View source for Hereditary angioedema

{{Short description|Disorder resulting in severe swelling}}
{{More medical citations needed|date=September 2024}}
{{Use dmy dates|date=July 2025}}
{{cs1 config |name-list-style=vanc |display-authors=6}}
{{Infobox medical condition
| name = Hereditary angioedema (HAE)
| synonyms = Hereditary angioneurotic edema (HANE),<ref name=GARD2017/> familial angioneurotic edema<ref name=Orpha211/>
| image = Swollen hand during a hereditary angioedema attack..jpg
| caption = Swollen right hand during a hereditary angioedema attack.
| field = [[Hematology]]
| symptoms = Recurrent attacks of [[angioedema|severe swelling]]<ref name=GHR2017/>
| complications = 
| onset = Childhood<ref name=GHR2017/>
| duration = Attacks last a few days (without treatment)<ref name=GHR2017/>
| types = Type I, II, III<ref name=GHR2017/>
| causes = [[Genetic disorder]] ([[autosomal dominant]])<ref name=GHR2017/>
| diagnosis = Measuring [[Complement component 4|C4]] and [[C1-inhibitor]] levels.<ref name=Orpha211/>
| differential = [[Intestinal obstruction]], other types of [[angioedema]]<ref name=Orpha211/>
| prevention = [[plasma kallikrein]] inhibitors, [[C1 inhibitor]] concentrates<ref name=GARD2017/>
| treatment = [[Supportive care]], medications<ref name=GARD2017/>
| medication = [[C1 inhibitor]], [[ecallantide]], [[icatibant]], [[sebetralstat]]<ref name=GARD2017/>
| prognosis = 25% risk of death if airway involved (without treatment)<ref name=Orpha211/>
| frequency = ~1 in 50,000<ref name=GHR2017/>
| deaths = 
}}

<!-- Definition and symptoms -->
'''Hereditary angioedema''' ('''HAE''') is a rare disease that results in recurrent attacks of [[angioedema|severe swelling]].<ref name=GHR2017>{{cite web|last1=Reference|first1=Genetics Home|title=hereditary angioedema|url=https://medlineplus.gov/genetics/condition/hereditary-angioedema/|website=Genetics Home Reference|access-date=10 July 2017 |date=5 July 2017|url-status=live|archive-url=https://web.archive.org/web/20170710111932/https://ghr.nlm.nih.gov/condition/hereditary-angioedema|archive-date=10 July 2017}}</ref> HAE affects approximately 1 in 50,000 people.<ref name="GHR2017" /> The condition is typically first noticed in childhood.<ref name="GHR2017" />

The swelling most commonly affects the arms, legs, face, intestinal tract, and airway.<ref name="GHR2017" /> If the intestinal tract is affected, [[abdominal pain]] and [[vomiting]] may occur.<ref name="GARD2017">{{cite web|title=Hereditary angioedema|url=https://rarediseases.info.nih.gov/diseases/5979/hereditary-angioedema|website=GARD|access-date=10 July 2017 |date=2017|url-status=live|archive-url=https://web.archive.org/web/20170704170150/https://rarediseases.info.nih.gov/diseases/5979/hereditary-angioedema|archive-date=4 July 2017}}</ref> Swelling of the airway can result in its obstruction and can cause trouble breathing.<ref name="GARD2017" /> Without treatment, this can cause a risk of death in about 25% of people.<ref name="Orpha211">{{cite web |date=August 2011 |title=Orphanet: Hereditary angioedema |url=http://www.orpha.net/consor/cgi-bin/Disease_Search.php?lng=EN&data_id=12136&Disease_Disease_Search_diseaseGroup=Hereditary-angioedema&Disease_Disease_Search_diseaseType=Pat&Disease(s)/group%20of%20diseases=Hereditary-angioedema&title=Hereditary-angioedema&search=Disease_Search_Simple |url-status=live |archive-url=https://web.archive.org/web/20151009223639/http://www.orpha.net/consor/cgi-bin/Disease_Search.php?lng=EN&data_id=12136&Disease_Disease_Search_diseaseGroup=hereditary-angioedema&Disease_Disease_Search_diseaseType=Pat&Disease%28s%29%2Fgroup%20of%20diseases=Hereditary-angioedema&title=Hereditary-angioedema&search=Disease_Search_Simple |archive-date=9 October 2015 |access-date=10 July 2017 |website=www.orpha.net}}</ref> With treatment, outcomes are generally good.<ref name="Orpha211" /> Without [[prophylaxis|preventive treatment]], attacks typically occur every two weeks and last for a few days.<ref name="GHR2017" />

<!-- Cause and diagnosis -->
There are three main types of HAE.<ref name="GHR2017" /> Types I and II are caused by a mutation in the ''[[SERPING1]]'' gene, which encodes the C1 inhibitor protein, and type III, now called HAE with normal C1 inhibitor (HAE-nl-C1INH).<ref name=":0" /> Types I and II affect females and males equally,<ref name="NORD2008">{{cite web |date=2008 |title=Hereditary Angioedema - NORD (National Organization for Rare Disorders) |url=https://rarediseases.org/rare-diseases/hereditary-angioedema/ |url-status=live |archive-url=https://web.archive.org/web/20170714223915/https://rarediseases.org/rare-diseases/hereditary-angioedema/ |archive-date=14 July 2017 |access-date=10 July 2017 |website=NORD (National Organization for Rare Disorders)}}</ref> while HAE with normal C1 inhibitor affects females more often than males.<ref name="Orpha211" />

Six known mutations are described in the literature under HAE with normal C1 inhibitor.<ref name=":0">{{Cite journal |last1=Smith |first1=Tukisa D. |last2=Riedl |first2=Marc A. |date=October 2024 |title=The future of therapeutic options for hereditary angioedema |url=https://linkinghub.elsevier.com/retrieve/pii/S1081120624002758 |journal=Annals of Allergy, Asthma & Immunology |volume=133 |issue=4 |pages=380–390 |doi=10.1016/j.anai.2024.04.029|pmid=38679158 |url-access=subscription }}</ref> The result is increased levels of [[kallikrein]] activity and [[bradykinin]], which promotes swelling.<ref name="GHR2017" /> The condition may be inherited in an [[autosomal dominant]] manner or occur as a spontaneous mutation.<ref name="GHR2017" />

Known common HAE triggers are:<ref>{{Cite web |title=US Hereditary Angioedema Association |url=https://www.haea.org/pages/p/what_is_hae#triggers |access-date=2025-07-24 |website=www.haea.org }}</ref>

* Stress
* Minor trauma
* Anxiety
* Surgery
* Ailments such as colds/flu/other viral infections

People with HAE have also reported exposure to cold and activities that cause mechanical trauma (gardening, hammering, shoveling) can also be triggers.<ref>{{Cite web |date=2022-07-04 |title=Attack Triggers |url=https://haei.org/what-is-hae/attack-triggers/ |access-date=2025-07-24 |website=HAE International (HAEi) }}</ref> Attacks can often occur without any obvious preceding events or a known trigger.<ref name="GHR2017" />

Diagnosis of HAE types I and II is based on measurement of [[Complement component 4|C4]] and C1-inhibitor levels or genetic testing.<ref>{{Cite web |date=2015-04-16 |title=Diagnosis |url=https://haei.org/what-is-hae/diagnosis/ |access-date=2025-07-24 |website=HAE International (HAEi) }}</ref>

<!-- Prevention and treatment -->
Management of HAE involves efforts to prevent attacks and the treatment of attacks if they occur.<ref name="GARD2017" /> During an attack, [[supportive care]] such as [[intravenous fluids]] and airway support may be required.<ref name="GARD2017" /> Preventative treatments include C1-inhibitor concentrates and [[plasma kallikrein]] inhibitors.<ref name="GARD2017" /> Acute treatment options include C1-inhibitor concentrates, bradykinin receptor antagonists like [[icatibant]], and plasma kallikrein inhibitors such as [[ecallantide]] and [[sebetralstat]].<ref>{{Cite web |date=2022-03-04 |title=How can HAE be treated? |url=https://haei.org/what-is-hae/treatment/ |access-date=2025-07-24 |website=HAE International (HAEi) }}</ref>

<!-- Epidemiology, porgnosis, and history -->
The condition was first described in 1888 by Canadian physician [[William Osler]].<ref>{{cite book |last1=Levin |first1=Alex V. |url=https://books.google.com/books?id=AvIoDwAAQBAJ&pg=PA71 |title=The Eye in Pediatric Systemic Disease |last2=Enzenauer |first2=Robert W. |date=2017 |publisher=Springer |isbn=978-3-319-18389-3 |page=71 |archive-url=https://web.archive.org/web/20170910173937/https://books.google.ca/books?id=AvIoDwAAQBAJ&pg=PA71 |archive-date=10 September 2017 |url-status=live}}</ref>

==Signs and symptoms==
People diagnosed with hereditary angioedema have recurrent swelling in the extremities, [[genitals]], [[face]], [[lip]]s, [[larynx]] or [[Gi tract|GI tract]].<ref name="Busse2020">{{cite journal| author=Busse PJ, Christiansen SC| title=Hereditary Angioedema. | journal=N Engl J Med | year= 2020 | volume= 382 | issue= 12 | pages= 1136–1148 | pmid=32187470 | doi=10.1056/NEJMra1808012 | pmc= | s2cid=214584080 }}</ref>

Swelling involving the respiratory and gastrointestinal systems can cause significant risk and distress. Involvement of respiratory structures, such as the throat or larynx, can cause difficulties in breathing and life-threatening airway obstruction.<ref name="Busse2020" /><ref name="Nzeako2001">{{cite journal | vauthors = Nzeako UC, Frigas E, Tremaine WJ | title = Hereditary angioedema: a broad review for clinicians | journal = Arch Intern Med | volume = 161 | issue = 20 | pages = 2417–29 | date = November 2001 | pmid = 11700154 | doi = 10.1001/archinte.161.20.2417 }}</ref> Episodes that attack the gastrointestinal tract can cause a number of complications including vomiting, crampy abdominal pain, diarrhea, and dehydration.<ref name="Nzeako2001" />

Some people may experience [[prodromal]] symptoms, including tingling, fatigue or weakness at the site of impending edema with one third of people experiencing an erythematous rash ([[erythema marginatum]]) as the prodromal symptom.<ref name="Busse2020" /> [[Urticaria]] is usually not seen in hereditary angioedema, as compared to other causes of angioedema such as histamine induced symptoms.<ref name="Busse2020" />

== Genetics ==
Because HAE is an [[autosomal dominant]] disease, there is no sex difference in transmission and both sexes are equally likely to receive the mutated gene from their parents. The autosomal dominant inheritance pattern with regards to hereditary angioedema requires receipt of only one copy of the mutated C1 inhibitor gene to have symptomatic disease.<ref name="pmid21623829">{{cite journal | vauthors = Ferraro MF, Moreno AS, Castelli EC, Donadi EA, Palma MS, Arcuri HA, Lange AP, Bork K, Sarti W, Arruda LK | title = A single nucleotide deletion at the C1 inhibitor gene as the cause of hereditary angioedema: insights from a Brazilian family | journal = Allergy | volume = 66 | issue = 10 | pages = 1384–90 | date = October 2011 | pmid = 21623829 | doi = 10.1111/j.1398-9995.2011.02658.x | s2cid = 23036731 }}</ref><ref name="pmid24456027">{{cite journal | vauthors = Bafunno V, Bova M, Loffredo S, Divella C, Petraroli A, Marone G, Montinaro V, Margaglione M, Triggiani M | title = Mutational spectrum of the c1 inhibitor gene in a cohort of Italian patients with hereditary angioedema: description of nine novel mutations | journal = Ann Hum Genet | volume = 78 | issue = 2 | pages = 73–82 | date = March 2014 | pmid = 24456027 | doi = 10.1111/ahg.12052 | doi-access = free }}</ref><ref name="pmid16835976">{{cite journal | vauthors = Weiler CR, van Dellen RG | title = Genetic test indications and interpretations in patients with hereditary angioedema | journal = Mayo Clin Proc | volume = 81 | issue = 7 | pages = 958–72 | date = July 2006 | pmid = 16835976 | doi = 10.4065/81.7.958 }}</ref><ref>{{cite web |url=http://www.bravecommunity.com/patients/conditions/hereditary-angioedema/information/inheritance.aspx |title=Inheritance of Hereditary Angioedema - Patient Information - Shire's Brave Community |access-date=5 May 2014 |archive-url=https://web.archive.org/web/20140506075307/http://www.bravecommunity.com/patients/conditions/hereditary-angioedema/information/inheritance.aspx |archive-date=6 May 2014 }}</ref> Further, hereditary angioedema with C1 inhibitor deficiency types 1 and 2 have complete [[penetrance]], meaning all of those who inherit the dysfunctional gene will have symptomatic disease. However, hereditary angioedema with normal C1 inhibitor levels (Type 3 disease) has incomplete penetrance, and men may be asymptomatic carriers despite inheriting a mutated gene.<ref name="Busse2020" />

With regards to the mutations in the SERPING1 gene that is seen in hereditary angioedema types 1 and 2 (hereditary angioedema with C1 inhibitor deficiency), 75% of the cases are due to an autosomal dominant inheritance of a mutated gene and 25% of cases are due to [[de novo mutations]] of the egg or sperm, or early in embryological development.<ref name="Busse2020" /> Hereditary angioedema type 3 (hereditary angioedema with normal C1 inhibitor levels) is associated with mutations in genes for [[Factor XII]], [[angiopoietin 1]], [[plasminogen]] or [[kininogen 1]].<ref name="Busse2020" />

==Pathophysiology==
The pathophysiologic mechanisms contributing to bradykinin mediated angioedema in hereditary angioedema have been described. C1 inhibitor usually acts as an inhibitor of the [[contact activation system|plasma contact system]], where it inhibits [[plasma kallikrein]], factor XIIa, and factor XIIf. However, in hereditary angioedema with C1 inhibitor deficiency, C1 inhibitor is either reduced in quantity and function (type 1) or dysfunctional (type 2), this leads to bradykinin disinhibition and bradykinin mediated activation of [[bradykinin receptor B1|bradykinin B1 receptor]] and [[bradykinin receptor B2|bradykinin B2 receptor]] on [[endothelial]] cells (cells lining blood vessels).<ref name="Busse2020" /> This activation leads to vascular endothelial [[cadherin]] (a type of cell adhesion molecule) phosphorylation, internalization and degradation. Cadherin degradation leads to [[actin cytoskeleton]] contraction and increased pore size of the vascular endothelial cells. [[Adherens junctions]] are also reduced due to bradykinin B1 and B2 receptor activation and [[vascular endothelial growth factor]] (VEGF) is also activated. The degradation of these endothelial intercellular barrier junctions mediated by histamine leads to increased vascular permeability, leading to vascular leakage into surrounding tissues and thus causing the characteristic swelling seen in hereditary angioedema.<ref name="Busse2020" /> The bradykinin B1 receptor (unlike the B2 receptor) is slowly and only partially [[homologous desensitization|desensitized]] after binding the bradykinin agonist, thus remaining constitutively active long after initial bradykinin exposure which can explain the protracted swelling seen in hereditary angioedema as compared to other causes of angioedema.<ref name="Busse2020" />

==Diagnosis==
{{Complement test comparisons|align=right}}
Recognizing HAE is often difficult due to the wide variability in disease expression, with the diagnosis often delayed for years.<ref name="Busse2020" /> The course of the disease is diverse and unpredictable, even within a single patient over their lifetime. This disease may be similar in its presentation to other forms of angioedema resulting from allergies or other medical conditions, but it is significantly different in cause and treatment. When HAE is misdiagnosed as an allergy it is most commonly treated with steroids, epinephrine or anti-histamines, drugs that are usually ineffective in treating a HAE episode.<ref name="Busse2020" /> Other misdiagnoses have resulted in unnecessary exploratory surgery for patients with abdominal swelling and other HAE patients report that their abdominal pain was wrongly diagnosed as psychosomatic or [[malingering]].<ref name="Busse2020" />

HAE accounts for only a small fraction of all cases of angioedema. To avoid potentially fatal consequences such as upper airway obstruction and unnecessary abdominal surgery, the importance of a correct diagnosis cannot be overemphasized.<ref>{{cite web |url=http://caep.ca/sites/caep.ca/files/caep/files/2012_conference_-_management_of_angioedema_in_the_er.pdf |title=Management of angioedema in the ER |access-date=3 November 2014 |archive-url=https://web.archive.org/web/20141103170445/http://caep.ca/sites/caep.ca/files/caep/files/2012_conference_-_management_of_angioedema_in_the_er.pdf |archive-date=3 November 2014 }}</ref>

==Types==
There are three types of hereditary angioedema (HAE). HAE types I and II are both caused by a deficiency of complement C1-inhibitor (C1-INH), a plasma protein that is an important inhibitor of several serine proteases, specially of the complement system and the contact activation/kallikrein-kinin pathway, but also the fibrinolytic system.<ref>{{cite journal | vauthors = Donaldson VH, Evans RR | title = A biochemical abnormality in hereditary angioneurotic edema: Absence of serum inhibitor of C' 1-esterase | journal = Am. J. Med. | volume = 35 | issue = 1 | pages = 37–44 | date = July 1963 | pmid = 14046003 | doi = 10.1016/0002-9343(63)90162-1 | publisher = The American Journal of Medicine }}</ref><ref>{{cite journal | vauthors = Rosen FS, Pensky J, Donaldson V, Charache P | title = Hereditary angioneurotic edema: Two genetic variants | journal = Science | volume = 148 | issue = 3672 | pages = 957–958 | date = 14 May 1965 | pmid = 14277836 | doi = 10.1126/science.148.3672.957 | bibcode = 1965Sci...148..957R | s2cid = 32776518 }}</ref><ref name="carugati">{{cite journal | vauthors = Carugati A, Pappalardo E, Zingale LC, Cicardi M | title = C1-inhibitor deficiency and angioedema | journal = Mol. Immunol. | volume = 38 | issue = 2–3 | pages = 161–173 | date = August 2001 | pmid = 11532278 | doi = 10.1016/s0161-5890(01)00040-2 | publisher = Molecular Immunology }}</ref>

In HAE type I, there is a quantitative C1-inhibitor deficiency, antigenic as well as functional C1-inhibitor levels in plasma are decreased. This type accounts for approximately 85% of HAE cases with C1-inhibitor deficiency.<ref name="Busse2020" />

In HAE type II, there is a qualitative deficiency, with normal - sometimes even elevated - C1-inhibitor protein levels, but decreased functional C1-inhibitor measurements. This type is seen in approximately 15% of HAE cases with C1-inhibitor deficiency.<ref name="carugati" /><ref name="ponard">{{cite journal | vauthors = Ponard D, Gaboriaud C, Charignon D, Ghannam A, ((Wagenaar-Bos IGA)), Roem D, López-Lera A, López-Trascasa M, Tosi M, Drouet C | title = SERPING1 mutation update: Mutation spectrum and C1 Inhibitor phenotypes | journal = Hum. Mutat. | volume = 41 | issue = 1 | pages = 38–57 | date = January 2020 | pmid = 31517426 | doi = 10.1002/humu.23917 | publisher = Human Mutation | doi-access = free }}</ref>

C1-inhibitor deficiency is caused by mutations of the SERPING1 gene, the gene encoding complement C1-inhibitor. More than 700 different mutations have been described.<ref name="ponard" /> The SERPING1 gene shows a considerable tendency for de novo mutations. As a result, it is not uncommon to observe patients with primary recurrent angioedema attacks and C1-inhibitor deficiency where both parents are unaffected.<ref>{{cite journal | vauthors = Pappalardo E, Cicardi M, Duponchel C, Carugati A, Choquet S, Agostoni A, Tosi M | title = Frequent de novo mutations and exon deletions in the C1inhibitor gene of patients with angioedema | journal = J. Allergy Clin. Immunol. | volume = 106 | issue = 6 | pages = 1147–1154 | date = December 2000 | pmid = 11112899 | doi = 10.1067/mai.2000.110471 | publisher = The Journal of Allergy and Clinical Immunology | doi-access = free }}</ref>

Another type of hereditary angioedema, originally named HAE type III, has been observed.<ref>{{cite journal | vauthors = Bork K, Barnstedt SE, Koch P, Traupe H | title = Hereditary angioedema with normal C1-inhibitor activity in women | journal = Lancet | volume = 356 | issue = 9225 | pages = 213–217 | date = 15 July 2000 | pmid = 10963200 | doi = 10.1016/S0140-6736(00)02483-1 | publisher = The Lancet | s2cid = 30105665 }}</ref><ref name="banday">{{cite journal | vauthors = Banday AZ, Kaur A, Jindal AK, Rawat A, Singh S | title = An update on the genetics and pathogenesis of hereditary angioedema | journal = Genes Dis. | volume = 7 | issue = 1 | pages = 75–83 | date = March 2020 | pmid = 32181278 | pmc = 7063419 | doi = 10.1016/j.gendis.2019.07.002 | publisher = Genes & Diseases | doi-access = free }}</ref><ref name="jones">{{cite journal | vauthors = Jones D, Zafra H, Anderson J | title = Managing Diagnosis, Treatment, and Burden of Disease in Hereditary Angioedema Patients with Normal C1-Esterase Inhibitor | journal = J Asthma Allergy | volume = 16 | pages = 447–460 | date = 22 April 2023 | pmid = 37124440 | pmc = 10132308 | doi = 10.2147/JAA.S398333 | publisher = Journal of Asthma and Allergy | doi-access = free }}</ref> In contrast to HAE types I and II, this type of the disease is characterized by normal C1-inhibitor measurements. Thus, the term "hereditary angioedema with normal C1-inhibitor" is now generally used for this HAE type. Normal C1 inhibitor level hereditary angioedema is thought to involve various mutations that increased bradykinin activity and cause a decreased threshold for activation of the plasma contact system thus leading to the symptoms of angioedema.<ref name="Busse2020" />

Hereditary angioedema with normal C1-inhibitor is a genetically heterogeneous disorder. Several molecular subtypes have been identified. A first subtype, identified in 2006, is caused by mutations of the F12 gene encoding coagulation factor XII (also known as Hageman factor).<ref name="dewald">{{cite journal | vauthors = Dewald G, Bork K | title = Missense mutations in the coagulation factor XII (Hageman factor) gene in hereditary angioedema with normal C1 inhibitor | journal = Biochem. Biophys. Res. Commun. | volume = 343 | issue = 4 | pages = 1286–1289 | date = 19 May 2006 | pmid = 16638441 | doi = 10.1016/j.bbrc.2006.03.092 | publisher = Biochemical-and-Biophysical-Research-Communications | bibcode = 2006BBRC..343.1286D }}</ref><ref name="santacroce">{{cite journal | vauthors = Santacroce R, D'Andrea G, Maffione AB, Margaglione M, d'Apolito M | title = The Genetics of Hereditary Angioedema: A Review | journal = J. Clin. Med. | volume = 10 | issue = 9 | page = 2023 | date = 9 May 2021 | pmid = 34065094 | pmc = 8125999 | doi = 10.3390/jcm10092023 | publisher = Journal of Clinical Medicine | doi-access = free }}</ref> All four mutations known so far, the two originally described missense mutations in exon 9 as well as the two additional, very rare mutations described later, affect the proline-rich region of coagulation factor XII.<ref name="dewald" /><ref name="santacroce" /><ref name="banday" /> An accelerated activation of the kallikrein-kinin system appears to represent the pathomechanism through that the F12 mutations cause angioedema.<ref>{{cite journal | vauthors = Shamanaev A, Dickeson SK, Ivanov I, Litvak M, Sun MF, Kumar S, Cheng Q, Srivastava P, He TZ, Gailani D | title = Mechanisms involved in hereditary angioedema with normal C1-inhibitor activity | journal = Front. Physiol. | volume = 14 | article-number = 1146834 | date = 23 May 2023 | pmid = 37288434 | pmc = 10242079 | doi = 10.3389/fphys.2023.1146834 | publisher = Frontiers in Physiology | doi-access = free }}</ref>

Clinical manifestation of hereditary angioedema due to a F12 mutation occurs preferably, but not exclusively in female mutation carriers. The remarkable estrogen-sensitivity is a characteristic feature of the HAE type caused by a F12 mutation. For example, estrogen-containing oral contraceptives play an important role in triggering angioedema attacks. Exacerbation of symptoms during pregnancy is also a common observation.<ref>{{cite journal | vauthors = Deroux A, Boccon-Gibod I, Fain O, Pralong P, Ollivier Y, Pagnier A, Djenouhat K, Du-Thanh A, Gompel A, Faisant C, Launay D, Bouillet L | title = Hereditary angioedema with normal C1 inhibitor and factor XII mutation: a series of 57 patients from the French National Center of Reference for Angioedema | journal = Clin. Exp. Immunol. | volume = 185 | issue = 3 | pages = 332–337 | date = September 2016 | pmid = 27271546 | pmc = 4991515 | doi = 10.1111/cei.12820 | publisher = Clinical & Experimental Immunology | doi-access = free }}</ref><ref name="jones" /> Hereditary angioedema due to Factor XII dysfunction is the most common subtype of type III angioedema.<ref name="Busse2020" />

A second molecular subtype of HAE with normal C1-inhibitor is caused by a mutation of the plasminogen gene, namely a rare missense mutation within the kringle 3 domain of plasminogen, resulting in a novel type of dysplasminogenemia.<ref name="dewald1">{{cite journal | vauthors = Dewald G | title = A missense mutation in the plasminogen gene, within the plasminogen kringle 3 domain, in hereditary angioedema with normal C1 inhibitor | journal = Biochem Biophys Res Commun | volume = 498 | issue = 1 | pages = 193–198 | date = 25 March 2018 | pmid = 29548426 | doi = 10.1016/j.bbrc.2017.12.060 | publisher = Biochemical-and-Biophysical-Research-Communications | bibcode = 2018BBRC..498..193D }}</ref> The mutation creates a new lysine-binding site within the kringle 3 domain and alters the glycosylation of plasminogen.<ref name="dewald1" /> The mutant plasminogen protein has been shown to be a highly efficient kininogenase that directly releases bradykinin from high- and low-molecular-weight kininogen.<ref>{{cite journal | vauthors = Dickeson SK, Kumar S, Sun MF, Mohammed BM, Phillips DR, Whisstock JC, Quek AJ, Feener EP, ((Law RHP)), Gailani D | title = A mechanism for hereditary angioedema caused by a lysine 311-to-glutamic acid substitution in plasminogen | journal = Blood. | volume = 139 | issue = 18 | pages = 2816–2829 | date = 5 May 2022 | pmid = 35100351 | pmc = 9074402 | doi = 10.1182/blood.2021012945 | publisher = Blood | doi-access = free }}</ref> Tongue swellings are a very frequent and characterizing symptom in patients with hereditary angioedema due to a plasminogen mutation.<ref name="dewald1" /><ref name="jones" />

Very rare observations have suggested that mutations of the following genes may also be responsible for the development of hereditary angioedema with normal C1-inhibitor: angiopoietin 1 [HAE with an angiopoietin 1 (ANGPT1) mutation]; myoferlin [HAE with a myoferlin (MYOF) mutation]; kininogen 1 [HAE with a kininogen 1 (KNG1) mutation]; and heparan sulfate-glucosamine 3-sulfotransferase 6 [HAE with a heparan sulfate-glucosamine 3-sulfotransferase 6 (HS3ST6) mutation].<ref name="santacroce" /><ref name="jones" />

However, for a large proportion of cases with hereditary angioedema with normal C1-inhibitor the genetic cause remains unknown.<ref name="Busse2020" />

==Prevention==
Treatment with [[ACE inhibitors]] is contraindicated in this condition, as these drugs can lead to bradykinin accumulation, which can precipitate disease episodes.<ref name="pmid11299220">{{cite journal |vauthors=Dendorfer A, Wolfrum S, Wagemann M, Qadri F, Dominiak P | title = Pathways of bradykinin degradation in blood and plasma of normotensive and hypertensive rats | journal = Am. J. Physiol. Heart Circ. Physiol. | volume = 280 | issue = 5 | pages = H2182–8 |date=May 2001 | pmid = 11299220 | doi = 10.1152/ajpheart.2001.280.5.H2182 | s2cid = 5898184 }}</ref><ref name="pmid10749699">{{cite journal |vauthors=Kuoppala A, Lindstedt KA, Saarinen J, Kovanen PT, Kokkonen JO | title = Inactivation of bradykinin by angiotensin-converting enzyme and by carboxypeptidase N in human plasma | journal = Am. J. Physiol. Heart Circ. Physiol. | volume = 278 | issue = 4 | pages = H1069–74 |date=April 2000 | pmid = 10749699 | doi = 10.1152/ajpheart.2000.278.4.H1069 | s2cid = 10371501 }}</ref>

===Long-term===
People in whom episodes occur at least once a month or who are at high risk of developing laryngeal edema require long-term prevention. There are several phase III clinical trials addressing HAE prophylaxis and therapy. These have led to the licensing of [[pdC1INH]] in many parts of the world; bradykinin receptor antagonists ([[icatibant]]) in Europe; [[kallikrein]] inhibitors ([[ecallantide]] and [[lanadelumab]]) in the United States; and recombinant C1-INH replacement therapy (rhC1INH; conestat alfa) in Europe. [[Tranexamic acid]] has been shown to be relatively ineffective therapy. [[Danazol]] prophylaxis remains an option but therapeutic agents are now being used more for prophylaxis because of danazol's adverse events.<ref>Hereditary angioedema: beyond international consensus - circa December 2010 - The Canadian Society of Allergy and Clinical Immunology Dr. David McCourtie Lecture</ref>

In 2018, the US [[Food and Drug Administration]] (FDA) approved lanadelumab, an injectable [[monoclonal antibody]], to prevent attacks of HAE types I and II in people twelve years of age and older. Lanadelumab inhibits the plasma enzyme [[kallikrein]], which liberates the [[kinin]]s [[bradykinin]] and [[kallidin]] from their [[kininogen]] precursors and is produced in excess in individuals with HAE types I and II.<ref>{{Cite web|url=https://www.drugs.com/newdrugs/fda-approves-takhzyro-lanadelumab-flyo-hereditary-angioedema-4809.html|title=FDA Approves Takhzyro (lanadelumab-flyo) for Hereditary Angioedema|website=Drugs.com}}</ref><ref>{{Cite web|url=https://www.medscape.com/viewarticle/901177|title=FDA OKs New Prophylactic Drug for Rare Hereditary Angioedema|website=Medscape}}</ref>

[[Berotralstat]] (Orladeyo) was approved in the US in December 2020, for the prevention of attacks of hereditary angioedema in people twelve years of age and older.<ref name="FDA snapshot">{{cite web | title=Drug Trials Snapshot: Orladeyo | website=U.S. Food and Drug Administration | date=3 December 2020 | url=https://www.fda.gov/drugs/drug-approvals-and-databases/drug-trials-snapshot-orladeyo | archive-url=https://web.archive.org/web/20201218144319/https://www.fda.gov/drugs/drug-approvals-and-databases/drug-trials-snapshot-orladeyo | archive-date=18 December 2020 | access-date=25 December 2020}} {{PD-notice}}</ref><ref>{{cite web | title=Orladeyo: FDA-Approved Drugs | website=U.S. [[Food and Drug Administration]] (FDA) | url=https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&varApplNo=214094 | access-date=25 December 2020}}</ref>

In February 2023, the FDA approved the expanded use of [[lanadelumab]] ([[Takhzyro]]) to prevent attacks of hereditary angioedema in children aged 2 to 12 years of age.<ref name=":1">{{Cite press release |title=U.S. FDA Approves Takeda's Takhzyro (lanadelumab-flyo) to Prevent Hereditary Angioedema (HAE) Attacks in Children 2 Years of Age and Older |url=https://www.takeda.com/newsroom/newsreleases/2023/us-fda-approves-takedas-takhzyro-lanadelumab-flyo-to-prevent-hereditary-angioedema-hae-attacks-in-children-2-years-of-age-and-older/ |access-date=6 February 2023 |website=Takeda}}</ref>

[[Donidalorsen]] (Dawnzera) was approved for medical use in the US in August 2025, for the prevention of attacks of hereditary angioedema in people twelve years of age and older.<ref>{{cite press release | title=Dawnzera (donidalorsen) approved in the U.S. as first and only RNA-targeted prophylactic treatment for hereditary angioedema | publisher=Ionis Pharmaceuticals | via=Business Wire | date=21 August 2025 | url=https://www.businesswire.com/news/home/20250818615141/en/DAWNZERA-donidalorsen-approved-in-the-U.S.-as-first-and-only-RNA-targeted-prophylactic-treatment-for-hereditary-angioedema | access-date=22 August 2025}}</ref>

===Short-term===
Short-term prevention is normally administered before surgery or dental treatment. In Germany, C1-INH concentrate is used for this and given 1–1.5 hours before the procedure. In countries where C1-inhibitor concentrate is not available or only available in an emergency (laryngeal edema), high-dose androgen treatment is administered for 5–7 days.<ref name="onlinelibrary.wiley.com">{{Cite journal |last1=Xu |first1=Y.-Y. |last2=Buyantseva |first2=L. V. |last3=Agarwal |first3=N. S. |last4=Olivieri |first4=K. |last5=Zhi |first5=Y.-X. |last6=Craig |first6=T. J. |date=April 2013 |title=Update on treatment of hereditary angioedema |url=https://onlinelibrary.wiley.com/doi/10.1111/cea.12080 |journal=Clinical & Experimental Allergy |volume=43 |issue=4 |pages=395–405 |doi=10.1111/cea.12080 |pmid=23517035 |issn=0954-7894|url-access=subscription }}</ref>

==HAE Attack Management==
The aim of acute treatment is to halt progression of the [[edema]] as quickly as possible, which can be life-saving, particularly if the swelling is in the [[larynx]]. Several C1 inhibitor treatments are available in the US and two C1 inhibitor products are available in Canada. Berinert P (CSL Behring), which is pasteurized, was approved by the US FDA in 2009 for acute attacks. Cinryze, which is nanofiltered, was approved by the FDA in 2008 for prophylaxis. Ruconest is a recombinant C1 inhibitor approved in the US and the EU that does not carry the risk of infectious disease transmission due to human blood-borne pathogens.<ref name="Morgan">Morgan</ref>{{Unreliable medical source|date=September 2024}}

[[Sebetralstat]] (Ekterly) was approved for medical use in the United States in July 2025.<ref name="KalVista PR">{{cite press release | title=KalVista Pharmaceuticals Announces FDA Approval of Ekterly (sebetralstat), First and Only Oral On-demand Treatment for Hereditary Angioedema | publisher=Kalvista | via=Business Wire | date=7 July 2025 | url=https://www.businesswire.com/news/home/20250702871458/en/KalVista-Pharmaceuticals-Announces-FDA-Approval-of-EKTERLY-sebetralstat-First-and-Only-Oral-On-demand-Treatment-for-Hereditary-Angioedema | access-date=9 July 2025}}</ref> It is an oral (pill) [[plasma kallikrein]] inhibitor that is for use in people aged twelve years of age and older.<ref name="KalVista PR" />

In Germany, most acute treatment consists of C1 inhibitor concentrate from donor blood, which must be administered intravenously; however, in most European countries, C1 inhibitor concentrate is only available to patients who are participating in special programs. In emergency situations where C1 inhibitor concentrate is not available, [[fresh frozen plasma]] (FFP) can be used as an alternative, as it also contains C1 inhibitor.<ref name="onlinelibrary.wiley.com"/>

Other treatment modalities can stimulate the synthesis of C1 inhibitor, or reduce C1 inhibitor consumption. Purified C1 inhibitor, derived from human blood, has been used in the EU since 1979.<ref name=":1" />

The medication [[ecallantide]] inhibits [[plasma kallikrein]] and was approved by the FDA in the United States for acute attacks in 2009. [[Icatibant]] inhibits the [[bradykinin]] B2 receptor, and was approved in the EU in 2008 and the US in 2011.<ref name="Morgan"/>{{Unreliable medical source|date=September 2024}}<ref name="Firazyr FDA label">{{cite web | title=Firazyr- icatibant acetate injection, solution | website=DailyMed | date=19 January 2024 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=ed6657ca-ab68-477a-9968-e12dc928b540 | access-date=24 September 2024}}</ref><ref>{{Cite press release |last=AG |first=Jerini |date=2008-07-15 |title=Jerini Receives European Commission Approval for Firazyr (Icatibant) in the Treatment of HAE |url=https://www.globenewswire.com/news-release/2008/07/15/381340/5428/en/Jerini-Receives-European-Commission-Approval-for-Firazyr-Icatibant-in-the-Treatment-of-HAE.html |access-date=2025-07-24 |website=GlobeNewswire News Room }}</ref>

== Prognosis ==
About 25% of those affected die in the first two decades of life, mainly due to lack of treatment.<ref>{{Cite journal|last1=Varga|first1=Lilian|last2=Farkas|first2=Henriette|date=1 November 2008|title=Treatment of type I and II hereditary angioedema with Rhucin, a recombinant human C1 inhibitor|journal=Expert Review of Clinical Immunology|volume=4|issue=6|pages=653–661|doi=10.1586/1744666X.4.6.653|pmid=20477114|s2cid=11656834|issn=1744-666X}}</ref> In an Italian study, people with HAE had an average life expectancy like that of the general population.<ref>{{Cite journal |last1=Perego |first1=Francesca |last2=Gidaro |first2=Antonio |last3=Zanichelli |first3=Andrea |last4=Cancian |first4=Mauro |last5=Arcoleo |first5=Francesco |last6=Senter |first6=Riccardo |last7=Bova |first7=Maria |last8=Pasquale |first8=Tiziana De |last9=Guarino |first9=Maria Domenica |last10=Pizzo |first10=Mariangela Lo |last11=Frigerio |first11=Chiara |last12=Duca |first12=Pier Giorgio |last13=Cicardi |first13=Marco |date=2020-05-01 |title=Life expectancy in Italian patients with hereditary angioedema due to C1-inhibitor deficiency |url=https://www.jaci-inpractice.org/article/S2213-2198(20)30046-5/fulltext |journal=The Journal of Allergy and Clinical Immunology: In Practice |volume=8 |issue=5 |pages=1772–1774 |doi=10.1016/j.jaip.2020.01.007 |issn=2213-2198 |pmid=31954853|doi-access=free }}</ref>

==Epidemiology==
Data regarding the [[epidemiology]] of angioedema is limited. The incidence of HAE is one in 50,000 worldwide.<ref name="GHR2017" /> Mortality rates are estimated at 15–33%, resulting primarily from laryngeal edema and asphyxiation. HAE leads to 15,000–30,000 emergency department visits per year.<ref>From the: Pinnacle Health System, Harrisburg Hospital, Department of Internal Medicine, 111 South Front Street, Harrisburg, PA 17101, Update on treatment for her</ref><ref>"Update on treatment of hereditary angioedema" Buyantseva, Larisa, Sardana, Niti and Craig, Timothy</ref>

==Society and culture==
There are national associations for HAE patients and their families in a number of countries around the world. Many of these national associations are members of the global organization Hereditary Angioedema International (HAEI). HAEI raises awareness about hereditary angioedema as well as facilitating coordination of research regarding the condition.<ref>{{cite web |title=HAEi website |url=http://www.haei.org/ |archive-url=https://web.archive.org/web/20170908170738/http://haei.org/ |archive-date=8 September 2017 |access-date=10 September 2017 }}</ref>

The US Hereditary Angioedema Association (HAEA) is a non-profit advocacy organization serving people with HAE and their caregivers. The association is a community of people affected by HAE and their loved ones who are leading the fight in HAE research, advocacy, and finding a cure. Through a passionate commitment to the HAE community, the HAEA offers a wide variety of services and resources that further HAE education, clinical research, community engagement, access to medications, personalized support networks, and a wide range of services to help people living with HAE lead a normal life.<ref>{{Cite web |title=- HAEA |url=https://www.haea.org/ |access-date=2025-07-24 |website=www.haea.org }}</ref>

Each year on 16 May, the HAEi, the HAEA, and the HAE community raise awareness of HAE with the international HAE day.<ref>{{Cite web |last=Chapman |first=Mary |title=HAE Awareness Day 'Stepping Up' With Activity Challenges, Storytelling |date=5 May 2022 |url=https://angioedemanews.com/2022/05/05/activities-afoot-more-hae-awareness-day-may-16/ |access-date=23 May 2022 }}</ref><ref>{{Cite web |last=Inouye |first=Daniel K. |date=31 January 2012 |title=S.Res.286 - 112th Congress (2011-2012): A resolution recognizing May 16, 2012, as Hereditary Angioedema Awareness Day and expressing the sense of the Senate that more research and treatments are needed for Hereditary Angioedema. |url=http://www.congress.gov/ |access-date=23 May 2022 |website=www.congress.gov}}</ref>

==Research==
Based CRISPR/Cas9 technology, a potential one-time gene editing therapy known as NTLA-2002 is being developed for the treatment of HAE. NTLA-2002 is designed to prevent HAE attacks by inactivating the kallikrein B1 (KLKB1) gene, which encodes for prekallikrein, the kallikrein precursor protein.<ref>{{cite journal | doi=10.1056/NEJMoa2309149 | title=CRISPR-Cas9 in Vivo Gene Editing of KLKB1 for Hereditary Angioedema | date=February 2024 | journal=The New England Journal of Medicine | volume=390 | issue=5 | pages=432–441 | pmid=38294975 | vauthors = Longhurst HJ, Lindsay K, Petersen RS, Fijen LM, Gurugama P, Maag D, Butler JS, Shah MY, Golden A, Xu Y, Boiselle C, Vogel JD, Abdelhady AM, Maitland ML, McKee MD, Seitzer J, Han BW, Soukamneuth S, Leonard J, Sepp-Lorenzino L, Clark ED, Lebwohl D, Cohn DM }}</ref><ref>{{cite web | title=Intellia Therapeutics Announces Initiation of HAELO Phase 3 Study of NTLA-2002, an Investigational In Vivo CRISPR Gene Editing Treatment for Hereditary Angioedema (HAE) | website=Intellia Therapeutics | date=7 October 2024 | url=https://ir.intelliatx.com/news-releases/news-release-details/intellia-therapeutics-announces-initiation-haelo-phase-3-study | access-date=30 September 2025}}</ref>

==References==
{{Reflist}}

== Further reading ==
* {{cite journal |vauthors=Busse PJ, Christiansen SC |title=Hereditary Angioedema |journal=N. Engl. J. Med. |volume=382 |issue=12 |pages=1136–48 |date=March 2020 |pmid=32187470 |doi=10.1056/NEJMra1808012 |s2cid=214584080 }} 
* {{Cite web |last=Cleveland Clinic |date=Mar 31, 2025 |title=Hereditary Angioedema |url=https://my.clevelandclinic.org/health/diseases/hereditary-angioedema}}   
*

== External links ==
* {{Commons category-inline}}

{{Lymphoid and complement immunodeficiency}}
{{Disorders of globin and globulin proteins}}
{{Medical resources
| DiseasesDB = 1821
| ICD10 = {{ICD10|D|84|1|d|80}} ([[ILDS]] D84.110)
| ICD9 = 277.6
| OMIM = 106100
| MedlinePlus = 001456
| eMedicineSubj = article
| eMedicineTopic = 1048994
| MeshID = D054179
| Orphanet = 91378
}}
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