eXtraordinarY Kids Program

• Intro from Dr. T
• Giving Back
• eXtraordinarY Babies Study: Updates for 2022-2023
• New XXYY Study Project
• Turner Syndrome Clinic Updates
• INSIGHTS Updates
• International X&Y Variations Conference
  
• Western Society for Pediatric Research Conference
• Team Member Highlights
• TRIXY Publications
• Additional NEW Publications
• Goodbye and Thanks to Dr. Rich Boada
• New Projects

Back to School time already! Time flies for sure, and each newsletter offers me opportunity to reflect on accomplishments and changes over the past 6-9 months, while also helping to set new goals (and renew previous goals with slow progress). Since the last newsletter, some of the negative impacts of COVID isolation became evident with challenges in social development, mental health and academics, and I'm grateful for all of the time our clinical teams spent working with kids and families to support and treat these challenges. While some of these negative effects aren't over, I feel optimistic as we finally start a "normal" school year that the dust is at least starting to settle to we can work to figure out next steps and move forward. We are definitely back to baseline levels of "busy", and it is great to see so many returning kids in person again and to welcome all our new families as well.

I'm also celebrating a big milestone this month - 15 years at Children's Hospital Colorado! It feels like yesterday and forever at the same time. The eXtraordinarY Kids Clinic started a few months after I came (and the eXtraOrdinary Turner Syndrome Clinic some years after that), so we will celebrate a big birthday for the clinic in early 2023.

There are many pieces of great news and updates related to research below, primarily with huge congratulations to Dr. Davis for some amazing awards and grant funding to continue to advance care for our eXtraOrdinarY Kids! Thanks again to all our families for their support and participation in our research and clinical programs. Sincerely, Nicole Tartaglia, MD "Dr. T"

It's my 15-Year work Birthday at Childen's Hospital Colorado! While our hospital is extremely supportive of our clinics and expertise, over 80% of the educational programs and clinical infrastructure of our eXtraOrdinarY Kids programs are supported by donations and family support. You can have a big impact celebrating my birthday and helping our eXtraOrdinarY Kids research and clinical program by making a donation! Many families tell us that while they cannot go back in time to change their own experiences of first hearing their child’s diagnosis or searching to understand what the diagnosis may mean for their child’s future, they have been supported by our team and are empowered to help change the future for other families by donating to our program. Families invested in giving impact their child’s future by helping to advance the science and care for children with X&Y variations. And donations to our program are tax deductible! Please join us in our shared goals and help celebrate my 15 Year Work Birthday by making a donation to our program.

Examples of projects that donations support:

• eXtraOrdinarY Kids Summer Research Internship Program stipends
• Journal article publication fees
• Conference presentation registration fees for students and trainees
• Research and clinical supplies and test kits
• Development of patient educational materials and printing for patients
• Much much more!
  

To make a donation for Dr. T's 15-Year Work Birthday and support future programs:

http://www.childrenscoloradofoundation.org/extraordinarykidsclinic

Thank you!

We recently reviewed news that we received funding from NIH for an additional year of the eXtraordinarY Babies Study through June 2023! This is great news and we have many updates and new plans for the following year described below. In October 2022, our grant requesting an additional 5 years of funding (July 2023-June 2028) will be reviewed. We are hopeful that this larger award will be funded and allow us to continue our important longitudinal research on the natural history of children with prenatal diagnoses of sex chromosome variations (SCVs).

The goals in the new grant include the following:

• to continue to study development of the eXtraordinarY Babies cohort into early school age years (6-12 years of age).
• to identify risk factors and predictors of positive and negative developmental and health outcomes.
• to develop evidence-based genetic counseling materials for families who have children with SCVs.

We will be able to give you an update on the review late this fall.

From now until June 2023, we will continue with telehealth study visits for all participants. Participants from the Nemours site will be contacted by the Denver team who will take over telehealth visits this year.

While most visits will be telehealth visits, the new funding has a small travel budget and we will invite some participants to be seen in-person for the important 36-month visit. These invitations will be made based on the need to have balanced data between study groups, and will mostly be limited to those with Trisomy X and XYY. We will also invite participants that live in the Denver area for in-person assessments.

Our research team has streamlined scheduling processes for telehealth visits to make it less complicated for everyone to schedule appointments. Here is a summary of the new plan for telehealth study visits:

1. You will receive an email when your child's study visit window is coming up

2. The email will contain links to complete the online questionnaires and surveys

3. When you have completed the surveys, you will receive another email with a link to select a time/date to schedule your 30 minute telehealth study visit with one of the study providers (Nicole Tartaglia, Shanlee Davis or Susan Howell)

4. During the telehealth study visit, your provider will review results of some of the surveys you completed, review health history, and answer questions

5. You will receive a report following the study visit that summarizes key results that you can keep for your files and share with others as you wish

We are VERY grateful for your time and contribution to the study, and we are working hard on publications to share results with the medical and family communities, and also working on other grants to keep this important project moving forward.

If you have any questions, please feel free to reach out to our AMAZING coordinators!

Mariah at mariah.brown2@childrenscolorado.org

We would also like to provide a link to our link to our public eXtraordinarY Babies Study Dashboard. It provides data on the participant enrollees and demographic backgrounds of our participants. Please check it out with the link below!

Link: https://redcap.ucdenver.edu/surveys/?__dashboard=MP8YY89AAYA

We are very excited to be working with The XXYY Project on a new and updated international study on XXYY syndrome. This study aims to learn more about medical problems and behavioral / mental health diagnoses and treatments throughout the lifespan.

Participation will include completion of questionnaires and surveys related to health/medical history, development/behaviors, and previous treatments. We want to invite XXYY guys of all ages and their families who have been part of previous studies to participate so we can obtain updates, and also hope to recruit up to 50 new XXYY kids, teens, or adults to join the study group.

We will combine new information collected with lots of information from the eXtraordinarY Kids Clinic to write new papers that will help guide medical screenings and treatment recommendations, and that will better describe the developmental and mental health features, and helpful treatments and supports for guys with XXYY.

If you are an XXYY family interested in participating in this study, please email us at extraordinarykidsclinic@childrenscolorado.org and we will get back to you with details for participation.

The Turner Syndrome Multidisciplinary Clinic saw a total of 107 girls last year, which is an all-time record! The graph below represents the number of new patient visits and follow-up visits since 2018 through 2021. Thank you to the families that have contributed!

Other updates to the clinic include the addition of our new cardiologist, Dr. Jessica Stansauk! We are excited to have her on the team. We are also in the process of developing multiple projects with the intention of providing better care for our girls. Currently, we are in the process of reviewing how the addition of our Ears, Nose and Throat and Audiology providers have aided our patients healthcare experience. More information to come!

The Inspiring New Science In Guiding Healthcare in Turner Syndrome (INSIGHTS) Registry recently celebrated hitting the 300 participant mark! The registry has enrolled 318 girls and women with Turner syndrome, including 123 at Children's Colorado. Participants are recruited from a total of eight (8) multidisciplinary clinics across the country (see map below), and two (2) more clinics are in the process of joining.

If you or your child are seen at one of the participating clinics and want to join the INSIGHTS registry, fill out the online consent form here!

We are honored to have been invited to play a key role in the upcoming international professional conference for X&Y variations that will be held in September 2022 in Leiden, the Netherlands. This conference will bring together invited clinicians and scientists from around the world to present research and allow collaborative discussions to advance care for X&Y conditions. Dr. Tartaglia was invited to be on the conference planning committee, and we are proud to have over a dozen different projects from our research team accepted for presentation at the conference. Check our next newsletter for highlights!

The WSPR is an organization that provides a forum for the presentation and dissemination of innovative ideas and research. The Society actively supports the development of future pediatric scientists and recognizes outstanding research and education in pediatrics through sponsored awards. Teams members of our eXtraordinarY Kids Program participated in the WSPR Conference in Carmel, California on 1/20/2022 - 1/22/2022. Below are our colleagues presentation outlines, mentored by Dr. Davis and Dr. T.

Presenting Author: Shanlee Davis, MD, PhD
Abstract Title: Stakeholder Engagement Efforts to Improve Diversity in Rare Disease

Session Name: Diversity, Equity, Inclusion I

Presenting Author: Shanlee Davis, MD, PhD

Abstract Title: Population-based Assessment of Cardiometabolic-Related Diagnoses in Youth with Klinefelter Syndrome: A PEDSnet Study
Session Name: Endocrinology and Metabolism II

Presenting Author: Megan Louderman, PsyD
Abstract Title: The Easy Baby: Exploring Temperament Profiles in Young Children with Prenatally Identified Sex Chromosome Trisomies
Session Name: Behavior and Development I

Presenting Author: Talia Thompson, PhD
Abstract Title: Educational Needs of Children with Chromosome Aneuploidies
Session Name: Behavior and Development I

Presenting Author: Jacqueline Nevarez, MS
Abstract Title: Low sensitivity of the Ages & Stages Questionnaires in Infants with Sex Chromosome Trisomy at 6 and 12 Months of Age
Session Name: Behavior and Development I

Presenting Author: Jennifer Rubin
Abstract Title: Expanding Behavioral Phenotypes in Sex Chromosome Trisomy with Parent Reported Character Strengths
Session Name: Behavior and Development II

In March of 2022, several members of our team attended the Annual Clinical Genetics Meeting hosted by the American College of Medical Genetics. We are excited to announce that Carly Peterson, a genetic counseling graduate student working with our eXtraordinarY Babies Study team, was honored to receive the Genetic Counseling Carolyn Mills Lovell award for her work with our study evaluating parental stress in the first year of life raising a child with a sex chromosome aneuploidy. She found that overall, parenting stress during the first year of life was LOWER than compared to the general population. She also found that higher levels of parenting stress was associated with parenting infants with multiple medical problems and single-parenting, among other findings. She was the first ever student to be given this prestigious award! We are so proud of her work and look forward to sharing her findings in a future publication. Congrats Carly!

We are thrilled to announce that Dr. Shanlee Davis is one of the 2022 Boettcher Foundation Webb-Waring biomedical research awardees! Dr. Davis’ research will study the role that fatty acid metabolism and mitochondrial oxidation play in the clinical manifestation and health consequences of Klinefelter Syndrome, investigating the use of a potential new therapy that targets the peroxisome proliferator-activated receptor alpha (PPAR-α) metabolic pathway. The Boettcher Foundation research award is the most prestigious biomedical research award in Colorado. We are so proud of this accomplishment and the publicity around this award is amazing for sex chromosome variation conditions. Congratulations Dr. Davis!

Christina Miller and Jillian Kirk are two genetic counseling student interns who joined our team in this past year. Please continue reading below to learn about their interests in research with the SCV population.

Christina is a genetic counseling student at the University of Colorado Anschutz campus. Genetic counseling is looking at individuals’ and families’ risks of being affected by a genetic condition and talking with them about what that means for their family. Christina is excited to be starting on a new project with Children's Hospital of Philadelphia called “Information needs in adolescents with differences of sex development (DSDs).” The goal of this project is to learn what information teens with DSDs feel is confusing or still unknown to them.

Jillian is a genetic counseling student at the University of Colorado. She graduated with a BS in Microbiology from the University of Massachusetts Amherst in 2016. During her undergraduate career, she assisted with research on honeybee viruses and served as a teaching assistant in the psychology department and medical microbiology laboratory. After graduation, she began working as a scribe in a developmental pediatrics clinic where she learned about the role of genetic counselors and fell in love with the profession. She currently aides our study through meticulous data entry and survey scoring.

Rich Boada, PhD has been a neuropsychologist with the eXtraordinarY Kids Clinic Team since 2008 and has provided countless evaluations of cognitive, learning, and executive functioning skills for our clinic. He has brought expertise and research in dyslexia/reading disabilities, ADHD, and executive functioning to our team, and has taught all of our team as well as countless students and trainees so much over the years. Rich was also bilingual and able to provide evaluations in Spanish, providing a unique service for Spanish-Speaking patients and helping families to advocate in the school systems. While he will be missed dearly in Colorado, we are not saying goodbye. He has accepted a faculty position at Kennedy Kreiger Institute in Baltimore, and we will continue to collaborate on research with Dr. Boada at his new position. Thank you Dr. Boada for all your time and commitment helping to build and grow our amazing eXtraordinarY Kids Program!

A message from The Netherlands to warmly thank you for your participation in the TRIXY Study!

With a team of researchers and clinicians, we conduct international research at the TRIXY Center of Expertise in Leiden (The Netherlands) into the early development of young children with an extra X or Y chromosome. The longitudinal TRIXY study focuses on neurodevelopmental vulnerabilities in young children with XXY, XXX and XYY, aged 1 to 6 years. The primary aim is understanding neurodevelopmental risks by focusing on three domains of development: understanding the social world (social cognition), acquisition and development of language and self-regulation (executive functioning).

We have worked closely together with Dr. Nicole Tartaglia at the Children's Hospital Colorado and a total of 60 families from the U.S.A. participated in the TRIXY study. Thank you for your enthusiasm for the study, for your willingness to travel and invest your time and effort in participating in research. Even in the global COVID pandemic, you were willing to cooperate online in the form of telephone interviews and filling out questionnaires, which we are grateful for.

Your contribution has resulted in a comprehensive insight at the early development of children with an extra X or Y chromosome. So far, the Leiden research group has written 15 scientific papers, some already published in international journals, others being currently considered for publication. Our research has identified profiles of strengths and challenges in early neurocognitive and neurobehavioral development that may help predict outcome of children later in life. Areas of vulnerability may also help to identify targets for (preventive) support and early intervention. It is important to take into account that vulnerabilities vary greatly per child, as individuals with an extra X or Y chromosome have unique and varying developmental pathways. These precursors also changed over time, even in the small age range between 1 and 6 years.

If you are interested in the published scientific papers, please do not hesitate to contact us at the following email address: trixy@fsw.leidenuniv.nl

We thank you for being committed to scientific research, aimed at improving the lives of children with X or Y chromosome variations.

See below in Additional Publications for highlights of two TRIXY papers!

Our research team and other have previously published findings that atopic conditions (allergies, eczema, asthma), feeding difficulties, and gastroesophageal reflux are more prevalent in children with SCAs. We conducted a retrospective chart review of 667 patients with SCA seen in our clinic to investigate the prevalence and presenting features of eosinophilic esophagitis (EoE). EoE is a disorder of the esophagus (the part of the digestive system that connects the mouth to the stomach) in which large numbers of a specific type of white blood cell called eosinophils are present in the esophagus. EoE can inflame or injure the esophageal tissue causing pain and making it difficult to swallow food. Our results showed that at least 4% of children with SCAs had a biopsy-confirmed diagnosis of EoE, which represents an odds ratio of 32 (95% CI 6–185) when compared to the prevalence rates reported in the general population. This means that children with SCA are at least 32 times more likely than the general population to have EOE. From these findings we suggest that routine screening for EoE symptoms may be warranted for individuals with SCA, especially those who have other atopic conditions. Some of the presenting symptoms are listed below. Dysphagia (difficulty swallowing or discomfort with swallowing) and reflux (heartburn) symptoms were the most common. If you have concerns your child might have EoE, then please share this information with your doctors for more evaluation.

Howell, S, Buchanan, C, Davis, S, Miyazawa, H, Furuta, GT, Tartaglia, NR, Nguyen, N. Eosinophilic Esophagitis in Individuals with Sex Chromosome Aneuploidies: Clinical Presentations and Management Implications. Molecular Genetics and Genomics Medicine. 2021 Dec; 9(12):e1833. PMID: 34738344; PMCID: PMC8683639.

LINK:https://www.researchgate.net/publication/355965315_Eosinophilic_esophagitis_in_individuals_with_sex_chromosome_aneuploidies_Clinical_presentations_and_management_implications

Students with sex chromosome aneuploidies (SCAs) are at increased risk for learning disabilities and often require individualized supports in the school setting. Parents of students with rare disorders such as SCA possess a unique understanding of their child’s educational experiences and play a crucial role in the development of successful school support plans. This international survey study aimed to inductively capture parent perspectives on educational needs and supports for students with SCAs. 305 parents of youth with SCAs provided free-text responses to open-ended questions about their child’s education. Analysis using a bioecological systems framework resulted in three overarching themes. Overall, parents identified multiple factors related to the SCA diagnosis that act as barriers to learning, a strong need for school-based social and emotional supports, and elusive or incomplete school support plans. Based on these findings, we recommend developing robust family-school partnerships, increased collaboration between the school and the child’s medical team, and acknowledgement of the significant role the genetic condition plays in the educational experiences of students with SCAs. Specific suggestions for school support plans for students with SCAs are explored, such as providing school-based behavioral health supports and explicit teaching of executive function strategies.

See the below table for some recommendations for providing support!

Thompson, T., Stinnett, N., Tartaglia, N., Davis, S., Janusz, J. ’I wish the school had a better understanding of the diagnosis’: Parent perspectives on educational needs for students with sex chromosome aneuploidies. Journal of Research Special Education Needs. 2022 April 22(2): 175-187. PMID: 35529320; PMCID: PMC9074887.

Previous research conducted with children and adolescents with sex chromosome trisomy (SCT), have suggested that these individuals show a higher percentage of psychosocial challenges, including difficulties in adaptive social functioning. In this study we wanted to investigate the impact of SCT on early social cognitive skills. We compared 105 children with SCT to 96 children without SCT, ranging in age from 1-7 years old. Our participants were recruited and assessed in the United States and the Netherlands. To measure our participants’ joint attention skills and abilities orienting to social interaction, we used an Eyetracking paradigm that followed our participants’ eye gaze patterns. Eyetracking results revealed that children with SCT, and aged 3 years or older, had less social orienting (looking toward faces versus objects) compared to the children without SCT. Since an impact of SCT on social cognitive abilities were found at an early age, there is a indication for the need to monitor and support early social cognition. Future research should explore the longitudinal trajectories of social development in order to evaluate the predictive relationships between early social cognition and outcomes later in life in terms of social functioning, as well as to develop interventions if this finding has meaningful implications for social functioning.

Bouw, N., Swaab, H., Tartaglia, N., & van Rijn, S. (2021, June). The impact of sex chromosome trisomies (XXX, XXY, XYY) on early social cognition: Social orienting, joint attention, and theory of mind. Archives of Clinical Neuropsychology, [published online ahead of print] acab042. doi:10.1093/arclin/acab042. PMID: 34101798. https://doi.org/10.1093/arclin/acab042

Children with sex chromosome trisomy (SCT) are at increased risk for developing language difficulties. Earlier studies have reported that as many as 70-80% of individuals with SCT show some form of language difficulties. Language develops rapidly in the first years of life; knowledge about language development at an early age is needed. The present study aims to identify the language abilities of young children with SCT across multiple language domains and to identify the percentage of children that, according to clinical guidelines, have language difficulties. 103 children with SCT and 102 children without SCT, between the ages of 1-6-years, were included. Nonverbal communication, early vocabulary, semantic, syntax, and phonological skills were assessed. Language difficulties were already present in many 1-year-old children with SCT and across the age range in various language domains. Clinical classification showed that, depending on the assessed domain, 14.8-50.0% of the children scored below the 16th percentile. There was no difference of time of diagnosis, ascertainment bias, research site, nor SCT specific karyotype (XXX, XXY, XYY) on language outcomes. Overall, language difficulties can already be present in very young children with SCT within various language domains. These results highlight the importance of monitoring both receptive and expressive language development already at the earliest stages of nonverbal communication. Finally, as early language skills are the building blocks for later social communication, literacy, and self-expression, studies that investigate the effect of early interventions on later language outcomes are warranted.

Urbanus, E., Swaab, H., Tartaglia, N., Boada, R., & van Rijn, S. (2021, August). A cross sectional study of early language abilities in children with sex chromosome trisomy (XXY, XXX, XYY) aged 1-6 years. Child Neuropsychology, [published online ahead of print], 1-26. doi:10.1080/09297049.2021.1960959. PMID: 34346838.

LINK:https://pubmed.ncbi.nlm.nih.gov/34346838/https://pubmed.ncbi.nlm.nih.gov/34346838/

We have recently launched the first phases of the GALAXY (Generating Advancements through Longitudinal Analysis in X and Y Syndromes) Registry. This registry is funded by AXYS and aims to advance clinical research by collecting on-going, de-identified uniform information about individuals with X & Y variations. The purpose of this registry is to improve outcomes for individuals with X & Y variations by understanding the medical, social, and behavioral changes they experiences throughout their life. The information provided in the database allows professionals to measure clinical outcomes, gives insights for future research, and provides evidence based results to improve patient health care.

For more information about the GALAXY Registry, please click on the provided link: Shanlee Davis, MD & Susan Howell, CGC - Introduction to the new Clinical Registry, GALAXY - YouTube

To join the GALAXY cohort, fill out the online consent form here!

Some of our work studying gene expression and small molecules in the blood of boys with XXY has led us to think there is a difference in how fats are turned into energy. This can cause symptoms of feeling more tired, more difficulty doing prolonged exercise, and a tendency to store (rather than burn) fat. Dr. Shanlee Davis has received funding from the NIH, Boettcher Foundation, and local resources to study this more rigorously, and do a short trial of a common medication that may help the metabolic pathway that seems to not be working correctly.

We will be posting more information about this study in the near future for adolescents and young men with XXY and typical males without XXY as controls -- STAY TUNED!

Email: extraordinarykids@childrenscolorado.org

Web: www.extraordinarykidsclinic.org

Social Media: www.facebook.com/eXtraordinarYKids.org/

Donate: childrenscoloradofoundation.org/extraordinarykidsclinic