Down syndrome (trisomy 21)

 

Down syndrome (trisomy 21)

Definition

• Down syndrome is the most common chromosomal cause of intellectual disability, caused by an extra copy of chromosome 21.

• Most common karyotype: 47,XX,+21 or 47,XY,+21.

Epidemiology

• Incidence: 1 in 700 live births.

• Risk increases with advanced maternal age.

Genetics

• Trisomy 21 due to meiotic nondisjunction (about 95%).

• Robertsonian translocation (about 4%).

• Mosaic Down syndrome (about 1%).

Pathophysiology

• Gene dosage effect from chromosome 21 causes abnormal development of the brain, heart, gastrointestinal tract, and immune system.

Clinical features

• Intellectual disability (mild to moderate).

• Neonatal hypotonia.

• Flat facial profile.

• Upward slanting palpebral fissures.

• Epicanthic folds.

• Small ears.

• Protruding tongue.

• Single transverse palmar crease.

• Clinodactyly of the fifth finger.

• Wide sandal gap between the first and second toes.

Associated abnormalities

• Cardiac: atrioventricular septal defect (most common), ventricular septal defect, atrial septal defect.

• Gastrointestinal: duodenal atresia, Hirschsprung disease.

• Endocrine: hypothyroidism.

• Hematologic: transient abnormal myelopoiesis, acute lymphoblastic leukemia, acute myeloid leukemia (megakaryoblastic type).

• Neurologic: early-onset Alzheimer disease.

• Others: hearing loss, vision problems, obstructive sleep apnea, atlantoaxial instability.

Diagnosis

• Prenatal screening: nuchal translucency, cell-free fetal DNA testing, first- and second-trimester maternal serum screening.

• Confirmatory tests: chorionic villus sampling or amniocentesis.

• Postnatal diagnosis: karyotyping (gold standard).

Management

• Early developmental intervention.

• Cardiac evaluation (echocardiography).

• Hearing and vision screening.

• Thyroid function monitoring.

• Management of congenital anomalies.

• Educational and psychosocial support.

Complications

• Congenital heart disease.

• Leukemia.

• Hypothyroidism.

• Recurrent respiratory infections.

• Obstructive sleep apnea.

• Early Alzheimer disease.

• Reduced life expectancy (improved markedly with modern care).

High-yield facts

• Most common chromosomal cause of intellectual disability.

• Most common cause: meiotic nondisjunction.

• Most common cardiac defect: atrioventricular septal defect.

• Associated with duodenal atresia and Hirschsprung disease.

• Increased risk of ALL, AML (M7), and early Alzheimer disease.

• Diagnosis is confirmed by karyotype analysis.

Academic references

1. Melmed S, et al. Williams Textbook of Endocrinology. 15th ed. Elsevier; 2024.

2. Jameson JL, et al. Harrison’s Principles of Internal Medicine. 21st ed. McGraw-Hill; 2022.

3. Kumar V, Abbas AK, Aster JC. Robbins & Cotran Pathologic Basis of Disease. 11th ed. Elsevier; 2020.

4. Kliegman RM, et al. Nelson Textbook of Pediatrics. 22nd ed. Elsevier; 2024.

5. Bull MJ; American Academy of Pediatrics. Health supervision for children and adolescents with Down syndrome. Pediatrics. 2022.

6. Antonarakis SE, et al. Down syndrome. Nature Reviews Disease Primers. 2020;6:9.

7. McPhee SJ, Papadakis MA. Current Medical Diagnosis & Treatment 2026. McGraw-Hill; 2026.