eXtraordinarY Babies Study News

Dear eXtraordinarY Families,

We are happy to share updates and accomplishments from our amazing research team. One of the most rewarding aspects of our job is seeing students become inspired while working with our team, and Dr. Davis and I were honored to mentor 12 students and junior faculty in research projects presented at the Western Society for Pediatric Research annual meeting in January. New publications from many of these abstracts are coming out soon, and we will share links as they become available.

We want to continue to emphasize how important it is to keep all participants involved in the study as they grow up. We appreciate the time you contribute for study visits, and recognize the challenges of finding time amidst the busy schedules of life with kids. Our coordinators are working hard to accommodate participants, so please reach out if any concerns about missing or upcoming study visits.

There has been a lot in the news lately about changes at the NIH (National Institutes of Health), which is the federal agency that funds the eXtraordinarY Babies Study. We have not received any news that funding for this study is going to be affected, so for now we remained dedicated to the study and will inform everyone if anything changes.

Respectfully,

Nicole Tartaglia, MD

• eXtraordinarY Babies Study Team Updates
• Study Operations and Enrollment Updates
• Presentations & Publications
• eXtraordinarY Babies Book
• Upcoming Events

Although it feels bittersweet, we would like to extend our congratulations to Karen Kowal, Physician Assistant at Nemours Children's Hospital Site for her upcoming retirement. Alongside Dr. Judith Ross, Karen has dedicated over 35 years towards research and care in the fields of pediatric endocrinology and sex chromosome disorders. She has achieved academic excellence in her field, participating in multiple presentations, mentoring team members, and as co-author on numerous research publications. In addition to her participation in many research trials that contributed knowledge to the field of X and Y variations, she has been a dedicated clinician in the Nemours eXtraordinarY Kids Clinic where she has cared for children and their families. We are very appreciative of all the hard work and contributions Karen made to our research program, and are especially grateful for the charm and wit she brought to our research team. Her team will miss her both as a PA and as a presence in the office, but we are thrilled for her to take this well-deserved next step in her life. Please join us in expressing our heartfelt gratitude and congratulations for an impactful and meaningful career!

Shaney is a pediatric nurse practitioner who has recently joined the eXtraordinarY Kids team at Nemours. She worked as a bedside nurse and clinical nurse educator in the pediatric cardiac intensive care unit before pursuing her graduate degree in Drexel University’s Pediatric Nurse Practitioner program. Before coming to Delaware, she was the lead NP and program manager for the Lysosomal Storage Disorder team at Children’s Hospital of Philadelphia, and has extensive experience working on natural history studies and clinical trials. She is excited to be contributing to the study and looks forward to seeing patients and families during their study visits at Nemours!

We are thrilled to share an exciting milestone in the eXtraordinarY Babies Study - enrollment of new participants is now officially closed! Thanks to the incredible support from families and collaborators, we have exceeded our original goal, enrolling 370 participants well beyond our original target of 200.

While enrollment has ended, our work is far from over. We now continue the next critical phases of research, including data analysis and longitudinal follow-up visits, which will help us gain deeper insights into the developmental trajectories and medical features of children with SCAs. As your eXtraordinarY Babies grow into toddlers and school-age children, we can start to look back at early predictors of outcomes. For example, we can compare kids who are showing early reading difficulties to those who are reading well, and then look back to identify which features predict those children at highest risk. This will help us make recommendations for treatments for high-risk children early in life.

Your ongoing participation is very meaningful and important to help us understand the variability in X&Y chromosome variations and develop treatment recommendations. Even if you have missed a visit or two due to busy lives, we still welcome you back to the study so we can catch up and reconnect.

Stay tuned for updates as we continue to share new findings!

We are excited to announce that Nemours Children's Hospital has reached a significant milestone enrolling its 100th participant! The dedication of the Nemours research team, along with the incredible commitment from participating families, has played a crucial role in reaching this milestone. With this milestone, Nemours continues to be a key partner in the study’s nationwide efforts, ensuring we have participation from across all parts of the US.

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 2025. Below is a list and brief description of all the presentations, mentored by Dr. Davis and Dr. Tartaglia.

Presenting Author: Alyssa Keller

Abstract Title: Prenatal, Birth, and Neonatal Outcomes In Sex Chromosome Aneuploidies: Data from the INSIGHTS and GALAXY Registries

Summary: Perinatal outcomes associated with sex chromosome aneuploidies (SCAs) using data from two longitudinal registries were examined. The cohort included 667 participants with Turner syndrome, Klinefelter syndrome, Triple X syndrome, XYY syndrome, and XXYY syndrome. Analysis revealed increased risks of maternal complications like preterm labor (10%) and fetal issues such as poor intrauterine growth (15%) and congenital heart malformations (13%). Neonates with SCAs experienced higher rates of NICU admissions, cardiac concerns (27%), respiratory difficulties (18%), and feeding challenges. These findings provide the first comprehensive update on SCA perinatal health in over 40 years, identifying increased risks that may refine clinical care and inform future research.

Presenting Author: Emma Todd

Abstract Title: Sleep and Physical Activity Health Behaviors Relate to Exercise Capacity in Adolescents and Young Adults with Klinefelter Syndrome

Summary: This study investigated the relationship between health behaviors and exercise capacity in adolescents and young adults with Klinefelter Syndrome (KS). Using wearable devices and self-reports, the study found that individuals with KS had lower exercise capacity (VO2 peak) and daily step counts, along with higher sedentary time, compared to controls. Although dietary intake and macronutrient composition were similar between groups, KS participants consumed fewer calories. Sleep patterns also differed, with later bedtimes and increased time in bed but lower sleep efficiency in the KS group. Positive correlations were observed between VO2 peak and step count and sleep efficiency, while negative correlations were seen with sedentary time and sleep onset latency. These findings highlight the potential for targeted interventions in physical activity, sleep, and diet to improve cardiovascular health in individuals with KS.

Take-home for parents: Exercise can be harder for some boys with KS, but it is important to incorporate healthy movement and exercise early in life to establish healthy habits. Find fun physical activities your kids enjoy and make it part of their lifestyle.

Presenting Author: Laura George PhD

Astract Title: LANGUAGE DEVELOPMENT IN CHILDREN WITH SEX CHROMOSOME TRISOMIES: ANALYSIS USING THE MACARTHUR-BATES CDI-III

Summary: Expressive language development was examined in 36-month-old children with prenatal diagnoses of Sex Chromosome Trisomies (SCTs), including XXY (Klinefelter syndrome), XYY, and Trisomy X. Using the MacArthur Bates Communicative Development Inventories-III (CDI-III), researchers found that all SCT groups scored below the normative median on expressive vocabulary, sentence complexity, and grammatical development, indicating an increased risk for language delays. Children with Trisomy X exhibited lower scores in vocabulary and sentence complexity compared to those with XXY, suggesting a heightened risk for language challenges in Trisomy X. These findings highlight the need for targeted interventions and further research to identify predictors of language development in SCT populations.

Presenting Author: Andrew Keene

Abstract Title: MINIPUBERTY PITUITARY-GONADAL HORMONE PROFILE IN INFANTS WITH 47,XXY

Summary: The pituitary-gonadal hormone profile during minipuberty in 85 infant males with Klinefelter Syndrome (KS) was examined to address inconsistencies in prior research. While most hormone levels fell within normal age-specific ranges, KS infants had lower median testosterone (TT) and anti-Müllerian hormone (AMH) levels but higher median levels of inhibin B (INHB), luteinizing hormone (LH), and follicle-stimulating hormone (FSH) compared to typical male reference populations. Positive correlations were found between TT and LH and between AMH and INHB, while negative correlations were observed between AMH and FSH and between INHB and FSH. No significant relationship was found between TT and penile or body length. The study’s important strength is that it includes the largest sample size of XXY infants to date.

Take-home for parents: Testosterone levels during minipuberty of infancy (age 2-3 months of life in males) in infants with XXY are lower on average compared to XY infants, however usually still within the average range. Currently, our clinic recommends checking testosterone levels during the minipuberty period in infants with XXY, and if values are low then further discussion with a pediatric endocrinologist or other licensed medical professional is important to consider whether testosterone treatment is recommended.

Presenting Author: Shalika Devireddy

Abstract Title: METABOLOMIC PROFILING IN KLINEFELTER SYNDROME: LINKING EARLY LIFE BIOMARKERS TO LATER NEURODEVELOPMENTAL OUTCOMES

Summary: This study investigated the potential for early systemic metabolites in infants with Klinefelter Syndrome (KS, 47, XXY) to predict later neurodevelopmental outcomes, addressing the phenotypic variability within this population. Plasma metabolites were analyzed in 2-month-old infants with XXY and correlated with longitudinal neurodevelopmental assessments up to 36 months. Elevated prostaglandins were associated with maternal weight gain during pregnancy, higher infant fat mass, and poorer neurodevelopmental scores, suggesting their role in fat accumulation and neurocognitive deficits. Additionally, impaired mitochondrial oxidation of fatty acids, indicated by negative correlations between acyl-carnitines and neurodevelopmental scores, emerged as a potential contributor to cognitive and adaptive challenges. These findings propose novel pathways underlying clinical heterogeneity in KS and emphasize the value of early metabolomic profiling for predicting and potentially intervening in adverse developmental outcomes.

Presenting Author: Karli Swenson, PhD, MPH

Abstract Title: Resting Energy Expenditure in Young Men with Klinefelter Syndrome

Summary: This study investigated whole-body substrate oxidation in adolescents with Klinefelter Syndrome (KS, 47,XXY) to test the hypothesis of impaired fatty acid beta-oxidation. It was found that individuals with KS had significantly higher adiposity compared to age- and BMI-matched controls, though their resting energy expenditure (REE) and efficiency in utilizing fat as a fuel source were lower. Despite similar BMI and REE between groups, the respiratory quotient (RQ) was higher in KS, indicating greater reliance on carbohydrates over fats. Fat oxidation rates were 15% lower in KS participants, and although fat oxidation correlated with lean mass, it did not correlate with adiposity. Treatment with a PPAR-α agonist (fenofibrate) did not improve metabolic outcomes. These results suggest altered lipid metabolism in KS, even with testosterone replacement, and highlight the need for further studies on fat oxidation in skeletal muscle tissue within this population.

Presenting Author: Megan Louderman

Abstract Title: USING TEMPERAMENT TO INFORM ANTICIPATORY GUIDANCE FOR YOUNG CHILDREN WITH SEX CHROMOSOME TRISOMIES.

Summary: Recent research has examined temperament profiles in children with XXY, XYY, and XXX during their first three years of life, revealing distinct behavioral patterns that may influence parenting strategies, clinical care, and early intervention approaches. Findings indicate that young children with SCTs generally exhibit an “easy baby” temperament, as caregivers overwhelmingly rated their child’s manageability as “easy” or “very easy.” More specifically, these children tend to be less active, more withdrawn, have a positive mood, display mild emotional intensity, and show lower persistence and sensitivity to sensory input. However, variations in adaptability, distractibility, and routine regularity emerged across different ages, emphasizing the importance of individualized support. To help caregivers navigate these developmental nuances, researchers have developed an anticipatory guidance program, which includes practical handouts for parents and educational materials for providers, such as genetic counselors and therapists. These resources aim to help families better understand their child’s inborn traits and create environments that support social-emotional, cognitive, motor, and language development.

Presenting Author: Morgan Joliffe

Abstract Title: EXTRAORDINARY BABIES STUDY: A LONGITUDINAL STUDY OF EARLY EXECUTIVE FUNCTIONING SKILLS IN TODDLERS WITH SEX CHROMOSOME ANEUPLOIDY

Summary: Given that children with XXY, XYY, and XXX are at an increased risk for EF challenges, this study examined how these skills evolve over time, assessing children at 24, 36, and 48 months of age using parent-reported measures. Findings reveal distinct developmental patterns based on karyotype. For children with XXY and XYY, emotional control difficulties increased significantly between 24 and 48 months, affecting their ability to manage emotions and adapt to change. Children with XXY also showed greater difficulties in planning and organization, while those with XXX exhibited challenges in cognitive flexibility (shifting between tasks) between 24 and 36 months. Notably, by 48 months, a significant percentage of children with XYY demonstrated EF deficits across multiple domains, though sample sizes for this group were smaller. These findings emphasize the importance of early intervention to support self-regulation and executive functioning in children with SCAs. By identifying early EF vulnerabilities, researchers and clinicians can develop targeted strategies to help children build essential skills that will support their long-term cognitive and social development.

Presenting Author: Jennifer Janusz PhD

Abstract Title: EXTRAORDINARY BABIES STUDY: A LONGITUDINAL STUDY OF EARLY COGNITIVE SKILLS IN INFANTS AND TODDLERS WITH SEX CHROMOSOME TRISOMY

Summary: Given the increased risk for cognitive and motor delays in children with XXY, XYY, and XXX, this study assessed developmental changes between 12 and 36 months of age to better understand early learning and growth patterns. Results revealed that, on average, cognitive scores remained stable across all SCT groups, suggesting that children with SCTs do not experience regression or slowed development in their early years. However, significant improvements were observed in language and motor skills for children with XXY and XXX, while children with XYY showed changes primarily in gross motor skills. Notably, by 36 months, a large percentage of children were receiving developmental therapies, with 59% in speech therapy, 31% in occupational therapy, and 36% in physical therapy—a significant increase from 12 months. These early interventions may have contributed to the developmental gains observed. These findings are encouraging, as they highlight positive developmental progress in children with SCTs despite the known risks for learning and motor difficulties later in childhood.

Presenting Author: Rebecca Wilson

Abstract Title: NEW IDEAS FOR IMPROVING SOCIAL DEVELOPMENT IN SEX CHROMOSOME TRISOMY INSPIRED BY MASKING REQUIREMENTS DURING THE COVID-19 PANDEMIC; THE EXTRAORDINARY BABIES STUDY

Summary: The eXtraordinarY Babies Study has uncovered an unexpected finding regarding social development in toddlers with sex chromosome trisomies (SCTs), particularly in relation to eye contact and social communication. Given that individuals with SCTs are at a higher risk for social difficulties and autism spectrum disorder (ASD), researchers sought to assess early social skills using the Autism Diagnostic Observation Schedule-2 (ADOS-2). However, due to COVID-19 safety protocols, examiners wore surgical masks during assessments, raising concerns about whether this would impact the children’s ability to engage socially. Surprisingly, results showed that toddlers displayed better social skills when assessed by masked examiners. In particular, children in the masked condition demonstrated improved eye contact, which contradicts the initial hypothesis that face coverings would hinder social communication. These findings align with prior eye-tracking studies, which indicate that individuals with SCT may avoid eye contact, often focusing on other facial features. The results suggest that masking may have helped direct children’s attention to the eyes, potentially enhancing their social engagement.

Take-away for parents: These findings are interesting, but we are not suggesting that all parents wear masks around their infants and young children. However, we do recommend that parents work with their infants and toddlers to make sure they establish eye contact when they are requesting something or vocalizing / talking with others. To encourage this, parents can hold the desired object up near their eyes, and then wait for the baby to look at their face and make eye contact before giving the object to the child. Social games such as peek-a-boo and making silly faces can also encourage babies to pay attention to eyes and facial expressions.

This new book was inspired by our families and the hundreds of calls our clinic receives from families just learning of the diagnosis during their pregnancy or after newborn testing. This 65 page book includes 5 chapters addressing all the "Frequently Asked Questions" from our clinic and research experiences:

1. All About XXY
2. Genetic Testing for XXY
3. Pregnancy when the Baby has XXY
4. After Your Baby is Born
5. Parent Perspectives and Support

The book, authored by Susan Howell, MS (Genetic Counselor), Nicole Tartaglia, MD (Developmental Pediatrician), Shanlee Davis, MD (Pediatric Endocrinologist) and Chloe Alviz (Genetic Counseling Student) is full of great information and is now available for sale at Amazon. All proceeds benefit the clinic, so buy 1 for yourself, or maybe buy a bunch to donate to local libraries and OB/GYN or Pediatrics practices? (Click on the book cover for the link; or https://a.co/d/6vkQfYC).

We are also working on similar books on all the other X&Y variations conditions, and donations to our program help speed up these efforts. If you would like to sponsor publication of a similar book on your child's condition or sponsor translation of the book to different languages, contact Dr. T.

The AXYS Community Conference brings together families, researchers, and advocates dedicated to supporting individuals with X and Y chromosome variations. This inspiring event features expert-led presentations on the latest advancements in research, treatments, and care strategies. Attendees have the opportunity to connect, share experiences, and gain valuable insights into managing the unique challenges associated with Sex Chromosome Trisomies (SCT). Interactive sessions and panel discussions fostered a sense of community, empowerment, and hope for the future. We look forward to contributing to this wonderful event this Summer. Stay tuned for more updates!

Email: extraordinarykids@UCdenver.edu

Web: www.extraordinarykidsclinic.org

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

Donate: childrenscoloradofoundation.org/extraordinarykidsclinic