Hereditary Angioedema

Mendelian MONDO:0019623 Pathograph 12 Angioedema Hereditary Skin Disorder

Hereditary angioedema is an autosomal dominant bradykinin-mediated angioedema spectrum with recurrent non-urticarial subcutaneous, gastrointestinal, and upper-airway edema attacks. Classic type 1 and type 2 disease result from quantitative or qualitative C1 inhibitor defects caused by SERPING1 variants; normal-C1-INH forms are genetically heterogeneous and include F12-, PLG-, KNG1-, ANGPT1-, HS3ST6-, and MYOF-associated disease.

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1
Mappings
2
Definitions
1
Inheritance
4
Pathophys.
19
Phenotypes
12
Pathograph
4
Genes
5
Treatments
7
Subtypes
19
References
1
Deep Research
🔗

Mappings

MONDO
MONDO:0019623 hereditary angioedema
skos:exactMatch Orphanet ORPHA:91378
MONDO:0019623 is the active MONDO disease term for the Orphanet clinical group ORPHA:91378.
📘

Definitions

2
C1-INH-deficiency hereditary angioedema definition
Hereditary angioedema with C1-INH deficiency is characterized by recurrent subcutaneous or submucosal edema without urticaria caused by quantitative or qualitative C1 inhibitor defects.
OTHER
Show evidence (1 reference)
ORPHA:528623 SUPPORT Other
"A rare hereditary angioedema characterized by potentially life-threatening episodes of subcutaneous and/or submucosal edema without urticaria, associated with C1 esterase inhibitor (C1-INH) deficiency."
Orphanet supports the C1-INH-deficiency disease definition.
Normal-C1-INH hereditary angioedema definition
Normal-C1-INH HAE has recurrent non-urticarial edema attacks despite normal C1 inhibitor level and function, with subtype-specific genetics and estrogen-sensitive triggers in some families.
OTHER
Show evidence (1 reference)
ORPHA:528647 SUPPORT Other
"Estrogen-containing oral contraceptives and pregnancy are precipitating factors, especially in patients with a factor XII mutation."
Orphanet supports normal-C1-INH HAE and estrogen-associated triggering.
👪

Inheritance

1
Autosomal dominant inheritance HP:0000006
HAE is usually autosomal dominant across SERPING1-related and normal-C1-INH subtypes.
Autosomal dominant inheritance
Show evidence (3 references)
PMID:36609679 SUPPORT Human Clinical
"Hereditary angioedema (HAE) is an autosomal dominant disorder caused by a mutation in the C1 esterase inhibitor gene."
The clinical review supports autosomal dominant inheritance for classic HAE.
ORPHA:100050 SUPPORT Other
"Autosomal dominant"
Orphanet records autosomal dominant inheritance for HAE type 1.
ORPHA:100054 SUPPORT Other
"Autosomal dominant"
Orphanet records autosomal dominant inheritance for F12-related normal-C1-INH HAE.
◆

Subtypes

7
Hereditary angioedema with C1 inhibitor deficiency MONDO:0033946
SERPING1 link
Disease branch encompassing type 1 quantitative C1-INH deficiency and type 2 qualitative C1-INH dysfunction caused by SERPING1 variants.
Show evidence (1 reference)
ORPHA:528623 SUPPORT Other
"Hereditary angioedema (HAE) type 1 is caused by quantitative, HAE type 2 by qualitative defects of C1-INH."
Orphanet defines the two C1-INH-deficiency subtypes.
Hereditary angioedema type 1 MONDO:0015053
SERPING1 link
Etiologic subtype with reduced circulating C1 inhibitor concentration caused by SERPING1 pathogenic variants.
Show evidence (2 references)
ORPHA:100050 SUPPORT Other
"MONDO:0015053 | Exact"
Orphanet maps HAE type 1 to MONDO:0015053.
ORPHA:100050 SUPPORT Other
"SERPING1 | serpin family G member 1 | hgnc:1228 | Disease-causing germline mutation(s) in"
Orphanet lists SERPING1 as the disease-causing gene for type 1 HAE.
Hereditary angioedema type 2 MONDO:0015054
SERPING1 link
Etiologic subtype with dysfunctional C1 inhibitor protein caused by SERPING1 pathogenic variants.
Show evidence (2 references)
ORPHA:100051 SUPPORT Other
"MONDO:0015054 | Exact"
Orphanet maps HAE type 2 to MONDO:0015054.
ORPHA:100051 SUPPORT Other
"SERPING1 | serpin family G member 1 | hgnc:1228 | Disease-causing germline mutation(s) in"
Orphanet lists SERPING1 as the disease-causing gene for type 2 HAE.
Hereditary angioedema with normal C1 inhibitor MONDO:0100567
Heterogeneous disease branch with normal C1 inhibitor level and function, including F12, PLG, KNG1, ANGPT1, HS3ST6, MYOF, and unknown-gene families.
Show evidence (2 references)
ORPHA:528647 SUPPORT Other
"A rare hereditary angioedema characterized by potentially life-threatening episodes of subcutaneous and/or submucosal edema without urticaria and with normal levels and function of C1 esterase inhibitor."
Orphanet defines the normal-C1-INH disease branch.
PMID:40053270 SUPPORT Other
"new types of apparent non-mast cell-mediated angioedema with normal quantity and activity of C1INH have been described"
The consensus paper supports normal-C1-INH HAE as a genetically heterogeneous branch.
F12-related hereditary angioedema with normal C1 inhibitor MONDO:0012526
F12 link
Normal-C1-INH subtype caused by gain-of-function F12 variants and often precipitated or worsened by high estrogen states.
Show evidence (2 references)
ORPHA:100054 SUPPORT Other
"F12 | coagulation factor XII | hgnc:3530 | Disease-causing germline mutation(s) (gain of function) in"
Orphanet identifies F12 gain-of-function variation as disease-causing.
ORPHA:100054 SUPPORT Other
"MONDO:0012526 | Exact"
Orphanet maps this subtype to MONDO:0012526.
PLG-related hereditary angioedema with normal C1 inhibitor MONDO:0035220
PLG link
Normal-C1-INH subtype associated with disease-causing PLG variants.
Show evidence (2 references)
ORPHA:537072 SUPPORT Other
"PLG | plasminogen | hgnc:9071 | Disease-causing germline mutation(s) in"
Orphanet identifies PLG as the disease-causing gene for this subtype.
ORPHA:537072 SUPPORT Other
"MONDO:0035220 | Exact"
Orphanet maps PLG-related HAE to MONDO:0035220.
Normal-C1-INH hereditary angioedema not related to F12 or PLG MONDO:0035734
ANGPT1 link HS3ST6 link KNG1 link MYOF link
Normal-C1-INH HAE subtype grouping non-F12, non-PLG families with ANGPT1-, HS3ST6-, KNG1-, or MYOF-associated disease.
Show evidence (2 references)
ORPHA:599418 SUPPORT Other
"MONDO:0035734 | Exact"
Orphanet maps this normal-C1-INH subtype group to MONDO:0035734.
ORPHA:599418 SUPPORT Other
"KNG1 | kininogen 1 | hgnc:6383 | Disease-causing germline mutation(s) in"
Orphanet lists KNG1 among disease-causing genes for this subtype group.
⚙

Pathophysiology

4
SERPING1 C1 inhibitor deficiency or dysfunction
SERPING1 pathogenic variants cause quantitative C1-INH deficiency in type 1 HAE or qualitative C1-INH dysfunction in type 2 HAE, reducing regulation of complement, coagulation, fibrinolytic, and contact-system cascades.
SERPING1 link
complement activation link ⚠ ABNORMAL blood coagulation link ⚠ ABNORMAL fibrinolysis link ⚠ ABNORMAL
Downstream
Excess bradykinin signaling Loss or dysfunction of C1-INH permits contact-system activation and excess bradykinin signaling.
Show evidence (2 references)
PMID:36609679 SUPPORT Human Clinical
"Type I and II HAE result from a mutation in the SERPING1 gene, which encodes C1-INH."
Review evidence supports SERPING1 as the classic HAE causal gene.
PMID:36609679 SUPPORT Human Clinical
"C1-INH is important in the coagulation complement, contact systems, and fibrinolysis."
Review evidence supports the regulated pathways affected by C1-INH deficiency.
Normal C1-INH contact-system gene dysregulation
Normal-C1-INH HAE includes genetically defined non-mast-cell angioedema families with F12, PLG, KNG1, ANGPT1, HS3ST6, MYOF, or other variants that converge on bradykinin-mediated or contact-system angioedema biology.
F12 link PLG link KNG1 link ANGPT1 link HS3ST6 link MYOF link
regulation of vascular permeability link ⚠ ABNORMAL
Downstream
Excess bradykinin signaling Normal-C1-INH HAE variants converge on non-mast-cell angioedema pathways that produce bradykinin-mediated swelling.
Show evidence (2 references)
PMID:40053270 SUPPORT Other
"proven genetic pathogenic variants that co-segregate with angioedema expression within families."
Consensus evidence supports familial pathogenic variants in normal-C1-INH HAE.
PMID:36609679 SUPPORT Human Clinical
"underlying mutations such as in kininogen-1 (HAE-KNG1), plasminogen gene (PLG-HAE), myoferlin gene mutation (MYOF-HAE), heparan sulfate-glucosamine 3-sulfotransferase 6 (HS3ST6), mutation in Hageman factor (factor XII), and in angiopoietin-1 (HAE-ANGPT-1)."
Review evidence lists the normal-C1-INH genetic heterogeneity captured in this node.
Excess bradykinin signaling
Excess bradykinin is the central mediator of HAE attacks, increasing vascular permeability in superficial tissues and gastrointestinal and respiratory mucosa.
regulation of vascular permeability link ↑ INCREASED
Downstream
Vascular permeability and recurrent edema attacks Bradykinin-driven permeability produces recurrent skin, gastrointestinal, and airway edema attacks.
Show evidence (2 references)
PMID:35442579 SUPPORT Human Clinical
"excessive bradykinin production, with subsequent increased vascular permeability"
Review evidence directly supports the bradykinin-to-permeability mechanism.
PMID:20818888 SUPPORT Human Clinical
"Bradykinin is the key mediator of symptoms."
Randomized-trial background identifies bradykinin as the mediator of HAE symptoms.
Vascular permeability and recurrent edema attacks
Increased vascular permeability causes transitory, recurrent, nonpitting subcutaneous and submucosal edema attacks involving skin, abdomen, genital tissues, pharynx, and larynx.
regulation of vascular permeability link ↑ INCREASED
Show evidence (2 references)
ORPHA:528623 SUPPORT Other
"recurrent attacks of nonpitting edema of the skin, severe abdominal symptoms such as pain and swelling, and/or respiratory distress due to upper respiratory airways involvement."
Orphanet supports recurrent edema attacks involving skin, abdomen, and airway.
ORPHA:528647 SUPPORT Other
"Patients present with prolonged attacks which last for approximately two to five days and may include nonpitting edema of the skin, severe abdominal symptoms such as pain and swelling, and/or respiratory distress due to upper respiratory airways involvement."
Orphanet supports the same recurrent edema-attack phenotype in normal-C1-INH disease.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Hereditary Angioedema Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

19
Digestive 2
Diarrhea FREQUENT Diarrhea (HP:0002014)
Temporal: RECURRENT
Show evidence (1 reference)
ORPHA:528623 SUPPORT Other
"HP:0002014 | Diarrhea | Frequent (79-30%)"
Orphanet records diarrhea as frequent in C1-INH-deficiency HAE.
Nausea and vomiting FREQUENT Nausea and vomiting (HP:0002017)
Temporal: RECURRENT
Show evidence (1 reference)
ORPHA:528623 SUPPORT Other
"HP:0002017 | Nausea and vomiting | Frequent (79-30%)"
Orphanet records nausea and vomiting as frequent in C1-INH-deficiency HAE.
Head and Neck 1
Facial edema FREQUENT Facial edema (HP:0000282)
Temporal: RECURRENT
Show evidence (1 reference)
ORPHA:528623 SUPPORT Other
"HP:0000282 | Facial edema | Frequent (79-30%)"
Orphanet records facial edema as frequent in C1-INH-deficiency HAE.
Immune 1
Skin rash FREQUENT Skin rash (HP:0000988)
Temporal: RECURRENT
Show evidence (1 reference)
ORPHA:528623 SUPPORT Other
"HP:0000988 | Skin rash | Frequent (79-30%)"
Orphanet records skin rash as frequent in C1-INH-deficiency HAE.
Metabolism 1
Joint swelling FREQUENT Joint swelling (HP:0001386)
Temporal: RECURRENT
Show evidence (1 reference)
ORPHA:528623 SUPPORT Other
"HP:0001386 | Joint swelling | Frequent (79-30%)"
Orphanet records joint swelling as frequent in C1-INH-deficiency HAE.
Constitutional 2
Abdominal pain FREQUENT Abdominal pain (HP:0002027)
Temporal: RECURRENT
Show evidence (1 reference)
ORPHA:528623 SUPPORT Other
"HP:0002027 | Abdominal pain | Frequent (79-30%)"
Orphanet records abdominal pain as frequent in C1-INH-deficiency HAE.
Painful angioedema attacks FREQUENT Pain (HP:0012531)
Temporal: RECURRENT
Show evidence (1 reference)
ORPHA:528623 SUPPORT Other
"HP:0012531 | Pain | Frequent (79-30%)"
Orphanet records pain as frequent in C1-INH-deficiency HAE.
Other 12
Angioedema VERY_FREQUENT Angioedema (HP:0100665)
Temporal: RECURRENT
Show evidence (1 reference)
ORPHA:528647 SUPPORT Other
"HP:0100665 | Angioedema | Very frequent (99-80%)"
Orphanet records angioedema as very frequent in normal-C1-INH disease.
Non-pitting edema FREQUENT Non-pitting edema (HP:6000507)
Temporal: RECURRENT
Show evidence (1 reference)
ORPHA:528623 SUPPORT Other
"HP:6000507 | Non-pitting edema | Frequent (79-30%)"
Orphanet records non-pitting edema as frequent in C1-INH-deficiency HAE.
Intestinal edema FREQUENT Intestinal edema (HP:0005225)
Temporal: RECURRENT
Show evidence (1 reference)
ORPHA:528647 SUPPORT Other
"HP:0005225 | Intestinal edema | Frequent (79-30%)"
Orphanet records intestinal edema as frequent in normal-C1-INH HAE.
Laryngeal edema FREQUENT Laryngeal edema (HP:0012027)
Temporal: RECURRENT
Show evidence (1 reference)
ORPHA:528623 SUPPORT Other
"HP:0012027 | Laryngeal edema | Frequent (79-30%)"
Orphanet records laryngeal edema as frequent in C1-INH-deficiency HAE.
Pharyngeal edema FREQUENT Pharyngeal edema (HP:0011855)
Temporal: RECURRENT
Show evidence (1 reference)
ORPHA:528623 SUPPORT Other
"HP:0011855 | Pharyngeal edema | Frequent (79-30%)"
Orphanet records pharyngeal edema as frequent in C1-INH-deficiency HAE.
Genital edema FREQUENT Genital edema (HP:0031188)
Temporal: RECURRENT
Show evidence (1 reference)
ORPHA:528623 SUPPORT Other
"HP:0031188 | Genital edema | Frequent (79-30%)"
Orphanet records genital edema as frequent in C1-INH-deficiency HAE.
Edema of the upper limbs FREQUENT Edema of the upper limbs (HP:0010742)
Temporal: RECURRENT
Show evidence (1 reference)
ORPHA:528647 SUPPORT Other
"HP:0010742 | Edema of the upper limbs | Frequent (79-30%)"
Orphanet records edema of the upper limbs as frequent in normal-C1-INH HAE.
Muscular edema FREQUENT Muscular edema (HP:0100748)
Temporal: RECURRENT
Show evidence (1 reference)
ORPHA:528623 SUPPORT Other
"HP:0100748 | Muscular edema | Frequent (79-30%)"
Orphanet records muscular edema as frequent in C1-INH-deficiency HAE.
Serpiginous cutaneous lesion FREQUENT Serpiginous cutaneous lesion (HP:0025527)
Temporal: RECURRENT
Show evidence (1 reference)
ORPHA:528623 SUPPORT Other
"HP:0025527 | Serpiginous cutaneous lesion | Frequent (79-30%)"
Orphanet records serpiginous cutaneous lesion as frequent in C1-INH-deficiency HAE.
Erythema marginatum FREQUENT Erythema marginatum (HP:6001012)
Temporal: RECURRENT
Show evidence (1 reference)
ORPHA:528623 SUPPORT Other
"HP:6001012 | Erythema marginatum | Frequent (79-30%)"
Orphanet records erythema marginatum as frequent in C1-INH-deficiency HAE.
Decreased circulating C1-esterase inhibitor concentration FREQUENT Decreased circulating C1-esterase inhibitor concentration (HP:0034204)
Show evidence (1 reference)
ORPHA:528623 SUPPORT Other
"HP:0034204 | Decreased circulating C1-esterase inhibitor concentration | Frequent (79-30%)"
Orphanet records decreased circulating C1-INH concentration as frequent in the C1-INH-deficiency branch.
Decreased circulating complement C4 concentration FREQUENT Decreased circulating complement C4 concentration (HP:0045042)
This phenotype is subtype-specific; ORPHA:528647 excludes decreased C4 in normal-C1-INH HAE.
Show evidence (1 reference)
ORPHA:528623 SUPPORT Other
"HP:0045042 | Decreased circulating complement C4 concentration | Frequent (79-30%)"
Orphanet records decreased circulating C4 as frequent in the C1-INH-deficiency branch.
🧬

Genetic Associations

4
SERPING1 (Causative gene for type 1 and type 2 HAE)
Autosomal dominant inheritance
Show evidence (2 references)
ORPHA:100050 SUPPORT Other
"SERPING1 | serpin family G member 1 | hgnc:1228 | Disease-causing germline mutation(s) in"
Orphanet lists SERPING1 as disease-causing for type 1 HAE.
ORPHA:100051 SUPPORT Other
"SERPING1 | serpin family G member 1 | hgnc:1228 | Disease-causing germline mutation(s) in"
Orphanet lists SERPING1 as disease-causing for type 2 HAE.
F12 (Causative gene for estrogen-sensitive normal-C1-INH HAE)
Autosomal dominant inheritance
Show evidence (1 reference)
ORPHA:100054 SUPPORT Other
"F12 | coagulation factor XII | hgnc:3530 | Disease-causing germline mutation(s) (gain of function) in"
Orphanet records F12 gain-of-function variants as disease-causing.
PLG (Causative gene for PLG-related normal-C1-INH HAE)
Autosomal dominant inheritance
Show evidence (1 reference)
ORPHA:537072 SUPPORT Other
"PLG | plasminogen | hgnc:9071 | Disease-causing germline mutation(s) in"
Orphanet records PLG as disease-causing for this subtype.
Normal-C1-INH genetic heterogeneity (Causative genes for non-F12/non-PLG normal-C1-INH HAE)
Show evidence (3 references)
ORPHA:599418 SUPPORT Other
"ANGPT1 | angiopoietin 1 | hgnc:484 | Disease-causing germline mutation(s) in"
Orphanet lists ANGPT1 as disease-causing in this subtype group.
ORPHA:599418 SUPPORT Other
"HS3ST6 | heparan sulfate-glucosamine 3-sulfotransferase 6 | hgnc:14178 | Disease-causing germline mutation(s) in"
Orphanet lists HS3ST6 as disease-causing in this subtype group.
ORPHA:599418 SUPPORT Other
"MYOF | myoferlin | hgnc:3656 | Disease-causing germline mutation(s) in"
Orphanet lists MYOF as disease-causing in this subtype group.
💊

Treatments

5
C1 inhibitor replacement prophylaxis
Action: Pharmacotherapy NCIT:C15986
Plasma-derived or recombinant C1-INH replacement restores the deficient regulator in C1-INH-deficiency HAE and can be used for long-term prophylaxis against attacks.
Mechanism Target:
RESTORES SERPING1 C1 inhibitor deficiency or dysfunction — C1-INH replacement restores the missing or dysfunctional inhibitor protein.
Show evidence (1 reference)
PMID:28328347 SUPPORT Human Clinical
"In patients with hereditary angioedema, the prophylactic use of a subcutaneous C1 inhibitor twice weekly significantly reduced the frequency of acute attacks."
Phase 3 COMPACT trial evidence supports C1-INH replacement prophylaxis.
Show evidence (1 reference)
PMID:28328347 SUPPORT Human Clinical
"In patients with hereditary angioedema, the prophylactic use of a subcutaneous C1 inhibitor twice weekly significantly reduced the frequency of acute attacks."
Randomized clinical-trial evidence supports subcutaneous C1 inhibitor prophylaxis.
Icatibant acute attack therapy
Action: Pharmacotherapy NCIT:C15986
Agent: icatibant ↗
Icatibant is a bradykinin B2 receptor antagonist used as on-demand treatment for acute HAE attacks.
Mechanism Target:
INHIBITS Excess bradykinin signaling — Icatibant blocks bradykinin B2 receptor signaling during an acute attack.
Show evidence (1 reference)
PMID:20818888 SUPPORT Human Clinical
"Icatibant is a selective bradykinin B2 receptor antagonist."
Trial background directly states the drug mechanism.
Show evidence (1 reference)
PMID:20818888 SUPPORT Human Clinical
"In FAST-2, the median time to clinically significant relief of the index symptom was 2.0 hours with icatibant versus 12.0 hours with tranexamic acid (P<0.001)"
Randomized trial evidence supports acute attack efficacy.
Ecallantide acute attack therapy
Action: Pharmacotherapy NCIT:C15986
Agent: ecallantide ↗
Ecallantide inhibits plasma kallikrein and thereby reduces bradykinin production during acute HAE attacks.
Mechanism Target:
INHIBITS Excess bradykinin signaling — Plasma kallikrein inhibition reduces bradykinin generation during attacks.
Show evidence (1 reference)
PMID:21481442 SUPPORT Human Clinical
"Ecallantide, a novel plasma kallikrein inhibitor, inhibits production of bradykinin, the key mediator of these angioedema attacks."
Integrated phase 3 evidence states the drug mechanism.
Show evidence (1 reference)
PMID:21481442 SUPPORT Human Clinical
"Compared with placebo, ecallantide resulted in significantly greater reduction in MSCS scores from baseline to 4 hours after dosing"
Integrated phase 3 evidence supports ecallantide efficacy for acute attacks.
Sebetralstat oral acute attack therapy
Action: Pharmacotherapy NCIT:C15986
Agent: sebetralstat ↗
Sebetralstat is an oral plasma kallikrein inhibitor for on-demand treatment of HAE attacks due to C1-INH deficiency.
Mechanism Target:
INHIBITS Excess bradykinin signaling — Oral kallikrein inhibition reduces attack-associated bradykinin signaling.
Show evidence (1 reference)
PMID:40886933 SUPPORT Human Clinical
"Sebetralstat, an oral plasma kallikrein inhibitor"
Open-label extension evidence states the oral kallikrein-inhibitor mechanism.
Show evidence (1 reference)
PMID:40886933 SUPPORT Human Clinical
"No new safety signals were observed, and effectiveness for repeated attacks was consistent with the KONFIDENT trial results."
Extension evidence supports repeated-attack effectiveness of sebetralstat.
Long-term kallikrein-pathway prophylaxis
Action: Pharmacotherapy NCIT:C15986
Agent: lanadelumab ↗ berotralstat ↗ donidalorsen ↗
Long-term prophylaxis can target plasma kallikrein or prekallikrein with agents such as lanadelumab, berotralstat, and donidalorsen to reduce attack frequency.
Mechanism Target:
INHIBITS Excess bradykinin signaling — Kallikrein or prekallikrein targeting reduces bradykinin generation upstream of edema attacks.
Show evidence (1 reference)
PMID:30480729 SUPPORT Human Clinical
"lanadelumab, a fully human monoclonal antibody that selectively inhibits active plasma kallikrein"
Phase 3 trial evidence states the lanadelumab mechanism.
Show evidence (3 references)
PMID:30480729 SUPPORT Human Clinical
"treatment with subcutaneous lanadelumab for 26 weeks significantly reduced the attack rate compared with placebo."
Randomized trial evidence supports lanadelumab prophylaxis.
PMID:33866032 SUPPORT Human Clinical
"Berotralstat (BCX7353) is a recently approved, oral, once-daily kallikrein inhibitor for hereditary angioedema (HAE) prophylaxis."
APeX-2 evidence supports oral berotralstat prophylaxis.
PMID:41767175 SUPPORT Human Clinical
"Donidalorsen demonstrated sustained reductions in HAE attack rate, improvements in QoL, and an acceptable safety profile after 1 year of treatment."
OASISplus extension evidence supports donidalorsen long-term prophylaxis.
🔬

Biochemical Markers

2
Reduced C1 inhibitor concentration or function (DECREASED)
Context: Type 1 HAE has low circulating C1-INH concentration, while type 2 HAE has dysfunctional C1-INH despite SERPING1-related disease.
Show evidence (2 references)
ORPHA:528623 SUPPORT Other
"Hereditary angioedema (HAE) type 1 is caused by quantitative, HAE type 2 by qualitative defects of C1-INH."
Orphanet supports both quantitative and qualitative C1-INH abnormalities.
PMID:36609679 SUPPORT Human Clinical
"Type I is characterized by a deficiency in C1-INH."
The review supports reduced C1-INH in type 1 HAE.
Reduced complement C4 during C1-INH-deficiency attacks (DECREASED)
Context: Low C4 supports the C1-INH-deficiency branch, but Orphanet specifically excludes decreased C4 for normal-C1-INH disease.
Show evidence (2 references)
ORPHA:528623 SUPPORT Other
"HP:0045042 | Decreased circulating complement C4 concentration | Frequent (79-30%)"
Orphanet records decreased circulating C4 as frequent in C1-INH-deficiency HAE.
PMID:36609679 SUPPORT Human Clinical
"C4 and D-dimer levels can also be monitored if an acute HAE attack is suspected."
Review evidence supports C4 as an acute-attack laboratory marker.
{ }

Source YAML

click to show 
name: Hereditary Angioedema
creation_date: "2026-05-09T10:09:02Z"
updated_date: "2026-05-09T10:09:02Z"
category: Mendelian
description: >-
  Hereditary angioedema is an autosomal dominant bradykinin-mediated angioedema
  spectrum with recurrent non-urticarial subcutaneous, gastrointestinal, and
  upper-airway edema attacks. Classic type 1 and type 2 disease result from
  quantitative or qualitative C1 inhibitor defects caused by SERPING1 variants;
  normal-C1-INH forms are genetically heterogeneous and include F12-, PLG-,
  KNG1-, ANGPT1-, HS3ST6-, and MYOF-associated disease.
disease_term:
  preferred_term: hereditary angioedema
  term:
    id: MONDO:0019623
    label: hereditary angioedema
synonyms:
- HAE
- hereditary angioneurotic edema
- familial angioneurotic edema
- hereditary bradykinin-induced angioedema
parents:
- Angioedema
- Hereditary Skin Disorder
notes: >-
  MONDO maps the broad disease concept to Orphanet ORPHA:91378, but ORPHA:91378
  is an Orphanet clinical-group record and is not emitted by the current
  structured Orphanet cache builder, which caches leaf disorders and subtypes.
  This entry therefore cites the generated Orphanet caches for the two principal
  disease records, ORPHA:528623 and ORPHA:528647, plus the generated subtype
  records. ORPHA:528647 currently emits obsolete MONDO:0033947 as its
  cross-reference; this entry uses the active replacement MONDO:0100567 for the
  normal-C1-INH subtype.
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0019623
      label: hereditary angioedema
    mapping_predicate: skos:exactMatch
    mapping_source: Orphanet ORPHA:91378
    mapping_justification: >-
      MONDO:0019623 is the active MONDO disease term for the Orphanet clinical
      group ORPHA:91378.
external_assertions:
- name: Orphanet hereditary angioedema with C1Inh deficiency record
  source: Orphanet
  assertion_type: structured_disease_record
  external_id: ORPHA:528623
  url: http://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=en&Expert=528623
  description: >-
    Orphanet's structured record for hereditary angioedema with C1 inhibitor
    deficiency provides the definition, epidemiology, phenotype-frequency table,
    and MONDO cross-reference used for the C1-INH-deficiency branch.
  evidence:
  - reference: ORPHA:528623
    reference_title: "Hereditary angioedema with C1Inh deficiency (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "MONDO:0033946 | Exact"
    explanation: Orphanet maps ORPHA:528623 to MONDO:0033946.
- name: Orphanet hereditary angioedema with normal C1Inh record
  source: Orphanet
  assertion_type: structured_disease_record
  external_id: ORPHA:528647
  url: http://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=en&Expert=528647
  description: >-
    Orphanet's structured record for hereditary angioedema with normal C1
    inhibitor provides the disease definition and HPO phenotype-frequency table
    used for the normal-C1-INH branch.
  evidence:
  - reference: ORPHA:528647
    reference_title: "Hereditary angioedema with normal C1Inh (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      A rare hereditary angioedema characterized by potentially life-threatening
      episodes of subcutaneous and/or submucosal edema without urticaria and
      with normal levels and function of C1 esterase inhibitor.
    explanation: Orphanet defines the normal-C1-INH HAE disease branch.
definitions:
- name: C1-INH-deficiency hereditary angioedema definition
  definition_type: OTHER
  description: >-
    Hereditary angioedema with C1-INH deficiency is characterized by recurrent
    subcutaneous or submucosal edema without urticaria caused by quantitative or
    qualitative C1 inhibitor defects.
  evidence:
  - reference: ORPHA:528623
    reference_title: "Hereditary angioedema with C1Inh deficiency (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      A rare hereditary angioedema characterized by potentially life-threatening
      episodes of subcutaneous and/or submucosal edema without urticaria,
      associated with C1 esterase inhibitor (C1-INH) deficiency.
    explanation: Orphanet supports the C1-INH-deficiency disease definition.
- name: Normal-C1-INH hereditary angioedema definition
  definition_type: OTHER
  description: >-
    Normal-C1-INH HAE has recurrent non-urticarial edema attacks despite normal
    C1 inhibitor level and function, with subtype-specific genetics and
    estrogen-sensitive triggers in some families.
  evidence:
  - reference: ORPHA:528647
    reference_title: "Hereditary angioedema with normal C1Inh (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Estrogen-containing oral contraceptives and pregnancy are precipitating
      factors, especially in patients with a factor XII mutation.
    explanation: Orphanet supports normal-C1-INH HAE and estrogen-associated triggering.
has_subtypes:
- name: C1-INH deficiency
  display_name: Hereditary angioedema with C1 inhibitor deficiency
  subtype_term:
    preferred_term: hereditary angioedema with C1Inh deficiency
    term:
      id: MONDO:0033946
      label: hereditary angioedema with C1Inh deficiency
  genes:
  - preferred_term: SERPING1
    term:
      id: hgnc:1228
      label: SERPING1
  description: >-
    Disease branch encompassing type 1 quantitative C1-INH deficiency and type 2
    qualitative C1-INH dysfunction caused by SERPING1 variants.
  evidence:
  - reference: ORPHA:528623
    reference_title: "Hereditary angioedema with C1Inh deficiency (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Hereditary angioedema (HAE) type 1 is caused by quantitative, HAE type 2
      by qualitative defects of C1-INH.
    explanation: Orphanet defines the two C1-INH-deficiency subtypes.
- name: Type 1
  display_name: Hereditary angioedema type 1
  subtype_term:
    preferred_term: hereditary angioedema type 1
    term:
      id: MONDO:0015053
      label: hereditary angioedema type 1
  genes:
  - preferred_term: SERPING1
    term:
      id: hgnc:1228
      label: SERPING1
  description: >-
    Etiologic subtype with reduced circulating C1 inhibitor concentration caused
    by SERPING1 pathogenic variants.
  evidence:
  - reference: ORPHA:100050
    reference_title: "Hereditary angioedema type 1 (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "MONDO:0015053 | Exact"
    explanation: Orphanet maps HAE type 1 to MONDO:0015053.
  - reference: ORPHA:100050
    reference_title: "Hereditary angioedema type 1 (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "SERPING1 | serpin family G member 1 | hgnc:1228 | Disease-causing germline mutation(s) in"
    explanation: Orphanet lists SERPING1 as the disease-causing gene for type 1 HAE.
- name: Type 2
  display_name: Hereditary angioedema type 2
  subtype_term:
    preferred_term: hereditary angioedema type 2
    term:
      id: MONDO:0015054
      label: hereditary angioedema type 2
  genes:
  - preferred_term: SERPING1
    term:
      id: hgnc:1228
      label: SERPING1
  description: >-
    Etiologic subtype with dysfunctional C1 inhibitor protein caused by
    SERPING1 pathogenic variants.
  evidence:
  - reference: ORPHA:100051
    reference_title: "Hereditary angioedema type 2 (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "MONDO:0015054 | Exact"
    explanation: Orphanet maps HAE type 2 to MONDO:0015054.
  - reference: ORPHA:100051
    reference_title: "Hereditary angioedema type 2 (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "SERPING1 | serpin family G member 1 | hgnc:1228 | Disease-causing germline mutation(s) in"
    explanation: Orphanet lists SERPING1 as the disease-causing gene for type 2 HAE.
- name: Normal C1-INH
  display_name: Hereditary angioedema with normal C1 inhibitor
  subtype_term:
    preferred_term: hereditary angioedema with normal C1Inh
    term:
      id: MONDO:0100567
      label: hereditary angioedema with normal C1Inh
  description: >-
    Heterogeneous disease branch with normal C1 inhibitor level and function,
    including F12, PLG, KNG1, ANGPT1, HS3ST6, MYOF, and unknown-gene families.
  evidence:
  - reference: ORPHA:528647
    reference_title: "Hereditary angioedema with normal C1Inh (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      A rare hereditary angioedema characterized by potentially life-threatening
      episodes of subcutaneous and/or submucosal edema without urticaria and
      with normal levels and function of C1 esterase inhibitor.
    explanation: Orphanet defines the normal-C1-INH disease branch.
  - reference: PMID:40053270
    reference_title: "Hereditary Angioedema with Normal C1 Inhibitor: an Updated International Consensus Paper on Diagnosis, Pathophysiology, and Treatment."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      new types of apparent non-mast cell-mediated angioedema with normal
      quantity and activity of C1INH have been described
    explanation: The consensus paper supports normal-C1-INH HAE as a genetically heterogeneous branch.
- name: F12-related normal C1-INH
  display_name: F12-related hereditary angioedema with normal C1 inhibitor
  subtype_term:
    preferred_term: hereditary angioedema type 3
    term:
      id: MONDO:0012526
      label: hereditary angioedema type 3
  genes:
  - preferred_term: F12
    term:
      id: hgnc:3530
      label: F12
  description: >-
    Normal-C1-INH subtype caused by gain-of-function F12 variants and often
    precipitated or worsened by high estrogen states.
  evidence:
  - reference: ORPHA:100054
    reference_title: "F12-related hereditary angioedema with normal C1Inh (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "F12 | coagulation factor XII | hgnc:3530 | Disease-causing germline mutation(s) (gain of function) in"
    explanation: Orphanet identifies F12 gain-of-function variation as disease-causing.
  - reference: ORPHA:100054
    reference_title: "F12-related hereditary angioedema with normal C1Inh (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "MONDO:0012526 | Exact"
    explanation: Orphanet maps this subtype to MONDO:0012526.
- name: PLG-related normal C1-INH
  display_name: PLG-related hereditary angioedema with normal C1 inhibitor
  subtype_term:
    preferred_term: PLG-related hereditary angioedema with normal C1inh
    term:
      id: MONDO:0035220
      label: PLG-related hereditary angioedema with normal C1inh
  genes:
  - preferred_term: PLG
    term:
      id: hgnc:9071
      label: PLG
  description: >-
    Normal-C1-INH subtype associated with disease-causing PLG variants.
  evidence:
  - reference: ORPHA:537072
    reference_title: "PLG-related hereditary angioedema with normal C1Inh (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "PLG | plasminogen | hgnc:9071 | Disease-causing germline mutation(s) in"
    explanation: Orphanet identifies PLG as the disease-causing gene for this subtype.
  - reference: ORPHA:537072
    reference_title: "PLG-related hereditary angioedema with normal C1Inh (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "MONDO:0035220 | Exact"
    explanation: Orphanet maps PLG-related HAE to MONDO:0035220.
- name: Other normal C1-INH
  display_name: Normal-C1-INH hereditary angioedema not related to F12 or PLG
  subtype_term:
    preferred_term: hereditary angioedema with normal C1inh not related to F12 or PLG variant
    term:
      id: MONDO:0035734
      label: hereditary angioedema with normal C1inh not related to F12 or PLG variant
  genes:
  - preferred_term: ANGPT1
    term:
      id: hgnc:484
      label: ANGPT1
  - preferred_term: HS3ST6
    term:
      id: hgnc:14178
      label: HS3ST6
  - preferred_term: KNG1
    term:
      id: hgnc:6383
      label: KNG1
  - preferred_term: MYOF
    term:
      id: hgnc:3656
      label: MYOF
  description: >-
    Normal-C1-INH HAE subtype grouping non-F12, non-PLG families with
    ANGPT1-, HS3ST6-, KNG1-, or MYOF-associated disease.
  evidence:
  - reference: ORPHA:599418
    reference_title: "Hereditary angioedema with normal C1Inh not related to F12 or PLG variant (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "MONDO:0035734 | Exact"
    explanation: Orphanet maps this normal-C1-INH subtype group to MONDO:0035734.
  - reference: ORPHA:599418
    reference_title: "Hereditary angioedema with normal C1Inh not related to F12 or PLG variant (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "KNG1 | kininogen 1 | hgnc:6383 | Disease-causing germline mutation(s) in"
    explanation: Orphanet lists KNG1 among disease-causing genes for this subtype group.
inheritance:
- name: Autosomal dominant inheritance
  description: >-
    HAE is usually autosomal dominant across SERPING1-related and normal-C1-INH
    subtypes.
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  evidence:
  - reference: PMID:36609679
    reference_title: "Hereditary Angioedema: Diagnosis, Clinical Implications, and Pathophysiology."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Hereditary angioedema (HAE) is an autosomal dominant disorder caused by a
      mutation in the C1 esterase inhibitor gene.
    explanation: The clinical review supports autosomal dominant inheritance for classic HAE.
  - reference: ORPHA:100050
    reference_title: "Hereditary angioedema type 1 (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Autosomal dominant"
    explanation: Orphanet records autosomal dominant inheritance for HAE type 1.
  - reference: ORPHA:100054
    reference_title: "F12-related hereditary angioedema with normal C1Inh (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Autosomal dominant"
    explanation: Orphanet records autosomal dominant inheritance for F12-related normal-C1-INH HAE.
prevalence:
- population: Worldwide
  percentage: Unknown
  notes: >-
    HAE is rare, with contemporary pooled prevalence around 1.22 per 100,000 and
    a systematic-review conclusion of approximately 1-2 individuals per 100,000.
  evidence:
  - reference: PMID:39827848
    reference_title: "Worldwide Prevalence of Hereditary Angioedema: A Systematic Review and Meta-Analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The pooled prevalence of HAE was 1.22 cases per 100,000 people
    explanation: Meta-analysis provides a worldwide pooled prevalence estimate.
  - reference: PMID:39827848
    reference_title: "Worldwide Prevalence of Hereditary Angioedema: A Systematic Review and Meta-Analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "HAE is a rare condition which affects 1-2 individuals per 100,000 people worldwide."
    explanation: The systematic review conclusion supports the global rarity estimate.
progression:
- phase: Recurrent episodic swelling attacks
  age_range: childhood to adulthood
  notes: >-
    HAE attacks are recurrent and prolonged, with childhood-to-adult onset across
    subtypes. C1-INH-deficiency disease most commonly presents in childhood,
    while some normal-C1-INH subtypes have adult onset.
  evidence:
  - reference: ORPHA:528623
    reference_title: "Hereditary angioedema with C1Inh deficiency (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Patients may present at any age (but most commonly in childhood) with
      recurrent attacks of nonpitting edema of the skin
    explanation: Orphanet supports variable onset and recurrent attacks for C1-INH-deficiency disease.
  - reference: ORPHA:528647
    reference_title: "Hereditary angioedema with normal C1Inh (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Patients present with prolonged attacks which last for approximately two
      to five days
    explanation: Orphanet supports prolonged recurrent attacks in normal-C1-INH disease.
pathophysiology:
- name: SERPING1 C1 inhibitor deficiency or dysfunction
  description: >-
    SERPING1 pathogenic variants cause quantitative C1-INH deficiency in type 1
    HAE or qualitative C1-INH dysfunction in type 2 HAE, reducing regulation of
    complement, coagulation, fibrinolytic, and contact-system cascades.
  genes:
  - preferred_term: SERPING1
    term:
      id: hgnc:1228
      label: SERPING1
  gene_products:
  - preferred_term: C1 esterase inhibitor
    term:
      id: NCIT:C181692
      label: Plasma Protease C1 Inhibitor
  biological_processes:
  - preferred_term: complement activation
    modifier: ABNORMAL
    term:
      id: GO:0006956
      label: complement activation
  - preferred_term: blood coagulation
    modifier: ABNORMAL
    term:
      id: GO:0007596
      label: blood coagulation
  - preferred_term: fibrinolysis
    modifier: ABNORMAL
    term:
      id: GO:0042730
      label: fibrinolysis
  evidence:
  - reference: PMID:36609679
    reference_title: "Hereditary Angioedema: Diagnosis, Clinical Implications, and Pathophysiology."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Type I and II HAE result from a mutation in the SERPING1 gene, which
      encodes C1-INH.
    explanation: Review evidence supports SERPING1 as the classic HAE causal gene.
  - reference: PMID:36609679
    reference_title: "Hereditary Angioedema: Diagnosis, Clinical Implications, and Pathophysiology."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "C1-INH is important in the coagulation complement, contact systems, and fibrinolysis."
    explanation: Review evidence supports the regulated pathways affected by C1-INH deficiency.
  downstream:
  - target: Excess bradykinin signaling
    description: Loss or dysfunction of C1-INH permits contact-system activation and excess bradykinin signaling.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - contact-system dysregulation
    evidence:
    - reference: PMID:36609679
      reference_title: "Hereditary Angioedema: Diagnosis, Clinical Implications, and Pathophysiology."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Laboratory testing shows abnormal levels of C1-INH and high levels of bradykinin."
      explanation: Clinical laboratory evidence links C1-INH abnormality with elevated bradykinin.
- name: Normal C1-INH contact-system gene dysregulation
  description: >-
    Normal-C1-INH HAE includes genetically defined non-mast-cell angioedema
    families with F12, PLG, KNG1, ANGPT1, HS3ST6, MYOF, or other variants that
    converge on bradykinin-mediated or contact-system angioedema biology.
  genes:
  - preferred_term: F12
    term:
      id: hgnc:3530
      label: F12
  - preferred_term: PLG
    term:
      id: hgnc:9071
      label: PLG
  - preferred_term: KNG1
    term:
      id: hgnc:6383
      label: KNG1
  - preferred_term: ANGPT1
    term:
      id: hgnc:484
      label: ANGPT1
  - preferred_term: HS3ST6
    term:
      id: hgnc:14178
      label: HS3ST6
  - preferred_term: MYOF
    term:
      id: hgnc:3656
      label: MYOF
  biological_processes:
  - preferred_term: regulation of vascular permeability
    modifier: ABNORMAL
    term:
      id: GO:0043114
      label: regulation of vascular permeability
  evidence:
  - reference: PMID:40053270
    reference_title: "Hereditary Angioedema with Normal C1 Inhibitor: an Updated International Consensus Paper on Diagnosis, Pathophysiology, and Treatment."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      proven genetic pathogenic variants that co-segregate with angioedema
      expression within families.
    explanation: Consensus evidence supports familial pathogenic variants in normal-C1-INH HAE.
  - reference: PMID:36609679
    reference_title: "Hereditary Angioedema: Diagnosis, Clinical Implications, and Pathophysiology."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      underlying mutations such as in kininogen-1 (HAE-KNG1), plasminogen gene
      (PLG-HAE), myoferlin gene mutation (MYOF-HAE),
      heparan sulfate-glucosamine 3-sulfotransferase 6 (HS3ST6), mutation in
      Hageman factor (factor XII), and in angiopoietin-1 (HAE-ANGPT-1).
    explanation: Review evidence lists the normal-C1-INH genetic heterogeneity captured in this node.
  downstream:
  - target: Excess bradykinin signaling
    description: Normal-C1-INH HAE variants converge on non-mast-cell angioedema pathways that produce bradykinin-mediated swelling.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:40053270
      reference_title: "Hereditary Angioedema with Normal C1 Inhibitor: an Updated International Consensus Paper on Diagnosis, Pathophysiology, and Treatment."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        new types of apparent non-mast cell-mediated angioedema with normal
        quantity and activity of C1INH have been described
      explanation: The consensus paper supports non-mast-cell mechanisms in normal-C1-INH HAE.
- name: Excess bradykinin signaling
  description: >-
    Excess bradykinin is the central mediator of HAE attacks, increasing
    vascular permeability in superficial tissues and gastrointestinal and
    respiratory mucosa.
  chemical_entities:
  - preferred_term: bradykinin
    term:
      id: CHEBI:3165
      label: bradykinin
  biological_processes:
  - preferred_term: regulation of vascular permeability
    modifier: INCREASED
    term:
      id: GO:0043114
      label: regulation of vascular permeability
  evidence:
  - reference: PMID:35442579
    reference_title: "Hereditary Angioedema: A Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "excessive bradykinin production, with subsequent increased vascular permeability"
    explanation: Review evidence directly supports the bradykinin-to-permeability mechanism.
  - reference: PMID:20818888
    reference_title: "Icatibant, a new bradykinin-receptor antagonist, in hereditary angioedema."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Bradykinin is the key mediator of symptoms."
    explanation: Randomized-trial background identifies bradykinin as the mediator of HAE symptoms.
  downstream:
  - target: Vascular permeability and recurrent edema attacks
    description: Bradykinin-driven permeability produces recurrent skin, gastrointestinal, and airway edema attacks.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:35442579
      reference_title: "Hereditary Angioedema: A Review."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        increased vascular permeability in the superficial tissues and
        gastrointestinal and respiratory mucosa.
      explanation: Review evidence supports the tissue edema distribution downstream of bradykinin.
- name: Vascular permeability and recurrent edema attacks
  description: >-
    Increased vascular permeability causes transitory, recurrent, nonpitting
    subcutaneous and submucosal edema attacks involving skin, abdomen, genital
    tissues, pharynx, and larynx.
  biological_processes:
  - preferred_term: regulation of vascular permeability
    modifier: INCREASED
    term:
      id: GO:0043114
      label: regulation of vascular permeability
  evidence:
  - reference: ORPHA:528623
    reference_title: "Hereditary angioedema with C1Inh deficiency (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      recurrent attacks of nonpitting edema of the skin, severe abdominal
      symptoms such as pain and swelling, and/or respiratory distress due to
      upper respiratory airways involvement.
    explanation: Orphanet supports recurrent edema attacks involving skin, abdomen, and airway.
  - reference: ORPHA:528647
    reference_title: "Hereditary angioedema with normal C1Inh (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Patients present with prolonged attacks which last for approximately two
      to five days and may include nonpitting edema of the skin, severe
      abdominal symptoms such as pain and swelling, and/or respiratory distress
      due to upper respiratory airways involvement.
    explanation: Orphanet supports the same recurrent edema-attack phenotype in normal-C1-INH disease.
biochemical:
- name: Reduced C1 inhibitor concentration or function
  presence: DECREASED
  context: >-
    Type 1 HAE has low circulating C1-INH concentration, while type 2 HAE has
    dysfunctional C1-INH despite SERPING1-related disease.
  evidence:
  - reference: ORPHA:528623
    reference_title: "Hereditary angioedema with C1Inh deficiency (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Hereditary angioedema (HAE) type 1 is caused by quantitative, HAE type 2
      by qualitative defects of C1-INH.
    explanation: Orphanet supports both quantitative and qualitative C1-INH abnormalities.
  - reference: PMID:36609679
    reference_title: "Hereditary Angioedema: Diagnosis, Clinical Implications, and Pathophysiology."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Type I is characterized by a deficiency in C1-INH."
    explanation: The review supports reduced C1-INH in type 1 HAE.
- name: Reduced complement C4 during C1-INH-deficiency attacks
  presence: DECREASED
  context: >-
    Low C4 supports the C1-INH-deficiency branch, but Orphanet specifically
    excludes decreased C4 for normal-C1-INH disease.
  evidence:
  - reference: ORPHA:528623
    reference_title: "Hereditary angioedema with C1Inh deficiency (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0045042 | Decreased circulating complement C4 concentration | Frequent (79-30%)"
    explanation: Orphanet records decreased circulating C4 as frequent in C1-INH-deficiency HAE.
  - reference: PMID:36609679
    reference_title: "Hereditary Angioedema: Diagnosis, Clinical Implications, and Pathophysiology."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "C4 and D-dimer levels can also be monitored if an acute HAE attack is suspected."
    explanation: Review evidence supports C4 as an acute-attack laboratory marker.
genetic:
- name: SERPING1
  association: Causative gene for type 1 and type 2 HAE
  relationship_type: CAUSATIVE
  gene_term:
    preferred_term: SERPING1
    term:
      id: hgnc:1228
      label: SERPING1
  inheritance:
  - name: Autosomal dominant inheritance
  features: >-
    SERPING1 variants cause C1-INH-deficiency disease, including type 1
    quantitative deficiency and type 2 qualitative dysfunction.
  evidence:
  - reference: ORPHA:100050
    reference_title: "Hereditary angioedema type 1 (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "SERPING1 | serpin family G member 1 | hgnc:1228 | Disease-causing germline mutation(s) in"
    explanation: Orphanet lists SERPING1 as disease-causing for type 1 HAE.
  - reference: ORPHA:100051
    reference_title: "Hereditary angioedema type 2 (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "SERPING1 | serpin family G member 1 | hgnc:1228 | Disease-causing germline mutation(s) in"
    explanation: Orphanet lists SERPING1 as disease-causing for type 2 HAE.
- name: F12
  association: Causative gene for estrogen-sensitive normal-C1-INH HAE
  relationship_type: CAUSATIVE
  gene_term:
    preferred_term: F12
    term:
      id: hgnc:3530
      label: F12
  inheritance:
  - name: Autosomal dominant inheritance
  features: >-
    F12 gain-of-function variants cause the historical HAE type 3 / F12-related
    normal-C1-INH subtype.
  evidence:
  - reference: ORPHA:100054
    reference_title: "F12-related hereditary angioedema with normal C1Inh (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "F12 | coagulation factor XII | hgnc:3530 | Disease-causing germline mutation(s) (gain of function) in"
    explanation: Orphanet records F12 gain-of-function variants as disease-causing.
- name: PLG
  association: Causative gene for PLG-related normal-C1-INH HAE
  relationship_type: CAUSATIVE
  gene_term:
    preferred_term: PLG
    term:
      id: hgnc:9071
      label: PLG
  inheritance:
  - name: Autosomal dominant inheritance
  features: PLG variants cause a rare normal-C1-INH HAE subtype.
  evidence:
  - reference: ORPHA:537072
    reference_title: "PLG-related hereditary angioedema with normal C1Inh (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "PLG | plasminogen | hgnc:9071 | Disease-causing germline mutation(s) in"
    explanation: Orphanet records PLG as disease-causing for this subtype.
- name: Normal-C1-INH genetic heterogeneity
  association: Causative genes for non-F12/non-PLG normal-C1-INH HAE
  relationship_type: CAUSATIVE
  features: >-
    ANGPT1, HS3ST6, KNG1, and MYOF are recorded as disease-causing genes for
    normal-C1-INH HAE not related to F12 or PLG.
  evidence:
  - reference: ORPHA:599418
    reference_title: "Hereditary angioedema with normal C1Inh not related to F12 or PLG variant (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "ANGPT1 | angiopoietin 1 | hgnc:484 | Disease-causing germline mutation(s) in"
    explanation: Orphanet lists ANGPT1 as disease-causing in this subtype group.
  - reference: ORPHA:599418
    reference_title: "Hereditary angioedema with normal C1Inh not related to F12 or PLG variant (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HS3ST6 | heparan sulfate-glucosamine 3-sulfotransferase 6 | hgnc:14178 | Disease-causing germline mutation(s) in"
    explanation: Orphanet lists HS3ST6 as disease-causing in this subtype group.
  - reference: ORPHA:599418
    reference_title: "Hereditary angioedema with normal C1Inh not related to F12 or PLG variant (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "MYOF | myoferlin | hgnc:3656 | Disease-causing germline mutation(s) in"
    explanation: Orphanet lists MYOF as disease-causing in this subtype group.
phenotypes:
- name: Angioedema
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Angioedema
    term:
      id: HP:0100665
      label: Angioedema
    temporality: RECURRENT
  evidence:
  - reference: ORPHA:528647
    reference_title: "Hereditary angioedema with normal C1Inh (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0100665 | Angioedema | Very frequent (99-80%)"
    explanation: Orphanet records angioedema as very frequent in normal-C1-INH disease.
- name: Non-pitting edema
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Non-pitting edema
    term:
      id: HP:6000507
      label: Non-pitting edema
    temporality: RECURRENT
  evidence:
  - reference: ORPHA:528623
    reference_title: "Hereditary angioedema with C1Inh deficiency (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:6000507 | Non-pitting edema | Frequent (79-30%)"
    explanation: Orphanet records non-pitting edema as frequent in C1-INH-deficiency HAE.
- name: Facial edema
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Facial edema
    term:
      id: HP:0000282
      label: Facial edema
    temporality: RECURRENT
  evidence:
  - reference: ORPHA:528623
    reference_title: "Hereditary angioedema with C1Inh deficiency (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000282 | Facial edema | Frequent (79-30%)"
    explanation: Orphanet records facial edema as frequent in C1-INH-deficiency HAE.
- name: Skin rash
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Skin rash
    term:
      id: HP:0000988
      label: Skin rash
    temporality: RECURRENT
  evidence:
  - reference: ORPHA:528623
    reference_title: "Hereditary angioedema with C1Inh deficiency (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000988 | Skin rash | Frequent (79-30%)"
    explanation: Orphanet records skin rash as frequent in C1-INH-deficiency HAE.
- name: Abdominal pain
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Abdominal pain
    term:
      id: HP:0002027
      label: Abdominal pain
    temporality: RECURRENT
  evidence:
  - reference: ORPHA:528623
    reference_title: "Hereditary angioedema with C1Inh deficiency (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002027 | Abdominal pain | Frequent (79-30%)"
    explanation: Orphanet records abdominal pain as frequent in C1-INH-deficiency HAE.
- name: Intestinal edema
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Intestinal edema
    term:
      id: HP:0005225
      label: Intestinal edema
    temporality: RECURRENT
  evidence:
  - reference: ORPHA:528647
    reference_title: "Hereditary angioedema with normal C1Inh (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0005225 | Intestinal edema | Frequent (79-30%)"
    explanation: Orphanet records intestinal edema as frequent in normal-C1-INH HAE.
- name: Laryngeal edema
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Laryngeal edema
    term:
      id: HP:0012027
      label: Laryngeal edema
    temporality: RECURRENT
  evidence:
  - reference: ORPHA:528623
    reference_title: "Hereditary angioedema with C1Inh deficiency (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0012027 | Laryngeal edema | Frequent (79-30%)"
    explanation: Orphanet records laryngeal edema as frequent in C1-INH-deficiency HAE.
- name: Pharyngeal edema
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Pharyngeal edema
    term:
      id: HP:0011855
      label: Pharyngeal edema
    temporality: RECURRENT
  evidence:
  - reference: ORPHA:528623
    reference_title: "Hereditary angioedema with C1Inh deficiency (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0011855 | Pharyngeal edema | Frequent (79-30%)"
    explanation: Orphanet records pharyngeal edema as frequent in C1-INH-deficiency HAE.
- name: Genital edema
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Genital edema
    term:
      id: HP:0031188
      label: Genital edema
    temporality: RECURRENT
  evidence:
  - reference: ORPHA:528623
    reference_title: "Hereditary angioedema with C1Inh deficiency (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0031188 | Genital edema | Frequent (79-30%)"
    explanation: Orphanet records genital edema as frequent in C1-INH-deficiency HAE.
- name: Edema of the upper limbs
  subtype: Normal C1-INH
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Edema of the upper limbs
    term:
      id: HP:0010742
      label: Edema of the upper limbs
    temporality: RECURRENT
  evidence:
  - reference: ORPHA:528647
    reference_title: "Hereditary angioedema with normal C1Inh (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0010742 | Edema of the upper limbs | Frequent (79-30%)"
    explanation: Orphanet records edema of the upper limbs as frequent in normal-C1-INH HAE.
- name: Muscular edema
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Muscular edema
    term:
      id: HP:0100748
      label: Muscular edema
    temporality: RECURRENT
  evidence:
  - reference: ORPHA:528623
    reference_title: "Hereditary angioedema with C1Inh deficiency (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0100748 | Muscular edema | Frequent (79-30%)"
    explanation: Orphanet records muscular edema as frequent in C1-INH-deficiency HAE.
- name: Joint swelling
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Joint swelling
    term:
      id: HP:0001386
      label: Joint swelling
    temporality: RECURRENT
  evidence:
  - reference: ORPHA:528623
    reference_title: "Hereditary angioedema with C1Inh deficiency (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001386 | Joint swelling | Frequent (79-30%)"
    explanation: Orphanet records joint swelling as frequent in C1-INH-deficiency HAE.
- name: Diarrhea
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Diarrhea
    term:
      id: HP:0002014
      label: Diarrhea
    temporality: RECURRENT
  evidence:
  - reference: ORPHA:528623
    reference_title: "Hereditary angioedema with C1Inh deficiency (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002014 | Diarrhea | Frequent (79-30%)"
    explanation: Orphanet records diarrhea as frequent in C1-INH-deficiency HAE.
- name: Nausea and vomiting
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Nausea and vomiting
    term:
      id: HP:0002017
      label: Nausea and vomiting
    temporality: RECURRENT
  evidence:
  - reference: ORPHA:528623
    reference_title: "Hereditary angioedema with C1Inh deficiency (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002017 | Nausea and vomiting | Frequent (79-30%)"
    explanation: Orphanet records nausea and vomiting as frequent in C1-INH-deficiency HAE.
- name: Painful angioedema attacks
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Pain
    term:
      id: HP:0012531
      label: Pain
    temporality: RECURRENT
  evidence:
  - reference: ORPHA:528623
    reference_title: "Hereditary angioedema with C1Inh deficiency (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0012531 | Pain | Frequent (79-30%)"
    explanation: Orphanet records pain as frequent in C1-INH-deficiency HAE.
- name: Serpiginous cutaneous lesion
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Serpiginous cutaneous lesion
    term:
      id: HP:0025527
      label: Serpiginous cutaneous lesion
    temporality: RECURRENT
  evidence:
  - reference: ORPHA:528623
    reference_title: "Hereditary angioedema with C1Inh deficiency (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0025527 | Serpiginous cutaneous lesion | Frequent (79-30%)"
    explanation: Orphanet records serpiginous cutaneous lesion as frequent in C1-INH-deficiency HAE.
- name: Erythema marginatum
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Erythema marginatum
    term:
      id: HP:6001012
      label: Erythema marginatum
    temporality: RECURRENT
  evidence:
  - reference: ORPHA:528623
    reference_title: "Hereditary angioedema with C1Inh deficiency (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:6001012 | Erythema marginatum | Frequent (79-30%)"
    explanation: Orphanet records erythema marginatum as frequent in C1-INH-deficiency HAE.
- name: Decreased circulating C1-esterase inhibitor concentration
  subtype: C1-INH deficiency
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Decreased circulating C1-esterase inhibitor concentration
    term:
      id: HP:0034204
      label: Decreased circulating C1-esterase inhibitor concentration
  evidence:
  - reference: ORPHA:528623
    reference_title: "Hereditary angioedema with C1Inh deficiency (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0034204 | Decreased circulating C1-esterase inhibitor concentration | Frequent (79-30%)"
    explanation: Orphanet records decreased circulating C1-INH concentration as frequent in the C1-INH-deficiency branch.
- name: Decreased circulating complement C4 concentration
  subtype: C1-INH deficiency
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Decreased circulating complement C4 concentration
    term:
      id: HP:0045042
      label: Decreased circulating complement C4 concentration
  notes: >-
    This phenotype is subtype-specific; ORPHA:528647 excludes decreased C4 in
    normal-C1-INH HAE.
  evidence:
  - reference: ORPHA:528623
    reference_title: "Hereditary angioedema with C1Inh deficiency (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0045042 | Decreased circulating complement C4 concentration | Frequent (79-30%)"
    explanation: Orphanet records decreased circulating C4 as frequent in the C1-INH-deficiency branch.
diagnosis:
- name: C1 inhibitor and complement C4 protein measurement
  description: >-
    Measurement of C1-INH level/function together with complement C4 helps
    establish C1-INH-deficiency HAE and distinguish it from normal-C1-INH HAE.
  diagnosis_term:
    preferred_term: protein measurement
    term:
      id: MAXO:0000605
      label: protein measurement
  markers: C1-INH level/function, complement C4
  results: Abnormal C1-INH level or function with supportive C4 reduction indicates C1-INH-deficiency HAE.
  evidence:
  - reference: PMID:36609679
    reference_title: "Hereditary Angioedema: Diagnosis, Clinical Implications, and Pathophysiology."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Laboratory testing shows abnormal levels of C1-INH and high levels of bradykinin."
    explanation: Review evidence supports C1-INH laboratory testing in HAE evaluation.
  - reference: PMID:36609679
    reference_title: "Hereditary Angioedema: Diagnosis, Clinical Implications, and Pathophysiology."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "C4 and D-dimer levels can also be monitored if an acute HAE attack is suspected."
    explanation: Review evidence supports C4 monitoring when an acute attack is suspected.
- name: Genetic testing for HAE subtype assignment
  description: >-
    Genetic testing can identify SERPING1-related classic HAE and genetically
    defined normal-C1-INH subtypes such as F12-, PLG-, KNG1-, ANGPT1-, HS3ST6-,
    and MYOF-associated disease.
  diagnosis_term:
    preferred_term: genetic testing
    term:
      id: MAXO:0000127
      label: genetic testing
  results: Pathogenic variants support subtype assignment and family counseling.
  evidence:
  - reference: PMID:36609679
    reference_title: "Hereditary Angioedema: Diagnosis, Clinical Implications, and Pathophysiology."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Current guidelines now recommend subdividing hereditary angioedema with
      normal C1 esterase inhibitor gene (HAE-nl-C1-INH formerly known as HAE
      type III) based on underlying mutations
    explanation: Review evidence supports genetic subtype assignment for normal-C1-INH HAE.
  - reference: ORPHA:100054
    reference_title: "F12-related hereditary angioedema with normal C1Inh (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "F12 | coagulation factor XII | hgnc:3530 | Disease-causing germline mutation(s) (gain of function) in"
    explanation: Orphanet supports F12 genetic testing for a defined normal-C1-INH subtype.
treatments:
- name: C1 inhibitor replacement prophylaxis
  description: >-
    Plasma-derived or recombinant C1-INH replacement restores the deficient
    regulator in C1-INH-deficiency HAE and can be used for long-term prophylaxis
    against attacks.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  target_mechanisms:
  - target: SERPING1 C1 inhibitor deficiency or dysfunction
    treatment_effect: RESTORES
    description: C1-INH replacement restores the missing or dysfunctional inhibitor protein.
    evidence:
    - reference: PMID:28328347
      reference_title: Prevention of Hereditary Angioedema Attacks with a Subcutaneous C1 Inhibitor.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        In patients with hereditary angioedema, the prophylactic use of a
        subcutaneous C1 inhibitor twice weekly significantly reduced the
        frequency of acute attacks.
      explanation: Phase 3 COMPACT trial evidence supports C1-INH replacement prophylaxis.
  evidence:
  - reference: PMID:28328347
    reference_title: Prevention of Hereditary Angioedema Attacks with a Subcutaneous C1 Inhibitor.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In patients with hereditary angioedema, the prophylactic use of a
      subcutaneous C1 inhibitor twice weekly significantly reduced the frequency
      of acute attacks.
    explanation: Randomized clinical-trial evidence supports subcutaneous C1 inhibitor prophylaxis.
- name: Icatibant acute attack therapy
  description: >-
    Icatibant is a bradykinin B2 receptor antagonist used as on-demand treatment
    for acute HAE attacks.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: icatibant
      term:
        id: CHEBI:68556
        label: icatibant
  target_mechanisms:
  - target: Excess bradykinin signaling
    treatment_effect: INHIBITS
    description: Icatibant blocks bradykinin B2 receptor signaling during an acute attack.
    evidence:
    - reference: PMID:20818888
      reference_title: "Icatibant, a new bradykinin-receptor antagonist, in hereditary angioedema."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Icatibant is a selective bradykinin B2 receptor antagonist."
      explanation: Trial background directly states the drug mechanism.
  evidence:
  - reference: PMID:20818888
    reference_title: "Icatibant, a new bradykinin-receptor antagonist, in hereditary angioedema."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In FAST-2, the median time to clinically significant relief of the index
      symptom was 2.0 hours with icatibant versus 12.0 hours with tranexamic
      acid (P<0.001)
    explanation: Randomized trial evidence supports acute attack efficacy.
- name: Ecallantide acute attack therapy
  description: >-
    Ecallantide inhibits plasma kallikrein and thereby reduces bradykinin
    production during acute HAE attacks.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: ecallantide
      term:
        id: NCIT:C65505
        label: Ecallantide
  target_mechanisms:
  - target: Excess bradykinin signaling
    treatment_effect: INHIBITS
    description: Plasma kallikrein inhibition reduces bradykinin generation during attacks.
    evidence:
    - reference: PMID:21481442
      reference_title: "Ecallantide (DX-88) for acute hereditary angioedema attacks: integrated analysis of 2 double-blind, phase 3 studies."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Ecallantide, a novel plasma kallikrein inhibitor, inhibits production of
        bradykinin, the key mediator of these angioedema attacks.
      explanation: Integrated phase 3 evidence states the drug mechanism.
  evidence:
  - reference: PMID:21481442
    reference_title: "Ecallantide (DX-88) for acute hereditary angioedema attacks: integrated analysis of 2 double-blind, phase 3 studies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Compared with placebo, ecallantide resulted in significantly greater
      reduction in MSCS scores from baseline to 4 hours after dosing
    explanation: Integrated phase 3 evidence supports ecallantide efficacy for acute attacks.
- name: Sebetralstat oral acute attack therapy
  description: >-
    Sebetralstat is an oral plasma kallikrein inhibitor for on-demand treatment
    of HAE attacks due to C1-INH deficiency.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: sebetralstat
      term:
        id: NCIT:C184930
        label: Sebetralstat
  target_mechanisms:
  - target: Excess bradykinin signaling
    treatment_effect: INHIBITS
    description: Oral kallikrein inhibition reduces attack-associated bradykinin signaling.
    evidence:
    - reference: PMID:40886933
      reference_title: "Long-Term Safety and Effectiveness of Sebetralstat: Interim Analysis of KONFIDENT-S Open-label Extension."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Sebetralstat, an oral plasma kallikrein inhibitor"
      explanation: Open-label extension evidence states the oral kallikrein-inhibitor mechanism.
  evidence:
  - reference: PMID:40886933
    reference_title: "Long-Term Safety and Effectiveness of Sebetralstat: Interim Analysis of KONFIDENT-S Open-label Extension."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      No new safety signals were observed, and effectiveness for repeated
      attacks was consistent with the KONFIDENT trial results.
    explanation: Extension evidence supports repeated-attack effectiveness of sebetralstat.
- name: Long-term kallikrein-pathway prophylaxis
  description: >-
    Long-term prophylaxis can target plasma kallikrein or prekallikrein with
    agents such as lanadelumab, berotralstat, and donidalorsen to reduce attack
    frequency.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: lanadelumab
      term:
        id: NCIT:C166535
        label: Lanadelumab
    - preferred_term: berotralstat
      term:
        id: NCIT:C169808
        label: Berotralstat
    - preferred_term: donidalorsen
      term:
        id: NCIT:C177101
        label: Donidalorsen
  target_mechanisms:
  - target: Excess bradykinin signaling
    treatment_effect: INHIBITS
    description: Kallikrein or prekallikrein targeting reduces bradykinin generation upstream of edema attacks.
    evidence:
    - reference: PMID:30480729
      reference_title: "Effect of Lanadelumab Compared With Placebo on Prevention of Hereditary Angioedema Attacks: A Randomized Clinical Trial."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        lanadelumab, a fully human monoclonal antibody that selectively inhibits
        active plasma kallikrein
      explanation: Phase 3 trial evidence states the lanadelumab mechanism.
  evidence:
  - reference: PMID:30480729
    reference_title: "Effect of Lanadelumab Compared With Placebo on Prevention of Hereditary Angioedema Attacks: A Randomized Clinical Trial."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      treatment with subcutaneous lanadelumab for 26 weeks significantly reduced
      the attack rate compared with placebo.
    explanation: Randomized trial evidence supports lanadelumab prophylaxis.
  - reference: PMID:33866032
    reference_title: "Randomized Trial of the Efficacy and Safety of Berotralstat (BCX7353) as an Oral Prophylactic Therapy for Hereditary Angioedema: Results of APeX-2 Through 48 Weeks (Part 2)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Berotralstat (BCX7353) is a recently approved, oral, once-daily kallikrein
      inhibitor for hereditary angioedema (HAE) prophylaxis.
    explanation: APeX-2 evidence supports oral berotralstat prophylaxis.
  - reference: PMID:41767175
    reference_title: "Donidalorsen for Long-Term Prophylaxis of Hereditary Angioedema Attacks: Results from the OASISplus Open-Label Extension Cohort at Year 1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Donidalorsen demonstrated sustained reductions in HAE attack rate,
      improvements in QoL, and an acceptable safety profile after 1 year of
      treatment.
    explanation: OASISplus extension evidence supports donidalorsen long-term prophylaxis.
references:
- reference: ORPHA:528623
  title: Hereditary angioedema with C1Inh deficiency
  found_in:
  - Hereditary_Angioedema-deep-research-fallback.md
  findings:
  - statement: Orphanet structured record for HAE with C1-INH deficiency.
    supporting_text: "MONDO:0033946 | Exact"
- reference: ORPHA:528647
  title: Hereditary angioedema with normal C1Inh
  found_in:
  - Hereditary_Angioedema-deep-research-fallback.md
  findings:
  - statement: Orphanet structured record for HAE with normal C1-INH.
    supporting_text: "HP:0100665 | Angioedema | Very frequent (99-80%)"
- reference: ORPHA:100050
  title: Hereditary angioedema type 1
  found_in:
  - Hereditary_Angioedema-deep-research-fallback.md
  findings:
  - statement: Orphanet subtype record for HAE type 1.
    supporting_text: "SERPING1 | serpin family G member 1 | hgnc:1228 | Disease-causing germline mutation(s) in"
- reference: ORPHA:100051
  title: Hereditary angioedema type 2
  found_in:
  - Hereditary_Angioedema-deep-research-fallback.md
  findings:
  - statement: Orphanet subtype record for HAE type 2.
    supporting_text: "MONDO:0015054 | Exact"
- reference: ORPHA:100054
  title: F12-related hereditary angioedema with normal C1Inh
  found_in:
  - Hereditary_Angioedema-deep-research-fallback.md
  findings:
  - statement: Orphanet subtype record for F12-related normal-C1-INH HAE.
    supporting_text: "F12 | coagulation factor XII | hgnc:3530 | Disease-causing germline mutation(s) (gain of function) in"
- reference: ORPHA:537072
  title: PLG-related hereditary angioedema with normal C1Inh
  found_in:
  - Hereditary_Angioedema-deep-research-fallback.md
  findings:
  - statement: Orphanet subtype record for PLG-related normal-C1-INH HAE.
    supporting_text: "PLG | plasminogen | hgnc:9071 | Disease-causing germline mutation(s) in"
- reference: ORPHA:599418
  title: Hereditary angioedema with normal C1Inh not related to F12 or PLG variant
  found_in:
  - Hereditary_Angioedema-deep-research-fallback.md
  findings:
  - statement: Orphanet subtype record for non-F12/non-PLG normal-C1-INH HAE genes.
    supporting_text: "KNG1 | kininogen 1 | hgnc:6383 | Disease-causing germline mutation(s) in"
- reference: PMID:36609679
  title: "Hereditary Angioedema: Diagnosis, Clinical Implications, and Pathophysiology."
  found_in:
  - Hereditary_Angioedema-deep-research-fallback.md
  findings:
  - statement: HAE type 1 and type 2 are SERPING1/C1-INH disorders, and normal-C1-INH HAE is genetically heterogeneous.
    supporting_text: "Type I and II HAE result from a mutation in the SERPING1 gene, which encodes C1-INH."
- reference: PMID:35442579
  title: "Hereditary Angioedema: A Review."
  found_in:
  - Hereditary_Angioedema-deep-research-fallback.md
  findings:
  - statement: Excess bradykinin increases vascular permeability in HAE.
    supporting_text: "excessive bradykinin production, with subsequent increased vascular permeability"
- reference: PMID:40053270
  title: "Hereditary Angioedema with Normal C1 Inhibitor: an Updated International Consensus Paper on Diagnosis, Pathophysiology, and Treatment."
  found_in:
  - Hereditary_Angioedema-deep-research-fallback.md
  findings:
  - statement: Normal-C1-INH HAE includes genetically defined non-mast-cell angioedema families.
    supporting_text: "proven genetic pathogenic variants that co-segregate with angioedema expression within families."
- reference: PMID:39827848
  title: "Worldwide Prevalence of Hereditary Angioedema: A Systematic Review and Meta-Analysis."
  found_in:
  - Hereditary_Angioedema-deep-research-fallback.md
  findings:
  - statement: Contemporary worldwide prevalence estimate for HAE.
    supporting_text: "The pooled prevalence of HAE was 1.22 cases per 100,000 people"
- reference: PMID:35006617
  title: The international WAO/EAACI guideline for the management of hereditary angioedema-The 2021 revision and update.
  found_in:
  - Hereditary_Angioedema-deep-research-fallback.md
  findings:
  - statement: Current guideline anchor for diagnosis and management.
    supporting_text: "Hereditary angioedema (HAE) is a rare and disabling disease for which early diagnosis and effective therapy are critical."
- reference: PMID:28328347
  title: Prevention of Hereditary Angioedema Attacks with a Subcutaneous C1 Inhibitor.
  found_in:
  - Hereditary_Angioedema-deep-research-fallback.md
  findings:
  - statement: C1 inhibitor replacement reduces attack frequency.
    supporting_text: "the prophylactic use of a subcutaneous C1 inhibitor twice weekly significantly reduced the frequency of acute attacks."
- reference: PMID:20818888
  title: "Icatibant, a new bradykinin-receptor antagonist, in hereditary angioedema."
  found_in:
  - Hereditary_Angioedema-deep-research-fallback.md
  findings:
  - statement: Icatibant blocks bradykinin B2 signaling and shortens attack symptoms in a randomized trial.
    supporting_text: "Icatibant is a selective bradykinin B2 receptor antagonist."
- reference: PMID:21481442
  title: "Ecallantide (DX-88) for acute hereditary angioedema attacks: integrated analysis of 2 double-blind, phase 3 studies."
  found_in:
  - Hereditary_Angioedema-deep-research-fallback.md
  findings:
  - statement: Ecallantide inhibits kallikrein and treats acute HAE attacks.
    supporting_text: "Ecallantide, a novel plasma kallikrein inhibitor, inhibits production of bradykinin, the key mediator of these angioedema attacks."
- reference: PMID:40886933
  title: "Long-Term Safety and Effectiveness of Sebetralstat: Interim Analysis of KONFIDENT-S Open-label Extension."
  found_in:
  - Hereditary_Angioedema-deep-research-fallback.md
  findings:
  - statement: Sebetralstat is an oral kallikrein inhibitor for repeated acute attacks.
    supporting_text: "Sebetralstat, an oral plasma kallikrein inhibitor"
- reference: PMID:30480729
  title: "Effect of Lanadelumab Compared With Placebo on Prevention of Hereditary Angioedema Attacks: A Randomized Clinical Trial."
  found_in:
  - Hereditary_Angioedema-deep-research-fallback.md
  findings:
  - statement: Lanadelumab prophylaxis reduces HAE attack rate.
    supporting_text: "treatment with subcutaneous lanadelumab for 26 weeks significantly reduced the attack rate compared with placebo."
- reference: PMID:33866032
  title: "Randomized Trial of the Efficacy and Safety of Berotralstat (BCX7353) as an Oral Prophylactic Therapy for Hereditary Angioedema: Results of APeX-2 Through 48 Weeks (Part 2)."
  found_in:
  - Hereditary_Angioedema-deep-research-fallback.md
  findings:
  - statement: Berotralstat is an oral once-daily kallikrein inhibitor for HAE prophylaxis.
    supporting_text: "Berotralstat (BCX7353) is a recently approved, oral, once-daily kallikrein inhibitor for hereditary angioedema (HAE) prophylaxis."
- reference: PMID:41767175
  title: "Donidalorsen for Long-Term Prophylaxis of Hereditary Angioedema Attacks: Results from the OASISplus Open-Label Extension Cohort at Year 1."
  found_in:
  - Hereditary_Angioedema-deep-research-fallback.md
  findings:
  - statement: Donidalorsen provides sustained long-term prophylactic attack-rate reductions.
    supporting_text: "Donidalorsen demonstrated sustained reductions in HAE attack rate, improvements in QoL, and an acceptable safety profile after 1 year of treatment."
📚

References & Deep Research

References

19
ORPHA:528623
Hereditary angioedema with C1Inh deficiency
1 finding
Orphanet structured record for HAE with C1-INH deficiency.
"MONDO:0033946 | Exact"
ORPHA:528647
Hereditary angioedema with normal C1Inh
1 finding
Orphanet structured record for HAE with normal C1-INH.
"HP:0100665 | Angioedema | Very frequent (99-80%)"
ORPHA:100050
Hereditary angioedema type 1
1 finding
Orphanet subtype record for HAE type 1.
"SERPING1 | serpin family G member 1 | hgnc:1228 | Disease-causing germline mutation(s) in"
ORPHA:100051
Hereditary angioedema type 2
1 finding
Orphanet subtype record for HAE type 2.
"MONDO:0015054 | Exact"
ORPHA:100054
F12-related hereditary angioedema with normal C1Inh
1 finding
Orphanet subtype record for F12-related normal-C1-INH HAE.
"F12 | coagulation factor XII | hgnc:3530 | Disease-causing germline mutation(s) (gain of function) in"
ORPHA:537072
PLG-related hereditary angioedema with normal C1Inh
1 finding
Orphanet subtype record for PLG-related normal-C1-INH HAE.
"PLG | plasminogen | hgnc:9071 | Disease-causing germline mutation(s) in"
ORPHA:599418
Hereditary angioedema with normal C1Inh not related to F12 or PLG variant
1 finding
Orphanet subtype record for non-F12/non-PLG normal-C1-INH HAE genes.
"KNG1 | kininogen 1 | hgnc:6383 | Disease-causing germline mutation(s) in"
PMID:36609679
Hereditary Angioedema: Diagnosis, Clinical Implications, and Pathophysiology.
1 finding
HAE type 1 and type 2 are SERPING1/C1-INH disorders, and normal-C1-INH HAE is genetically heterogeneous.
"Type I and II HAE result from a mutation in the SERPING1 gene, which encodes C1-INH."
PMID:35442579
Hereditary Angioedema: A Review.
1 finding
Excess bradykinin increases vascular permeability in HAE.
"excessive bradykinin production, with subsequent increased vascular permeability"
PMID:40053270
Hereditary Angioedema with Normal C1 Inhibitor: an Updated International Consensus Paper on Diagnosis, Pathophysiology, and Treatment.
1 finding
Normal-C1-INH HAE includes genetically defined non-mast-cell angioedema families.
"proven genetic pathogenic variants that co-segregate with angioedema expression within families."
PMID:39827848
Worldwide Prevalence of Hereditary Angioedema: A Systematic Review and Meta-Analysis.
1 finding
Contemporary worldwide prevalence estimate for HAE.
"The pooled prevalence of HAE was 1.22 cases per 100,000 people"
PMID:35006617
The international WAO/EAACI guideline for the management of hereditary angioedema-The 2021 revision and update.
1 finding
Current guideline anchor for diagnosis and management.
"Hereditary angioedema (HAE) is a rare and disabling disease for which early diagnosis and effective therapy are critical."
PMID:28328347
Prevention of Hereditary Angioedema Attacks with a Subcutaneous C1 Inhibitor.
1 finding
C1 inhibitor replacement reduces attack frequency.
"the prophylactic use of a subcutaneous C1 inhibitor twice weekly significantly reduced the frequency of acute attacks."
PMID:20818888
Icatibant, a new bradykinin-receptor antagonist, in hereditary angioedema.
1 finding
Icatibant blocks bradykinin B2 signaling and shortens attack symptoms in a randomized trial.
"Icatibant is a selective bradykinin B2 receptor antagonist."
PMID:21481442
Ecallantide (DX-88) for acute hereditary angioedema attacks: integrated analysis of 2 double-blind, phase 3 studies.
1 finding
Ecallantide inhibits kallikrein and treats acute HAE attacks.
"Ecallantide, a novel plasma kallikrein inhibitor, inhibits production of bradykinin, the key mediator of these angioedema attacks."
PMID:40886933
Long-Term Safety and Effectiveness of Sebetralstat: Interim Analysis of KONFIDENT-S Open-label Extension.
1 finding
Sebetralstat is an oral kallikrein inhibitor for repeated acute attacks.
"Sebetralstat, an oral plasma kallikrein inhibitor"
PMID:30480729
Effect of Lanadelumab Compared With Placebo on Prevention of Hereditary Angioedema Attacks: A Randomized Clinical Trial.
1 finding
Lanadelumab prophylaxis reduces HAE attack rate.
"treatment with subcutaneous lanadelumab for 26 weeks significantly reduced the attack rate compared with placebo."
PMID:33866032
Randomized Trial of the Efficacy and Safety of Berotralstat (BCX7353) as an Oral Prophylactic Therapy for Hereditary Angioedema: Results of APeX-2 Through 48 Weeks (Part 2).
1 finding
Berotralstat is an oral once-daily kallikrein inhibitor for HAE prophylaxis.
"Berotralstat (BCX7353) is a recently approved, oral, once-daily kallikrein inhibitor for hereditary angioedema (HAE) prophylaxis."
PMID:41767175
Donidalorsen for Long-Term Prophylaxis of Hereditary Angioedema Attacks: Results from the OASISplus Open-Label Extension Cohort at Year 1.
1 finding
Donidalorsen provides sustained long-term prophylactic attack-rate reductions.
"Donidalorsen demonstrated sustained reductions in HAE attack rate, improvements in QoL, and an acceptable safety profile after 1 year of treatment."

Deep Research

1
Hereditary Angioedema Deep Research Fallback ▸

Hereditary Angioedema Deep Research Fallback

Provider Attempts

  • falcon: timeout --foreground 120s just research-disorder falcon Hereditary_Angioedema produced no usable content and was terminated with signal 15.
  • openai: timeout --foreground 120s just research-disorder openai Hereditary_Angioedema produced no usable content and was terminated with signal 15.

Because the preferred deep-research providers did not return usable content in bounded attempts, this fallback records the literature scope used for curation. All YAML evidence was taken from generated Orphanet and PubMed reference caches, not from hand-created reference text.

Structured Source Scope

Hereditary angioedema corresponds to MONDO:0019623 and Orphanet ORPHA:91378. ORPHA:91378 is an Orphanet clinical-group record and was not emitted by the current structured Orphanet cache builder, which caches generated leaf disease and subtype records. The curation therefore used generated caches for ORPHA:528623 hereditary angioedema with C1Inh deficiency, ORPHA:528647 hereditary angioedema with normal C1Inh, and subtype records ORPHA:100050, ORPHA:100051, ORPHA:100054, ORPHA:537072, and ORPHA:599418.

ORPHA:528647 currently lists obsolete MONDO:0033947 as its cross-reference. Local MONDO resolves the active replacement as MONDO:0100567 hereditary angioedema with normal C1Inh, and the YAML uses that active term.

Literature Scope

Clinical definition, inheritance, genetic heterogeneity, diagnostic testing, and pathophysiology were anchored with contemporary review, guideline, consensus, and prevalence papers: PMID:36609679, PMID:35442579, PMID:35006617, PMID:40053270, and PMID:39827848. These sources support autosomal dominant classic HAE, SERPING1-related type 1 and type 2 disease, normal-C1-INH genetic subdivision, C1-INH/C4 laboratory testing, excess bradykinin production, increased vascular permeability, and worldwide rarity.

Treatment evidence was anchored to human clinical trials or extensions: PMID:28328347 for subcutaneous C1 inhibitor prophylaxis, PMID:20818888 for icatibant acute attack therapy, PMID:21481442 for ecallantide acute attack therapy, PMID:40886933 for oral sebetralstat attack therapy, PMID:30480729 for lanadelumab prophylaxis, PMID:33866032 for berotralstat prophylaxis, and PMID:41767175 for donidalorsen long-term prophylaxis.

Curation Decisions

  • Used MONDO:0019623 as the disease term and modeled the major clinical and etiologic branches as subtypes.
  • Included active subtype terms for C1-INH deficiency, type 1, type 2, normal-C1-INH HAE, F12-related HAE, PLG-related HAE, and the non-F12/non-PLG normal-C1-INH subtype group.
  • Recorded ORPHA frequent and very frequent phenotype rows from ORPHA:528623 and ORPHA:528647, but did not retain contradictory urticaria rows from the HAE type 1 subtype table because the disease-level records define HAE attacks as occurring without urticaria and mark urticaria as excluded.
  • Recorded decreased C4 and decreased C1 inhibitor concentration as C1-INH-deficiency-specific findings because ORPHA:528647 excludes decreased C4 in normal-C1-INH HAE.
  • Did not bind a C1 inhibitor therapeutic agent in the treatment section: the available local NCIT C1 inhibitor term validates as a protein/gene product but not as a pharmacologic-substance descendant for the therapeutic_agent slot. The same NCIT term is retained in the pathophysiology gene-product descriptor, where it validates.