Hereditary angioedema

Hereditary angioedema is a rare, potentially life-threatening multisystem disorder characterised by recurrent episodes of subcutaneous and submucosal oedema affecting the skin, gastrointestinal tract, upper airway, face, genitourinary tract, and extremities. Cutaneous attacks present as non-pitting, non-pruritic swellings; gastrointestinal involvement produces abdominal pain, distension, nausea, and vomiting that may mimic an acute surgical abdomen; laryngeal and oropharyngeal oedema is the most dangerous manifestation and can progress to asphyxiation if untreated. Symptoms typically manifest during childhood or adolescence, with a mean onset age of approximately 10 to 12 years and near-complete penetrance by early adulthood. In contrast, non-C1-inhibitor forms of hereditary angioedema frequently present later, commonly emerging during the late teens or early adulthood. Clinical expression is highly variable between and within families, with a higher frequency of symptoms reported in females with HAE with normal C1-inhibitor; stress, trauma, and hormonal influences are commonly reported triggers or exacerbating factors.

The estimated prevalence of HAE is 1/50,000. European population-based studies report prevalences for HAE with C1-inhibitor deficiency from approximately 1/200,000 (Latvia) to 1/30,000 (Austria), while HAE with normal C1-inhibitor is markedly rarer.

Hereditary angioedema is inherited in an autosomal dominant manner. Each child of an affected individual has a 50% risk of inheriting the familial pathogenic variant. Approximately 25% of families harbor a de novo pathogenic variant in SERPING1. Prenatal molecular testing is technically possible once the familial pathogenic variant has been identified.

Diagnosis is established by measuring plasma C1-inhibitor concentration and activity, along with C4 complement concentration. Laboratory findings vary by subtype:

• Type 1 HAE: shows reduced C4, C1-inhibitor concentration, and C1-inhibitor activity
• Type 2 HAE: shows reduced C1-inhibitor activity and reduced C4, alongside normal or elevated C1-inhibitor concentration
• HAE with normal C1-inhibitor: shows normal C1-inhibitor concentration and activity

Because standard complement biochemistry is non-diagnostic for this form, identifying the causative gene variant is required to establish the diagnosis.

• To establish the diagnosis at the molecular level.
• Confirming the molecular cause supports individualised clinical management, including selection of long-term prophylaxis and on-demand therapy and identification of triggers, with decisions made by the treating physicians in consultation with the affected individual.
• Identification of the familial pathogenic variant enables predictive testing of at-risk relatives, allowing early recognition and timely management of attacks.

• Abstracts of the 14th C1-inhibitor Deficiency and Angioedema Workshop. Allergy, asthma, and clinical immunology: official journal of the Canadian Society of Allergy and Clinical Immunology. 2026;21(Suppl 2):55. doi: 10.1186/s13223-025-00992-1. PMID: . PMCID: PMC12763819.
• Guryanova I, Suffritti C, Parolin D, Zanichelli A, Ishchanka N, Polyakova E, et al. Hereditary angioedema due to C1 inhibitor deficiency in Belarus: epidemiology, access to diagnosis and seven novel mutations in SERPING1 gene. Clinical and molecular allergy: CMA. 2021;19(1):3. doi: 10.1186/s12948-021-00141-0. PMID: . PMCID: PMC8028818.