Klinefelter Syndrome and ADHD: a short systematic review

Lorenzo Zamboni^1,2*Francesca Fusina^3,4Rebecca Casari¹Fabio Lugoboni¹Thomas Zandonai^5,6Sara Cappelletti⁷Angela Federico^1,7

• ¹Department of Internal Medicine, Integrated University Hospital Verona, Verona, Veneto, Italy
• ²University of Verona, Verona, Veneto, Italy
• ³Department of General Psychology, School of Psychology, University of Padua, Padua, Veneto, Italy
• ⁴Padua Neuroscience Center, University of Padua, Padua, Veneto, Italy
• ⁵Addiction Science Laboratory, Department of Psychology and Cognitive Science, University of Trento, Rovereto, Italy
• ⁶Department of Pharmacology, Pediatrics and Organic Chemistry, Miguel Hernández University of Elche, Elche, Spain
• ⁷Centro Trentino di Solidarietà ETS, Trento, Trentino-Alto Adige/Südtirol, Italy

Klinefelter Syndrome (KS) is the most common sex chromosome anomaly in the world, and it is characterized by the presence of an extra X chromosome (47, XXY). It affects approximately 1 in 500 to 1 in 1000 male births and it has been associated with various neurodevelopmental conditions, including Attention Deficit Hyperactivity Disorder (ADHD). This systematic review aims to collect and analyze existing literature on the comorbidity of KS and ADHD.A comprehensive search was conducted following PRISMA guidelines in Medline and Web of Science, covering studies from 1959 to 2024. After screening and applying inclusion/exclusion criteria, 15 studies were selected for analysis. The findings suggest a significant association between KS and ADHD, particularly concerning the inattentive subtype. Several studies reported an increased prevalence of ADHD in individuals with KS compared to the general population, with estimates ranging from 25% to 63%. Some research also indicated a higher risk for comorbid conditions such as Autism Spectrum Disorder (ASD) and mood disorders.Neuroimaging studies highlighted structural and functional differences in KS patients compared with controls, particularly in brain regions involved in executive function, working memory, and attention regulation. Despite these findings, no study provided conclusive evidence regarding a causal relationship between KS and ADHD. Additionally, pharmacological treatment for ADHD appears to be effective and well-tolerated in KS patients, with minimal side effects.Overall, this review underscores the complex and heterogeneous nature of KS-ADHD comorbidity; however, variability in study populations and methodologies limits the ability to draw definitive conclusions. Further research is necessary to clarify the potential mechanisms linking KS and ADHD and to develop tailored clinical approaches for individuals affected by both conditions.