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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
Consensus on treatment goals in hereditary angioedema: A global Delphi initiative.
Maurer M, Aygören-Pürsün E, Banerji A, Bernstein JA, Balle Boysen H, Busse PJ, Bygum A, Caballero T, Castaldo AJ, Christiansen SC, Craig T, Farkas H, Grumach AS, Hide M, Katelaris CH, Li HH, Longhurst H, Lumry WR, Magerl M, Martinez-Saguer I, Riedl MA, Zhi Y, Zuraw B
J Allergy Clin Immunol 2021 Dec;148(6):1526-1532. Epub 2021 May 25 doi: 10.1016/j.jaci.2021.05.016. PMID: 34048855
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

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
Screening for Plasminogen Mutations in Hereditary Angioedema Patients.
Farkas H, Dóczy A, Szabó E, Varga L, Csuka D
Genes (Basel) 2021 Mar 11;12(3) doi: 10.3390/genes12030402. PMID: 33799813Free 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
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
Ecallantide: its pharmacology, pharmacokinetics, clinical efficacy and tolerability.
Bernstein JA, Qazi M
Expert Rev Clin Immunol 2010 Jan;6(1):29-39. doi: 10.1586/eci.09.60. PMID: 20383888

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
Differentiating histaminergic and nonhistaminergic angioedema with or without urticaria.
Farkas H, Balla Z, Riedl MA
J Allergy Clin Immunol 2022 Dec;150(6):1405-1409. doi: 10.1016/j.jaci.2022.10.016. PMID: 36481049
Informed decision-making in hereditary angioedema prophylaxis.
Burnette AF
Int Forum Allergy Rhinol 2021 Jun;11(6):965-966. Epub 2021 Jan 13 doi: 10.1002/alr.22764. PMID: 33439551Free PMC Article
Hereditary angioedema.
Frank MM
Curr Opin Pediatr 2005 Dec;17(6):686-9. doi: 10.1097/01.mop.0000182382.28552.1c. PMID: 16282771
Hereditary angioedema.
Gigli I
J Invest Dermatol 1973 Jun;60(6):516-21. doi: 10.1111/1523-1747.ep12703581. PMID: 4122980

Therapy

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
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
Hereditary angioedema in women: specific challenges.
Bouillet L, Gompel A
Immunol Allergy Clin North Am 2013 Nov;33(4):505-11. Epub 2013 Aug 26 doi: 10.1016/j.iac.2013.07.006. PMID: 24176215
Cinryze (C1-inhibitor) for the treatment of hereditary angioedema.
Gompels MM, Lock RJ
Expert Rev Clin Immunol 2011 Sep;7(5):569-73. doi: 10.1586/eci.11.50. PMID: 21895469
Therapeutic complement inhibition: new developments.
Emlen W, Li W, Kirschfink M
Semin Thromb Hemost 2010 Sep;36(6):660-8. Epub 2010 Sep 23 doi: 10.1055/s-0030-1262888. PMID: 20865643

Prognosis

Angioedema: Clinical Presentations and Pharmacological Management.
Collins-Yoder AS
Dimens Crit Care Nurs 2016 Jul-Aug;35(4):181-9. doi: 10.1097/DCC.0000000000000188. PMID: 27258954
Hereditary Angioedema Attacks: Local Swelling at Multiple Sites.
Hofman ZL, Relan A, Hack CE
Clin Rev Allergy Immunol 2016 Feb;50(1):34-40. doi: 10.1007/s12016-014-8463-6. PMID: 25527240
Assessment of hereditary angioedema treatment risks.
Kalaria S, Craig T
Allergy Asthma Proc 2013 Nov-Dec;34(6):519-22. doi: 10.2500/aap.2013.34.3702. PMID: 24169059
Hereditary angioedema.
Frank MM
Curr Opin Pediatr 2005 Dec;17(6):686-9. doi: 10.1097/01.mop.0000182382.28552.1c. PMID: 16282771
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
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
Efficacy assessments in randomized controlled studies of acute therapy for hereditary angioedema.
Caballero T
J Clin Immunol 2012 Dec;32(6):1204-12. Epub 2012 Jul 15 doi: 10.1007/s10875-012-9734-8. PMID: 22797816
Ecallantide: in acute hereditary angioedema.
Garnock-Jones KP
Drugs 2010 Jul 30;70(11):1423-31. doi: 10.2165/11205850-000000000-00000. PMID: 20614949
Complement deficiencies.
Frank MM
Pediatr Clin North Am 2000 Dec;47(6):1339-54. doi: 10.1016/s0031-3955(05)70274-1. PMID: 11130999

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
Clinical features of genetically characterized types of hereditary angioedema with normal C1 inhibitor: a systematic review of qualitative evidence.
Bork K, Machnig T, Wulff K, Witzke G, Prusty S, Hardt J
Orphanet J Rare Dis 2020 Oct 15;15(1):289. doi: 10.1186/s13023-020-01570-x. PMID: 33059692Free 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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