A 3-year-old boy born to a 38-year-old mother is brought to the pediatric clinic for developmental delay. On examination, he has a broad flat face, upslanting palpebral fissures, a single palmar crease, and hypotonia. Cardiac auscultation reveals a systolic murmur at the left sternal border. His mother reports he achieved sitting at 10 months and is not yet walking. Karyotype analysis is ordered. What is the most likely chromosomal abnormality?

Explanation

## Clinical Presentation of Trisomy 21 **Key Point:** The constellation of facial features (broad flat face, upslanting palpebral fissures), single palmar crease, hypotonia, developmental delay, and congenital heart disease (systolic murmur suggesting ventricular septal defect) is pathognomonic for Down syndrome (trisomy 21). ## Characteristic Features of Down Syndrome ### Craniofacial Features - Broad, flat face with midface hypoplasia - Upslanting palpebral fissures (lateral upward slant) - Epicanthal folds - Low-set, malformed ears - Protruding tongue (macroglossia) - High-arched palate ### Hand and Foot Features - Single palmar crease (simian crease) — present in ~45% of cases - Short, broad hands - Clinodactyly (incurving of 5th finger) - Wide gap between 1st and 2nd toes (sandal gap) ### Developmental and Neurological Features - Hypotonia in infancy - Developmental delay (sitting ~10 months, walking ~18–24 months) - Intellectual disability (IQ typically 35–55) - Increased risk of seizures ### Cardiac Abnormalities - **Most common:** Endocardial cushion defects (atrioventricular septal defect) — 40–50% - Ventricular septal defect (VSD) — 30% - Atrial septal defect (ASD) — 10% - Tetralogy of Fallot — 5% ### Associated Conditions - Gastrointestinal: duodenal atresia, Hirschsprung disease - Hematologic: increased risk of leukemia (10–30 times higher) - Thyroid: hypothyroidism (10–15%) - Vision: refractive errors, strabismus, cataracts - Hearing: conductive and sensorual hearing loss **High-Yield:** Maternal age >35 years is the strongest risk factor. The incidence increases from 1/1500 at age 20 to 1/30 at age 45. ## Karyotype Findings in Down Syndrome | Type | Frequency | Karyotype | Inheritance | |------|-----------|-----------|-------------| | **Nondisjunction (Regular trisomy 21)** | 95% | 47,XX,+21 or 47,XY,+21 | Sporadic; maternal meiosis I error | | **Translocation** | 3–4% | 46,XX,der(14;21) or 46,XY,der(14;21) | Can be inherited; 10–15% have carrier parent | | **Mosaicism** | 1–2% | Mix of 46 and 47 chromosome lines | Milder phenotype | **Clinical Pearl:** The systolic murmur in this child is most consistent with a VSD or endocardial cushion defect, both common in trisomy 21. Echocardiography should be performed for all infants with suspected Down syndrome. ## Diagnostic Confirmation 1. **Karyotype** — gold standard; shows 47 chromosomes with trisomy 21 2. **Fluorescence in situ hybridization (FISH)** — rapid confirmation (24–48 hours) 3. **Microarray** — detects segmental aneuploidies and mosaicism 4. **Prenatal screening:** - First trimester: combined screening (nuchal translucency + PAPP-A + β-hCG) - Second trimester: quad screen (α-fetoprotein, hCG, uE3, inhibin A) - Cell-free fetal DNA (cfDNA) testing — >99% sensitivity **Mnemonic: "DOWN" = Developmental delay, Oblique palpebral fissures, Wide gap (sandal gap), Nondisjunction (trisomy 21)**