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The eXtraordinarY Baby Study: Natural History of Infants Identified with XXYY in the Prenatal Period

Clinical Genetics and Therapeutics
  • Primary Categories:
    • Clinical- Pediatric
  • Secondary Categories:
    • Clinical- Pediatric
Introduction:
XXYY syndrome is a rare sex chromosome aneuploidy (SCA) occurring in 1:18,000-1:40,000 males characterized by a complex clinical presentation, including neurodevelopmental and medical challenges. While much of the literature focuses on males with XXYY diagnosed due to clinical features during childhood, there is limited information on individuals who were identified with XXYY prenatally. Noninvasive prenatal cell free DNA screening has expanded, resulting in an increased number of infants identified with SCA in the prenatal period. Literature from individuals with postnatal diagnoses of XXYY describes more frequent medical comorbidities and more significant neurodevelopmental and psychological features compared to 47,XXY. This study aims to describe the early medical and developmental features of prenatally identified 48,XXYY infants, with comparisons to 47,XXY and 47,XYY cohorts enrolled in the eXtraordinarY Babies Study. 

Methods:
The eXtraordinarY Babies Study is a prospective natural history study following infants with prenatal identification of SCA from birth. Study visits begin at or prior to 12 months of age, and data collection includes physician-validated health and developmental history. Parents complete the Vineland Adaptive Behavior Scales – 3rd edition to gather data about developmental functioning (subdomain mean v-scale score=15, sd 3). Data presented includes early medical complications, Vineland-3 scores and therapy utilization during the first year of life for participants with XXYY syndrome. Prevalence of congenital malformations are compared to existing literature. Comparisons of medical features and Vineland-3 domains to 47,XXY and 47,XYY cohorts also enrolled in the eXtraordinarY Babies Study were analyzed using Fisher’s Exact and Wilcoxon tests with an assumed type 1 error rate of 0.05. 

 

Results:
15 infants were prenatally identified with 47,XXY or 47,XYY via NIPS, however, confirmatory genetic testing was discordant and showed an unexpected diagnosis of 48,XXYY. 13 of 15 infants have reached 12-months of age or older (current ages, 8-months – 7 years old). Infants with XXYY exhibited a range of early medical issues, including feeding difficulties (93.3%), hypotonia (80%), food/environmental allergies (73.3%), gastroesophageal reflux (60%), and torticollis (46%). Developmental delays in language (80%) and motor (60%) skills were identified by 12-months. Nearly all infants received early intervention services (93%), including physical therapy (87%), speech therapy (87%), and occupational therapy (80%). Rates of congenital malformations are similar to published literature in postnatally identified cases, including cardiac septal defects (20% in our sample vs 11.8% literature), cleft palate (13.3% vs 2.2%), club foot (6.7% vs 2.1%), and cryptorchidism (13.0% vs 16.8%). Comparisons with 47,XXY and 47,XYY cohorts revealed similar rates of some medical features (plagiocephaly, breastfeeding problems, eczema), however rates of congenital anomalies (cleft palate, cardiac defects, cryptorchidism) and environmental allergies were higher in XXYY (p<0.05). Vineland scores at 12 months indicated lower scores in motor and communication domains compared to 47,XXY and 47,XYY (Gross Motor XXYY v-scale score median 10 [IQR 8.75, 13.25] vs. XYY 14 [10.25, 15] p=0.006, and XXY 13 [10, 15.75] p=0.049; Fine Motor XXYY 15 [14, 15.25] vs XYY 15 [15, 16] p=0.039, and XXY 16 [15, 17] p=0.014); Expressive Communication XXYY 12.5 [9.75, 13.25] vs XYY 13 [11.5, 15] p=0.073 and XXY 14 [12, 16] p=0.006).  

Conclusion:
Compared to male sex chromosome trisomies (STCs), XXYY presents with more complex clinical features. While a small sample size, our findings are not suggesting a significantly milder phenotype compared to the published literature of postnatally identified cases. These findings describing medical features of XXYY in the first year of life provide valuable information for genetic counselors and healthcare providers to guide medical screenings and developmental interventions. Longitudinal follow-up will identify further medical features of XXYY syndrome in childhood and beyond, allowing for more detailed comparisons in developmental trajectory to SCT conditions and published literature. 

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