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Angioedema, hereditary, 6(HAE6)

MedGen UID:
1785484
•Concept ID:
C5543516
•
Disease or Syndrome
Synonyms: ANGIOEDEMA, HEREDITARY, 6; HAE6
 
Gene (location): KNG1 (3q27.3)
 
Monarch Initiative: MONDO:0023660
OMIM®: 619363

Definition

Hereditary angioedema-6 (HAE6) is an autosomal dominant disorder characterized by onset of episodic subcutaneous and submucosal swelling in adulthood. The face, mouth, and tongue are often affected; some patients have distal limb or abdominal edema. Levels of complement component inhibitor (C1INH; 606860) are normal (summary by Bork et al., 2019). For a discussion of genetic heterogeneity of HAE, 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
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Professional guidelines

PubMed

Isolated angioedema: A review of classification and update on management.
Kesh S, Bernstein JA
Ann Allergy Asthma Immunol 2022 Dec;129(6):692-702. Epub 2022 Aug 19 doi: 10.1016/j.anai.2022.08.003. PMID: 35988876
Current and emerging biologics for the treatment of hereditary angioedema.
Perego F, Wu MA, Valerieva A, Caccia S, Suffritti C, Zanichelli A, Bergamaschini L, Cicardi M
Expert Opin Biol Ther 2019 Jun;19(6):517-526. Epub 2019 Mar 26 doi: 10.1080/14712598.2019.1595581. PMID: 30912460
Icatibant as acute treatment for hereditary angioedema in adults.
Farkas H
Expert Rev Clin Pharmacol 2016 Jun;9(6):779-88. Epub 2016 May 13 doi: 10.1080/17512433.2016.1182425. PMID: 27123689

Recent clinical studies

Etiology

Efficacy and Safety of Donidalorsen for Hereditary Angioedema.
Riedl MA, Tachdjian R, Lumry WR, Craig T, Karakaya G, Gelincik A, Stobiecki M, Jacobs JS, Gokmen NM, Reshef A, Gompels MM, Manning ME, Bordone L, Newman KB, Treadwell S, Wang S, Yarlas A, Cohn DM; OASIS-HAE Team
N Engl J Med 2024 Jul 4;391(1):21-31. Epub 2024 May 31 doi: 10.1056/NEJMoa2402478. PMID: 38819395
Lanadelumab in Patients 2 to Less Than 12 Years Old With Hereditary Angioedema: Results From the Phase 3 SPRING Study.
Maurer M, Lumry WR, Li HH, Aygören-Pürsün E, Busse PJ, Jacobs J, Nurse C, Ahmed MA, Watt M, Yu M; SPRING Investigators
J Allergy Clin Immunol Pract 2024 Jan;12(1):201-211.e6. Epub 2023 Sep 18 doi: 10.1016/j.jaip.2023.09.009. PMID: 37730089
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.
Craig TJ, Reshef A, Li HH, Jacobs JS, Bernstein JA, Farkas H, Yang WH, Stroes ESG, Ohsawa I, Tachdjian R, Manning ME, Lumry WR, Saguer IM, Aygören-Pürsün E, Ritchie B, Sussman GL, Anderson J, Kawahata K, Suzuki Y, Staubach P, Treudler R, Feuersenger H, Glassman F, Jacobs I, Magerl M
Lancet 2023 Apr 1;401(10382):1079-1090. Epub 2023 Feb 28 doi: 10.1016/S0140-6736(23)00350-1. PMID: 36868261
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
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

Hereditary Angioedema: Diagnosis, Clinical Implications, and Pathophysiology.
Sinnathamby ES, Issa PP, Roberts L, Norwood H, Malone K, Vemulapalli H, Ahmadzadeh S, Cornett EM, Shekoohi S, Kaye AD
Adv Ther 2023 Mar;40(3):814-827. Epub 2023 Jan 7 doi: 10.1007/s12325-022-02401-0. PMID: 36609679Free PMC Article
Isolated angioedema: A review of classification and update on management.
Kesh S, Bernstein JA
Ann Allergy Asthma Immunol 2022 Dec;129(6):692-702. Epub 2022 Aug 19 doi: 10.1016/j.anai.2022.08.003. PMID: 35988876
Angioedema as a systemic disease.
Kazandjieva J, Christoff G
Clin Dermatol 2019 Nov-Dec;37(6):636-643. Epub 2019 Aug 1 doi: 10.1016/j.clindermatol.2019.07.035. PMID: 31864442
Idiopathic anaphylaxis.
Guo C, Greenberger PA
Allergy Asthma Proc 2019 Nov 1;40(6):457-461. doi: 10.2500/aap.2019.40.4271. PMID: 31690394
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

Therapy

Efficacy and Safety of Donidalorsen for Hereditary Angioedema.
Riedl MA, Tachdjian R, Lumry WR, Craig T, Karakaya G, Gelincik A, Stobiecki M, Jacobs JS, Gokmen NM, Reshef A, Gompels MM, Manning ME, Bordone L, Newman KB, Treadwell S, Wang S, Yarlas A, Cohn DM; OASIS-HAE Team
N Engl J Med 2024 Jul 4;391(1):21-31. Epub 2024 May 31 doi: 10.1056/NEJMoa2402478. PMID: 38819395
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.
Craig TJ, Reshef A, Li HH, Jacobs JS, Bernstein JA, Farkas H, Yang WH, Stroes ESG, Ohsawa I, Tachdjian R, Manning ME, Lumry WR, Saguer IM, Aygören-Pürsün E, Ritchie B, Sussman GL, Anderson J, Kawahata K, Suzuki Y, Staubach P, Treudler R, Feuersenger H, Glassman F, Jacobs I, Magerl M
Lancet 2023 Apr 1;401(10382):1079-1090. Epub 2023 Feb 28 doi: 10.1016/S0140-6736(23)00350-1. PMID: 36868261
Isolated angioedema: A review of classification and update on management.
Kesh S, Bernstein JA
Ann Allergy Asthma Immunol 2022 Dec;129(6):692-702. Epub 2022 Aug 19 doi: 10.1016/j.anai.2022.08.003. PMID: 35988876
Long-term prevention of hereditary angioedema attacks with lanadelumab: The HELP OLE Study.
Banerji A, Bernstein JA, Johnston DT, Lumry WR, Magerl M, Maurer M, Martinez-Saguer I, Zanichelli A, Hao J, Inhaber N, Yu M, Riedl MA; HELP OLE Investigators
Allergy 2022 Mar;77(3):979-990. Epub 2021 Aug 13 doi: 10.1111/all.15011. PMID: 34287942Free 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

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
Development of the Hereditary Angioedema Rapid Triage Tool.
Betschel S, Avilla E, Kanani A, Kastner M, Keith P, Binkley K, Lacuesta G, Borici-Mazi R, Badiou J, Rowe A, Yang WH, Waserman S
J Allergy Clin Immunol Pract 2020 Jan;8(1):310-317.e3. Epub 2019 Jun 22 doi: 10.1016/j.jaip.2019.05.056. PMID: 31238160
Hereditary angioedema.
Frank MM
Curr Opin Pediatr 2005 Dec;17(6):686-9. doi: 10.1097/01.mop.0000182382.28552.1c. PMID: 16282771
Inherited disorders of complement.
Guenther LC
J Am Acad Dermatol 1983 Dec;9(6):815-39. doi: 10.1016/s0190-9622(83)70195-7. PMID: 6315788
Hereditary angioedema.
Gigli I
J Invest Dermatol 1973 Jun;60(6):516-21. doi: 10.1111/1523-1747.ep12703581. PMID: 4122980

Clinical prediction guides

Efficacy and Safety of Donidalorsen for Hereditary Angioedema.
Riedl MA, Tachdjian R, Lumry WR, Craig T, Karakaya G, Gelincik A, Stobiecki M, Jacobs JS, Gokmen NM, Reshef A, Gompels MM, Manning ME, Bordone L, Newman KB, Treadwell S, Wang S, Yarlas A, Cohn DM; OASIS-HAE Team
N Engl J Med 2024 Jul 4;391(1):21-31. Epub 2024 May 31 doi: 10.1056/NEJMoa2402478. PMID: 38819395
Lanadelumab in Patients 2 to Less Than 12 Years Old With Hereditary Angioedema: Results From the Phase 3 SPRING Study.
Maurer M, Lumry WR, Li HH, Aygören-Pürsün E, Busse PJ, Jacobs J, Nurse C, Ahmed MA, Watt M, Yu M; SPRING Investigators
J Allergy Clin Immunol Pract 2024 Jan;12(1):201-211.e6. Epub 2023 Sep 18 doi: 10.1016/j.jaip.2023.09.009. PMID: 37730089
Increased thromboinflammatory load in hereditary angioedema.
Gramstad OR, Schjalm C, Mollnes TE, Nielsen EW
Clin Exp Immunol 2023 Dec 12;214(2):170-181. doi: 10.1093/cei/uxad091. PMID: 37561062Free PMC Article
Inhibition of Prekallikrein for Hereditary Angioedema.
Fijen LM, Riedl MA, Bordone L, Bernstein JA, Raasch J, Tachdjian R, Craig T, Lumry WR, Manning ME, Alexander VJ, Newman KB, Revenko A, Baker BF, Nanavati C, MacLeod AR, Schneider E, Cohn DM
N Engl J Med 2022 Mar 17;386(11):1026-1033. doi: 10.1056/NEJMoa2109329. PMID: 35294812
Long-term prevention of hereditary angioedema attacks with lanadelumab: The HELP OLE Study.
Banerji A, Bernstein JA, Johnston DT, Lumry WR, Magerl M, Maurer M, Martinez-Saguer I, Zanichelli A, Hao J, Inhaber N, Yu M, Riedl MA; HELP OLE Investigators
Allergy 2022 Mar;77(3):979-990. Epub 2021 Aug 13 doi: 10.1111/all.15011. PMID: 34287942Free PMC Article

Recent systematic reviews

Epidemiology, economic, and humanistic burden of hereditary angioedema: a systematic review.
Guan X, Sheng Y, Liu S, He M, Chen T, Zhi Y
Orphanet J Rare Dis 2024 Jul 8;19(1):256. doi: 10.1186/s13023-024-03265-z. PMID: 38978028Free PMC Article
Leukotriene receptor antagonists as add-on therapy to antihistamines for urticaria: Systematic review and meta-analysis of randomized clinical trials.
Rayner DG, Liu M, Chu AWL, Chu X, Guyatt GH, Oykhman P, Cao DJ, Moellman J, Ben-Shoshan M, Baker DR, Waserman S, Lang D, Sheikh J, Mathur SK, Beck LA, Khan DA, Oliver ET, Asiniwasis RN, Cole EF, Wheeler KE, Runyon L, Chan J, Trayes KP, Eftekhari S, Gardner DD, Winders T, Saini SS, Bernstein JA, Chu DK
J Allergy Clin Immunol 2024 Oct;154(4):996-1007. Epub 2024 Jun 7 doi: 10.1016/j.jaci.2024.05.026. PMID: 38852861
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
Epidemiology of Bradykinin-mediated angioedema: a systematic investigation of epidemiological studies.
Aygören-Pürsün E, Magerl M, Maetzel A, Maurer M
Orphanet J Rare Dis 2018 May 4;13(1):73. doi: 10.1186/s13023-018-0815-5. PMID: 29728119Free PMC Article
Plasma-derived C1-INH for managing hereditary angioedema in pediatric patients: A systematic review.
Craig TJ, Schneider LC, MacGinnitie AJ
Pediatr Allergy Immunol 2015 Sep;26(6):537-44. doi: 10.1111/pai.12425. PMID: 26111105

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