Trial participant Mia Maric is measured by Dr. Andrew Dauber.
Researchers from Children’s National Hospital presented findings from the first clinical trial of the medication vosoritide for children with hypochondroplasia – a rare genetic growth disorder. The results were presented at the 2024 American College of Medical Genetics and Genomics (ACMG) Annual Clinical Genetics Meeting.
The big picture
Recently approved to increase linear growth and open growth plates in children with achondroplasia, vosoritide is a C-type natriuretic peptide analog that binds its receptor on chondrocytes, leading to increased chondrocyte proliferation and differentiation by inhibiting the ERK1/2-MAPK pathway.
“Vosoritide directly targets the pathway in the growth plate that is affected by the genetic mutation causing hypochondroplasia,” said Andrew Dauber M.D., M.M.Sc., chief of Endocrinology at Children’s National and lead author of the study.
During the phase 2 trial, researchers found vosoritide increased the growth rate in children with hypochondroplasia, allowing them to grow on average an extra 1.8 cm per year.
The patient benefit
Ivan Maric’s 11-year-old daughter, Mia, has been participating in the trial for the last 18 months. In 2022, they moved from Croatia to be part of the study.
“This has been life-changing for Mia,” Maric said. “Soon after receiving the initial doses, we immediately noticed growth. Now, she can independently manage everyday tasks such as washing her hair and reaching the sink to wash her hands.”
What’s next
Vosoritide treatment may work as a precision therapy to improve growth in multiple genetic conditions that interact with the ERK1/2-MAPK pathway.
“This study provides a proof of principle that this medicine will work for these children and supports further research in this area,” said Dr. Dauber. “I was excited to see how well tolerated the medication was and how some patients had excellent responses.”
This clinical trial funded by BioMarin is the first-of-its-kind to treat children with genetic short stature who do not have achondroplasia. Other growth-related conditions included in this phase 2 trial were Noonan syndrome, NPR2 mutations and Aggrecan mutations.
“Select patients will have the opportunity to participate in research studies focused on cutting-edge genomic investigations into their growth disorders,” says Youn Hee Jee, M.D., M.Med., endocrinologist.
“We’re dedicated to unraveling the mysteries that families have long sought answers to,” says Andrew Dauber, M.M.Sc., M.D., chief of Endocrinology at Children’s National Hospital. “There are numerous endocrine and genetic conditions with the potential to impact a child’s growth. That’s why we’ve assembled a team of leading endocrinologists and geneticists to create a new Growth Specialty Clinic and address these issues with a fresh perspective.”
This team, combined with the expertise of the hospital’s translational scientists, is making significant progress in identifying the causes of a variety of growth disorders and developing innovative treatments. And at the core of this work, Dr. Dauber says, is a recognition of the unique impact endocrine disorders have on each individual child.
Dr. Shur emphasizes the commitment to providing answers for these families. “This collaborative effort goes beyond diagnosis; it opens doors to potential treatment options.”
The Growth Specialty Clinic is for children with severe undiagnosed growth disorders that are suspected to have a genetic etiology and children with rare genetic diagnoses who would benefit from the expertise of practitioners more familiar with those disorders. It is also closely linked to the Center for Genetic Medicine Research.
“Select patients will have the opportunity to participate in research studies focused on cutting-edge genomic investigations into their growth disorders,” says Youn Hee Jee, M.D., M.Med., endocrinologist.
In one case, Dr. Jee identified a new genetic cause of an overgrowth syndrome. Rare genetic conditions known as generalized overgrowth syndromes manifest as excessive body growth during fetal life and/or childhood, frequently resulting in tall stature. She is investigating the mechanisms that promote healthy bone growth.
Additionally, Dr. Jee identified a new genetic cause of short stature. Her research showed that the identified genetic cause impairs the recycling of essential proteins for growth, expanding our knowledge of human growth.
Moving the field forward
“We’re taking innovative approaches to treatment by leveraging our insights into the genetic origin of each patient’s growth disorder,” says Dr. Dauber.
In the brief time since the clinic’s launch, several new diagnoses and treatment pathways have already been offered. In one single-patient study, researchers were able to successfully overcome the patient’s growth hormone resistance using a targeted approach, and the patient has shown significant catch-up growth after one year of treatment.
Children’s National is also at the forefront of other groundbreaking research, launching novel clinical trials that are advancing the field of endocrinology:
Vosoritide clinical trial: Children’s National has the first clinical trial in the world testing Vosoritide in children with certain genetic causes of short stature. Researchers have enrolled approximately 50 subjects with exciting preliminary results for patients with Noonan syndrome, Aggrecan gene mutations and NPR2 gene mutations. All 24 hypochondroplasia patients have completed the 18-month trial. Dr. Dauber intends to present results at the 2024 American College of Medical Genetics meeting in Toronto.
Hypochondroplasia study: Children’s National is the first site to launch BioMarin’s new natural history study for children with hypochondroplasia which will also be a lead into their future Phase 3 trial.
https://innovationdistrict.childrensnational.org/wp-content/uploads/2023/12/Youn-Hee-Jee-feature.png300400Innovation Districthttps://innovationdistrict.childrensnational.org/wp-content/uploads/2023/12/innovationdistrict_logo-1-1030x165.pngInnovation District2023-12-22 10:02:152024-01-02 13:24:04Shaping the future of pediatric endocrinology
By conducting whole-genome sequencing, doctors were able to discover the cause of a patient’s severe precocious puberty.
A true medical anomaly — a patient with severe precocious puberty starting in infancy later developed bilateral testicular tumors. Despite extensive testing at multiple other hospitals, no one had been able to understand the underlying cause of his precocious puberty. That is until now, through a study led by Andrew Dauber, M.D., M.M.Sc., chief of Endocrinology at Children’s National Hospital.
The hold-up in the field
Before receiving care at Children’s National, the patient’s diagnostic workup was limited by genetic testing modalities and the ability to enroll him in an innovative research protocol.
Moving the field forward
“We were able to enroll the patient in a research protocol that allowed them to sequence his whole genome,” says Dr. Dauber. “Both in a DNA sample from his blood as well as in a sample from one of his testicular tumors, which was being removed surgically.”
Dr. Dauber then performed an analysis of the genome data and found that the patient had a mutation in the luteinizing hormone receptor (LHR), which was present in the testicle but not in his blood. This is called a somatic mutation. The LHR receives the signal from the pituitary gland, which tells the testicle to make testosterone. In this case, the LHR is always turned on, which makes him develop Leydig cell tumors in his testes, overproducing testosterone, causing him to have very early puberty.
By conducting whole-genome sequencing of the tumor and blood samples, the patient was confirmed to have bilateral, diffuse Leydig cell tumors harboring the somatic gain-of-function p.Asp578His variant in the LHCGR gene.
This mutation had been identified before in patients with isolated tumors but never in someone with diffuse bilateral tumors.
The patient benefit
By using cutting-edge genomic approaches, medical providers can identify unknown causes of endocrine disorders. It also stresses the importance of the clinical team working with translational researchers to determine answers for patients.
“With a more definitive diagnosis and understanding of what these tumors are, researchers can better counsel the family about the treatment options,” says Dr. Dauber. Other members of the Children’s National team that contributed to this work include Seth Berger, M.D., Ph.D.; Daniel Casella, M.D.; and Emmanuèle C Délot, Ph.D.
You can read the full study, Precocious Puberty in a Boy With Bilateral Leydig Cell Tumors due to a Somatic Gain-of-Function LHCGR Variant, in the Journal of the Endocrine Society.
In this study, the authors at Shanghai Children’s Medical Center utilized next-generation sequencing (NGS) to analyze the data of patients with short stature to better understand the etiologies of short stature.
Andrew Dauber, M.D., M.M.Sc., division chief of Endocrinology at Children’s National Hospital, shared expert commentary on a recent study published in The Journal of Clinical Endocrinology & Metabolism that explores associated risk factors of short stature as identified by exome sequencing in children.
In this study, the authors at Shanghai Children’s Medical Center utilized next-generation sequencing (NGS) to analyze the data of patients with short stature to better understand the etiologies of short stature.
The big picture
“This was a large-scale study looking at 814 children with short stature and at least one more clinical feature suggestive of a genetic condition who underwent comprehensive genetic testing at Shanghai Children’s Medical Center,” explains Dr. Dauber. In this study, the authors identified a potential genetic etiology in 361 of the patients, which is 44% of the cohort.
“It is important to note that the yield of genetic testing was highly variable depending on the clinical presentation of the child,” said Dr. Dauber. “For example, patients with associated congenital anomalies or a suspected skeletal dysplasia had a diagnostic yield of 56% and 65% respectively, while patients with isolated severe short stature (defined as a height below -3 SDS) only had a yield of 11%.”
Dr. Dauber noted that the overall high yield is reflective of the types of patients who are referred to this specialty center, and the expected yield in a more general pediatric setting is likely much lower.
The patient benefit
“This study helps shed light on the prevalence of those patients in a large cohort of children presenting for evaluation of short stature,” shared Dr. Dauber. “I am hopeful that targeted treatments will improve growth in these children.”
While this study provides new insights into the underlying causes behind short stature in patients with differing phenotypes, the authors indicate that additional large-scale studies on short stature exome sequencing are warranted.
Moving the field forward
Dr. Dauber also pointed to the fact that the authors note a large number of the patients in this study had undiagnosed Rasopathies, such as Noonan syndrome. “There were also 31 patients with FGFR3 mutations, 6 patients found with ACAN (Aggrecan) mutations and 2 with NPR2 mutations,” said Dr. Dauber.
“At Children’s National, we are currently conducting a clinical trial of vosoritide, a novel growth promoting agent which targets the growth plate in children with selected genetic conditions including Noonan syndrome and patients with mutations in FGFR3, ACAN, and NPR2,” included Dr. Dauber. Preliminary results from this clinical trial were recently presented by Dr. Dauber at the Pediatric Endocrine Society annual meeting.
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This is the first clinical trial in the world testing vosoritide in children with certain genetic causes of short stature, including hypochondroplasia, Noonan syndrome, NPR2 mutations and Aggrecan mutations.
Andrew Dauber, M.D., M.M.Sc., endocrinologist at Children’s National Hospital, presented preliminary results from a phase II clinical trial of a new drug, vosoritide, used to treat children with certain growth disorders, at the Pediatric Endocrine Society annual meeting held virtually on May 1.
Vosoritide is a C-type natriuretic peptide analog that binds its receptor on chondrocytes, leading to increased chondrocyte proliferation and differentiation via its inhibition of the ERK1/2-MAPK pathway.
This is the first clinical trial in the world testing vosoritide in children with certain genetic causes of short stature, including hypochondroplasia, Noonan syndrome, NPR2 mutations and Aggrecan mutations.
To date, 34 participants have enrolled in the trial with a median baseline height of -3.2 SD (interquartile range (IQR) -3.7, -2.6). 18 subjects have initiated on vosoritide and twelve have completed six months of therapy. The authors note that the mean increase in annualized growth velocity (AGV) was 1.8 cm/yr for subjects with hypochondroplasia and 6.1 cm/yr for subjects with Noonan syndrome or NPR2 mutations. The two subjects with NPR2 mutations had increased AGVs of 4.4 and 9.2 cm/yr, while the two subjects with Noonan syndrome had increased in AGVs of 7.5 and 3.3 cm/yr. One of the Noonan syndrome subjects was previously treated with growth hormone (GH) for 2 years and AGV was 6.7 cm/yr while on GH, 4.1 cm/yr during the trial 6-month observation period and 11.6 cm/year during the first six months of vosoritide treatment.
To the researchers, the safety profile is quite reassuring. So far, the preliminary results showed increased growth in all the genetic subgroups with the patients with hypochondroplasia demonstrating a response similar to that seen previously in patients with achondroplasia. While the results are very promising for patients with Noonan syndrome and NPR2 mutations, the clinical trial must be completed before drawing further conclusions. The experts also plan to submit the study to a peer-reviewed journal in the future to validate the findings.
The big picture
This is the first medication that directly targets the pathway in chondrocytes (cells in the growth plate that make the bones grow longer) affected by these specific mutations. This means that the novel approach may give patients additional therapeutic options outside of growth hormone.
Why we’re excited
“These are the first patients in the world to ever receive this medication for their conditions,” said Dr. Dauber. “The results are very promising and may change the way we practice medicine. Patients have come from all over the world to participate in the study.”
Children’s National leads the way
This clinical trial funded by BioMarin is the first of its kind to treat children with genetic short stature who do not have achondroplasia. Children’s National is the only site in the world offering this therapy for patients with these conditions.
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Aggrecan (ACAN) is a large protein found in joint cartilage and growth plates.
Andrew Dauber, M.D., M.M.Sc., division chief of Endocrinology at Children’s National Hospital, and colleagues recently published two papers that describe the phenotypic spectrum of aggrecan deficiency and look at treating the condition with human growth hormone.
Aggrecan (ACAN) is a large protein found in joint cartilage and growth plates. It allows joints to move smoothly and without pain. Aggrecan deficiency — due to heterozygous mutations in the ACAN gene — causes dominantly inherited short stature and, in many patients, early-onset osteoarthritis and degenerative disc disease.
Clinical phenotype of patients with aggrecan deficiency
In 2017, Dr. Dauber led an international consortium of researchers that published a manuscript describing the phenotypic spectrum of 103 individuals – 70 adults and 33 children, including 57 females and 46 males – from 20 families with ACAN mutations. In the study, Dr. Dauber and his colleagues established that short stature and accelerated bone age is common among people with ACAN mutations.
In a new study published in the American Journal of Medical Genetics Part A, Dr. Dauber and colleagues further characterize the phenotypic spectrum of aggrecan deficiency, with an emphasis on musculoskeletal health.
Twenty-two individuals from nine families were enrolled in the study. Recorded histories and examinations focused on joint health, gait analysis, joint specific patient reported outcomes and imaging.
“We performed a detailed analysis of the musculoskeletal manifestations in patients with mutations in the aggrecan gene,” says Dr. Dauber. “We found that patients with mutations in this gene had significant short stature which worsened with age. There was a high prevalence of joint complaints and arthritis in adults, and we were able to detect pre-symptomatic joint damage in children using knee MRIs.”
Treating short stature in aggrecan-deficient patients with human growth hormone
Until now, it was unknown how to treat children with aggrecan deficiency. “Providing growth hormone therapy to children with ACAN gene mutations is relatively new in the field of pediatric endocrinology,” explains Dr. Dauber. “Previously, the assumption was that this was just short stature.”
In a new study, published in The Journal of Clinical Endocrinology and Metabolism, Dr. Dauber and colleagues reported the results of a trial that evaluated the efficacy and safety of recombinant human growth hormone (rhGH) therapy on linear growth in children with ACAN deficiency.
“This is the first prospective trial of growth hormone therapy in patients with mutations in the aggrecan gene,” says Dr. Dauber. “Mutations in the gene are the cause for short stature in approximately 2% of individuals with idiopathic short stature.”
The open-label, single-arm, prospective study enrolled ten treatment-naïve patients with a confirmed heterozygous mutation in ACAN. Participants were treated with rhGH (50 µg/kg/day) over 1 year. Main outcomes measured were height velocity and change in height standard deviation score.
The authors found that growth hormone led to short term improvements in growth rate over the course of the year. The treated patients had their growth rate increase from 5.2 centimeters per year to 8.3 centimeters per year while on therapy.
In 2019, the researchers received the 2019 Human Growth Award at the Pediatric Endocrine Society’s Annual Meeting for an abstract related to this work, entitled “Clinical Characterization and Trial of Growth Hormone in Patients with Aggrecan Deficiency: 6 Month Data.”
https://innovationdistrict.childrensnational.org/wp-content/uploads/2022/03/aggrecan-protein.png300400Innovation Districthttps://innovationdistrict.childrensnational.org/wp-content/uploads/2023/12/innovationdistrict_logo-1-1030x165.pngInnovation District2022-03-02 15:29:582022-03-04 11:14:43Two new papers advance aggrecan deficiency research
Andrew Dauber, M.D., MMSc., chief of Endocrinology at Children’s National Hospital, participated as the faculty chair of a Med Games CME educational online activity, to provide continuing medical education for physicians. This game-based activity is intended to meet the educational needs of endocrinologists, endocrine fellows, primary care physicians, physician assistants, nurse practitioners and health care professionals who diagnose and manage children with growth hormone deficiency (CGHD). This CME educational program is provided by Med Learning Group and supported by an educational grant from Novo Nordisk Inc.
https://innovationdistrict.childrensnational.org/wp-content/uploads/2022/02/med-games-logo.png300400Innovation Districthttps://innovationdistrict.childrensnational.org/wp-content/uploads/2023/12/innovationdistrict_logo-1-1030x165.pngInnovation District2022-02-16 09:13:222022-02-18 10:27:42Continuing medical education through online games
Anti-Mullerian hormone (AMH), also known as Mullerian inhibiting substance (MIS), is a hormone produced exclusively in the gonads. It was originally described in the context of sexual differentiation in the male fetus but has gained prominence now as a marker of ovarian reserve and fertility in females.
In a mini-review published in The Journal of Clinical Endocrinology and Metabolism, Roopa Kanakatti Shankar, M.D., pediatric endocrinologist at Children’s National Hospital and an associate professor of pediatrics at the George Washington University School of Medicine and Health Sciences, and co-authors offer an updated synopsis on AMH and its clinical utility in pediatric patients.
The authors performed a systematic search for studies related to the physiology of AMH, normative data and clinical role in pediatrics. After reviewing 70 clinical studies and systematic reviews, they conclude that, “AMH has widespread clinical diagnostic utility in pediatrics but interpretation is often challenging and should be undertaken in the context of not only age and sex but also developmental and pubertal stage of the child.”
https://innovationdistrict.childrensnational.org/wp-content/uploads/2021/11/Blood-sample-tube-for-anti-Mullerian-hormone.png300400Innovation Districthttps://innovationdistrict.childrensnational.org/wp-content/uploads/2023/12/innovationdistrict_logo-1-1030x165.pngInnovation District2021-11-16 11:42:412021-11-16 12:39:59A look at the clinical utility of anti-Mullerian hormone
Children’s National Hospital in Washington, D.C., was ranked in the top 10 nationally in the U.S. News & World Report 2021-22 Best Children’s Hospitals annual rankings. This marks the fifth straight year Children’s National has made the Honor Roll list, which ranks the top 10 children’s hospitals nationwide. In addition, its neonatology program, which provides newborn intensive care, ranked No.1 among all children’s hospitals for the fifth year in a row.
For the eleventh straight year, Children’s National also ranked in all 10 specialty services, with seven specialties ranked in the top 10.
“It is always spectacular to be named one of the nation’s best children’s hospitals, but this year more than ever,” says Kurt Newman, M.D., president and CEO of Children’s National. “Every member of our organization helped us achieve this level of excellence, and they did it while sacrificing so much in order to help our country respond to and recover from the COVID-19 pandemic.”
“When choosing a hospital for a sick child, many parents want specialized expertise, convenience and caring medical professionals,” said Ben Harder, chief of health analysis and managing editor at U.S. News. “The Best Children’s Hospitals rankings have always highlighted hospitals that excel in specialized care. As the pandemic continues to affect travel, finding high-quality care close to home has never been more important.”
The annual rankings are the most comprehensive source of quality-related information on U.S. pediatric hospitals. The rankings recognize the nation’s top 50 pediatric hospitals based on a scoring system developed by U.S. News. The top 10 scorers are awarded a distinction called the Honor Roll.
The bulk of the score for each specialty service is based on quality and outcomes data. The process includes a survey of relevant specialists across the country, who are asked to list hospitals they believe provide the best care for patients with the most complex conditions.
Below are links to the seven Children’s National specialty services that U.S. News ranked in the top 10 nationally:
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Drs. Dewesh Agrawal, Andrew Dauber, Robert Freishtat and Vittorio Gallo were named as 2021 American Pediatric Society members.
The American Pediatric Society (APS) has announced 55 new members, four of which are experts from Children’s National Hospital. Founded in 1888, the APS is the first and most prestigious academic pediatric organization in North America.
APS members are recognized child health leaders of extraordinary achievement who work together to shape the future of academic pediatrics. New members are nominated by current members through a process that recognizes individuals who have distinguished themselves as child health leaders, teachers, scholars, policymakers and/or clinicians.
“Our members represent the most distinguished and accomplished academic leaders in pediatrics whose outstanding work has advanced child health,” said APS President Steven Abman, M.D. “I am honored to welcome this exceptional group of individuals to the APS. The APS is especially looking forward to the active engagement of our membership with many exciting programs within the organization that are directed towards improvements in academic pediatric medicine, including more vigorous approaches to express our values of anti-racism, equity, diversity and inclusion.”
APS 2021 active new members from Children’s National are:
Dewesh Agrawal, M.D., vice-chair for Medical Education at Children’s National. Agrawal’s career has been marked by academic honors and teaching awards at every stage of his training and faculty employment. He has relentlessly devoted his energy to improving the educational experience for students, residents and fellows at Children’s National.
Andrew Dauber, M.D., M.M.Sc., chief of Endocrinology at Children’s National. Dr. Dauber’s leadership is reflected, nationally and internationally, in his ability to create research consortia, bringing together investigators to tackle complex questions. For example, he leads an NIH-funded consortium on the genetics of short statures, with multiple top children’s hospitals as partners. He also leads a large clinical trial testing a novel therapeutic agent for genetic short stature.
Robert Freishtat, M.D., M.P.H., senior investigator in the Center for Genetic Medicine of the Children’s National Research Institute (CNRI). Dr. Freishtat has authored or co-authored more than 100 articles and book chapters in the fields of pediatric lung injury, asthma, obesity, exosomes and emergency medicine. His research has been continuously funded by the NIH since 2003.
Vittorio Gallo, Ph.D., chief research officer at Children’s National and scientific director of CNRI. Dr. Gallo’s scientific success is attested to by over 130 peer-reviewed publications, many in very high-profile journals, as well as over 30 review articles and book chapters. He has received many national and international awards, including the NINDS Javits award in Neuroscience in 2018. Dr. Gallo has served on the editorial boards of many neuroscience journals, including Glia and the Annual Review in Neuroscience, and has been reviewing editor for the Journal of Neuroscience, all of which is a testament to the tremendous impact that his studies have had on the advancement of neurosciences.
“These new members represent multiple areas of Children’s National and have all leveraged the intersection of science, medicine and clinical education to make advances in their field of study,” said Stephen J. Teach, M.D., M.P.H., chair of the Department of Pediatrics at Children’s National. “Their work has, and will continue to, advance pediatric health care, and I congratulate them on their APS membership.”
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A new Phase 2 study at Children’s National will look at using the drug vosoritide to promote growth in children with growth disorders.
A child’s growth is often measured by pediatricians during routine physicals to identify abnormalities of growth and stature. An abnormality in these measurements could mean a child has a growth disorder. There are many different causes of growth disorders. Some can be the result of defects in genes related to the growth plate, which is the tissue near the end of long bones that grows as the child grows. Children with a growth disorder can present many different symptoms including short stature, joint pain, heart problems, bone problems and developmental delays. Scientists still have a lot to learn about what exactly causes these genetic growth disorders and treatments are limited, especially in the pediatric population. Growth hormone is not uniformly helpful and has only been approved for a small number of conditions.
Vosoritide is an investigational drug that directly targets the growth plate to promote growth. It is an analog of the amino acid C-type natriuretic peptide (CNP). It binds its receptor on healthy cartilage cells called chondrocytes and is currently under investigation in clinical trials as a treatment for the bone growth disorder achondroplasia.
“Vosoritide for Selected Genetic Causes of Short Stature” is a Phase 2 study currently open at Children’s National Hospital. This study will target five types of genetic short stature including SHOX deficiency, hypochondroplasia, Rasopathies (which includes Noonan syndrome), heterozygous NPR2 defects and CNP deficiency.
Thirty-five children with short stature will be enrolled and followed for a six-month observation period to obtain baseline growth velocity, safety profile and quality of life assessment. Study participants will then be treated with vosoritide for 12 months and will be assessed for safety and improvement in growth outcomes.
“Many patients who present with short stature likely have genetic defects in genes involved in growth plate physiology. Those patients with selected causes of short stature that interact with the CNP pathway may benefit from treatment with vosoritide, which directly targets the growth plate,” said Andrew Dauber, M.D., MMSc., lead investigator of this clinical study and chief of Endocrinology at Children’s National Hospital, a program ranked in the top 10 by U.S. News & World Report. “In this study, our goal is to understand if vosoritide may be a safe and effective treatment option for certain genetically defined short stature syndromes.”
This clinical trial has been approved by the FDA and funded by BioMarin. Children’s National is the only site in the world offering this therapy for patients with these conditions. The study is currently underway and subject recruitment is ongoing. There are 9 participants enrolled to date.
“This study could fundamentally change the way we treat certain growth disorders”, says Dr. Dauber.
For more information on the clinical trial, click here.
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Growth hormone therapy is one of the most common treatments for short stature in children. However, endocrinologists report mixed outcomes, even when children have the same underlying condition as the cause of their short stature. Despite research into a variety of potential causes for this unpredictable response, there is still very little scientific evidence to help physicians predict whether children with short stature who are treated with growth hormone will respond to the treatment or not.
“Previous disease-specific models have been developed using multiple clinical variables such as parental height, age at treatment start, peak hormone levels and doses, and birth parameters, however, these clinical parameters only partially predict variation in response,” wrote the study authors, including Andrew Dauber, M.D., first author and chief of the division of Endocrinology at Children’s National Hospital. “Our goal was to perform a large-scale genome-wide study to provide a comprehensive assessment of how common genetic variation may play a role in growth hormone response.”
To accomplish this, the study combined five cohorts from across the world to identify 614 individuals for further review. All patients had short stature caused by conditions including growth hormone deficiency, small for gestational age, or idiopathic short stature (no previously identified cause), who received growth hormone as treatment.
Interestingly, the researchers found no overwhelming genetic predictors of response to growth hormone. They did identify a few signals that may potentially play a role in the body’s response to growth hormone but noted those signals will need further exploration. The study also ruled out the idea that genetic predictors of height in the general population might predict response to growth hormone.
“Identifying genetic predictors of how a child with short stature will respond to growth hormone would be an important step forward for clinicians and parents to make informed decisions about the right treatment approach,” says Dr. Dauber. “Though we didn’t find any specific indicators, this large-scale study has allowed us to rule out some previously held assumptions and offers several new avenues to explore.”
The study was conducted in collaboration with Pfizer and Boston Children’s Hospital.
Unfortunately, we’ve been notified that the ENDO2020 conference has been canceled due to concerns of COVID-19. Because of this, we will not be hosting our reception in honor of Andrew Dauber, M.D., on Sunday, March 29.
We hope to see you at a future Endocrinology or Pediatric Endocrinology event.
Children’s National Hospital is incredibly proud of the work Dr. Dauber has done in the endocrinology community.
Andrew Dauber, M.D., MMSc, division chief of Endocrinology at Children’s National Hospital, will be awarded the 2020 Richard E. Weitzman Outstanding Early Career Investigator Award at ENDO 2020. The prestigious award will be presented at the annual meeting of the Endocrine Society in recognition of Dauber’s work in understanding the regulation of growth and puberty, and applying innovative genetic technologies to studying pediatric endocrinology. Dauber credits many collaborators throughout the world, as well as the team at Children’s National for the award.
With a five-year grant from the National Institutes of Health (NIH), Dauber and colleagues from the Cincinnati Children’s Hospital Medical Center, Boston Children’s Hospital and the Children’s Hospital of Philadelphia are using electronic health records to identify children who likely have rare genetic growth disorders. Using cutting-edge DNA sequencing technologies, including whole exome sequencing, the researchers are aiming to identify novel genetic causes of severe growth disorders. The first paper describing genetic findings in patients with high IGF-1 levels was published in Hormone Research in Paediatrics in December 2019.
Dauber and researchers at Cincinnati Children’s Hospital Medical Center are exploring how to treat patients with mutations in the PAPPA2 gene. In 2016, the group described the first patients with mutations in this gene who had decreased the bioavailability of IGF-1, stunting their growth and development. In their current phase of research, findings are emphasizing the importance of this gene in regulating IGF-1 bioavailability throughout childhood. The ultimate aim is to create therapies to increase IGF-1 bioavailability, thereby supporting healthy growth and development in children. Their first study to track PAPPA2 and intact IBGBP-3 concentrations throughout childhood was published in the European Journal of Endocrinology in January 2020.
Dauber is particularly interested in studying children with dominantly inherited forms of short stature. Along with collaborators in Cincinnati, he currently has an ongoing treatment trial using growth hormone in patients with Aggrecan gene mutations. Dauber hopes to announce soon a new clinical trial for children with all forms of dominantly inherited short stature.
Study upon study has shown us that there are many factors that affect an individual’s height and growth. As these studies and the conversation around how to identify and address genomic anomalies become more prevalent, the team at Children’s National is increasingly interested in engaging with other centers around the country. In the coming months, the Children’s National Research & Innovation Campus will open on the grounds of the former Walter Reed Army Medical Center, which will serve as a one-of-a-kind pediatric research and innovation hub. A critical component to this campus is the co-location of Children’s National research with key partners and incubator space.
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On Nov. 10, 2019, more than 30 pediatric endocrine physicians and nurse practitioners from Washington, D.C., Maryland and Northern Virginia gathered at Children’s National Hospital to discuss the latest in pediatric endocrinology research.
Organized by Paul Kaplowitz, M.D., Professor Emeritus of Pediatrics, this was the third regional pediatric endocrinology meeting since 2012 and the second held at the hospital. “The meetings are a great opportunity for providers to meet regional colleagues who they may communicate with about patients but rarely see face to face,” explains Dr. Kaplowitz.
The providers spent half a day at Children’s National viewing presentations and connecting with their colleagues. Among the presentations was a talk by new Children’s National faculty member Brynn Marks, M.D., MSHPEd, titled, “Medical Education in Diabetes Technologies.”
The presentation highlighted Dr. Marks’ research on how to best teach providers to make optimal use of the information provided by continuous blood glucose monitoring, as well as how to adjust insulin pump settings based on frequent blood glucose testing.
Another notable presentation was by Richard Kahn, Ph.D., recently retired former chief scientific and medical officer at the American Diabetes Association. Dr. Kahn’s talk was titled “Prediabetes: Is it a meaningful diagnosis?”
“This was an excellent talk whose message was that making a diagnosis of ‘prediabetes’ may not be nearly as helpful as we thought, since most patients tests either revert to normal or remain borderline, and there is no treatment or lifestyle change which greatly reduces progression to type 2 diabetes,” says Dr. Kaplowitz.
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Children’s National regional pediatric endocrinology meeting presentations
Welcome from Paul Kaplowitz, M.D., and Children’s National Endocrinology Division Chief Andrew Dauber, M.D.
“Prediabetes: Is it a meaningful diagnosis?”
Richard Kahn, Ph.D., University of North Carolina at Chapel Hill
“Overlapping genetic architecture of Type 2 diabetes and Cystic fibrosis-related diabetes”
Scott Blackman, M.D., Ph.D., Johns Hopkins Medicine
“Pediatric Pituitary Tumors: What we have learned from the NIH cohort”
Christina Tatsi, M.D., Ph.D., National Institutes of Health
“Medical Education in Diabetes Technologies”
Brynn Marks, M.D., MSHPEd, Children’s National Hospital
“A phenotypic female infant with bilateral palpable gonads”
Cortney Bleach, M.D., Walter Reed National Military Medical Center
“Estimating plasma glucose with the FreeStyle Libre Pro CGM in youth: An accuracy analysis”
Miranda Broadney, M.D., MPH, University of Maryland School of Medicine
“Recruiting for research project on “Arginine-Stimulated Copeptin in the diagnosis of central diabetes insipidus”
Chelsi Flippo, M.D., Fellow, National Institutes of Health
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Unfortunately, we’ve been notified that the ENDO2020 conference has been canceled due to concerns of COVID-19. Because of this, we will not be hosting our reception in honor of Andrew Dauber, M.D., on Sunday, March 29.
We hope to see you at a future Endocrinology or Pediatric Endocrinology event.
Children’s National Hospital is incredibly proud of the work Dr. Dauber has done in the endocrinology community.
Andrew Dauber, M.D., MMSc, division chief of Endocrinology at Children’s National Hospital, will receive the 2020 Richard E. Weitzman Outstanding Early Career Investigator Award from The Endocrine Society. Given annually, the award was established in 1982 and honors the memory of the late Richard E. Weitzman, who had a brief but outstanding career studying neurohypophyseal hormone and cardiovascular-endocrine physiology – two seminal areas of modern endocrinology.
Dr. Dauber was selected as a recipient for the prestigious award for his contributions to understanding the regulation of growth and puberty, and his success at applying innovative genetic technologies to studying pediatric endocrinology.
“I feel extremely honored and humbled to be the recipient of the Richard E. Weitzman Outstanding Early Career Investigator Award from the Endocrine Society,” says Dr. Dauber. “I am so grateful to my many collaborators throughout the world as well as to my entire research team whose hard work and friendship are the basis for this award. I am excited to continue our work at Children’s National, an institution dedicated to innovation and team science.”
Dr. Dauber joined Children’s National in 2018 and specializes in studying and treating growth disorders. He has published over 75 studies examining genetic clues to endocrine disorders, with a focus on short stature and growth disorders.
The award will be presented at ENDO 2020, The Endocrine Society’s annual meeting, March 28-31, 2020, in San Francisco, California.
A 10-week pilot study at Children’s National Health System integrated weekly caregiver coaching, personalized glucose monitoring and incentives into standard treatment for 25 pediatric patients with type 1 diabetes, lowering A1c by .5%
The life of a type 1 diabetes patient – taking daily insulin shots or wearing an insulin pump, monitoring blood sugar, prioritizing healthful food choices and fitting in daily exercise – can be challenging at age 5 or 15, especially as holidays, field trips and sleepovers can disrupt diabetes care routines, creating challenges with compliance. This is why endocrinologists from Children’s National Health System experimented with using health coaches over a 10-week period to help families navigate care for children with type 1 diabetes.
By assembling a team of diabetes educators, dietitians, social workers, psychologists and health care providers, Fran Cogen, M.D., C.D.E., director of diabetes care at Children’s National, helped pediatric patients with type 1 diabetes manage their glycemic status, or blood-sugar control.
On Saturday, June 8, 2019, Dr. Cogen will share results of the pilot program as poster 1260-P, entitled “A Clinical Care Improvement Pilot Program: Individualized Health Coaching and Use of Incentives for Youth with Type 1 Diabetes and their Caregivers,” at the American Diabetes Association’s 79th Scientific Sessions, which takes place June 7-11 at the Moscone Center in San Francisco.
Dr. Cogen’s study was offered at no cost to caregivers of 179 patients at Children’s National seeking treatment for type 1 diabetes. The pilot program included two components: 1) Weekly phone calls or emails from a health coach to a caregiver with personalized insulin adjustments, based on patient blood sugars submitted through continuous glucose monitoring apps; and 2) Incentives for patients to participate in the program and reach health targets.
Twenty-five participants, ages 4-18, with a mean age of 11.6 and A1c ranges between 8.6 – 10% joined the study. The average A1c was 9.4% at the beginning of the program and dropped by an average of .5% at the end of the trial. Twenty of the 25 participants, 80%, improved A1c levels by .5%. Seventeen participants, 68%, improved A1c levels by more than .5%, while seven participants, 28%, improved A1c levels by more than 1%.
“Chronic disease is like a marathon,” says Dr. Cogen. “You need to have constant reinforcement and coaching to get people to do their best. Sometimes what drives people is to have people on the other end say, ‘Keep it up, you’re doing a good job, keep sending us information so that we can make changes to improve your child’s blood sugar management,’ which gives these new apps and continuous glucose monitoring devices a human touch.”
Instead of waiting three months between appointments to talk about ways a family can make changes to support a child’s insulin control and function, caregivers received feedback from coaches each week. Health coaches benefitted, too: They reported feeling greater empathy for patients, while becoming more engaged in personalizing care plans.
Families who participated received a gift card to a local grocery store, supporting a child’s dietary goals. Children who participated were also entered into an iPad raffle. Improvements in A1c levels generated extra raffle tickets per child, which motivated participants, especially teens.
“These incentives are helpful in order to get kids engaged in their health and in an immediate way,” says Dr. Cogen. “Teenagers aren’t always interested in long-term health outcomes, but they are interested in what’s happening right now. Fluctuating blood sugars can cause depression and problems with learning, while increasing risk for future complications, including eye problems, kidney problems and circulation problems. As health care providers, we know the choices children make today can influence their future health outcomes, which is why we designed this study.”
Moving forward, Dr. Cogen and the endocrinologists at Children’s National would like to study the impact of using this model over several months, especially for high-risk patients, while asynchronously targeting information to drive behavior change – accommodating the needs of families, while delivering dose-specific recommendations from health care providers.
Dr. Cogen adds, “We’re moving away from office-centric research models and creating interventions where they matter: at home and with families in real time.”
Additional study authors, all of whom work within the division of diabetes and endocrinology at Children’s National, include Lauren Clary, Ph.D., Sue-Ann Airborne, C.D.E., Andrew Dauber, M.D., Meredith Dillon, R.D., L.D.N., C.D.E., Beakel Eshete, B.S.N., R.N., C.D.E., Shaina Hatchell, B.S.N., R.N., Shari Jones, R.N., C.D.E., and Priya Vaidyanathan, M.D.
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M takes a photo with her daughter in Washington, where they learned they have an ACAN gene mutation that causes short stature.
On Sunday, April 28, 2019 a team of researchers received the 2019 Human Growth Award at the Pediatric Endocrine Society’s Annual Meeting for their abstract, entitled “Clinical Characterization and Trial of Growth Hormone in Patients with Aggrecan Deficiency: 6 Month Data,” and presented this at the PES Presidential Poster Session.
Eirene Alexadrou, M.D., a fellow at Cincinnati Children’s Hospital Medical Center, accepted the award and honorarium, while ongoing research is underway. This study started in 2017, with the objective of characterizing the phenotypic spectrum and response to a standardized regimen of growth hormone in a small cohort of 10 patients and their families.
In 2017, Andrew Dauber, M.D., MMSc., the division chief of endocrinology at Children’s National Health System, led an international consortium of researchers in publishing a manuscript describing the phenotypic spectrum of 103 individuals – 70 adults and 33 children, including 57 females and 46 males – from 20 families with aggrecan gene (ACAN) mutations.
Dr. Dauber and his colleagues have established that short stature and accelerated bone age is common among people with ACAN mutations. In a review of retrospective data, including patients treated with a variety of growth-promoting therapies at varying doses, the research team found that over the first one, two and three years of treatment, the standard deviation scores (SDS) for height increased by .4, .7 and 1, respectively. The current abstract now describes seven children enrolled in a prospective standardized trial of growth hormone therapy. After six months of treatment, the children have increased their height SDS by an average of 0.46.
Additionally, the researchers are performing an in-depth look at the joint effects, including special MRIs of the knees. They found that two of the children had a problem with their knee cartilage called osteochondritis dissecans. They had not yet presented with clinical symptoms. The researchers hope that early intervention with physical therapy can help prevent significant joint disease in the future.
M, her daughter, and M’s mother take a photo in Cincinnati, where they are participating in a clinical trial for aggrecan deficiency.
“Providing growth hormone therapy to children with ACAN gene mutations is relatively new in the field of pediatric endocrinology,” notes Dr. Dauber. “Previously, the assumption was that this was just short stature. We’ll continue to diagnose ACAN mutations in a clinical setting and work with families to reduce the risk of complications, such as joint problems or early-onset arthritis, which may co-occur with this gene mutation.”
As an example, Dr. Dauber met an 8-year-old patient several months ago who presented with symptoms of short stature. The patient is healthy, confident and still growing so her mother wasn’t worried about her but she made the appointment to see if there was an underlying cause to her daughter’s short stature. Her family history revealed clues to an ACAN mutation, which was later confirmed through genetic tests. Her mom, M, stands 4’8; her grandmother is 4’9. Her great grandmother was short and her great, great grandfather was 5’1. Short stature and joint problems run in the family. Once M mentioned she had osteochondritis dissecans and a hip replacement, she provided a textbook case study for carrying the ACAN mutation.
After the appointment, M shared the news with her mother about the possibility of having aggrecan deficiency. After taking genetic tests, M, her mother and M’s daughter learned they all have the ACAN mutation, and enrolled in the study that Dr. Dauber is guiding. Suddenly, it all made sense. After examining family photos, they traced the ACAN mutation back through four generations.
They could tell what relatives had an altered copy of the ACAN gene. M had it, while her two sisters did not. M’s mother was an only child, so she didn’t have aunts or uncles to compare her mother’s height to, but M’s grandmother was short, while her grandmother’s brother was average height. Although her mother’s family was from Germany, she learned that there is no specific ancestry associated with this mutation. It happens by chance and is passed down from a single parent to, on average, half of their children, a form of genetic inheritance called autosomal dominant transmission.
M’s great grandfather was noticeably shorter than her great grandmother, who was 5’4.
Through further research, M learned that the ACAN gene provides instructions for producing aggrecan protein, which is essential for bone growth, as well as for the stability of cartilage that lines bones and joints, explaining her recurring joint problems.
She also looked into the future, examining potential risk factors for her daughter: joint pain and bone conditions, which could contribute to arthritis, hip dysplasia and back problems.
The diagnosis now makes it easier for M and her daughter to favor bone-building activities that are easy on the joints, like swimming or water aerobics, instead of gymnastics and weight lifting. After having a hip replacement, M was careful to supplement with calcium and vitamin D. Now, she’ll take the same steps to ensure optimal bone health for her daughter. She’ll work with orthopedic specialists as her daughter grows into her pre-teen and adolescent years, carefully monitoring joint pain – altering activities that are tough on the joints, as necessary.
M let her daughter make a decision about growth hormone therapy, which she decided to try. The benefits of the treatment, increased height, carry inconveniences, such as taking daily shots, but they are sticking with it.
“We’re at the tip of the iceberg with research that explores this gene mutation,” says Dr. Dauber. “We’ll continue to study these families, and more, over time to assess growth patterns and gene expression, which may reveal other mutations associated with short stature or joint problems, and guide future treatment options. It was a coincidence that this family had the ACAN mutation and scheduled an appointment, while we’re conducting this study. Otherwise, they may not have had an answer since this is fairly new research.”
M and her daughter are happy to be part of this study, which they will participate in for the next few years. M’s mother is also glad to participate. She made a different choice, decades ago, to reject hormone treatment when it was offered to her for undiagnosed short stature, but she’s sharing genetic clues, which may influence treatment options for her granddaughter and for her family’s next generation.
Thirty-six researchers collaborated on this original paper, which was funded by 16 international health institutes and foundations, including the Eunice Kennedy Shriver National Institute of Child Health and Human Development at the National Institutes of Health, the Swedish Research Council, the Swedish Governmental Agency for Innovation Systems, the Marianne and Marcus Wallenberg Foundation, the Stockholm County Council, the Swedish Society of Medicine, Byggmastare Olle Engkvist’s Foundation, the Sao Paulo Research Foundation, the Spanish Ministry of Education and Science, the Czech Health Research Council and the Ministry of Health, Czech Republic.
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“The advent of different technologies and techniques over the years allowed pieces of her diagnosis to be made – and then brought all together,” says Andrew Dauber, M.D., MMSc.
After 20 years, a patient’s family received an answer to a decades-long genetic mystery. Their daughter had two rare disorders, Angelman syndrome and P450scc deficiency, which was detected after researchers found out she had uniparental disomy, two copies of chromosome 15 from one parent and none from another.
By using a variety of genetic tools, including whole-exome sequencing, microarray analyses and in-vitro modeling for gene splicing, the researchers were able to confirm this patient had uniparental disomy, a recessive genetic condition. They learned that after she received two impaired copies of chromosome 15 from her father, this woman developed a hormonal problem that led to adrenal insufficiency and sex reversal. This explained why she physically presented as a female, despite having testes and a Y-chromosome. It also explained other symptoms, including developmental delays and seizures.
“It’s a unique conglomeration of symptoms, manifested by the combination of these two very rare disorders,” says Andrew Dauber, M.D., MMSc., the division chief of endocrinology at Children’s National Health System and a guiding research author of this study. “The advent of different technologies and techniques over the years allowed pieces of her diagnosis to be made – and then brought together, commencing a 20-year diagnostic odyssey.”
For example, each of the conditions this patient has is known and rare: Angelman syndrome affects about one in 10 to 20,000 people in the U.S. Typical symptoms include those observed in this patient: delayed development, intellectual disability, speech impairment and seizures. Side-chain cleavage disorder, which leads to adrenal disorders and sex reversal, is also very rare. In 2005 the chances of survival with a P450scc defect were slim, but since then more than 28 infants have been diagnosed with this gene deficiency, which is required to convert cholesterol to pregnenolone, a hormone in the adrenal gland.
Dr. Dauber notes the chances of this occurring again are highly unlikely. The odds here are one in a gazillion. In this case, one disorder unmasked another, leaving researchers with new insights into the methodology for unraveling ultra-rare genetic disorders or for more common rare conditions.
“Knowing about the gene that caused the adrenal insufficiency and understanding this etiology won’t change medical care for this patient, but it will change the way researchers think about genetic detective work and about combining different technologies,” says Dr. Dauber. “We know that genetic disorders can be complex presentations of different disorders combined. This patient didn’t have one disorder, but three.”
When asked about the significance of the award, Dr. Dauber notes that, “It’s not that other people haven’t recognized this concept before, but this case is a striking example of it. Different technologies will unveil different types of genetic changes, which is why you have to use the right technology or the right technologies in the right combination to piece together the whole picture.”
Ahlee Kim, M.D., the lead study author and a clinical research fellow at Cincinnati Children’s Hospital Medical Center, will receive the award and the honorarium.
Additional study authors include Masanobu Fujimoto, Ph.D., Vivian Hwa, Ph.D., and Philippe Backeljauw, M.D., from Cincinnati Children’s Hospital.
The research was supported by grant K23HD07335, awarded to Dr. Dauber, from the Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health (NIH). Additional funding included grant 1UL1TR001425 from the NIH’s National Center for Advancing Translational Sciences.
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Dr. Gerard Martin, center, accepts an award before delivering the 2019 Dan G. McNamara Keynote lecture at ACC.19.
“Innovation meets tradition,” is how many attendees and journalists described the American College of Cardiology’s 68th Scientific Sessions (ACC.19), which took place March 16-18, 2019 in New Orleans, La.
Gerard Martin, M.D., F.A.A.P., F.A.C.C., F.A.H.A., a pediatric cardiologist and the medical director of Global Services at Children’s National, supported this narrative by referencing both themes in his 2019 Dan G. McNamara keynote lecture, entitled “Improved Outcomes in Congenital Heart Disease through Advocacy and Collaboration.” Dr. Martin highlighted advancements in the field of pediatric cardiology that took place over the past 15 years, while touting modern advancements – such as pulse oximetry screenings for critical congenital heart disease – that were a result of physician-led advocacy and collaboration.
Dr. Martin’s message was to continue to invest in research and technology that leads to medical breakthroughs, but to remember the power of partnerships, such as those formed by the National Pediatric Cardiology Quality Improvement Collaborative. These alliances, which generated shared protocols and infrastructure among health systems, improved interstage mortality rates between surgeries for babies born with hypoplastic left heart syndrome.
A dozen cardiologists and clinicians from the Children’s National Heart Institute also participated in CME panel discussions or delivered poster presentations to support future versions of this template, touching on early-stage innovations and multi-institution research collaborations. The themes among Children’s National Heart Institute faculty, presented to a diverse crowd of 12,000-plus professional attendees representing 108 countries, included:
Personalized guidelines:
Sarah Clauss, M.D., F.A.C.C., a cardiologist, presented “Unique Pediatric Differences from Adult Cholesterol Guidelines: Lipids and Preventive Cardiology,” before Charles Berul, M.D., division chief of cardiology and co-director of the Children’s National Heart Institute, presented “Unique Pediatric Differences from Adult Guidelines: Arrhythmias in Adults with Congenital Heart Disease,” in a joint symposium with the American Heart Association and the American College of Cardiology.
Berul, who specializes in electrophysiology, co-chaired a congenital heart disease pathway session, entitled “Rhythm and Blues: Electrophysiology Progress and Controversies in Congenital Heart Disease,” featuring components of pediatric electrophysiology, including heart block, surgical treatment of arrhythmias and sudden death risk.
Early detection:
Anita Krishnan, M.D., associate director of the echocardiography lab, presented “Identifying Socioeconomic and Geographic Barriers to Prenatal Detection of Hypoplastic Left Heart Syndrome and Transposition of the Great Arteries” as a moderated poster in Fetal Cardiology: Quickening Discoveries.
Jennifer Romanowicz, M.D., a cardiology fellow, and Russell Cross, M.D., director of cardiac MRI, presented the “Neonatal Supraventricular Tachycardia as a Presentation of Critical Aortic Coarctation” poster in FIT Clinical Decision Making: Congenital Heart Disease 2.
Pranava Sinha, M.D., a cardiac surgeon, presented the poster “Neuroprotective Effects of Vitamin D Supplementation in Children with Cyanotic Heart Defects: Insights from a Rodent Hypoxia Model” in Congenital Heart Disease: Therapy 2.
Coordinated care:
Ashraf Harahsheh, M.D., F.A.C.C., F.A.A.P., a cardiologist with a focus on hyperlipidemia and preventive cardiology, co-presented an update about BMI quality improvement (Q1) activity from the American College of Cardiology’s Adult Congenital and Pediatric Quality Network – BMI Q1 leadership panel.
Niti Dham, M.D., director of the cardio-oncology program, and Deepa Mokshagundam, M.D., cardiology fellow, presented the poster “Cardiac Changes in Pediatric Cancer Survivors” in Heart Failure and Cardiomyopathies: Clinical 3.
Nancy Klein, B.S.N., R.N., C.P.N., clinical program coordinator of the Washington Adult Congenital Heart program at Children’s National, presented the poster “Improving Completion of Advanced Directives in Adults with Congenital Heart Disease” in Risks and Rewards in Adult Congenital Heart Disease.
Innovation:
Jai Nahar, M.D., a cardiologist, moderated “Future Hub: Augmented Cardiovascular Practitioner: Giving Doctors and Patients a New Voice.” The session focused on technical aspects of artificial intelligence, such as language processing and conversational artificial intelligence, as well as how applications are used in patient-physician interactions.
Nahar also participated in a key event on the Heart-to-Heart stage, entitled “Rise of Intelligent Machines: The Potential of Artificial Intelligence in Cardiovascular Care.”
“While I enjoyed the significant representation of Children’s National faculty at the meeting and all of the presentations this year, one research finding that I found particularly compelling was Dr. Krishnan’s poster about geographical disparities in detecting congenital heart disease,” says Dr. Berul. “Her research finds obstetricians providing care to women in the lowest quartile of socioeconomic areas were twice as likely to miss a diagnosis for a critical congenital heart defect during a fetal ultrasound, compared to obstetricians providing care for women in the highest quartiles.”
Dr. Krishnan’s study was the collaborative effort of 21 centers in the United States and Canada, and investigated how socioeconomic and geographic factors affect prenatal detection of hypoplastic left heart syndrome and transposition of the great arteries.
“We studied over 1,800 patients, and chose these diseases because they require early stabilization by a specialized team at a tertiary care center,” says Dr. Krishnan, who led the research in conjunction with the Fetal Heart Society Research Collaborative. “We hope that by understanding what the barriers are, we can reduce disparities in care through education and community-based outreach.”
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Elizabeth Estrada, M.D., was struck by the increasing number of children with obesity and type 2 diabetes when she finished her fellowship in 1996. That fascination, along with increasingly alarming statistics about the rise in type 2 diabetes in youth over the past 20 years, steered her to a career focused on pediatric diabetes and metabolism that eventually led her to Children’s National Health System, where she will become the director of the type 2 diabetes program this spring.
Coming most recently from the University of North Carolina, where she served as Chief of the Division of Pediatric Endocrinology and Diabetes, Dr. Estrada will work closely with Children’s National Endocrinology Division Chief Andrew Dauber, M.D., and Diabetes Services Director Fran Cogen, M.D., to create a multidisciplinary type 2 diabetes care structure that she has seen success with throughout her career.
“Children with type 2 diabetes have very different needs than children with type 1,” Dr. Estrada explains. “They need more nutrition, more social work, and psychological support.”
Children’s National presents Dr. Estrada with a unique opportunity at a time when the field of care and treatment options for children with type 2 diabetes is expanding. She aims to develop a comprehensive, multidisciplinary program integrating the established Children’s National obesity program with the nationally-ranked endocrinology and diabetes team, which has a strong foundation in providing psychological support to families, which is part of a larger toolkit at Children’s National to help families manage a diabetes diagnosis.
The obesity program at Children’s National emphasizes personalized clinical care and education to prevent and reduce the prevalence of obesity, incorporating multiple aspects of medical and surgical care for obese children and adolescents through the Improving Diet, Energy and Activity for Life (IDEAL) clinic and the bariatric surgery program. The IDEAL clinic helps children with dietary counseling, health education classes, physical activity and weight-management techniques, as well as psychosocial support to help children reach and maintain a healthy weight.
One of the first children’s hospitals to be accredited by the Metabolic and Bariatric Surgery Accreditation and Quality Improvement Program (MBSAQIP®) and the only hospital in the area to be accredited to perform bariatric surgery on adolescents, the bariatric surgery program at Children’s National is directed by Evan Nadler, M.D., who has been safely performing surgeries for nearly 15 years.
The American Diabetes Association (ADA) recently published updates to the “Standards of Medical Care in Diabetes,” which provides research-based practice recommendations for children and adolescents with type 2 diabetes, including metabolic surgery as a treatment recommendation, stating:
The results of weight-loss and lifestyle interventions for obesity in children and adolescents have been disappointing, and no effective and safe pharmacologic intervention is available or approved by the U.S. Food and Drug Administration in youth. Over the last decade, weight-loss surgery has been increasingly performed in adolescents with obesity. Small retrospective analyses and a recent prospective multicenter nonrandomized study suggest that bariatric or metabolic surgery may have benefits in obese adolescents with type 2 diabetes similar to those observed in adults.
The recommendations further stipulate that metabolic surgery should only be considered under certain circumstances, including for those adolescents with T2D who are markedly obsess (BMI > 35 kg/m2) and who have uncontrolled glycemia and/or serious comorbidities despite lifestyle and pharmacologic intervention, and it should only be performed by an experienced surgeon working as part of a well-organized and engaged multidisciplinary team.
Working closely with Dr. Nadler and the obesity team will be a hallmark of Dr. Estrada’s role.
Her goal is to organize a clinic that not only provides clinical care and surgical options, but also includes research and provides medical education and training to medical students, residents and fellows. Dr. Estrada’s own research has focused on insulin resistance, one of the underlying problems in type 2 diabetes.
“There are several clinical trials currently exploring the efficacy and safety of medications for type 2 diabetes in children, something that is incredibly important since Metformin and insulin are the only approved options at this point,” Estrada says. “It is imperative that we bring research to Children’s National as a complement to the existing programs and to continue providing the highest level of care for these patients.”
The Division of Diabetes and Endocrinology works with the National Institutes of Health, conducts independent research and received support from the Washington Nationals Dream Foundation for its diabetes program, the largest pediatric diabetes program in the region, which provides community education and counsels 1,800 pediatric patients each year.
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