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

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.

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