✅ Model Answer:
• Diagnosis: Alport syndrome (X-linked COL4A5 mutation).
• Evidence: Microscopic hematuria, sensorineural hearing loss, anterior lenticonus, X-linked family history (maternal uncle with ESKD).
• Next step: Skin biopsy (absent α5 chain of type IV collagen) or genetic testing (COL4A5). ACE inhibitor if proteinuria develops. Monitor creatinine, BP, and hearing annually.

✅ Model Answer:
• Genes: COL4A5 (X-linked, ~80%), COL4A3, COL4A4 (autosomal recessive, ~15%), COL4A3/COL4A4 (autosomal dominant, rare).
• Chromosome: COL4A5 on Xq22.3; COL4A3/COL4A4 on chromosome 2.
• Protein: Type IV collagen α3/α4/α5 chains – essential for glomerular basement membrane (GBM) integrity.
• Pathophysiology: Mutation leads to defective GBM → thinning and splitting → hematuria, proteinuria, progressive CKD.
• Inheritance: X-linked dominant (most common) – males are severely affected; females variable (lyonization).
• Prevalence: 1 in 5,000-10,000.

✅ Model Answer:
• Classic triad:
- Hematuria: Persistent microscopic hematuria (present from childhood) – may have episodic gross hematuria.
- Sensorineural hearing loss: High-frequency loss (progressive, usually by adolescence).
- Ocular abnormalities: Anterior lenticonus (pathognomonic), posterior cataracts, retinopathy (dot-and-fleck).
• Renal: Proteinuria (develops later), progressive CKD → ESKD by 20-40 years in males.
• Other features: Leiomyomatosis (esophageal, tracheobronchial – rare), thrombocytopenia (rare).
• Females: Usually milder; microscopic hematuria, hearing loss (less common), ESKD rare.

✅ Model Answer:
• Urinalysis: Microscopic hematuria (dysmorphic RBCs), progressive proteinuria.
• Family history: X-linked pattern (maternal uncles, male cousins affected).
• Audiometry: High-frequency sensorineural hearing loss.
• Ophthalmology: Anterior lenticonus (pathognomonic), retinopathy.
• Skin biopsy: Immunofluorescence for α5 chain of type IV collagen – absent in males (X-linked) or reduced in females.
• Renal biopsy: Electron microscopy shows GBM thinning and splitting ("basket-weave" appearance).
• Genetic testing: COL4A5, COL4A3, COL4A4 – confirmatory.
• Creatinine/eGFR: Monitor renal function.

✅ Model Answer:
• ACE inhibitors/ARBs:
- First-line: Even in normotensive patients with microalbuminuria (slows progression of CKD).
- Dose: Enalapril 0.1-0.5 mg/kg/day or lisinopril 0.1-0.4 mg/kg/day.
- Goal: Reduce proteinuria, delay ESKD.
• Blood pressure control: Target <130/80 mm Hg (or <120/75 in children).
• Hearing aids: For sensorineural hearing loss.
• Ophthalmology follow-up: For cataracts, lenticonus.
• Renal transplantation: For ESKD – excellent outcomes; recurrence is rare (<5%).
• Gene therapy: Emerging (not yet standard).
• Avoid: NSAIDs, aminoglycosides (nephrotoxic).

✅ Model Answer:
• End-stage kidney disease (ESKD): Males develop ESKD by 20-40 years; females rarely develop ESKD.
• Hearing loss: Progressive sensorineural hearing loss; may require hearing aids.
• Ocular complications: Anterior lenticonus (may require cataract surgery), retinopathy, macular holes.
• Hypertension: Often develops with declining renal function.
• Leiomyomatosis: Smooth muscle tumors (esophagus, trachea, bronchi) – rare.
• Thrombocytopenia: Rare, associated with COL4A5 mutations.
• Recurrent gross hematuria: After infections or exercise.
• Post-transplant anti-GBM disease: Rare (<5%) – can cause rapid graft loss.

✅ Model Answer:
• Prognosis:
- Males (X-linked): ESKD by 20-40 years (90% by age 40).
- Females (X-linked): Usually normal life expectancy; ESKD in <10%.
- Autosomal recessive: Similar to X-linked males (severe).
- Autosomal dominant: Milder course; ESKD in adulthood.
- ACE inhibitors: Slow progression of CKD.
• Long-term follow-up:
- Monitor BP: Every 3-6 months.
- Monitor proteinuria: Spot urine protein/creatinine ratio every 3-6 months.
- Monitor creatinine/eGFR: Every 6-12 months.
- Audiometry: Every 1-2 years.
- Ophthalmology: Annual eye exams.
- Genetic counseling: For family members (X-linked, autosomal recessive/dominant).
- Transplantation: Renal transplantation has excellent outcomes.

✅ Model Answer:
• Alport syndrome:
- Inheritance: X-linked (most), AR, AD.
- Hematuria: Persistent microscopic + episodic gross.
- Proteinuria: Progressive.
- Hearing loss: Sensorineural (progressive).
- Ocular: Anterior lenticonus, retinopathy.
- Renal biopsy: GBM thinning AND splitting (basket-weave).
- Prognosis: ESKD by 20-40 years (males).
- Treatment: ACE inhibitors, transplantation.
• Thin basement membrane disease (TBMD):
- Inheritance: Autosomal dominant (COL4A3/COL4A4).
- Hematuria: Persistent microscopic only (no gross hematuria).
- Proteinuria: Minimal or absent.
- Hearing loss: Absent.
- Ocular: Normal.
- Renal biopsy: GBM thinning ONLY (no splitting).
- Prognosis: Benign (no ESKD).
- Treatment: None (reassurance).