The eXtroardinarY Babies Study: Natural History of Health and Neurodevelopment in Infants and Young Children With Sex Chromosome Trisomy

Recruiting

• Conditions: Xxyyy Syndrome; Klinefelter Syndrome; Trisomy X; Xxyy Syndrome; XXXY and XXXXY Syndrome; Xxxx Syndrome; Xxxxx Syndrome; Xxxyy Syndrome; Xyyyy Syndrome; XYY Syndrome
• Interventions: Other: Assessments of Development and Growth

• Registration Number: NCT03396562
• Lead Sponsor: University of Colorado, Denver

Brief Summary

This study is designed to research the natural history of neurodevelopment, health and early hormonal function in infants with XXY/Klinefelter syndrome, XYY, XXX and other sex chromosome variations in an effort to identify early predictors of developmental and health outcomes. The Investigators will also evaluate different developmental screening tools in infants with sex chromosome variations so the investigators can develop recommendations for pediatrician caring for infants and young children with XXY/Klinefelter syndrome, XYY, XXX, and other sex chromosome variations.

Detailed Description

Background: Sex Chromosome Trisomies (SCT) including Klinefelter (XXY), Trisomy X (XXX), and XYY syndromes occur in 1 out of every 500 births and are associated with a broad phenotypic spectrum including increased risk for developmental delays (DD), language/learning disorders, and autism spectrum disorder (ASD). XXY is also associated with testicular failure, XXX increases risk for ovarian failure, and disorders of insulin resistance and other medical problems resulting in increased morbidity and mortality occur in all 3 SCTs. Historically, less than 10% of SCT diagnoses occur in childhood, however the rate of newborns with SCT has markedly increased with new noninvasive prenatal cell-free DNA (cfDNA) screening. SCT natural history research is limited to studies from the 1970's, and the investigators have little knowledge of early predictors of the wide heterogeneity in later outcomes. The high risk for DD in SCT suggests that newborn screening may improve identification for DD and timely initiation of interventions. However, it is not clear whether all SCT infants indeed require intensive developmental assessments and therapies, or if primary care screenings are sufficient to identify those in need. The surge in prenatal SCT diagnoses from cfDNA methods provides an opportunity for longitudinal study of a cohort of infants to explore natural history, and to improve care.

Aims: This study aims to: (1) describe and compare the natural history of neurodevelopment, health and early gonadal function in infants with the 3 SCT conditions through a national prospective eXtraordinarY Babies Study in partnership with the Newborn Screening Translational Research Network (NBSTRN), (2) identify early predictors of poor neurodevelopmental and cardiometabolic outcomes, and (3) evaluate the sensitivities of common primary care developmental screening measures to detect DD and ASD in this high-risk population to inform recommendations for an early neurodevelopmental care protocol.

Approach: Infants with a prenatal diagnosis of XXY, XYY, or XXX will be followed prospectively every 6-12 months for 2-4 years at 2 eXtraordinarY Kids Clinic sites. Demographics, health history, development, interventions, and social/family history will be collected. Assessments will include: (1) measures of cognitive, language, social, motor, and adaptive function, (2) physical exam, gonadal function labs, cardiometabolic measures, and body composition, and (3) quality of life outcomes. Impact: Prospective study of the natural history of prenatally diagnosed infants with SCT will allow investigation of important questions to inform newborn screening considerations, such as the interplay between early hormonal profiles and developmental outcomes. Results will be immediately relevant for counseling and establishing evidence-based care guidelines for the rapidly increasing rate of SCT diagnoses from cfDNA screening. Results will serve as the basis for ongoing longitudinal studies of health and psychological outcomes of SCTs through the lifespan.

Study Timeline

• Study Start: 2017-09-29
• Study First Submitted: 2017-12-05
• Study First Submitted QC: 2018-01-09
• Study First Posted: 2018-01-11
• Status Verified: 2024-05
• Last Update Submitted: 2024-05-07
• Last Update Posted: 2024-05-09
• Primary Completion: 2028-03-01
• Study Completion: 2028-03-01

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 300

Inclusion Criteria

1. Prenatal diagnosis of sex chromosome aneuploidy (by cfDNA, chorionic villi sampling, and/or amniocentesis)
2. Postnatal confirmatory karyotype of XXY, XYY, XXX, XXYY, XYYY, XXXY, XXXX, XXXXX, XXXXY, XXXYY, XXYYY, XYYYY (including any mosaicism with <80% 46,XX or 46,XY cell line)
3. English or Spanish speaking
4. Age 6 weeks to 12 months 30 days on enrollment

Exclusion Criteria

1. Previous diagnosis of a different genetic or metabolic disorder with neurodevelopmental or endocrine involvement
2. Prematurity less than 34 weeks gestational age
3. Complex congenital malformation not previously associated with sex chromosome aneuploidy
4. History of significant neonatal complications (ie intraventricular hemorrhage, meningitis, hypoxic-ischemic encephalopathy)
5. Known complex Central Nervous System (CNS) malformation identified by neuroimaging

Study & Design

• Study Type: OBSERVATIONAL
• Study Design: Not specified

Arm && Interventions

Group	Intervention	Description
SCT Conditions	Assessments of Development and Growth	Sex Chromosome Trisomies Conditions including Klinefelter (XXY), Trisomy X (XXX), XXY Syndromes. Interventions: Longitudinal observational assessments of development and growth at ages: 2 months, 6 months, 12 months, 18 months, 24 months, 36 months, 48 months, and 5 or 6 years.

Primary Outcome Measures

Name	Time	Method
Longitudinal Descriptive Statistics of Cognitive Scores on the Bayley-III	36 months	Cognitive skills will be assessed using the standardized Bayley Scales of Infant Development--3rd Edition (Bayley-3)
Longitudinal Descriptive Statistics of Motor Scores on the Bayley-III	36 months	Motor development will be assessed using the standardized Bayley Scales of Infant Development--3rd Edition (Bayley-3)
Longitudinal Descriptive Statistics of Language Scores on Bayley-III	36 months	Language development will be assessed using the Bayley Scales of Infant Development--3rd Edition (Bayley-3)

Secondary Outcome Measures

Name	Time	Method
Body Mass Index (BMI)	36 months	BMI will be determined through measurement of length and weight at the research visit.
Z Score	36 months	The z score will be calculated for age group at the research visit.
Body Composition (% body fat)	3 year old visit	Body fat percentage will be measured using air Dual Energy X-Ray Absorptiometry (DEXA) at 3 year old visit.

Trial Locations

Locations (2)

Nemours at Thomas Jefferson University; 🇺🇸 Philadelphia, Pennsylvania, United States

Children's Hospital Colorado; 🇺🇸 Aurora, Colorado, United States