a compelling argument by examining the impact exposure to chemicals from plastics used in dialysis have on a patient’s short- and long-term health outcomes, including sudden cardiac death (SCD).

“As our society modifies our exposure to plastics to mitigate health risks, we should think about overexposure to plastics in a medical setting,” says Posnack. “The purpose of the review in HeartRhythm is to gather data about the impact chemical compounds, leached from plastic devices, have on cardiovascular outcomes for patients spending prolonged periods of time in the hospital.”

In this review, the authors explore chemical risk exposures in a medical setting, starting with factors that influence sudden cardiac death (SCD) among dialysis patients.

Why study dialysis patients?

SCD in dialysis patients accounts for one-third of deaths in this population. This prompts a need to develop prevention strategies, especially among patients with end-stage renal disease (ESRD).

The highest mortality rate observed among dialysis patients is during the first year of hemodialysis, a dialysis process that requires a machine to take the place of the kidneys and remove waste from the bloodstream and replenish it with minerals, such as potassium, sodium and calcium. During this year, mortality during hemodialysis is observed more frequently during the first three months of treatment, especially among older patients.

Possible reasons for an increased risk of an earlier death include chemical exposure, which is casually associated with altered cardiac function, as well as genetic risks for irregular heart rhythms and heart failure. In the HeartRhythm review, Drs. Tereshchenko and Posnack analyze factors that influence mortality:

Hemodialysis treatment, dialysis, is associated with plastic chemical exposure

Drs. Tereshchenko and Posnack note that dialysis tubing and catheters are commonly manufactured using polyvinyl chloride (PVC) polymers. The phthalate plastics used to soften PVC can easily leech if exposed to lipid-like substances, like blood. Research shows phthalate chemical concentrations increase during a four-hour dialysis.

Di(2-ethylhexyl) phthalate (DEHP) is a common plastic used to manufacture dialysis tubes, thanks to its structure and economy.

Bisphenol-A (BPA) is another common material used in medical device manufacturing. From the membranes of medical tools to resins, or external coatings and adhesives, BPA leaves behind a chemical residue on PVC medical devices.

In reviewing the research, the authors find dialysis patients are often exposed to high levels of DEHP and BPA. The amount of exposure to these chemicals varies in regards to room temperature, time of contact, other circuit coatings and the flow rate of dialysis. A faster flow rate correlates with reductions in chemical leaching and lower mortality rates.

Plastic chemical exposure is casually associated with altered cardiac function

Drs. Tereshchenko and Posnack note a causal relationship already exists between chemicals absorbed from plastics and cardiovascular outcomes.

Dr. Posnack’s previous research found BPA concentrations impaired electrical conduction in neonatal cardiomyocytes – young, developing heart cells – potentially altering the heart’s normal rhythm and function.

To the best of their knowledge, no clinical research has been conducted on DEHP exposure and SCD. However, proof-of-concept models find in vivo phthalate exposure alters autonomic regulation, which can slow down natural heart-rate rhythm and create a lag in recovery time to stressful stimuli. For humans, this type of stressful stimulation would be equivalent to recovering from a bike ride, car accident, or in this case, ongoing dialysis treatment with impaired immune function.

In other models, BPA exposure has been shown to cause bradycardia, or a delayed heart rate. In excised whole heart models, BPA has also been shown to alter cardiac electrical activity.

Abnormal electrophysiological substrate in end-stage renal disease

Since the heart and kidneys work in tandem to transport blood throughout the body, and manage vital functions, such as our heart rate, blood flow and breathing, the authors cite additional factors that lead to ongoing heart and kidney problems, with a look at end-stage renal disease (ESRD).

General heart-function kidney risks include abnormal electrophysiological (EP) substrate, the underlying electrical activity of the cardiac tissue, and genetic risk factors, including the TBX3 gene, a gene associated with a unique positioning of the heart and SCD.

“We don’t want to cite alarm about having a medical procedure or about relying on external help, such as dialysis, for proper kidney function,” says Posnack. “Especially since dialysis is a life-saving medical intervention for patients with inadequate kidney function.”

Pre-existing abnormal EP substrate interacts with plastic chemical exposure in incident dialysis, which increases risk of SCD in genetically predisposed ESRD patients

To summarize their findings, Drs. Tereshchenko and Posnack list a handful of support areas, starting with observations about reductions in cardiovascular mortality and SCD following kidney transplants. They note hemodialysis catheters are associated with larger DEHP exposure and a higher risk of SCD, compared to arteriovenous fistulas, highways surgically created to connect blood from the artery to the vein.

Drs. Posnack and Tereshchenko also note a correlative observation about higher SCD rates observed six hours after hemodialysis, when peak levels of DEHP and BPA are circulating in the bloodstream.

To compare and control for these factors among dialysis patients, the researchers cite different mortality patterns with hemodialysis and peritoneal dialysis. Patients on hemodialysis experience higher mortality during the first year of treatment, compared to peritoneal dialysis, who have higher mortality rates after the second year of treatment. Hemodialysis relies on a machine to take the place of kidney function, while peritoneal dialysis relies on a catheter, a small tube surgically inserted into the stomach.

“Our goal is to build on our previous research findings by analyzing variables that have yet to be studied before, and to update the field of medicine in the process,” says Dr. Posnack. “This includes investigating the cardiovascular risks of using BPA- and DEHP-materials to construct medical devices. Ultimately, we hope to determine whether plastic materials contribute to cardiovascular risks, and investigate whether patients might benefit from the use of alternative materials for medical devices.

Drs. Tereshchenko and Posnack note that despite the associations between chemical exposure from medical devices and increased cardiovascular risks, there are no restrictions in the United States on the use of phthalates and BPA chemicals used to manufacture medical devices.

Their future research will explore how replacing BPA- and DEHP-leaching plastics influence mortality and morbidity rates of ESRD patients on dialysis, as well as other patients exposed to repeat chemical exposure, such as patients having cardiac surgery.

“We want to make sure we identify and then work to minimize any potential risks of plastic exposure in a medical setting,” adds Dr. Posnack. “Our goal is to put the health and safety of patients first.”

Dr. Posnack’s research is funded by two grants (R01HL139472, R00ES023477) from the National Institutes of Health.

Making the grade: Children’s National is nation’s Top 5 children’s hospital

Children’s National rose in rankings to become the nation’s Top 5 children’s hospital according to the 2018-19 Best Children’s Hospitals Honor Roll released June 26, 2018, by U.S. News & World Report. Additionally, for the second straight year, Children’s Neonatology division led by Billie Lou Short, M.D., ranked No. 1 among 50 neonatal intensive care units ranked across the nation.

Children’s National also ranked in the Top 10 in six additional services:

For the eighth year running, Children’s National ranked in all 10 specialty services, which underscores its unwavering commitment to excellence, continuous quality improvement and unmatched pediatric expertise throughout the organization.

“It’s a distinct honor for Children’s physicians, nurses and employees to be recognized as the nation’s Top 5 pediatric hospital. Children’s National provides the nation’s best care for kids and our dedicated physicians, neonatologists, surgeons, neuroscientists and other specialists, nurses and other clinical support teams are the reason why,” says Kurt Newman, M.D., Children’s President and CEO. “All of the Children’s staff is committed to ensuring that our kids and families enjoy the very best health outcomes today and for the rest of their lives.”

The excellence of Children’s care is made possible by our research insights and clinical innovations. In addition to being named to the U.S. News Honor Roll, a distinction awarded to just 10 children’s centers around the nation, Children’s National is a two-time Magnet® designated hospital for excellence in nursing and is a Leapfrog Group Top Hospital. Children’s ranks seventh among pediatric hospitals in funding from the National Institutes of Health, with a combined $40 million in direct and indirect funding, and transfers the latest research insights from the bench to patients’ bedsides.

“The 10 pediatric centers on this year’s Best Children’s Hospitals Honor Roll deliver exceptional care across a range of specialties and deserve to be highlighted,” says Ben Harder, chief of health analysis at U.S. News. “Day after day, these hospitals provide state-of-the-art medical expertise to children with complex conditions. Their U.S. News’ rankings reflect their commitment to providing high-quality care.”

The 12th annual rankings recognize the top 50 pediatric facilities across the U.S. in 10 pediatric specialties: cancer, cardiology and heart surgery, diabetes and endocrinology, gastroenterology and gastrointestinal surgery, neonatology, nephrology, neurology and neurosurgery, orthopedics, pulmonology and urology. Hospitals received points for being ranked in a specialty, and higher-ranking hospitals receive more points. The Best Children’s Hospitals Honor Roll recognizes the 10 hospitals that received the most points overall.

This year’s rankings will be published in the U.S. News & World Report’s “Best Hospitals 2019” guidebook, available for purchase in late September.

IV Bag

New study examines treatment for diabetic ketoacidosis

IV Bag

Brain injuries that happen during episodes of diabetic ketoacidosis (DKA) – where the body converts fat instead of sugar into energy, and where the pancreas is unable to process insulin, such as in type 1 diabetes – are rare, and happen in less than 1 percent of DKA episodes, but these injuries can carry lasting consequences – including mild to severe neurological damage.

A new 13-center, randomized, controlled trial published on June 13, 2018, in the New England Journal of Medicine finds two variables – the speed of rehydration fluids administered to patients and the sodium concentrations in these intravenous fluids – don’t impact neurological function or brain damage.

“One medical center would never be able to study this independently because of the relatively small volume of children with DKA that present to any one site,” says Kathleen Brown, M.D., a study author, the medical director of the emergency medicine and trauma center at Children’s National Health System and a professor of pediatrics and emergency medicine at George Washington University School of Medicine. “The strength of this research lies in our ability to work with 13 medical centers to study almost 1,400 episodes of children with DKA over five years to see if these variables make a difference. The study design showcases the efficiency of the Pediatric Emergency Center Applied Research Network, or PECARN, a federally-funded initiative that powers collaboration and innovation.”

Researchers have speculated about the techniques of administering intravenous fluids, specifically speed and sodium concentrations, to patients experiencing a DKA episode, with many assuming a faster administration rate of fluids would produce brain swelling. Others argued, from previous data, that these variables may not matter – especially since higher levels of brain damage were noted among children with higher rates of dehydration before they were treated. Some thought DKA created a state of inflammation in the brain, which caused the damage, and that speed and sodium concentration wouldn’t reverse this initial event. The researchers set out to determine the answers to these questions.

The PECARN research team put the data to the test: They created a 2-by-2 factorial design to test the impact of providing 1,255 pediatric patients, ages zero to 18, with higher (.9 percent) and lower (.45 percent) concentrations of sodium chloride at rapid and slow-rate administration speeds during a DKA episode. They administered tests during the first DKA episode and again during a recurrent episode. After analyzing 1,389 episodes, they found that the four different combinations did not have a statistically significant impact on the rate of cognitive decline during the DKA episode or during the 2-month and 6-month recovery periods.

“One of the most important lessons from this study is that diabetic ketoacidosis should be avoided because it can cause harm,” says Dr. Brown. “But the best way to treat diabetic ketoacidosis is to prevent it. Parents can monitor this by checking blood sugar for insulin control and taking their children for treatment as soon as they show signs or symptoms that are concerning.”

According to the National Institute of Diabetes and Kidney Disease, symptoms of diabetic ketoacidosis include nausea and vomiting, stomach pain, fruity breath odor and rapid breathing. Untreated DKA can lead to coma and death.

An accompanying video and editorial are available online in the New England Journal of Medicine.

The study was funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development at the Health Resources and Services Administration. The PECARN DKA FLUID ClinicalTrials.gov number is NCT00629707.

Children’s National Health System’s Division of Pediatric Emergency Medicine has been a lead site for the PECARN network since its inception in 2001.

child measuring belly with tape measure

Children’s obesity research team presents compelling new findings

child measuring belly with tape measure

Faculty from Children’s National Health System’s Department of Psychology & Behavioral Health set out to learn if any demographic, psychiatric, or cognitive factors play a role in determining if an adolescent should be eligible for bariatric surgery, and what their weight loss outcomes might be. Presenting at the Society for Pediatric Psychology Annual Conference earlier this month, a group of researchers, fellows and clinicians, including surgeons from Children’s National showcased their findings. One of the posters developed by Meredith Rose, LGSW, ML, who works as an interventionist on a Children’s National clinical research team, received special recognition in the Obesity Special Interest Group category.

One presentation reported on a total of 222 pediatric patients with severe obesity, which is defined as 120 percent of the 95th percentile for Body Mass Index. Mean age of the participants was 16 years of age, 71 percent were female and 80 percent where Hispanic or non-White. As part of their preparation for surgery, all patients were required to complete a pre-bariatric surgery psychological evaluation, including a clinical interview and Schedule for Affective Disorders and Schizophrenia (KSADS-PL) screening. The studies by the Children’s teams were based on a medical record review of the pre-screening information. Adolescents being evaluated for surgery had high rates of mental health diagnoses, particularly anxiety and depression, but also included Attention Deficit Hyperactivity Disorder, eating disorders, and intellectual disability.

Another Children’s presentation at the conference looked at weight loss outcomes for adolescents based on IQ and intellectual disability. Overall, neither Full Scale IQ from the Wechsler Abbreviated Intelligence Scale – 2nd edition, nor the presence of an intellectual disability predicted weight loss following surgery.

“The sum of our research found that kids do really well with surgery,” said Eleanor Mackey, PhD, assistant professor of psychology and behavioral health. “Adolescents, regardless of the presence of intellectual disability areas are likely to lose a significant amount of weight following surgery,” added Dr. Mackey.

“This is a particularly important fact to note because many programs and insurers restrict weight loss surgery to ‘perfect’ candidates, while these data points demonstrate that our institution does not offer or deny surgery on the basis of any cognitive characteristics,” says Evan P. Nadler, M.D., associate professor of surgery and pediatrics. “Without giving these kids a chance with surgery, we know they face a lifetime of obesity, as no other intervention has shown to work long-term in this patient population. Our research should empower psychologists and physicians to feel more confident recommending bariatric surgery for children who have exhausted all other weight loss options.”

The research team concluded that examining how individual factors, such as intellectual disability, psychiatric diagnoses, and demographic factors are associated with the surgery process is essential to ensuring adequate and empirically supported guidelines for referral for, and provision of bariatric surgery in adolescents. Next steps by the team will include looking into additional indicators of health improvement, like glucose tolerance, quality of life, or other lab values, to continue evaluating the benefits of surgery for this population.

Janelle Vaughns

Few prescribing options exist for obese kids

Janelle Vaughns

“We are making progress in expanding the number of medicines with pediatric labeling, but we need to do more concerning providing dosing guidelines for children with obesity,” says Janelle D. Vaughns, M.D., director of bariatric anesthesia at Children’s National and the lead study author.

Despite years of study and numerous public health interventions, overweight and obesity continue to grow in the U.S. Currently, more than two-thirds of adults have these issues, according to data from the Centers for Disease Control and Prevention. Children and adolescents also are being affected at an increasing rate: About one in five is obese. Obesity and overweight have been linked with a bevy of health problems, including Type 2 diabetes, high blood pressure, coronary heart disease and stroke.

Additionally, because obesity increases the percentage of fat tissue in relation to lean tissue and enlarges kidney size, it can affect how readily the body takes up, metabolizes and excretes medicines.

This latter issue can be particularly problematic in children, a population for whom relatively few drug studies exist. Now, a study team that includes Children’s National Health System researchers suggests that, despite the U.S. Congress providing incentives to drug manufacturers to encourage the study of medications in children, few approved drugs include safe dosing information for obese kids.

The study, performed in conjunction with the Food and Drug Administration’s (FDA) Center for Drug Evaluation and Research, surveyed pediatric medical and clinical pharmacology reviews under the FDA Amendments Act of 2007 and the FDA Safety and Innovation Act of 2012. The researchers used search terms related to weight and size to determine the current incorporation of obesity as a covariate in pediatric drug development.

Of the 89 product labels identified, none provided dosing information related to obesity. The effect of body mass index on drug pharmacokinetics was mentioned in only four labels, according to the study “Obesity and Pediatric Drug Development,” published online Jan. 19, 2018, in The Journal of Clinical Pharmacology.

“We are making progress in expanding the number of medicines with pediatric labeling, but we need to do more concerning providing dosing guidelines for children with obesity,” says Janelle D. Vaughns, M.D., director of bariatric anesthesia at Children’s National and the lead study author. “Moving forward, regulators, clinicians and the pharmaceutical industry should consider enrolling more obese patients in pediatric clinical trials to facilitate the safe and effective use of the next generation of medicines by obese children and adolescents.”

Study co-authors include Children’s Gastroenterologist Laurie Conklin, M.D., and Children’s Division Chief of Clinical Pharmacology Johannes N. van den Anker, M.D., Ph.D.; Ying Long, Pharm.D., University of Southern California; Panli Zheng, Pharm.D., University of North Carolina at Chapel Hill; Fahim Faruque, Pharm.D., University of Maryland; and Dionna Green, M.D., and Gilbert Burckart, Pharm.D., both of the FDA.

Research reported in this news release was supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health under award number 5T32HD087969.

Maureen Monaghan

Using text messages and telemedicine to improve diabetes self-management

Maureen Monaghan

Maureen Monaghan, Ph.D., C.D.E., clinical psychologist and certified diabetes educator in the Childhood and Adolescent Diabetes Program at Children’s National Health System, awarded nearly $1.6 million grant from American Diabetes Association.

Adolescents and young adults ages 17-22 with Type 1 diabetes are at high risk for negative health outcomes. If fact, some studies show that less than 20 percent of patients in this population meet targets for glycemic control, and visits to the Emergency Department for acute complications like diabetic ketoacidosis peak around the same age.

The American Diabetes Association (ADA) awarded Maureen Monaghan, Ph.D., C.D.E., clinical psychologist and certified diabetes educator in the Childhood and Adolescent Diabetes Program at Children’s National Health System, nearly $1.6 million to evaluate an innovative behavioral intervention to improve patient-provider communication, teach and help patients maintain self-care and self-advocacy skills and ultimately prepare young adults for transition into adult diabetes care, limiting the negative adverse outcomes that are commonly seen in adulthood.

Dr. Monaghan is the first psychologist funded through the ADA’s Pathway to Stop Diabetes program, which awards six annual research grants designed to spur breakthroughs in fundamental diabetes science, technology, diabetes care and potential cures. Dr. Monaghan received the Accelerator Award, given to diabetes researchers early in their careers, which will assist her in leading a behavioral science project titled, “Improving Health Communication During the Transition from Pediatric to Adult Diabetes Care.”

“Behavior is such a key component in diabetes care, and it’s wonderful that the American Diabetes Association is invested in promoting healthy behaviors,” says Dr. Monaghan. “I’m excited to address psychosocial complications of diabetes and take a closer look at how supporting positive health behavior during adolescence and young adulthood can lead to a reduction in medical complications down the road.”

During the five year study, Dr. Monaghan will recruit patients ages 17-22 and follow their care at Children’s National through their first visit with an adult endocrinologist. Her team will assess participants’ ability to communicate with providers, including their willingness to disclose diabetes-related concerns, share potentially risky behaviors like drinking alcohol and take proactive steps to monitor and regularly review glucose data.

“The period of transition from pediatric to adult diabetes care represents a particularly risky time. Patients are going through major life changes, such as starting new jobs, attending college, moving out of their parents’ homes and ultimately managing care more independently,” says Dr. Monaghan. “Behavioral intervention can be effective at any age, but we are hopeful that we can substantially help youth during this time of transition when they are losing many of their safety nets.”

Study leaders will help participants download glucose device management tools onto their smartphones and explain how to upload information from patients’ diabetes devices into the system. Participants will then learn how to review the data and quickly spot issues for intervention or follow-up with their health care provider.

Patients also will participate in behavioral telemedicine visits from the convenience of their own homes, and receive text messages giving them reminders about self-care and educational information, such as “Going out with your friends tonight? Make sure you check your glucose level before you drive.”

At the study’s conclusion, Dr. Monaghan anticipates seeing improvements in psychosocial indicators, mood and transition readiness, as well as improved diabetes self-management and engagement in adult medicine.

Veronica-Gomez-Lobo

Multidisciplinary care for children with urogenital differences

Veronica-Gomez-Lobo

Veronica Gomez-Lobo, M.D., brought together a multidisciplinary team to form the Positive Reevaluation of Urogenital Differences (PROUD) Clinic.

When a child is born with urogenital differences, the chromosomes, internal organs or external genitalia are considered to be atypical. While these differences were once thought to be rare, they are more common than people realize, with about 1 in 100 newborns affected.

The complexities of caring for children with urogenital differences, also known as differences of sex development (DSD), were not fully understood for many years. In the past, if a child was born with DSD, the family would see an endocrinologist for hormone therapy and a urologist for surgical options. Counseling was not part of the standard of care, so there was little support available to help families understand the tremendous psychosocial impacts of DSD.

In the last decade, fundamental changes have occurred in the way physicians care for children affected by DSD, with psychosocial health becoming a prominent focus. Veronica Gomez-Lobo, M.D., a Children’s National pediatric and adolescent gynecologist, was one of the physicians who embraced this focus and sought out a new care paradigm for her patients.

Creating the PROUD Clinic

Dr. Gomez-Lobo brought together a multidisciplinary team – including medical geneticist Eyby Leon Janampa, M.D., geneticist Eric Vilain, M.D., Ph.D., urologist Daniel Casella, M.D., endocrinologist Kim Shimy, M.D., psychiatrist David Call, M.D., and psychologist Elaine Goldberg, Ph.D. – to form the Positive Reevaluation of Urogenital Differences (PROUD) Clinic. It can be very challenging to bring together diverse specialists in a complex area like DSD, but her team possesses a similar philosophy – to care for the whole family by managing both the psychosocial and medical aspects of care in one location.

The team meets before each clinic to discuss the patients they will see that day. Patients vary significantly by the type of DSD and also by age – some patients are still in utero, while others may be newborns, children, adolescents or even occasionally adults.

Families see the entire team during their appointment, which can often last two to three hours to ensure that families receive the full support resources offered by the team.

“Even in difficult cases without a clear answer, we present the facts we know to the families, discussing all possibilities about psychosocial issues, gender identity, sexuality, function and fertility,” says Dr. Gomez-Lobo.

Long after the initial appointment, the PROUD Clinic continues to work closely with families and individual providers, following up as needed for medical diagnosis and care and providing continued psychosocial support with the entire team. Due to the efforts of the PROUD Clinic, patients and their families are now receiving compassionate care that looks at all facets of DSD, from childhood through adulthood.

Increasing DSD knowledge in the medical community

In order to give her patients the most thorough understanding of DSD and to expand the medical community’s knowledge, Dr. Gomez-Lobo’s program also participates in the Disorders of Sex Development Translational Research Network (DSD-TRN), which is led by Dr. Vilain. Supported by the National Institutes of Health (NIH), the DSD-TRN provides physicians across the country with the ability to perform research to advance knowledge regarding these conditions, as well as learn how to improve the care of these individuals and families. The DSD-TRN also provides a forum to seek advice about complex cases and to communicate how to transition patients from pediatric to adult medicine.

The relationship with the DSD-TRN helps the PROUD Clinic team further their goal of creating care for their patients that is current, individualized and compassionate.

 

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.

Electronic medical record on tablet

Children’s National submissions make hackathon finals

Electronic medical record on tablet

This April, the Clinical and Translational Science Institute at Children’s National (CTSI-CN) and The George Washington University (GW) will hold their 2nd Annual Medical and Health App Development Workshop. Of the 10 application (app) ideas selected for further development at the hackathon workshop, five were submitted by clinicians and researchers from Children’s National.

The purpose of the half-day hackathon is to develop the requirements and prototype user interface for 10 medical software applications that were selected from ideas submitted late in 2017. While idea submissions were not restricted, the sponsors suggested that they lead to useful medical software applications.

The following five app ideas from Children’s National were selected for the workshop:

  • A patient/parent decision tool that could use a series of questions to determine if the patient should go to the Emergency Department or to their primary care provider; submitted by Sephora Morrison, M.D., and Ankoor Shah, M.D., M.P.H.
  • The Online Treatment Recovery Assistance for Concussion in Kids (OnTRACK) smartphone application could guide children/adolescents and their families in the treatment of their concussion in concert with their health care provider; submitted by Gerard Gioia, Ph.D.
  • A genetic counseling app that would provide a reputable, easily accessible bank of counseling videos for a variety of topics, from genetic testing to rare disorders; submitted by Debra Regier, M.D.
  • An app that would allow the Children’s National Childhood and Adolescent Diabetes Program team to communicate securely and efficiently with diabetes patients; submitted by Cynthia Medford, R.N., and Kannan Kasturi, M.D.
  • An app that would provide specific evidence-based guidance for medical providers considering PrEP (pre-exposure prophylaxis) for HIV prevention; submitted by Kyzwana Caves, M.D.

Kevin Cleary, Ph.D., technical director of the Bioengineering Initiative at Children’s National Health System, and Sean Cleary, Ph.D., M.P.H., associate professor in epidemiology and biostatistics at GW, created the hackathon to provide an interactive learning experience for people interested in developing medical and health software applications.

The workshop, which will be held on April 13, 2018, will start with short talks from experts on human factors engineering and the regulatory environment for medical and health apps. Attendees will then divide into small groups to brainstorm requirements and user interfaces for the 10 app ideas. After each group presents their concepts to all the participants, the judges will pick the winning app/group. The idea originator will receive up to $10,000 of voucher funding for their prototype development.

iLet-Bionic-Pancreas

Children’s National to test bionic pancreas

iLet-Bionic-Pancreas

The iLet bionic pancreas helps patients manage their diabetes by both monitoring blood glucose levels and administering insulin and glucagon.

Children’s National Health System has been selected to participate in a multi-center clinical trial to test the efficacy of the iLet bionic pancreas — a device that automatically regulates blood sugar levels in patients with Type 1 diabetes.

Patients generally manage diabetes by constantly monitoring their blood sugar levels and administering insulin when necessary. Unfortunately, too much insulin can cause hypoglycemia, or low blood sugar, which can result in hypoglycemic seizures, coma or rarely, death. Thus, it is extremely important for people with diabetes to regulate their insulin dosages and maintain their blood sugar levels within a range decided by the family and diabetes team.

“The burden of caring for diabetes on a daily basis is grueling,” says Seema Meighan, FNP, a nurse practitioner involved in the upcoming clinical trial. “It is by far one of the most challenging chronic diseases to manage, and requires vigilant participation 100 percent of the time to stay well controlled.”

The iLet bionic pancreas helps patients manage their diabetes by both monitoring blood glucose levels and administering insulin and glucagon — a pancreatic hormone that raises blood sugar levels.

“In a traditional infusion pump, patients only have access to insulin to control glucose levels,” explains Meighan. “This can become problematic when it comes to hypoglycemia. The hope with a bi-hormonal system is that glucagon can be delivered during times that the glucose is low in order to stabilize levels without user interaction.”

Developed at Boston University by Edward Damiano, Ph.D., and Firas El-Khatib, Ph.D., the iLet is a hand-held device about the size of an iPhone but twice as thick, and can easily fit into a pocket. The unit consists of a dual chamber infusion pump that can be configured to deliver only insulin, only glucagon or both hormones. The device uses a wireless glucose sensor on the patient’s body to test blood sugar levels every five minutes. It then determines which hormone is needed and administers it via catheters connected to the patient.

In short-term studies, the iLet was able to maintain blood glucose levels close to normal in both adults and children in carefully controlled environments.

In 2016, the Children’s National Health System Division of Endocrinology and Diabetes, led by diabetologist Fran Cogen, M.D., C.D.E., was one of several pediatric sites that were selected to participate in pivotal clinical trials to further test the efficacy of the bionic pancreas. Later this year, the team at Children’s National will begin enrolling five to 10 children to test iLet devices that only deliver insulin. Once these initial studies are completed, the team will perform an additional trial to test iLet devices configured to deliver both insulin and glucagon.

“This trial is important as it represents the first dual chamber pump to manage glucose levels,” says Meighan. “It could potentially change the way we treat diabetes entirely. It represents a hope to our patients and families that one day this disease will have far less of a daily burden than it currently does.”