Let’s DANCE with Diagnosis: Harmonizing Nomenclature and Differential Diagnosis in Angioedema

Angioedema (AE) is defined as a paroxysmal, localized, self-limiting swelling of the subcutaneous and/or submucosal tissue due to transiently increased vascular permeability. Despite its seemingly straightforward clinical appearance, AE represents a heterogeneous group of disorders with distinct pathomechanisms, prognoses, and therapeutic implications. Up to one-third of emergency consultations for edematous states raise the question of AE, making accurate classification crucial for optimal management. The landmark consensus by Marco Cicardi and the Hereditary Angioedema International Working Group established the first structured, evidence-based framework for AE. More recently, the international Definition, Acronyms, Nomenclature, and Classification of Angioedema initiative (DANCE) proposed a comprehensive endotype-driven model integrating clinical expression, biomarkers, genetics, and underlying mechanisms. The DANCE classification recognizes five principal endotypes: mast cell–mediated AE (AE-MC), bradykinin-mediated AE (AE-BK), vascular endothelial dysfunction–associated AE (AE-VE), drug-induced AE (AE-DI), and angioedema of unknown cause (AE-UNK). AE-MC, the most prevalent form, is driven by mast cell degranulation and includes urticaria-associated AE and anaphylaxis-related swelling. AE-BK encompasses hereditary angioedema with C1 inhibitor deficiency due to SERPING1 variants and hereditary angioedema with normal C1 inhibitor linked to mutations in genes such as F12, PLG, and KNG1, as well as acquired C1 inhibitor deficiency. AE-VE introduces the concept of intrinsic endothelial dysfunction, including rare genotypes (e.g., ANGPT1, MYOF, HS3ST6, and DAB2IP) and systemic capillary leak syndrome (Clarkson disease). AE-DI highlights renin–angiotensin–aldosterone system modifiers, nonsteroidal anti-inflammatory drugs, estrogens, and related agents as triggers or amplifiers; AE-UNK remains a heterogeneous and therapeutically underserved category, warranting longitudinal follow-up and re-evaluation. A major clinical challenge remains the differential diagnosis of AE-like conditions. Careful history, targeted laboratory assessment, and awareness of endotype-specific features are essential. An updated, harmonized nomenclature and endotype-based classification enhances diagnostic precision, facilitates interdisciplinary communication, and ultimately improves patient outcomes in both common and rare forms of angioedema.