thin basement membrane disease

**Genetics/Pathophysiology:** Most commonly autosomal dominant heterozygous mutations in COL4A3 or COL4A4 (chromosome 2q), which encode the alpha-3 and alpha-4 chains of type IV collagen (the α3α4α5 network in the GBM). Carrier state of the genes that, when homozygous or compound heterozygous, cause autosomal recessive Alport syndrome. The defective collagen network produces a uniformly thin GBM that is fragile, allowing RBCs to leak into urine.

**Clinical features:** - Persistent (often lifelong) isolated microscopic hematuria, often found incidentally in childhood or on screening; episodic gross hematuria may occur with infection or exercise. - Dysmorphic RBCs and sometimes RBC casts (glomerular origin). - Minimal or no proteinuria, normal BP, normal GFR. - Positive family history of hematuria (but no renal failure, deafness, or eye findings). - Usually benign; a minority develop mild proteinuria, hypertension, or CKD later (some cases with COL4A3/4 variants progress, and the term is increasingly viewed as part of a spectrum with Alport).

**Diagnosis:** - Urinalysis: hematuria with dysmorphic RBCs; rule out other causes (IgA nephropathy, Alport, stones, UTI). - Renal biopsy (rarely needed): light microscopy normal; immunofluorescence negative; **electron microscopy shows diffuse thinning of GBM (<~200–250 nm in adults; normal ~300–400 nm)** without splitting/lamellation. - Genetic testing for COL4A3/COL4A4 can confirm.

**Differential (high-yield comparisons):** - **Alport syndrome:** X-linked (COL4A5) most commonly; hematuria + progressive renal failure + sensorineural hearing loss + anterior lenticonus/retinal flecks; EM shows basket-weave/lamellated GBM ("split" GBM). - **IgA nephropathy (Berger):** hematuria 1–3 days after URI (synpharyngitic); mesangial IgA deposits on IF. - **Post-strep GN:** latent period 1–3 weeks, low C3, subepithelial humps.

**Management:** Reassurance, no specific therapy. Monitor BP, urine protein, and renal function periodically (e.g., annually). If proteinuria or hypertension develops, treat with ACE inhibitor/ARB. Family counseling and screening. Prognosis is generally excellent.

**Board pearl:** Child/young adult with isolated hematuria, family history of hematuria, normal creatinine, no hearing loss, and EM showing diffuse GBM thinning = thin basement membrane disease (benign familial hematuria).