Carmelo Cuffari, M.D., the new director of Inflammatory Bowel Disease (IBD) Program at Children’s National Hospital is a pediatric gastroenterologist with over 25 years of expertise in managing children and adolescents with Crohn’s disease and ulcerative colitis. His areas of research include drug development and the pharmacology and genomics of immunomodulatory drugs in inflammatory bowel disease and in transplantation.
Here, Dr. Cuffari tells us more about the program he is leading and what it means for the future of pediatric IBD patients at Children’s National.
Q: What are some of the most valuable changes or advancements for the program you hope to see in the next couple of years?
A: In my position as director of IBD, Children’s National supports my goals for the program which include:
Expanded regional accessibility to an IBD specialist
Potential to develop international services
Potential to develop a multidisciplinary pediatric IBD program that would include surgery, psychology and genetics
Expanding staff to include another IBD specialist to increase our reach
Q: What makes the IBD at Children’s National unique from other programs in the country?
A: We have the unique possibility of developing a colorectal team with our surgical colleagues. This level of collaboration is unique and is a function of our division being under the department of pediatric surgery.
Q: Where do you see research in IBD going in the next few years?
A: There are many areas of exciting growth in research. The areas I am most excited about include:
Developing a tailored therapeutic approach to disease management that is disease phenotype specific
Developing biomarkers that may help identify which part of the immune system is dysregulated
Very early onset IBD (<6yrs) will be better defined genetically and immunologically
https://innovationdistrict.childrensnational.org/wp-content/uploads/2022/02/blocks-that-spell-out-IBD.png300400Innovation Districthttps://innovationdistrict.childrensnational.org/wp-content/uploads/2023/12/innovationdistrict_logo-1-1030x165.pngInnovation District2022-02-15 11:45:292022-02-15 11:47:08Q&A with Carmelo Cuffari, M.D., on inflammatory bowel disease
Experts leading the Headache Program at Children’s National Hospital recognize how common these disorders are. They also know how disruptive they can be in the day-to-day of children.
Marc DiSabella, D.O., is the director of the program. He is currently leading five pediatric headache trials. In this Q&A, he tells us about the ongoing trials, offering insight into innovative solutions and how he’s carving a new path to improve the quality of life of his patients.
Q: How has your team advised other neurologists on innovative care for patients with headaches that have been refractory to medicines?
A: We receive referrals from outside institutions when they need additional input for diagnostic and management options. We receive patient consult requests from around the country – and sometimes out of the country – to help improve symptoms. In most instances, these headaches tend to be difficult to control and do not respond to available medications. We really try to take a holistic approach to their care, and use treatments in parallel. For example, diagnostic, lifestyle techniques, medications, pain focused cognitive behavioral therapy and physical therapy. We also use complementary medicine as needed, such as acupuncture, injections and infusions.
Q: It is unusual for neurology divisions to run multiple pediatric trials focused on headaches. You are currently leading five that are open. How does this work move the field forward?
A: The medications we offer through our trials allow us to offer treatments that would otherwise not be available to pediatric patients. We do this in hopes of providing them relief while advancing the field. We are hopeful that these new therapies are as effective in pediatrics as they have shown to be in adults. But it is necessary to complete randomized clinical trials to prove this is the case. Historically, pediatric patients in clinical trials investigating painful conditions like migraines have had a disproportionately high placebo response rate. This means even the patients receiving a benign placebo have a high chance of symptom improvement. The newer medications show much better tolerability to the drugs used historically.
Q: What excites you about this work?
A: Pediatric pain disorders are unbelievably gratifying to treat because we take a mysterious disorder that waxes and wanes with no clear reason and give patients back control of their lives. It is extremely frustrating for a patient and their family to know that their day-to-day life can be abruptly derailed by a pain crisis. We work to provide them with several tools they can use daily to take back their lives.
Q: How is this work unique?
A: Our program was created organically over the years through our experiences with our patients. First, we noticed the disruption to patients’ personal and school performance from having untreated pain and recognized the need for pain psychology. Then, we expanded to have physical therapy to recondition patients and perform desensitization. Finally, we recognized our patients need additional medication options not offered through the standard of care. So, we expanded to open our various clinical trials, including those with pharma and internal protocols. As a result, we incorporated the use of Botox injections, for example, and soon will use a novel remote electro-neuromodulatory device.
https://innovationdistrict.childrensnational.org/wp-content/uploads/2022/02/kid-with-headache.png300400Innovation Districthttps://innovationdistrict.childrensnational.org/wp-content/uploads/2023/12/innovationdistrict_logo-1-1030x165.pngInnovation District2022-02-08 15:46:102022-02-11 10:11:15Kids’ headaches can be disruptive. We need solutions.
Pediatric colorectal specialists are in short supply, and this is particularly true in many areas of the developing world. When Marc Levitt, M.D., travels abroad, he consistently finds eager surgeons and nurses who wish to obtain advanced colorectal skills to help their patients. To meet this need Dr. Levitt has established an international observership program that brings leading physicians and nurses from around the globe to participate in one- to three-month-long observerships.
During 2022, the program will welcome participants from 13 different countries including Spain, Belgium, Vietnam, Indonesia, Chile, Pakistan, Uganda, Iraq, Mexico, Brazil, Saudi Arabia and Singapore.
Under the colorectal team’s instruction, participating physicians and nurses will learn how to diagnose and care for children with complex colorectal conditions. They will learn about the wide range of malformations and successful treatment options so they can bring these skills to patients in their home countries. Those selected for these observerships are among the most promising providers in their communities who currently work to improve treatment for children with colorectal issues. The patients they care for are those who would otherwise have no or limited access to this specialty care.
To keep in-person learning and protect students in schools, pediatricians and public health officials must advocate for evidence-based mitigation strategies that can reduce COVID-19 transmission — especially the Delta variant, which overwhelmed pediatric emergency rooms and hospitals, argued Yang et al. in a Perspective published in the journal Pediatrics.
To keep in-person learning and protect students in schools, pediatricians and public health officials must advocate for evidence-based mitigation strategies that can reduce COVID-19 transmission — especially the Delta variant, which overwhelmed pediatric emergency rooms and hospitals, argued Yang et al. in a Perspective published in the journal Pediatrics.
The authors propose that pediatricians and their associated institutions actively advocate for masking in schools and debunk myths and misinformation during well and sick visits. In addition, they encourage doctors to develop and disseminate behavioral strategies to support children’s compliance with masking based on individual abilities and needs. Finally, providers can partner with educators at the local, district, state and national levels to advocate for evidence-based masking policies.
“As pediatricians, it is our responsibility to advocate for universal masking to facilitate safe in-person schooling for all children,” said Sarah Schaffer DeRoo, M.D., pediatrician at Children’s National Hospital and co-author of the Perspective. “Children have readily adapted to masking during the pandemic and continuing this practice in schools is not a significant change from their recent experience.”
To date, nine states have enacted policies to prohibit school masking mandates, disregarding evidence that masking is a crucial COVID-19 preventive measure, Yang et al. wrote. The court overturned these mandates in four states out of the nine because they either exceeded the governor’s executive authority or did not comply with the law granting the executive order’s authority. In other instances, judges have only placed a temporary block.
“Despite politically charged rhetoric and headline-grabbing lawsuits, evidence shows that schools without mask mandates are more likely to have COVID-19 outbreaks,” said Y. Tony Yang, Sc.D., endowed professor of health policy and executive director of the Center for Health Policy and Media Engagement at the George Washington University, and lead author of the Perspective. “Pediatricians have generally commanded a heightened level of public trust, which suggests that pediatricians who make the case for policies that advance sound medical and public health science may have a greater chance than other advocates of generating the public and political will needed to make evidence-based policy ideas, such as school mask mandates, a reality.”
Some localities have found creative ways to circumvent state mask mandate bans by altering the school dress code to include face coverings and finding loopholes that do not apply to individual cities. Parents have also tried to challenge the policies in court, asserting that mask mandate bans violate federal anti-discrimination laws.
“Continued efforts are needed to ensure schools are able to promote reasonable, evidence-based strategies to promote the health of their students, teachers and communities, and we, as advocates for children, are obligated to emphatically support these efforts,” said Yang et al.
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Marc Levitt, M.D., served as guest editor of a special December Seminars in Pediatric Surgery dedicated to the care and treatment of anorectal malformations.
By Marc Levitt, M.D., chief of the Division of Colorectal and Pelvic Reconstruction at Children’s National Hospital
We had 64 contributing authors from 12 countries; Australia, Austria, Germany, Ghana, Italy, Israel, the Netherlands, Nigeria, Spain, South Africa, the United Kingdom and the United States, and 12 U.S. colorectal collaborating programs; Children’s National, Boston Children’s, Children’s Mercy, Children’s Wisconsin, C.S. Mott Children’s, Cincinnati Children’s, Nationwide Children’s, Nicklaus Children’s, Omaha Children’s, Primary Children’s, Seattle Children’s, and UC Davis Children’s.
The series of articles included in this collection illustrate new techniques and ideas that over time have made a dramatic and positive impact on the care and quality of life of children who suffer from colorectal problems. With an integrated approach to the care of this complex group of patients, great things can be achieved. As we endeavor to advance this field, we need to always remember that, as Alberto Pena, M.D., often said, “it is not the unanswered questions, but rather the unquestioned answers that one must pursue.”
In my own article on advances in the field, a 2021 update, I reproduce a piece by my daughter, Jess Levitt, who wrote something applicable to the care of children with colorectal problems, with the message that helping to create order is vital to improve a somewhat chaotic medical process traditionally available for the care of complex care. Her essay is reproduced here:
“A” must come before “B,” which must come before “C,” everybody knows that. But what if the Millercamp’s of this world did not have to sit next to the Millerchip’s when it comes to seating arrangements? Can Pat Zawatsky be called before Jack Aaronson when the teacher is taking attendance? Do those 26 letters that make up all the dialogue, signs, thoughts, books, and titles in the English-speaking departments of the world need their specific spots in line? Everyone can sing you the well-known jingle from A to Z, but not many people can tell you why the alphabet is the way it is. For almost as long as humans have had the English language, they have had the alphabet. The good ole ABCs.
However, the alphabet represents the human need for order and stability. I believe that the same thinking that went into the construct of time and even government went into the alphabet. Justifiably, lack of order leads to chaos. Knife-throwing, gun-shooting chaos, in the case of lack of governmental order. Listen to me when I tell you that there is absolutely no reason that the alphabet is arranged the way that it is. Moreover, the alphabet is simply a product of human nature and how it leads people to establish order for things that do not require it.
Now I know this sounds crazy but bear with me. Only if you really peel away the layers of the alphabet will you find the true weight it carries. People organized the letters of our speech into a specific order simply because there wasn’t already one. Questioning this order will enlighten you on the true meaning of it. Really dig deep into the meaning behind the social construct that is the alphabet. Short and sweet as it may be, the order of the ABCs is much less than meets the eye. There is no reason that “J” should fall before “K!” Understand this. Very important as order is, it is only a result of human nature. What’s next? X-rays become independent of Xylophones in children’s books of ABCs?
You know what the best part is? Zero chance you even noticed that each sentence in this essay is in alphabetical order.
Her literary contribution inspired me to do something similar. Take a look at the list of articles in this Seminars edition:
Creating a collaborative program for the care of children with colorectal and pelvic problems. Alejandra Vilanova-Sánchez, Julie Choueiki, Caitlin A. Smith, Susan Callicot, Jason S. Frischer and Marc A. Levitt
Optimal management of the newborn with an anorectal malformation and evaluation of their continence potential. Sebastian K. King, Wilfried Krois, Martin Lacher, Payam Saadai, Yaron Armon and Paola Midrio
Lasting impact on children with an anorectal malformations with proper surgical preparation, respect for anatomic principles, and precise surgical management. Rebecca M. Rentea, Andrea T. Badillo, Stuart Hosie, Jonathan R. Sutcliffe and Belinda Dickie
Long-term urologic and gynecologic follow-up and the importance of collaboration for patients with anorectal malformations. Clare Skerritt, Daniel G. Dajusta, Molly E. Fuchs, Hans Pohl, Veronica Gomez-Lobo and Geri Hewitt
Assessing the previously repaired patient with an anorectal malformation who is not doing well. Victoria A. Lane, Juan Calisto, Ivo Deblaauw, Casey M. Calkins, Inbal Samuk and Jeffrey R. Avansino
Bowel management for the treatment of fecal incontinence and constipation in patients with anorectal malformations. Onnalisa Nash, Sarah Zobell, Katherine Worst and Michael D. Rollins
Organizing the care of a patient with a cloacal malformation: Key steps and decision making for pre-, intra-, and post-operative repair. Richard J. Wood, Carlos A. Reck-Burneo, Alejandra Vilanova-Sanchez and Marc A. Levitt
Radiology of anorectal malformations: What does the surgeon need to know? Matthew Ralls, Benjamin P. Thompson, Brent Adler, Grace Ma, D. Gregory Bates, Steve Kraus and Marcus Jarboe
Adjuncts to bowel management for fecal incontinence and constipation, the role of surgery; appendicostomy, cecostomy, neoappendicostomy, and colonic resection. Devin R. Halleran, Cornelius E.J. Sloots, Megan K. Fuller and Karen Diefenbach
Treating pediatric colorectal patients in low and middle income settings: Creative adaptation to the resources available. Giulia Brisighelli, Victor Etwire, Taiwo Lawal, Marion Arnold and Chris Westgarth-Taylor
Importance of education and the role of the patient and family in the care of anorectal malformations. Greg Ryan, Stephanie Vyrostek, Dalia Aminoff, Kristina Booth, Sarah Driesbach, Meghan Fisher, Julie Gerberick, Michel Haanen, Chelsea Mullins, Lori Parker and Nicole Schwarzer
Ongoing care for the patient with an anorectal malfromation; transitioning to adulthood. Alessandra Gasior, Paola Midrio, Dalia Aminoff and Michael Stanton
New and exciting advances in pediatric colorectal and pelvic reconstructive surgery – 2021 update. Marc A. Levitt
The first letter of each article forms an acrostic of the word “COLLABORATION” which is the secret sauce behind any success in the field of pediatric colorectal care.
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Our neurosurgery team is among the most experienced in the nation. We have performed thousands of surgeries and are dedicated to giving the best possible care. The Children’s National Hospital Division of Neurosurgery consistently ranks among the country’s top programs according to U.S. News & World Report.
Patients travel to us from all over the world because we have the resources and expertise necessary to care for their neurological conditions through multidisciplinary programs such as:
Spine Disorders
Deep Brain Stimulation Program
Neuro Intensive Care Unit (Neuro ICU)
Neuro-ophthalmology
Spina Bifida Program
Brain and Spinal Cord Tumors
Craniofacial Disorders
Chiari Malformations
Epilepsy
Brachial Plexus Injury
Spasticity Program
Neurovascular diseases such as AVM’s and Moyamoya
Minimally invasive surgery
The Children’s National Hospital Division of Neurosurgery is among the first in the country to develop new techniques and adopt the latest technologies that make minimally invasive neurosurgery possible by utilizing state of the art equipment and developing new techniques, including:
ROSA surgical robot / SEEG placement
Surgical Theater with virtual reality visualization
Visualase® magnetic resonance imaging (MRI)-guided laser ablation
5T intra-operative MRI (iMRI)
Deep brain stimulation
Neuropace epilepsy control
Advanced treatment and cutting edge research
Children’s National is involved in cutting edge scientific research offering new hope for our patients and new methods of treatment. Our doctors have developed some of the most advanced treatments and clinics for our patients including:
Multidisciplinary skull base neurosurgery program
Participating in the 1st generation of genetic modulation trials
CAR T-Cell Therapy research
Ehlers-Danlos syndrome (EDS) /Hypermobility Program
Pseudotumor Cerebri Multidisciplinary panel
Leader in open and endoscopic craniosynostosis surgery
Ranked No. 5 in the nation
U.S. News & World Report ranks our neurosurgery program number five in the nation, reflecting our commitment to excellence in care for our patients and families.
Level 1 surgery verification
Children’s National is one of only 12 children’s hospitals in the country to attain Level 1 Surgery Verification from the American College of Surgeons.
Successful outcomes
Children with rare and medically complex conditions, such as brain tumors, craniofacial disorders, Chiari malformations, vascular disorders and brachial plexus palsy, to name a few, achieve exceptional outcomes at Children’s National. Our patients experience fewer complications, go home sooner and maintain long-term symptom relief.
Specialized expertise
Our entire team is dedicated to meeting your child’s unique needs. Our Neuro-Intensive Care Unit nurses recognize signs of pain and complications your child may not be able to explain.
Pioneering new treatments
Children’s National is at the forefront of new device-based treatments that not only fix neurologic problems, but also restore brain function. We are one of the few pediatric programs in the country offering dedicated pediatric deep brain stimulation, which uses a pacemaker-like device to significantly reduce the burden of movement disorders and difficult-to-control epilepsy, as well as Neuropace implantation to help with seizures in eloquent areas of the brain.
Training the next generation of top neurosurgeons
We are proudly training the next generation of pediatric neurosurgeons through residency programs and fellowships in conjunction with several area medical schools.
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Kurt Newman, M.D., president and chief executive officer of Children’s National, shares his poignant journey as a pediatric surgeon, offering a new perspective for approaching the most chronic and debilitating health conditions. In this independently-organized TEDx event, Dr. Newman also shares his passion for Children’s National and the need to increase pediatric innovations in medicine.
https://innovationdistrict.childrensnational.org/wp-content/uploads/2018/02/Kurt-Newman-capitol-building.jpg300400Innovation Districthttps://innovationdistrict.childrensnational.org/wp-content/uploads/2023/12/innovationdistrict_logo-1-1030x165.pngInnovation District2019-03-15 13:09:132023-07-03 10:43:43Kurt Newman, M.D., shares journey as a pediatric surgeon in TEDx Talk
Dr. Martin and a patient share a smile after a visit at Children’s National Health System.
For pediatric cardiologists, February, National Heart Month, is a special time. We share health tips in the hospital and talk about heart health with those looking for advice, especially with patients and families impacted by congenital heart disease (CHD). It’s also a time to look back at what’s worked well in the field, while accelerating advancements for CHD treatment.
To start, congenital heart disease, a structural abnormality of the heart or of the blood vessels surrounding it, is the most common birth defect and occurs in about one in every 100 live births, affecting 40,000 babies born in the U.S. each year. One million children and 1.4 million adults in the U.S. have CHD. Over the past 15 years, pediatric cardiologists have cut mortality rates for CHD in half. Gratefully, now instead of saving children’s lives, the emphasis is on improving them. The catalyst for this paradigm shift isn’t simply due to a medical breakthrough, but is also the result of collaboration and advocacy.
Pediatric cardiologists worked together with other stakeholders – nurses, neonatologists, parents, state and federal agencies – to implement newborn screening methods in hospitals, with the introduction pulse oximetry screenings for critical congenital heart defects (CCHD). The screening, which measures blood oxygen levels in newborns, focuses on screening babies for CCHD before they leave the hospital. The concept and a national protocol for screening began with a small project in 2002, was endorsed by medical associations by 2012 and required by all states in 2018. The impact of CCHD screening of newborns is remarkable. Data published in JAMA showed a 33 percent reduction in CCHD infant deaths associated with states that required CCHD screening.
The pulse oximetry screening’s impact on the number of lives saved goes beyond identifying newborns with CCHD. Worldwide, though the detection of secondary conditions, such as hypothermia, pneumonia, and sepsis, the pulse oximetry screening is estimated to save roughly 772,000 lives by 2030.
In addition to newborn screening recommendations for CCHD, a group of cardiologists, including myself, worked for the Joint Council on Congenital Heart Disease (JCCHD) to form and support the National Pediatric Cardiology Quality Improvement Collaborative (NPC-QIC). We developed measures to see how we could improve survival rates between surgeries for infants born with hypoplastic left heart syndrome (HLHS), one of the most common and severe forms of CCHD.
Babies born with HLHS require two heart surgeries within the baby’s first six months. Babies that survived the first operation had a significant mortality rate (15 percent) and frequent growth failure, while waiting for the second operation. Our focused aims were to both decrease the death rate and improve growth in these children. We analyzed data from medical centers, utilized quality improvement principals from the Institute for Health Care Improvement, talked with doctors and families, and invited teams from across the U.S. to partner with us to put quality and safety measures into place.
We emphasized the following points:
Clear communication. Parents leaving the hospital received consistent messages about CHD, the type of surgery their baby had, next steps and how to care for their child at home.
Improved nutrient intake. Parents received clear guidelines about how many calories babies needed to consume, were asked to weigh their baby each day, and taught how to augment feeding.
Warning signs.Parents received a list of typical infant behaviors and HLHS red flags to watch out for, such as if a baby isn’t gaining a certain amount of weight. They received monitors to measure oxygen saturation levels at home. If oxygen saturation dropped significantly or if parents noticed a problem, they called their doctor immediately.
The implementation of these procedures reduced interstage mortality rates and the number of growth failures for HLHS patients. In 2008, six centers participated in the NPC-QIC pilot. By 2018, 65 medical centers in the U.S. and Canada used these methods. Similar to the pulse oximetry screening guidelines, this new method wasn’t the result of a medical breakthrough, but the result of shared learning and shared infrastructure.
Now, we’re referring more adult congenital heart patients to board-certified adult congenital heart disease (ACHD) specialists, a better fit than internists or pediatric cardiologists. Adults with congenital heart defects should have their heart examined at least once by a specialist and those with complex needs should meet with a specialist at least every two years. More than 300 board-certified ACHD specialists practice in the U.S. and the field is growing. The third ACHD board exam takes place this year.
Over the next few decades, I hope we’ll make even more progress with understanding, diagnosing and treating CHD.
Emerging research examines genetic clues for congenital heart defects, which were once thought to account for 8 percent of cases and may now account for 30 percent of conditions. We’re working with neurologists to examine the timing and pathway of potential oxygen inefficiencies that occur as the brain develops in utero, infancy, and after neonatal surgery. We’ve come a long way, but we continue looking at new frontiers and for innovative solutions.
Fortunately, as cardiologists, we’re good at fixing problems. We work with surgeons and medical teams to repair holes in hearts, or replace them, and reroute blood from an underdeveloped left ventricle to improve circulation. For almost every heart defect, we have evidence-based solutions. However, to continue to help children worldwide, it’s imperative that we don’t forget about what works well: good science, tracking data, sharing best practices, active listening, transparency and constant collaboration.
Lisa M. Guay-Woodford, M.D., is internationally recognized for her examination of the mechanisms that make certain inherited renal disorders particularly lethal, a research focus inspired by her patients.
When Children’s National pediatric nephrologist Lisa Guay-Woodford, M.D., was an intern at Boston Children’s Hospital, a baby with autosomal recessive polycystic kidney disease (ARPKD) was admitted to one of the hospital’s neonatal intensive care units (NICU). This disease, which causes cysts to form in the kidney and liver, kills about one-fifth of babies within the newborn period due to related problems that affect lung development.
But this baby seemed like a survivor, Dr. Guay-Woodford remembers. The child passed the newborn period and graduated from the NICU, although she went home with severe blood pressure issues. Along with a team of colleagues, Dr. Guay-Woodford helped to manage this patient’s care, juggling normal infant concerns with her ARPKD.
As far as Dr. Guay-Woodford knew at the time, this baby was beating the odds against her, growing and thriving. But one day near the end of her internship period, Dr. Guay-Woodford was called to the emergency department. Her patient was in a hypertensive crisis that ultimately killed her.
“It was absolutely devastating to all of us. This was supposed to be a good news kind of story, that she survived the newborn period and had gone home and was growing and developing,” Dr. Guay-Woodford says. “I realized then that a big part of the tragedy of this disease is how little we knew about it.”
Dr. Guay-Woodford vowed to change that. Since then, she’s devoted her career to studying ARPKD and other inherited kidney diseases.
After finishing her residency and fellowship in Boston, Dr. Guay-Woodford was recruited to the University of Alabama, where she began caring for a cadre of 40 patients with inherited renal disorders. Fueled by the research questions that arose while working with these patients, she and her colleagues searched for PKD-related genes in the cpk mouse model, an animal that mimics many of the features of human ARPKD.
Dr. Guay-Woodford and her team cloned several of the key genes that caused recessive PKD in this mouse and other mouse models and eventually went on to identify the first major genetic modifier of PKD in these animals – a gene that wasn’t directly responsible for the disease but could sway its course. In time, her collaborative group became one of two that co-indentified the major gene responsible for human ARPKD. In 2005, Dr. Guay-Woodford led a team of investigators at the University of Alabama-Birmingham to establish one of just four PKD translational core centers funded by a National Institutes of Health P30 grant.
After moving to Children’s National in 2012, Dr. Guay-Woodford still co-directs this PKD translational core center while also caring for patients at her inherited renal disorders clinic. She and her colleagues here and beyond continue to work with mouse models of this disease, trying to ferret out the vast network of genes that interact in ARPKD and their specific roles.
“You can use a variety of strategies to compare these patients’ gene portfolios with those of healthy patients and pick out the disease genes. But at the end of the day, to me, that’s just the opening chapter,” she says. “To really make a story, you’ve got to understand what is it that gene does, what protein it makes, and how that protein works together with others involved in this disease.”
She and her team also are currently working with a pharmaceutical company to develop the first clinical trial to test a treatment for ARPKD. This effort has relied heavily on a clinical database that Dr. Guay-Woodford and colleagues worldwide maintain to track patients with this and related conditions. Through the extensive collection of clinical information in this database – including a variety of data on patients’ gestation and birth, growth, and kidney structure and function – the team has identified a core cohort of patients whose disease is rapidly progressing, a characteristic that makes them prime candidates to test this potential new treatment.
“Everything I do in the clinic informs the work I do in the lab, and everything I do in the lab is to help the patients I see in the clinic. It’s this constant dance back and forth between our human patients and animal models,” she says. “One day, this dance will help lessen the burden of this disease for these kids and their families.”
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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.”
https://innovationdistrict.childrensnational.org/wp-content/uploads/2018/12/Dauber-Reddit-AMA.jpg300400Innovation Districthttps://innovationdistrict.childrensnational.org/wp-content/uploads/2023/12/innovationdistrict_logo-1-1030x165.pngInnovation District2018-12-27 10:27:082024-05-16 14:49:48Thirteen questions for a pediatric endocrinologist
Q&A with Carmelo Cuffari, M.D., on inflammatory bowel disease
Here, Dr. Cuffari tells us more about the program he is leading and what it means for the future of pediatric IBD patients at Children’s National.
Q: What are some of the most valuable changes or advancements for the program you hope to see in the next couple of years?
A: In my position as director of IBD, Children’s National supports my goals for the program which include:
Q: What makes the IBD at Children’s National unique from other programs in the country?
A: We have the unique possibility of developing a colorectal team with our surgical colleagues. This level of collaboration is unique and is a function of our division being under the department of pediatric surgery.
Q: Where do you see research in IBD going in the next few years?
A: There are many areas of exciting growth in research. The areas I am most excited about include:
Kids’ headaches can be disruptive. We need solutions.
Marc DiSabella, D.O., is the director of the program. He is currently leading five pediatric headache trials. In this Q&A, he tells us about the ongoing trials, offering insight into innovative solutions and how he’s carving a new path to improve the quality of life of his patients.
Q: How has your team advised other neurologists on innovative care for patients with headaches that have been refractory to medicines?
A: We receive referrals from outside institutions when they need additional input for diagnostic and management options. We receive patient consult requests from around the country – and sometimes out of the country – to help improve symptoms. In most instances, these headaches tend to be difficult to control and do not respond to available medications. We really try to take a holistic approach to their care, and use treatments in parallel. For example, diagnostic, lifestyle techniques, medications, pain focused cognitive behavioral therapy and physical therapy. We also use complementary medicine as needed, such as acupuncture, injections and infusions.
Q: It is unusual for neurology divisions to run multiple pediatric trials focused on headaches. You are currently leading five that are open. How does this work move the field forward?
A: The medications we offer through our trials allow us to offer treatments that would otherwise not be available to pediatric patients. We do this in hopes of providing them relief while advancing the field. We are hopeful that these new therapies are as effective in pediatrics as they have shown to be in adults. But it is necessary to complete randomized clinical trials to prove this is the case. Historically, pediatric patients in clinical trials investigating painful conditions like migraines have had a disproportionately high placebo response rate. This means even the patients receiving a benign placebo have a high chance of symptom improvement. The newer medications show much better tolerability to the drugs used historically.
Q: What excites you about this work?
A: Pediatric pain disorders are unbelievably gratifying to treat because we take a mysterious disorder that waxes and wanes with no clear reason and give patients back control of their lives. It is extremely frustrating for a patient and their family to know that their day-to-day life can be abruptly derailed by a pain crisis. We work to provide them with several tools they can use daily to take back their lives.
Q: How is this work unique?
A: Our program was created organically over the years through our experiences with our patients. First, we noticed the disruption to patients’ personal and school performance from having untreated pain and recognized the need for pain psychology. Then, we expanded to have physical therapy to recondition patients and perform desensitization. Finally, we recognized our patients need additional medication options not offered through the standard of care. So, we expanded to open our various clinical trials, including those with pharma and internal protocols. As a result, we incorporated the use of Botox injections, for example, and soon will use a novel remote electro-neuromodulatory device.
Observership program builds worldwide expertise to treat colorectal issues
During 2022, the program will welcome participants from 13 different countries including Spain, Belgium, Vietnam, Indonesia, Chile, Pakistan, Uganda, Iraq, Mexico, Brazil, Saudi Arabia and Singapore.
Under the colorectal team’s instruction, participating physicians and nurses will learn how to diagnose and care for children with complex colorectal conditions. They will learn about the wide range of malformations and successful treatment options so they can bring these skills to patients in their home countries. Those selected for these observerships are among the most promising providers in their communities who currently work to improve treatment for children with colorectal issues. The patients they care for are those who would otherwise have no or limited access to this specialty care.
For information about applying for the observership program, please contact the colorectal department at ColorectalVisitors@childrensnational.org.
Pediatricians and public health officials should unite against controversial school masking bans
To keep in-person learning and protect students in schools, pediatricians and public health officials must advocate for evidence-based mitigation strategies that can reduce COVID-19 transmission — especially the Delta variant, which overwhelmed pediatric emergency rooms and hospitals, argued Yang et al. in a Perspective published in the journal Pediatrics.
To keep in-person learning and protect students in schools, pediatricians and public health officials must advocate for evidence-based mitigation strategies that can reduce COVID-19 transmission — especially the Delta variant, which overwhelmed pediatric emergency rooms and hospitals, argued Yang et al. in a Perspective published in the journal Pediatrics.
The authors propose that pediatricians and their associated institutions actively advocate for masking in schools and debunk myths and misinformation during well and sick visits. In addition, they encourage doctors to develop and disseminate behavioral strategies to support children’s compliance with masking based on individual abilities and needs. Finally, providers can partner with educators at the local, district, state and national levels to advocate for evidence-based masking policies.
“As pediatricians, it is our responsibility to advocate for universal masking to facilitate safe in-person schooling for all children,” said Sarah Schaffer DeRoo, M.D., pediatrician at Children’s National Hospital and co-author of the Perspective. “Children have readily adapted to masking during the pandemic and continuing this practice in schools is not a significant change from their recent experience.”
To date, nine states have enacted policies to prohibit school masking mandates, disregarding evidence that masking is a crucial COVID-19 preventive measure, Yang et al. wrote. The court overturned these mandates in four states out of the nine because they either exceeded the governor’s executive authority or did not comply with the law granting the executive order’s authority. In other instances, judges have only placed a temporary block.
“Despite politically charged rhetoric and headline-grabbing lawsuits, evidence shows that schools without mask mandates are more likely to have COVID-19 outbreaks,” said Y. Tony Yang, Sc.D., endowed professor of health policy and executive director of the Center for Health Policy and Media Engagement at the George Washington University, and lead author of the Perspective. “Pediatricians have generally commanded a heightened level of public trust, which suggests that pediatricians who make the case for policies that advance sound medical and public health science may have a greater chance than other advocates of generating the public and political will needed to make evidence-based policy ideas, such as school mask mandates, a reality.”
Some localities have found creative ways to circumvent state mask mandate bans by altering the school dress code to include face coverings and finding loopholes that do not apply to individual cities. Parents have also tried to challenge the policies in court, asserting that mask mandate bans violate federal anti-discrimination laws.
“Continued efforts are needed to ensure schools are able to promote reasonable, evidence-based strategies to promote the health of their students, teachers and communities, and we, as advocates for children, are obligated to emphatically support these efforts,” said Yang et al.
Reflections on Seminars in Pediatric Surgery December 2020
Marc Levitt, M.D., served as guest editor of a special December Seminars in Pediatric Surgery dedicated to the care and treatment of anorectal malformations.
By Marc Levitt, M.D., chief of the Division of Colorectal and Pelvic Reconstruction at Children’s National Hospital
I was honored to serve as the Guest Editor on the topic of “Anorectal Malformations” in the prestigious Seminars in Pediatric Surgery Volume 29, Issue 6, December 2020.
We had 64 contributing authors from 12 countries; Australia, Austria, Germany, Ghana, Italy, Israel, the Netherlands, Nigeria, Spain, South Africa, the United Kingdom and the United States, and 12 U.S. colorectal collaborating programs; Children’s National, Boston Children’s, Children’s Mercy, Children’s Wisconsin, C.S. Mott Children’s, Cincinnati Children’s, Nationwide Children’s, Nicklaus Children’s, Omaha Children’s, Primary Children’s, Seattle Children’s, and UC Davis Children’s.
There were eight authors from the Children’s National team; myself, Colorectal Director Andrea Badillo, M.D., Colorectal Program Manager Julie Choueiki, MSN, RN, Surgical Center Director Susan Callicott, Katie Worst, CPNP-AC, Grace Ma, M.D., Chief of Urology Hans Pohl, M.D., and Chief of Gynecology Veronica Gomez-Lobo, M.D.
The series of articles included in this collection illustrate new techniques and ideas that over time have made a dramatic and positive impact on the care and quality of life of children who suffer from colorectal problems. With an integrated approach to the care of this complex group of patients, great things can be achieved. As we endeavor to advance this field, we need to always remember that, as Alberto Pena, M.D., often said, “it is not the unanswered questions, but rather the unquestioned answers that one must pursue.”
In my own article on advances in the field, a 2021 update, I reproduce a piece by my daughter, Jess Levitt, who wrote something applicable to the care of children with colorectal problems, with the message that helping to create order is vital to improve a somewhat chaotic medical process traditionally available for the care of complex care. Her essay is reproduced here:
“A” must come before “B,” which must come before “C,” everybody knows that. But what if the Millercamp’s of this world did not have to sit next to the Millerchip’s when it comes to seating arrangements? Can Pat Zawatsky be called before Jack Aaronson when the teacher is taking attendance? Do those 26 letters that make up all the dialogue, signs, thoughts, books, and titles in the English-speaking departments of the world need their specific spots in line? Everyone can sing you the well-known jingle from A to Z, but not many people can tell you why the alphabet is the way it is. For almost as long as humans have had the English language, they have had the alphabet. The good ole ABCs.
However, the alphabet represents the human need for order and stability. I believe that the same thinking that went into the construct of time and even government went into the alphabet. Justifiably, lack of order leads to chaos. Knife-throwing, gun-shooting chaos, in the case of lack of governmental order. Listen to me when I tell you that there is absolutely no reason that the alphabet is arranged the way that it is. Moreover, the alphabet is simply a product of human nature and how it leads people to establish order for things that do not require it.
Now I know this sounds crazy but bear with me. Only if you really peel away the layers of the alphabet will you find the true weight it carries. People organized the letters of our speech into a specific order simply because there wasn’t already one. Questioning this order will enlighten you on the true meaning of it. Really dig deep into the meaning behind the social construct that is the alphabet. Short and sweet as it may be, the order of the ABCs is much less than meets the eye. There is no reason that “J” should fall before “K!” Understand this. Very important as order is, it is only a result of human nature. What’s next? X-rays become independent of Xylophones in children’s books of ABCs?
You know what the best part is? Zero chance you even noticed that each sentence in this essay is in alphabetical order.
Her literary contribution inspired me to do something similar. Take a look at the list of articles in this Seminars edition:
The first letter of each article forms an acrostic of the word “COLLABORATION” which is the secret sauce behind any success in the field of pediatric colorectal care.
Spotlight on Children’s National Hospital Neurosurgery
Our neurosurgery team is among the most experienced in the nation. We have performed thousands of surgeries and are dedicated to giving the best possible care. The Children’s National Hospital Division of Neurosurgery consistently ranks among the country’s top programs according to U.S. News & World Report.
Patients travel to us from all over the world because we have the resources and expertise necessary to care for their neurological conditions through multidisciplinary programs such as:
Minimally invasive surgery
The Children’s National Hospital Division of Neurosurgery is among the first in the country to develop new techniques and adopt the latest technologies that make minimally invasive neurosurgery possible by utilizing state of the art equipment and developing new techniques, including:
Advanced treatment and cutting edge research
Children’s National is involved in cutting edge scientific research offering new hope for our patients and new methods of treatment. Our doctors have developed some of the most advanced treatments and clinics for our patients including:
Ranked No. 5 in the nation
U.S. News & World Report ranks our neurosurgery program number five in the nation, reflecting our commitment to excellence in care for our patients and families.
Level 1 surgery verification
Children’s National is one of only 12 children’s hospitals in the country to attain Level 1 Surgery Verification from the American College of Surgeons.
Successful outcomes
Children with rare and medically complex conditions, such as brain tumors, craniofacial disorders, Chiari malformations, vascular disorders and brachial plexus palsy, to name a few, achieve exceptional outcomes at Children’s National. Our patients experience fewer complications, go home sooner and maintain long-term symptom relief.
Specialized expertise
Our entire team is dedicated to meeting your child’s unique needs. Our Neuro-Intensive Care Unit nurses recognize signs of pain and complications your child may not be able to explain.
Pioneering new treatments
Children’s National is at the forefront of new device-based treatments that not only fix neurologic problems, but also restore brain function. We are one of the few pediatric programs in the country offering dedicated pediatric deep brain stimulation, which uses a pacemaker-like device to significantly reduce the burden of movement disorders and difficult-to-control epilepsy, as well as Neuropace implantation to help with seizures in eloquent areas of the brain.
Training the next generation of top neurosurgeons
We are proudly training the next generation of pediatric neurosurgeons through residency programs and fellowships in conjunction with several area medical schools.
Kurt Newman, M.D., shares journey as a pediatric surgeon in TEDx Talk
Kurt Newman, M.D., president and chief executive officer of Children’s National, shares his poignant journey as a pediatric surgeon, offering a new perspective for approaching the most chronic and debilitating health conditions. In this independently-organized TEDx event, Dr. Newman also shares his passion for Children’s National and the need to increase pediatric innovations in medicine.
Prescription for a healthy heart: pediatric-driven partnerships
Dr. Martin and a patient share a smile after a visit at Children’s National Health System.
For pediatric cardiologists, February, National Heart Month, is a special time. We share health tips in the hospital and talk about heart health with those looking for advice, especially with patients and families impacted by congenital heart disease (CHD). It’s also a time to look back at what’s worked well in the field, while accelerating advancements for CHD treatment.
To start, congenital heart disease, a structural abnormality of the heart or of the blood vessels surrounding it, is the most common birth defect and occurs in about one in every 100 live births, affecting 40,000 babies born in the U.S. each year. One million children and 1.4 million adults in the U.S. have CHD. Over the past 15 years, pediatric cardiologists have cut mortality rates for CHD in half. Gratefully, now instead of saving children’s lives, the emphasis is on improving them. The catalyst for this paradigm shift isn’t simply due to a medical breakthrough, but is also the result of collaboration and advocacy.
Pediatric cardiologists worked together with other stakeholders – nurses, neonatologists, parents, state and federal agencies – to implement newborn screening methods in hospitals, with the introduction pulse oximetry screenings for critical congenital heart defects (CCHD). The screening, which measures blood oxygen levels in newborns, focuses on screening babies for CCHD before they leave the hospital. The concept and a national protocol for screening began with a small project in 2002, was endorsed by medical associations by 2012 and required by all states in 2018. The impact of CCHD screening of newborns is remarkable. Data published in JAMA showed a 33 percent reduction in CCHD infant deaths associated with states that required CCHD screening.
The pulse oximetry screening’s impact on the number of lives saved goes beyond identifying newborns with CCHD. Worldwide, though the detection of secondary conditions, such as hypothermia, pneumonia, and sepsis, the pulse oximetry screening is estimated to save roughly 772,000 lives by 2030.
In addition to newborn screening recommendations for CCHD, a group of cardiologists, including myself, worked for the Joint Council on Congenital Heart Disease (JCCHD) to form and support the National Pediatric Cardiology Quality Improvement Collaborative (NPC-QIC). We developed measures to see how we could improve survival rates between surgeries for infants born with hypoplastic left heart syndrome (HLHS), one of the most common and severe forms of CCHD.
Babies born with HLHS require two heart surgeries within the baby’s first six months. Babies that survived the first operation had a significant mortality rate (15 percent) and frequent growth failure, while waiting for the second operation. Our focused aims were to both decrease the death rate and improve growth in these children. We analyzed data from medical centers, utilized quality improvement principals from the Institute for Health Care Improvement, talked with doctors and families, and invited teams from across the U.S. to partner with us to put quality and safety measures into place.
We emphasized the following points:
The implementation of these procedures reduced interstage mortality rates and the number of growth failures for HLHS patients. In 2008, six centers participated in the NPC-QIC pilot. By 2018, 65 medical centers in the U.S. and Canada used these methods. Similar to the pulse oximetry screening guidelines, this new method wasn’t the result of a medical breakthrough, but the result of shared learning and shared infrastructure.
Now, we’re referring more adult congenital heart patients to board-certified adult congenital heart disease (ACHD) specialists, a better fit than internists or pediatric cardiologists. Adults with congenital heart defects should have their heart examined at least once by a specialist and those with complex needs should meet with a specialist at least every two years. More than 300 board-certified ACHD specialists practice in the U.S. and the field is growing. The third ACHD board exam takes place this year.
Over the next few decades, I hope we’ll make even more progress with understanding, diagnosing and treating CHD.
Emerging research examines genetic clues for congenital heart defects, which were once thought to account for 8 percent of cases and may now account for 30 percent of conditions. We’re working with neurologists to examine the timing and pathway of potential oxygen inefficiencies that occur as the brain develops in utero, infancy, and after neonatal surgery. We’ve come a long way, but we continue looking at new frontiers and for innovative solutions.
Fortunately, as cardiologists, we’re good at fixing problems. We work with surgeons and medical teams to repair holes in hearts, or replace them, and reroute blood from an underdeveloped left ventricle to improve circulation. For almost every heart defect, we have evidence-based solutions. However, to continue to help children worldwide, it’s imperative that we don’t forget about what works well: good science, tracking data, sharing best practices, active listening, transparency and constant collaboration.
Gerard Martin, M.D., F.A.A.P., F.A.C.C., F.A.H.A., is a cardiologist and the medical director of global services at Children’s National Health System. Dr. Martin has practiced pediatric cardiology for 34 years and is the Dan G. McNamara keynote speaker at the American College of Cardiology’s 2019 Scientific Sessions. Follow Dr. Martin on Twitter @Gerard_MD.
This article first appeared on KevinMD.com.
Serving patients with polycystic kidney disease
Lisa M. Guay-Woodford, M.D., is internationally recognized for her examination of the mechanisms that make certain inherited renal disorders particularly lethal, a research focus inspired by her patients.
When Children’s National pediatric nephrologist Lisa Guay-Woodford, M.D., was an intern at Boston Children’s Hospital, a baby with autosomal recessive polycystic kidney disease (ARPKD) was admitted to one of the hospital’s neonatal intensive care units (NICU). This disease, which causes cysts to form in the kidney and liver, kills about one-fifth of babies within the newborn period due to related problems that affect lung development.
But this baby seemed like a survivor, Dr. Guay-Woodford remembers. The child passed the newborn period and graduated from the NICU, although she went home with severe blood pressure issues. Along with a team of colleagues, Dr. Guay-Woodford helped to manage this patient’s care, juggling normal infant concerns with her ARPKD.
As far as Dr. Guay-Woodford knew at the time, this baby was beating the odds against her, growing and thriving. But one day near the end of her internship period, Dr. Guay-Woodford was called to the emergency department. Her patient was in a hypertensive crisis that ultimately killed her.
“It was absolutely devastating to all of us. This was supposed to be a good news kind of story, that she survived the newborn period and had gone home and was growing and developing,” Dr. Guay-Woodford says. “I realized then that a big part of the tragedy of this disease is how little we knew about it.”
Dr. Guay-Woodford vowed to change that. Since then, she’s devoted her career to studying ARPKD and other inherited kidney diseases.
After finishing her residency and fellowship in Boston, Dr. Guay-Woodford was recruited to the University of Alabama, where she began caring for a cadre of 40 patients with inherited renal disorders. Fueled by the research questions that arose while working with these patients, she and her colleagues searched for PKD-related genes in the cpk mouse model, an animal that mimics many of the features of human ARPKD.
Dr. Guay-Woodford and her team cloned several of the key genes that caused recessive PKD in this mouse and other mouse models and eventually went on to identify the first major genetic modifier of PKD in these animals – a gene that wasn’t directly responsible for the disease but could sway its course. In time, her collaborative group became one of two that co-indentified the major gene responsible for human ARPKD. In 2005, Dr. Guay-Woodford led a team of investigators at the University of Alabama-Birmingham to establish one of just four PKD translational core centers funded by a National Institutes of Health P30 grant.
After moving to Children’s National in 2012, Dr. Guay-Woodford still co-directs this PKD translational core center while also caring for patients at her inherited renal disorders clinic. She and her colleagues here and beyond continue to work with mouse models of this disease, trying to ferret out the vast network of genes that interact in ARPKD and their specific roles.
“You can use a variety of strategies to compare these patients’ gene portfolios with those of healthy patients and pick out the disease genes. But at the end of the day, to me, that’s just the opening chapter,” she says. “To really make a story, you’ve got to understand what is it that gene does, what protein it makes, and how that protein works together with others involved in this disease.”
She and her team also are currently working with a pharmaceutical company to develop the first clinical trial to test a treatment for ARPKD. This effort has relied heavily on a clinical database that Dr. Guay-Woodford and colleagues worldwide maintain to track patients with this and related conditions. Through the extensive collection of clinical information in this database – including a variety of data on patients’ gestation and birth, growth, and kidney structure and function – the team has identified a core cohort of patients whose disease is rapidly progressing, a characteristic that makes them prime candidates to test this potential new treatment.
“Everything I do in the clinic informs the work I do in the lab, and everything I do in the lab is to help the patients I see in the clinic. It’s this constant dance back and forth between our human patients and animal models,” she says. “One day, this dance will help lessen the burden of this disease for these kids and their families.”
Thirteen questions for a pediatric endocrinologist
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.”
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