Original Article Autism Spectrum Disorder in Males with Sex Chromosome Aneuploidy: XXY/Klinefelter Syndrome, XYY, and XXYY Nicole R. Tartaglia, MD,*† Rebecca Wilson, PsyD,† Judith S. Miller, PhD,‡ Jessica Rafalko, BS,§ Lisa Cordeiro, MS,*† Shanlee Davis, MD,*† David Hessl, PhD,\¶ Judith Ross, MD§ ABSTRACT: 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 (n520), XYY (n557) and XXYY (n521) 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. (J Dev Behav Pediatr 38:197–207, 2017) Index terms: XXY, Klinefelter syndrome, XYY, XXYY, autism spectrum disorder, Y chromosome. Autism spectrum disorder (ASD) is a behaviorally de- fined neurodevelopmental disorder characterized by varying degrees of deficits in domains of social commu- nication, reciprocal social interaction, and restricted, re- petitive patterns of behavior. With the publication of the DSM-5 in May 2013, there was a significant change in the diagnostic criteria of ASD to reflect the commonalities and interrelationships of these core symptoms across a wide spectrum of severities, and all cases are now classified under a single diagnosis of ASD rather than the distinct disorders in the DSM-IV of Autistic Disorder, Asperger Syndrome, and Pervasive Developmental Disorder—Not Otherwise Specified (PDD-NOS). Furthermore, the DSM-5 diagnostic criteria also emphasize the importance of neurobiological and genetic factors that may underlie the ASD symptoms, and the presence of any genetic disorders or other medical conditions known to be associated with ASD are now part of the “specifiers” to be included in the diagnostic description. This has led to an increased in- terest in genetic disorders with behavioral phenotypes that include increased rates of ASD and other social and/ or communication impairments. Genetic studies in children with ASD identify an etio- logic diagnosis in approximately 10 to up to 40% of cases, for example, chromosomal duplications and deletions, fragile X syndrome, and mutations in specific genes such as MECP2 or PTEN mutations. 1 In many studies evaluating genetic etiologies in cohorts of children with ASD, cases of sex chromosome aneuploidy (SCA) conditions in- cluding XXY/Klinefelter Syndrome (XXY/KS), XYY, and XXYY have been identified. 2–4 There have also been many case reports and case series of ASD in males with XXY/KS, XYY, and XXYY. 5–8 From the *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 Pediat- rics, 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. Received April 2016; accepted January 2017. 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 Trans- formational Science Award, US Department of Defense CDMRP AR140197, and 1 R21 MH109158. Contents are the authors’ sole responsibility and do not neces- sarily represent official NIH views. Disclosure: The authors declare no conflict of interest. Address for reprints: Nicole R. Tartaglia, MD, Developmental Pediatrics, Child- ren’s Hospital Colorado, 13123 East 16th Avenue, B140, Aurora, CO 80045; e- mail: Nicole.tartaglia@childrenscolorado.org. Copyright Ó 2017 Wolters Kluwer Health, Inc. All rights reserved. Vol. 38, No. 3, April 2017 www.jdbp.org | 197 Copyright Ó 2017 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.