Quantifying the Spectrum of Early Motor and Language Milestones in Sex Chromosome Trisomy

The sex chromosome trisomies (SCT), including XXY, XYY, and XXX, are common chromosomal aneuploidies associated with increased risk for early developmental delays and later neurodevelopmental disorders. Precise data on the timing and variability of early milestones in this population remain limited, so despite rising rates of prenatal SCT diagnosis, clinicians and families lack clear, evidence-based expectations for early motor and language development. This study aims to quantify the spectrum of early developmental milestones in infants with SCT and compare their timing with well-established standards for unaffected children to better contextualize early developmental risk. This analysis used data from the eXtraordinarY Babies Natural History Study, a prospective cohort of prenatally identified infants with SCT followed from infancy through early childhood. Between 2 and 36 months of life, parents reported easily observable gross motor and expressive language milestones, and clinicians validated these findings at regularly scheduled study visits as part of a broader assessment of development and health trajectories. A total of 12 milestones were collected for each participant: 8 gross motor skills and 4 expressive communication milestones. To compare these values with a normative reference group, data were retrieved from the Denver II Scales, the WHO Motor Development Study, and the Primitive Reflex Profile. Analyses assessed the median age of acquisition, variance, and differences across SCT karyotypes, as well as the proportion of children who fell outside CDC milestone expectations. Among 298 infants with SCT (174 with XXY, 50 with XYY, and 74 with XXX), results showed a later median age of acquisition for 9 of the 12 milestones evaluated, including rolling front to back, sitting, cruising, walking, running, cooing, babbling, first words, and 2-word phrases. There was also greater variance in milestone timing for the SCT group compared with the reference population, with extended upper percentiles across most skills indicating a wider range of typical achievement. While these delays were statistically significant, there was considerable overlap between the SCT group and the general pediatric population, and only a minority of infants met the CDC criteria for developmental delay. Differences across SCT karyotypes were small and generally not significant, although children with XXY achieved several skills slightly earlier than those with XYY or XXX. These findings provide an evidence-based schedule for early motor and language milestones in infants with SCT to aid early childhood surveillance and counseling. The later median age of acquisition and greater variability observed across all SCT conditions support the need for periodic developmental assessment beyond guidelines for the general population to identify children requiring additional support earlier. Although many infants with SCT will experience developmental trajectories similar to unaffected peers, this study shows that they remain at higher developmental risk and may benefit from increased monitoring, clearer parent guidance, and earlier referral for intervention when indicated.(Abstracted from Pediatrics (2025) 156 (2): e2024068773. doi: 10.1542/peds.2024-068773.).