XXYY syndrome occurs in approximately 1:18,000-1:40,000 males. Although the physical phenotype is similar to 47,XXY (tall stature, hypergonadotropic hypogonadism, and infertility), XXYY is associated with additional medical problems and more significant neurodevelopmental and psychological features. We report on the results of a cross-sectional, multicenter study of 95 males age 1-55 with XXYY syndrome (mean age 14.9 years), describing diagnosis, physical features, medical problems, medications, and psychological features stratified by age groups. The mean age of diagnosis was 7.7 years. Developmental delays and behavioral problems were the most common primary indication for genetic testing (68.4%). Physical and facial features varied with age, although hypertelorism, clinodactyly, pes planus, and dental problems were common across all age groups. Tall stature was present in adolescents and adults, with a mean adult stature of 192.4 cm (SD 7.5; n = 22). Common medical problems included allergies and asthma (>50%), congenital heart defects (19.4%), radioulnar synostosis (17.2%), inguinal hernia and/or cryptorchidism (16.1%), and seizures (15%). Medical features in adulthood included hypogonadism (100%), DVT (18.2%), intention tremor (71%) and type II diabetes (18.2%). Brain MRI (n = 35) showed white matter abnormalities in 45.7% of patients and enlarged ventricles in 22.8%. Neurodevelopmental and psychological difficulties were a significant component of the behavioral phenotype, with developmental delays and learning disabilities universal but variable in severity. Twenty-six percent had full-scale IQs in the range of intellectual disability (MR), and adaptive functioning was significantly impacted with 68% with adaptive composite scores <70. Rates of neurodevelopmental disorders, including ADHD (72.2%), autism spectrum disorders (28.3%), mood disorders (46.8%), and tic disorders (18.9%), were elevated with 55.9% on psychopharmacologic medication overall. Recommendations for evaluation and treatment are summarized.

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Objective Neurodevelopmental concerns in males with sex chromosome aneuploidy (SCA) (XXY/Klinefelter syndrome, XYY, and XXYY) include many symptoms seen in autism spectrum disorder (ASD), such as speech-language impairment, verbal cognitive deficits, and social difficulties. Studies using standardized ASD assessment measures in SCA are few, and rates of ASD diagnosis in SCA using DSM-5 criteria for ASD have not been explored. We aimed to: (1) evaluate ASD characteristics in research cohorts of males with SCA using standardized assessments under DSM-IV compared to DSM-5 criteria, and (2) analyze whether type of SCA, prenatal vs. postnatal diagnosis, cognitive abilities, adaptive functioning, and socioeconomic status are associated with ASD diagnosis. Methods Participants from two sites with XXY/KS (n=20), XYY (n=57) and XXYY (n=21) were evaluated using protocols including medical history, cognitive testing, adaptive functioning, the Social Communication Questionnaire, Social Responsiveness Scale, Autism Diagnostic Observations Schedule (ADOS), the Autism Diagnostic Interview-Revised (ADI-R), and DSM criteria for ASD. Clinical impressions of ASD diagnostic category using the ADOS and DSM-IV criteria were compared to the ADOS-2 and DSM-5 criteria. T-tests were used to compare cognitive, adaptive, SES and prenatal vs. postnatal diagnoses between ASD versus no ASD groups determined by DSM-5 criteria. Results ASD rates in these research cohorts using DSM-IV criteria were 5% in XXY/KS, 33% in XYY, and 43% in XXYY. Rates of 10% in XXY/KS, 38% in XYY, and 52% in XXYY using ADOS-2 and DSM-5 criteria were not statistically higher. In both XYY and XXYY, the ASD group had lower verbal IQ and adaptive functioning compared to the group without ASD. Many children with SCA who did not meet full ASD criteria showed some deficits in social communication or social interaction skills. Conclusion The rate of ASD in children with SCA in this study was higher than expected compared to 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 based on the 2010 Centers for Disease Control (CDC) estimate of 1 in 42 males. ASD is an important consideration when evaluating social difficulties for children with SCA. Studies of males with SCA and Y-chromosome genes may provide insight into idiopathic ASD and male predominance in ASD.

ClinicalTrials.gov: NCT00348946.