A 28-year-old Indian woman presents with recurrent episodes of angioedema affecting her lips, tongue, and throat over the past 6 months. She denies urticaria or pruritus. Her family history is significant for similar episodes in her mother and maternal uncle. Laboratory investigations reveal normal C1 esterase inhibitor (C1-INH) levels and normal C1q levels. C4 levels are markedly reduced. What is the most likely diagnosis?

Explanation

## Clinical Presentation and Diagnosis This patient presents with classic hereditary angioedema (HAE) with a positive family history and recurrent angioedema without urticaria. ### Laboratory Findings Analysis | Feature | HAE Type I | HAE Type II | HAE Type III | |---------|-----------|-----------|-------------| | **C1-INH Level** | ↓ (< 50%) | Normal or ↑ | Normal | | **C1-INH Function** | Deficient | Dysfunctional | Normal | | **C4 Level** | ↓ | ↓ | Normal | | **C1q Level** | Normal | Normal | Normal | | **Frequency** | 85% of HAE | 15% of HAE | Rare | **Key Point:** In this patient, C1-INH levels are NORMAL but C4 is markedly reduced. This pattern is pathognomonic for HAE Type II (dysfunctional C1-INH). ### Pathophysiology of HAE Type II 1. Mutations in the C1-INH gene produce a structurally abnormal but quantitatively normal protein 2. The dysfunctional C1-INH cannot adequately inhibit Factor XIIa and kallikrein 3. Uncontrolled activation of the contact system leads to excessive bradykinin production 4. Bradykinin causes increased vascular permeability → angioedema 5. Persistent complement activation consumes C4 → low C4 levels despite normal C1-INH quantity **High-Yield:** The key distinguishing feature is NORMAL C1-INH quantity with LOW C4. This indicates the protein is present but not functioning properly. **Clinical Pearl:** HAE Type II patients often have higher C1-INH levels than Type I patients (sometimes even elevated), making functional assays essential for diagnosis. Serum C1-INH level alone is insufficient. ### Mnemonic: C1-INH Dysfunction Pattern **"Normal Quantity, Low Function, Low C4"** = Type II HAE ## Why This Diagnosis Fits - Recurrent angioedema without urticaria (classic for HAE) - Positive family history (autosomal dominant inheritance) - Normal C1-INH level (rules out Type I) - Low C4 (indicates complement consumption despite normal inhibitor quantity) - Normal C1q (excludes acquired C1-INH deficiency) **Tip:** Always measure C1-INH FUNCTION (by serine protease inhibition assay) in addition to quantity when HAE is suspected with normal C1-INH levels.