Mbbs Md Study Group 1

🧬 Down Syndrome (Trisomy 21) – Comprehensive Medical Review

📌 Definition

Down syndrome is a chromosomal aneuploidy caused by the presence of an extra copy of chromosome 21, resulting in multisystem developmental abnormalities, intellectual disability, and characteristic phenotypic features.

🧪 Genetics & Etiology

Full Trisomy 21 (≈95%)
Caused by meiotic nondisjunction (most commonly maternal meiosis I error)

Robertsonian Translocation (≈3–4%)
Long arm of chromosome 21 translocated to chromosome 14 or 22
→ May be inherited (important for genetic counseling)

Mosaic Down Syndrome (≈1–2%)
Postzygotic mitotic error → mixture of normal and trisomic cells
→ Usually milder phenotype

⚠️ Risk Factors

Advanced maternal age (>35 years)

Prior affected pregnancy

Parental balanced translocation carrier

Increased maternal age → ↑ nondisjunction risk

🧬 Pathophysiology

Gene overexpression from chromosome 21 (gene dosage effect)

Key genes: DYRK1A, APP (Alzheimer link), SOD1

Leads to abnormal neuronal development, immune dysfunction, and organ malformations

👶 Clinical Features

A. Dysmorphic Features

Flat facial profile

Brachycephaly

Epicanthal folds, upslanting palpebral fissures

Brushfield spots (iris)

Small ears, protruding tongue

Short neck with excess skin

B. Musculoskeletal

Hypotonia (floppy infant)

Single transverse palmar crease

Clinodactyly (5th finger)

Sandal gap deformity

C. Growth & Development

Short stature

Delayed milestones

Mild–moderate intellectual disability

❤️ Systemic Associations

Cardiac (40–50%)

Atrioventricular septal defect (most common)

VSD, ASD

Gastrointestinal

Duodenal atresia (“double bubble” sign)

Hirschsprung disease

Endocrine

Hypothyroidism (common)

Obesity risk

Hematologic

Acute lymphoblastic leukemia (ALL)

Acute megakaryoblastic leukemia (AML-M7)

Neurological

Early-onset Alzheimer disease (APP gene)

ENT / Ophthalmology

Hearing loss

Cataracts, refractive errors

Orthopedic

Atlantoaxial instability (C1–C2)

Immunological

Increased susceptibility to infections

🔬 Diagnosis

Prenatal Screening

First trimester: Nuchal translucency + PAPP-A + β-hCG

Second trimester (Quad screen): AFP ↓, hCG ↑, Estr

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