Hereditary Angioedema

Mendelian MONDO:0019623 Pathograph 42 Show in embeddings browser 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
10
Pathophys.
19
Phenotypes
4
Gaps
42
Pathograph
4
Genes
10
Medical Actions
7
Subtypes
1
Datasets
3
Trials
32
References
2
Deep Research
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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 (1 reference)
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.
◆

Subtypes

7
Hereditary angioedema with C1 inhibitor deficiency MONDO:0033946
SERPING1 hgnc:1228 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in SERPING1 (hgnc:1228). hgnc:1228 is a gene from the HUGO Gene Nomenclature Committee.
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 hgnc:1228 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in SERPING1 (hgnc:1228). hgnc:1228 is a gene from the HUGO Gene Nomenclature Committee.
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 hgnc:1228 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in SERPING1 (hgnc:1228). hgnc:1228 is a gene from the HUGO Gene Nomenclature Committee.
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.
Normal-C1-INH hereditary angioedema not related to F12 or PLG MONDO:0035734
ANGPT1 hgnc:484 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in ANGPT1 (hgnc:484). hgnc:484 is a gene from the HUGO Gene Nomenclature Committee. HS3ST6 hgnc:14178 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in HS3ST6 (hgnc:14178). hgnc:14178 is a gene from the HUGO Gene Nomenclature Committee. KNG1 hgnc:6383 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in KNG1 (hgnc:6383). hgnc:6383 is a gene from the HUGO Gene Nomenclature Committee. MYOF hgnc:3656 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in MYOF (hgnc:3656). hgnc:3656 is a gene from the HUGO Gene Nomenclature Committee.
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.
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Discussions and Knowledge Gaps

4
What actually initiates contact-system activation at the start of an HAE attack, and is an activating surface required at all?
KNOWLEDGE GAP OPEN gap_hae_contact_activation_trigger
Attached to
pathophysiology#Unrestrained factor XII activation pathophysiology#SERPING1 C1 inhibitor deficiency or dysfunction
The pathograph downstream of contact activation is well established, but the initiating event is not. C1-INH deficiency is constant while attacks are episodic and localized, so something must license activation at a particular time and site. Classical models invoke an anionic activating surface for factor XII autoactivation, but it is questionable whether a surface is responsible in HAE, and the recognized clinical triggers (trauma, procedures, estrogens, stress) have no established molecular mapping onto the cascade. This gap is why attack prediction remains impossible and why prophylaxis must be continuous rather than targeted.
Proposed experiments
Peri-attack contact-system biomarker time course
hae_attack_onset_biomarker_timecourse
Serially sample patients through spontaneous and procedure-provoked attacks and quantify cleaved high-molecular-weight kininogen, FXIIa-inhibitor and kallikrein-inhibitor complexes, and candidate surface activators, to establish which species moves first relative to symptom onset.
Decision criterion
A reproducible ordering of biomarker changes preceding symptom onset that distinguishes surface-dependent from surface-independent initiation.
Would support
pathophysiology#Unrestrained factor XII activation
Show evidence (2 references)
PMID:27459852 SUPPORT Other
"Important areas that remain poorly understood include the factors that lead to very low plasma functional C1 inhibitor levels, the triggers of contact system activation in hereditary angioedema, and the role of the bradykinin B1 receptor."
Names the triggers of contact-system activation as an explicitly unresolved area.
PMID:29920929 SUPPORT Other
"In addition, it is questionable whether a surface is responsible for contact system activation in HAE."
States the open question of whether an activating surface is required in HAE.
Does the bradykinin B1 receptor contribute materially to HAE swelling alongside the B2 receptor?
KNOWLEDGE GAP OPEN gap_hae_bradykinin_b1_receptor_role
Attached to
pathophysiology#Excess bradykinin signaling pathophysiology#Endothelial adherens junction destabilization
Icatibant establishes the B2 receptor as an operative and druggable target, but B2 blockade does not abolish all attacks and the B1 receptor is inducible under inflammatory conditions and mediates vascular hyperpermeability in other settings. If B1 signalling contributes, it would predict a therapeutic ceiling for B2-selective antagonism and identify a complementary target. The question is currently unresolved rather than negative.
Proposed experiments
B1 versus B2 receptor contribution in patient-derived endothelium
hae_b1_receptor_endothelial_contribution
Expose endothelial monolayers to patient plasma or bradykinin with selective B1 and B2 antagonists, alone and combined, and measure barrier resistance and junctional protein localization to quantify any residual B1-dependent permeability.
Decision criterion
A reproducible B1-antagonist-sensitive component of permeability that persists under full B2 blockade.
Would support
pathophysiology#Excess bradykinin signaling
Show evidence (1 reference)
PMID:27459852 SUPPORT Other
"Important areas that remain poorly understood include the factors that lead to very low plasma functional C1 inhibitor levels, the triggers of contact system activation in hereditary angioedema, and the role of the bradykinin B1 receptor."
Explicitly names the role of the bradykinin B1 receptor as poorly understood.
Which modifiers explain the extreme variability in attack frequency, severity, and site among people carrying the same SERPING1 variant?
KNOWLEDGE GAP OPEN gap_hae_phenotypic_variability_modifiers
Attached to
pathophysiology#Endothelial adherens junction destabilization pathophysiology#Vascular permeability and recurrent edema attacks
Attack burden ranges from essentially asymptomatic carriage to frequent life-threatening laryngeal attacks within the same family and the same variant, and C1-INH level does not predict it. No validated genetic, hormonal, or endothelial modifier explains this, which prevents risk-stratified prophylaxis and means treatment intensity is chosen on observed burden rather than predicted risk.
Proposed experiments
Genotype-matched discordant-severity modifier study
hae_modifier_cohort_genotype_endothelial_phenotype
Recruit pairs of relatives sharing a SERPING1 variant but discordant for attack burden and compare modifier-gene genotypes, sex-hormone status, and endothelial barrier responsiveness to bradykinin in patient-derived cells.
Decision criterion
A modifier that segregates with attack burden independently of the primary variant and reproduces in an independent cohort.
Would support
pathophysiology#Vascular permeability and recurrent edema attacks
Show evidence (1 reference)
PMID:27459852 SUPPORT Other
"The phenotypic variability of hereditary angioedema has been extensively documented but never understood."
States directly that HAE phenotypic variability remains unexplained.
How should normal-C1-INH HAE be defined and diagnosed when most suspected cases have no identifiable pathogenic variant?
KNOWLEDGE GAP OPEN gap_hae_normal_c1inh_definition_and_yield
Attached to
pathophysiology#Normal C1-INH contact-system gene dysregulation pathophysiology#Plasmin-mediated contact-system amplification
Normal-C1-INH HAE has no confirmatory biochemical test, so diagnosis rests on clinical pattern plus a variant in one of a small gene set. Comprehensive sequencing resolves only a small minority of suspected cases, and broad testing generates variants of uncertain significance and risks overdiagnosis. Consequently management recommendations for this branch are largely expert opinion, and it is not established that every normal-C1-INH subtype is bradykinin-mediated at all.
Proposed experiments
Prospective validation of a functional contact-activation assay
hae_nc1inh_functional_contact_assay_validation
Apply candidate functional readouts (cleaved kininogen, kallikrein activity, plasma-induced endothelial permeability) to prospectively enrolled suspected normal-C1-INH patients, gene-positive controls, and mimic conditions, and test whether any readout separates them independently of genotype.
Decision criterion
An assay with reproducible sensitivity and specificity against an independently adjudicated clinical diagnosis.
Would support
pathophysiology#Normal C1-INH contact-system gene dysregulation
Show evidence (2 references)
PMID:38555427 SUPPORT Human Clinical
"Despite extensive genetic analyses, the diagnostic yield for nC1-INH HAE remains low in our study, the pathogenic variant for nC1-INH HAE was identified in only 1 patient (n = 21)."
Quantifies the low molecular diagnostic yield that defines this gap.
PMID:38555427 SUPPORT Human Clinical
"Investigation into candidate genes yielded no pathogenic variants, prompting a re-evaluation of patients' diagnoses."
Shows that negative testing led to diagnostic re-evaluation, supporting the overdiagnosis concern.
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Pathophysiology

10
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 hgnc:1228 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves SERPING1 (hgnc:1228). hgnc:1228 is a gene from the HUGO Gene Nomenclature Committee.
complement activation GO:0006956 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal complement activation (GO:0006956). GO:0006956 is a biological process from the Gene Ontology. ⚠ ABNORMAL blood coagulation GO:0007596 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal blood coagulation (GO:0007596). GO:0007596 is a biological process from the Gene Ontology. ⚠ ABNORMAL fibrinolysis GO:0042730 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal fibrinolysis (GO:0042730). GO:0042730 is a biological process from the Gene Ontology. ⚠ ABNORMAL
Downstream
Unrestrained factor XII activation C1-INH is the principal plasma inhibitor of the contact-system enzymes, so its loss or dysfunction removes the brake on factor XII activation.
Excess bradykinin signaling Loss or dysfunction of C1-INH permits contact-system activation and excess bradykinin signaling.
C1-INH intracellular retention and endoplasmic reticulum stress Some SERPING1 missense variants are secretion-defective and accumulate intracellularly rather than simply lowering synthesis.
Decreased circulating C1-esterase inhibitor concentration
Decreased circulating complement C4 concentration
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.
Unrestrained factor XII activation
With C1-INH absent or dysfunctional, factor XII autoactivates to factor XIIa without adequate inhibition. FXIIa is the apex protease of the plasma contact (kallikrein-kinin) system in HAE, and gain-of-function F12 variants produce the same excess activation in F12-related normal-C1-INH disease. FXIIa is a validated drug target: the anti-FXIIa antibody garadacimab prevents attacks.
F12 hgnc:3530 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves F12 (hgnc:3530). hgnc:3530 is a gene from the HUGO Gene Nomenclature Committee.
Factor XII activation GO:0002542 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased Factor XII activation (GO:0002542). GO:0002542 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Plasma kallikrein activation FXIIa cleaves plasma prekallikrein to active plasma kallikrein.
Show evidence (2 references)
PMID:36868261 SUPPORT Human Clinical
"Hereditary angioedema is a rare and potentially life-threatening genetic disease that is associated with kallikrein-kinin system dysregulation."
The pivotal FXIIa-inhibitor trial frames HAE as a kallikrein-kinin dysregulation disorder, supporting contact-system activation as a core mechanism node.
PMID:29920929 SUPPORT Other
"Bradykinin, which is considered to be a byproduct of the plasma contact system during in vitro coagulation, is the main disease mediator in HAE."
Places the plasma contact system upstream of bradykinin, the main HAE mediator.
Plasma kallikrein activation
Active plasma kallikrein is the central effector protease of the HAE cascade. It cleaves high-molecular-weight kininogen to liberate bradykinin and also reciprocally activates more factor XII, creating a self-amplifying loop that explains the explosive, self-sustaining character of attacks. Plasma kallikrein is the most heavily drugged node in HAE: ecallantide, lanadelumab, berotralstat, and sebetralstat inhibit the active enzyme, while donidalorsen lowers the prekallikrein zymogen pool.
plasma kallikrein-kinin cascade GO:0002353 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased plasma kallikrein-kinin cascade (GO:0002353). GO:0002353 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
High-molecular-weight kininogen cleavage and bradykinin liberation Plasma kallikrein cleaves high-molecular-weight kininogen to release bradykinin.
Unrestrained factor XII activation Plasma kallikrein reciprocally activates factor XII, forming the self-amplifying contact-system loop that is normally restrained by C1-INH.
Show evidence (2 references)
PMID:21481442 SUPPORT Human Clinical
"Ecallantide, a novel plasma kallikrein inhibitor, inhibits production of bradykinin, the key mediator of these angioedema attacks."
Establishes plasma kallikrein as the protease whose inhibition blocks bradykinin production in HAE.
PMID:30656274 SUPPORT Other
"As C1 inhibitor also possesses a central regulatory role of other plasma systems, including the contact activation system of coagulation and the plasminogen-plasmin system that governs endogenous fibrinolysis"
Supports C1-INH regulation of the contact and fibrinolytic systems that converge on kallikrein activity.
High-molecular-weight kininogen cleavage and bradykinin liberation
Kallikrein-mediated proteolysis of high-molecular-weight kininogen (the KNG1 gene product) releases the nonapeptide bradykinin. Cleaved kininogen is a contact-activation biomarker, and a KNG1 variant altering the N-terminal bradykinin cleavage site causes a normal-C1-INH HAE subtype, placing this step directly on the disease path.
KNG1 hgnc:6383 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves KNG1 (hgnc:6383). hgnc:6383 is a gene from the HUGO Gene Nomenclature Committee.
bradykinin biosynthetic process GO:0002936 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased bradykinin biosynthetic process (GO:0002936). GO:0002936 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Excess bradykinin signaling Liberated bradykinin is the mediator that acts on the vascular endothelium.
Show evidence (1 reference)
PMID:35442579 SUPPORT Human Clinical
"excessive bradykinin production, with subsequent increased vascular permeability"
Supports excess bradykinin generation as the step preceding increased permeability.
C1-INH intracellular retention and endoplasmic reticulum stress
A subset of SERPING1 missense variants are not simply null alleles: the mutant C1-INH protein is retained and aggregates in the endoplasmic reticulum. In a reported Han Chinese family the c.708T>G variant raised intracellular C1-INH, upregulated GRP75, and produced calcium overload, mitochondrial damage, and apoptosis. This arm is a proposed cell-intrinsic contributor and biomarker route rather than an established driver of the swelling itself, which remains bradykinin-mediated.
SERPING1 hgnc:1228 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves SERPING1 (hgnc:1228). hgnc:1228 is a gene from the HUGO Gene Nomenclature Committee.
Downstream
Decreased circulating C1-esterase inhibitor concentration Retention of mutant C1-INH inside the cell reduces the amount of functional inhibitor secreted into plasma.
Show evidence (2 references)
PMID:39272138 SUPPORT In Vitro
"This cascade of events resulted in Ca2+ overload, disruption of mitochondrial structure and function, and eventually triggered apoptosis."
Documents the ER-retention consequences in a cellular model of a SERPING1 variant.
PMID:39272138 SUPPORT In Vitro
"Using siRNA to knock down GRP75 mitigates cellular calcium overload and mitochondrial damage induced by the SERPING1 mutation."
Rescue by GRP75 knockdown supports GRP75 as the mediator of the retention phenotype.
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. The subtype genes enter the shared pathograph at different points rather than through one common step: F12 gain of function amplifies contact activation, KNG1 alters the bradykinin cleavage site of its own substrate, PLG variants act through the plasmin arm, and ANGPT1 and HS3ST6 act on the endothelial barrier itself. Whether every normal-C1-INH subtype is strictly bradykinin-mediated is not established.
F12 hgnc:3530 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves F12 (hgnc:3530). hgnc:3530 is a gene from the HUGO Gene Nomenclature Committee. PLG hgnc:9071 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves PLG (hgnc:9071). hgnc:9071 is a gene from the HUGO Gene Nomenclature Committee. KNG1 hgnc:6383 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves KNG1 (hgnc:6383). hgnc:6383 is a gene from the HUGO Gene Nomenclature Committee. ANGPT1 hgnc:484 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves ANGPT1 (hgnc:484). hgnc:484 is a gene from the HUGO Gene Nomenclature Committee. HS3ST6 hgnc:14178 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves HS3ST6 (hgnc:14178). hgnc:14178 is a gene from the HUGO Gene Nomenclature Committee. MYOF hgnc:3656 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves MYOF (hgnc:3656). hgnc:3656 is a gene from the HUGO Gene Nomenclature Committee.
regulation of vascular permeability GO:0043114 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal regulation of vascular permeability (GO:0043114). GO:0043114 is a biological process from the Gene Ontology. ⚠ ABNORMAL
Downstream
Excess bradykinin signaling Normal-C1-INH HAE variants converge on non-mast-cell angioedema pathways that produce bradykinin-mediated swelling.
Unrestrained factor XII activation F12 gain-of-function variants (for example p.Thr309Lys/p.Thr309Arg) drive excess contact activation directly, the entry point for the F12-related subtype.
High-molecular-weight kininogen cleavage and bradykinin liberation A KNG1 variant that changes the N-terminal cleavage site of bradykinin acts on the kininogen-processing step itself.
Endothelial adherens junction destabilization ANGPT1 and HS3ST6 variants act on the endothelial barrier rather than on kinin generation, entering the pathograph at the endothelial node.
Plasmin-mediated contact-system amplification PLG variants act through the plasmin arm of the fibrinolytic system, which C1-INH also normally restrains.
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.
Plasmin-mediated contact-system amplification
C1-INH restrains the plasminogen-plasmin (fibrinolytic) system in addition to the contact system, and plasmin can feed back into contact activation and kinin generation. This arm is the mechanistic rationale for the PLG-related normal-C1-INH subtype and for the historical use of the antifibrinolytic tranexamic acid, and it underlies the raised D-dimer seen during attacks.
PLG hgnc:9071 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves PLG (hgnc:9071). hgnc:9071 is a gene from the HUGO Gene Nomenclature Committee.
fibrinolysis GO:0042730 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased fibrinolysis (GO:0042730). GO:0042730 is a biological process from the Gene Ontology. ↑ INCREASED positive regulation of plasma kallikrein-kinin cascade GO:0002550 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased positive regulation of plasma kallikrein-kinin cascade (GO:0002550). GO:0002550 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
High-molecular-weight kininogen cleavage and bradykinin liberation Plasmin activity promotes kinin generation, converging on the same bradykinin-liberating step as the kallikrein arm.
Show evidence (2 references)
PMID:30656274 SUPPORT Other
"As C1 inhibitor also possesses a central regulatory role of other plasma systems, including the contact activation system of coagulation and the plasminogen-plasmin system that governs endogenous fibrinolysis"
Establishes C1-INH regulation of the plasminogen-plasmin system alongside the contact system.
PMID:28795768 SUPPORT Human Clinical
"We detected a mutation in the plasminogen (PLG) gene in patients with HAEnCI."
Supports a plasminogen-dependent route to normal-C1-INH HAE.
Excess bradykinin signaling
Excess bradykinin is the central mediator of HAE attacks. It acts on the bradykinin B2 receptor on vascular endothelium to increase permeability in superficial tissues and gastrointestinal and respiratory mucosa. The B2 receptor is the target of icatibant; the contribution of the bradykinin B1 receptor remains unresolved and is recorded as a knowledge gap.
regulation of vascular permeability GO:0043114 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased regulation of vascular permeability (GO:0043114). GO:0043114 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Endothelial adherens junction destabilization Bradykinin B2 receptor signalling on vascular endothelium disassembles interendothelial adherens junctions, the proximate cellular lesion of the swelling attack.
Vascular permeability and recurrent edema attacks Bradykinin-driven permeability produces recurrent skin, gastrointestinal, and airway edema attacks.
Show evidence (3 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
"Icatibant is a selective bradykinin B2 receptor antagonist."
Efficacy of a selective B2 receptor antagonist supports B2 receptor engagement as the operative bradykinin signalling step.
PMID:20818888 SUPPORT Human Clinical
"Bradykinin is the key mediator of symptoms."
Randomized-trial background identifies bradykinin as the mediator of HAE symptoms.
Endothelial adherens junction destabilization
The proximate cellular lesion of an HAE attack is loss of interendothelial adherens junction integrity in postcapillary vessels, with reduced VE-cadherin and beta-catenin at the cell surface, F-actin stress-fibre reorganization, and interendothelial gap formation. This node is the point of convergence for the bradykinin-mediated arm and for the normal-C1-INH "endothelial barrier" genes: ANGPT1 haploinsufficiency impairs the Tie2-dependent counter-regulation that normally opposes bradykinin- and VEGF-induced leak, and HS3ST6 loss alters endothelial heparan sulfate involved in cell-surface interactions of angioedema mediators.
vascular endothelial cell CL:0002139 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves vascular endothelial cell, annotated with endothelial cell of vascular tree (CL:0002139). CL:0002139 is a cell type from the Cell Ontology.
ANGPT1 hgnc:484 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves ANGPT1 (hgnc:484). hgnc:484 is a gene from the HUGO Gene Nomenclature Committee. HS3ST6 hgnc:14178 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves HS3ST6 (hgnc:14178). hgnc:14178 is a gene from the HUGO Gene Nomenclature Committee.
adherens junction organization GO:0034332 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal adherens junction organization (GO:0034332). GO:0034332 is a biological process from the Gene Ontology. ⚠ ABNORMAL regulation of vascular permeability GO:0043114 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased regulation of vascular permeability (GO:0043114). GO:0043114 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Vascular permeability and recurrent edema attacks Interendothelial gap formation permits plasma extravasation into subcutaneous and submucosal tissue, producing the clinical attack.
Show evidence (3 references)
PMID:27459852 SUPPORT Other
"This knowledge is driving increased attention to the role of endothelial biology in determining disease activity in hereditary angioedema."
Supports endothelial biology as the determinant of HAE disease activity, justifying a dedicated endothelial node.
PMID:30689269 SUPPORT In Vitro
"Likewise, cell surface expression of β-catenin was reduced and severe gap formation between adjacent HUVECs developed."
Endothelial-cell experiments demonstrate junctional protein loss and gap formation, the cellular readout of this node.
PMID:30689269 SUPPORT In Vitro
"The ANGPT1 reduced ability to counteract the increment of endothelial permeability produced by inducers, such as VEGF and bradykinin, stimulate vascular leakage and reorganization of the F-actin cytoskeletal elements."
Links ANGPT1 loss of function to failure of counter-regulation against bradykinin-induced endothelial leak.
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. The lesion is interstitial fluid accumulation from postcapillary endothelial leak, not primary tissue destruction, which is why attacks resolve completely and leave no fibrosis or scarring.
regulation of vascular permeability GO:0043114 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased regulation of vascular permeability (GO:0043114). GO:0043114 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Angioedema
Non-pitting edema
Facial edema
Skin rash
Abdominal pain
Intestinal edema
Laryngeal edema
Pharyngeal edema
Genital edema
Edema of the upper limbs
Muscular edema
Joint swelling
Diarrhea
Nausea and vomiting
Painful angioedema attacks
Serpiginous cutaneous lesion
Erythema marginatum
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 HP:0002014 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Diarrhea (HP:0002014), qualified as temporality recurrent. HP:0002014 is a phenotype from the Human Phenotype Ontology.
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 HP:0002017 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Nausea and vomiting (HP:0002017), qualified as temporality recurrent. HP:0002017 is a phenotype from the Human Phenotype Ontology.
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 HP:0000282 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Facial edema (HP:0000282), qualified as temporality recurrent. HP:0000282 is a phenotype from the Human Phenotype Ontology.
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 HP:0000988 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Skin rash (HP:0000988), qualified as temporality recurrent. HP:0000988 is a phenotype from the Human Phenotype Ontology.
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 HP:0001386 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Joint swelling (HP:0001386), qualified as temporality recurrent. HP:0001386 is a phenotype from the Human Phenotype Ontology.
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 HP:0002027 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abdominal pain (HP:0002027), qualified as temporality recurrent. HP:0002027 is a phenotype from the Human Phenotype Ontology.
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 HP:0012531 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Pain (HP:0012531), qualified as temporality recurrent. HP:0012531 is a phenotype from the Human Phenotype Ontology.
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 HP:0100665 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Angioedema (HP:0100665), qualified as temporality recurrent. HP:0100665 is a phenotype from the Human Phenotype Ontology.
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 HP:6000507 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Non-pitting edema (HP:6000507), qualified as temporality recurrent. HP:6000507 is a phenotype from the Human Phenotype Ontology.
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 HP:0005225 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Intestinal edema (HP:0005225), qualified as temporality recurrent. HP:0005225 is a phenotype from the Human Phenotype Ontology.
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 HP:0012027 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Laryngeal edema (HP:0012027), qualified as temporality recurrent. HP:0012027 is a phenotype from the Human Phenotype Ontology.
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 HP:0011855 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Pharyngeal edema (HP:0011855), qualified as temporality recurrent. HP:0011855 is a phenotype from the Human Phenotype Ontology.
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 HP:0031188 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Genital edema (HP:0031188), qualified as temporality recurrent. HP:0031188 is a phenotype from the Human Phenotype Ontology.
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 HP:0010742 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Edema of the upper limbs (HP:0010742), qualified as temporality recurrent. HP:0010742 is a phenotype from the Human Phenotype Ontology.
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 HP:0100748 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Muscular edema (HP:0100748), qualified as temporality recurrent. HP:0100748 is a phenotype from the Human Phenotype Ontology.
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 HP:0025527 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Serpiginous cutaneous lesion (HP:0025527), qualified as temporality recurrent. HP:0025527 is a phenotype from the Human Phenotype Ontology.
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 HP:6001012 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Erythema marginatum (HP:6001012), qualified as temporality recurrent. HP:6001012 is a phenotype from the Human Phenotype Ontology.
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 HP:0034204 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Decreased circulating C1-esterase inhibitor concentration (HP:0034204). HP:0034204 is a phenotype from the Human Phenotype Ontology.
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 HP:0045042 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Decreased circulating complement C4 concentration (HP:0045042). HP:0045042 is a phenotype from the Human Phenotype Ontology.
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)
Gene: SERPING1 hgnc:1228 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is SERPING1 (hgnc:1228). hgnc:1228 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
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)
Gene: F12 hgnc:3530 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is F12 (hgnc:3530). hgnc:3530 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
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)
Gene: PLG hgnc:9071 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is PLG (hgnc:9071). hgnc:9071 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Autosomal dominant inheritance
Show evidence (2 references)
ORPHA:537072 SUPPORT Other
"PLG | plasminogen | hgnc:9071 | Disease-causing germline mutation(s) in"
Orphanet records PLG as disease-causing for this subtype.
PMID:28795768 SUPPORT Human Clinical
"The mutation c.988A>G was located in exon 9 leading to the missense mutation p.Lys330Glu (K330E) in the kringle 3 domain of the PLG protein."
Identifies the recurrent PLG K330E kringle-3 variant in normal-C1-INH HAE.
Normal-C1-INH genetic heterogeneity (Causative genes for non-F12/non-PLG normal-C1-INH HAE)
relationship_type: CAUSATIVE
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.
🗃️

External Assertions

2
Orphanet hereditary angioedema with C1Inh deficiency record
Orphanet structured disease record ORPHA:528623
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.
Show evidence (1 reference)
ORPHA:528623 SUPPORT Other
"MONDO:0033946 | Exact"
Orphanet maps ORPHA:528623 to MONDO:0033946.
Orphanet hereditary angioedema with normal C1Inh record
Orphanet structured disease record ORPHA:528647
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.
Show evidence (1 reference)
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 HAE disease branch.
💊

Medical Actions

10
C1 inhibitor replacement prophylaxis
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. 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: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: icatibant CHEBI:68556 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses icatibant (CHEBI:68556). CHEBI:68556 is a therapeutic agent from Chemical Entities of Biological Interest.
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: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: ecallantide NCIT:C65505 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses ecallantide (NCIT:C65505). NCIT:C65505 is a therapeutic agent from the NCI Thesaurus.
Ecallantide inhibits plasma kallikrein and thereby reduces bradykinin production during acute HAE attacks.
Mechanism Target:
INHIBITS Plasma kallikrein activation — 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: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: sebetralstat NCIT:C184930 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses sebetralstat (NCIT:C184930). NCIT:C184930 is a therapeutic agent from the NCI Thesaurus.
Sebetralstat is an oral plasma kallikrein inhibitor for on-demand treatment of HAE attacks due to C1-INH deficiency.
Mechanism Target:
INHIBITS Plasma kallikrein activation — 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.
Lanadelumab long-term prophylaxis
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: lanadelumab NCIT:C166535 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses lanadelumab (NCIT:C166535). NCIT:C166535 is a therapeutic agent from the NCI Thesaurus.
Lanadelumab is a fully human monoclonal antibody that selectively inhibits active plasma kallikrein, given subcutaneously for long-term prophylaxis. It is split from berotralstat here despite sharing a target: the two differ in modality, route and dosing interval in ways that drive real clinical choice, and bundling them made per-drug modality tagging impossible.
Mechanism Target:
INHIBITS Plasma kallikrein activation — Direct plasma kallikrein inhibition 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 (1 reference)
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.
Berotralstat oral long-term prophylaxis
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: berotralstat NCIT:C169808 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses berotralstat (NCIT:C169808). NCIT:C169808 is a therapeutic agent from the NCI Thesaurus.
Berotralstat is an orally administered, once-daily small-molecule plasma kallikrein inhibitor for long-term prophylaxis. Same molecular target as lanadelumab, different platform - which is precisely why the two are curated separately.
Mechanism Target:
INHIBITS Plasma kallikrein activation — Oral small-molecule kallikrein inhibition reduces bradykinin generation upstream of edema attacks.
Show evidence (1 reference)
PMID:33866032 SUPPORT Human Clinical
"Berotralstat (BCX7353) is a recently approved, oral, once-daily kallikrein inhibitor for hereditary angioedema (HAE) prophylaxis."
Names the drug's molecular target directly, which is exactly what this edge asserts: berotralstat acts on the plasma kallikrein node by inhibiting kallikrein itself.
Show evidence (1 reference)
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.
Attenuated androgen (danazol) long-term prophylaxis
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: danazol CHEBI:4315 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses danazol (CHEBI:4315). CHEBI:4315 is a therapeutic agent from Chemical Entities of Biological Interest.
Danazol is the historical mainstay of long-term prophylaxis and remains in guideline algorithms as a second-line option where modern targeted agents are unavailable or unaffordable - which is most of the world. It works indirectly, raising hepatic C1-INH and C4 production rather than blocking the contact cascade, and it is the only prophylactic option in this entry that acts by increasing the deficient protein rather than inhibiting a downstream enzyme. Its displacement by kallikrein-targeted agents is driven by tolerability - androgenic effects, dyslipidaemia, hepatic adenoma and virilisation risk - rather than by lack of efficacy.
Mechanism Target:
MODULATES SERPING1 C1 inhibitor deficiency or dysfunction — Attenuated androgens are thought to raise circulating C1-INH rather than inhibiting a downstream enzyme, which is why they are placed on the deficiency node itself. The hedge is deliberate: the prophylactic benefit is well attested, but the mechanism by which attenuated androgens produce it is not fully settled.
Show evidence (2 references)
PMID:19477491 SUPPORT Human Clinical
"Effective treatments included C1 inhibitor concentrate for angioedema attacks (6 women) and, for prophylaxis, progesterone (8 women), danazol (2 women), and tranexamic acid (1 woman)."
Documents danazol as effective prophylaxis in hereditary angioedema. PARTIAL, and the limits matter: this is an FXII-HAE (normal C1-INH) cohort and only two women received danazol, so it is not the randomized evidence that underpins the modern agents in this entry.
PMID:20818888 SUPPORT Other
"Attenuated androgens can reduce the number and severity of attacks when used prophylactically but have important adverse effects and are ineffective during acute attacks."
Prophylaxis-specific support for the attenuated-androgen class, and the stronger of the two items attached here: it states the prophylactic benefit and both of the limitations that put danazol behind the targeted agents. Tagged OTHER because the sentence is background framing in the introduction to an icatibant trial report, summarizing prior evidence rather than reporting that trial's own data.
Tranexamic acid long-term prophylaxis
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: tranexamic acid CHEBI:48669 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses tranexamic acid (CHEBI:48669). CHEBI:48669 is a therapeutic agent from Chemical Entities of Biological Interest.
An antifibrinolytic used for long-term prophylaxis, chiefly where attenuated androgens are contraindicated - notably in children and in pregnancy. It is the treatment that gives the plasmin amplification arm of this pathograph its therapeutic rationale: by inhibiting plasmin, it blocks the plasmin-mediated feedback that amplifies contact-system activation, rather than acting on kallikrein or bradykinin directly. Efficacy is modest compared with the targeted agents.
Mechanism Target:
INHIBITS Plasmin-mediated contact-system amplification — Antifibrinolytic blockade of plasmin interrupts the plasmin-driven amplification loop that feeds contact-system activation - the mechanism this node describes and the reason tranexamic acid is used at all.
Show evidence (1 reference)
PMID:19477491 SUPPORT Human Clinical
"Effective treatments included C1 inhibitor concentrate for angioedema attacks (6 women) and, for prophylaxis, progesterone (8 women), danazol (2 women), and tranexamic acid (1 woman)."
Documents tranexamic acid as effective prophylaxis in hereditary angioedema. PARTIAL and thinly so: a single patient in an FXII-HAE cohort. It is curated because the drug closes a treatment join point on the plasmin node that would otherwise have no intervention attached, not because this observation is strong.
Garadacimab
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: garadacimab NCIT:C166633 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses garadacimab (NCIT:C166633). NCIT:C166633 is a therapeutic agent from the NCI Thesaurus.
Garadacimab (CSL312) is a fully human monoclonal antibody that inhibits activated factor XII (FXIIa), given once monthly by subcutaneous injection for long-term prophylaxis of HAE attacks. Mechanistically it is distinctive in acting at the apex of the contact cascade rather than at plasma kallikrein or the bradykinin receptor. In the pivotal VANGUARD phase 3 trial in type I and type II HAE it lowered the monthly attack rate significantly versus placebo, a mean difference of -87%.
Mechanism Target:
INHIBITS Unrestrained factor XII activation — Garadacimab binds and inhibits activated factor XII, blocking the apex protease of the contact system and preventing downstream kallikrein activation and bradykinin generation.
Show evidence (1 reference)
PMID:36868261 SUPPORT Human Clinical
"Garadacimab (CSL312), a novel, fully-human monoclonal antibody that inhibits activated factor XII (FXIIa), is being studied for the prevention of hereditary angioedema attacks."
States that garadacimab inhibits activated factor XII, the mechanism of this treatment edge.
Show evidence (1 reference)
PMID:36868261 SUPPORT Human Clinical
"During the 6-month treatment period (day 1 to day 182), the mean number of investigator-confirmed hereditary angioedema attacks per month was significantly lower in the garadacimab group"
Phase 3 randomized trial evidence supports garadacimab prophylaxis efficacy.
Donidalorsen
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: donidalorsen NCIT:C177101 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses donidalorsen (NCIT:C177101). NCIT:C177101 is a therapeutic agent from the NCI Thesaurus.
Donidalorsen (Dawnzera) is a prekallikrein-directed antisense oligonucleotide approved for long-term prophylaxis of hereditary angioedema attacks. RNase H1-mediated knockdown of KLKB1 (prekallikrein) mRNA lowers plasma prekallikrein, reducing bradykinin generation upstream of edema attacks.
Mechanism Target:
INHIBITS Plasma kallikrein activation — Prekallikrein knockdown lowers the plasma prekallikrein pool available for conversion to active kallikrein, reducing bradykinin generation upstream of edema attacks.
Show evidence (2 references)
PMID:41767175 SUPPORT Human Clinical
"Donidalorsen, a prekallikrein-directed antisense oligonucleotide indicated for prophylaxis of hereditary angioedema (HAE) attacks"
The trial report identifies donidalorsen as a prekallikrein-directed antisense oligonucleotide for HAE prophylaxis.
PMID:35294812 SUPPORT Human Clinical
"Selective inhibition of plasma prekallikrein production by antisense oligonucleotide treatment (donidalorsen) may reduce the frequency of attacks and the burden of disease."
Phase 2 trial background statement identifies donidalorsen as an antisense oligonucleotide that selectively suppresses prekallikrein production.
Show evidence (2 references)
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.
PMID:35294812 SUPPORT Human Clinical
"donidalorsen treatment resulted in a significantly lower rate of angioedema attacks than placebo in this small, phase 2 trial."
Phase 2 randomized trial evidence supports donidalorsen prophylactic efficacy.
🌍

Environmental Factors

4
Estrogen exposure
This is a modifier of an inherited disease, not a cause of it. Avoidance is a tertiary-prevention measure rather than a treatment.
Estrogen-containing oral contraceptives, pregnancy, and hormone replacement therapy precipitate or worsen attacks. The effect is strongest in F12-related normal-C1-INH disease, where symptom onset frequently coincides with starting an oral contraceptive, but estrogen also modulates C1-INH-deficiency disease. Progestin-only contraception is generally preferred.
Show evidence (3 references)
PMID:33109323 SUPPORT Human Clinical
"The main triggers are estrogens, Angiotensin Converting Enzyme Inhibitors (ACI) inhibitors, trauma, dental work, stress, surgery, manipulation of the upper airway, and medical procedures."
Lists estrogens first among the main attack triggers in HAE.
PMID:19477491 SUPPORT Human Clinical
"Clinical symptoms started mainly after intake of oral contraceptives (17 women) or pregnancy (3 women)."
In an F12-HAE cohort, disease onset was most often triggered by oral contraceptives or pregnancy.
ORPHA:528647 SUPPORT Other
"Estrogen-containing oral contraceptives and pregnancy are precipitating factors, especially in patients with a factor XII mutation."
Orphanet records estrogen exposure and pregnancy as precipitating factors.
Angiotensin-converting enzyme inhibitor exposure
Clinically important as a drug to avoid. Recorded here as an exogenous exposure; the shared bradykinin mechanism also underlies the separate entity of ACE-inhibitor-induced angioedema.
ACE (kininase II) is a principal enzyme degrading bradykinin, so ACE inhibitors raise bradykinin availability and can precipitate or worsen attacks. ACE inhibitors are therefore avoided in HAE. Angiotensin receptor blockers have also been implicated in individual cases.
Show evidence (2 references)
PMID:33109323 SUPPORT Human Clinical
"The main triggers are estrogens, Angiotensin Converting Enzyme Inhibitors (ACI) inhibitors, trauma, dental work, stress, surgery, manipulation of the upper airway, and medical procedures."
Identifies ACE inhibitors among the main attack triggers.
PMID:19477491 SUPPORT Human Clinical
"Exacerbation of the symptoms occurred after oral contraceptive use (8 women), pregnancy (7 women), hormone replacement therapy (3 women), intake of angiotensin-converting enzyme inhibitors (2 women), and an angiotensin 1 receptor blocker (1 woman)."
Documents symptom exacerbation after ACE inhibitor and angiotensin receptor blocker exposure in F12-HAE patients.
Mechanical trauma and medical or dental procedures
The actionable consequence is short-term prophylaxis before the procedure, with rescue therapy and airway capability still available.
Local mechanical trauma, dental work, surgery, and instrumentation of the upper airway are the most predictable and actionable precipitants of attacks. Because upper-airway manipulation can provoke potentially fatal laryngeal edema, procedural short-term prophylaxis with intravenous C1 inhibitor is standard practice.
Show evidence (2 references)
PMID:33109323 SUPPORT Human Clinical
"there is consensus that, whenever the upper airway is manipulated, STP is essential."
Establishes upper-airway manipulation as a procedural trigger requiring short-term prophylaxis.
PMID:19477491 SUPPORT Human Clinical
"Some factors that triggered angioedema attacks were trauma, physical pressure, and emotional stress."
Documents trauma and physical pressure as attack triggers.
Emotional stress
Psychological and emotional stress is a commonly reported attack precipitant. It is not reliably avoidable, so it informs counselling and treatment readiness rather than restriction of normal activity.
Show evidence (2 references)
PMID:33109323 SUPPORT Human Clinical
"The main triggers are estrogens, Angiotensin Converting Enzyme Inhibitors (ACI) inhibitors, trauma, dental work, stress, surgery, manipulation of the upper airway, and medical procedures."
Lists stress among the main attack triggers.
PMID:19477491 SUPPORT Human Clinical
"Some factors that triggered angioedema attacks were trauma, physical pressure, and emotional stress."
Documents emotional stress as an attack trigger.
🔬

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.
🔬

Diagnosis

2
C1 inhibitor and complement C4 protein measurement
Measurement of C1-INH level/function together with complement C4 helps establish C1-INH-deficiency HAE and distinguish it from normal-C1-INH HAE.
protein measurement NCIT:C64430 NCI Thesaurus (NCIT)
Markers: C1-INH level/function, complement C4
Results: Abnormal C1-INH level or function with supportive C4 reduction indicates C1-INH-deficiency HAE.
Show evidence (2 references)
PMID:36609679 SUPPORT Human Clinical
"Laboratory testing shows abnormal levels of C1-INH and high levels of bradykinin."
Review evidence supports C1-INH laboratory testing in HAE evaluation.
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 monitoring when an acute attack is suspected.
Genetic testing for HAE subtype assignment
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.
genetic testing NCIT:C15709 NCI Thesaurus (NCIT)
Results: Pathogenic variants support subtype assignment and family counseling.
Show evidence (2 references)
PMID:36609679 SUPPORT Human Clinical
"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"
Review evidence supports genetic subtype assignment for normal-C1-INH HAE.
ORPHA:100054 SUPPORT Other
"F12 | coagulation factor XII | hgnc:3530 | Disease-causing germline mutation(s) (gain of function) in"
Orphanet supports F12 genetic testing for a defined normal-C1-INH subtype.
📈

Progression

1
Recurrent episodic swelling attacks
Age: childhood to adulthood
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.
Show evidence (2 references)
ORPHA:528623 SUPPORT Other
"Patients may present at any age (but most commonly in childhood) with recurrent attacks of nonpitting edema of the skin"
Orphanet supports variable onset and recurrent attacks for C1-INH-deficiency disease.
ORPHA:528647 SUPPORT Other
"Patients present with prolonged attacks which last for approximately two to five days"
Orphanet supports prolonged recurrent attacks in normal-C1-INH disease.
📊

Prevalence

3
Hereditary angioedema patients, by type
Cases In Literature Not yet documented
Type distribution within diagnosed HAE, curated as the subtype case-fraction breakdown rather than a population rate: type I about 85% of cases, type II about 15%, and normal-C1-INH (historically type III) about 5-10%. Those figures do not sum to 100 because the normal-C1-INH estimate is drawn from a differently ascertained denominator and is the least secure of the three - it depends on diagnostic access, since normal-C1-INH disease cannot be found by C1-INH assay and requires genetic testing that most centres do not perform. The overall HAE prevalence figures are recorded in the records below.
Show evidence (2 references)
PMID:39456231 SUPPORT Other
"Type I HAE, which accounts for 85% of cases, is characterized by a deficiency of the C1 esterase inhibitor (C1-INH) gene. Type II HAE, making up 15% of cases, involves a dysfunctional C1-INH."
Supplies the type I and type II case fractions. evidence_source is OTHER because this is a narrative review stating established proportions rather than reporting a cohort.
PMID:39456231 SUPPORT Other
"Type III HAE, which represents about 5% to 10% of cases, is often estrogen-dependent and although several mutations have been identified, it typically involves normal C1-INH activity."
Supplies the normal-C1-INH fraction. PARTIAL because the estimate is a range, is ascertainment-dependent in a way the other two are not, and uses the superseded "type III" label for what this entry curates as the normal-C1-INH subtype group.
Worldwide
Point Prevalence 1.22 per 100,000 (1.0–2.0) 1–9 per 100,000
Pooled worldwide point prevalence 1.22 per 100,000 (meta-analysis), with the systematic-review conclusion stated as approximately 1-2 individuals per 100,000. Reported national estimates vary widely because of ascertainment differences and probable underdiagnosis.
Show evidence (2 references)
PMID:39827848 SUPPORT Human Clinical
"The pooled prevalence of HAE was 1.22 cases per 100,000 people"
Meta-analysis provides the normalized worldwide pooled point-prevalence estimate.
PMID:39827848 SUPPORT Human Clinical
"HAE is a rare condition which affects 1-2 individuals per 100,000 people worldwide."
The systematic review conclusion supports the 1-2 per 100,000 range recorded here.
Worldwide
Point Prevalence 0.67–2.0 per 100,000 1–9 per 100,000
Independent contemporary review states a global prevalence of 1 in 50,000 to 1 in 150,000, i.e. 0.67-2.0 per 100,000, concordant with the meta-analytic band above.
Show evidence (1 reference)
PMID:39456231 SUPPORT Other
"with a global prevalence estimated between 1 in 50,000 and 1 in 150,000 individuals."
Provides an independent global prevalence range, converted here to cases per 100,000.
📊

Related Datasets

1
A catalog of the genetic causes of Hereditary Angioedema in the Canary Islands (Spain) ega:EGAS00001006547
Hereditary angioedema (HAE) is a rare disease where known causes involve C1 inhibitor dysfunction or dysregulation of the kinin cascade. The updated HAE management guidelines recommend performing genetic tests to reach a precise diagnosis. Unfortunately, genetic tests are still uncommon in the diagnosis routine. Here, we characterized for the first time the genetic causes of HAE in affected families from the Canary Islands (Spain). Whole-exome sequencing data was obtained from 41 affected patients and unaffected relatives from 29 unrelated families identified in the archipelago.
human
European Genome-phenome Archive study, matched because the disease is named in the study's own title ("Hereditary Angioedema"); description-level mentions were not accepted. EGA study_type: Other. Controlled access -- data require a Data Access Agreement. EGA metadata retrieved 2026-08-01.
🔬

Clinical Trials

3
NCT05120830 PHASE_I ACTIVE_NOT_RECRUITING
First-in-human phase 1/2 study of NTLA-2002, a CRISPR/Cas9 in vivo gene editing therapy targeting KLKB1 - the prekallikrein gene. Mechanistically it is the most radical entry in this entry's therapeutic landscape: rather than inhibiting plasma kallikrein repeatedly, it aims to knock down its precursor permanently in a single dose, converting lifelong prophylaxis into a one-time intervention on the same pathograph node the antibody and small-molecule inhibitors act on.
Show evidence (1 reference)
clinicaltrials:NCT05120830 SUPPORT Human Clinical
"This study will be conducted to evaluate the safety, tolerability, activity, pharmacokinetics, and pharmacodynamics of NTLA-2002 in adults with Hereditary Angioedema (HAE)."
Confirms the design and population of the first-in-human NTLA-2002 study.
NCT06634420 PHASE_III ACTIVE_NOT_RECRUITING
HAELO, the phase 3 randomized placebo-controlled trial of NTLA-2002. Its existence is the substantive fact - a CRISPR therapy for this disease has reached phase 3, which is what would move single-dose KLKB1 knockdown from concept to option.
Show evidence (1 reference)
clinicaltrials:NCT06634420 SUPPORT Human Clinical
"This Phase 3 study aims to evaluate the efficacy and safety of NTLA-2002 compared to placebo in participants with HAE."
Confirms the phase 3 placebo-controlled design.
NCT05121376 PHASE_I ACTIVE_NOT_RECRUITING
Phase 1/2 open-label dose-escalation study of BMN 331, an AAV5 vector delivering wild-type human SERPING1 under a liver-selective promoter. This is the mechanistic complement of the editing approach: rather than removing the substrate downstream, it restores the deficient inhibitor itself, acting on the SERPING1 deficiency node at the head of the pathograph. It is restricted to C1-INH deficiency, so it does not apply to the normal-C1-INH subtypes this entry also models.
Show evidence (1 reference)
clinicaltrials:NCT05121376 SUPPORT Human Clinical
"The study drug BMN 331is identified as AAV5 hSERPING1, an adeno-associated virus (AAV5)-based gene therapy vector that expresses wild-type human C1 Esterase Inhibitor (hC1-INH), under the control of a liver-selective promoter"
States the vector and transgene, which is what places this trial on the SERPING1 deficiency node rather than on the kallikrein node.
{ }

Source YAML

click to show 
name: Hereditary Angioedema
creation_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.

  No GeneReviews chapter exists for hereditary angioedema (searched by disease
  name, by SERPING1, and by "C1 inhibitor deficiency"; all returned no
  GeneReviews record), so the usual GeneReviews phenotype baseline is
  unavailable. The WAO/EAACI international guideline (PMID:35006617) and the
  normal-C1-INH international consensus paper (PMID:40053270) serve as the
  expert-consensus substitutes.

  The pathograph deliberately models the contact (kallikrein-kinin) cascade as
  discrete nodes -- factor XII activation, plasma kallikrein activation,
  high-molecular-weight kininogen cleavage, bradykinin B2 receptor signalling,
  and endothelial adherens junction destabilization -- rather than collapsing
  them into a single "excess bradykinin" step, so that each approved drug class
  attaches to the node it actually acts on (garadacimab at FXIIa; ecallantide,
  lanadelumab, berotralstat, sebetralstat, and donidalorsen at plasma
  kallikrein; icatibant at the B2 receptor) and so that the normal-C1-INH
  subtype genes can enter the graph at their distinct points.

  No `conforms_to` link to the `antisense_oligonucleotide_therapy` module is
  asserted. That module names KLKB1/donidalorsen as an instance of its
  "Pathogenic mRNA Accumulation" node, but prekallikrein transcript abundance is
  not itself abnormal in HAE -- it is a normal protein exploited as a drug
  target -- so a conformance claim would misstate the disease mechanism. The ASO
  paradigm is captured instead by `aso_details` on the donidalorsen treatment.
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"
    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"
    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"
    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"
    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"
    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"
    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"
    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"
    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"
    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"
    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"
    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"
    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"
    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"
    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"
    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"
    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.
prevalence:
- population: Hereditary angioedema patients, by type
  measure_type: CASES_IN_LITERATURE
  prevalence_class: NOT_YET_DOCUMENTED
  notes: >-
    Type distribution within diagnosed HAE, curated as the subtype case-fraction
    breakdown rather than a population rate: type I about 85% of cases, type II
    about 15%, and normal-C1-INH (historically type III) about 5-10%. Those
    figures do not sum to 100 because the normal-C1-INH estimate is drawn from a
    differently ascertained denominator and is the least secure of the three -
    it depends on diagnostic access, since normal-C1-INH disease cannot be found
    by C1-INH assay and requires genetic testing that most centres do not
    perform. The overall HAE prevalence figures are recorded in the records
    below.
  evidence:
  - reference: PMID:39456231
    reference_title: "Unveiling the Complexities of Hereditary Angioedema."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Type I HAE, which accounts for 85% of cases, is characterized by a
      deficiency of the C1 esterase inhibitor (C1-INH) gene. Type II HAE, making
      up 15% of cases, involves a dysfunctional C1-INH.
    explanation: >-
      Supplies the type I and type II case fractions. evidence_source is OTHER
      because this is a narrative review stating established proportions rather
      than reporting a cohort.
  - reference: PMID:39456231
    reference_title: "Unveiling the Complexities of Hereditary Angioedema."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Type III HAE, which represents about 5% to 10% of cases, is often
      estrogen-dependent and although several mutations have been identified, it
      typically involves normal C1-INH activity.
    explanation: >-
      Supplies the normal-C1-INH fraction. PARTIAL because the estimate is a
      range, is ascertainment-dependent in a way the other two are not, and uses
      the superseded "type III" label for what this entry curates as the
      normal-C1-INH subtype group.
- population: Worldwide
  measure_type: POINT_PREVALENCE
  prevalence_class: BAND_1_9_PER_100000
  rate_per_100000: 1.22
  rate_low: 1.0
  rate_high: 2.0
  notes: >-
    Pooled worldwide point prevalence 1.22 per 100,000 (meta-analysis), with the
    systematic-review conclusion stated as approximately 1-2 individuals per
    100,000. Reported national estimates vary widely because of ascertainment
    differences and probable underdiagnosis.
  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 the normalized worldwide pooled point-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 1-2 per 100,000 range recorded here.
- population: Worldwide
  measure_type: POINT_PREVALENCE
  prevalence_class: BAND_1_9_PER_100000
  rate_low: 0.67
  rate_high: 2.0
  notes: >-
    Independent contemporary review states a global prevalence of 1 in 50,000 to
    1 in 150,000, i.e. 0.67-2.0 per 100,000, concordant with the meta-analytic
    band above.
  evidence:
  - reference: PMID:39456231
    reference_title: Unveiling the Complexities of Hereditary Angioedema.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      with a global prevalence estimated between 1 in 50,000 and 1 in 150,000
      individuals.
    explanation: >-
      Provides an independent global prevalence range, converted here to cases
      per 100,000.
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"
    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"
    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
  biological_scale: MOLECULAR
  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: Unrestrained factor XII activation
    description: >-
      C1-INH is the principal plasma inhibitor of the contact-system enzymes, so
      its loss or dysfunction removes the brake on factor XII activation.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:29920929
      reference_title: "Hereditary angioedema: the plasma contact system out of control."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        C1-INH is the key plasma inhibitor of the contact system enzymes, and its
        deficiency causes hereditary angioedema (HAE).
      explanation: >-
        Identifies C1-INH as the key inhibitor of the contact-system enzymes,
        supporting a direct link from C1-INH loss to unrestrained contact
        activation.
  - 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:
    - Unrestrained factor XII activation
    - Plasma kallikrein activation
    - High-molecular-weight kininogen cleavage and bradykinin liberation
    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.
    - reference: PMID:30656274
      reference_title: "Hereditary angioedema: Linking complement regulation to the coagulation system."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        There is a central role for bradykinin that is released upon activation
        of the kallikrein-kinin system that is insufficiently controlled by
        adequate levels of C1 inhibitor.
      explanation: >-
        States the intermediate steps between inadequate C1-INH and bradykinin
        release that this edge summarizes.
  - target: C1-INH intracellular retention and endoplasmic reticulum stress
    description: >-
      Some SERPING1 missense variants are secretion-defective and accumulate
      intracellularly rather than simply lowering synthesis.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:39272138
      reference_title: "Uncovering a novel SERPING1 pathogenic variant: insights into the aggregation of C1-INH in hereditary angioedema."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        this variant leads to an increase in the accumulation of C1-INH within
        the endoplasmic reticulum (ER), resulting in the upregulation of GRP75
        protein expression.
      explanation: >-
        Cellular study of a SERPING1 variant showing intracellular C1-INH
        accumulation, supporting a retention arm downstream of the variant.
  - target: Decreased circulating C1-esterase inhibitor concentration
    causal_link_type: DIRECT
    evidence:
    - 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: Supports the direct link from SERPING1 variants to reduced circulating C1-INH in type 1 disease.
  - target: Decreased circulating complement C4 concentration
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - unopposed C1 esterase activity consuming C4
    evidence:
    - reference: ORPHA:528623
      reference_title: "Hereditary angioedema with C1Inh deficiency"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0045042 | Decreased circulating complement C4 concentration | Frequent (79-30%)"
      explanation: Orphanet records decreased circulating C4 as a frequent consequence in C1-INH-deficiency HAE.
- name: Unrestrained factor XII activation
  biological_scale: MOLECULAR
  description: >-
    With C1-INH absent or dysfunctional, factor XII autoactivates to factor XIIa
    without adequate inhibition. FXIIa is the apex protease of the plasma contact
    (kallikrein-kinin) system in HAE, and gain-of-function F12 variants produce
    the same excess activation in F12-related normal-C1-INH disease. FXIIa is a
    validated drug target: the anti-FXIIa antibody garadacimab prevents attacks.
  genes:
  - preferred_term: F12
    term:
      id: hgnc:3530
      label: F12
  biological_processes:
  - preferred_term: Factor XII activation
    modifier: INCREASED
    term:
      id: GO:0002542
      label: Factor XII activation
  evidence:
  - reference: PMID:36868261
    reference_title: "Efficacy and safety of garadacimab, a factor XIIa inhibitor for hereditary angioedema prevention (VANGUARD): a global, multicentre, randomised, double-blind, placebo-controlled, phase 3 trial."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Hereditary angioedema is a rare and potentially life-threatening genetic
      disease that is associated with kallikrein-kinin system dysregulation.
    explanation: >-
      The pivotal FXIIa-inhibitor trial frames HAE as a kallikrein-kinin
      dysregulation disorder, supporting contact-system activation as a core
      mechanism node.
  - reference: PMID:29920929
    reference_title: "Hereditary angioedema: the plasma contact system out of control."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Bradykinin, which is considered to be a byproduct of the plasma contact
      system during in vitro coagulation, is the main disease mediator in HAE.
    explanation: >-
      Places the plasma contact system upstream of bradykinin, the main HAE
      mediator.
  downstream:
  - target: Plasma kallikrein activation
    description: FXIIa cleaves plasma prekallikrein to active plasma kallikrein.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:27459852
      reference_title: "HAE Pathophysiology and Underlying Mechanisms."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        the fundamental cause of swelling is enhanced contact system activation
        leading to increased generation of bradykinin
      explanation: >-
        Supports enhanced contact-system activation as the step generating
        bradykinin through kallikrein.
- name: Plasma kallikrein activation
  biological_scale: MOLECULAR
  description: >-
    Active plasma kallikrein is the central effector protease of the HAE cascade.
    It cleaves high-molecular-weight kininogen to liberate bradykinin and also
    reciprocally activates more factor XII, creating a self-amplifying loop that
    explains the explosive, self-sustaining character of attacks. Plasma
    kallikrein is the most heavily drugged node in HAE: ecallantide, lanadelumab,
    berotralstat, and sebetralstat inhibit the active enzyme, while donidalorsen
    lowers the prekallikrein zymogen pool.
  gene_products:
  - preferred_term: plasma kallikrein
    term:
      id: NCIT:C95409
      label: Plasma Kallikrein
  biological_processes:
  - preferred_term: plasma kallikrein-kinin cascade
    modifier: INCREASED
    term:
      id: GO:0002353
      label: plasma kallikrein-kinin cascade
  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: >-
      Establishes plasma kallikrein as the protease whose inhibition blocks
      bradykinin production in HAE.
  - reference: PMID:30656274
    reference_title: "Hereditary angioedema: Linking complement regulation to the coagulation system."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      As C1 inhibitor also possesses a central regulatory role of other plasma
      systems, including the contact activation system of coagulation and the
      plasminogen-plasmin system that governs endogenous fibrinolysis
    explanation: >-
      Supports C1-INH regulation of the contact and fibrinolytic systems that
      converge on kallikrein activity.
  downstream:
  - target: High-molecular-weight kininogen cleavage and bradykinin liberation
    description: Plasma kallikrein cleaves high-molecular-weight kininogen to release bradykinin.
    causal_link_type: DIRECT
    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: Kallikrein inhibition prevents bradykinin production, supporting this direct step.
  - target: Unrestrained factor XII activation
    description: >-
      Plasma kallikrein reciprocally activates factor XII, forming the
      self-amplifying contact-system loop that is normally restrained by C1-INH.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:29920929
      reference_title: "Hereditary angioedema: the plasma contact system out of control."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Finally, we propose a central enzymatic axis that we hypothesize to be
        responsible for bradykinin production in health and disease.
      explanation: >-
        The review proposes a central contact-system enzymatic axis; this edge
        records the reciprocal kallikrein-to-FXII amplification within it.
- name: High-molecular-weight kininogen cleavage and bradykinin liberation
  biological_scale: MOLECULAR
  description: >-
    Kallikrein-mediated proteolysis of high-molecular-weight kininogen (the KNG1
    gene product) releases the nonapeptide bradykinin. Cleaved kininogen is a
    contact-activation biomarker, and a KNG1 variant altering the N-terminal
    bradykinin cleavage site causes a normal-C1-INH HAE subtype, placing this
    step directly on the disease path.
  genes:
  - preferred_term: KNG1
    term:
      id: hgnc:6383
      label: KNG1
  gene_products:
  - preferred_term: high-molecular-weight kininogen
    term:
      id: NCIT:C114390
      label: Kininogen-1
  biological_processes:
  - preferred_term: bradykinin biosynthetic process
    modifier: INCREASED
    term:
      id: GO:0002936
      label: bradykinin biosynthetic process
  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: Supports excess bradykinin generation as the step preceding increased permeability.
  downstream:
  - target: Excess bradykinin signaling
    description: Liberated bradykinin is the mediator that acts on the vascular endothelium.
    causal_link_type: DIRECT
    evidence:
    - 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: Identifies liberated bradykinin as the symptom-producing mediator.
- name: C1-INH intracellular retention and endoplasmic reticulum stress
  biological_scale: CELLULAR
  description: >-
    A subset of SERPING1 missense variants are not simply null alleles: the
    mutant C1-INH protein is retained and aggregates in the endoplasmic
    reticulum. In a reported Han Chinese family the c.708T>G variant raised
    intracellular C1-INH, upregulated GRP75, and produced calcium overload,
    mitochondrial damage, and apoptosis. This arm is a proposed cell-intrinsic
    contributor and biomarker route rather than an established driver of the
    swelling itself, which remains bradykinin-mediated.
  genes:
  - preferred_term: SERPING1
    term:
      id: hgnc:1228
      label: SERPING1
  evidence:
  - reference: PMID:39272138
    reference_title: "Uncovering a novel SERPING1 pathogenic variant: insights into the aggregation of C1-INH in hereditary angioedema."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      This cascade of events resulted in Ca2+ overload, disruption of
      mitochondrial structure and function, and eventually triggered apoptosis.
    explanation: >-
      Documents the ER-retention consequences in a cellular model of a SERPING1
      variant.
  - reference: PMID:39272138
    reference_title: "Uncovering a novel SERPING1 pathogenic variant: insights into the aggregation of C1-INH in hereditary angioedema."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Using siRNA to knock down GRP75 mitigates cellular calcium overload and
      mitochondrial damage induced by the SERPING1 mutation.
    explanation: >-
      Rescue by GRP75 knockdown supports GRP75 as the mediator of the retention
      phenotype.
  downstream:
  - target: Decreased circulating C1-esterase inhibitor concentration
    description: >-
      Retention of mutant C1-INH inside the cell reduces the amount of
      functional inhibitor secreted into plasma.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - impaired secretion of mutant C1-INH
    evidence:
    - reference: PMID:39272138
      reference_title: "Uncovering a novel SERPING1 pathogenic variant: insights into the aggregation of C1-INH in hereditary angioedema."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Our observations indicate that this variant leads to an increase in the
        accumulation of C1-INH within the endoplasmic reticulum (ER)
      explanation: >-
        Support is partial: intracellular accumulation is demonstrated, but the
        study does not directly quantify the resulting fall in secreted plasma
        C1-INH, so the secretion step remains inferred.
- name: Normal C1-INH contact-system gene dysregulation
  biological_scale: MOLECULAR
  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. The
    subtype genes enter the shared pathograph at different points rather than
    through one common step: F12 gain of function amplifies contact activation,
    KNG1 alters the bradykinin cleavage site of its own substrate, PLG variants
    act through the plasmin arm, and ANGPT1 and HS3ST6 act on the endothelial
    barrier itself. Whether every normal-C1-INH subtype is strictly
    bradykinin-mediated is not established.
  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.
  - target: Unrestrained factor XII activation
    description: >-
      F12 gain-of-function variants (for example p.Thr309Lys/p.Thr309Arg) drive
      excess contact activation directly, the entry point for the F12-related
      subtype.
    causal_link_type: DIRECT
    evidence:
    - reference: ORPHA:100054
      reference_title: "F12-related hereditary angioedema with normal C1Inh"
      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, supporting entry at the FXII node.
  - target: High-molecular-weight kininogen cleavage and bradykinin liberation
    description: >-
      A KNG1 variant that changes the N-terminal cleavage site of bradykinin acts
      on the kininogen-processing step itself.
    causal_link_type: DIRECT
    evidence:
    - reference: ORPHA:599418
      reference_title: "Hereditary angioedema with normal C1Inh not related to F12 or PLG variant"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "KNG1 | kininogen 1 | hgnc:6383 | Disease-causing germline mutation(s) in"
      explanation: Orphanet lists KNG1 as disease-causing, supporting entry at the kininogen-cleavage node.
  - target: Endothelial adherens junction destabilization
    description: >-
      ANGPT1 and HS3ST6 variants act on the endothelial barrier rather than on
      kinin generation, entering the pathograph at the endothelial node.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:28601681
      reference_title: "Mutation of the angiopoietin-1 gene (ANGPT1) associates with a new type of hereditary angioedema."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        ANGPT1 impairment is associated with angioedema, and ANGPT1 variants can
        be the basis of HAE.
      explanation: Establishes ANGPT1 impairment as a cause of HAE acting through endothelial angiopoietin signalling.
    - reference: PMID:33508266
      reference_title: "Novel hereditary angioedema linked with a heparan sulfate 3-O-sulfotransferase 6 gene mutation."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        This likely affects cell surface interactions of key players in
        angioedema formation and is a novel mechanism for disease development.
      explanation: >-
        Supports HS3ST6-dependent heparan sulfate changes acting on cell-surface
        interactions at the endothelium.
  - target: Plasmin-mediated contact-system amplification
    description: >-
      PLG variants act through the plasmin arm of the fibrinolytic system, which
      C1-INH also normally restrains.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:28795768
      reference_title: Hereditary angioedema with a mutation in the plasminogen gene.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The mutation c.988A>G was located in exon 9 leading to the missense
        mutation p.Lys330Glu (K330E) in the kringle 3 domain of the PLG protein.
      explanation: Identifies the PLG K330E variant defining the plasminogen-related normal-C1-INH subtype.
- name: Plasmin-mediated contact-system amplification
  biological_scale: MOLECULAR
  description: >-
    C1-INH restrains the plasminogen-plasmin (fibrinolytic) system in addition to
    the contact system, and plasmin can feed back into contact activation and
    kinin generation. This arm is the mechanistic rationale for the PLG-related
    normal-C1-INH subtype and for the historical use of the antifibrinolytic
    tranexamic acid, and it underlies the raised D-dimer seen during attacks.
  genes:
  - preferred_term: PLG
    term:
      id: hgnc:9071
      label: PLG
  biological_processes:
  - preferred_term: fibrinolysis
    modifier: INCREASED
    term:
      id: GO:0042730
      label: fibrinolysis
  - preferred_term: positive regulation of plasma kallikrein-kinin cascade
    modifier: INCREASED
    term:
      id: GO:0002550
      label: positive regulation of plasma kallikrein-kinin cascade
  evidence:
  - reference: PMID:30656274
    reference_title: "Hereditary angioedema: Linking complement regulation to the coagulation system."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      As C1 inhibitor also possesses a central regulatory role of other plasma
      systems, including the contact activation system of coagulation and the
      plasminogen-plasmin system that governs endogenous fibrinolysis
    explanation: >-
      Establishes C1-INH regulation of the plasminogen-plasmin system alongside
      the contact system.
  - reference: PMID:28795768
    reference_title: Hereditary angioedema with a mutation in the plasminogen gene.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We detected a mutation in the plasminogen (PLG) gene in patients with
      HAEnCI.
    explanation: Supports a plasminogen-dependent route to normal-C1-INH HAE.
  downstream:
  - target: High-molecular-weight kininogen cleavage and bradykinin liberation
    description: >-
      Plasmin activity promotes kinin generation, converging on the same
      bradykinin-liberating step as the kallikrein arm.
    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: >-
        Consensus support is indirect: it establishes non-mast-cell mechanisms in
        normal-C1-INH HAE without specifying the plasmin-to-kinin step, which
        remains incompletely defined.
- name: Excess bradykinin signaling
  biological_scale: MOLECULAR
  description: >-
    Excess bradykinin is the central mediator of HAE attacks. It acts on the
    bradykinin B2 receptor on vascular endothelium to increase permeability in
    superficial tissues and gastrointestinal and respiratory mucosa. The B2
    receptor is the target of icatibant; the contribution of the bradykinin B1
    receptor remains unresolved and is recorded as a knowledge gap.
  chemical_entities:
  - preferred_term: bradykinin
    term:
      id: CHEBI:3165
      label: bradykinin
  gene_products:
  - preferred_term: bradykinin B2 receptor
    term:
      id: NCIT:C26101
      label: B2 Bradykinin Receptor
  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: "Icatibant is a selective bradykinin B2 receptor antagonist."
    explanation: >-
      Efficacy of a selective B2 receptor antagonist supports B2 receptor
      engagement as the operative bradykinin signalling step.
  - 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: Endothelial adherens junction destabilization
    description: >-
      Bradykinin B2 receptor signalling on vascular endothelium disassembles
      interendothelial adherens junctions, the proximate cellular lesion of the
      swelling attack.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:27459852
      reference_title: "HAE Pathophysiology and Underlying Mechanisms."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        tissue swelling in hereditary angioedema primarily involves the function
        of endothelial cell adherens junctions
      explanation: >-
        Identifies endothelial adherens junction function as the mechanism
        through which bradykinin produces swelling.
  - target: Vascular permeability and recurrent edema attacks
    description: Bradykinin-driven permeability produces recurrent skin, gastrointestinal, and airway edema attacks.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Endothelial adherens junction destabilization
    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: Endothelial adherens junction destabilization
  biological_scale: CELLULAR
  description: >-
    The proximate cellular lesion of an HAE attack is loss of interendothelial
    adherens junction integrity in postcapillary vessels, with reduced
    VE-cadherin and beta-catenin at the cell surface, F-actin stress-fibre
    reorganization, and interendothelial gap formation. This node is the point of
    convergence for the bradykinin-mediated arm and for the normal-C1-INH
    "endothelial barrier" genes: ANGPT1 haploinsufficiency impairs the
    Tie2-dependent counter-regulation that normally opposes bradykinin- and
    VEGF-induced leak, and HS3ST6 loss alters endothelial heparan sulfate
    involved in cell-surface interactions of angioedema mediators.
  cell_types:
  - preferred_term: vascular endothelial cell
    term:
      id: CL:0002139
      label: endothelial cell of vascular tree
  genes:
  - preferred_term: ANGPT1
    term:
      id: hgnc:484
      label: ANGPT1
  - preferred_term: HS3ST6
    term:
      id: hgnc:14178
      label: HS3ST6
  biological_processes:
  - preferred_term: adherens junction organization
    modifier: ABNORMAL
    term:
      id: GO:0034332
      label: adherens junction organization
  - preferred_term: regulation of vascular permeability
    modifier: INCREASED
    term:
      id: GO:0043114
      label: regulation of vascular permeability
  evidence:
  - reference: PMID:27459852
    reference_title: "HAE Pathophysiology and Underlying Mechanisms."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      This knowledge is driving increased attention to the role of endothelial
      biology in determining disease activity in hereditary angioedema.
    explanation: >-
      Supports endothelial biology as the determinant of HAE disease activity,
      justifying a dedicated endothelial node.
  - reference: PMID:30689269
    reference_title: "Angiopoietin-1 haploinsufficiency affects the endothelial barrier and causes hereditary angioedema."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Likewise, cell surface expression of β-catenin was reduced and severe gap
      formation between adjacent HUVECs developed.
    explanation: >-
      Endothelial-cell experiments demonstrate junctional protein loss and gap
      formation, the cellular readout of this node.
  - reference: PMID:30689269
    reference_title: "Angiopoietin-1 haploinsufficiency affects the endothelial barrier and causes hereditary angioedema."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      The ANGPT1 reduced ability to counteract the increment of endothelial
      permeability produced by inducers, such as VEGF and bradykinin, stimulate
      vascular leakage and reorganization of the F-actin cytoskeletal elements.
    explanation: >-
      Links ANGPT1 loss of function to failure of counter-regulation against
      bradykinin-induced endothelial leak.
  downstream:
  - target: Vascular permeability and recurrent edema attacks
    description: >-
      Interendothelial gap formation permits plasma extravasation into
      subcutaneous and submucosal tissue, producing the clinical attack.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:30689269
      reference_title: "Angiopoietin-1 haploinsufficiency affects the endothelial barrier and causes hereditary angioedema."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        ANGPT1 p.A119S variant in homozygous condition further diminished
        VE-cadherin and β-catenin expression and failed to reduce stress fibre
        formation significantly affecting the endothelial barrier functionality.
      explanation: >-
        Demonstrates that junctional destabilization degrades endothelial barrier
        function, the step producing extravasation.
- name: Vascular permeability and recurrent edema attacks
  biological_scale: TISSUE
  description: >-
    Increased vascular permeability causes transitory, recurrent, nonpitting
    subcutaneous and submucosal edema attacks involving skin, abdomen, genital
    tissues, pharynx, and larynx. The lesion is interstitial fluid accumulation
    from postcapillary endothelial leak, not primary tissue destruction, which is
    why attacks resolve completely and leave no fibrosis or scarring.
  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"
    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"
    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.
  downstream:
  - target: Angioedema
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:39456231
      reference_title: Unveiling the Complexities of Hereditary Angioedema.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        HAE leads to recurrent episodes of non-pruritic angioedema, which occurs
        in the absence of urticaria.
      explanation: >-
        Supports recurrent non-urticarial angioedema as the direct clinical
        expression of the permeability lesion.
  - target: Non-pitting edema
    causal_link_type: DIRECT
    evidence:
    - reference: ORPHA:528623
      reference_title: "Hereditary angioedema with C1Inh deficiency"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:6000507 | Non-pitting edema | Frequent (79-30%)"
      explanation: Orphanet records non-pitting edema as a frequent manifestation of the permeability lesion.
  - target: Facial edema
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:19477491
      reference_title: "Hereditary angioedema caused by missense mutations in the factor XII gene: clinical features, trigger factors, and therapy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Recurrent facial swellings occurred in all patients"
      explanation: >-
        In an F12-HAE cohort recurrent facial swelling occurred in every patient,
        supporting facial edema as a direct consequence.
  - target: Skin rash
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: ORPHA:528623
      reference_title: "Hereditary angioedema with C1Inh deficiency"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0000988 | Skin rash | Frequent (79-30%)"
      explanation: >-
        Orphanet records skin rash as frequent; the intermediate steps linking
        permeability to rash are not defined.
  - target: Abdominal pain
    causal_link_type: DIRECT
    evidence:
    - reference: ORPHA:528623
      reference_title: "Hereditary angioedema with C1Inh deficiency"
      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 links the edema attacks directly to severe abdominal pain and swelling.
  - target: Intestinal edema
    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: >-
        Explicitly places the permeability lesion in gastrointestinal mucosa,
        supporting bowel-wall edema.
  - target: Laryngeal edema
    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: >-
        Places the permeability lesion in respiratory mucosa, the basis of
        laryngeal edema, which is the lethal manifestation.
  - target: Pharyngeal edema
    causal_link_type: DIRECT
    evidence:
    - reference: ORPHA:528623
      reference_title: "Hereditary angioedema with C1Inh deficiency"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0011855 | Pharyngeal edema | Frequent (79-30%)"
      explanation: Orphanet records pharyngeal edema as a frequent site of the permeability lesion.
  - target: Genital edema
    causal_link_type: DIRECT
    evidence:
    - reference: ORPHA:528623
      reference_title: "Hereditary angioedema with C1Inh deficiency"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0031188 | Genital edema | Frequent (79-30%)"
      explanation: Orphanet records genital edema as a frequent site of the permeability lesion.
  - target: Edema of the upper limbs
    causal_link_type: DIRECT
    evidence:
    - reference: ORPHA:528647
      reference_title: "Hereditary angioedema with normal C1Inh"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0010742 | Edema of the upper limbs | Frequent (79-30%)"
      explanation: Orphanet records upper-limb edema as frequent in normal-C1-INH disease.
  - target: Muscular edema
    causal_link_type: DIRECT
    evidence:
    - reference: ORPHA:528623
      reference_title: "Hereditary angioedema with C1Inh deficiency"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0100748 | Muscular edema | Frequent (79-30%)"
      explanation: Orphanet records muscular edema as a frequent site of the permeability lesion.
  - target: Joint swelling
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: ORPHA:528623
      reference_title: "Hereditary angioedema with C1Inh deficiency"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0001386 | Joint swelling | Frequent (79-30%)"
      explanation: >-
        Orphanet records joint swelling as frequent; whether it reflects
        periarticular edema directly is not specified.
  - target: Diarrhea
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: ORPHA:528623
      reference_title: "Hereditary angioedema with C1Inh deficiency"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0002014 | Diarrhea | Frequent (79-30%)"
      explanation: >-
        Orphanet records diarrhea as frequent, presumed secondary to bowel-wall
        edema through undefined intermediates.
  - target: Nausea and vomiting
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: ORPHA:528623
      reference_title: "Hereditary angioedema with C1Inh deficiency"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0002017 | Nausea and vomiting | Frequent (79-30%)"
      explanation: >-
        Orphanet records nausea and vomiting as frequent, presumed secondary to
        bowel-wall edema.
  - target: Painful angioedema attacks
    causal_link_type: DIRECT
    evidence:
    - reference: ORPHA:528623
      reference_title: "Hereditary angioedema with C1Inh deficiency"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0012531 | Pain | Frequent (79-30%)"
      explanation: Orphanet records pain as a frequent accompaniment of the edema attacks.
  - target: Serpiginous cutaneous lesion
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: ORPHA:528623
      reference_title: "Hereditary angioedema with C1Inh deficiency"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0025527 | Serpiginous cutaneous lesion | Frequent (79-30%)"
      explanation: >-
        Orphanet records the serpiginous prodromal rash as frequent; its
        mechanism is not established.
  - target: Erythema marginatum
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: ORPHA:528623
      reference_title: "Hereditary angioedema with C1Inh deficiency"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:6001012 | Erythema marginatum | Frequent (79-30%)"
      explanation: >-
        Orphanet records erythema marginatum as frequent; this prodromal rash
        precedes attacks through undefined intermediates.
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"
    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"
    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
    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: Directly states autosomal dominant inheritance for SERPING1/C1-INH disease.
  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"
    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"
    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
    inheritance_term:
      preferred_term: Autosomal dominant inheritance
      term:
        id: HP:0000006
        label: Autosomal dominant inheritance
    description: >-
      Autosomal dominant, per the Orphanet record for this entity. No evidence
      item is attached: Orphanet states inheritance as a bare enumerated value
      rather than in a sentence, so there is nothing quotable that carries the
      claim, and a two-word snippet would assert the fact without evidencing it.
  features: >-
    F12 gain-of-function variants cause the historical HAE type 3 / F12-related
    normal-C1-INH subtype. Expression is strongly estrogen-modulated and clinical
    penetrance is markedly higher in women.
  evidence:
  - reference: ORPHA:100054
    reference_title: "F12-related hereditary angioedema with normal C1Inh"
    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
    inheritance_term:
      preferred_term: Autosomal dominant inheritance
      term:
        id: HP:0000006
        label: Autosomal dominant inheritance
    description: >-
      Autosomal dominant, per the Orphanet record for this entity. No evidence
      item is attached: Orphanet states inheritance as a bare enumerated value
      rather than in a sentence, so there is nothing quotable that carries the
      claim, and a two-word snippet would assert the fact without evidencing it.
  features: >-
    PLG variants cause a rare normal-C1-INH HAE subtype; the recurrent
    p.Lys330Glu (K330E) substitution in kringle domain 3 is the characteristic
    lesion.
  evidence:
  - reference: ORPHA:537072
    reference_title: "PLG-related hereditary angioedema with normal C1Inh"
    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.
  - reference: PMID:28795768
    reference_title: Hereditary angioedema with a mutation in the plasminogen gene.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The mutation c.988A>G was located in exon 9 leading to the missense
      mutation p.Lys330Glu (K330E) in the kringle 3 domain of the PLG protein.
    explanation: Identifies the recurrent PLG K330E kringle-3 variant in normal-C1-INH HAE.
- 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"
    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"
    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"
    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.
environmental:
- name: Estrogen exposure
  description: >-
    Estrogen-containing oral contraceptives, pregnancy, and hormone replacement
    therapy precipitate or worsen attacks. The effect is strongest in
    F12-related normal-C1-INH disease, where symptom onset frequently coincides
    with starting an oral contraceptive, but estrogen also modulates
    C1-INH-deficiency disease. Progestin-only contraception is generally
    preferred.
  effect: Precipitates and exacerbates angioedema attacks; a major modifier of disease expression in F12-related HAE
  chemicals:
  - estrogen
  - combined oral contraceptive
  notes: >-
    This is a modifier of an inherited disease, not a cause of it. Avoidance is a
    tertiary-prevention measure rather than a treatment.
  evidence:
  - reference: PMID:33109323
    reference_title: Triggers and short-term prophylaxis in patients with hereditary angioedema.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The main triggers are estrogens, Angiotensin Converting Enzyme Inhibitors
      (ACI) inhibitors, trauma, dental work, stress, surgery, manipulation of the
      upper airway, and medical procedures.
    explanation: Lists estrogens first among the main attack triggers in HAE.
  - reference: PMID:19477491
    reference_title: "Hereditary angioedema caused by missense mutations in the factor XII gene: clinical features, trigger factors, and therapy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Clinical symptoms started mainly after intake of oral contraceptives (17
      women) or pregnancy (3 women).
    explanation: >-
      In an F12-HAE cohort, disease onset was most often triggered by oral
      contraceptives or pregnancy.
  - reference: ORPHA:528647
    reference_title: "Hereditary angioedema with normal C1Inh"
    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 records estrogen exposure and pregnancy as precipitating factors.
- name: Angiotensin-converting enzyme inhibitor exposure
  description: >-
    ACE (kininase II) is a principal enzyme degrading bradykinin, so ACE
    inhibitors raise bradykinin availability and can precipitate or worsen
    attacks. ACE inhibitors are therefore avoided in HAE. Angiotensin receptor
    blockers have also been implicated in individual cases.
  effect: Precipitates and exacerbates attacks by reducing bradykinin catabolism; contraindicated in HAE
  chemicals:
  - angiotensin-converting enzyme inhibitor
  notes: >-
    Clinically important as a drug to avoid. Recorded here as an exogenous
    exposure; the shared bradykinin mechanism also underlies the separate entity
    of ACE-inhibitor-induced angioedema.
  evidence:
  - reference: PMID:33109323
    reference_title: Triggers and short-term prophylaxis in patients with hereditary angioedema.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The main triggers are estrogens, Angiotensin Converting Enzyme Inhibitors
      (ACI) inhibitors, trauma, dental work, stress, surgery, manipulation of the
      upper airway, and medical procedures.
    explanation: Identifies ACE inhibitors among the main attack triggers.
  - reference: PMID:19477491
    reference_title: "Hereditary angioedema caused by missense mutations in the factor XII gene: clinical features, trigger factors, and therapy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Exacerbation of the symptoms occurred after oral contraceptive use (8
      women), pregnancy (7 women), hormone replacement therapy (3 women), intake
      of angiotensin-converting enzyme inhibitors (2 women), and an angiotensin 1
      receptor blocker (1 woman).
    explanation: >-
      Documents symptom exacerbation after ACE inhibitor and angiotensin receptor
      blocker exposure in F12-HAE patients.
- name: Mechanical trauma and medical or dental procedures
  description: >-
    Local mechanical trauma, dental work, surgery, and instrumentation of the
    upper airway are the most predictable and actionable precipitants of attacks.
    Because upper-airway manipulation can provoke potentially fatal laryngeal
    edema, procedural short-term prophylaxis with intravenous C1 inhibitor is
    standard practice.
  effect: Provokes localized attacks; airway manipulation carries risk of life-threatening laryngeal edema
  notes: >-
    The actionable consequence is short-term prophylaxis before the procedure,
    with rescue therapy and airway capability still available.
  evidence:
  - reference: PMID:33109323
    reference_title: Triggers and short-term prophylaxis in patients with hereditary angioedema.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      there is consensus that, whenever the upper airway is manipulated, STP is
      essential.
    explanation: >-
      Establishes upper-airway manipulation as a procedural trigger requiring
      short-term prophylaxis.
  - reference: PMID:19477491
    reference_title: "Hereditary angioedema caused by missense mutations in the factor XII gene: clinical features, trigger factors, and therapy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Some factors that triggered angioedema attacks were trauma, physical
      pressure, and emotional stress.
    explanation: Documents trauma and physical pressure as attack triggers.
- name: Emotional stress
  description: >-
    Psychological and emotional stress is a commonly reported attack precipitant.
    It is not reliably avoidable, so it informs counselling and treatment
    readiness rather than restriction of normal activity.
  effect: Precipitates attacks in a subset of patients
  evidence:
  - reference: PMID:33109323
    reference_title: Triggers and short-term prophylaxis in patients with hereditary angioedema.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The main triggers are estrogens, Angiotensin Converting Enzyme Inhibitors
      (ACI) inhibitors, trauma, dental work, stress, surgery, manipulation of the
      upper airway, and medical procedures.
    explanation: Lists stress among the main attack triggers.
  - reference: PMID:19477491
    reference_title: "Hereditary angioedema caused by missense mutations in the factor XII gene: clinical features, trigger factors, and therapy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Some factors that triggered angioedema attacks were trauma, physical
      pressure, and emotional stress.
    explanation: Documents emotional stress as an attack trigger.
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"
    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"
    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"
    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"
    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"
    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"
    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"
    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"
    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"
    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"
    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"
    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"
    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"
    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"
    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"
    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"
    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"
    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"
    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"
    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: NCIT:C64430
      label: Protein or Enzyme Type 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: NCIT:C15709
      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"
    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.
  therapeutic_modality: PROTEIN_REPLACEMENT
  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.
  therapeutic_modality: SMALL_MOLECULE
  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.
  therapeutic_modality: PEPTIDE
  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: Plasma kallikrein activation
    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.
  therapeutic_modality: SMALL_MOLECULE
  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: Plasma kallikrein activation
    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: Lanadelumab long-term prophylaxis
  description: >-
    Lanadelumab is a fully human monoclonal antibody that selectively inhibits
    active plasma kallikrein, given subcutaneously for long-term prophylaxis. It
    is split from berotralstat here despite sharing a target: the two differ in
    modality, route and dosing interval in ways that drive real clinical choice,
    and bundling them made per-drug modality tagging impossible.
  therapeutic_modality: MONOCLONAL_ANTIBODY
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: lanadelumab
      term:
        id: NCIT:C166535
        label: Lanadelumab
  target_mechanisms:
  - target: Plasma kallikrein activation
    treatment_effect: INHIBITS
    description: Direct plasma kallikrein inhibition 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.
- name: Berotralstat oral long-term prophylaxis
  description: >-
    Berotralstat is an orally administered, once-daily small-molecule plasma
    kallikrein inhibitor for long-term prophylaxis. Same molecular target as
    lanadelumab, different platform - which is precisely why the two are curated
    separately.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: berotralstat
      term:
        id: NCIT:C169808
        label: Berotralstat
  target_mechanisms:
  - target: Plasma kallikrein activation
    treatment_effect: INHIBITS
    description: Oral small-molecule kallikrein inhibition reduces bradykinin generation upstream of edema attacks.
    evidence:
    - 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: >-
        Names the drug's molecular target directly, which is exactly what this
        edge asserts: berotralstat acts on the plasma kallikrein node by
        inhibiting kallikrein itself.
  evidence:
  - 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.
- name: Attenuated androgen (danazol) long-term prophylaxis
  description: >-
    Danazol is the historical mainstay of long-term prophylaxis and remains in
    guideline algorithms as a second-line option where modern targeted agents are
    unavailable or unaffordable - which is most of the world. It works
    indirectly, raising hepatic C1-INH and C4 production rather than blocking the
    contact cascade, and it is the only prophylactic option in this entry that
    acts by increasing the deficient protein rather than inhibiting a downstream
    enzyme. Its displacement by kallikrein-targeted agents is driven by
    tolerability - androgenic effects, dyslipidaemia, hepatic adenoma and
    virilisation risk - rather than by lack of efficacy.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: danazol
      term:
        id: CHEBI:4315
        label: danazol
  target_mechanisms:
  - target: SERPING1 C1 inhibitor deficiency or dysfunction
    treatment_effect: MODULATES
    description: >-
      Attenuated androgens are thought to raise circulating C1-INH rather than
      inhibiting a downstream enzyme, which is why they are placed on the
      deficiency node itself. The hedge is deliberate: the prophylactic benefit
      is well attested, but the mechanism by which attenuated androgens produce
      it is not fully settled.
  evidence:
  - reference: PMID:19477491
    reference_title: "Hereditary angioedema caused by missense mutations in the factor XII gene: clinical features, trigger factors, and therapy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Effective treatments included C1 inhibitor concentrate for angioedema
      attacks (6 women) and, for prophylaxis, progesterone (8 women), danazol (2
      women), and tranexamic acid (1 woman).
    explanation: >-
      Documents danazol as effective prophylaxis in hereditary angioedema.
      PARTIAL, and the limits matter: this is an FXII-HAE (normal C1-INH) cohort
      and only two women received danazol, so it is not the randomized evidence
      that underpins the modern agents in this entry.
  - reference: PMID:20818888
    reference_title: "Icatibant, a new bradykinin-receptor antagonist, in hereditary angioedema."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Attenuated androgens can reduce the number and severity of attacks when
      used prophylactically but have important adverse effects and are
      ineffective during acute attacks.
    explanation: >-
      Prophylaxis-specific support for the attenuated-androgen class, and the
      stronger of the two items attached here: it states the prophylactic
      benefit and both of the limitations that put danazol behind the targeted
      agents. Tagged OTHER because the sentence is background framing in the
      introduction to an icatibant trial report, summarizing prior evidence
      rather than reporting that trial's own data.
  notes: >-
    The two evidence items differ in what each can carry, and neither is the
    randomized trial evidence that underpins the modern targeted agents in this
    entry. PMID:20818888 is prophylaxis-specific but class-level, covering
    attenuated androgens rather than danazol by name. PMID:19477491 names danazol
    but comes from normal-C1-INH (FXII) disease, whereas danazol's proposed
    mechanism of raising hepatic C1-INH is most relevant to C1-INH deficiency.
    The edge to the deficiency node is therefore evidenced for its effect and
    hedged on its mechanism.
- name: Tranexamic acid long-term prophylaxis
  description: >-
    An antifibrinolytic used for long-term prophylaxis, chiefly where attenuated
    androgens are contraindicated - notably in children and in pregnancy. It is
    the treatment that gives the plasmin amplification arm of this pathograph its
    therapeutic rationale: by inhibiting plasmin, it blocks the plasmin-mediated
    feedback that amplifies contact-system activation, rather than acting on
    kallikrein or bradykinin directly. Efficacy is modest compared with the
    targeted agents.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: tranexamic acid
      term:
        id: CHEBI:48669
        label: tranexamic acid
  target_mechanisms:
  - target: Plasmin-mediated contact-system amplification
    treatment_effect: INHIBITS
    description: >-
      Antifibrinolytic blockade of plasmin interrupts the plasmin-driven
      amplification loop that feeds contact-system activation - the mechanism
      this node describes and the reason tranexamic acid is used at all.
  evidence:
  - reference: PMID:19477491
    reference_title: "Hereditary angioedema caused by missense mutations in the factor XII gene: clinical features, trigger factors, and therapy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Effective treatments included C1 inhibitor concentrate for angioedema
      attacks (6 women) and, for prophylaxis, progesterone (8 women), danazol (2
      women), and tranexamic acid (1 woman).
    explanation: >-
      Documents tranexamic acid as effective prophylaxis in hereditary
      angioedema. PARTIAL and thinly so: a single patient in an FXII-HAE cohort.
      It is curated because the drug closes a treatment join point on the
      plasmin node that would otherwise have no intervention attached, not
      because this observation is strong.
  notes: >-
    The attached cohort evidence is thin, but thinness is not the substantive
    limitation here — uncertainty is. PMID:20818888 records that tranexamic acid
    "reportedly improves symptoms during acute attacks, although its efficacy
    has not been proved in controlled studies". That statement is about acute
    treatment rather than the long-term prophylaxis this entry curates, so it is
    cited here as prose rather than attached as an evidence item, which would
    hang acute-attack data on a prophylaxis claim. Its mechanistic placement on
    the plasmin node is the more important claim here and follows from the drug
    class rather than from the cited cohort.
- name: Garadacimab
  description: >-
    Garadacimab (CSL312) is a fully human monoclonal antibody that inhibits
    activated factor XII (FXIIa), given once monthly by subcutaneous injection for
    long-term prophylaxis of HAE attacks. Mechanistically it is distinctive in
    acting at the apex of the contact cascade rather than at plasma kallikrein or
    the bradykinin receptor. In the pivotal VANGUARD phase 3 trial in type I and
    type II HAE it lowered the monthly attack rate significantly versus placebo,
    a mean difference of -87%.
  therapeutic_modality: MONOCLONAL_ANTIBODY
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: garadacimab
      term:
        id: NCIT:C166633
        label: Garadacimab
  target_mechanisms:
  - target: Unrestrained factor XII activation
    treatment_effect: INHIBITS
    description: >-
      Garadacimab binds and inhibits activated factor XII, blocking the apex
      protease of the contact system and preventing downstream kallikrein
      activation and bradykinin generation.
    evidence:
    - reference: PMID:36868261
      reference_title: "Efficacy and safety of garadacimab, a factor XIIa inhibitor for hereditary angioedema prevention (VANGUARD): a global, multicentre, randomised, double-blind, placebo-controlled, phase 3 trial."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Garadacimab (CSL312), a novel, fully-human monoclonal antibody that
        inhibits activated factor XII (FXIIa), is being studied for the prevention
        of hereditary angioedema attacks.
      explanation: States that garadacimab inhibits activated factor XII, the mechanism of this treatment edge.
  evidence:
  - reference: PMID:36868261
    reference_title: "Efficacy and safety of garadacimab, a factor XIIa inhibitor for hereditary angioedema prevention (VANGUARD): a global, multicentre, randomised, double-blind, placebo-controlled, phase 3 trial."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      During the 6-month treatment period (day 1 to day 182), the mean number of
      investigator-confirmed hereditary angioedema attacks per month was
      significantly lower in the garadacimab group
    explanation: Phase 3 randomized trial evidence supports garadacimab prophylaxis efficacy.
- name: Donidalorsen
  description: >-
    Donidalorsen (Dawnzera) is a prekallikrein-directed antisense oligonucleotide
    approved for long-term prophylaxis of hereditary angioedema attacks. RNase
    H1-mediated knockdown of KLKB1 (prekallikrein) mRNA lowers plasma
    prekallikrein, reducing bradykinin generation upstream of edema attacks.
  therapeutic_modality: ANTISENSE_OLIGONUCLEOTIDE
  aso_details:
    aso_mechanism: RNASE_H_KNOCKDOWN
    target_gene:
      preferred_term: KLKB1
      term:
        id: hgnc:6371
        label: KLKB1
    target_transcript: KLKB1 (prekallikrein) mRNA
    aso_chemistry: TWO_PRIME_O_METHOXYETHYL
    conjugation: GALNAC
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: donidalorsen
      term:
        id: NCIT:C177101
        label: Donidalorsen
  target_mechanisms:
  - target: Plasma kallikrein activation
    treatment_effect: INHIBITS
    description: >-
      Prekallikrein knockdown lowers the plasma prekallikrein pool available for
      conversion to active kallikrein, reducing bradykinin generation upstream of
      edema attacks.
    evidence:
    - 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, a prekallikrein-directed antisense oligonucleotide
        indicated for prophylaxis of hereditary angioedema (HAE) attacks
      explanation: The trial report identifies donidalorsen as a prekallikrein-directed antisense oligonucleotide for HAE prophylaxis.
    - reference: PMID:35294812
      reference_title: "Inhibition of Prekallikrein for Hereditary Angioedema."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Selective inhibition of plasma prekallikrein production by antisense
        oligonucleotide treatment (donidalorsen) may reduce the frequency of
        attacks and the burden of disease.
      explanation: >-
        Phase 2 trial background statement identifies donidalorsen as an
        antisense oligonucleotide that selectively suppresses prekallikrein
        production.
  evidence:
  - 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.
  - reference: PMID:35294812
    reference_title: "Inhibition of Prekallikrein for Hereditary Angioedema."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      donidalorsen treatment resulted in a significantly lower rate of angioedema
      attacks than placebo in this small, phase 2 trial.
    explanation: Phase 2 randomized trial evidence supports donidalorsen prophylactic efficacy.
clinical_trials:
- name: NCT05120830
  phase: PHASE_I
  status: ACTIVE_NOT_RECRUITING
  description: >-
    First-in-human phase 1/2 study of NTLA-2002, a CRISPR/Cas9 in vivo gene
    editing therapy targeting KLKB1 - the prekallikrein gene. Mechanistically it
    is the most radical entry in this entry's therapeutic landscape: rather than
    inhibiting plasma kallikrein repeatedly, it aims to knock down its precursor
    permanently in a single dose, converting lifelong prophylaxis into a
    one-time intervention on the same pathograph node the antibody and
    small-molecule inhibitors act on.
  evidence:
  - reference: clinicaltrials:NCT05120830
    reference_title: "Phase 1/2 Study to Evaluate Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of NTLA-2002 in Adults With Hereditary Angioedema (HAE)"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This study will be conducted to evaluate the safety, tolerability,
      activity, pharmacokinetics, and pharmacodynamics of NTLA-2002 in adults
      with Hereditary Angioedema (HAE).
    explanation: Confirms the design and population of the first-in-human NTLA-2002 study.
  notes: >-
    Status ACTIVE_NOT_RECRUITING per the ClinicalTrials.gov record. Curated as
    investigational context, not as evidence that gene editing is an available
    treatment; no NTLA-2002 treatment entry is curated for that reason.
- name: NCT06634420
  phase: PHASE_III
  status: ACTIVE_NOT_RECRUITING
  description: >-
    HAELO, the phase 3 randomized placebo-controlled trial of NTLA-2002. Its
    existence is the substantive fact - a CRISPR therapy for this disease has
    reached phase 3, which is what would move single-dose KLKB1 knockdown from
    concept to option.
  evidence:
  - reference: clinicaltrials:NCT06634420
    reference_title: "HAELO: A Phase 3, Multinational, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy and Safety of NTLA-2002 in Participants With Hereditary Angioedema (HAE)"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This Phase 3 study aims to evaluate the efficacy and safety of NTLA-2002
      compared to placebo in participants with HAE.
    explanation: Confirms the phase 3 placebo-controlled design.
- name: NCT05121376
  phase: PHASE_I
  status: ACTIVE_NOT_RECRUITING
  description: >-
    Phase 1/2 open-label dose-escalation study of BMN 331, an AAV5 vector
    delivering wild-type human SERPING1 under a liver-selective promoter. This
    is the mechanistic complement of the editing approach: rather than removing
    the substrate downstream, it restores the deficient inhibitor itself, acting
    on the SERPING1 deficiency node at the head of the pathograph. It is
    restricted to C1-INH deficiency, so it does not apply to the normal-C1-INH
    subtypes this entry also models.
  evidence:
  - reference: clinicaltrials:NCT05121376
    reference_title: "A Phase 1/2 Open-Label, Dose-Escalation Study to Determine the Safety Tolerability & Efficacy of BMN 331 an AAV Vector-Mediated Gene Transfer of Human SERPING1 Gene in Subjects With HAE Due to Human C1-INH Deficiency"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The study drug BMN 331is identified as AAV5 hSERPING1, an adeno-associated
      virus (AAV5)-based gene therapy vector that expresses wild-type human C1
      Esterase Inhibitor (hC1-INH), under the control of a liver-selective
      promoter
    explanation: >-
      States the vector and transgene, which is what places this trial on the
      SERPING1 deficiency node rather than on the kallikrein node.
discussions:
- discussion_id: gap_hae_contact_activation_trigger
  prompt: What actually initiates contact-system activation at the start of an HAE attack, and is an activating surface required at all?
  kind: KNOWLEDGE_GAP
  status: OPEN
  rationale: >-
    The pathograph downstream of contact activation is well established, but the
    initiating event is not. C1-INH deficiency is constant while attacks are
    episodic and localized, so something must license activation at a particular
    time and site. Classical models invoke an anionic activating surface for
    factor XII autoactivation, but it is questionable whether a surface is
    responsible in HAE, and the recognized clinical triggers (trauma,
    procedures, estrogens, stress) have no established molecular mapping onto
    the cascade. This gap is why attack prediction remains impossible and why
    prophylaxis must be continuous rather than targeted.
  attaches_to:
  - pathophysiology#Unrestrained factor XII activation
  - pathophysiology#SERPING1 C1 inhibitor deficiency or dysfunction
  proposed_experiments:
  - experiment_id: hae_attack_onset_biomarker_timecourse
    name: Peri-attack contact-system biomarker time course
    description: >-
      Serially sample patients through spontaneous and procedure-provoked attacks
      and quantify cleaved high-molecular-weight kininogen, FXIIa-inhibitor and
      kallikrein-inhibitor complexes, and candidate surface activators, to
      establish which species moves first relative to symptom onset.
    decision_criterion: >-
      A reproducible ordering of biomarker changes preceding symptom onset that
      distinguishes surface-dependent from surface-independent initiation.
    would_support:
    - pathophysiology#Unrestrained factor XII activation
  evidence:
  - reference: PMID:27459852
    reference_title: "HAE Pathophysiology and Underlying Mechanisms."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Important areas that remain poorly understood include the factors that lead
      to very low plasma functional C1 inhibitor levels, the triggers of contact
      system activation in hereditary angioedema, and the role of the bradykinin
      B1 receptor.
    explanation: Names the triggers of contact-system activation as an explicitly unresolved area.
  - reference: PMID:29920929
    reference_title: "Hereditary angioedema: the plasma contact system out of control."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      In addition, it is questionable whether a surface is responsible for
      contact system activation in HAE.
    explanation: States the open question of whether an activating surface is required in HAE.
- discussion_id: gap_hae_bradykinin_b1_receptor_role
  prompt: Does the bradykinin B1 receptor contribute materially to HAE swelling alongside the B2 receptor?
  kind: KNOWLEDGE_GAP
  status: OPEN
  rationale: >-
    Icatibant establishes the B2 receptor as an operative and druggable target,
    but B2 blockade does not abolish all attacks and the B1 receptor is
    inducible under inflammatory conditions and mediates vascular
    hyperpermeability in other settings. If B1 signalling contributes, it would
    predict a therapeutic ceiling for B2-selective antagonism and identify a
    complementary target. The question is currently unresolved rather than
    negative.
  attaches_to:
  - pathophysiology#Excess bradykinin signaling
  - pathophysiology#Endothelial adherens junction destabilization
  proposed_experiments:
  - experiment_id: hae_b1_receptor_endothelial_contribution
    name: B1 versus B2 receptor contribution in patient-derived endothelium
    description: >-
      Expose endothelial monolayers to patient plasma or bradykinin with
      selective B1 and B2 antagonists, alone and combined, and measure barrier
      resistance and junctional protein localization to quantify any residual
      B1-dependent permeability.
    decision_criterion: >-
      A reproducible B1-antagonist-sensitive component of permeability that
      persists under full B2 blockade.
    would_support:
    - pathophysiology#Excess bradykinin signaling
  evidence:
  - reference: PMID:27459852
    reference_title: "HAE Pathophysiology and Underlying Mechanisms."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Important areas that remain poorly understood include the factors that lead
      to very low plasma functional C1 inhibitor levels, the triggers of contact
      system activation in hereditary angioedema, and the role of the bradykinin
      B1 receptor.
    explanation: Explicitly names the role of the bradykinin B1 receptor as poorly understood.
- discussion_id: gap_hae_phenotypic_variability_modifiers
  prompt: Which modifiers explain the extreme variability in attack frequency, severity, and site among people carrying the same SERPING1 variant?
  kind: KNOWLEDGE_GAP
  status: OPEN
  rationale: >-
    Attack burden ranges from essentially asymptomatic carriage to frequent
    life-threatening laryngeal attacks within the same family and the same
    variant, and C1-INH level does not predict it. No validated genetic,
    hormonal, or endothelial modifier explains this, which prevents
    risk-stratified prophylaxis and means treatment intensity is chosen on
    observed burden rather than predicted risk.
  attaches_to:
  - pathophysiology#Endothelial adherens junction destabilization
  - pathophysiology#Vascular permeability and recurrent edema attacks
  proposed_experiments:
  - experiment_id: hae_modifier_cohort_genotype_endothelial_phenotype
    name: Genotype-matched discordant-severity modifier study
    description: >-
      Recruit pairs of relatives sharing a SERPING1 variant but discordant for
      attack burden and compare modifier-gene genotypes, sex-hormone status, and
      endothelial barrier responsiveness to bradykinin in patient-derived cells.
    decision_criterion: >-
      A modifier that segregates with attack burden independently of the primary
      variant and reproduces in an independent cohort.
    would_support:
    - pathophysiology#Vascular permeability and recurrent edema attacks
  evidence:
  - reference: PMID:27459852
    reference_title: "HAE Pathophysiology and Underlying Mechanisms."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The phenotypic variability of hereditary angioedema has been extensively
      documented but never understood.
    explanation: States directly that HAE phenotypic variability remains unexplained.
- discussion_id: gap_hae_normal_c1inh_definition_and_yield
  prompt: How should normal-C1-INH HAE be defined and diagnosed when most suspected cases have no identifiable pathogenic variant?
  kind: KNOWLEDGE_GAP
  status: OPEN
  rationale: >-
    Normal-C1-INH HAE has no confirmatory biochemical test, so diagnosis rests on
    clinical pattern plus a variant in one of a small gene set. Comprehensive
    sequencing resolves only a small minority of suspected cases, and broad
    testing generates variants of uncertain significance and risks
    overdiagnosis. Consequently management recommendations for this branch are
    largely expert opinion, and it is not established that every normal-C1-INH
    subtype is bradykinin-mediated at all.
  attaches_to:
  - pathophysiology#Normal C1-INH contact-system gene dysregulation
  - pathophysiology#Plasmin-mediated contact-system amplification
  proposed_experiments:
  - experiment_id: hae_nc1inh_functional_contact_assay_validation
    name: Prospective validation of a functional contact-activation assay
    description: >-
      Apply candidate functional readouts (cleaved kininogen, kallikrein
      activity, plasma-induced endothelial permeability) to prospectively
      enrolled suspected normal-C1-INH patients, gene-positive controls, and
      mimic conditions, and test whether any readout separates them
      independently of genotype.
    decision_criterion: >-
      An assay with reproducible sensitivity and specificity against an
      independently adjudicated clinical diagnosis.
    would_support:
    - pathophysiology#Normal C1-INH contact-system gene dysregulation
  evidence:
  - reference: PMID:38555427
    reference_title: "Hereditary or acquired? Comprehensive genetic testing assists in stratifying angioedema patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Despite extensive genetic analyses, the diagnostic yield for nC1-INH HAE
      remains low in our study, the pathogenic variant for nC1-INH HAE was
      identified in only 1 patient (n = 21).
    explanation: Quantifies the low molecular diagnostic yield that defines this gap.
  - reference: PMID:38555427
    reference_title: "Hereditary or acquired? Comprehensive genetic testing assists in stratifying angioedema patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Investigation into candidate genes yielded no pathogenic variants,
      prompting a re-evaluation of patients' diagnoses.
    explanation: Shows that negative testing led to diagnostic re-evaluation, supporting the overdiagnosis concern.
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."
- reference: PMID:29920929
  title: "Hereditary angioedema: the plasma contact system out of control."
  findings:
  - statement: C1-INH is the key plasma inhibitor of the contact-system enzymes, and bradykinin is the main disease mediator in HAE.
    supporting_text: "C1-INH is the key plasma inhibitor of the contact system enzymes, and its deficiency causes hereditary angioedema (HAE)."
  - statement: Whether an activating surface is responsible for contact-system activation in HAE is an open question.
    supporting_text: "In addition, it is questionable whether a surface is responsible for contact system activation in HAE."
- reference: PMID:27459852
  title: "HAE Pathophysiology and Underlying Mechanisms."
  findings:
  - statement: Enhanced contact-system activation generating bradykinin is the fundamental cause of swelling, and tissue swelling operates through endothelial adherens junctions.
    supporting_text: "tissue swelling in hereditary angioedema primarily involves the function of endothelial cell adherens junctions"
  - statement: The triggers of contact-system activation, the role of the bradykinin B1 receptor, and HAE phenotypic variability remain unexplained.
    supporting_text: "The phenotypic variability of hereditary angioedema has been extensively documented but never understood."
- reference: PMID:30656274
  title: "Hereditary angioedema: Linking complement regulation to the coagulation system."
  findings:
  - statement: C1-INH regulates the contact activation and plasminogen-plasmin systems in addition to complement, with bradykinin central to angioedema.
    supporting_text: "There is a central role for bradykinin that is released upon activation of the kallikrein-kinin system that is insufficiently controlled by adequate levels of C1 inhibitor."
- reference: PMID:36868261
  title: "Efficacy and safety of garadacimab, a factor XIIa inhibitor for hereditary angioedema prevention (VANGUARD): a global, multicentre, randomised, double-blind, placebo-controlled, phase 3 trial."
  found_in:
  - Hereditary_Angioedema-deep-research-falcon.md
  findings:
  - statement: Garadacimab, an anti-FXIIa monoclonal antibody, significantly reduces HAE attack rate in a phase 3 trial.
    supporting_text: "Garadacimab (CSL312), a novel, fully-human monoclonal antibody that inhibits activated factor XII (FXIIa), is being studied for the prevention of hereditary angioedema attacks."
- reference: PMID:30689269
  title: Angiopoietin-1 haploinsufficiency affects the endothelial barrier and causes hereditary angioedema.
  findings:
  - statement: ANGPT1 haploinsufficiency reduces endothelial VE-cadherin and beta-catenin and impairs counter-regulation of bradykinin-induced permeability.
    supporting_text: "The ANGPT1 reduced ability to counteract the increment of endothelial permeability produced by inducers, such as VEGF and bradykinin, stimulate vascular leakage and reorganization of the F-actin cytoskeletal elements."
- reference: PMID:28601681
  title: Mutation of the angiopoietin-1 gene (ANGPT1) associates with a new type of hereditary angioedema.
  findings:
  - statement: ANGPT1 variants can cause HAE with normal C1 inhibitor.
    supporting_text: "ANGPT1 impairment is associated with angioedema, and ANGPT1 variants can be the basis of HAE."
- reference: PMID:28795768
  title: Hereditary angioedema with a mutation in the plasminogen gene.
  findings:
  - statement: The recurrent PLG p.Lys330Glu kringle-3 variant defines the plasminogen-related normal-C1-INH subtype.
    supporting_text: "The mutation c.988A>G was located in exon 9 leading to the missense mutation p.Lys330Glu (K330E) in the kringle 3 domain of the PLG protein."
- reference: PMID:33508266
  title: Novel hereditary angioedema linked with a heparan sulfate 3-O-sulfotransferase 6 gene mutation.
  findings:
  - statement: HS3ST6 loss of function yields incomplete heparan sulfate biosynthesis, a novel endothelial-surface mechanism for angioedema.
    supporting_text: "This likely affects cell surface interactions of key players in angioedema formation and is a novel mechanism for disease development."
- reference: PMID:33109323
  title: Triggers and short-term prophylaxis in patients with hereditary angioedema.
  findings:
  - statement: Estrogens, ACE inhibitors, trauma, dental work, stress, surgery, and airway manipulation are the main attack triggers.
    supporting_text: "The main triggers are estrogens, Angiotensin Converting Enzyme Inhibitors (ACI) inhibitors, trauma, dental work, stress, surgery, manipulation of the upper airway, and medical procedures."
- reference: PMID:19477491
  title: "Hereditary angioedema caused by missense mutations in the factor XII gene: clinical features, trigger factors, and therapy."
  findings:
  - statement: F12-HAE presents with recurrent facial swelling in all patients and is typically unmasked by estrogen exposure.
    supporting_text: "Clinical symptoms started mainly after intake of oral contraceptives (17 women) or pregnancy (3 women)."
- reference: PMID:39456231
  title: Unveiling the Complexities of Hereditary Angioedema.
  found_in:
  - Hereditary_Angioedema-deep-research-falcon.md
  findings:
  - statement: Global HAE prevalence is estimated between 1 in 50,000 and 1 in 150,000.
    supporting_text: "with a global prevalence estimated between 1 in 50,000 and 1 in 150,000 individuals."
- reference: PMID:39272138
  title: "Uncovering a novel SERPING1 pathogenic variant: insights into the aggregation of C1-INH in hereditary angioedema."
  found_in:
  - Hereditary_Angioedema-deep-research-falcon.md
  findings:
  - statement: A SERPING1 variant caused endoplasmic reticulum accumulation of C1-INH with GRP75 upregulation, calcium overload, and apoptosis in cells.
    supporting_text: "this variant leads to an increase in the accumulation of C1-INH within the endoplasmic reticulum (ER), resulting in the upregulation of GRP75 protein expression."
- reference: PMID:38555427
  title: "Hereditary or acquired? Comprehensive genetic testing assists in stratifying angioedema patients."
  found_in:
  - Hereditary_Angioedema-deep-research-falcon.md
  findings:
  - statement: Comprehensive sequencing identified a pathogenic variant in only 1 of 21 suspected normal-C1-INH HAE patients.
    supporting_text: "Despite extensive genetic analyses, the diagnostic yield for nC1-INH HAE remains low in our study, the pathogenic variant for nC1-INH HAE was identified in only 1 patient (n = 21)."
datasets:
- accession: ega:EGAS00001006547
  title: A catalog of the genetic causes of Hereditary Angioedema in the Canary Islands (Spain)
  description: Hereditary angioedema (HAE) is a rare disease where known causes involve C1 inhibitor dysfunction or dysregulation of the kinin cascade. The updated HAE management guidelines recommend performing genetic tests to reach a precise diagnosis. Unfortunately, genetic tests are still uncommon in the diagnosis routine. Here, we characterized for the first time the genetic causes of HAE in affected families from the Canary Islands (Spain). Whole-exome sequencing data was obtained from 41 affected patients and unaffected relatives from 29 unrelated families identified in the archipelago.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  notes: 'European Genome-phenome Archive study, matched because the disease is named in the study''s own title ("Hereditary Angioedema"); description-level mentions were not accepted. EGA study_type: Other. Controlled access -- data require a Data Access Agreement. EGA metadata retrieved 2026-08-01.'
📚

References & Deep Research

References

32
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."
PMID:29920929
Hereditary angioedema: the plasma contact system out of control.
2 findings
C1-INH is the key plasma inhibitor of the contact-system enzymes, and bradykinin is the main disease mediator in HAE.
"C1-INH is the key plasma inhibitor of the contact system enzymes, and its deficiency causes hereditary angioedema (HAE)."
Whether an activating surface is responsible for contact-system activation in HAE is an open question.
"In addition, it is questionable whether a surface is responsible for contact system activation in HAE."
PMID:27459852
HAE Pathophysiology and Underlying Mechanisms.
2 findings
Enhanced contact-system activation generating bradykinin is the fundamental cause of swelling, and tissue swelling operates through endothelial adherens junctions.
"tissue swelling in hereditary angioedema primarily involves the function of endothelial cell adherens junctions"
The triggers of contact-system activation, the role of the bradykinin B1 receptor, and HAE phenotypic variability remain unexplained.
"The phenotypic variability of hereditary angioedema has been extensively documented but never understood."
PMID:30656274
Hereditary angioedema: Linking complement regulation to the coagulation system.
1 finding
C1-INH regulates the contact activation and plasminogen-plasmin systems in addition to complement, with bradykinin central to angioedema.
"There is a central role for bradykinin that is released upon activation of the kallikrein-kinin system that is insufficiently controlled by adequate levels of C1 inhibitor."
PMID:36868261
Efficacy and safety of garadacimab, a factor XIIa inhibitor for hereditary angioedema prevention (VANGUARD): a global, multicentre, randomised, double-blind, placebo-controlled, phase 3 trial.
1 finding
Garadacimab, an anti-FXIIa monoclonal antibody, significantly reduces HAE attack rate in a phase 3 trial.
"Garadacimab (CSL312), a novel, fully-human monoclonal antibody that inhibits activated factor XII (FXIIa), is being studied for the prevention of hereditary angioedema attacks."
PMID:30689269
Angiopoietin-1 haploinsufficiency affects the endothelial barrier and causes hereditary angioedema.
1 finding
ANGPT1 haploinsufficiency reduces endothelial VE-cadherin and beta-catenin and impairs counter-regulation of bradykinin-induced permeability.
"The ANGPT1 reduced ability to counteract the increment of endothelial permeability produced by inducers, such as VEGF and bradykinin, stimulate vascular leakage and reorganization of the F-actin cytoskeletal elements."
PMID:28601681
Mutation of the angiopoietin-1 gene (ANGPT1) associates with a new type of hereditary angioedema.
1 finding
ANGPT1 variants can cause HAE with normal C1 inhibitor.
"ANGPT1 impairment is associated with angioedema, and ANGPT1 variants can be the basis of HAE."
PMID:28795768
Hereditary angioedema with a mutation in the plasminogen gene.
1 finding
The recurrent PLG p.Lys330Glu kringle-3 variant defines the plasminogen-related normal-C1-INH subtype.
"The mutation c.988A>G was located in exon 9 leading to the missense mutation p.Lys330Glu (K330E) in the kringle 3 domain of the PLG protein."
PMID:33508266
Novel hereditary angioedema linked with a heparan sulfate 3-O-sulfotransferase 6 gene mutation.
1 finding
HS3ST6 loss of function yields incomplete heparan sulfate biosynthesis, a novel endothelial-surface mechanism for angioedema.
"This likely affects cell surface interactions of key players in angioedema formation and is a novel mechanism for disease development."
PMID:33109323
Triggers and short-term prophylaxis in patients with hereditary angioedema.
1 finding
Estrogens, ACE inhibitors, trauma, dental work, stress, surgery, and airway manipulation are the main attack triggers.
"The main triggers are estrogens, Angiotensin Converting Enzyme Inhibitors (ACI) inhibitors, trauma, dental work, stress, surgery, manipulation of the upper airway, and medical procedures."
PMID:19477491
Hereditary angioedema caused by missense mutations in the factor XII gene: clinical features, trigger factors, and therapy.
1 finding
F12-HAE presents with recurrent facial swelling in all patients and is typically unmasked by estrogen exposure.
"Clinical symptoms started mainly after intake of oral contraceptives (17 women) or pregnancy (3 women)."
PMID:39456231
Unveiling the Complexities of Hereditary Angioedema.
1 finding
Global HAE prevalence is estimated between 1 in 50,000 and 1 in 150,000.
"with a global prevalence estimated between 1 in 50,000 and 1 in 150,000 individuals."
PMID:39272138
Uncovering a novel SERPING1 pathogenic variant: insights into the aggregation of C1-INH in hereditary angioedema.
1 finding
A SERPING1 variant caused endoplasmic reticulum accumulation of C1-INH with GRP75 upregulation, calcium overload, and apoptosis in cells.
"this variant leads to an increase in the accumulation of C1-INH within the endoplasmic reticulum (ER), resulting in the upregulation of GRP75 protein expression."
PMID:38555427
Hereditary or acquired? Comprehensive genetic testing assists in stratifying angioedema patients.
1 finding
Comprehensive sequencing identified a pathogenic variant in only 1 of 21 suspected normal-C1-INH HAE patients.
"Despite extensive genetic analyses, the diagnostic yield for nC1-INH HAE remains low in our study, the pathogenic variant for nC1-INH HAE was identified in only 1 patient (n = 21)."

Deep Research

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Hereditary Angioedema: Disease-Characteristics Research Report
Edison Scientific Literature 30 citations 2026-07-30T19:48:41.686471

Hereditary Angioedema: Disease-Characteristics Research Report

Executive summary

Hereditary angioedema (HAE) is a rare, usually autosomal-dominant disorder causing recurrent, self-limited, nonpruritic swelling of subcutaneous and submucosal tissues without urticaria. Most disease is caused by heterozygous SERPING1 variants producing quantitative C1-inhibitor deficiency (HAE type I) or dysfunctional C1 inhibitor (type II). Less common HAE with normal C1 inhibitor (HAE-nC1INH) is genetically heterogeneous. Excess bradykinin and loss of endothelial-barrier integrity are the final common mechanisms; consequently, antihistamines, glucocorticoids, and epinephrine generally do not control established HAE swelling. Laryngeal attacks are medical emergencies.

The principal recent developments are broader genomic testing, recognition of endothelial-barrier mechanisms, oral and long-acting kallikrein/bradykinin-pathway therapies, RNA silencing, and in-vivo CRISPR editing of KLKB1. Nevertheless, evidence for many HAE-nC1INH genotypes remains based on small families or expert consensus rather than randomized trials.

1. Disease information

Definition and classification

HAE comprises intermittent, localized, self-limited episodes of increased vascular permeability and tissue edema. Attacks affect skin, gastrointestinal mucosa, upper airway, oral cavity, face, genital/urogenital tissues, or combinations thereof. The clinically useful classification is:

  1. HAE-C1INH type I: low C1-INH antigen and function, usually from a loss-of-function SERPING1 allele.
  2. HAE-C1INH type II: normal/high C1-INH antigen but low function, usually from a dysfunctional SERPING1 allele.
  3. HAE-nC1INH: normal C1-INH quantity and activity, with genetically defined or unknown subtypes. “Type III” is now discouraged because it obscures molecular heterogeneity. HAE-nC1INH was first described in 2000. (zuraw2025hereditaryangioedemawith pages 1-2, tutunaru2024unveilingthecomplexities pages 1-2)

A 2024 review summarized HAE as approximately 2% of clinical angioedema and estimated type I at 80–85%, type II at 15–20%, with HAE-nC1INH substantially rarer; percentages vary because ascertainment and subtype definitions differ. (tutunaru2024unveilingthecomplexities pages 2-4, tutunaru2024unveilingthecomplexities pages 1-2)

Identifiers and synonyms

  • MONDO: MONDO:0019623, hereditary angioedema. More specific entries include MONDO:0033946, HAE with C1-INH deficiency; MONDO:0015053, type I; MONDO:0015054, type II; and MONDO:0012526, historically “type III.” (OpenTargets Search: hereditary angioedema)
  • OMIM: commonly mapped disease entries include HAE type I/II (#106100) and factor-XII-associated HAE with normal C1-INH (#610618). Database versioning should be checked before ingestion.
  • Orphanet: ORPHA:91378 is widely used for hereditary angioedema; molecular subtypes have child terms.
  • ICD-10-CM: D84.1, defects in the complement system, includes C1 esterase inhibitor deficiency/HAE but is not molecularly specific.
  • ICD-11: HAE is represented under complement-system defects; implementation-specific coding should be verified against the current ICD-11 release.
  • MeSH: “Hereditary Angioedema Types I and II” and related angioedema/C1-inhibitor headings.
  • Synonyms: hereditary angioneurotic edema/oedema, hereditary angio-oedema, HAE, C1-INH-HAE, C1 esterase inhibitor deficiency, HAE-1, HAE-2, HAE-nC1INH.

This report synthesizes aggregated disease-level resources, reviews, guidelines, trials, and cohorts, not identifiable EHR records. Individual case/family studies are explicitly identified below.

The subtype-oriented summary is:

Subtype/entity Principal gene/protein C4 / C1-INH antigen / function pattern Core mechanism Typical clinical clue Targeted treatment classes
HAE type I (HAE-C1INH-1) SERPING1 / C1 inhibitor Low C4; low C1-INH antigen; low C1-INH function (classic pattern) (caballero2022medicalalgorithmmanagement pages 2-2, tutunaru2024unveilingthecomplexities pages 1-2) C1-INH deficiency permits excess contact-system activation, kallikrein activity, and bradykinin generation → endothelial leak (tutunaru2024unveilingthecomplexities pages 1-2, recke2025statusquoand pages 1-2) Childhood/adolescent onset, recurrent nonurticarial skin swelling, abdominal attacks, possible laryngeal edema; attacks often last 2-5 days untreated (tutunaru2024unveilingthecomplexities pages 2-4, recke2025statusquoand pages 1-2) On-demand pdC1-INH/rhC1-INH, icatibant, ecallantide; long-term prophylaxis SC/IV C1-INH, lanadelumab, berotralstat (johnson2025unravelingangioedemadiagnostic pages 9-10, caballero2022medicalalgorithmmanagement pages 2-2)
HAE type II (HAE-C1INH-2) SERPING1 / dysfunctional C1 inhibitor Low C4; normal or elevated C1-INH antigen; low C1-INH function (caballero2022medicalalgorithmmanagement pages 2-2) Dysfunctional C1-INH fails to restrain kallikrein-kinin and related protease cascades → bradykinin-mediated angioedema (caballero2022medicalalgorithmmanagement pages 2-2, tutunaru2024unveilingthecomplexities pages 1-2) Similar phenotype to type I; family history may be present; recurrent angioedema without wheals and poor response to antihistamines/steroids (tutunaru2024unveilingthecomplexities pages 1-2, caballero2022medicalalgorithmmanagement pages 2-2) Same targeted classes as HAE type I: C1-INH replacement, B2 receptor antagonism, kallikrein inhibition; prophylaxis with C1-INH, lanadelumab, berotralstat (johnson2025unravelingangioedemadiagnostic pages 9-10, caballero2022medicalalgorithmmanagement pages 2-2)
HAE-nC1INH, F12-associated F12 / factor XII Usually normal C4, normal C1-INH antigen, normal C1-INH function (zuraw2025hereditaryangioedemawith pages 1-2, caballero2022medicalalgorithmmanagement pages 2-2) Increased factor XII-driven contact activation with downstream bradykinin excess (zuraw2025hereditaryangioedemawith pages 1-2, santacroce2021thegeneticsof pages 8-9) Often estrogen-sensitive; attacks can be triggered/worsened by estrogens; normal complement studies despite convincing hereditary angioedema phenotype (tutunaru2024unveilingthecomplexities pages 2-4, zuraw2025hereditaryangioedemawith pages 1-2) Evidence-based use in practice/expert consensus: icatibant, C1-INH, kallikrein-pathway prophylaxis in selected patients; evidence base weaker than for HAE-C1INH (zuraw2025hereditaryangioedemawith pages 1-2)
HAE-nC1INH, PLG-associated PLG / plasminogen Usually normal C4, normal C1-INH antigen, normal C1-INH function (zuraw2025hereditaryangioedemawith pages 1-2, rozevska2024hereditaryoracquired? pages 2-3) Likely plasminogen/plasmin-linked promotion of bradykinin formation; mechanistic evidence supports bradykinin-mediated disease (zuraw2025hereditaryangioedemawith pages 1-2, santacroce2021thegeneticsof pages 8-9) Recurrent hereditary angioedema phenotype with normal C1-INH studies; diagnosis generally requires genetics when suspected clinically (zuraw2025hereditaryangioedemawith pages 1-2, rozevska2024hereditaryoracquired? pages 2-3) Often treated with bradykinin-pathway agents used for HAE-C1INH; response reported but evidence remains limited/consensus-based (zuraw2025hereditaryangioedemawith pages 1-2)
HAE-nC1INH, ANGPT1-associated ANGPT1 / angiopoietin-1 Usually normal C4, normal C1-INH antigen, normal C1-INH function (zuraw2025hereditaryangioedemawith pages 1-2, santacroce2021thegeneticsof pages 8-9) Endothelial barrier dysfunction/vascular permeability mechanism rather than pure upstream C1-INH deficiency; may intersect with bradykinin pathways (gao2025expandingthegenetic pages 1-2, zuraw2025hereditaryangioedemawith pages 1-2) Familial nonurticarial angioedema with normal complement/C1-INH studies; clinical heterogeneity (zuraw2025hereditaryangioedemawith pages 1-2, gao2025expandingthegenetic pages 1-2) No subtype-specific approved therapy; HAE-directed acute/prophylactic agents are used empirically, with expert-opinion support and variable response (zuraw2025hereditaryangioedemawith pages 1-2, gao2025expandingthegenetic pages 1-2)
HAE-nC1INH, KNG1-associated KNG1 / high-molecular-weight kininogen precursor Usually normal C4, normal C1-INH antigen, normal C1-INH function (zuraw2025hereditaryangioedemawith pages 1-2, santacroce2021thegeneticsof pages 8-9) Altered kininogen biology with downstream bradykinin dysregulation (santacroce2021thegeneticsof pages 8-9, zuraw2025hereditaryangioedemawith pages 1-2) Hereditary angioedema phenotype despite normal standard complement workup; often requires sequencing for confirmation (rozevska2024hereditaryoracquired? pages 2-3, santacroce2021thegeneticsof pages 8-9) Managed with standard HAE targeted classes in practice; subtype-specific efficacy evidence remains sparse (zuraw2025hereditaryangioedemawith pages 1-2)
HAE-nC1INH, MYOF-associated MYOF / myoferlin Usually normal C4, normal C1-INH antigen, normal C1-INH function (gao2025expandingthegenetic pages 1-2) Proposed endothelial/vesicular membrane regulation abnormality; not as securely established as classic bradykinin-only forms (gao2025expandingthegenetic pages 1-2, santacroce2021thegeneticsof pages 8-9) In one cohort, recurrent edema with prolonged duration; treatment response to lanadelumab variable (gao2025expandingthegenetic pages 1-2) HAE-directed acute/prophylactic therapies used off-label/empirically; variable response reported (gao2025expandingthegenetic pages 1-2)
HAE-nC1INH, HS3ST6-associated HS3ST6 / heparan sulfate 3-O-sulfotransferase 6 Usually normal C4, normal C1-INH antigen, normal C1-INH function (gao2025expandingthegenetic pages 1-2, santacroce2021thegeneticsof pages 8-9) Proposed endothelial/glycocalyx or permeability regulation defect; causal confidence lower than F12/PLG (gao2025expandingthegenetic pages 1-2, santacroce2021thegeneticsof pages 8-9) Reported association with refractory angioedema and persistent lower-extremity involvement in a small cohort (gao2025expandingthegenetic pages 1-2) Empiric use of HAE-directed agents; personalized management needed; evidence limited (gao2025expandingthegenetic pages 1-2)
HAE-nC1INH, rarer/newer candidate genes with weaker evidence Reported/candidate: CPN1, DAB2IP; some literature also discusses other rare candidates with uncertain validation Usually normal standard complement/C1-INH studies (gao2025expandingthegenetic pages 1-2, recke2025statusquoand pages 1-2) Mixed hypotheses: bradykinin dysregulation and/or VEGF/endothelial permeability pathways; evidence weaker and not yet equivalent to established genes (gao2025expandingthegenetic pages 1-2, recke2025statusquoand pages 1-2) Consider when phenotype is convincing but common genes are negative; diagnosis remains expert-dependent and may change after re-evaluation (rozevska2024hereditaryoracquired? pages 2-3, gao2025expandingthegenetic pages 1-2) No gene-specific approved treatment; use individualized HAE-directed acute/prophylactic therapy with cautious interpretation of response (rozevska2024hereditaryoracquired? pages 2-3, gao2025expandingthegenetic pages 1-2)
Acquired C1-INH deficiency (important differential) Acquired loss/consumption of C1-INH rather than inherited pathogenic variant Low C4; low C1-INH function; often low C1-INH antigen; C1q often low (helps distinguish from hereditary C1-INH deficiency) (caballero2022medicalalgorithmmanagement pages 2-2, tutunaru2024unveilingthecomplexities pages 1-2) Acquired C1-INH depletion/consumption with bradykinin-mediated angioedema (caballero2022medicalalgorithmmanagement pages 2-2, tutunaru2024unveilingthecomplexities pages 1-2) Usually later onset, absent family history, evaluation for acquired causes warranted; C1q more informative here than in routine pediatric hereditary testing (tutunaru2024unveilingthecomplexities pages 1-2, caballero2022medicalalgorithmmanagement pages 2-2) Acute therapy may overlap with HAE agents (C1-INH, icatibant, kallikrein-pathway agents), but management also requires treating the underlying acquired disorder (tutunaru2024unveilingthecomplexities pages 1-2, caballero2022medicalalgorithmmanagement pages 2-2)

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

2. Etiology, risk, protective factors, and gene–environment interaction

Causal factors

HAE is principally genetic. In HAE-C1INH, reduced effective C1-INH removes inhibition of factor XIIa and plasma kallikrein, allowing cleavage of high-molecular-weight kininogen and excessive bradykinin formation. Bradykinin activates endothelial B2 receptors and increases paracellular fluid movement. HAE is therefore not primarily an IgE-mediated allergy. (OpenTargets Search: hereditary angioedema, tutunaru2024unveilingthecomplexities pages 1-2, caballero2022medicalalgorithmmanagement pages 2-2)

Genetic risk

The strongest association is SERPING1. OpenTargets also supports disease associations involving F12, PLG, KNG1, ANGPT1, MYOF, and HS3ST6, while KLKB1 and BDKRB2 are strongly supported therapeutic-mechanism targets rather than usual germline causes. (OpenTargets Search: hereditary angioedema)

Approximately one quarter of HAE-C1INH cases are reported without an affected parent and may reflect de-novo SERPING1 variation; absence of family history therefore does not exclude HAE. Each child of a heterozygous affected person has a 50% transmission probability. (tutunaru2024unveilingthecomplexities pages 2-4)

Attack-promoting environmental and physiological factors

Mechanical trauma, dental work, surgery, intubation, infection, psychological stress, fatigue, and hormonal changes can precipitate attacks, but many attacks have no identifiable trigger. Estrogen-containing contraception, estrogen replacement, pregnancy in some patients, and puberty can increase attacks—especially in HAE-FXII and some HAE-nC1INH phenotypes. ACE inhibitors reduce bradykinin degradation and should generally be avoided. These exposures modify attack expression rather than cause the inherited disease.

Protective factors

No validated germline “protective allele” prevents HAE. Reduced estrogen exposure or withdrawal of exogenous estrogen may lower attack activity in estrogen-sensitive disease. Avoiding ACE inhibitors and known individual mechanical triggers is prudent. Effective on-demand treatment and prophylaxis reduce manifestations but do not eliminate the inherited genotype. Evidence for special diets, smoking cessation, alcohol restriction, or exercise as HAE-specific protection is insufficient.

Proposed modifiers include F12 regulatory polymorphisms and, more recently, candidate modifier loci, but findings are not sufficiently replicated for routine prognostication. (santacroce2021thegeneticsof pages 8-9)

3. Phenotypes

Core phenotype and suggested HPO mappings

  • Recurrent subcutaneous edema, usually nonpitting, nonpruritic and asymmetric: HP:0100665, Angioedema; HP:0010741, Edema of the limbs; HP:0001999, Facial edema.
  • Abdominal attacks: cramping pain, nausea, vomiting, diarrhea, bowel-wall edema and ascites: HP:0002027, Abdominal pain; HP:0002013, Vomiting; HP:0002014, Diarrhea; HP:0003270, Abdominal distention; HP:0001541, Ascites.
  • Upper-airway/laryngeal edema: voice change, dysphagia, stridor, dyspnea and asphyxiation risk: HP:0100659, Laryngeal edema; HP:0002094, Dyspnea; HP:0001650, Dysphonia; HP:0002015, Dysphagia.
  • Oropharyngeal, tongue, lip, genital, facial, hand or foot swelling: use site-specific edema terms where available.
  • Prodrome: erythema marginatum, fatigue, paresthesias, mood change or localized discomfort may precede swelling. Erythema marginatum is not urticaria.
  • Laboratory phenotype: low C4 and low functional C1-INH in HAE-C1INH; low antigenic C1-INH in type I but normal/high antigen in type II.

A 2024 review reported cutaneous swelling in about 75%, recurrent abdominal pain in 52%, and facial/airway edema in 36%; estimates vary by cohort and phenotype definitions. About 25% were described as having severe abdominal attacks. (tutunaru2024unveilingthecomplexities pages 2-4)

Onset, severity, course, and frequency

Symptoms often begin in childhood and intensify around puberty. One review estimated onset before age five in 40% of type I/II patients and symptoms by age 15 in 75%; approximately 5% of adult variant carriers remained asymptomatic. HAE-nC1INH often becomes evident later, particularly after estrogen exposure. (tutunaru2024unveilingthecomplexities pages 2-4)

Attacks generally evolve over hours and resolve in approximately 2–5 days without treatment, although a broader 1–7-day range is reported. Disease activity is episodic and highly variable both within and between families; genotype does not reliably predict attack site or frequency. (tutunaru2024unveilingthecomplexities pages 2-4, recke2025statusquoand pages 1-2)

Quality of life

The unpredictable possibility of pain, visible swelling, emergency airway compromise, missed school/work, travel restrictions, and treatment burden causes substantial anticipatory anxiety. In a multinational survey of 242 adults, mean age at first symptoms was 11.5 years and diagnosis at 20.8 years; participants reported a mean 12.5 attacks over six months. Moderate-to-severe anxiety affected 38.0%, depression 17.4%, 6.6% of most recent attacks involved the larynx, and 21.9% lasted at least three days. This was patient-reported cross-sectional evidence and may overrepresent symptomatic patients.

A 2024 systematic review of 65 studies and 10,310 patients found marked impairment across AE-QoL, anxiety, depression, stress, productivity, and direct medical utilization. (recke2025statusquoand pages 1-2)

4. Genetic and molecular information

Causal genes and strength of evidence

  • SERPING1, chromosome 11q12–q13.1, encodes C1 inhibitor: definitive cause of HAE types I and II.
  • F12: established cause of a subset of HAE-nC1INH; several gain-of-function or activation-enhancing variants affect factor XII.
  • PLG: established familial HAE-nC1INH, classically associated with a recurrent plasminogen variant.
  • ANGPT1, KNG1, MYOF, HS3ST6: reported segregating causes in rare families, but aggregate evidence and replication are less extensive than for SERPING1, F12, and PLG.
  • CPN1 and DAB2IP: newer reported associations requiring continuing validation and careful ClinGen-style evidence appraisal. (recke2025statusquoand pages 1-2, gao2025expandingthegenetic pages 1-2, santacroce2021thegeneticsof pages 8-9)

Variant classes and origin

SERPING1 disease variants include missense, nonsense, frameshift, canonical and noncanonical splice variants, small insertions/deletions, exon-level deletions/duplications, and whole-gene deletions. They are constitutional/germline, usually heterozygous; somatic HAE is not a recognized common category. A cohort of 106 patients from 46 families found 41 causal variants: 45.65% missense, 19.57% frameshift, 17.36% nonsense, 8.7% splice defects, 6.52% large deletions and 2.17% nonstop variants. Protein-truncating/large-deletion variants were associated with severe or very severe disease in 55.39% versus 29.18% for missense variants, but individual prediction remains unreliable. (kariko2026abstractsofthe pages 31-32)

A 2024 primary study showed the utility of genome plus RNA sequencing: it detected a SERPING1 exon-4 deletion, chr11(GRCh38):g.57600729_57603011del, and demonstrated intron retention from NM_000062.2:c.1249+4A>G. Among 21 suspected HAE-nC1INH cases, only one received a molecular diagnosis, emphasizing the low yield and risk of misclassification in this group. (rozevska2024hereditaryoracquired? pages 2-3)

Functional consequences

Most type-I alleles cause haploinsufficiency through absent synthesis, defective secretion, degradation, or unstable protein. Some missense alleles cause intracellular polymerization/retention and dominant-negative effects. A 2024 family study identified SERPING1 c.708T>G and linked C1-INH retention in the endoplasmic reticulum to GRP75 upregulation, calcium overload, mitochondrial injury, and apoptosis in cellular experiments. Intracellular calcium was proposed—not validated—as an attack biomarker. (jiang2024uncoveringanovel pages 1-2)

A Colombian cluster study identified heterozygous c.1420C>T (p.Gln474*) and novel c.1238T>G (p.Met413Arg). Structural modeling suggested reactive-center-loop insertion, latent C1-INH conformation, impaired secretion, clearance, or aggregation. This is computational/mechanistic support, not proof of clinical severity. (ariasflorez2024phenotypicandmolecular pages 13-14)

Population frequency and classification

Pathogenic HAE alleles are individually rare and generally absent or extremely rare from population databases such as gnomAD. Classification should use ACMG/AMP criteria, segregation, phenotype/biochemistry, RNA evidence for splice variants, and copy-number analysis. A VUS should not independently establish HAE-nC1INH. Variant interpretation must use current ClinVar/ClinGen records because classifications change.

Epigenetics and chromosomal abnormalities

No reproducible disease-defining DNA-methylation or histone signature is established. Large intragenic or whole-gene SERPING1 deletions occur, but HAE is not usually a cytogenetic syndrome. Conventional karyotyping and FISH have negligible routine yield; chromosomal microarray is reserved for broader syndromic presentations or suspected large rearrangements.

5. Environmental, lifestyle, and infectious information

HAE is not caused by toxins, radiation, pollution, occupation, diet, smoking, alcohol, or a pathogen. Infections can trigger individual attacks through inflammation/contact-system activation. Trauma and procedures are the most actionable external precipitants. Estrogens and ACE inhibitors are clinically important pharmacological exposures. There is no evidence that vaccination causes HAE, although any inflammatory or mechanical stress could coincidentally precede an attack.

Lifestyle management should focus on individualized trigger recognition without excessive restriction. Patients should not be advised to avoid ordinary activity when effective treatment and an emergency plan are available.

6. Mechanism and pathophysiology

Causal chain

Upstream: pathogenic SERPING1 allele → insufficient functional C1-INH.
Intermediate: inadequately restrained factor XIIa/plasma kallikrein activity → high-molecular-weight kininogen cleavage → excess local bradykinin.
Downstream: bradykinin binds BDKRB2 on vascular endothelial cells → cytoskeletal and junctional changes, vasodilation and increased permeability → plasma extravasation into subcutaneous/submucosal tissue → edema, bowel-wall pain/ascites, or airway obstruction. (OpenTargets Search: hereditary angioedema, tutunaru2024unveilingthecomplexities pages 1-2, caballero2022medicalalgorithmmanagement pages 2-2)

C1-INH also regulates complement and fibrinolytic proteases, explaining low C4 and biochemical cross-talk, but complement-derived anaphylatoxins are not considered the principal mediator of HAE swelling.

In HAE-FXII, PLG and KNG1, altered contact/fibrinolytic processing converges on kinin production. ANGPT1, MYOF, HS3ST6 and DAB2IP observations support a complementary “endothelial-barrier disorder” model involving angiopoietin/Tie2, glycocalyx or VEGF-related permeability. The proximate mechanism across angioedema is endothelial leak, but not every nC1INH subtype has been definitively shown to be exclusively bradykinin mediated. (zuraw2025hereditaryangioedemawith pages 1-2, gao2025expandingthegenetic pages 1-2)

Cells, tissues, GO and CL suggestions

  • Endothelial cell — CL:0000115: principal effector cell.
  • Hepatocyte — CL:0000182: major source of circulating C1-INH and contact-system proteins.
  • Possible modulatory cells include mast cells — CL:0000097, but HAE is not primarily mast-cell-mediated.
  • Suggested GO biological processes: regulation of vascular permeability (GO:0043114), kallikrein–kinin system, complement activation (GO:0006956), proteolysis (GO:0006508), blood coagulation (GO:0007596), inflammatory response (GO:0006954), regulation of endothelial barrier.
  • Suggested GO molecular functions/components: serine-type endopeptidase inhibitor activity (GO:0004867), extracellular region (GO:0005576), blood microparticle (GO:0072562), endoplasmic-reticulum lumen (GO:0005788) for retained variants.

Molecular profiling and advanced technology

Potential biomarkers include cleaved high-molecular-weight kininogen, activated plasma kallikrein, enzyme–inhibitor complexes, D-dimer, endothelial activation markers, and attack-related transcript/protein signatures. Direct bradykinin measurement is technically difficult because it is generated locally and rapidly degraded. No transcriptomic, proteomic, metabolomic, lipidomic, single-cell, or spatial signature is sufficiently validated for routine diagnosis. Genome plus RNA sequencing can resolve cryptic splice/CNV cases, whereas broad sequencing of clinically uncertain nC1INH cases has low yield. (rozevska2024hereditaryoracquired? pages 2-3)

7. Anatomical structures affected

  • Skin/subcutis: face, lips, hands, feet, limbs, trunk and genitalia; UBERON:0002097 skin of body and UBERON:0002190 subcutaneous adipose tissue.
  • Gastrointestinal tract: stomach and small/large intestine, mesentery and peritoneal cavity; bowel-wall edema may produce ascites and mimic an acute surgical abdomen.
  • Upper respiratory tract: tongue, soft palate, pharynx, epiglottis and larynx; laryngeal edema is the critical lethal lesion.
  • Urogenital tissues: genital edema and less commonly urinary-tract symptoms.

The lesion is extracellular/interstitial fluid accumulation caused by postcapillary endothelial leak rather than primary epithelial destruction. Swelling is often asymmetric; lateralization has no diagnostic significance. There is no characteristic chronic fibrosis or necrosis after ordinary attacks.

8. Temporal development

HAE is congenital at the genetic level but usually not symptomatic neonatally. Childhood onset is common, activity often increases at puberty, and HAE-nC1INH may emerge after hormonal exposure. Attacks are acute/subacute, increase over hours and remit spontaneously over days. The lifelong course is episodic rather than continuously progressive; there are no accepted early/intermediate/end-stage categories. (tutunaru2024unveilingthecomplexities pages 2-4, recke2025statusquoand pages 1-2)

Periods without attacks are not molecular remission. Pregnancy may improve, worsen, or not change disease. Critical windows include airway symptoms, the hours after dental/airway procedures, and early attack onset, when self-administered therapy generally works best.

9. Inheritance and population

Epidemiology

A 2024 systematic review found reported prevalence from 0.13 to 1.6 per 100,000, with major geographic ascertainment differences and probable underdiagnosis. Another contemporary synthesis uses approximately 1:50,000 to 1:150,000. Among 10,310 collated patients, 5,861 were female; among cases with subtype data, 81% were type I, 9% type II, and 8% HAE-nC1INH. Diagnostic delay ranged from 3.9 to 26 years. (tutunaru2024unveilingthecomplexities pages 2-4, tutunaru2024unveilingthecomplexities pages 1-2)

HAE occurs worldwide across ancestries and both sexes. HAE-C1INH has no strong biological sex bias, although women may have greater hormonal modulation and are overrepresented in clinical cohorts. Incidence is difficult to estimate because HAE is inherited and often diagnosed years after birth.

Mendelian properties

Inheritance is predominantly autosomal dominant, with incomplete/age-dependent penetrance and markedly variable expressivity. About 5% of adult carriers may remain asymptomatic in some series. There is no established anticipation. Germline mosaicism is possible but appears uncommon. Consanguinity is not a usual risk factor for dominant HAE, although rare biallelic SERPING1 cases exist. Founder clusters occur; a 2024 study described four Colombian families with 79 suspected affected members and distinct SERPING1 variants. (tutunaru2024unveilingthecomplexities pages 2-4, ariasflorez2024phenotypicandmolecular pages 13-14)

10. Diagnostics

Clinical suspicion

Suspect HAE with recurrent angioedema without wheals, recurrent severe unexplained abdominal attacks, laryngeal edema, childhood/adolescent onset, family history, prodromes, and failure of adequate antihistamine/glucocorticoid therapy. Family history is absent in de-novo disease.

Laboratory algorithm

  1. Measure C4, antigenic C1-INH and functional C1-INH together.
  2. Repeat abnormal or discordant results in a properly handled fresh sample, preferably when the patient is well and before labeling the condition lifelong.
  3. Type I: low C4, low C1-INH antigen and function.
  4. Type II: low C4, normal/high antigen, low function.
  5. Measure C1q when acquired C1-INH deficiency is plausible—especially adult onset with no family history. C1q is often low in acquired disease and usually normal in hereditary C1-INH deficiency.
  6. Normal C4 does not absolutely exclude HAE, especially outside attacks, and all complement tests are normal in HAE-nC1INH. (tutunaru2024unveilingthecomplexities pages 1-2, caballero2022medicalalgorithmmanagement pages 2-2)

Antigenic C1-INH can be measured by nephelometry/turbidimetry; function by chromogenic assay or ELISA. Preanalytics are important because delayed processing or improper storage can artifactually reduce function.

Genetics

For biochemically confirmed HAE-C1INH, sequence SERPING1 with deletion/duplication analysis such as MLPA. If negative despite convincing biochemistry, consider genome sequencing and RNA studies. For nC1INH, use a carefully curated panel including F12, PLG, ANGPT1, KNG1, MYOF, HS3ST6, with cautious inclusion of newer genes. WES/WGS may discover structural or intronic variants but also generate VUS. In a 2024 cohort, conventional testing diagnosed 10/32 patients, while broad investigation produced a molecular answer in only 1/21 suspected nC1INH cases. (rozevska2024hereditaryoracquired? pages 2-3)

CMA, karyotyping, FISH, mitochondrial analysis and repeat-expansion testing are not routine HAE tests. Cascade biochemical/genetic testing is recommended for first-degree relatives. Complement results in infants can be difficult to interpret; repeat age-appropriate testing is needed.

Imaging and pathology

Imaging is supportive only. During abdominal attacks, ultrasound or CT can show transient bowel-wall thickening, mesenteric edema and ascites. Airway evaluation must not delay treatment and should be undertaken where airway intervention is available. Biopsy, histopathology, electrophysiology and liquid biopsy have no routine role.

Differential diagnosis

Key alternatives are mast-cell-mediated angioedema/anaphylaxis, chronic spontaneous urticaria, ACE-inhibitor angioedema, acquired C1-INH deficiency, idiopathic non-mast-cell angioedema, contact dermatitis, cellulitis, superior vena-cava syndrome, nephrotic/cardiac/hepatic edema, and gastrointestinal surgical/inflammatory disease. Wheals, pruritus, rapid response to antihistamine/epinephrine and an allergic exposure favor mast-cell disease; low C1q and late onset favor acquired C1-INH deficiency.

11. Outcome and prognosis

HAE does not ordinarily cause progressive organ failure or shorten life when recognized and adequately treated. The dominant mortality mechanism is acute upper-airway obstruction. A 2024 systematic review estimated asphyxiation death risk at 8.6% in historical/heterogeneous data, while older untreated laryngeal-attack series report much higher case fatality; these estimates should not be applied to patients with modern therapy and emergency plans. (zhao2026advancesinhereditary pages 1-2, recke2025statusquoand pages 1-2)

Delayed diagnosis remains a major adverse prognostic factor. Other burden predictors include high attack frequency, prior laryngeal attacks, poor access to on-demand treatment, uncontrolled disease, estrogen/ACE-inhibitor exposure, and anxiety. A Chinese scoping review reported 129 deaths in literature through 2021 versus five during 2021–September 2024, consistent with—but not proving—benefit from awareness and modern treatment. (zhao2026advancesinhereditary pages 1-2)

Recovery from each treated or untreated nonfatal attack is usually complete. Morbidity includes pain, dehydration, unnecessary abdominal surgery, emergency visits, work/school loss, anxiety, depression and treatment burden. Recommended patient-reported outcomes include AE-QoL, AECT, HAE Activity Score and treatment-satisfaction instruments.

12. Treatment

Treatment goals and strategy

Management has three layers: on-demand treatment of every attack, short-term prophylaxis before high-risk procedures, and individualized long-term prophylaxis (LTP). Every patient should have rapid access to enough on-demand medicine for at least two attacks and a written emergency/airway plan. Treat early; any tongue, pharyngeal or laryngeal involvement requires immediate therapy and emergency airway assessment.

Suggested MAXO mappings include pharmacotherapy (MAXO:0000058), intravenous medication administration, subcutaneous medication administration, prophylactic treatment, genetic counseling, molecular genetic testing and emergency airway management; exact identifiers should be validated against the deployed MAXO release.

On-demand therapy

  • Plasma-derived or recombinant C1-INH: replaces deficient inhibition and suppresses upstream contact-system activation. Intravenous administration is effective across attack sites.
  • Icatibant: subcutaneous bradykinin-B2 receptor antagonist; may require repeat dosing.
  • Ecallantide: subcutaneous plasma-kallikrein inhibitor, US-specific availability; must be administered by a healthcare professional because of anaphylaxis risk.
  • Where specific agents are unavailable, solvent/detergent-treated plasma or fresh frozen plasma may be considered, but are not preferred.

Antihistamines and glucocorticoids do not treat the bradykinin mechanism; epinephrine remains appropriate if anaphylaxis cannot initially be excluded.

Short-term prophylaxis

Intravenous plasma-derived C1-INH shortly before dental work, upper-airway instrumentation or surgery is preferred when procedure-related trauma could provoke edema. Even with prophylaxis, rescue treatment and airway capability must be available. Attenuated androgens may be used where modern options are unavailable but have slower onset and toxicity.

Long-term prophylaxis

Established options include:

  • Lanadelumab: subcutaneous monoclonal antibody against active plasma kallikrein.
  • Berotralstat: once-daily oral plasma-kallikrein inhibitor; 150 mg daily is a common adult regimen where approved.
  • Subcutaneous or intravenous plasma-derived C1-INH.
  • Attenuated androgens such as danazol and antifibrinolytics such as tranexamic acid are generally later-line because efficacy/tolerability are inferior. Androgens can cause virilization, menstrual disturbance, dyslipidemia, hypertension, hepatic toxicity and mood effects.

Choice should incorporate attack burden, prior airway events, age, pregnancy, comorbidities, route, access, preference and QoL—not an arbitrary attack-count threshold. Breakthrough attacks still require on-demand therapy. OpenTargets evidence independently supports approved intervention at KLKB1 and bradykinin/contact-system targets. (OpenTargets Search: hereditary angioedema, johnson2025unravelingangioedemadiagnostic pages 9-10)

Emerging and recent therapy research

  • Garadacimab: long-acting monoclonal antibody inhibiting activated factor XII for LTP.
  • Donidalorsen: antisense oligonucleotide reducing prekallikrein RNA; a phase III study reported approximately 81% attack-rate reduction with 80 mg every four weeks. NCT05139810 is the pivotal OASIS-HAE study; NCT05392114 is a long-term study. (johnson2025unravelingangioedemadiagnostic pages 9-10, recke2025statusquoand pages 13-14)
  • Sebetralstat and deucrictibant: oral B2-receptor antagonists intended to reduce injection burden. Phase-II deucrictibant data reported median symptom-resolution times around 25–26 minutes; phase III on-demand study NCT06343779 enrolled 134 participants. (johnson2025unravelingangioedemadiagnostic pages 9-10)
  • Navenibart/STAR-0215: long-acting kallikrein antibody designed for infrequent administration; phase-II reports showed approximately 90–95% mean monthly attack-rate reductions. NCT06007677 is a long-term study. (johnson2025unravelingangioedemadiagnostic pages 9-10)
  • ADX-324: RNA-targeting prophylaxis under phase I–III evaluation, including NCT05691361 and NCT06960213.
  • BMN 331: AAV-mediated SERPING1 gene transfer, NCT05121376.
  • NTLA-2002: systemic in-vivo CRISPR/Cas9 editing of hepatic KLKB1, designed as one-time therapy. Early-phase reports described 97–99% attack reductions over about 20 months, but long-term off-target, hepatic, reproductive and irreversible-editing risks remain incompletely characterized. NCT05120830 is phase I/II; NCT06634420 is the HAELO phase III study. (johnson2025unravelingangioedemadiagnostic pages 9-10, recke2025statusquoand pages 13-14)

These investigational results are not interchangeable with regulatory approval, and cross-trial efficacy comparisons are unreliable.

Special populations

Plasma-derived C1-INH has the broadest experience in pregnancy and lactation. Pediatric approvals differ by product and jurisdiction. Androgens are contraindicated in pregnancy and generally avoided in children. HAE-nC1INH treatment evidence is much weaker and often consists of case series/expert opinion; response should support management but not be used as a stand-alone diagnostic test. (zuraw2025hereditaryangioedemawith pages 1-2)

No validated HAE pharmacogenomic dosing guideline comparable to CPIC recommendations currently exists.

13. Prevention

Primary prevention of the inherited genotype is not possible after conception. Reproductive options include genetic counseling, natural conception with prenatal testing where desired, and preimplantation genetic testing for a known familial pathogenic variant. Counseling must address variable expressivity and the availability of effective therapy.

Secondary prevention consists of early biochemical diagnosis, cascade screening of relatives, confirmatory genetics where useful, and education before symptoms occur. Population or newborn screening is not standard. Dried-blood-spot C1-INH approaches remain investigational.

Tertiary prevention includes avoiding ACE inhibitors and estrogen where appropriate, procedure-specific prophylaxis, ready access to on-demand medication, self-administration training, medical identification, emergency plans, regular disease-control/QoL assessment, and LTP when burden remains unacceptable. Vaccination should follow routine recommendations; there is no HAE vaccine.

14. Other species and natural disease

The relevant genes and contact-system biology are evolutionarily conserved across vertebrates, including mouse Serping1, F12, Klkb1, Kng1, and bradykinin receptors. However, the searched evidence did not identify a well-established, naturally occurring veterinary counterpart that is routinely classified as hereditary angioedema in a specific dog, cat, horse, livestock or wildlife population. Reports of animal angioedema more commonly describe allergic reactions rather than a genetically proven C1-INH-deficient syndrome.

Accordingly, no validated VBO breed term, animal carrier frequency, zoonotic transmission or cross-species transmission applies. HAE is noninfectious and nonzoonotic.

15. Model organisms

Mouse models

Serping1-deficient mice show increased vascular permeability measurable by Evans-blue extravasation, supporting the causal link between C1-INH loss and endothelial leak. Pharmacological C1-INH replacement and blockade of downstream bradykinin signaling can reverse permeability, providing target validation for human treatment. (OpenTargets Search: hereditary angioedema)

Other useful models include contact-system or bradykinin-receptor knockout combinations, acute permeability models, and mice exposed to agents that activate kallikrein–kinin pathways. These systems are used to study endothelial permeability, factor-XII/kallikrein activation and preclinical drug activity.

Cellular and in-vitro systems

Hepatocyte-like expression systems assess secretion, polymerization and intracellular retention of C1-INH variants. Endothelial monolayers quantify barrier resistance and permeability after bradykinin or patient-plasma exposure. The 2024 c.708T>G study used cellular experiments to connect ER retention, GRP75, calcium overload, mitochondrial injury and apoptosis. (jiang2024uncoveringanovel pages 1-2)

Limitations

Mice do not spontaneously reproduce the full stochastic human pattern of abdominal, cutaneous and laryngeal attacks, hormonal modulation, or psychosocial burden. Homozygous knockout is also not equivalent to the usual human heterozygous state. Cell models isolate particular pathways and cannot reproduce systemic contact-system, hepatic and endothelial interactions. No widely accepted HAE organoid, zebrafish, Drosophila or naturally affected companion-animal model currently supersedes mouse and endothelial-cell platforms.

Evidence-quality and knowledge-gap assessment

The highest-confidence evidence concerns SERPING1, C1-INH biochemistry, bradykinin/contact-system pathophysiology, complement testing, and approved therapies for HAE-C1INH. HAE-nC1INH is less secure: the 2025 international consensus explicitly states that recommendations are largely expert opinion because high-level evidence is sparse. (zuraw2025hereditaryangioedemawith pages 1-2)

Recent primary studies strengthen genomic diagnosis but also caution against overdiagnosis. In the 2024 32-patient investigation, extensive sequencing found a recognized HAE-nC1INH pathogenic variant in only one of 21 suspected cases, and clinical re-evaluation changed several diagnoses. (rozevska2024hereditaryoracquired? pages 2-3)

Important unresolved questions are reliable attack-prediction biomarkers, penetrance modifiers, standardized HAE-nC1INH criteria, comparative effectiveness among modern prophylactics, pregnancy data for newer drugs, equitable global access, and the lifetime safety of RNA/gene-editing interventions.

Selected recent sources and exact abstract language

  • Rozevska et al., March 2024, Allergy, Asthma & Clinical Immunology, DOI: https://doi.org/10.1186/s13223-024-00889-5. Primary genomic cohort. Abstract: “the diagnostic yield for nC1-INH HAE remains low in our study.” (rozevska2024hereditaryoracquired? pages 2-3)
  • Jiang et al., September 2024, Orphanet Journal of Rare Diseases, DOI: https://doi.org/10.1186/s13023-024-03306-7. Primary family/cellular study. Abstract: “this variant leads to an increase in the accumulation of C1-INH within the endoplasmic reticulum.” (jiang2024uncoveringanovel pages 1-2)
  • Arias-Flórez et al., December 2024, PLOS ONE 19:e0311316, DOI: https://doi.org/10.1371/journal.pone.0311316. Primary founder-cluster study. Abstract describes “sudden local, often asymmetric, and episodic subcutaneous and submucosal swelling.” (ariasflorez2024phenotypicandmolecular pages 13-14)
  • Tutunaru et al., October 2024, Biomolecules 14:1298, DOI: https://doi.org/10.3390/biom14101298. Review. Abstract: HAE causes “recurrent episodes of non-pruritic angioedema, which occurs in the absence of urticaria.” (tutunaru2024unveilingthecomplexities pages 1-2)
  • Zuraw et al., March 2025, Clinical Reviews in Allergy & Immunology, DOI: https://doi.org/10.1007/s12016-025-09027-4. International expert consensus derived from a September 2023 symposium. It emphasizes that HAE-nC1INH recommendations are expert opinion because of limited high-level evidence. (zuraw2025hereditaryangioedemawith pages 1-2)

PMIDs explicitly available in the retrieved disease-target evidence include 26452350, 29316335, 22994404, 28795768, 29548426, 29952006, 31087670, 31860755, 33508266, 33799813, among others linking SERPING1, PLG, KNG1, ANGPT1 and HS3ST6 to HAE. These should be reconciled with current PubMed/ClinVar records during database curation. (OpenTargets Search: hereditary angioedema)

References

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  2. (tutunaru2024unveilingthecomplexities pages 1-2): Cristina Violeta Tutunaru, Oana Maria Ică, George G. Mitroi, Carmen Daniela Neagoe, George F. Mitroi, Olguța Anca Orzan, Beatrice Bălăceanu-Gurău, and Simona Laura Ianoși. Unveiling the complexities of hereditary angioedema. Biomolecules, 14:1298, Oct 2024. URL: https://doi.org/10.3390/biom14101298, doi:10.3390/biom14101298. This article has 22 citations.

  3. (tutunaru2024unveilingthecomplexities pages 2-4): Cristina Violeta Tutunaru, Oana Maria Ică, George G. Mitroi, Carmen Daniela Neagoe, George F. Mitroi, Olguța Anca Orzan, Beatrice Bălăceanu-Gurău, and Simona Laura Ianoși. Unveiling the complexities of hereditary angioedema. Biomolecules, 14:1298, Oct 2024. URL: https://doi.org/10.3390/biom14101298, doi:10.3390/biom14101298. This article has 22 citations.

  4. (OpenTargets Search: hereditary angioedema): Open Targets Query (hereditary angioedema, 16 results). Buniello, A. et al. (2025). Open Targets Platform: facilitating therapeutic hypotheses building in drug discovery. Nucleic Acids Research.

  5. (caballero2022medicalalgorithmmanagement pages 2-2): Teresa Caballero, Rosario Cabañas, and María Pedrosa. Medical algorithm: management of c1 inhibitor hereditary angioedema. Allergy, 77:1060-1063, Oct 2022. URL: https://doi.org/10.1111/all.15115, doi:10.1111/all.15115. This article has 4 citations and is from a highest quality peer-reviewed journal.

  6. (recke2025statusquoand pages 1-2): Andreas Recke. Status quo and future developments in the diagnosis and treatment of hereditary angioedema. JDDG: Journal der Deutschen Dermatologischen Gesellschaft, 23:1512-1525, Sep 2025. URL: https://doi.org/10.1111/ddg.15889, doi:10.1111/ddg.15889. This article has 0 citations.

  7. (johnson2025unravelingangioedemadiagnostic pages 9-10): Felix Johnson and Benedikt Hofauer. Unraveling angioedema: diagnostic challenges and emerging therapies. Frontiers in Immunology, Oct 2025. URL: https://doi.org/10.3389/fimmu.2025.1681763, doi:10.3389/fimmu.2025.1681763. This article has 3 citations and is from a peer-reviewed journal.

  8. (santacroce2021thegeneticsof pages 8-9): Rosa Santacroce, Giovanna D'Andrea, Angela Bruna Maffione, Maurizio Margaglione, and Maria d'Apolito. The genetics of hereditary angioedema: a review. Journal of Clinical Medicine, 10:2023, May 2021. URL: https://doi.org/10.3390/jcm10092023, doi:10.3390/jcm10092023. This article has 178 citations.

  9. (rozevska2024hereditaryoracquired? pages 2-3): Marija Rozevska, Adine Kanepa, Signe Purina, Linda Gailite, Inga Nartisa, Henriette Farkas, Dmitrijs Rots, and Natalja Kurjane. Hereditary or acquired? comprehensive genetic testing assists in stratifying angioedema patients. Allergy, Asthma, and Clinical Immunology : Official Journal of the Canadian Society of Allergy and Clinical Immunology, Mar 2024. URL: https://doi.org/10.1186/s13223-024-00889-5, doi:10.1186/s13223-024-00889-5. This article has 7 citations.

  10. (gao2025expandingthegenetic pages 1-2): Haiqing Gao, Ying Zhao, Shengan Chen, Zhen Zhang, Fanping Yang, Zihua Chen, Lanting Wang, Jin Yang, Shan He, Chang Tang, Shenyuan Zheng, Chenggong Guan, Yu Xu, Lin Tang, Aiyuan Zhang, Marcus Maurer, Dylan Lee, Li Ma, and Xiaoqun Luo. Expanding the genetic and clinical spectrum of hereditary angioedema with normal c1 inhibitor: novel variants and treatment insights. Journal of Clinical Immunology, Aug 2025. URL: https://doi.org/10.1007/s10875-025-01912-z, doi:10.1007/s10875-025-01912-z. This article has 4 citations and is from a domain leading peer-reviewed journal.

  11. (kariko2026abstractsofthe pages 31-32): PhD Katalin Karikó, S. Thiel, A. Germenis, László Cervenak, F. Marceau, Ahmed Sahli, R. C.-Gaudreault, E. Pardali, H. Horváth, Oliver Domenig, D. V. Oyen, D. Sexton, G. Zahn, A. Lesage, H. Farkas, D. Parolin, S. Berra, Sonia Caccia, J. Gil-Serrano, M. Labrador-Horrillo, P. Galvan-Blasco, A. Sala-Cunill, J. Pereira-González, M. Planas-Vinos, Victoria Cardona, Yingyang Xu, Xiangyi Cui, Zejian Zhang, Yuxiang Zhi, A. S. Pinheiro, Douglas E. Teixiera, R. Silva-Aguiar, A. Merkulova, Y. Skomorovska-Prokvolit, Y. J. Shim, Keith R. McCrae, D. Midem, S. Ogolla, Celso Caruso Neves, A. S. Pinheiro, J. Kazura, A. H. Schmaier, M. Guilarte, A. López-Lera, Ethel Ibáñez-Echevarría, K. Baynova, C. Marcos-Bravo, Eugenia Sanchis-Merino, Gabriela Leon-Zambrana, Patricia Bigas Peñuela, Leah Landaveri-Sánchez, S. Cimbollek, Marta Goyanes-Malumbres, Isora Vidal-Sernandez, Roger Colobran, T. Caballero, M. Barešić, Boris Karanović, D. Vergles, B. Anić, A. Bocquet, David Launay, I. Boccon-Gibod, A. Du-Thanh, D. Gobert, S. Sanges, L. Bouillet, Emel Aygören-Pursun, N. Bara, T. Buttgereit, D. Cohn, S. Kiani-Alikhan, M. Magerl, Johanna M. Mandelin, Marc Riedl, Sinisa Savic, M. Sobotková, M. Stobiecki, A. Zanichelli, D. Gobert, Mélanie Javaud, E. Cohen, O. Fain, Boris Bienvenu, E. Aygören‐Pürsün, Mona Al-Ahmad, A. Recke, K. Hartmann, Maureen Watt, Daniel Nova Estepan, Irmgard Andresen, Natalie Khutoryansky, Aharon Kessel, M. Cancian, H. Longhurst, Paul K Keith, Harsha Shetty, M. Pollen, H. Feuersenger, J. Bernstein, A. Banerji, J. Jacobs, Allen P. Kaplan, James S. Butler, David Maag, Catherine Miller, Jonathan Phillips, I. Guryanova, A. V. Liubushkin, E. Polyakova, A. Salivonchik, V. Vertelko, M. Belevtsev, A. Solntsava, A. Valerieva, Alex Fam, Ferhat Maksudov, E. Petkova, Teresa De Aramburu, J. Lucena, M. Staevska, W. Lumry, John Anderson, Henry Li, James Hao, Michael Smith8, P. Bajcic, P. Audhya, Teresa De, Aramburu Mera, J. Raúl, G. Lozano, J. Manuel, L. Soto, F. Perego, A. C. Marcelli, R. Senter, Federica Ruin, L. Zingale, A. Gidaro, V. P. Janu, F. Arcoleo, P. Accardo, Mariangela Lo Pizzo, Giada De Angeli, F. Giardino, E. Cataudella, A. Vultaggio, A. Matucci, A. Petraroli, Roberta Gatti, Giuseppe Spadaro, Luisa Brussino, Stefania Nicola, Luca Lo Sardo, M. Guarino, Helena Jakopič, M. Košnik, M. Zidarn, J. Šelb, Peter Korošec, and M. Rijavec. Abstracts of the 14th c1-inhibitor deficiency and angioedema workshop. Allergy, Asthma & Clinical Immunology, Jan 2026. URL: https://doi.org/10.1186/s13223-025-00992-1, doi:10.1186/s13223-025-00992-1. This article has 1 citations.

  12. (jiang2024uncoveringanovel pages 1-2): Lingxi Jiang, Chao Dai, Suyang Duan, Tingting Wang, Chunbao Xie, Luhan Zhang, Zimeng Ye, Xiumei Ma, and Yi Shi. Uncovering a novel serping1 pathogenic variant: insights into the aggregation of c1-inh in hereditary angioedema. Orphanet Journal of Rare Diseases, Sep 2024. URL: https://doi.org/10.1186/s13023-024-03306-7, doi:10.1186/s13023-024-03306-7. This article has 5 citations and is from a peer-reviewed journal.

  13. (ariasflorez2024phenotypicandmolecular pages 13-14): Juan Sebastian Arias-Flórez, Sandra Ximena Ramirez, Bibiana Bayona-Gomez, Lina Castro-Castillo, Valeria Correa-Martinez, Yasmín Sanchez-Gomez, William Usaquén-Martínez, Lilian Andrea Casas-Vargas, Carlos Eduardo Olmos Olmos, Nora Contreras Bravo, Camilo Andres Velandia-Piedrahita, Adrien Morel, Rodrigo Cabrera-Perez, Natalia Santiago-Tovar, Cristian Camilo Gaviria-Sabogal, Ingrid Tatyana Bernal, Dora Janeth Fonseca-Mendoza, and Carlos M. Restrepo. Phenotypic and molecular characterization of the largest worldwide cluster of hereditary angioedema type 1. PLOS ONE, 19:e0311316, Dec 2024. URL: https://doi.org/10.1371/journal.pone.0311316, doi:10.1371/journal.pone.0311316. This article has 1 citations and is from a peer-reviewed journal.

  14. (zhao2026advancesinhereditary pages 1-2): Ye Zhao and Duowu Zou. Advances in hereditary angioedema in the modern treatment era in china: a focus on diagnosis, treatment, and prognosis. Orphanet Journal of Rare Diseases, Mar 2026. URL: https://doi.org/10.1186/s13023-026-04314-5, doi:10.1186/s13023-026-04314-5. This article has 0 citations and is from a peer-reviewed journal.

  15. (recke2025statusquoand pages 13-14): Andreas Recke. Status quo and future developments in the diagnosis and treatment of hereditary angioedema. JDDG: Journal der Deutschen Dermatologischen Gesellschaft, 23:1512-1525, Sep 2025. URL: https://doi.org/10.1111/ddg.15889, doi:10.1111/ddg.15889. This article has 0 citations.

Artifacts

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.