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

  • End date
    Sep 4, 2022
  • participants needed
  • sponsor
    University of Colorado, Denver
Updated on 4 May 2021
klinefelter syndrome
screening procedure
chorionic villi sampling
sex chromosome aneuploidy


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.


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.

Condition XYY Karyotype, Hypogonadism, Klinefelter's Syndrome, Trisomy X, XXXY and XXXXY Syndrome, Xxyy Syndrome, Xyyy Syndrome, Xxxx Syndrome, Xxxxx Syndrome, Xxxyy Syndrome, Xxyyy Syndrome, Xyyyy Syndrome, Male With Sex Chromosome Mosaicism, hypogonadotropic hypogonadism, klinefelter syndrome, double y syndrome, triple x syndrome
Treatment Assessments of Development and Growth
Clinical Study IdentifierNCT03396562
SponsorUniversity of Colorado, Denver
Last Modified on4 May 2021


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Inclusion Criteria

Is your age between 1 yrs and 1 yrs?
Gender: Male or Female
Do you have any of these conditions: Xxxyy Syndrome or XYY Karyotype or XXXY and XXXXY Syndrome or Hypogonadism or Klinefelter's Syndrome or Xxxx Syndrome or Xxyyy Syndrome or Xxyy Syndro...?
Do you have any of these conditions: double y syndrome or klinefelter syndrome or Xyyy Syndrome or Klinefelter's Syndrome or XXXY and XXXXY Syndrome or Xxxx Syndrome or Xyyyy Syndrome or ...?
Do you have any of these conditions: Xxyyy Syndrome or Xxyy Syndrome or Hypogonadism or Trisomy X or Xxxx Syndrome or Xyyy Syndrome or Xxxyy Syndrome or XYY Karyotype or hypogonadotropic ...?
Do you have any of these conditions: Xxyy Syndrome or Klinefelter's Syndrome or hypogonadotropic hypogonadism or klinefelter syndrome or double y syndrome or Hypogonadism or Xyyyy Syndrom...?
Prenatal diagnosis of sex chromosome aneuploidy (by cfDNA, chorionic villi sampling, and/or amniocentesis)
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)
English or Spanish speaking
Age 6 weeks to 12 months 30 days on enrollment

Exclusion Criteria

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