Random Dermatology MCQ - Hereditary Angioedema

A 4-year-old boy presents with recurrent episodes of non-pitting edema of the face, extremities, and genitals. The episodes are not associated with urticaria or pruritus. His laboratory workup reveals a significantly low level of complement component C4, but a normal level of C3. Which of the following is the most likely diagnosis and the underlying complement pathway dysfunction?

A) Hereditary Angioedema (HAE); dysregulation of the classical pathway
B) Systemic Lupus Erythematosus (SLE); consumption of C3 via classical pathway
C) Bullous Pemphigoid; complement activation at the basement membrane
D) Leukocytoclastic Vasculitis; complement-mediated vessel damage
E) C3 Glomerulopathy; dysregulation of the alternative pathway

Correct Answer: A) Hereditary Angioedema (HAE); dysregulation of the classical pathway

Explanation

This presentation is classic for Hereditary Angioedema (HAE), a disorder characterized by recurrent, self-limiting attacks of angioedema without urticaria.

Key Clinical Features of HAE:

• Angioedema: Swelling of the face, extremities, gastrointestinal tract (causing abdominal pain), and airways (can be life-threatening).

• Absence of Urticaria: This is a critical distinguishing feature from histamine-mediated angioedema (e.g., in allergic reactions).

• Family History: Often autosomal dominant.

Role of Complement and Pathophysiology:

• Deficiency: HAE is most commonly caused by a deficiency of C1 esterase inhibitor (C1-INH).

• Complement Pathway Dysregulation: C1-INH normally inhibits the classical complement pathway (by inhibiting C1r and C1s) and the lectin pathway. It also inhibits the contact system (Factor XII and kallikrein) in the kinin pathway.

• Mechanism of Swelling: In HAE, the lack of C1-INH leads to uncontrolled activation of the contact system. This results in excessive production of bradykinin, a potent vasodilator that causes vascular leakage and edema. The complement system is a "bystander" in this process.

• Lab Findings:

  • Low C4: Because C1 is continuously activated without inhibition, C4 is constantly cleaved, leading to chronically low levels, even between attacks. This is a hallmark diagnostic finding.

  • Normal C3: The enzymatic cascade does not proceed far enough to significantly consume C3, which is downstream of C4. This is a key differentiator from other complement-consuming diseases.

Why Not the Other Options?

• (B) Systemic Lupus Erythematosus (SLE): Causes consumption of both C3 and C4 due to widespread immune complex formation and classical pathway activation.

• (C) Bullous Pemphigoid: Complement (C3) is deposited at the basement membrane, but levels in the blood are typically normal. It does not cause angioedema.

• (D) Leukocytoclastic Vasculitis: Can involve complement, but it is not characterized by isolated C4 consumption or recurrent non-urticarial angioedema.

• (E) C3 Glomerulopathy: Involves dysregulation of the alternative pathway, leading to low C3 but normal C4 levels.

Management of HAE:

• Acute Attacks: C1-INH concentrate, icatibant (bradykinin B2 receptor antagonist), ecallantide (kallikrein inhibitor).

• Prophylaxis: Attenuated androgens (danazol), tranexamic acid, or regular C1-INH infusions.

Prognosis:
With modern treatments, the prognosis is good, but untreated, HAE carries a significant risk of mortality from laryngeal edema.

Note: The lab finding of low C4 with normal C3 is a crucial clue for HAE. It reflects the specific, limited complement consumption in this bradykinin-mediated disorder, distinguishing it from other complement-deficient or consuming conditions. The absence of urticaria points away from mast cell-mediated (histaminergic) angioedema.