Hereditary angioedema (HAE), also called hereditary angioneurotic edema, is a rare autosomal dominant disorder characterized by recurrent episodes of nonpruritic, nonpitting swelling of the skin, submucosal tissues, and internal organs.
Attacks may be unpredictable, disabling, and sometimes life-threatening, especially with laryngeal involvement.
Epidemiology
Prevalence: Approximately 1 in 10,000–50,000 individuals worldwide. Affects both sexes and all ethnic groups equally. About 25% of cases arise from a de novo mutation without a family history. Children of affected individuals have a 50% chance of inheriting the disorder.
Primary defect Mutations in the SERPING1 gene on chromosome 11, leading to deficiency or dysfunction of C1 esterase inhibitor (C1‑INH).
C1‑INH is a serine protease inhibitor that regulates the complement, kallikrein‑kinin system, contact activation, coagulation, and fibrinolysis pathways.
Deficient or dysfunctional C1‑INH results in excess bradykinin, which increases vascular permeability and causes swelling.
In HAE Type I, C1‑INH levels are typically 5–30% of normal.
A functional threshold of 40% is needed to prevent attacks.
Type I HAE (≈85%): Low C1‑INH protein and low function. Type II HAE (≈15%):Normal or elevated C1‑INH levels, but reduced functional activity often due to missense mutations in exon 8. Type III HAE (5–10%): Normal C1‑INH levels and function; related to mutations in other bradykinin pathway components-factor XII, plasminogen. Type III is seen primarily in women and may be estrogen-dependent.
Failure of C1‑INH regulation permits uncontrolled activation of factor XIIa and plasma kallikrein, generating excessive bradykinin.
Bradykinin binds B2 receptors on endothelial cells that promote localized vascular permeability and swelling.
Despite extensive activation of coagulation and fibrinolytic cascades, patients do not have increased bleeding or thrombosis risks.
Typical childhood (mean age 8–12 years), often worsening during puberty.
Symptoms are of recurrent, circumscribed episodes of swelling affecting: Skin (face, extremities, genitals, trunk)
Gastrointestinal tract (severe colicky abdominal pain, nausea, vomiting, diarrhea; may mimic acute abdomen)
Upper airway (laryngeal edema occurs in ~0.9% of attacks; lifetime risk 10–15%)
Attacks may last 2–5 days and recur as often as every few days.
Prodromal signs-erythema marginatum, tingling, fatigue, or numbness.
Swelling is nonpitting, and nonpruritic.
Swelling is not associated with urticaria.
Severity is unpredictable, and delay in diagnosis may be up to 8–10 years.
Triggers:
Stress, trauma, infections, medical/surgical procedures, fatigue, and hormonal changes.
Certain drugs, notably angiotensin-converting enzyme (ACE) inhibitors and estrogen therapy, can precipitate or worsen attacks.
Diagnosis is suspected in patients with recurrent angioedema without urticaria and abdominal symptoms.
Laboratory markers: Low C4 levels C1‑INH antigenic level and functional activity assay confirm abnormalities.
Imaging such as ultrasound or CT may demonstrate bowel wall edema during abdominal attacks.
Treatment:
Prompt therapy is critical, especially for airway compromise.
First-line agents include: Intravenous or subcutaneous C1‑INH concentrate, plasma-derived or recombinant. Icatibant-bradykinin B2 receptor antagonist (subcutaneous). Ecallantidex plasma kallikrein inhibitor (subcutaneous). Antihistamines, corticosteroids, and epinephrine are usually ineffective.
Prophylaxis First-line long-term options Subcutaneous or IV C1‑INH. Lanadelumab (monoclonal antibody against plasma kallikrein). Berotralstat (oral kallikrein inhibitor).
Short-term prophylaxis before surgery/dental procedures: C1‑INH administration is preferred.
Second-line: androgens (danazol, stanozolol) and antifibrinolytics (tranexamic acid), but these have more side effects and are now less common. Donidalorsen-antisense oligonucleotide suppressing prekallikrein mRNA, reducing attack frequency. CRISPR/Cas9 gene-editing therapy targeting KLKB1 (prekallikrein), showing durable reduction in attacks. Sebetralstal-oral on-demand kallikrein inhibitor in late-stage trials.
The quality of life can be significantly impaired by frequent, unpredictable attacks.
Mortality is primarily due to asphyxiation from laryngeal edema.