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Clinically, hereditary angioedema with normal C1 inhibitor (HAE-nC1) is similar to hereditary angioedema caused by C1 inhibitor (C1-INH) deficiency, but not identical. About a quarter of HAE-nC1 cases are attributed to mutations in the F12 gene; in three-quarters of the cases the pathomechanism is still widely unknown.
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Swelling attacks in patients with HAE-nC1 are thought to be caused by bradykinin.
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As of now, there are no routine laboratory tests to confirm the diagnosis of HAE-nC1, so the
Hereditary Angioedema with Normal C1 Inhibitor: Update on Evaluation and Treatment
Section snippets
Key points
The pathophysiology of hereditary angioedema with normal C1 inhibitor
Swelling attacks in patients with HAE-C1-INH are brought about by activation of the contact system and the subsequent generation of bradykinin, which causes extravasation by activating the bradykinin 2 receptor. This pathomechanism is thought to also be involved in HAE-nC1. The contact system, a side-branch enzyme system of the coagulation system, consists of factor XII (FXII), plasma prekallikrein (PPK), and high-molecular-weight kininogen (HK). These factors generate spontaneous enzymatic
The genetics of hereditary angioedema with normal C1 inhibitor
About a quarter of HAE-nC1 cases are attributed to mutations in the F12 gene located in chromosome 5 (5q33-qter) and encoding for coagulation factor XII (Hageman factor, FXII). Up to now, four F12 mutations have been identified and are thought to be causal for HAE-nC1 based on their cosegregation patterns.39 All of them are located in the proline-rich linker peptide between the Kringle and trypsinlike serine protease (Tryp-SPc) domains of the FXII protein39; these are two distinct missense
Clinical features of hereditary angioedema with normal C1 inhibitor
Similar to HAE-C1-INH, patients with HAE-nC1 experience angioedema attacks of the skin, gastrointestinal tract, and airways. The episodes are transient and generally separated by intervals of complete remission. Individual HAE-nC1 attacks are indistinguishable from HAE-C1-INH attacks. However, HAE-nC1 is different from HAE-C1-INH in many aspects, and the subgroups of HAE-nC1, HAE-FXII, and HAE-UNK also show differences.
The mean age of onset of HAE-nC1 symptoms is reported to be 26.8 years
Diagnosis
The diagnostic work-up of HAE-C1-INH is usually straightforward. The history and pattern of signs and symptoms are typical and prompt the assessment of levels of C4 and C1-INH as well as its function. In rare cases, genetic testing may be needed to confirm the diagnosis. Nevertheless, patients with HAE-C1-INH are commonly misdiagnosed, most frequently with allergic angioedema and appendicitis, resulting in long delays in the correct diagnosis.70, 71
In contrast, the diagnosis of HAE-nC1 is more
Treatment of hereditary angioedema with normal C1 inhibitor
No prospective, randomized controlled studies have been performed so far in patients with HAE-nC1, and there are, therefore, no licensed treatments available as of now. However, several observational studies have assessed various medications for the treatment of HAE-nC1, although most of these studies do not clearly distinguish between HAE-UNK and HAE-FXII. There is consensus that angioedema attacks in patients with HAE-nC1 do not respond to corticosteroids or antihistamines, even at high doses.
References (99)
- et al.
A biochemical abnormality in hereditary angioneurotic edema: absence of serum inhibitor of C' 1-esterase
Am J Med
(1963) - et al.
Plasma bradykinin in angio-oedema
Lancet
(1998) - et al.
Clinical, biochemical, and genetic characterization of a novel estrogen-dependent inherited form of angioedema
J Allergy Clin Immunol
(2000) - et al.
Hereditary angioedema with normal C1-inhibitor activity in women
Lancet
(2000) - et al.
Missense mutations in the coagulation factor XII (Hageman factor) gene in hereditary angioedema with normal C1 inhibitor
Biochem Biophys Res Commun
(2006) - et al.
A novel mutation in the coagulation factor 12 gene in subjects with hereditary angioedema and normal C1-inhibitor
Clin Immunol
(2011) - et al.
Novel duplication in the F12 gene in a patient with recurrent angioedema
Clin Immunol
(2013) - et al.
Platelet polyphosphates are proinflammatory and procoagulant mediators in vivo
Cell
(2009) - et al.
Mast cells increase vascular permeability by heparin-initiated bradykinin formation in vivo
Immunity
(2011) - et al.
Factor XII: form determines function
J Thromb Haemost
(2016)
Activation of the contact system in insect-sting anaphylaxis: association with the development of angioedema and shock
Blood
Controlled insect-sting challenge in 55 patients: correlation between activation of plasminogen and the development of anaphylactic shock
Blood
Increased activity of coagulation factor XII (Hageman factor) causes hereditary angioedema type III
Am J Hum Genet
Idiopathic angioedema with F12 mutation: is it a new entity?
Ann Allergy Asthma Immunol
A common genetic polymorphism (46 C to T substitution) in the 5'-untranslated region of the coagulation factor XII gene is associated with low translation efficiency and decrease in plasma factor XII level
Blood
Pathogenic mechanisms of bradykinin mediated diseases: dysregulation of an innate inflammatory pathway
Adv Immunol
Hereditary angioedema with normal C1 inhibitor: clinical symptoms and course
Am J Med
Hereditary angioedema with F12 mutation: clinical features and enzyme polymorphisms in 9 southwestern Spanish families
Ann Allergy Asthma Immunol
Hereditary angioedema caused by missense mutations in the factor XII gene: clinical features, trigger factors, and therapy
J Allergy Clin Immunol
Hereditary angioedema: new findings concerning symptoms, affected organs, and course
Am J Med
Characterization of patients with angioedema without wheals: the importance of F12 gene screening
Clin Immunol
Misdiagnosis trends in patients with hereditary angioedema from the real-world clinical setting
Ann Allergy Asthma Immunol
Hereditary angioedema presenting in late middle age after angiotensin-converting enzyme inhibitor treatment
Ann Allergy Asthma Immunol
Hereditary angioedema type III, angioedema associated with angiotensin II receptor antagonists, and female sex
Am J Med
The effectiveness of levocetirizine and desloratadine in up to 4 times conventional doses in difficult-to-treat urticaria
J Allergy Clin Immunol
Successful treatment of 3 patients with recurrent idiopathic angioedema with omalizumab
J Allergy Clin Immunol
First molecular confirmation of an Australian case of type III hereditary angioedema
Pathology
Treatment of an acute attack of type III hereditary angioedema with ecallantide
Ann Allergy Asthma Immunol
Bradykinin receptor 2 antagonist (icatibant) for hereditary angioedema type III attacks
Ann Allergy Asthma Immunol
Re: successful management of hereditary angioedema with normal C1-INH (type III HAE) when using on-demand ecallantide
J Allergy Clin Immunol Pract
C1-esterase inhibitor for short-term prophylaxis in a patient with hereditary angioedema with normal C1 inhibitor function
J Clin Anesth
Ueber acutes Oedem [Inaugural-Dissertation]
Über akutes umschriebenes Hautödem
Monatsh Prakt Dermatol
Hereditary angio-neurotic oedema
Am J Med Sci
Hereditary angioneurotic edema: two genetic variants
Science
Permeability-increasing activity in hereditary angioneurotic edema plasma. II. Mechanism of formation and partial characterization
J Clin Invest
Vascular reactions in hereditary angioneurotic edema
Acta Derm Venereol
A factor XIIa inhibitory antibody provides thromboprotection in extracorporeal circulation without increasing bleeding risk
Sci Transl Med
A nanobody-based method for tracking factor XII activation in plasma
Thromb Haemost
Extracellular RNA constitutes a natural procoagulant cofactor in blood coagulation
Proc Natl Acad Sci U S A
Misfolded proteins activate factor XII in humans, leading to kallikrein formation without initiating coagulation
J Clin Invest
Activation of the factor XII-driven contact system in Alzheimer's disease patient and mouse model plasma
Proc Natl Acad Sci U S A
Elevated D-dimers in attacks of hereditary angioedema are not associated with increased thrombotic risk
Allergy
Bradykinin in idiopathic nonhistaminergic angioedema
Clin Exp Allergy
Plasma contact system activation drives anaphylaxis in severe mast cell-mediated allergic reactions
J Allergy Clin Immunol
Bradykinin-mediated angioedema
N Engl J Med
Plasmin cleavage of von Willebrand factor as an emergency bypass for ADAMTS13 deficiency in thrombotic microangiopathy
Circulation
A prealbumin activator of prekallikrein. II. Derivation of activators of prekallikrein from active Hageman factor by digestion with plasmin
J Exp Med
Orolingual angioedema during or after thrombolysis for cerebral ischemia
Stroke
Cited by (41)
Summary and future of medicine for hereditary angioedema
2024, Drug Discovery TodaySuccessful use of lanadelumab in a patient with hereditary angioedema with normal C1 inhibitor and negative genetic testing
2023, Journal of Allergy and Clinical Immunology: GlobalHereditary Angioedema During Pregnancy: Considerations in Management
2023, Immunology and Allergy Clinics of North AmericaCitation Excerpt :A third subtype of HAE is HAE with normal C1INH (HAE-nl-C1INH).4 Laboratory studies of C1INH level and function are normal in this condition, although the clinical phenotype is extremely similar to HAE-C1INH.5 HAE-nl-C1INH is further subcategorized into identified associated mutations in factor XII (FXII), plasminogen (PLG), angiopoetin-1 (AGPT1), kininogen-1 (KNG1), myoferlin (MYO), and heparan sulfate 3-O-sulfotransferase 6 (HS3ST6).6
The international WAO/EAACI guideline for the management of hereditary angioedema – The 2021 revision and update
2022, World Allergy Organization JournalCitation Excerpt :In addition, some patients have HAE due to unknown mutations (HAE-UNK). The different forms of HAE share some clinical features and, possibly, therapeutic options.37,38 There are several types of bradykinin-mediated acquired angioedema.
Clinical profile and treatment outcomes in patients with hereditary angioedema with normal C1 esterase inhibitor
2022, World Allergy Organization JournalCitation Excerpt :The prevalence, etiology, and pathophysiology of HAE-nl-C1INH are not well understood.2,4,6 Although some patients have a mutation in a gene that encodes coagulation FXII (F12), plasminogen (PLG), angiopoietin 1 (ANGPT1), kininogen 1 (KNG1), myoferlin (MYOF), or heparan sulfate glucosamine 3-O-sulfotransferase 6 (HS3ST6), most HAE-nl-C1INH patients are classified as HAE-unknown (ie, no mutation identified).2,6–12 Dysregulation of the contact system (kallikrein–bradykinin formation) appears to play a role in the pathophysiology of HAE-nl-C1INH,3 with evidence of higher plasma kallikrein activity in patients with HAE-nl-C1INH versus controls without swelling or patients with idiopathic histaminergic angioedema.13
Conflicts of interest: M. Magerl has received consultancy/honorarium fees from Shire, Viropharma, CSL Behring, and Sobi. A.E. Germenis has received research support from Shire (grant no: IIR-GRC-000905), Amgen, and Novartis; has received consultancy fees from Shire; has received lecture fees from Novartis and Amgen; and has received travel support from Shire. C. Maas is consultant to Shire, Pharming. M. Maurer has received research support, consultancy/lecture fees, and/or travel support from Biocryst, CSL Behring, and Shire/Dyax/Viropharma.