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Autism Spectrum Disorder in Males with Sex Chromosome Aneuploidy: XXY/Klinefelter Syndrome, XYY, and XXYY

Tartaglia, Nicole R. MD; Wilson, Rebecca PsyD; Miller, Judith S. PhD; Rafalko, Jessica BS; Cordeiro, Lisa MS; Davis, Shanlee MD; Hessl, David PhD; Ross, Judith MD

Journal of Developmental & Behavioral Pediatrics: April 2017 - Volume 38 - Issue 3 - p 197–207
doi: 10.1097/DBP.0000000000000429
Original Articles

Objective: Neurodevelopmental concerns in males with sex chromosome aneuploidy (SCA) (XXY/Klinefelter syndrome, XYY, XXYY) include symptoms seen in autism spectrum disorder (ASD), such as language impairments and social difficulties. We aimed to: (1) evaluate ASD characteristics in research cohorts of SCA males under DSM-IV compared to DSM-5 criteria, and (2) analyze factors associated with ASD diagnoses in SCA.

Methods: Evaluation of participants with XXY/KS (n=20), XYY (n=57) and XXYY (n=21) included medical history, cognitive/adaptive testing, Social Communication Questionnaire, Social Responsiveness Scale, Autism Diagnostic Observation Schedule, Autism Diagnostic Interview-Revised, and DSM ASD criteria. Clinical impressions of ASD diagnostic category using the ADOS and DSM-IV criteria were compared to ADOS-2 and DSM-5 criteria. T-tests compared cognitive, adaptive, SES and prenatal vs. postnatal diagnoses between ASD and no ASD groups.

Results: ASD rates in these research cohorts were 10% in XXY/KS, 38% in XYY, and 52% in XXYY using ADOS-2/DSM-5, and were not statistically different compared to DSM-IV criteria. In XYY and XXYY, the ASD group had lower verbal IQ and adaptive functioning compared to those without ASD. Many children without ASD still showed some social difficulties.

Conclusion: ASD rates in males with SCA are higher than reported for the general population. Males with Y chromosome aneuploidy (XYY and XXYY) were 4.8 times more likely to have a diagnosis of ASD than the XXY/KS group, and 20 times more likely than males in the general population (1 in 42 males, CDC 2010). ASD should be considered when evaluating social difficulties in SCA. Studies of SCA and Y-chromosome genes may provide insight into male predominance in idiopathic ASD.

*Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO;

eXtraordinarY Kids Clinic, Developmental Pediatrics, Children's Hospital Colorado, Aurora, CO;

Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA;

§Department of Pediatrics, Nemours/DuPont Hospital for Children, Thomas Jefferson University, Philadelphia, PA;

MIND Institute, University of California Davis Medical Center, Sacramento, CA;

Department of Psychiatry and Behavioral Sciences, University of California Davis School of Medicine, Davis, CA.

Address for reprints: Nicole R. Tartaglia, MD, Developmental Pediatrics, Children's Hospital Colorado, 13123 East 16th Avenue, B140, Aurora, CO 80045; e-mail:

Supported by The Children's Miracle Network of the UC Davis Medical Center, NIH/NCATS Colorado CTSA Grant Number UL1 TR001082, NIH Pediatric LRP and NINDS K23NS070337 to N. R. Tartaglia; and NIH MH77554 to D. Hessl. JR acknowledges support from the Thomas Jefferson University Dean's Transformational Science Award, US Department of Defense CDMRP AR140197, and 1 R21 MH109158. Contents are the authors' sole responsibility and do not necessarily represent official NIH views.

Disclosure: The authors declare no conflict of interest.

Received April , 2016

Accepted January , 2017

Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved.