A 28-year-old woman from Delhi presents with recurrent episodes of angioedema affecting her face, lips, and throat over the past 6 months. She denies urticaria. Her family history reveals that her mother and maternal uncle also suffered from similar episodes. Laboratory investigations show normal C1q levels, normal C4 levels during symptom-free periods, but markedly reduced C4 during acute attacks. C1-esterase inhibitor (C1-INH) functional assay is abnormal. What is the most likely diagnosis?

Explanation

## Clinical Presentation The patient presents with: - Recurrent angioedema without urticaria - Positive family history (mother and maternal uncle affected) - Normal C1q and C4 at baseline - Markedly reduced C4 during acute attacks - **Abnormal C1-INH functional assay despite normal antigen levels** ## Complement Pathway Mechanism **Key Point:** C1-INH is a serine protease inhibitor that regulates the classical complement pathway (C1s inhibition) and the contact system (kallikrein inhibition). Dysfunction of C1-INH leads to uncontrolled activation of these pathways, resulting in excessive bradykinin production and angioedema. ## Differential Diagnosis of Hereditary Angioedema | Feature | Type I | Type II | Type III | |---------|--------|---------|----------| | **C1-INH Antigen** | Reduced (<50%) | Normal or elevated | Normal | | **C1-INH Function** | Reduced | Reduced/Absent | Normal | | **C4 Level** | Low (baseline) | Low (baseline) | Normal | | **Frequency** | 85% of HAE cases | 15% of HAE cases | Rare | | **Genetic Defect** | SERPING1 gene (quantitative) | SERPING1 gene (qualitative) | FACTOR XII or other genes | **High-Yield:** Type II HAE is characterized by **normal or elevated C1-INH antigen levels but dysfunctional protein**. The C1-INH molecule is present in normal quantity but has impaired inhibitory capacity. ## Why This Patient Has Type II 1. Normal C1-INH antigen levels (not mentioned as low) 2. **Abnormal functional assay** — the critical finding 3. Normal C4 at baseline, reduced during attacks (reflects acute consumption) 4. Autosomal dominant inheritance pattern (family history) **Clinical Pearl:** C4 levels fluctuate in Type II HAE — they may be normal between attacks but drop during acute episodes due to complement activation. This is different from Type I, where C4 is persistently low. ## Diagnostic Algorithm ```mermaid flowchart TD A[Recurrent Angioedema without Urticaria]:::outcome --> B{Family History?}:::decision B -->|Yes| C[Measure C1-INH Antigen & Function]:::action C --> D{C1-INH Antigen Level}:::decision D -->|Low| E[HAE Type I]:::outcome D -->|Normal/High| F{Functional Assay}:::decision F -->|Abnormal| G[HAE Type II]:::outcome F -->|Normal| H[HAE Type III or other]:::outcome B -->|No| I[Acquired C1-INH or ACE-I related]:::outcome ``` **Mnemonic:** **ANTI** for Type II — **A**ntigen Normal, **N**ormal or elevated, **T**ype II, **I**mpaired function.