Kayla Molison

Sex chromosome aneuploidies (SCAs), including Klinefelter syndrome (47,XXY), Turner syndrome (45,X), XYY syndrome, trisomy X (47,XXX), and rarer tetrasomies and pentasomies, affect approximately 1 in 400 births and are associated with a wide range of developmental, cognitive, and physical health outcomes. While clinical research on SCAs has expanded over the past two decades, it is unclear whether the populations included in these studies reflect the demographic diversity of those affected. Assessing representation is critical to ensuring research findings are generalizable and applicable to diverse patient populations. We conducted a systematic review of global clinical research on SCAs published in English between January 2004 and May 2024. Searches were performed in Ovid MEDLINE ALL, Embase, and Web of Science. Studies were included if they enrolled ≥ 10 participants and excluded if they were case reports, reviews, or meta‐analyses. We extracted data from 1474 studies on geographic location, participant karyotypes, and demographic metrics, including race, ethnicity, and socioeconomic status (SES) reported. Trends in demographic reporting were examined over time and by geographic region. For US‐based studies reporting race/ethnicity, we compared pooled participant demographics to national census data. SCA research is concentrated within a small number of geographic areas, primarily in Europe (51.4%) and the United States (23.6%). Reporting rates of race or ethnicity for US papers increased over the 20‐year observation period, with an average increase of 1.5% ± 0.4% per year ( p = 0.003), peaking in 2024 with 61.4% of US‐based papers presenting demographics. When reported, studies consistently overrepresented White non‐Hispanic ( p < 0.001) and college‐educated ( p < 0.001) participants relative to US census benchmarks. This systematic review reveals persistent gaps in the demographic reporting and representation of participants in SCA research. Even in the United States, where population diversity is high, published studies do not reflect the expected racial, ethnic, and socioeconomic makeup of affected individuals. To ensure that research findings are equitable and clinically relevant, future studies should adopt standardized demographic reporting and prioritize inclusive enrollment strategies to reflect the full spectrum of individuals with SCAs.

48,XXYY syndrome is a rare sex chromosome aneuploidy (SCA) condition affecting 1 in 18,000–40,000 male births. Clinical features include tall stature, hypergonadotropic hypogonadism (testosterone deficiency), infertility, developmental delays, learning disabilities, and intellectual impairment. Co‐occurring behavior and mental health challenges are common in this population, with high rates of attention‐deficit hyperactivity disorder (ADHD), anxiety, depression, sleep disorders, irritability, and aggressive behaviors. We evaluated psychotropic medication use by parent report and retrospective chart review. Treatment success was defined as a positive response per parent report, positive clinician rating, or a treatment duration of at least 6 months. Nearly three‐quarters of participants (71/101) with a median age of 15.9 (range 4.5–38 years) had received psychotropic medications. The most common medication classes used were stimulant ADHD medications (78.9% of those with medication use), with a median age of first use of 9 years ([IQR] 7, 11 years), followed by anti‐anxiety/antidepressant medications (60.6%), with a median age of first use of 10 years ([IQR] 8, 14 years). Treatment success rates ranged from 43.9% to 84.2% for individual medication trials. Subsequent trials of medications within the same class improved success rates per person in all medication classes except for sleep and mood stabilizer medications. Treatment failure due to side effects was greatest among neuroleptics/atypical antipsychotics, whereas treatment failure due to inefficacy was greatest among anti‐anxiety/antidepressants and mood stabilizers. The findings of this study suggest that psychotropic medications targeting behavior and mental health are common and overall helpful for individuals with 48,XXYY.