trisomy 21

Trisomy 21 arises most commonly (~95%) from meiotic nondisjunction of chromosome 21, resulting in three full copies of the chromosome; incidence rises sharply with advanced maternal age (e.g., 1/1500 at age 20 vs 1/25 at age 45) due to age-related increase in meiotic errors. Less common causes include Robertsonian translocation (~4%, not associated with maternal age, may be inherited from a carrier parent) and mosaicism (~1%, often milder phenotype). Clinical features include flat facies, epicanthal folds, upslanting palpebral fissures, Brushfield spots, single palmar crease, hypotonia, short stature, and intellectual disability. Down syndrome is associated with numerous comorbidities: congenital heart defects (especially endocardial cushion defects/AV septal defect, VSD), duodenal atresia, Hirschsprung disease, increased risk of ALL and AML, early-onset Alzheimer disease (due to triplicated APP gene on chromosome 21), hypothyroidism, atlantoaxial instability, and obstructive sleep apnea. Prenatal screening involves first-trimester combined test (nuchal translucency, β-hCG increased, PAPP-A decreased) and second-trimester quad screen (↓AFP, ↑β-hCG, ↓estriol, ↑inhibin A); cell-free fetal DNA testing offers high sensitivity/specificity. Definitive diagnosis requires karyotype via chorionic villus sampling or amniocentesis. Management is multidisciplinary, addressing cardiac, endocrine, developmental, and orthopedic issues throughout life.