eXtraOrdinarY Kids Program

• Intro from Dr. T
• eXtraordinarY Babies Study Updates
• TESTO Study Completed
• Hometowns of Participants
• TRIXY Study Completed
• Research Opportunities
• INSIGHT Registry Update
• Highlights from AXYS Conference
• Focusing on Strengths instead of Weaknesses
• Other New Research Publications
• New Research Team Staff
• eXtraOrdinary Intern Program & Student Interns
• Goodbye to Tanea/Tanea Tanda Award (TTA)
• Winner of the TTA

Summer is here and hopefully everyone is enjoying some outdoor fun and a little extra time with all your eXtraOrdinarY Kids. We have lots of updates and news about our research projects and accomplishments since our newsletter. Some of our studies such as the TRIXY study (led by Dr. van Rijn) and the TESTO study (led by Dr. Davis) are wrapping up with some preliminary highlights below and much more to come. The eXtraordinarY Babies study is starting its final year of the current funding period. We are busy preparing the renewal application for which we are feeling positive and hopeful the NIH sees the value of continuing this project. Some of our first patients enrolled are already over 4 years old - it's been such a pleasure to see them grow from infancy, and we can't believe we are already talking about preschool and kindergarten! Dr. Davis also has 3 new publications on Turner syndrome, from medical features to transition services (see the summaries below), and is clearly showing her leadership nationally in TS care and research. I also want to highlight a publication I am especially proud of led by Dr. Talia Thompson that focuses on the strengths of kids with X&Y trisomies in the academic setting. Dr. Thompson brings expertise in positive psychology which has been lacking in our field, and it is refreshing to use new research methods that can focus on the strengths and skills of your eXtraOrdinarY Kids. I hope you enjoy reading about our progress, projects, and research team!

Sincerely, Dr. T

Our natural history study continues to gather valuable data on the early neurodevelopmental and medical features in children prenatally diagnosed with sex chromosome variations. Over 225 participants and over 650 research visits have been completed at the Colorado and Nemours Delaware/Philadelphia sites. Thank you to the families that participate!

*IMPORTANT UPDATES*

As many of you know, due to COVID-19 restrictions, the past year has provided challenges for conducting research studies. Although we were successful in collecting considerable portions of data through virtual visits, there still presents a gap in various areas of data we collect during in-person assessments. These areas include biospecimen samples, body composition analyses, developmental testing, etc. We are also unfortunately behind on follow-up visits and will need to prioritize our remaining funding resources for selective in-person visits. This means, at this time, we are prioritizing 36 month/3 year old visits as these visits provide the data needed for the main outcome for this funding cycle. Parents, if your child is due for a 36 month follow-up visit this year, please be sure to communicate with our research staff at extraordinarykids@cudenver.edu to let them know if you available to come in for this study visit.

We are hopeful to fit in other participant visits as well, but please be aware that you may be asked by our research staff to conduct your study visit virtually due to limited slots or high travel costs. For those families that want to come in-person for your visit, we will do our best to arrange this BUT there may be limited options for for scheduling and travel reimbursement. Our ability to accommodate will be dependent on where our budget stands. If you have resources to fund your own travel, please reach out as this may make additional visits possible for you and others! Thank you for you patience and understanding.

The TESTO study officially wrapped up with our final visit in May 2021. In total, we enrolled 71 wonderful infants with XXY from across the United States! The average age at enrollment was 66 days old. As you may recall, there were two treatment groups in the study: group A, who received 3 testosterone injections during the first 12 weeks, followed by 3 placebo (saline) injections during the second 12 weeks; and group B, who received 3 placebo injections followed by 3 testosterone injections. If you participated in the study, you will be receiving a letter with more detailed results and what treatment group your child was in. If you do not receive this by the end of August and would like to know this information, please contact us at testo@ucdenver.edu.

And now for a little teaser of our preliminary results!

We are still analyzing the results of all other outcomes. Our preliminary analysis shows that testosterone seems to have a positive impact on body fat percentage. However, so far it has not revealed major differences in developmental outcomes.

We hope you found your participation in the TESTO study as meaningful as we have. We will have the full, unblinded analysis completed soon, so stay tuned! On behalf of our entire team, we sincerely thank you for your contribution to our research. We could not have done it without you!

We are incredibly GRATEFUL for the families located all over the nation who dedicate their time and contribute to our research studies.

The eXtraordinarY Kids Clinic was the U.S. site for the TRIXY study (TRIsomy of the X and Y chromosomes) led by Dr. Sophie van Rijn at Leiden University in the Netherlands. It was a fantastic international collaboration, and we are grateful to the families who participated in this study. The goal of the study was to evaluate features of X&Y trisomies in children, younger than 6 years of age, to determine if and when early behavioral features emerge that we know can be seen in older ages. Two papers have been published so far, with many more to come. It has been such a pleasure to collaborate with the Leiden team!

The first paper looked at early social skills using eye tracking technology, which compared how much time TRIXY kids spent looking at social aspects of a video compared to controls. It also looked at the emergence of a skill called Theory of Mind, which is when kids start to demonstrate that they can take the perspective of others in different situations. Overall, results showed that the TRIXY group had more difficulties with social orienting and Theory of Mind compared to controls. However, there was a lot of variability between participants and only 25% of the TRIXY group had impaired Theory of Mind. These results are important because they show that some difficulties in early social skills can be seen from a young age, and strategies to build these skills from early childhood should be studies to see if they may improve later social skills.

Bouw N, Swaab H, Tartaglia N, van Rijn S. The Impact of Sex Chromosome Trisomies (XXX, XXY, XYY) on Early Social Cognition: Social Orienting, Joint Attention, and Theory of Mind. Arch Clin Neuropsychol. 2021 Jun 9:acab042. doi: 10.1093/arclin/acab042. Epub ahead of print. PMID: 34101798.

There is a known risk for ADHD in X&Y variations, and the second paper looked at early behaviors associated with attentional disorders in young children generally much too young for a formal diagnosis of ADHD. Results showed that challenges with attention span were seen in all trisomy conditions (XXX, XXY, and XYY), however boys with XYY also showed more hyperactivity and impulsivity symptoms. The attention difficulties became more pronounced with increasing age as well. As with other studies, there was a lot of variability within the groups, and only 24% of the TRIXY children showed ADHD symptoms that were at a clinical level.

Kuiper K, Swaab H, Tartaglia N, van Rijn S. Early developmental impact of sex chromosome trisomies on attention deficit-hyperactivity disorder symptomology in young children. Am J Med Genet A. 2021 Jul 8. doi: 10.1002/ajmg.a.62418. Epub ahead of print. PMID: 34240550.

Perkin Elmer Study

As you know, the eXtraOrdinarY Kids Clinic is dedicated to helping all individuals with X&Y Variations. We have recently been asked to help the company, PerkinElmer, (they make medical tests) develop a new test to diagnose X&Y Variations before birth. The hope is that by helping parents learn the diagnosis of their baby before birth, they can best advocate for his or her needs starting in infancy by seeking appropriate medical care and early intervention therapies if needed.

We need your help! Adults with X&Y Variations can help by donating blood needed for this important research to develop this new test. If you are interested in helping, PerkinElmer would send a licensed phlebotomist (person who is trained to draw blood) to your home to collect 10 tubes of blood from you (this is 1/5 of the amount given during a regular Red Cross blood donation). In exchange for your time and generosity, PerkinElmer will send you a $200 Amazon gift card.

Please Note: You must be over 18 years of age, live in the U.S.A., be medically able to give this amount of blood and have a lab report diagnosing you with an X&Y Variation in order to be eligible to participate. You will also need to sign an informed consent form.

For more information, Sign-Up here: PerkinElmer Research Study (google.com)

If you have questions or would like to learn more, please email Vanadis.research@perkinelmer.com.

GALAXY Registry

We are delighted to announce the upcoming launch 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 deidentified uniform information about individuals with X & Y variations. The purpose of this registry is to improve outcomes for X & Y variation individuals by understanding the medical, social, and behavioral changes they experiences throughout a lifespan. The collective information provided in the database allows professionals to measure clinical outcomes, design future research for clinical trials, and provides evidence based results to improve patient health care and treatment. We will send further details about participation as soon as it is up and running.

Also, showcase your creativity and artistic talents by participating in the GALAXY LOGO contest. Submit ideas for the study logo (or any other questions) to galaxy@ucdenver.edu.

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

The INSIGHT Registry is a multi-institutional collaborative research registry, partnered with Turner Syndrome Global Alliance, that collects patient data used to learn more about Turner Syndrome (TS). In developing this large dataset, there is the ability to create more interest and opportunities in funding research for girls with TS. Recruitment for this registry is making headway! As of now, we have 6 sites actively enrolling. Check out the recruitment numbers below, 116 in total from our active sites! If you are interested in joining the registry or would like more information, please sign-up here: http://tsgalliance.org/research/the-insights-registry-for-research-enroll-now/

The eXtraordinarY Kids team was honored to participate in the AXYS 2021 Virtual Families Conference. Team members gave the following presentations:

Dr. T

Translating Research Findings into Helpful Information for Parents and Caretakers

eXtraordinarY Babies

Dr. Davis

What is Testosterone? What is TRT?

Fertility and Ovary Function in Trisomy X

Infant Testosterone studies

Dr. Thompson

Early Intervention for Young Children with X & Y Variations - Dr. Talia Thompson

Collaborations

Introduction to the new Clinical Registry, GALAXY (Generating Advancements through Longitudinal Analysis in X and Y syndromes) - Dr. Davis & Susan Howell

Can We Talk? Confabulations: When your child does not tell the truth - Erin Frith & Dr. Thompson

There were also great talks on preliminary research findings from the TRIXY study led by the expert team at Leiden University in the Netherlands led by Dr. Sophie van Rijn and Nienke Bouw, and many of our U.S. babies participated in this study. There are also research and clinical talks as well as many other experts from the AXYS Clinics and Research Consortium (ACRC) such as Drs. Alan Rogol, David Hong, Armin Raznahan, Alan Reiss, Lilian Cohen, and many more….

Videos from the conference will be posted to the AXYS YouTube channel sometime in August 2021. Please visit https://www.youtube.com/channel/UC_68UQ9Z29PUBGYDfbsQBNg for videos from past webinars and conferences – the 2021 conference videos will be posted soon!

We love working with our awesome patients and see so many strengths and so much potential in all of them. However, research papers typically focus on the challenges we treat, and the many strengths and positive aspects don't receive enough attention. Dr. Talia Thompson has been a shining star on our team and brings with her expertise in the field of positive psychology - focusing instead on the positive aspects of different populations instead of just the negatives. He we present results of the first study (of many to come) celebrating strengths in our eXtraOrdinarY Kids, with this paper specifically focused on strengths in the school setting.

Academic & Character Strengths in Students with Sex Chromosome Aneuplodies

This paper focuses on the many strengths of children with X&Y chromosome variations in the academic setting. 377 parents of children age 3-21 responded to a survey asking them to describe their child’s strengths in school settings. Parents described Social Strengths, such as extraordinary kindness and an eagerness to please teachers and classmates. Assets for Learning included relative strengths in STEM coursework, creative thinkers, hardworking students, and a love for learning. There were overlapping strengths including reports of perseverance and love of learning for all three conditions. Parents of children with extra X chromosomes (XXY, XXX) reported strengths in kindness, and those with an additional Y chromosome (XYY) were more likely to report strengths in curiosity, humor, and teamwork. Results show that despite known risks for academic difficulties, children with X & Y variations possess many assets that can help them succeed in school and life. Recognition of positive traits has the potential to enlighten educators and guide research aimed at developing motivating and strengths-based interventions to optimize outcomes and ameliorate risks for educational and psychosocial problems.

Thompson, T., Davis, S., Takamatsu, S., Howell, S., Tartaglia, N., (2021). Exploring academic and character strengths in students with sex chromosome aneuploidies. Journal of Positive School Psychology. https://journalppw.com/index.php/JPPW/article/view/262/100

Publications on Turner Syndrome

1) Neurodevelopmental and Mental Health Screening for Patients with Turner Syndrome

The International Turner syndrome (TS) Clinical Practice Guidelines recommends for girls with TS to receive appropriate neurodevelopmental and mental health screening through their pediatric endocrinologists as these girls develop into adulthood. Through an electronic survey, we wanted to access pediatric endocrinologists’ screening practices for girls with TS to see if these two health assessments were being implemented. 124 surveys on screening practices were completed by Pediatric Endocrine Society members who provide care for girls with TS. Findings suggested only 25% of providers currently perform both neurodevelopmental or mental health screenings for TS patients, which conveys that there is a large variability in care practices provided across the country. Other results revealed that more than 93% of these providers would be interested in implementing a brief screening tool for TS patients in their clinical practice. Given almost all girls with a TS diagnosis receive care from pediatric endocrinologists, at least annually, this may be an effective method to increase the proportion of girls with TS who receive recommended screenings.

Davis SM, Crerand C, Hutaff-Lee C, Thompson T, Tishelman A, Samara O, Umbaugh H, Nahata L, Kremen J. Neurodevelopmental and Mental Health Screening for Patients with Turner Syndrome in Pediatric Endocrine Clinics: Results of a Pediatric Endocrine Society Survey, Hormone Research in Pediatrics, 2020;93(11-12):643-650.

https://pubmed.ncbi.nlm.nih.gov/33915553/

2) Individuals with Mosaic Monosomy X with Y Chromosome Material & Genital Phenotype

Individuals mosaic for monosomy X and a cell line with Y chromosome material can have genitalia that appear characteristically female (typical diagnosed as Turner syndrome), male, or ambiguous (mixed gonad development). There is limited information on whether medical and neurodevelopmental risks are similar among individuals with monosomy X and Y chromosome material across genital characteristics. We wanted to compare features between those with monosomy X and Y material with male/ambiguous genitalia to those with typical female genitalia. Medical records review of 76 patients from two large U.S. pediatric centers showed that the male/ambiguous genitalia group was just as likely to have congenital heart disease, autoimmune disease, and neurodevelopmental disorders as those with female genitalia. We also found that clinical management differed for patients that had male/ambiguous genitalia compared to individuals with Turner syndrome. These findings suggest that clinical management should be based on the presence of a monosomy X cell line rather ton the presentation of genitalia.

Guzewicz L*, Howell S, Crerand C, Umbaugh H, Nokoff N, Barker J, Davis S, Clinical Phenotype and Management of Individuals with Mosaic Monosomy X with Y Chromosome Material Stratified by Genital Phenotype, American Journal of Medical Genetics, 2021 May, 195(5):1437-1447. PMID 33616298.

https://onlinelibrary.wiley.com/doi/full/10.1002/ajmg.a.62127

3) Transition-Related Discussions Among Adolescent Females with Turner Syndrome

The transition from adolescence to adulthood is challenging for many individuals with TS. This study looked at current transition practices among adolescents with TS. We reviewed 112 medical charts of patients with TS from 12-25 years of age. The medical documents contained transition-related discussions and transition readiness assessment tools (i.e. questionnaires). Results showed that only 22% of TS patients had documented discussions regarding to transition to adult care. Also, this study found no evidence of a TS-specific transition assessment tool created by the Endocrine Society being used in clinical practice. The topics most frequently discussed were estrogen treatment and cardiovascular health. Other transition-related discussions regarding reproductive, lifestyle, and psychosocial counseling occurred for less than half the patients. In summary, transition-related discussions are not consistently occurring in adolescents with TS as recommended. To improve transition-related care, we recommend development and implementation of a standard transition process coordinating efforts from multiple specialists and beginning in early adolescence.

Patel N, Davis S, Nahata L. Transition-related discussions among adolescent females with Turner syndrome: Current practices and associated factors, Endocrine Practice, 2021 Jan, 27(1):56-62. PMID 33475502.

Publication on Klinefelter Syndrome

1) Cortical bone Mass is Low in Boys with Klinefelter Syndrome and Improves with Oxandrolone

Males with Klinefelter syndrome (KS) are affected with hypogonadism, which results in increased risk for osteoporosis and bone fractures. Our research investigated the effects of androgen treatment on bone mass measured by X-rays in children with KS. We conducted a double-blind, placebo-controlled trial of oxandrolone (OX) (a weak androgen) versus placebo for a two-year duration on 40 boys with KS, ages 4-12 years. Results documented lower cortical bone mass at baseline, verifying that low bone mass is present in these young boys. Results also showed an improvement in bone mass in the boys treated with OX compared to placebo. These findings support the need for further study of the role of genetics and androgen treatment in bone health for boys with XXY.

Vogiatzi M, Davis S, Ross J. Cortical bone mass is low in boys with Klinefelter Syndrome and improves with oxandrolone, Journal of Endocrine Society, 2021 Feb, 5(4):bvab016. PMID 33733020. https://pubmed.ncbi.nlm.nih.gov/33733020/

This summer we welcome THREE new members to the eXtraOrdinarY Kids Research Team! Please get to know them and how they will be able to provide assistance to our research families through their personal biographies.

We are excited to announce the start of a formal research internship in the eXtraOrdinarY Kids Program! We have been mentoring students for many years (in fact, Dr. Davis was Dr. Tartaglia’s first research intern 16 years ago!) We now have a formal training program where undergraduate, medical and graduate students who are interested in health science careers can work with our team for a summer or semester. Interns learn about X&Y variations, assist with research projects and participate in professional development opportunities. We are proud to be able to teach the next generation of professionals who will have a much better understanding of X&Y variations than historically taught in traditional curriculums, and maybe a few may even continue to work in this field in their future! We truly appreciate all of you who have graciously allowed our interns to observe your visits and learn from your families! Also, a big thank you to those who have donated to our program to make this initiative possible. If you feel passionately about the mission of educating these bright and eager students about X&Y variations, see childrenscoloradofoundation.org/extraordinarykidsclinic to donate – every little bit helps!

Congratulations to Tanea for her acceptance into the Physician Associate Program at the University of Alabama! Staff and our research families are so sad to see her go! She has dedicated 11 years to our team and we are incredibly grateful for all her hard work and commitment to research. We wish her the best in her endeavors and are incredibly proud of her. For eXtraordinary kids study scheduling or questions, please contact Mariah at Mariah.Brown2@childrenscolorado.org or Sierra at Sierra.Kaiser@childrenscolorado.org

Personal Words from Tanea

"I've been lucky to be a part of not only the eXtraordinarY Kids Clinic team, but the lives of our eXtraordinarY families as well. I started working with the clinic in 2010 as a volunteer, then progressed into a student assistant role, eventually became a clinical assistant, and now have spent the last 4 years as one of the coordinators for the eXtraordinarY Babies Study. I've enjoyed working alongside a fantastic team of extremely accomplished, compassionate, and skilled providers. My experience with our families has been one of the most defining aspects in my career path, and I can't express enough how grateful I am to have been able to work with them throughout their study participation. It is the definition of "bittersweet" as I leave my amazing team and my rewarding role as study coordinator at the end of the summer to join the University of Alabama's Physician Associate Class of 2023. While saying goodbye to my research team and our families will be difficult, if not a little heartbreaking, you have all served as inspiration as I continue my journey into the medical field. Being a part of our research efforts means also being a part of my personal and professional development, and I cannot thank everyone enough. I wish nothing but the best for our study community and I will miss every one of you! Please always feel free to keep in touch!"

With the most heartfelt wishes -Tanea

The Tanea Tanda Award

In Tanea's remembrance, we have created the Tanea Tanda Award for our PRAs and trainees on the eXtraOrdinarY Kids team. This award will be given yearly to any team member that is recognized for providing exceptional support for our patients, families, and contributions to the study team. The award includes a gift certificate to Dominos (Tanea's favorite pizza source) and a box of Oreos (Tanea's guilty pleasure).

Mariah Brown is the first ever recipient of this award! She has been on our research staff for three years and is a vital component to our team. Please congratulate her when you see her during your research visit.

Phone: (720) 808-0873

Email: extraordinarykids@childrenscolorado.org

Web: www.extraordinarykidsclinic.org

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

Donate: childrenscoloradofoundation.org/extraordinarykidsclinic