Updated International Consensus on HAE-nC1INH Diagnosis and Treatment

A new international consensus review in Clinical Reviews in Allergy & Immunology developed by global experts convened by HAE International (HAEi) and the US HAE Association (HAEA), clarifies classification, diagnosis, pathophysiology, and treatment approaches for clinicians managing HAE-nC1IN, a a rare, often under-recognized subtype of hereditary angioedema (HAE).

HAE-nC1INH presents unique diagnostic and management challenges relative to classical C1 inhibitor-deficient HAE and mast cell–mediated angioedema. Given the rarity and heterogeneity of the condition, high-level evidence remains scarce; recommendations are grounded in extensive expert consensus.

Summary of Consensus Findings

The 2025 consensus categorizes recurrent angioedema without hives into distinct mechanistic subtypes and emphasizes the importance of accurate differentiation from other forms of angioedema. HAE-nC1INH is characterized by normal C1 inhibitor quantity and function, with pathogenic variants identified in multiple genes.

Despite the low prevalence—estimates suggest fewer than 1 in 100,000 to 1 in 250,000 individuals worldwide may have HAE-nC1INH—the review notes a growing registry of genetically confirmed cases and an expanding understanding of underlying mechanisms. Attack characteristics often include slower onset, longer duration, and frequent abdominal involvement compared with mast cell–mediated angioedema, and standard antihistamine or corticosteroid therapy is ineffective.

The consensus outlines a stepwise diagnostic algorithm incorporating clinical history (recurrent angioedema without urticaria); exclusion of C1INH deficiency via laboratory testing; response to therapeutic trials; and targeted genetic testing when indicated. Early referral to angioedema specialists is recommended when conventional workup is inconclusive.

Clinical Implications for Practice

For clinicians in immunology, allergy, and emergency care, recognizing HAE-nC1INH is crucial because misclassification delays appropriate bradykinin-targeted therapy such as C1INH concentrates, bradykinin B2 receptor antagonists (e.g., icatibant), or plasma kallikrein inhibitors. Unlike mast cell–mediated angioedema, HAE-nC1INH does not respond to antihistamines, steroids, or epinephrine, underscoring the need for mechanism-specific management.

The review highlights genotype-phenotype variability and the role of estrogen exposure in triggering attacks, particularly in some subtypes (e.g., HAE-FXII). Clinicians should assess hormonal factors and consider prophylactic strategies tailored to individual risk profiles.

Expert Commentary

The inability to make definitive diagnoses severely limits our ability to conduct clinical trials to elucidate treatment options,” the authors wrote. “Thus, we recommend that concerted efforts be made to validate accurate biomarkers that can improve diagnosis and treatment of these patients. Since HAE-nC1INH is a rare disease, national or international registries will be essential for learning more about the natural history and response to treatment .”

Reference:

 Zuraw BL, Bork K, Bouillet L, et al. Hereditary angioedema with normal C1 inhibitor: an updated international consensus paper on diagnosis, pathophysiology, and treatment. Clin Rev Allergy Immunol. 2025;68:24. DOI:10.1007/s12016-025-09027-4.