Rare Disease Symposium 2024 Program

10TH ANNUAL RARE DISEASE SYMPOSIUM 2024 PROGRAM Friday October 18, 2024 | 1:00 – 5:00 pm Frank H. Netter MD School of Medicine | Connecticut Children’s Research Institute Event Address: 370 Bassett Road, North Haven, CT 06473 We are proud to be supported by The Pullano Family Endowed Fund for Rare Disease Education and Research

QR Code for CME Credit OPENING REMARKS Room MNH-101 [1:00 – 1:15 pm] Carolyn M. Macica, MS, PhD “Looking Back on a Decade of Research, Advocacy, and Education” Director, Research Operations and Development Co-Director, Scientific Center for Rare Disease Connecticut Children’s Research Institute Affiliate Professor, Frank H. Netter MD School of Medicine Annamarie Beaulieu, MBA, MPH Podium Vice President Academic Affairs Connecticut Children's Research Institute SESSION 1: KEYNOTE SPEAKER Room MNH-101 [1:15 pm – 2:15 pm] Talk/Q&A Patience H. White, MD “Update on Health Care Transition from Pediatric to Adult Health Care: The Key Role of Clinicians” Co-Director, Center for Health Care Transition Improvement Emeritus Professor of Medicine and Pediatrics, George Washington University School of Medicine and Health Sciences https://www.gottransition.org/ SESSION 2: KEYNOTE SPEAKER Room MNH-101 [2:15 – 3:15 pm] Talk/Q&A Emily Germain-Lee, MD “From Bedside to Bench and Back Through the Lens of Albright Hereditary Osteodystrophy” Professor, Department of Pediatrics, University of Connecticut School of Medicine Director, Scientific Center for Rare Disease

10th Annual Rare Disease Symposium | October 18, 2024

Connecticut Children’s Research Institute COFFEE BREAK Lobby [3:15- 3:30 pm] Coffee and snacks SESSION 3: PATIENT AND PROVIDER PANEL Room MNH-101 [3:30 -4:30] "Adapting to Change: Navigating the Rare Disease Journey" Moderator: Marsha Lanes, MS, CGC National Organization for Rare Disorders, Inc. (NORD) Genetic Counselor/Medical Educator Panelists: Siobhain- Patient representing the Congenital Myasthenic Syndrome community Kinser- Family member representing the Juvenile Huntington Disease community Anne- Family member representing the Williams Syndrome community Brendan- Patient representing the Williams Syndrome community SESSION 4: ORAL PRESENTATIONS Proudly sponsored by the Peace Love ACCESSibility organization Room MNH-101 [4:30 – 4:45 pm] Talk/Q&A The 2024 Pullano Scholarship for Rare Disease Award The Pullano scholarship supports education and research in rare disease at the Frank H. Netter MD School of Medicine Introductions by Holly LaPrade, on behalf of the Pullano family Recipient: Amber Parson “Revision and Adaptation of a Pediatric-to-Adult Care Transition Toolkit for X-Linked Hypophosphatemia (XLH)” The 2024 Young Investigator Award Room MNH-101 [4:45 – 5:00 pm] Talk/Q&A In recognition of an outstanding contribution through original scholarship & research to individuals with rare disease.

Recipient: Jing Marrero, MD, MPH “ Dupilumab improves histologic manifestations of eosinophilic esophagitis in a real-world cohort of pediatric patients” CLOSING REMARKS Room MNH-101 Phillip M. Boiselle, MD William and Barbara Weldon Dean's Chair in Medicine RECEPTION Lobby and Room MNH-105 [Immediately following] POSTER SESSION and Rare Disease Organization Exhibits

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WHO WE ARE: Rare Disease Symposium Committee Members Carolyn M. Macica, MS, PhD Dr. Macica is the Director of Research Operations and Development at Connecticut Children’s Research Institute. She also serves as Co-Director for the Scientific Center for Rare Disease at CCRI. She chairs the symposium annually and is thrilled to host the 10th-anniversary event. She completed her doctoral training in pharmacology at New York Medical College, followed by postdoctoral fellowships in neuroscience and endocrinology at Yale University School of Medicine. Dr. Macica maintains joint affiliate professor appointments at the Frank H. Netter MD School of Medicine and Yale University School of Medicine and has recently been appointed as a Visiting Professor at the University of Connecticut. In addition to her commitment to medical education, she is a research scientist in basic, clinical, and translational research in rare metabolic bone disease. She also serves as a scientific advisor, educator, and advocate for patients and families who are impacted by rare diseases. Notably, Dr. Macica chairs and executes the annual CMEaccredited Rare Disease Day Symposium. She maintains a strong commitment to the creation and execution of STEM and mentoring programs for underrepresented youth in Connecticut and has been recognized for work in this domain.

Maureen Helgren PhD, PT Dr. Helgren is an Associate Professor of Medical Sciences and Director of Anatomy at the Frank H. Netter MD School of Medicine and is serving as co-host for this year’s rare disease event. In the early years as a physical therapist her passion for advocating for the disenfranchised strengthened. The idea of healthcare as a human right permeates her work as an educator, scientist, and member of the rare disease community. Dr. Helgren is thankful for, and inspired by, her students; confident that they will be good stewards in “Painting a brighter healthcare future for all”.

Katrina Etts, BS Katrina is a second-year medical student at the Frank H. Netter MD School of Medicine. Katrina developed a passion for advocating in the rare disease community after a college project about research/treatments (or lack thereof at the time) for Fibrodysplasia Ossificans Progressiva. She is interested in using her background of advocacy to facilitate open communication and evidencebased medicine to provide high-quality care. Katrina hopes to continue her passion of showing support for individualized healthcare for her future patients.

Tom Giannasca, BS Tom is a second-year medical student at the Frank H. Netter MD School of Medicine. With a passion for advocating for the rare disease community, Tom is dedicated to improving healthcare systems by promoting interdisciplinary, long-term care that supports both the mental and physical well-being of patients. Tom is pursuing a career in pediatric orthopedics, focusing on treating congenital and traumatic musculoskeletal conditions. His mission is to provide specialized care that helps children overcome complex physical challenges, improving their mobility and overall quality of life.

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Sin Ting Hui (Abbie), BA, MS Abbie is a second-year medical student at the Frank H. Netter MD School of Medicine. Her passion for complex medical care, interdisciplinary support, and patient education and advocacy was ignited by her exposure to rare diseases and patient presentations in a Human Genetics and Genomics course. She is currently drawn to the med-peds field, dedicated to providing excellent longitudinal care for patients with complex medical needs and their families particularly during the transition from pediatric to adulthood. Abbie finds ongoing inspiration in the intersection of patient stories and humanistic care.

Amber Parson, BA 2024 Pullano Scholarship for Rare Disease Amber is a second-year medical student at the Frank H. Netter MD School of Medicine with a passion for pediatrics. It is her aim to provide physical and mental health care that centers young patients while actively involving their families and support systems. To support patients and families affected by a rare disease called X-linked hypophosphatemia (XLH), Amber is currently developing a toolkit website that focuses on pediatric-to-adult care transition for young XLH patients. Through pursuits like this, Amber enjoys using creative outlets such as writing and graphic design to enhance patient education and engagement. Amber is also the 2024 recipient of the Pullano Scholarship for Rare Disease.

Holly LaPrade, BA Holly LaPrade is a patient and advocate living with Fibrodysplasia Ossificans Progressiva. Holly was diagnosed with the ultra-rare genetic bone disorder known as FOP at the age of 16. Holly has been extremely active with both the International FOP Association and the rare disease community in terms of fundraising, advocacy and community programming. It is her mission to use her diagnosis in a positive manner in order to empower future generations to lead fulfilling lives!

Tim Schubarg, BS Tim is a second year graduate student at Quinnipiac University studying Molecular & Cellular Biology. Tim is dedicated to advocating for research of understudied diseases, and fighting for treatment development. Tim is actively researching protein transfection with Dr. Francone at Frank H. Netter School of Medicine, and one day hopes to pursue a career in rare disease drug development. He hopes to improve the quality of life for those afflicted by furthering knowledge of rare diseases.

We are indebted to Rosa Rodrigues and Mara Saccente for excellent administrative support!

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WHO WE ARE: Our Speakers Annamarie Beaulieu, MBA, MPH Annamarie Beaulieu is the Vice President, Academic Affairs & Connecticut Children’s Research Institute.

She has been with Connecticut Children’s since 2010, when she was hired as a Program Coordinator for the Center for Children’s Community Research. Annamarie’s public health career has focused primarily on women and children’s health. In her role as Vice President, Annamarie oversees all operational and financial aspects of Connecticut Children’s academic mission including the appointments and promotions of teaching faculty, development across the medical education continuum, federal, state and private grant submissions that support academic medicine, strategic and business planning for Connecticut Children’s Research Institute and the Center for Innovation. Prior to joining Connecticut Children’s, Annamarie served as Campaign Director for the Connecticut Public Health Association, advocating for public policy in support of children’s health, and facilitating the growth and development of the non-profit’s infrastructure.

Patience White, MD, MA, FAAP, MACP, MACR Dr. White is professor emeritus of medicine and pediatrics at George Washington University School of Medicine and Health Sciences and co-director, of the federally funded Got Transition/National Center for Health Care Transition Improvement in Washington, DC. Dr. White received her MD from Harvard Medical School and a master’s in education from GWU School of Education and Human Development. Throughout her career, she has been active in academic medicine, clinical care, research, and public policy. She is a practicing pediatric and adult rheumatologist. In 2000-2001 she received a Robert Wood Johnson Health Policy Fellowship and worked in the Senate Finance Committee on the Family Opportunity Act and Medicare part D. As part of her work at Got Transition, she developed the nationally recognized Six Core Elements of Health Care Transition and provides quality improvement technical assistance on transition from pediatric to adult health care to integrated health care delivery systems, health plans, Title V agencies, pediatric and adult primary and specialty care practices, school-based health clinics, patient organizations and health provider professional societies. Over her career, she has published many peer reviewed articles and policy papers including the recent 2023 reaffirmation of the 2018 AAP/AAFP/ACP joint clinical report, “Supporting the Health Care Transition from Adolescence to Adulthood in the Medical Home” published in Pediatrics.

Emily Germain-Lee, MD Dr. Germain-Lee received her M.D. degree from the Johns Hopkins University School of Medicine and continued at Johns Hopkins for her internship and residency in Pediatrics as well as her fellowship in Pediatric Endocrinology. Dr. Germain-Lee has a distinguished history of caring for children and adults from around the world with all types of bone disorders, most notably Albright hereditary osteodystrophy (AHO), a condition including two subtypes termed pseudohypoparathyroidism type 1a and pseudopseudohypoparathyroidism.

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Over the past two decades, she has built extensive clinical and research programs focused on AHO and currently follows the largest population of these patients worldwide. Her clinical and research interests also include other rare disorders leading to bone and/or endocrine abnormalities such as osteogenesis imperfecta, skeletal dysplasias, and Sturge-Weber Syndrome. Her goal is to develop new treatments to improve the overall health and quality of life for patients with these disorders and to translate scientific investigations in her laboratory into therapeutic applications.

Outside of Connecticut Children’s and UConn Health, Dr. Germain-Lee serves as Vice President of the Human Growth Foundation to help children with growth disorders through advocacy, education, and research.

Jing Marrero, MD, MPH 2024 Young Investigator Award Dr. Jing Marrero grew up in the small college town of Corvallis, Oregon and attended Oregon State University. After graduation, she joined Teach for America, and taught middle school science and high school biology prior to starting medical school at the University of Connecticut. Dr. Marrero continued her training at UConn and was a pediatric resident and pediatric gastroenterology fellow at Connecticut Children’s. She is currently a Pediatric Gastroenterologist at Connecticut Children’s. Her clinical interests include general gastroenterology, community health, and medical education. In her spare time, Dr. Marrero enjoys catching up on pop culture, learning to bake, and spending time with her family.

Phillip M. Boiselle, MD Dr. Boiselle is the William and Barbara Weldon Dean's Chair in Medicine. He earned his bachelor of arts in chemistry and communications from the University of North Carolina at Chapel Hill and his MD from the Duke University School of Medicine, followed by residency training at Yale University and a thoracic imaging fellowship from Massachusetts General Hospital and Harvard Medical School.

Dr. Boiselle is recognized as an international expert in the field of thoracic imaging. His scholarship includes more than 250 research articles, review articles, editorials, book chapters and books. He served as editor-in-chief of the Journal of Thoracic Imaging from 2009-18.

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WHO WE ARE: Our Panelists Marsha Lanes, MS, is a board certified genetic counselor and medical editor at the National Organization for Rare Disorders (NORD). As a member of NORD’s Educational Initiatives Department, she oversees the Rare Disease Database and contributes to the development of educational programs and resources related to rare disorders for patients, caregivers, medical professionals and students preparing for healthcare careers. Prior to NORD, Marsha held positions in genetics education and research at Tufts-New England Medical Center, the Center for Human Genetics at Boston University, and the Massachusetts Department of Public Health and clinical genetic counselor in the Boston area.

Siobhain Siobhain is 39 and lives in New London, CT. She is a patient advocate, and a rare patient with Congenital Myasthenic Syndrome. She works for the National Organization for Rare Disorders as a patient service representative. She is also a freelance columnist for the Rare Disease Advisor. She was recently named the new chair for the Boston division awareness walk, for the Myasthenia Gravis Foundation of America.

Siobhain was born with Congenital Myasthenic Syndrome (CMS) but misdiagnosed for almost 10 years. She was correctly diagnosed after spending 3 days at Columbia Hospital in NY in 1995.

Siobhain also has nephrotic syndrome and was on prednisone from age 2-8, which masked her CMS symptoms. She has taken Mestinon since 1995 and started trials in 2011 for 3,4 DAP. She now takes Firdapse and Mestinon. Siobhain has to fight for her medication every year as she takes it off label as it is not FDA approved for her diagnosis. It is over $800,00 a year, if insurance denies it.

One week a year, Rare Disease Week is held on Capitol Hill. Siobhain has gone as a patient and team coordinator for the state of CT the last two years, and has attended as a patient since 2019.

It’s a great event for rare advocates to meet with legislation, share their personal stories, and encourage state legislators to get involved with the rare community.

Brendan Brendan is 37 and co-host of the William Syndrome Association's "Starry-Eyed Podcast," and has been on the WSA Board of Trustees since 2021. He was diagnosed with Williams syndrome at age twelve-and-a-half.

Brendan graduated from Daniel Hand High School in Madison, CT in 2006. He attended the Berkshire Hills Music Academy in MA, followed by New Haven's Neighborhood Music School, graduating with honors from their 3-year certificate program in percussion studies. An accomplished musician, Brendan plays drums, guitar, and bass.

From 2007 through 2017, Brendan had his own band with five other WS musicians: the "Kandoo Band." They performed for many disability-related events, such as the Hyannis Port Challenge bike ride. They also travelled throughout the northeast, sharing their "D.R.E.A.M. - Dare to Realize Everyone's Abilities Matter" musical Ability Awareness program with school audiences

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from elementary through high school. The Kandoo Band was named one of the "top twenty-five stars of the Best Buddies Movement" by Anthony Kennedy Shriver in 2014.

Brendan began public speaking and advocacy through the Best Buddies Leadership program as an ambassador. He is currently a member of the Westchester Institute of Human Development Speakers Bureau, through which he speaks annually to graduate students in the Clinical Genetics program at Sarah Lawrence College, and 1st-year medical students at New York Medical College about his experiences as a person with Williams syndrome in the medical system.

While in his twenties, Brendan worked for MTV as a band member and reporter for the “How’s Your News” reality television series. Over the past decade, Brendan has been a member of several bands including: the Sarah LeMieux Quintet jazz band and The Girls from Ruby Falls, Americana Band, both winners of CT Music Awards. While the pandemic closed down the live music scene, opportunities are opening up again and Brendan currently plays percussion with 80ies and 90ies cover bands, The Future Heavies and The Usual Lebowskis, performing recently at Wesleyan University's Graduation/Reunion tent party. Earlier this year, he played at the New York Stock Exchange with the band Hotel Fiction at a fundraiser for the vocational advocacy organization Creative Spirit-US. Brendan enjoys Special Olympics swimming and golfing. Other interests include tattoo art and gardening.

Anne Anne Anne C. LeMieux, in addition to being Brendan's mom and advocate, is a published journalist, and author of a dozen young adult and children's books. She is also a retired paralegal specialist in government benefits and disability matters, a field she entered after Brendan was diagnosed with Williams syndrome in middle school, at which point learning to navigate the intricacies of special education law became a necessity.

The various health problems Brendan had prior to his diagnosis constituted an ongoing puzzle for which his family did not have the most important piece -- a definitive diagnosis. Once Brendan was diagnosed with Williams syndrome, Anne's writing took a back seat as she turned to researching the condition, with what research was available at that time.

Anne is a former member of the Board of Directors for HART United Inc., a social services nonprofit that provides housing and residential services for adults with disabilities. She also served on the Advisory Board of Best Buddies, Connecticut. Her most rewarding volunteer service (with major heavy-lifting and audio-engineer help from Brendan's step-dad Tim Pocock) was during her ten year stint as band manager/agent/shepherd/chauffeur/chef and fill-in rhythm and bass guitar player, for the Kandoo Band.

Anne holds a B.A. in Writing and Illustration from Simmons College in Boston, MA. She also studied music theory and jazz guitar at the University of Bridgeport with Sal Salvador, and acoustic fingerstyle guitar with Eric Schoenberg.

In 1993, she co-founded the AOL Children's Writers Group, the first national live online writing

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forum for children's book authors, and over the years has been a speaker in school classrooms and at professional organization gatherings, including The National Council of Teachers of English annual convention. She is a member the Society of Children's Book Writers & Illustrators and of The Adolescent Literature Assembly of NCTE. Her novels for teens and middle schoolers won several awards, including ALA Best Book for Young Adults and Parents' Choice Silver Honors.

Last year, Anne began writing again, resulting in an ongoing Medium.com series of mini-essays on the medical mystery of Brendan's first thirteen years, which incorporates the wide range of updated research now available, and interweaves the new information with Brendan's and their family's story. It is titled: "Being & Becoming: A Williams Syndrome 'Mom-oir." She also recently finished a Young YA novel about a high school freshman with Williams syndrome.

Anne enjoys spending time with her grandchildren, drawing and painting, noodling on her guitar, gardening, and inventing homemade soups.

Kinser My husband was diagnosed with Huntington's Disease at the age of 36. He passed away at the age of 51. He inherited the gene from his father. This was not talked about much when John and I got married. My daughter Meaghan was diagnosed with Juvenile Huntington's Disease at the age of 10.

She passed away at the age of 15. She struggled dearly with this disease because there were next to no healthcare professionals that knew anything about this rare disease.

My daughter Alyssa was diagnosed with Huntington's/Juvenile Huntington's at the age of 24. She is currently 28 years old. Each child has a 50/50 chance of inheriting this gene from a parent that carries it.

I have been very active in advocacy. I have been a board member of the Huntington's Disease Association of America Massachusetts/Rhode Island Chapter for many years. I currently have taken the last couple of years off but still help with the annual golf tournament where we raise in excess of $50,000. I started a non profit organization in memory of my daughter Meaghan: Meg's Fight for a Cure Juvenile Huntington's Disease Foundation, Ince. I raise money for research and also help underrepresented families with needs that pertain to JHD. I've also worked with Help for HD International presenting at symposiums and on behalf of Meg's Fight for a Cure.

I’ve also enjoyed working in the rare disease space: Stellar Story Company : What Huntington's Tells us About Living Global Genes Interview - Rare Diseases Mass Bio's 5th Annual Patient Advocacy Summit representing Meg's Fight for a Cure JHD Life Interrupted, Volume 2. - I've written a chapter in this book I’ve participated in a March to Washington DC to speak with Senators about HD and the need to approve this disease as one that does not need the 2 year waiting period for Medicare coverage Woodie Guthrie Award for Advocacy from the Huntington's Disease Society of America My story with Meaghan was a powerful one as I involved many Massachusetts State agencies as well as Senators when the hospital was against working with me/her to provide the necessary care that she needed and deserved.

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OUR EXHIBITORS: Please stop by and learn more from our exhibitors!

Edward and Barbara Netter Library Resources: https://rarediseases.info.nih.gov/ https://www.clinicaltrials.gov/ https://www.medline.com/ The National Organization for Rare Disorders (NORD) https://rarediseases.org/ Professional Patient Advocates in Life Sciences (PPALS) https://ppals.org/ Cystinosis Research Network https://cystinosis.org/ QU Center for Interprofessional Healthcare Education (CIHE) MdDS Foundation (Mal de Débarquement Syndrome) https://www.mddsfoundation.org National Marrow Donor Program https://www.nmdp.org/ Peace Love ACCESSibility https://www.facebook.com/PeaceLoveACCESSibility/ International FOP Association https://www.ifopa.org/

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We are grateful to Dean Boiselle for sponsoring poster scholarships for early-stage investigators.

ABSTRACTS: RDS01 Age at Diagnosis of X-Linked Hypophosphatemia in Children With vs. Without a Family History of the Disorder: Results from the Disease Monitoring Program.

Thomas Carpenter MD1, Hamilton Cassinelli, MD2, Pablo Florenzano, MD3, Erik Imel, MD4, Jill Simmons, MD5, Leanne Ward, MD6, Shubham Tewari, MSc7, Osman Cigeroglu, MD8, Angela Williams, PhD9, Kerry Sandilands, BSc9, *Brien Schliep, DPM10, Marc Vincent, DPT, MS10, Jerry Li, MBA10 *Presenting author 1. Yale University School of Medicine, New Haven, CT, USA 2. Hospital de Niños Ricardo Gutierrez, Buenos Aires, Argentina 3. Pontificia Universidad Católica de Chile, Santiago, Chile 4. Indiana University School of Medicine, Indianapolis, IN, USA 5. Vanderbilt University School of Medicine, Nashville, TN, USA 6. Children’s Hospital of Eastern Ontario, Ottawa, ON, Canada 7. KMK Consulting Inc., Morristown, NJ, USA 8. Ultragenyx Pharmaceutical Inc., Novato, CA, USA 9. Kyowa Kirin International, Marlow, UK 10. Kyowa Kirin, Inc., Princeton, NJ, USA Objectives: X-linked hypophosphatemia (XLH) is caused by inherited or de novo PHEX gene variants. The objective of this study was to examine whether a known family history (FH) of XLH influences the timing of diagnosis in children using data from the XLH Disease Monitoring Program (XLH-DMP).

Methods: The XLH-DMP is an ongoing, prospective, multicenter study of patients in the Americas designed to characterize the presentation and outcomes of XLH over 10 years (NCT03651505). This analysis included pediatric patients enrolled during 2018–2022. Patients were divided into two groups based on presence or absence of a family member with XLH. Age at XLH diagnosis was compared using t-test and Kaplan–Meier analyses. Cox proportional hazards modeling was used to analyze the associations between patient characteristics and age at XLH diagnosis.

Results: Among 347 children, 231 had a FH and 116 did not (mean age 8.4 and 10.2 years, respectively). Patients without a FH were significantly more likely to be female than those with a FH (73% vs. 55%; P=0.001). Most patients (66%) in both groups were from the United States. Kaplan– Meier analysis demonstrated that age at diagnosis was significantly earlier in children with a FH than in those without (log rank P<0.0001). Examining groups by age at enrollment, the finding persisted: mean age at diagnosis was lower in patients with versus without a FH who were aged 1–4 years (0.8 vs. 2.6 years; P<0.0001), 5–11 years (1.8 vs. 2.6 years; P=0.0145), and 12–17 years (2.5 vs. 2.9 years; P=0.5064) at DMP enrollment (Table 1). Notably, patients with a FH who were enrolled at younger ages reported earlier initial diagnosis than those who were enrolled at older ages, suggesting that age at diagnosis may be decreasing in families with known affected members. Cox modeling adjusting for age at enrollment, country, gender, and race/ethnicity demonstrated a significant association between FH and age at diagnosis.

Conclusions: This real-world study demonstrates that children with XLH without a FH were

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diagnosed significantly later than those with a FH. Children in the younger age categories with a FH appeared to be diagnosed earlier than those who were older at enrollment, suggesting that testing and diagnostic practices may have improved in recent years. Future research is needed to evaluate whether earlier XLH diagnosis is associated with reductions in the time to treatment initiation or improved clinical outcomes.

Table 1. Age at Diagnosis in Patients With vs. Without a Family History of XLH. Age Category at Enrollment (Years)

<1

1–4

5–11

12–17

Age at XLH Diagnosis (Years)

XLH Family History Total

No

Yes

(n=0)

(n=8)

(n=8)

Mean (SD)

–

0.2 (0.2)

0.2 (0.2)

Median (IQR)

–

0.2 (0.0, 0.3)

0.2 (0.0, 0.3)

Range

–

–0.04, 0.46

–0.04, 0.46

(n=17)

(n=63)

(n=80)

Mean (SD)

2.6 (1.0)

0.8 (1.0)

1.2 (1.2)

Median (IQR)

2.6 (1.9, 3.0)

0.5 (0.1, 1.3)

0.8 (0.2, 1.9)

Range

1.09, 4.65

–0.09, 4.26

–0.09, 4.65

(n=53)

(n=101)

(n=154)

Mean (SD)

2.6 (1.7)

1.8 (2.3)

2.1 (2.1)

Median (IQR)

2.2 (1.7, 2.9)

0.9 (0.2, 2.3)

1.5 (0.5, 2.8)

Range

0.45, 9.79

–0.09, 10.91

–0.09, 10.91

(n=46)

(n=59)

(n=105)

Mean (SD)

2.9 (2.7)

2.5 (3.8)

2.7 (3.3)

Median (IQR)

2.2 (1.6, 3.0)

0.9 (0.2, 3.5)

1.9 (0.5, 3.0)

Range

–0.07, 13.52

–0.10, 17.29

–0.10, 17.29

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P

–

<0.0001

0.0145

0.5064

RDS02 Improving Transition to Adult Care Jessica Fennell 1,2, Jennifer Twachtman-Bassett3, and Carolyn M. Macica1,3 1. University of Connecticut School of Medicine 2. Connecticut Children’s 3. Connecticut Children’s Research Institute Background The lack of transition for pediatric patients with chronic medical conditions to the adult healthcare system often leads to increased disease activity and adverse outcomes. A structured transition process is pivotal in preparing adolescents and young adults for this shift. Formal transitions have demonstrated significant improvements in patient outcomes, yet there is currently no formal transition process for patients in the Rheumatology Department at Connecticut Children’s. This study sought to understand the opinions of the medical team and patients/guardians about the usefulness of a transition program, concerns about transition, current transition practices, and the necessary components of a transition program to help build a formal transition process.

Methods The Connecticut Children’s IRB reviewed the study and determined it met the requirements for exemption. A survey assessing attitudes related to transition care was created and distributed to the medical team and patients/guardians at the Hartford office from 10/11/23 to 12/31/23.

Results One hundred percent (n=6) of the medical staff responded, and 25 patients/guardians participated in the survey. The number of patients/guardians offered the survey was not recorded. Eighty-one percent (25/31) of participants felt a transition process would be helpful (>5 on likert scale). All 6 medical staff agreed that patients needed to understand the following: they would be expected to manage their care independently, including knowing their medications, taking medications independently, refilling medication, and explaining their condition. Patients’/guardians’ top priority in transition education was learning how to find an adult doctor, 77% (17/22), and learning how to contact their insurance company, 41% (9/22). Patients’ top concern was finding a new doctor, 55% (12/22), and guardians’ top concern was continued participation in their adolescents’ care, 50% (11/22).

Conclusions While the most common single transition practice was talking to patients about finding an adult rheumatologist, 100% (6/6), this process does not follow the temporal or formal process outlined by the Six Core Elements of Health Care TransitionTM guidelines. Given the volume of needs expressed by respondents, both clinician training and a formal transition process are needed. It should include education about diagnoses, medications, insurance, how to find adult doctors and their expectations, as well as guardians’ role in their adolescents’ care.

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RDS03 Putting Healthcare Transition into Action: Supports to Help Providers Facilitate Medical Transition for Young Adults and their Families.

Jennifer Twachtman-Bassett1,2; Jessica Fennell1,3, and Carolyn M. Macica2,3 1. Connecticut Children’s 2. Connecticut Children’s Research Institute 3. University of Connecticut School of Medicine Background: While age 18 is considered the legal age of adulthood, research has shown that many executive function (EF) skills continue to develop well past this age1,2. This disparity complicates healthcare transition, as these skills are essential to independence and ensuring that adolescents and young adults (AYA) obtain needed medical care. To be most effective, education regarding healthcare transition needs to consider the support needed by a still-developing brain3. This need is greater for those with rare diseases that require significant medical management. Research has suggested a direct relationship between the level of EF and competence in medical transition4.

Additionally, when asked about healthcare transition, 57% of college students stated that they would have liked more support than they received5. Since direct medical provider support and education are linked to higher healthcare responsibility5, pediatric providers need to educate AYAs in a manner that supports their developing EF skills to ensure the most favorable outcomes.

Methods: A literature review was conducted regarding EF development and the interface between EF and key aspects of healthcare transition. Published research regarding surveys conducted with AYAs, along with our internal survey results were also reviewed. From this information, we designed support materials for young adults and families that practitioners can use to provide concrete transition guidance. These materials were formatted as “smartphrases” to facilitate incorporation into the patient’s medical record. Materials were designed to accommodate the EF support needs of this age group.

Results: Patient education and instruction sheets and event-specific planning sheets were designed according to established principles of executive function supports6. These principles include instructions and educational materials that are visual/written (to ensure future reference), customizable (to increase their utility), concrete and action-oriented, organized according to healthcare topic, and concise.

Conclusions: Healthcare transition supports that take into account developmental readiness in EF are likely to have the greatest level of success. Since many AYAs express a desire for more support from their providers, pediatric providers should tailor their educational interventions to ensure that they reflect the developmental level of the patient. This is essential to ensuring better outcomes in healthcare transition.

10th Annual Rare Disease Symposium | October 18, 2024

RDS04 Qualitative Analysis of Pain Impact in Adult Patients with X-Linked Hypophosphatemia (XLH) to Inform the Development of a Digital Pain Self-Management Intervention Nicole Nishime1, Christopher Theriault2, and Carolyn M. Macica1,2,3 1. Quinnipiac University, Frank H. Netter MD School of Medicine, North Haven, CT; 2. Connecticut Children's Research Institute, Hartford, CT 3. University of Connecticut School of Medicine Background: X-linked hypophosphatemia (XLH) is a rare genetic disorder that results in phosphate wasting. Since phosphate plays an essential role in the biomineralization and maintenance of bone, teeth, and ossicles, XLH manifests systemically. As a progressive disease, these patients often experience chronic pain and an increasingly limited range of motion due to the formation of bone spurs (enthesophytes) at fibrocartilaginous tendon and ligament insertion sites. While previous studies have reported pain as a predominant finding in adult patients with XLH, this study aims to address the knowledge gap related to pain in these individuals to better inform the creation of a digital pain management tool.

Methods: To gain insight into individual experiences and health-related quality of life, participants were asked to complete the 36-Item Short Form Survey Instrument (SF-36) and semi-structured interviews, developed with input from adult patients, to enhance our understanding of the experiences that adults with XLH face when living with pain. Data were reported as age-adjusted differences relative to the general population, and qualitative analysis of interviews was conducted using NVivo (Lumivero) software. Interviews of 15 adult patients (11F/4M) diagnosed with XLH were conducted, transcribed, and analyzed.

Results: Age-adjusted differences for SF-36 responses were lower than the general population in all domains of health-related quality of life, with significant differences notably related to physical function and pain. Qualitative data analysis of interviews identified 10 emergent themes: 1.

Chronic and variable pain; 2. Impact on mobility and daily life; 3. Pain management techniques; 4.

Healthcare and accessibility challenges; 5. Emotional and psychological impact; 6. Social isolation and dependency; 7. Desire for improved information and support; 8. Challenges with inactivity and the need to keep moving; 9. Long-term outlook and concerns; 10. Advocacy and awareness.

Conclusions: These data illustrate the profound impact of XLH on multiple aspects of patients' lives and highlight the critical need for effective pain management strategies, better healthcare accessibility, supportive tools, and a more knowledgeable medical community to improve the quality of life for individuals with XLH. These data will be used to develop a tailored digital intervention for pain self-management previously developed for other chronic pain populations.

10th Annual Rare Disease Symposium | October 18, 2024

RDS05 Folate Receptor Alpha Autoantibodies in the Pediatric Acute-Onset Neuropsychiatric Syndrome (PANS) and Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections (PANDAS) Population.

Neeshi Hullavarad1, Lindsey Wells2, Nancy O’Hara3, Richard E. Frye4, and Erica Smith5 1. Frank H. Netter MD School of Medicine, Quinnipiac University, North Haven, CT; Massachusetts General Hospital, Boston, MA 2. Lindsey Wells ND LLC, Wilton, CT 3. Nancy O'Hara and Associates LLC, Wilton, CT 4. Autism Discovery and Treatment Foundation, Phoenix, AZ 5. Natural Pediatrics of CT, Stamford, CT Background: The folate receptor alpha autoantibodies (FRAAs) are associated with cerebral folate deficiency (CFD) and autism spectrum disorder (ASD). Both of these syndromes have overlapping characteristics with Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections (PANDAS) and Pediatric Acute-Onset Neuropsychiatric Syndrome (PANS).

Thus, we propose that the FRAAs may contribute to the symptomatology of PANS/PANDAS. Methods: To test this hypothesis, 1 mL of serum from 47 patients (age range = 6–18 years old) clinically diagnosed with PANS/PANDAS was sent to Vascular Strategies (Plymouth Meeting, PA, USA) for analysis of FRAAs. Results: 63.8% of PANS/PANDAS patients (male = 15; female = 15) were found to have either the blocking and/or binding FRAAs, with 25 (83.3%; male = 14; female = 11) having binding FRAAs, two (6.7%; all female = 2) having blocking FRAAs, and 3 (10%; male = 1; female = 2) having both binding and blocking. Furthermore, surprisingly, ASD was associated with a 0.76 lower binding titer (p= 0.02), and severe tics were associated with a 0.90 higher binding titer (p= 0.01). A case of a FRAApositive patient is provided to illustrate that a treatment plan including leucovorin can result in symptom improvement in patients with PANS/PANDAS who are FRAA-positive.

Conclusions: These data, for the first time, demonstrate that PANS/PANDAS is associated with FRAAs and suggest folate metabolism abnormalities may contribute to PANS/PANDAS symptomatology. Further studies investigating the therapeutic nature of leucovorin in the treatment of PANS/PANDAS are needed. Such studies may open up an alternative, safe, and welltolerated treatment for those with the PANS/PANDAS diagnosis.

10th Annual Rare Disease Symposium | October 18, 2024

RDS06 Eating Disorders in Patients with Glycogen Storage Disease.

Malaya Mount, RD1, Lauren Ayr-Volta PhD2, Alyssa Bennett MD3, Rebecca Riba-Wolman, MD1 1. Division of Endocrinology, Connecticut Children’s, Hartford, CT 2. Division of Pediatric Psychology, Connecticut Children’s, Hartford, CT 3. Division of Adolescent Medicine, Connecticut Children’s, Hartford, CT, USA Background: Glycogen Storage Disease type Ia (GSDIa) is a severe genetic metabolic disorder treated primarily by diet. Patients with GSDIa must follow a restrictive diet with significant emphasis on timeliness, amount and characteristics of intake. Necessary metabolic control minimizes hypoglycemia which can impair hunger cues and eliminate flexibility in eating patterns.

Nutritional rehabilitation of an eating disorder (ED) is often counter to the management of GSD. Eating problems (ie. selective, aversive symptoms, etc.) have been described in patients with GSD, but frank clinical eating disorders have not been described in this population.

Methods: We present two cases of eating disorders in GSDIa patients.

Results: Case 1: Patient, a female with GSDIa, was diagnosed with atypical anorexia nervosa at age 15. She presented with weight loss of 5.7kg over 8.5months (87% of the 90th percentile BMI), excessive exercising, and caloric restriction. She developed frequent hypoglycemia (glucose <55mg/dL), worsening metabolic markers (hypertriglyceridemia, hyperuricemia, and transaminitis) and acute hypophosphatemia, hypokalemia and lactic acidosis requiring inpatient medical admission under an ED protocol modified for GSDIa. Once medically stable, inpatient admission to an ED program was recommended but not possible due to complexity of GSD care. She enrolled in an intensive outpatient ED program. Weight gain and improved stability of ED was associated with increasing hepatomegaly, and adjustment of treatment goals allowed for stable weight and improved metabolic control.

Case 2: Patient, a female with GSDIa, was diagnosed at 15-years of age with depression and an unspecified ED. She presented with endorsement of self-induced vomiting, intermittent restricted eating, reported goal of significant weight loss and stress around eating in the context of significant depression and suicidal ideation. She did not experience weight loss, change in metabolic control or frequency of hypoglycemia. Her intrusive behaviors and thoughts have stabilized with multidisciplinary care.

Conclusions: Eating disorders can be life threatening, and in association with GSD there can be additional difficulties with diagnosis, management and recovery. Although ED with GSD is rarely described in the literature, it may be underdiagnosed. The treatment of ED and GSD can be in opposition based on nutritional goals and eating patterns. Early detection and high intensity multidisciplinary treatment is necessary to balance the management of GSD and ED.

10th Annual Rare Disease Symposium | October 18, 2024

RDS07 Improved Outcomes for Primary Refractory Classical Hodgkin Lymphoma: A Retrospective Analysis.

Alayna M. Santarosa, MPH1, Nivetha Ganesan, MPH2, Tiffany Chang, MS2, Kelly Hannigan2, Ellie Casper, MS, DPT2, Gunjan Shah, MD2, Alexander Boardman, MD2, Philip Caron, MD2, Kevin David, MD2, Ahmet Dogan, MD, PhD2, Zachary Epstein-Peterson, MD2, Lorenzo Falchi, MD2, Paola Ghione, MD2, Paul Hamlin, MD2, Steven Horwitz, MD2, Andrew Intlekofer, MD, PhD2, William Johnson, DO2, Ariel Krivisky, RN2, Anita Kumar, MD2, Jennifer Lue, MD2, Efrat Luttwak, MD2, Ariela Noy, MD2, Colette Owens, MD2, Maria Palomba, MD2, Gilles Salles, MD, PhD2, Heiko Schoder, MD2, Raphael Steiner, MD2, Robert Stuver, MD2, Pallawi Torka, MD2, Santosha Vardhana, MD, PhD2, Joachim Yahalom, MD2, Andrew D. Zelenetz, MD, PhD2, Craig Moskowitz, MD3, Alison Moskowitz, MD2.

1. Frank H. Netter MD School of Medicine, Quinnipiac University, North Haven, CT 2. Department of Medicine/Lymphoma, Memorial Sloan Kettering Cancer Center, New York, NY 3. Department of Medicine/Lymphoma, University of Miami, Miami, FL Background: While most pts with classical Hodgkin Lymphoma (cHL) are cured following frontline therapy, up to 10% develop relapsed (rel) disease and 5-10% have primary refractory (ref) disease.

We previously reported 5-year overall survival (OS) of 60% for 192 ref pts treated on sequential clinical trials from 1994 through 2015. The approval of brentuximab vedotin (BV) and checkpoint inhibitors (CPI) has significantly impacted cHL treatment, likely leading to improved outcomes for rel/ref pts. We aimed to characterize outcomes for pts with ref cHL treated with these modern therapies.

Methods: We identified consecutive pts age 18+ with ref cHL from 01/2010 to 01/2024. Overall survival (OS) was calculated from C1D1 of first salvage to date of death or last follow-up.

Progression free survival (PFS) was calculated from C1D1 of first salvage. When analyzing pts who underwent ASCT, OS and PFS were calculated from date of transplant. Log rank tests were used to assess for differences in survival stratified by prognostic factors and treatment categories.

Treatment was categorized as chemotherapy-based, BV-based, and CPI-based therapy.

Results: Among 215 pts identified, median age at diagnosis was 34 years. At time of diagnosis, 55% had advanced stage disease (stage III/IV), 47% had extra-nodal involvement, and 56% had Bsymptoms. Upon confirming ref disease, 44% had advanced stage disease, 39% had extra-nodal involvement, and 18% had B-symptoms. For first salvage, 37% received chemotherapy-based, 32% BV-based, and 31% CPI-based therapy. 165 (77%) pts underwent ASCT of whom 123 (75%) were PET-negative prior to transplant. Among all pts, 4-year OS was 86% (95CI: 81-92), and 4-year PFS was 61% (95CI: 53-69). For pts treated with CPI-based salvage, only stage IV disease status was predictive for inferior survival (p=0.016) and was associated with 4-year OS of 70% vs 94% for pts with or without stage IV disease. Among the 165 pts who received ASCT, 4-year OS was 91% (95CI: 85-96), and 4-year PFS was 70% (95CI: 63-78). Receipt of PD1-based salvage any time before transplant significantly improved PFS (4-year PFS 85% vs 65%, p=0.020).

Conclusion: This report represents one of the largest series of refractory cHL cases treated with modern therapy. 4-year OS was 86%, which compares favorably to prior series. Primary refractory cHL no longer appears to be a negative prognostic factor for pts treated with CPI-based salvage, especially for those with stage I-III disease.

10th Annual Rare Disease Symposium | October 18, 2024

RDS08 Sustained Fracture Rate Reduction with Setrusumab in Patients with OI: Fourteen Month Data from Phase 2 of the Orbit Study.

Velliyur Viswesh1, Gary S. Gottesman2, Thomas O. Carpenter3, Danita Velasco4, Maegen Wallace5, Peter Smith6, Erik A. Imel7, Diana Luca1, Heather M. Byers1, Stanley Krolczyk1, E. Michael Lewiecki8 1. Ultragenyx Pharmaceutical Inc., Novato, CA2. Washington University School of Medicine, Divisions of Endocrinology and Diabetes, Genetics and Genomics Medicine, Bone and Mineral Diseases, St. Louis, Missouri 3 Yale University School of Medicine, New Haven, CT 4. Children’s Nebraska, Omaha, NE, USA 5. Phoenix Children’s Hospital, Phoenix, AZ 6. Shriner’s Hospitals for Children, Chicago, IL 7. Indiana University School of Medicine, Indianapolis, Indiana 8. University of New Mexico Health Sciences Center, Albuquerque, NM Background: Osteogenesis imperfecta (OI) is a rare genetic disorder of bone fragility and low bone mass with no universally-accepted treatment. Setrusumab is a fully human anti-sclerostin monoclonal antibody that improves bone mineral density (BMD), bone strength, and bone remodeling in adults with OI. Methods: Phase 2 of the ongoing Phase 2/3 Orbit study (NCT05125809) assessed the efficacy and safety of setrusumab in pediatric and young-adult cohorts with OI. Subjects with OI Types I, III, or IV, ages 5 to <26 years, were randomized 1:1 to receive 20 or 40 mg/kg setrusumab intravenously monthly. Once the last subject completed 6 months of treatment, all subjects were switched to 20 mg/kg for the remainder of the study. Dose groups were pooled for this analysis.

Results: Twenty-four subjects (50% female, 75% <18 years old) with OI Type I (n=17/24, 71%) or III/IV (n=7/24, 29%) were assessed (mean, median treatment duration: 16, 15 months).

Subjects showed continued meaningful improvement in BMD. A mean (SE) change from baseline (BL) in lumbar spine BMD of 14.19% (2.15%) was seen at Month (M) 6, and 22.25% (2.71%) at M12 (p<0.0001). Mean (SE) BL BMD Z-score improved by 0.85 (0.13) at M6, and by 1.25 (0.17) at M12 (p<0.0001).

The median annualized pre-treatment skeletal fracture rate (excluding fingers, toes, face, skull, and morphometric vertebral fractures) fell from 0.72 to 0 (p=0.0014) after a mean treatment duration of 16 months, representing a 67% reduction. No safety concerns were identified at M14.

Reported treatment-emergent adverse events (TEAE) were consistent with the anticipated safety profile of setrusumab. Most related TEAEs (11/12, 92%) were mild (Grade 1) in severity, with no related serious TEAEs reported. No cardiovascular adverse events were reported. No TEAEs led to study/treatment discontinuation or disruption.

Conclusions: In Orbit Phase 2, we observed significant, clinically meaningful improvements from BL in lumbar spine BMD and BMD Z-score at M14. A clinically meaningful reduction in skeletal fracture rate was achieved with setrusumab (67%). These data further build upon those reported after 6 months of setrusumab, demonstrating the robustness and durability of this therapy in patients with OI.

10th Annual Rare Disease Symposium | October 18, 2024

RDS09 Strengths and Limitations of Healthcare Transition Programs for Patients with Spina Bifida: A Systematic Review.

Katrina Etts, BS1, Jimin Shin, BS2, Reynaldo Zamora, BS1, David Hersh, MD3 1. Frank H. Netter MD School of Medicine, North Haven, CT 2. University of Connecticut School of Medicine, Farmington, CT 3. Neurosurgery, Connecticut Children’s Medical Center, Hartford, CT Background: Due to the complex needs of patients with spina bifida, many pediatric clinics adopted a multidisciplinary approach, which allows the patient to see multiple specialists in one setting. However, patients with spina bifida require ongoing care throughout their lifetime, and many patients experience interruptions in care when they transition to adulthood; therefore, many centers have begun to develop programs to streamline the transition. The goal of this review is to summarize the current strengths and limitations of existing healthcare transition programs for patients with spina bifida.

Methods: A systematic review was conducted using PubMed, Scopus, and SpringerLink. Articles were screened first by title and abstract, followed by a full-text review. The following data were extracted from articles that were included: number of respondents, type of study, intervention, the type of survey (if applicable), and outcomes. The Triple Aim framework (population health outcomes, experience of care, utilization and cost outcomes) was used to assess outcomes.

Results: Overall, 1,288 articles were screened and 15 were included in this review. 14 assessed individual patients, while 1 assessed clinics/programs. The included studies had a mean of 52 subjects per study (range 13-162 subjects). 14 studies evaluated population health outcomes, 13 evaluated the experience of care, and 7 evaluated utilization and cost outcomes. 12 studies utilized a survey or interview-based methodology, while the other 3 utilized quantitative data obtained through a retrospective chart review.

Conclusions: The transition from pediatric to adult healthcare for patients with spina bifida is complex and requires input from everyone involved. Most transition programs are characterized by common themes: patients seek increased independence and more self-management of their own condition, and overall satisfaction with transition programs is usually high. Not all transition programs in this review improved patient outcomes following implementation of the program, indicating areas for improvement.

10th Annual Rare Disease Symposium | October 18, 2024

RDS10 A de novo Variant in PAK2 Detected in an Individual with Knobloch Type 2 Syndrome.

Elizabeth A. Werren1, Louisa Kalsner2,3,4, Jessica Ewald1, Michael Peracchio3, *Cameron King5, Purva Vats1, Peter A. Audano1, Peter N. Robinson1, Mark D. Adams1, Melissa A. Kelly1, Adam P. Matson2,6,7 *Presenting author 1. The Jackson Laboratory for Genomic Medicine, Farmington, CT 2. Department of Pediatrics, University of Connecticut School of Medicine 3. Division of Genetics Connecticut Children's Medical Center, Hartford, CT 4. Division of Neurology, Connecticut Children's Medical Center, Hartford, CT 5. Department of Research Operations, Connecticut Children's Medical Center, Hartford, CT 6. Division of Neonatology, Connecticut Children's Medical Center, Hartford, CT 7.

Department of Immunology, UConn Health, Farmington, CT Background: P21-activated kinase 2 (PAK2) is a serine/threonine kinase essential for a variety of cellular processes including signal transduction, cellular survival, proliferation, and migration. A recent report proposed monoallelic PAK2 variants cause Knobloch syndrome type 2 (KNO2)—a developmental disorder primarily characterized by ocular anomalies.

Methods: An individual with congenital retinal detachment, hypotonia, global developmental delay, cerebral ventriculomegaly, failure to thrive, pyloric stenosis, persistent feeding intolerance, patent ductus arteriosus, and mild dysmorphisms was enrolled in a collaborative study to explore the ability whole genome sequencing (WGS) to identify genetic disorders in pediatric patients. Prior clinical testing, including exome sequencing and chromosomal microarray, was negative.

Research trio long-read (LR)-WGS and singleton short-read (SR)-WGS were performed at The Jackson Laboratory for Genomic Medicine. Variant confirmation was performed by review of prior exome sequencing at GeneDx. Results: A novel de novo heterozygous variant was discovered in PAK2 (c.1273G>A, p.(D425N)).

The p.(D425N) variant lies within the protein kinase domain and is predicted to be functionally damaging by in silico analysis. Given the phenotypic overlap with previously published KNO2 cases, PAK2 c.1273G>A, p.(D425N) was identified as a candidate pathogenic variant in KNO2.

Conclusion: Previous clinical genetic testing did not report this variant due to unknown relevance of PAK2 variants at the time of testing, highlighting the importance of reanalysis. Our findings also substantiate the candidacy of PAK2 variants in KNO2 and expand the KNO2 clinical spectrum.

10th Annual Rare Disease Symposium | October 18, 2024

RDS11 2024 YOUNG INVESTIGATOR AWARD Dupilumab improves histologic manifestations of eosinophilic esophagitis in a real world cohort of pediatric patients.

Jing Marrero, MD, MPH1,3, *Emanuela Pinci, BS1,2, Jeffrey S. Hyams, MD1,3, Michael Brimacombe, PhD1,3, Fabiola Balarezo, MD4 *Presenting author 1. Connecticut Children’s, Hartford, CT 2. Quinnipiac University School of Health Sciences, Hamden, CT 3. University of Connecticut School of Medicine, Farmington, CT 4. Hartford Hospital Department of Anatomy & Clinical Pathology, Hartford, CT Background: Eosinophilic esophagitis (EoE) is a chronic inflammatory disease diagnosed by the presence of ≥15 eos/hpf on esophageal biopsy. The EoE histologic scoring system (EoEHSS) is a validated index, accounting for peak eosinophil count (PEC) and seven additional features characteristic of EoE. This comprehensive scoring system accounts for both the severity (grade) and extent (stage) of these abnormalities. Dupilumab, an anti – IL-4receptor antagonist, is the first medication approved for the treatment of EoE and is effective in reducing EoEHSS scores in clinical trials. We sought to evaluate the efficacy of dupilumab in improving histologic manifestations in a real-world cohort of pediatric patients at our center.

Methods: Patients with EoE who failed previous dietary, acid suppression, or corticosteroid treatments and were being started on dupilumab were enrolled starting December 2023. Patients had a baseline endoscopy and after receiving 12 weeks of weekly subcutaneous dupilumab, underwent repeat endoscopy to evaluate response. All pre- and post-dupilumab esophageal biopsies were reviewed by a single pathologist (FB) and scored using EoEHSS. Grade and stage scores for each feature ranged from 0 (normal) to 3 (maximum change) with total scores divided by possible maximum, resulting in final scores ranging from 0 to 1.

Results: Ten patients (mean age 16.5years, 70% male) received dupilumab. The median EoEHSS grade score improved from 0.5 to 0.08 (p<0.001) and median stage score improved from 0.46 to 0.07 (p<0.001). All patients had improvement in their PEC with 90% having ≥ 50% decrease in eos/hpf and 70% having PEC <15 eos/hpf. 30% of patients had no eosinophils in their postdupilumab biopsies.

Conclusion/Significance: In our real-world cohort of 10 pediatric patients on dupilumab, all had significant improvement in their EoEHSS following a 12-week course. This medication is effective in improving the severity and extent of mucosal inflammation.

10th Annual Rare Disease Symposium | October 18, 2024

RDS12 Epigenetic regulator, DOT1L, contributes to disease severity and neuropathology in Globoid Cell Leukodystrophy Erica R. Lavoie1, Jake T. Lustig1, Pearl A. Sutter1, Zaenab Dhari1,2,3, Evan T. Lombardo1, Rosa M. Guzzo1, Stephen J. Crocker1 1. Department of Neuroscience, University of Connecticut School of Medicine, Farmington, CT 2.

Trinity Health of New England, Hartford, CT 3. Frank Netter School of Medicine, Quinnipiac University, North Haven, CT Background: Globoid cell leukodystrophy (GLD) is a fatal demyelinating disease identified by a loss of function mutation in the gene encoding galactosylceramidase (galc). Galc mutations in GLD result in the accumulation of psychosine, a lipid thought to underlie GLD pathology. DOT1L is a histone methyltransferase that regulates the expression of various proinflammatory genes. Our lab has previously determined by immunohistochemistry that DOT1L activity is high in CD11b+ cells in the brains of Twitcher (Twi) mice, an authentic mouse model of GLD. Single-cell RNA sequencing of microglia from Twi brains determined that approximately one-third of all differentially expressed genes were known to be regulated by DOT1L. Thus, we hypothesize that DOT1L activity in the Twi mouse brain contributes to neuroinflammation and neuropathology. We investigated, “Does modulation of DOT1L activity by a known DOT1L inhibitor, EPZ5676, impact disease severity, neuropathology, and neuroinflammation in the Twi mouse?”

Methods: Daily EPZ5676 (10 mg/kg, i.p.) or vehicle (1:8 dilution of ethanol in PBS) injections were given to Twi mice (n=3 per group) beginning on postnatal (p) day 14 (p14) to p28. Western blotting for a histone H3 methylation mark (H3K79me2) of DOT1L activity was performed on hemibrains to verify the efficacy of EPZ5676 on DOT1L activity. Transmission electron microscopy on myelinated axons for g-ratio analysis was used to evaluate CNS myelination.

Results: Western blotting for H3K79me2 verified that EPZ5676 effectively reduced DOT1L activity in the brain. Treated mice experienced a slightly delayed onset of disease symptoms. Treated Twi mice also exhibited more weight gain than their vehicle-treated counterparts. Twi mice treated with EPZ5676 had significantly reduced CNS demyelination, as measured by lower g-ratio of myelinated axons in the corpus callosum.

Conclusions: These data indicate that elevated DOT1L activity in the Twi brain contributes to neuropathology, as inhibition reduced CNS demyelination. This was also associated with slightly delayed onset of symptoms and improved weight gain. These preliminary data, while underpowered for valid conclusions at this time, support further investigation into the role of DOT1L in this disease. Ongoing studies are investigating DOT1L transcriptional networks in microglia to define how this enzyme influences cell behavior and disease. Ongoing studies are challenging DOT1L in Twi mice by using transgenic mouse lines.

10th Annual Rare Disease Symposium | October 18, 2024

RDS13 Seizing an Opportunity: Turning an Anatomy Lesson into Interprofessional Learning about Rare Diseases.

Nora Singh BA1 Frank H. Netter MD School of Medicine, Quinnipiac University Caitlin L. Gallagher BS1, James Graham BS1, John G. Angeles BS1, Romy Alame BA2, Jacqueline Schoer BA2 Danielle Heady BS2, Tania Grgurich DHSc, MHS, RT(R)(M)(CT), ARRT3, Maureen E. Helgren PhD1 1. Frank H. Netter MD School of Medicine, Quinnipiac University North Haven, CT 2. Pathologists’ Assistant Program School of Health Sciences, Quinnipiac University 3. Diagnostic Imaging School of Health Sciences, Quinnipiac University Background: Rare diseases (RD) present challenges to medical education due to their large number (7000), phenotypic diversity, and limited evidence-based data on diagnosis and treatment.

1 in 10 people in the U.S. have a RD and collectively form a significant patient population, yet medical expertise remains limited. Educational programs must equip students with the knowledge and skills to address the needs of RD patients. While covering the full scope of RD in health curricula is difficult, it is crucial to offer experiences that highlight the journey from diagnosis to lifetime management of a RD. The Frank H. Netter MD School of Medicine (Netter SOM) integrated a 'teachable moment' into its anatomy curriculum, demonstrating a multifaceted approach to addressing RD patient care.

Approach: Full body dissection is a standard component of the curriculum at the Netter SOM, with four students per anatomical donor. During the anatomy lab dissection, one group of students discovered multiple masses in various locations (skin, subcutaneous tissue, lung, liver, kidney) in a donor whose cause of death was neuroendocrine carcinoma with metastases. Within and outside of scheduled lab sessions, the team collaborated with students in the diagnostic imaging and pathologists’ assistant programs to expand their understanding of this rare cancer. In addition to research on neuroendocrine carcinoma, computed tomography (CT) scan and histopathologic processing of selected tissue samples were obtained and discussed amongst the interprofessional team.

Key Findings: With the opportunity to learn through anatomical donation, students questioned the lived experiences of a person with neuroendocrine carcinoma. After learning that this is a rare cancer, we reflected on the challenges of people living with RD. We learned about disciplinespecific roles and responsibilities and the value of teamwork through our collaboration with different healthcare professionals. Most relevant is the lesson on how to gain the knowledge and skills required to better serve patients with RD. Conclusion: An interprofessional approach reinforced anatomical and pathological knowledge and mirrored the importance of a holistic view and team-based care in complex cases of RD. By promoting interdisciplinary collaboration, the curriculum equips future providers to confidently approach rare and complex conditions with both medical expertise and a humanistic perspective.

10th Annual Rare Disease Symposium | October 18, 2024

RDS14 Perithyroidal Lipoma: Case Report in an Adolescent Male with Euthyroid Hashimoto’s Thyroiditis.

Caroline Figgie, MD1,5, James Healy, MD, MHS2, Lindsay Griffin, MD3, Ron Araneta III, MD4, Nordie Bilbao, MD1 1. Connecticut Children's, Department of Endocrinology, Farmington, CT 2. Connecticut Children's, Department of Pediatric Surgery, Hartford, CT 3. Connecticut Children's, Department of Radiology, Hartford, CT 4. Connecticut Children's, Department of Pathology, Hartford, CT 5.

University of Connecticut School of Medicine, Farmington, CT Background: A small percentage of lipomas are found in the head/neck region, more so in the posterior neck. Anterior neck lipomas are rare, and thyrolipomas (within the thyroid gland), are even rarer, with few pediatric cases reported in the literature. These lipomas can mimic thyroid nodules, often leading to thyroidectomy. When certain of the diagnosis, lipoma enucleation allows for avoidance of thyroidectomy. We present a perithyroidal lipoma in a 13-year-old male with euthyroid Hashimoto’s thyroiditis.

Methods: A 13-year-old male with positive thyroid antibodies and normal thyroid function tests (TFTs) found during evaluation for short stature at 10-years-of-age, later developed gradual thyroid enlargement at 12-years-old, with still normal TFTs. Exam revealed a palpable 2x2cm non-tender nodule on the right thyroid lobe. Ultrasound demonstrated asymmetric enlargement of the right lobe with 2 nodules (>1cm). Fine needle aspiration (FNA) of the nodules was ordered. Repeat ultrasound prior to FNA indicated an echogenic U-shaped structure around the thyroid cartilage arising from the right thyroid lobe, rather than 2 separate nodules previously described. Computed tomography (CT) of the neck with IV contrast confirmed a U-shaped lesion in the right thyroid lobe containing mostly fat, herniating around the thyroid cartilage.

Results: The patient underwent enucleation of the lipoma embedded in the right lobe, without lobectomy. Pathology examination showed a lipomatous neoplasm with associated skeletal muscle fibers and hyaline cartilage, but no thyroid parenchyma and negative thyroglobulin staining, suggests an intramuscular lipoma of a perithyroidal skeletal muscle, secondarily compressing the thyroid. Genetic testing was negative for MDM2 gene amplification, excluding well-differentiated liposarcoma. PTEN immunohistochemistry staining revealed intact expression without loss, excluding PTEN hamartoma tumor syndrome. The postoperative period was uneventful.

Conclusion: Anterior neck lipomas and thyrolipomas are rare but important differential diagnoses to consider in the case of already uncommon pediatric thyroid nodules. Due to these rare mimics, evaluation of such nodules is significantly improved when done in a multidisciplinary setting with a team experienced in the care of thyroid disease. In our case, this allowed us to establish the alternative diagnosis through use of more detailed imaging modalities (CT), without requiring the patient to undergo FNA first.

10th Annual Rare Disease Symposium | October 18, 2024

RDS15 Enhancing Diversity in Clinical Trials Enrollment: A Cultural Awareness Training for Coordinators and Research Staff.

Julieta Bonvin-Sallago, MD1, 2 Carolyn M. Macica, PhD1, 2, 3, Alison Oville A, BA1,Ferreira M1 1. Connecticut Children's Research Institute; 2. University of Connecticut School of Medicine; 3.

Frank H. Netter School MD of Medicine Background: The growing diversity of the U.S. population1 underscores the heightened need for cultural awareness training among clinical staff. Given the broader goal of reducing health disparities and improving patient outcomes with novel therapeutics for rare disorders, the importance of enhanced cultural awareness training for clinical trials becomes even more significant. Research Question: How can targeted cultural awareness training for research staff improve the enrollment of diverse populations in clinical trials within the clinical setting?

Methods: From 3/24-9/24, the clinical trial team at Connecticut Children's received an intervention of 5 didactic sessions with the following learning objectives: Session 1: Recognize the importance of cultural competence in healthcare; Identify barriers to effective healthcare delivery in diverse populations; Apply cross-cultural communication strategies; Develop strategies to improve health equity Session 2: Recognize the concept of cultural competence in healthcare; Increase awareness of health disparities faced by individuals with disabilities; Apply person-first language in clinical settings; Enhance communication and interaction skills with persons with disabilities.

Session 3: Define cultural competence in healthcare; Recognize the importance of intersectionality in patient care; Enhance communication with diverse patient populations; Evaluate the significance of using correct language and terminology Session 4: Recognize the significance of health literacy in patient interactions; Apply inclusive language and pronoun usage; Recognize and address intersectionality in patient care; Incorporate best practices in gender-inclusive communication Session 5: Recognize the benefits of intersectional healthcare; Improve communication in clinical research and healthcare; Develop and practice key communication skills; Apply the Ask-Tell-Ask communication model. The sessions were beta-tested on a population (n=14) who scored in the range of Very High (11/14), High (2/14) and Mid (1/14) on a Cultural Diversity Awareness Questionnaire. A questionnaire was also administered before and after each session to assess learning.

Results: Despite the pilot population’s high level of cultural awareness and a decrease in enrollment over time, an 80% increase in competency was reported. Our next steps will be to test the cultural awareness didactic sessions on a population with lower cultural diversity awareness to evaluate the effectiveness of the training in enhancing understanding and improving the enrollment of diverse populations in clinical trials. To increase engagement, we plan to introduce program scheduling flexibility and include case-based interactive examples.

Conclusion: Cultural awareness training can be employed as a strategy to successfully increase enrollment diversity into clinical trials for rare disorders.

1.

Workbook: Racial and Ethnic Diversity in the United States: 2010 and 2020 Census (tableau.com).

10th Annual Rare Disease Symposium | October 18, 2024

RDS16 PULLANO SCHOLARSHIP (SUMMER RESEARCH) AWARD Revision and Adaptation of a Pediatric-to-Adult Care Transition Toolkit for X-Linked Hypophosphatemia.

Amber Parson, BA , Carolyn Macica, PhD1,2 1Quinnipiac University Frank H. Netter MD School of Medicine, North Haven, CT 2Connecticut Children’s Research Institute, Hartford, CT Background: X-linked hypophosphatemia (XLH) is a rare, progressive genetic phosphate-wasting disorder that has distinctive clinical features in children and adults. Without an evidence-based healthcare transition, patients are susceptible to increased disease activity and adverse outcomes which can reduce gains of prior care. Structured transition programs, such as the nationally funded Got Transition model and Six Core Elements of Health Care Transition (HCT), are crucial for preparing patients for shifts in care. To meet the specific needs of transition care in XLH, we aim to revise the existing XLH toolkit to incorporate results from a gap-analysis between the toolkit, Six Core Elements of HCT, and 2023 XLH Transition of Care Advisory Board recommendations. We plan to create a companion website allowing patients, family members, and clinicians to access the toolkit via an interactive mobile website platform.

Methods: Toolkit adaptation will include a comprehensive evaluation of the Six Core Elements of HCT and consultations with XLH patients and providers. A prototype website will be created by the research team using an institutional license for Microsoft Visual Studio. Post-development, the website will undergo beta-testing with a select group of stakeholders to evaluate usability, content, and accessibility.

Results: To date, we have completed: 1) website content development and iterative review based on expert consultation and a gap analysis of the existing toolkit compared to the Got Transition model of HCT, 2) development and creation of a functioning website prototype 3) creation of survey items and interview prompts for website beta-testing. Next steps include beta-testing by XLH patients and clinicians who contributed to the initial development of the XLH Transitions Toolkit.

Conclusion(s): After its adaptation, the XLH Transitions Toolkit will be more engaging and effective for young individuals with XLH, better aligned with recommended HCT guidelines, and reduce adverse outcomes associated with ineffective HCTs.

10th Annual Rare Disease Symposium | October 18, 2024

RDS17 Look-Alike: A Novel Tool Utilizing Epic’s Cosmos Dataset to Accelerate Rare Disease Diagnosis.

Timothy A. Schubarg1, Emerson Briggs2, and Carolyn M. Macica, PhD3,4 1. Quinnipiac University Department of Biological Sciences 2. University of Chicago 3. Frank H. Netter MD School of Medicine 4. Connecticut Children’s Research Institute Background: Rare genetic disorders encapsulate a large category of varying conditions, from mild to severe, that negatively impact the quality of life for thousands of patients across the US. Diagnosis for rare disorders is often delayed or inaccurate. A tool known as Look-Alike is a new feature of the Epic Cosmos dataset that has been developed to mitigate delayed or inaccurate rare disease diagnoses1. The Look-Alike tool utilizes Epic's Cosmos dataset of de-identified information from millions of patients and patient encounters across the network of Epic-affiliated hospitals and their physicians worldwide. Physicians can search the dataset to find and connect with others who have treated patients with similar symptoms. Additionally, doctors who diagnose rare conditions can mark their cases in the Cosmos dataset, allowing others to consult them when they face similar cases. We aimed to determine if the Look-Alike framework offered advantages compared to other diagnostic approaches for rare diseases.

Methods: We performed a literature review and compared the Look-Alike framework to other methods used to reduce diagnostic time such as genetic testing, AI-based models, and non-DNA based tests.

Results: We found substantial evidence for the effectiveness of connecting providers with similar patients2, implementing clinical genetic testing3, and interdisciplinary collaborations4. Since Look-Alike seeks to combine these main concentrations into one hub, it has the potential to drastically shorten diagnosis time for patients and for physicians to consult with content experts.

Conclusion: Look-Alike is still in its infancy and spreading awareness of this tool can help network more physicians with different treatment backgrounds, and thus improve the quality of information available to everyone.

10th Annual Rare Disease Symposium | October 18, 2024