Brain Tumours in Individuals with Down Syndrome: An Individual Patient Data Meta-analysis of Incidence, Patterns and Outcomes

Background Brain tumours in individuals with Down syndrome (DS) are extremely rare, and little is known about their types, locations, molecular features, or outcomes. While DS is associated with a high risk of leukemia, solid tumours—including those of the central nervous system—appear unusually uncommon. Methods We performed a systematic review and individual patient data meta-analysis of published cases of brain tumours in DS, following PRISMA guidelines. Searches of PubMed, Scopus, and Web of Science up to 2025 identified studies reporting clinical, histological, treatment, or outcome data. Data on demographics, tumour characteristics, molecular markers, therapies, and survival were extracted and analyzed using descriptive statistics, survival analysis, and risk modeling. Results Among 41 patients (mean age 13.6 years), most were pediatric (70.7%) and male (85.4%). Germ cell tumors predominated (46.3%), mainly in the basal ganglia/thalamus and pineal regions. All informative molecular tests confirmed trisomy 21 with diverse secondary alterations but no recurrent “second hit.” Intraventricular and pineal tumors showed significantly higher mortality risk (p < 0.001), while germ cell (HR 0.09, p < 0.001) and glial tumors (HR 0.22, p = 0.022) were associated with better outcomes. SALL4 (HR 16.9, p = 0.013) and GFAP positivity (HR 5.3, p = 0.039) predicted worse survival. Recurrence increased mortality risk (HR 2.98, p = 0.044). Overall survival plateaued above 50% at 5 years, with no median survival reached. Conclusions Brain tumours in DS show a distinct pattern, clustering in deep and midline structures and dominated by germ cell tumours, medulloblastomas, and high-grade gliomas. Outcomes depend primarily on tumour location and type rather than underlying comorbidities. These findings emphasize the need for careful, tailored management and highlight the importance of collaborative studies to improve understanding and treatment strategies in this vulnerable population.