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Angioedema, hereditary, 5(HAE5)

MedGen UID:
1780904
•Concept ID:
C5543508
•
Disease or Syndrome
Synonyms: ANGIOEDEMA, HEREDITARY, 5; HAE5
 
Gene (location): ANGPT1 (8q23.1)
 
Monarch Initiative: MONDO:0030293
OMIM®: 619361

Definition

Hereditary angioedema-5 (HAE5) is an autosomal dominant disorder characterized by localized and self-limiting edema of the subcutaneous or submucosal tissue due to an episodic increase in vascular permeability. Affected individuals have onset of episodic swelling of the face, lips, hands, and abdomen in the second decade of life. Treatment with tranexamic acid may be effective in reducing the severity and frequency of the attacks (summary by Bafunno et al., 2018). For a discussion of genetic heterogeneity of hereditary angioedema, see 106100. [from OMIM]

Clinical features

From HPO
Edema of the dorsum of hands
MedGen UID:
752076
•Concept ID:
C2732374
•
Finding
An abnormal accumulation of fluid beneath the skin on the back of the hands.
See: Feature record | Search on this feature
Swollen lip
MedGen UID:
116100
•Concept ID:
C0240211
•
Sign or Symptom
Enlargement of the lip typically due to fluid buildup or inflammation.
See: Feature record | Search on this feature
Facial edema
MedGen UID:
154241
•Concept ID:
C0542571
•
Pathologic Function
Swelling due to an excessive accumulation of fluid in facial tissues.
See: Feature record | Search on this feature
Angioedema
MedGen UID:
1543
•Concept ID:
C0002994
•
Pathologic Function
Rapid swelling (edema) of the dermis, subcutaneous tissue, mucosa and submucosal tissues of the skin of the face, normally around the mouth, and the mucosa of the mouth and/or throat, as well as the tongue during a period of minutes to several hours. The swelling can also occur elsewhere, typically in the hands. Angioedema is similar to urticaria, but the swelling is subcutaneous rather than on the epidermis.
See: Feature record | Search on this feature
Nail bed hemorrhage
MedGen UID:
830602
•Concept ID:
C0877087
•
Sign or Symptom
Small areas of bleeding (hemorrhage) under the fingernail or toenail.
See: Feature record | Search on this feature
Nailfold capillary tortuosity
MedGen UID:
863168
•Concept ID:
C4014731
•
Finding
An increased number of turns of the blood vessels of the nailfold with a charactereistic winded or twisted appearance of the blood vessels.
See: Feature record | Search on this feature
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Professional guidelines

PubMed

Management of pediatric hereditary angioedema types 1 and 2: A search for international consensus.
Norris M, Ashoor Z, Craig T
Allergy Asthma Proc 2022 Sep 1;43(5):388-396. doi: 10.2500/aap.2022.43.220052. PMID: 36065112
The international WAO/EAACI guideline for the management of hereditary angioedema-The 2021 revision and update.
Maurer M, Magerl M, Betschel S, Aberer W, Ansotegui IJ, Aygören-Pürsün E, Banerji A, Bara NA, Boccon-Gibod I, Bork K, Bouillet L, Boysen HB, Brodszki N, Busse PJ, Bygum A, Caballero T, Cancian M, Castaldo A, Cohn DM, Csuka D, Farkas H, Gompels M, Gower R, Grumach AS, Guidos-Fogelbach G, Hide M, Kang HR, Kaplan AP, Katelaris C, Kiani-Alikhan S, Lei WT, Lockey R, Longhurst H, Lumry WR, MacGinnitie A, Malbran A, Martinez Saguer I, Matta JJ, Nast A, Nguyen D, Nieto-Martinez SA, Pawankar R, Peter J, Porebski G, Prior N, Reshef A, Riedl M, Ritchie B, Rafique Sheikh F, Smith WB, Spaeth PJ, Stobiecki M, Toubi E, Varga LA, Weller K, Zanichelli A, Zhi Y, Zuraw B, Craig T
Allergy 2022 Jul;77(7):1961-1990. Epub 2022 Feb 3 doi: 10.1111/all.15214. PMID: 35006617
European Society for Immunodeficiencies (ESID) and European Reference Network on Rare Primary Immunodeficiency, Autoinflammatory and Autoimmune Diseases (ERN RITA) Complement Guideline: Deficiencies, Diagnosis, and Management.
Brodszki N, Frazer-Abel A, Grumach AS, Kirschfink M, Litzman J, Perez E, Seppänen MRJ, Sullivan KE, Jolles S
J Clin Immunol 2020 May;40(4):576-591. Epub 2020 Feb 17 doi: 10.1007/s10875-020-00754-1. PMID: 32064578Free PMC Article

Recent clinical studies

Etiology

CRISPR-Cas9 In Vivo Gene Editing of KLKB1 for Hereditary Angioedema.
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
N Engl J Med 2024 Feb 1;390(5):432-441. doi: 10.1056/NEJMoa2309149. PMID: 38294975
Interventions for the long-term prevention of hereditary angioedema attacks.
Beard N, Frese M, Smertina E, Mere P, Katelaris C, Mills K
Cochrane Database Syst Rev 2022 Nov 3;11(11):CD013403. doi: 10.1002/14651858.CD013403.pub2. PMID: 36326435Free PMC Article
The international WAO/EAACI guideline for the management of hereditary angioedema-The 2021 revision and update.
Maurer M, Magerl M, Betschel S, Aberer W, Ansotegui IJ, Aygören-Pürsün E, Banerji A, Bara NA, Boccon-Gibod I, Bork K, Bouillet L, Boysen HB, Brodszki N, Busse PJ, Bygum A, Caballero T, Cancian M, Castaldo A, Cohn DM, Csuka D, Farkas H, Gompels M, Gower R, Grumach AS, Guidos-Fogelbach G, Hide M, Kang HR, Kaplan AP, Katelaris C, Kiani-Alikhan S, Lei WT, Lockey R, Longhurst H, Lumry WR, MacGinnitie A, Malbran A, Martinez Saguer I, Matta JJ, Nast A, Nguyen D, Nieto-Martinez SA, Pawankar R, Peter J, Porebski G, Prior N, Reshef A, Riedl M, Ritchie B, Rafique Sheikh F, Smith WB, Spaeth PJ, Stobiecki M, Toubi E, Varga LA, Weller K, Zanichelli A, Zhi Y, Zuraw B, Craig T
Allergy 2022 Jul;77(7):1961-1990. Epub 2022 Feb 3 doi: 10.1111/all.15214. PMID: 35006617
Phlebotonics for venous insufficiency.
Martinez-Zapata MJ, Vernooij RW, Simancas-Racines D, Uriona Tuma SM, Stein AT, Moreno Carriles RMM, Vargas E, Bonfill Cosp X
Cochrane Database Syst Rev 2020 Nov 3;11(11):CD003229. doi: 10.1002/14651858.CD003229.pub4. PMID: 33141449Free PMC Article
Effect of Lanadelumab Compared With Placebo on Prevention of Hereditary Angioedema Attacks: A Randomized Clinical Trial.
Banerji A, Riedl MA, Bernstein JA, Cicardi M, Longhurst HJ, Zuraw BL, Busse PJ, Anderson J, Magerl M, Martinez-Saguer I, Davis-Lorton M, Zanichelli A, Li HH, Craig T, Jacobs J, Johnston DT, Shapiro R, Yang WH, Lumry WR, Manning ME, Schwartz LB, Shennak M, Soteres D, Zaragoza-Urdaz RH, Gierer S, Smith AM, Tachdjian R, Wedner HJ, Hebert J, Rehman SM, Staubach P, Schranz J, Baptista J, Nothaft W, Maurer M; HELP Investigators
JAMA 2018 Nov 27;320(20):2108-2121. doi: 10.1001/jama.2018.16773. PMID: 30480729Free PMC Article

Diagnosis

The international WAO/EAACI guideline for the management of hereditary angioedema-The 2021 revision and update.
Maurer M, Magerl M, Betschel S, Aberer W, Ansotegui IJ, Aygören-Pürsün E, Banerji A, Bara NA, Boccon-Gibod I, Bork K, Bouillet L, Boysen HB, Brodszki N, Busse PJ, Bygum A, Caballero T, Cancian M, Castaldo A, Cohn DM, Csuka D, Farkas H, Gompels M, Gower R, Grumach AS, Guidos-Fogelbach G, Hide M, Kang HR, Kaplan AP, Katelaris C, Kiani-Alikhan S, Lei WT, Lockey R, Longhurst H, Lumry WR, MacGinnitie A, Malbran A, Martinez Saguer I, Matta JJ, Nast A, Nguyen D, Nieto-Martinez SA, Pawankar R, Peter J, Porebski G, Prior N, Reshef A, Riedl M, Ritchie B, Rafique Sheikh F, Smith WB, Spaeth PJ, Stobiecki M, Toubi E, Varga LA, Weller K, Zanichelli A, Zhi Y, Zuraw B, Craig T
Allergy 2022 Jul;77(7):1961-1990. Epub 2022 Feb 3 doi: 10.1111/all.15214. PMID: 35006617
European Society for Immunodeficiencies (ESID) and European Reference Network on Rare Primary Immunodeficiency, Autoinflammatory and Autoimmune Diseases (ERN RITA) Complement Guideline: Deficiencies, Diagnosis, and Management.
Brodszki N, Frazer-Abel A, Grumach AS, Kirschfink M, Litzman J, Perez E, Seppänen MRJ, Sullivan KE, Jolles S
J Clin Immunol 2020 May;40(4):576-591. Epub 2020 Feb 17 doi: 10.1007/s10875-020-00754-1. PMID: 32064578Free PMC Article
Hereditary and acquired angioedema.
Patel G, Pongracic JA
Allergy Asthma Proc 2019 Nov 1;40(6):441-445. doi: 10.2500/aap.2019.40.4267. PMID: 31690390
Hereditary angioedema revisited.
Bellanti JA, Settipane RA
Allergy Asthma Proc 2018 Sep 1;39(5):329-331. doi: 10.2500/aap.2018.39.4169. PMID: 30153885Free PMC Article
Urticaria and angioedema.
Axelrod S, Davis-Lorton M
Mt Sinai J Med 2011 Sep-Oct;78(5):784-802. doi: 10.1002/msj.20288. PMID: 21913206

Therapy

CRISPR-Cas9 In Vivo Gene Editing of KLKB1 for Hereditary Angioedema.
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
N Engl J Med 2024 Feb 1;390(5):432-441. doi: 10.1056/NEJMoa2309149. PMID: 38294975
Interventions for the long-term prevention of hereditary angioedema attacks.
Beard N, Frese M, Smertina E, Mere P, Katelaris C, Mills K
Cochrane Database Syst Rev 2022 Nov 3;11(11):CD013403. doi: 10.1002/14651858.CD013403.pub2. PMID: 36326435Free PMC Article
The international WAO/EAACI guideline for the management of hereditary angioedema-The 2021 revision and update.
Maurer M, Magerl M, Betschel S, Aberer W, Ansotegui IJ, Aygören-Pürsün E, Banerji A, Bara NA, Boccon-Gibod I, Bork K, Bouillet L, Boysen HB, Brodszki N, Busse PJ, Bygum A, Caballero T, Cancian M, Castaldo A, Cohn DM, Csuka D, Farkas H, Gompels M, Gower R, Grumach AS, Guidos-Fogelbach G, Hide M, Kang HR, Kaplan AP, Katelaris C, Kiani-Alikhan S, Lei WT, Lockey R, Longhurst H, Lumry WR, MacGinnitie A, Malbran A, Martinez Saguer I, Matta JJ, Nast A, Nguyen D, Nieto-Martinez SA, Pawankar R, Peter J, Porebski G, Prior N, Reshef A, Riedl M, Ritchie B, Rafique Sheikh F, Smith WB, Spaeth PJ, Stobiecki M, Toubi E, Varga LA, Weller K, Zanichelli A, Zhi Y, Zuraw B, Craig T
Allergy 2022 Jul;77(7):1961-1990. Epub 2022 Feb 3 doi: 10.1111/all.15214. PMID: 35006617
Effect of Lanadelumab Compared With Placebo on Prevention of Hereditary Angioedema Attacks: A Randomized Clinical Trial.
Banerji A, Riedl MA, Bernstein JA, Cicardi M, Longhurst HJ, Zuraw BL, Busse PJ, Anderson J, Magerl M, Martinez-Saguer I, Davis-Lorton M, Zanichelli A, Li HH, Craig T, Jacobs J, Johnston DT, Shapiro R, Yang WH, Lumry WR, Manning ME, Schwartz LB, Shennak M, Soteres D, Zaragoza-Urdaz RH, Gierer S, Smith AM, Tachdjian R, Wedner HJ, Hebert J, Rehman SM, Staubach P, Schranz J, Baptista J, Nothaft W, Maurer M; HELP Investigators
JAMA 2018 Nov 27;320(20):2108-2121. doi: 10.1001/jama.2018.16773. PMID: 30480729Free PMC Article
Bradykinin-mediated angioedema.
Obtułowicz K
Pol Arch Med Wewn 2016;126(1-2):76-85. doi: 10.20452/pamw.3273. PMID: 26842379

Prognosis

COVID-19 and hereditary angioedema: Incidence, outcomes, and mechanistic implications.
Veronez CL, Christiansen SC, Smith TD, Riedl MA, Zuraw BL
Allergy Asthma Proc 2021 Nov 1;42(6):506-514. doi: 10.2500/aap.2021.42.210083. PMID: 34871158Free PMC Article
Hereditary Angioedema with and Without C1-Inhibitor Deficiency in Postmenopausal Women.
Billebeau A, Fain O, Launay D, Boccon-Gibod I, Bouillet L, Gobert D, Plu-Bureau G, Gompel A; French National Reference Center for Hereditary Angioedema (CREAK)
J Clin Immunol 2021 Jan;41(1):163-170. Epub 2020 Oct 31 doi: 10.1007/s10875-020-00902-7. PMID: 33130967
CT Findings of Acute Small-Bowel Entities.
Sugi MD, Menias CO, Lubner MG, Bhalla S, Mellnick VM, Kwon MH, Katz DS
Radiographics 2018 Sep-Oct;38(5):1352-1369. doi: 10.1148/rg.2018170148. PMID: 30207931
Epidemiology of angioedema without wheals in an allergy and immunology center.
Malbrán E, Fernández Romero D, Juri MC, Larrauri BJ, Malbrán A
Medicina (B Aires) 2015;75(5):273-6. PMID: 26502460
Urticaria and angioedema.
Spickett G
J R Coll Physicians Edinb 2014;44(1):50-4. doi: 10.4997/JRCPE.2014.112. PMID: 24995449

Clinical prediction guides

CRISPR-Cas9 In Vivo Gene Editing of KLKB1 for Hereditary Angioedema.
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
N Engl J Med 2024 Feb 1;390(5):432-441. doi: 10.1056/NEJMoa2309149. PMID: 38294975
Efficacy and safety of ligelizumab in adults and adolescents with chronic spontaneous urticaria: results of two phase 3 randomised controlled trials.
Maurer M, Ensina LF, Gimenez-Arnau AM, Sussman G, Hide M, Saini S, Grattan C, Fomina D, Rigopoulos D, Berard F, Canonica GW, Rockmann H, Irani C, Szepietowski JC, Leflein J, Bernstein JA, Peter JG, Kulthanan K, Godse K, Ardusso L, Ukhanova O, Staubach P, Sinclair R, Gogate S, Thomsen SF, Tanus T, Ye YM, Burciu A, Barve A, Modi D, Scosyrev E, Hua E, Letzelter K, Varanasi V, Patekar M, Severin T; PEARL-1 and PEARL-2 trial investigators
Lancet 2024 Jan 13;403(10422):147-159. Epub 2023 Nov 23 doi: 10.1016/S0140-6736(23)01684-7. PMID: 38008109
Long-term lanadelumab treatment improves health-related quality of life in patients with hereditary angioedema.
Lumry WR, Maurer M, Weller K, Riedl MA, Watt M, Yu M, Devercelli G, Meunier J, Banerji A; HELP OLE Study Group
Ann Allergy Asthma Immunol 2023 Jul;131(1):101-108.e3. Epub 2023 Apr 5 doi: 10.1016/j.anai.2023.03.028. PMID: 37028510
Recurrent angioedema in childhood: hereditary angioedema or histaminergic angioedema?
Ocak M, Nain E, Şahiner ÜM, Akin MŞ, Karabiber E, Şekerel BE, Soyer Ö
Pediatr Dermatol 2021 Jan;38(1):143-148. Epub 2020 Dec 4 doi: 10.1111/pde.14467. PMID: 33275322
Hereditary Angioedema with and Without C1-Inhibitor Deficiency in Postmenopausal Women.
Billebeau A, Fain O, Launay D, Boccon-Gibod I, Bouillet L, Gobert D, Plu-Bureau G, Gompel A; French National Reference Center for Hereditary Angioedema (CREAK)
J Clin Immunol 2021 Jan;41(1):163-170. Epub 2020 Oct 31 doi: 10.1007/s10875-020-00902-7. PMID: 33130967

Recent systematic reviews

Interventions for the long-term prevention of hereditary angioedema attacks.
Beard N, Frese M, Smertina E, Mere P, Katelaris C, Mills K
Cochrane Database Syst Rev 2022 Nov 3;11(11):CD013403. doi: 10.1002/14651858.CD013403.pub2. PMID: 36326435Free PMC Article
Phlebotonics for venous insufficiency.
Martinez-Zapata MJ, Vernooij RW, Simancas-Racines D, Uriona Tuma SM, Stein AT, Moreno Carriles RMM, Vargas E, Bonfill Cosp X
Cochrane Database Syst Rev 2020 Nov 3;11(11):CD003229. doi: 10.1002/14651858.CD003229.pub4. PMID: 33141449Free PMC Article
Long-term safety outcomes of prekallikrein (Fletcher factor) deficiency: A systematic literature review of case reports.
Girolami A, Rolland C, Sexton D, Vardi M, Bernstein JA
Allergy Asthma Proc 2020 Jan 17;41(1):10-18. doi: 10.2500/aap.2020.41.190005. PMID: 31888778
Pharmacotherapy for Angiotensin-Converting Enzyme Inhibitor-Induced Angioedema: A Systematic Review.
Lawlor CM, Ananth A, Barton BM, Flowers TC, McCoul ED
Otolaryngol Head Neck Surg 2018 Feb;158(2):232-239. Epub 2017 Nov 7 doi: 10.1177/0194599817737974. PMID: 29112487
Novel Therapies for Angiotensin-Converting Enzyme Inhibitor-Induced Angioedema: A Systematic Review of Current Evidence.
Riha HM, Summers BB, Rivera JV, Van Berkel MA
J Emerg Med 2017 Nov;53(5):662-679. Epub 2017 Sep 20 doi: 10.1016/j.jemermed.2017.05.037. PMID: 28939396

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