eXtraordinarY Babies Study News

Dear eXtraordinarY Babies Study participants,

Here is a long awaited update from our study teams in Colorado and Delaware. We are working hard and now have over 350 participants - some are still infants and others are approaching 8 years of age. We are proud as this is the largest and most comprehensive study of X&Y chromosome variations ever! We continue to enroll new participants who can make our study group more diverse and to even out the number of participants in each group.

Study visits continue to be yearly either by telehealth or in-person. The in-person study visits occur at ages of 12 months, 3 years, 6 years, and 8 years of age. Our goal is to continue to follow all of our participants into adulthood, so we can learn about the spectrum of features across the lifespan and early features that predict later outcomes. It's been such a pleasure to watch your children grow and we are learning so much that will be very helpful to future families and will help shape medical care recommendations.

Recently we've heard from a few participants that they are unsure about future participation for a couple reasons:

"My child is doing so well and I don't have any big concerns." This is fantastic! Many of our participants have had few or no health or developmental concerns. But, WE STILL NEED YOU because we want to be able to study all outcomes and strengths as well as the challenges that may occur. Our results will be skewed toward poorer outcomes if those without concerns drop out.

"We haven't told our child yet about their diagnosis, and we don't feel it is time to talk about it." The decision about how and when to tell your child about their diagnosis is personal. It is important to know that we can still conduct an in-person visit without talking about sex chromosomes. Prior to the visit, we can discuss their knowledge of the diagnosis and make a plan about the terminology most appropriate for your child and family if questions come up during the visit. In general, we tell kids they are helping us study how different kids learn and solve problems, their health, and how their bodies grow. Each situation is unique, and we will work with families to develop a plan that is best for them and the developmental stage of their child. Since talking about the diagnosis is a common question asked by parents as kids get older, I have also added some links for resources on this topic developed by our team about how to talk about the diagnosis at the end of this newsletter.

Please reach out with an email to me if you are thinking about dropping out of the study or have any other concerns. If you've missed a visit (or more), you are definitely welcome back. Email: extraordinarykids@ucdenver.edu

We continue to be so appreciative of all the time you provide for the study. We know the questionnaires take a lot of time (we are cutting back on a few based on your feedback), and travelling with young ones can be difficult!

Please read about some of our research findings and presentations that have resulted from the study below. We are just getting rolling with results, and look forward to sharing more in the future!

Sincerely,

Nicole Tartaglia, MD (AKA "Dr. T")

• eXtraordinarY Babies Study Updates
• Spreading the Word: Presenting our Research and Teaching Professionals
• Team Updates
• Looking Ahead: Educating Professionals of the Future!
• Resources for Talking about the Diagnosis

In July of 2023, the study was awarded an additional 5 years of funding (July 2023-June 2028) by the National Institutes of Health (NIH)! This funding will allow us to continue our important longitudinal research on the natural history of children with prenatal diagnoses of sex chromosome variations.

The aims of the new grant include the following:

• to continue to study health and 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 health and developmental outcomes.
• to develop evidence-based genetic counseling materials for families who have children with SCVs.

The most exciting part of Phase 2 of the eXtraordinarY Babies Study is that we will start having school age visits with participants that involve more mature activities and challenges! These in person visits that occur in school age will be similar to those experienced in infancy and toddlerhood and will maintain similar components. An in-person visit will still entail the collection of biological samples, Developmental/Academic/Social Skills testing, and a physical exam visit with either Dr. Tartaglia or Dr. Davis.

The schedule of yearly visits is shown in the timeline to the right. The alternating pattern of in-person evaluation and telehealth remains steady with in-person visits to occur at ages 3, 6, and 8 while telehealth will be conducted at ages 4, 5, and 7. This next age cohort is very exciting as we will continue to witness and celebrate the growth and progress each participant has made since birth and enters into the first years of elementary school.

We have a dashboard directly from our study database that updates with each enrollment. Click the link below to check it out!

The eXtraordinarY Babies Study and Natural History of Prenatally Identified Infants with Sex Chromosome Trisomies (SCTs): Analysis of Medical Problems in the First Year of Life

Dr. Tartaglia and Susan Howell CGC presented at a conference for genetic counselors in Maryland to share medical outcomes from the first year of life observed in the eXtraordinarY Baby Study. This dual faceted presentation was unique because it provided new findings for counselors and also addressed strategies for how genetic counselors deliver information to families. For example, our results show that over 50% of infants have challenges with breastfeeding and 20% develop food allergies by 12 months of age. These rates are similar between all three conditions (XXY, XYY and XXX), and genetic counselors can help families prepare for these possibilities. Overall, 18% of babies had growth problems in the first year of life, but this was more common in XXX (29%) compared to 15% in XXY and only 8% in XYY. These are just a few examples of medical findings from the study, and we are actively working on a publication that will detail all the health findings from the first year of life that we will share with everyone very soon.

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 in January 2024. Below is a list and brief description of all the presentations, mentored by Dr. Davis and Dr. Tartaglia.

Presenting Author: Susan Howell, MS – BEST GENETICS ABSTRACT AWARD WINNER

Abstract Title: eXtraordinarY Babies Study: Genetic Counseling implications of Discordant Prenatal Noninvasive Screening Results in Sex Chromosome Aneuploidies

Summary: This presentation highlighted 15 participants in our study where prenatal screening showed results of a trisomy (XXY, XYY or XXX), but genetic testing of the infant after birth showed different results (most commonly a tetrasomy or XXYY). It is important that physicians and genetic counselors understand the possibility of discordant results so they can guide families to additional genetic testing and follow-up since tetrasomy conditions can be associated with more significant health problems and developmental delays.

Presenting Author: Emma Todd

Abstract Title: Dietary supplement use in infants and toddlers in the eXtraOrdinarY Babies Study

Summary: 262 parents completed a survey on vitamin and dietary supplement use during pregnancy and in their children with XXY, XXX, XYY, XXYY, XXXY and XXXX. 66% of children were using or had used dietary supplements, which is higher than previously reported for Trisomy 21 (49%), autism spectrum disorder (42%) and developmental delays (30%). Parents reported giving supplements to benefit the child’s neurodevelopment, immune health, digestive health, and general health overall. The most used supplements in addition to daily multivitamins vitamins and vitamin D were prebiotics and probiotics, essentially fatty acids/fish oils, iron, and zinc. Future studies will look at the relationship of supplement use to health and developmental outcomes.

Presenting Author: Rebecca Wilson, PsyD

Abstract Title: eXtraordinarY Babies Study: Parenting stress in families with a prenatal diagnosis of sex chromosome trisomies, 36-month old follow up

Summary: In a previous study, the eXtraordinarY Babies study surprisingly found lower parenting stress in the first year of life compared to parents in the general population. This study aimed to further assess parenting stress at the 36-month follow-up. 134 participants completed the Parenting Stress Index survey at the 36 month visit, and results showed continued ongoing lower stress levels. For those who had higher stress, their child was more likely to have developmental delays in speech, motor and social skills. Future research will examine individual changes over time and analyze the interplay between parenting stress and child temperament, adaptive functioning, and social communication skills.

Presenting Author: Kayla Nocon

Abstract Title: The eXtraordinarY Baby Study: Natural History of Infants Diagnosed with XXYY in the Prenatal Period

Summary: A prenatal diagnosis of XXYY syndrome is very rare, and this project described the first 10 infants in the study with XXYY syndrome. Congenital malformations (heart and ear anomalies) were present in 40%, 70% had early feeding problems, and 90% had food allergies. Developmental delays were present in 80%. All of these rates are higher compared to the trisomy groups in the study. Strengths were seen in motor and social skills, and weaknesses in communication skills. Longitudinal follow-up will allow for more comparisons of developmental and health outcomes to postnatally identified samples to help guide care and genetic counseling.

Presenting Author: Kayla Molison

Abstract Title: Initial Data from the GALAXY Registry: Generating Advancements in Longitudinal Analysis in X & Y Chromosome Variations

Summary: The Generating Advancements in Longitudinal Analysis in X & Y Chromosome Variations (GALAXY) Registry is a national multicenter clinical data registry that stores medical data and biospecimens of individuals with X&Y variations across the lifespan led by Dr. Davis in Colorado. This project summarized features of the first 272 participants. 54.2% were diagnosed postnatally, with a median diagnosis age of 7.9 years (range: 0 - 48 years) and a median diagnostic delay of 2.6 years (range: 0 - 14 years). Advanced maternal age was the most common reason for prenatal testing (54.7%), while developmental delay before age 3 (34.1%), learning and behavioral concerns (16.5%), and “other” (19.8%) were the most common reasons for postnatal testing. GALAXY is just beginning, and this data base and registry will allow for lifespan research in all X&Y conditions.

Presenting Author: Aleks Radunovic

Abstract Title: The eXtraordinarY Babies Study: Comparison of 3 Developmental Screening Measures for Identifying Developmental Delays in Young Children with Prenatal Diagnosis of Sex Chromosome Trisomies.

Summary: This project evaluated 3 different developmental screening questionnaires commonly used in general pediatrics practice to see if they were good at identifying developmental delays in our study participants. Parents completed the questionnaires prior to their child being tested, and we compared results to the child's performance on the Bayley Scales of Infant and Toddler Development. All 3 developmental screening tools evaluated had low sensitivities in young children with SCT due to high false negative rates (questionnaire results in the normal range when testing showed they had a delay). The 3 measures all had high specificity, however, indicating few false positives (questionnaire results flagging as "delay" when testing results fell in the normal range). Given these results, the screening tools alone cannot be relied upon by pediatricians for identifying all cases of developmental delays, and periodic direct developmental assessments are recommended for infants with SCT due to the heighted risk for delays to ensure necessary referrals to early intervention therapy. Future directions include analyses of items most predictive of delays to determine if alternative scoring or new screening measure specific to the profile in children with SCT may be developed.

Dr. Jennifer Janusz presented preliminary data from The eXtraordinarY Babies Study on early executive functioning skills. Previous research of school-age children with sex chromosome trisomies has shown weaknesses in various domains of executive functioning including working memory, cognitive flexibility, planning, and strategic problem solving. However, little is known about emerging executive functioning skills in very young children with a prenatal diagnosis.

To evaluate this question, parents of children in the eXtraordinarY Babies Study completed the Behavior Rating Inventory of Executive Function- Preschool (BRIEF-P) questionnaire at the 24-month (n=142), 36-month (n=88), and 48-month (n=98) visits. Results showed that the percentage of children with scores falling in the clinically significant range (showing problems with executive functioning) was relatively low at both the 24- and 36-month timepoints for domains of inhibitory self control and flexibility, ranging from 5% to 7% of the sample. In contrast, at the 48-month visit, 17% and 28% had scores in the clinically significant range in these domains. However low scores in working memory and planning/organization were seen as early as 24 months for approximately 25% of the group.

These findings show that early deficits in executive functioning skills are not seen for the majority of children with SCT, especially at 2-3 years of age. However, by 4 years, a larger percentage of the children are showing deficits across multiple domains of executive functioning skills. Overall, these were seen in less than 30% of the group. These results provide information that can be used for monitoring and developing interventions in these areas. Future research will explore developmental patterns into school age.

This past November Dr. Tartaglia, Susan Howell CGC, and Lidia Grzybacz from the Colorado team had the chance to visit the East Coast and connect with the Delaware team at partnering site Nemours Children's Hospital. The Delaware team is led by Dr. Judith Ross and is supported by Dr. Ikomi and Karen Kowal P.A, as well as coordinators Victoria Reynolds and Annabelle Goetter. The visit to Wilmington, Delaware was an excellent chance for the two teams to collaborate and strategize for next phase of our study.

Kayla Nocon is the lead study coordinator for the eXtraordinarY Babies study. She received her B.S. in Biology from University of Denver and her Masters in Biomedical Sciences from Regis University. She first became involved in research as an undergraduate research assistant in an ecology lab in 2019 and joined the eXtraordinarY Babies Study as an intern in 2021. She is excited to be working with infant participants, rather than the ecology lab, and to be part of the eXtraordinarY kids research team!

Lidia is one of the newest research coordinators to join the eXtraordinarY Kids team. Before coming to Denver, she completed her undergraduate education at Penn State University where she began her research journey with infants and toddlers. After graduating she gained experience at Nemours Children's Hospital in Behavioral Health and Genetics. She is now applying the intersection of her education and clinical experience to The eXtraordinarY Babies Study!

Kayla Molison is the genetic counseling assistant for the eXtraordinarY Kids Program, and also a research coordinator for the eXtraordinarY Babies Study. She joined the team as an intern in the summer of 2023. She aspires to be a genetic counselor in the future, and her work with the eXtraordinarY Kids team is providing her with important experiences for her future career.

Andrew is a medical student working with the study and doing his medical student research project with the eXtraordinarY Kids team. Before medical school, he was a firefighter, EMT, and GI endoscopy technician. He is interest in potential careers in gastroenterology, urology, or endocrinology, and we hope to convince him to continue working with our eXtraordinarY kids in the future.

Charlotte Ward is a new clinical research coordinator at Nemours Children’s Hospital Delaware. She received her MA in Linguistics and Cognitive Science from the University of Delaware in 2020 and began working as a research assistant and study coordinator with the Center for Pediatric Auditory and Speech Sciences at Nemours. There they worked on a study of 5- to 11-year-old children’s speech and hearing. They are excited to help the eXtraordinarY Kids team with this project!

Heather is one of the newest research coordinators to join the eXtraordinarY Kids team. She completed her undergraduate education at West Chester University with a major in education. Before coming to Delaware, she was a Senior Psychometrist II at the Mayo Clinic in Jacksonville, FL for 12 years along with assisting in a Deep brain stimulation study and Lewy body Dementia study. She is excited to bring her experience and passion to the eXtraordinary Baby Study.

See below for an overview on the team members in Delaware and Colorado

Prenatal Diagnoses are increasing around the world, but there are still not enough professionals who know about these conditions. We need more genetic counselors, physicians, therapist, educators, and researchers in this field.

Your participation in the study helps all these future families!!

Starting April 1, 2024, the California Prenatal Screening Program added sex chromosome aneuploidy screening to the state cell-free DNA screening panel. This means ALL pregnancies in California will be screened for X&Y variations - leading to a significant increase in diagnoses and need for accurate prenatal counseling and pediatric care.

The interdisciplinary eXtraOrdinarY Kids Team offers a Research Internship for trainees interested in learning more about sex chromosome variations and pediatric clinical research. The program is directed by Dr. Shanlee Davis, and the interdisciplinary team of mentors includes Developmental Pediatrics (Dr. Tartaglia), Pediatric Endocrinology (Dr. Davis), neuropsychology, psychology, genetic counseling, speech and occupational therapy, and study coordinators. Interns are matched with a mentor and a project suited to their experience and goals. In addition to working on their research project, interns attend career lectures, have the opportunity to assist with patient visits for our ongoing studies including the eXtraordinarY Babies study, and present their work at the eXtraordinarY eXpo at the end of each summer. We hope to inspire future clinical researchers, and have had interns from the program go on to medical school and graduate school for psychology, genetic counseling, public health, and other related fields where they will have background and experience with sex chromosome variations. Grants and family donations fund this important program (see donation link below!). Below is a photo of our happy interns and research team from last summer.

As our study participants have started getting older, parents have increasingly asked for our recommendations and input about when and how to talk to their children about their genetic condition. Since this question has come up so often over the years, our team conducted a project with children, adults, and parents of all ages to learn about their experience learning about their genetic condition or discussing the diagnosis with their child. From this input and together with our clinical expertise, we developed materials to help families with this topic. Each family and child is different, and these resources can provide some guidance and considerations about the disclosure process.

Brochures for families and a video presentation from a previous AXYS family conference by our genetic counselor Susan Howell:

https://genetic.org/im-parent-affected-child/tell-child-diagnosis/

Children's Books for kids: https://genetic.org/books/

Elizabeth and her Extra X, Gregory and his Extra X, Jack and his Extra Y, and Kyle and his Extra X&Y by Arlie Colvin.

Link to our publication: "How should I tell my child?" Disclosing the diagnosis of sex chromosome aneuploidies, by Dennis A, Howell S, Cordeiro L, and Tartaglia N. Published in Journal of Genetic Counseling, 2015 Feb;24(1):88-103.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5340499/

We hope everyone has a great summer!

Email: extraordinarykids@childrenscolorado.org

Web: www.extraordinarykidsclinic.org

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

Donate: childrenscoloradofoundation.org/extraordinarykidsclinic