| Subtype/entity | Principal gene/protein | C4 / C1-INH antigen / function pattern | Core mechanism | Typical clinical clue | Targeted treatment classes |
|---|---|---|---|---|---|
| HAE type I (HAE-C1INH-1) | **SERPING1** / C1 inhibitor | **Low C4; low C1-INH antigen; low C1-INH function** (classic pattern) (pqac-00000016, pqac-00000005) | C1-INH deficiency permits excess contact-system activation, kallikrein activity, and **bradykinin** generation → endothelial leak (pqac-00000005, pqac-00000003) | Childhood/adolescent onset, recurrent nonurticarial skin swelling, abdominal attacks, possible laryngeal edema; attacks often last 2-5 days untreated (pqac-00000002, pqac-00000003) | On-demand **pdC1-INH/rhC1-INH**, **icatibant**, **ecallantide**; long-term prophylaxis **SC/IV C1-INH**, **lanadelumab**, **berotralstat** (pqac-00000007, pqac-00000016) |
| HAE type II (HAE-C1INH-2) | **SERPING1** / dysfunctional C1 inhibitor | **Low C4; normal or elevated C1-INH antigen; low C1-INH function** (pqac-00000016) | Dysfunctional C1-INH fails to restrain kallikrein-kinin and related protease cascades → **bradykinin-mediated** angioedema (pqac-00000016, pqac-00000005) | Similar phenotype to type I; family history may be present; recurrent angioedema without wheals and poor response to antihistamines/steroids (pqac-00000005, pqac-00000016) | Same targeted classes as HAE type I: C1-INH replacement, B2 receptor antagonism, kallikrein inhibition; prophylaxis with C1-INH, lanadelumab, berotralstat (pqac-00000007, pqac-00000016) |
| HAE-nC1INH, **F12**-associated | **F12** / factor XII | Usually **normal C4, normal C1-INH antigen, normal C1-INH function** (pqac-00000004, pqac-00000016) | Increased factor XII-driven contact activation with downstream **bradykinin** excess (pqac-00000004, pqac-00000015) | Often estrogen-sensitive; attacks can be triggered/worsened by estrogens; normal complement studies despite convincing hereditary angioedema phenotype (pqac-00000002, pqac-00000009) | Evidence-based use in practice/expert consensus: **icatibant**, **C1-INH**, kallikrein-pathway prophylaxis in selected patients; evidence base weaker than for HAE-C1INH (pqac-00000004, pqac-00000009) |
| HAE-nC1INH, **PLG**-associated | **PLG** / plasminogen | Usually **normal C4, normal C1-INH antigen, normal C1-INH function** (pqac-00000004, pqac-00000011) | Likely plasminogen/plasmin-linked promotion of **bradykinin** formation; mechanistic evidence supports bradykinin-mediated disease (pqac-00000004, pqac-00000015) | Recurrent hereditary angioedema phenotype with normal C1-INH studies; diagnosis generally requires genetics when suspected clinically (pqac-00000004, pqac-00000011) | Often treated with bradykinin-pathway agents used for HAE-C1INH; response reported but evidence remains limited/consensus-based (pqac-00000004, pqac-00000009) |
| HAE-nC1INH, **ANGPT1**-associated | **ANGPT1** / angiopoietin-1 | Usually **normal C4, normal C1-INH antigen, normal C1-INH function** (pqac-00000004, pqac-00000015) | **Endothelial barrier dysfunction**/vascular permeability mechanism rather than pure upstream C1-INH deficiency; may intersect with bradykinin pathways (pqac-00000014, pqac-00000004) | Familial nonurticarial angioedema with normal complement/C1-INH studies; clinical heterogeneity (pqac-00000004, pqac-00000014) | No subtype-specific approved therapy; HAE-directed acute/prophylactic agents are used empirically, with expert-opinion support and variable response (pqac-00000004, pqac-00000014) |
| HAE-nC1INH, **KNG1**-associated | **KNG1** / high-molecular-weight kininogen precursor | Usually **normal C4, normal C1-INH antigen, normal C1-INH function** (pqac-00000004, pqac-00000015) | Altered kininogen biology with downstream **bradykinin** dysregulation (pqac-00000015, pqac-00000004) | Hereditary angioedema phenotype despite normal standard complement workup; often requires sequencing for confirmation (pqac-00000011, pqac-00000015) | Managed with standard HAE targeted classes in practice; subtype-specific efficacy evidence remains sparse (pqac-00000004, pqac-00000009) |
| HAE-nC1INH, **MYOF**-associated | **MYOF** / myoferlin | Usually **normal C4, normal C1-INH antigen, normal C1-INH function** (pqac-00000014) | Proposed endothelial/vesicular membrane regulation abnormality; not as securely established as classic bradykinin-only forms (pqac-00000014, pqac-00000015) | In one cohort, recurrent edema with **prolonged duration**; treatment response to lanadelumab variable (pqac-00000014) | HAE-directed acute/prophylactic therapies used off-label/empirically; **variable** response reported (pqac-00000014) |
| HAE-nC1INH, **HS3ST6**-associated | **HS3ST6** / heparan sulfate 3-O-sulfotransferase 6 | Usually **normal C4, normal C1-INH antigen, normal C1-INH function** (pqac-00000014, pqac-00000015) | Proposed endothelial/glycocalyx or permeability regulation defect; causal confidence lower than **F12/PLG** (pqac-00000014, pqac-00000015) | Reported association with **refractory angioedema** and persistent lower-extremity involvement in a small cohort (pqac-00000014) | Empiric use of HAE-directed agents; personalized management needed; evidence limited (pqac-00000014) |
| HAE-nC1INH, rarer/newer candidate genes with weaker evidence | Reported/candidate: **CPN1, DAB2IP**; some literature also discusses other rare candidates with uncertain validation | Usually **normal standard complement/C1-INH studies** (pqac-00000014, pqac-00000003) | Mixed hypotheses: bradykinin dysregulation and/or **VEGF/endothelial permeability** pathways; evidence weaker and not yet equivalent to established genes (pqac-00000014, pqac-00000003) | Consider when phenotype is convincing but common genes are negative; diagnosis remains expert-dependent and may change after re-evaluation (pqac-00000011, pqac-00000014) | No gene-specific approved treatment; use individualized HAE-directed acute/prophylactic therapy with cautious interpretation of response (pqac-00000011, pqac-00000014) |
| **Acquired C1-INH deficiency** (important differential) | Acquired loss/consumption of **C1-INH** rather than inherited pathogenic variant | **Low C4; low C1-INH function; often low C1-INH antigen; C1q often low** (helps distinguish from hereditary C1-INH deficiency) (pqac-00000016, pqac-00000005) | Acquired C1-INH depletion/consumption with bradykinin-mediated angioedema (pqac-00000016, pqac-00000005) | Usually later onset, absent family history, evaluation for acquired causes warranted; C1q more informative here than in routine pediatric hereditary testing (pqac-00000005, pqac-00000016) | Acute therapy may overlap with HAE agents (C1-INH, icatibant, kallikrein-pathway agents), but management also requires treating the underlying acquired disorder (pqac-00000005, pqac-00000016) |


*Table: This table summarizes the main hereditary angioedema entities and the key differential of acquired C1-INH deficiency, highlighting diagnostic laboratory patterns, mechanisms, clinical clues, and targeted treatment classes. It is designed as a compact reference for subtype-oriented interpretation of HAE workup and management.*