Trisomy 21 results from meiotic nondisjunction (95%), Robertsonian translocation (3-4%), or mosaicism (1-2%), producing an extra copy of chromosome 21 with overexpression of over 300 genes. The DSCR (Down Syndrome Critical Region) on 21q22 drives many phenotypic features. Overexpression of DYRK1A contributes to intellectual disability, while COL6A1 and COL6A2 overexpression affects connective tissue integrity. Cardiac septal development is disrupted by altered VEGF-A signaling, resulting in endocardial cushion defects. The clinician must manage the full spectrum of health surveillance including prescribing thyroid replacement, managing cardiac follow-up, screening for hematologic malignancies, evaluating for atlantoaxial instability, and coordinating transition to adult care.