Down syndrome

Etiology & Genetics - The Extra Chromosome

• Trisomy 21: Caused by an extra copy of chromosome 21.
• Primary Mechanism (95%): Meiotic nondisjunction.
  • Predominantly due to maternal gamete error (~90%), linked to advanced maternal age.
• Other Mechanisms:
  • Robertsonian Translocation (~4%): Unbalanced fusion, e.g., t(14;21). Recurrence risk is high; not age-dependent.
  • Mosaicism (~1%): Post-zygotic nondisjunction results in two cell lines. Milder features.

⭐ Risk of Trisomy 21 significantly increases with maternal age >35 years.

Clinical Features - Spotting the Signs

• General: Neonatal hypotonia, poor Moro reflex, joint hypermobility.
• Craniofacial & Neck:
  • Flat facial profile, brachycephaly (flat occiput).
  • Upslanting palpebral fissures, prominent epicanthic folds.
  • Brushfield spots (grey-white spots on iris).
  • Small nose with depressed nasal bridge.
  • Protruding tongue, high-arched palate.
  • Short neck with excess nuchal skin.
• Extremities:
  • Single transverse palmar crease (Simian crease).
  • Short, broad hands; clinodactyly (incurved 5th finger).
  • Wide space between 1st & 2nd toes (Sandal gap).

⭐ The most common associated congenital heart defect is an Atrioventricular Septal Defect (AVSD).

Systemic Associations - The Domino Effect

• Cardiovascular (~50%): Endocardial cushion defect (AVSD) is pathognomonic. Ventricular Septal Defect (VSD) and Atrial Septal Defect (ASD) are also common.
• Gastrointestinal: Duodenal atresia presents with bilious vomiting & the classic "double bubble" sign on X-ray. Also associated with Hirschsprung disease and celiac disease.
• Hematologic: ↑ risk (~20x) of Acute Lymphoblastic Leukemia (ALL). Also, Transient Myeloproliferative Disorder (TMD) in neonates.
• Endocrine: Congenital and acquired hypothyroidism are frequent; regular screening is crucial.
• Musculoskeletal/Neurologic: Atlanto-axial instability (⚠️ screen before anesthesia/sports), generalized hypotonia. Inevitable early-onset Alzheimer's disease.
• Sensory: Brushfield spots in the iris, refractive errors, and congenital cataracts. Chronic ear infections and hearing loss.

⭐ The Amyloid Precursor Protein (APP) gene is located on Chromosome 21, explaining the strong link and early onset of Alzheimer's disease.

Diagnosis & Management - Plan of Action

• Prenatal Screening:

  • 1st Trimester: ↓PAPP-A, ↑β-hCG, ↑Nuchal translucency.
  • 2nd Trimester (Quad): ↓AFP, ↓uE3, ↑β-hCG, ↑Inhibin A.

• Definitive Diagnosis: Karyotyping (postnatal) or CVS/Amniocentesis (prenatal).

• Anticipatory Guidance & Screening:

![Karyotype showing Trisomy 21 (Down Syndrome)](https://ylbwdadhbcjolwylidja.supabase.co/storage/v1/object/public/notes/L1/Pediatrics_Genetic_disorders_Down_syndrome/4b501952-5785-4fdc-8dfa-3c44dfc0a8a8.png)
- **Growth:** Use specific Down syndrome growth charts.
- **Development:** Early intervention programs (Physio, Speech therapy).

⭐ Most common heart defect is Atrioventricular Septal Defect (AVSD). Increased risk (~20x) of Acute Lymphoblastic Leukemia (ALL).

High‑Yield Points - ⚡ Biggest Takeaways

• Trisomy 21 is the most common genetic cause, strongly linked to advanced maternal age.
• Key features include a flat facies, upward-slanting eyes, Brushfield spots, and a single transverse palmar crease.
• Atrioventricular septal defect (AVSD) is the most common and characteristic cardiac anomaly.
• Look for the "double bubble" sign on X-ray, indicating duodenal atresia.
• There's a significantly increased risk of acute leukemias (ALL, AML).