Hereditary angioedema: An orphan but an original disease?

Abstract

Nosology is the branch of medical science that deals with the classification of diseases. In the past a disease was classified by its cause, by its pathogenesis (ie, the mechanism by which the disease progresses), and/or by its symptom(s). The recent development of molecular biology together with machine and deep learning methods, however, allows for leveraging real-life information about diseases to refine genetic and phenotypic disease relationships,1Dozmorov M.G. Disease classification: from phenotypic similarity to integrative genomics and beyond.Brief Bioinform. 2019; 20: 1769-1780Crossref PubMed Scopus (13) Google Scholar which might change our current classifications. The first case of hereditary angioedema (HAE) was published by the German surgeon and internist Quincke in 1882.2Reshef A. Kidon M. Leibovich I. The story of angioedema: from Quincke to bradykinin.Clin Rev Allergy Immunol. 2016; 51: 121-139Crossref PubMed Scopus (29) Google Scholar His diagnosis was based on the patient's symptom, which was an acute, self-limited and localized skin swelling. In 1888, the Canadian physician Sir William Osler added the criterion of heredity transmission.2Reshef A. Kidon M. Leibovich I. The story of angioedema: from Quincke to bradykinin.Clin Rev Allergy Immunol. 2016; 51: 121-139Crossref PubMed Scopus (29) Google Scholar He reported on a 24-year-woman with recurrent attacks of angioedema in the fifth generation and named the disease hereditary angioneurotic edema. Almost a century later, the disease could be classified by its pathogenesis, when Donaldson detected the absence of serum inhibitor of C1-esterase in 19632Reshef A. Kidon M. Leibovich I. The story of angioedema: from Quincke to bradykinin.Clin Rev Allergy Immunol. 2016; 51: 121-139Crossref PubMed Scopus (29) Google Scholar and its effect on the complement system. Shortly thereafter, Rosen separated the disease, which was still denoted by the Osler term angioneurotic edema, into 2 genetic variants (HAE-1 and HAE-2), albeit with identical symptoms and course.2Reshef A. Kidon M. Leibovich I. The story of angioedema: from Quincke to bradykinin.Clin Rev Allergy Immunol. 2016; 51: 121-139Crossref PubMed Scopus (29) Google Scholar On the basis of these findings, the adjective angioneurotic, with its inclusion in the name of the disease, was abandoned by Rosen2Reshef A. Kidon M. Leibovich I. The story of angioedema: from Quincke to bradykinin.Clin Rev Allergy Immunol. 2016; 51: 121-139Crossref PubMed Scopus (29) Google Scholar and Pickering,2Reshef A. Kidon M. Leibovich I. The story of angioedema: from Quincke to bradykinin.Clin Rev Allergy Immunol. 2016; 51: 121-139Crossref PubMed Scopus (29) Google Scholar who then gave it the current name of HAE. The latter term expresses the clinical symptom of angioedema and its hereditary nature.2Reshef A. Kidon M. Leibovich I. The story of angioedema: from Quincke to bradykinin.Clin Rev Allergy Immunol. 2016; 51: 121-139Crossref PubMed Scopus (29) Google Scholar Ironically, it was only in 2016 that Caballero demonstrated emotional distress as the most prominent trigger factor for HAE,3Caballero T. Maurer M. Longhurst H.J. Aberer W. Bouillet L. Fabien V. for the IOS 4 Study Group. Triggers and prodromal symptoms of angioedema attacks in patients with hereditary angioedema.J Investig Allergol Clin Immunol. 2016; 26: 383-386Crossref PubMed Scopus (48) Google Scholar thus confirming Osler’s long ago clinical observations regarding the role of psychological stress as a factor in HAE. The nosology of HAE was now clearly defined4Maurer M. Magerl M. Ansotegui I. Aygören-Pürsün E. Betschel D. Bork K. et al.The international WAO/EAACI guideline for the management of hereditary angioedema – the 2017 revision and update.Allergy. 2018; 73: 1575-1596Crossref PubMed Scopus (307) Google Scholar by (1) its cause (HAE is caused by 1 of more than 450 different mutations in the SERPING1 gene, which codes for C1 inhibitor [C1-INH]), (2) its pathogenesis (increased permeability of blood vessels due to increased bradykinin production secondary to limited C1-INH inhibitory action in the contact system), and (3) its symptoms (episodic swellings of cutaneous and mucosal surfaces). Most importantly, effective and safe modalities were developed for on-demand treatment as well as for short- and long-term prophylaxis.4Maurer M. Magerl M. Ansotegui I. Aygören-Pürsün E. Betschel D. Bork K. et al.The international WAO/EAACI guideline for the management of hereditary angioedema – the 2017 revision and update.Allergy. 2018; 73: 1575-1596Crossref PubMed Scopus (307) Google Scholar However, questions remained, as stressed in the consensus by Cicardi et al in 20145Cicardi M. Aberer W. Banerji A. Bas M. Bernstein J.A. Bork K. et al.Classification, diagnosis, and approach to treatment for angioedema: consensus report from the Hereditary Angioedema International Working Group.Allergy. 2014; 69: 602-616Crossref PubMed Scopus (446) Google Scholar: how should patients with HAE and a normal C1-INH level be diagnosed and managed? And does the same name mean an identical disease? In 2000, 2 groups independently described families with HAE in which the affected persons had entirely normal C1-INH levels and function.6Zuraw B.L. Hereditary angioedema with normal C1 inhibitor: four types and counting.J Allergy Clin Immunol. 2018; 141: 884-885Abstract Full Text Full Text PDF PubMed Scopus (54) Google Scholar The term HAE-3 was proposed and accepted for the next decade despite immediate concerns about its accuracy7Kränke B. Salmhofer W. Aberer W. Hereditary angioedema and normal C1-inhibitor activity in women.Lancet. 2000; 356: 1440-1441Abstract Full Text Full Text PDF PubMed Google Scholar; meanwhile, it was renamed as HAE with normal C1-INH (HAEnC1).8Bork K. Wulff K. Möhl B.S. Steinmüller-Magin L. Witzke G. Hardt J. et al.Novel hereditary angioedema linked with a heparan sulfate 3-O-sulfotransferase 6 gene mutation.J Allergy Clin Immunol. 2021; 148: 1041-1048Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar Obviously, its cause and pathomechanism differed from those of HAE-1 and HAE-2; just its symptoms resembled those of the original condition. Several genetically defined types of HAE with a normal C1-INH level have meanwhile been described, with mutations in different genes (ie, genes encoding for factor XII, plasminogen, angiopoietin-1, kininogen-1, myoferlin, and heparan sulfate 3-O-sulfotransferase 6 [as presented in this issue of the Journal of Allergy and Clinical Immunology8Bork K. Wulff K. Möhl B.S. Steinmüller-Magin L. Witzke G. Hardt J. et al.Novel hereditary angioedema linked with a heparan sulfate 3-O-sulfotransferase 6 gene mutation.J Allergy Clin Immunol. 2021; 148: 1041-1048Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar]), together with specific cDNA and protein changes (Table I) (reviewed in Zuraw6Zuraw B.L. Hereditary angioedema with normal C1 inhibitor: four types and counting.J Allergy Clin Immunol. 2018; 141: 884-885Abstract Full Text Full Text PDF PubMed Scopus (54) Google Scholar and Bork et al8Bork K. Wulff K. Möhl B.S. Steinmüller-Magin L. Witzke G. Hardt J. et al.Novel hereditary angioedema linked with a heparan sulfate 3-O-sulfotransferase 6 gene mutation.J Allergy Clin Immunol. 2021; 148: 1041-1048Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar). These patients fulfill the criteria for the diagnosis of HAEnC1, which are as follows: (1) recurrent swellings of the skin and/or mucosal surfaces, (2) absence of urticaria, (3) a positive family history for angioedema, and (4) normal C1-INH function and concentration in plasma. However, the cause and/or pathomechanisms leading to the phenotype of HAE may differ from those of classical HAE-1 and HAE-2 depending on the affected mutations, and a variety of systems and mediators may be influenced (Table I). Most important for the patients, the treatment established for HAE-1 and HAE-2 may or may not work in these patients. The numerous mutations of which we are now aware have permitted a specific diagnosis in many patients whose HAE was formerly classified as idiopathic, but the diagnosis of those experiencing HAEnC1 without a detectable mutation still remains ambiguous. In view of the several disclosed mutations, the diagnosis HAE-UNK (with UNK standing for unknown6Zuraw B.L. Hereditary angioedema with normal C1 inhibitor: four types and counting.J Allergy Clin Immunol. 2018; 141: 884-885Abstract Full Text Full Text PDF PubMed Scopus (54) Google Scholar) is now applicable to fewer individuals, although it remains a matter of shakiness.Table ICurrent types of HAEHAE typeGenePathomechanismMediatorHAE-1SERPING1Impaired C1-INH secretionBradykininHAE-2SERPING1Dysfunctional C1-INHBradykininHAE-FXIIF12↑ Activation of contact systemBradykininHAE-ANGPT1ANGPT1↓ Limitation of vascular permeabilityUnknownHAE-PLGPLGUnknownUnknownHAE-KNG1KNG1UnknownBradykininHAE-myoferlinMYOF↑ VEGF-mediated intracellular signalingUnknownHAE-HS3OST6HS3ST6Facilitated binding and activation on nonproteoglycan alternatives such as gC1qR-cytokeratin 18Bork K. Wulff K. Möhl B.S. Steinmüller-Magin L. Witzke G. Hardt J. et al.Novel hereditary angioedema linked with a heparan sulfate 3-O-sulfotransferase 6 gene mutation.J Allergy Clin Immunol. 2021; 148: 1041-1048Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar,9Joseph K. Ghebrehiwet B. Kaplan A.P. Cytokeratin 1 and gC1qR mediates high molecular weight kininogen and factor XII binding to endothelial cells.Clin Immunol. 1999; 92: 246-255Crossref PubMed Scopus (71) Google ScholarBradykininHAE-UNKUnknownUnknownUnknownHAE types are shown along with the affected genes, the most likely mechanisms leading to angioedema, and the mediator of swelling.Adapted from Zuraw6Zuraw B.L. Hereditary angioedema with normal C1 inhibitor: four types and counting.J Allergy Clin Immunol. 2018; 141: 884-885Abstract Full Text Full Text PDF PubMed Scopus (54) Google Scholar and Bork et al.8Bork K. Wulff K. Möhl B.S. Steinmüller-Magin L. Witzke G. Hardt J. et al.Novel hereditary angioedema linked with a heparan sulfate 3-O-sulfotransferase 6 gene mutation.J Allergy Clin Immunol. 2021; 148: 1041-1048Abstract Full Text Full Text PDF PubMed Scopus (19) Google ScholarANGPT1, Angiopoietin-1 gene; F12, factor XII gene; HS3ST6, heparan sulfate 3-O-sulfotransferase 6 gene; KNG1, kininogen-1 gene; MYOF, myoferlin gene; PLG, plasminogen gene. Open table in a new tab HAE types are shown along with the affected genes, the most likely mechanisms leading to angioedema, and the mediator of swelling. Adapted from Zuraw6Zuraw B.L. Hereditary angioedema with normal C1 inhibitor: four types and counting.J Allergy Clin Immunol. 2018; 141: 884-885Abstract Full Text Full Text PDF PubMed Scopus (54) Google Scholar and Bork et al.8Bork K. Wulff K. Möhl B.S. Steinmüller-Magin L. Witzke G. Hardt J. et al.Novel hereditary angioedema linked with a heparan sulfate 3-O-sulfotransferase 6 gene mutation.J Allergy Clin Immunol. 2021; 148: 1041-1048Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar ANGPT1, Angiopoietin-1 gene; F12, factor XII gene; HS3ST6, heparan sulfate 3-O-sulfotransferase 6 gene; KNG1, kininogen-1 gene; MYOF, myoferlin gene; PLG, plasminogen gene. The detection of potentially relevant genetic mutations for some types of angioedema has brought enormous and commendable progress in the past decade.6Zuraw B.L. Hereditary angioedema with normal C1 inhibitor: four types and counting.J Allergy Clin Immunol. 2018; 141: 884-885Abstract Full Text Full Text PDF PubMed Scopus (54) Google Scholar,8Bork K. Wulff K. Möhl B.S. Steinmüller-Magin L. Witzke G. Hardt J. et al.Novel hereditary angioedema linked with a heparan sulfate 3-O-sulfotransferase 6 gene mutation.J Allergy Clin Immunol. 2021; 148: 1041-1048Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar However, it is important to divide patients according to their specific genetic mutations. Mixing these rare and heterogeneous groups in clinical trials might weaken—or even nullify—therapeutic trials. As reported in the past, some patients in the respective groups respond well to HAE-specific medications such as C1-INH for replacing this missing factor and icatibant for blocking the bradykinin B2 receptor, whereas others do not. HAE has taught us much of what we know about the plasma contact system.9Joseph K. Ghebrehiwet B. Kaplan A.P. Cytokeratin 1 and gC1qR mediates high molecular weight kininogen and factor XII binding to endothelial cells.Clin Immunol. 1999; 92: 246-255Crossref PubMed Scopus (71) Google Scholar But at least some of the newly described defects play a role in different systems, such as the angiopoietin gene mutation, but have no direct connection with the contact system or its mediator bradykinin.6Zuraw B.L. Hereditary angioedema with normal C1 inhibitor: four types and counting.J Allergy Clin Immunol. 2018; 141: 884-885Abstract Full Text Full Text PDF PubMed Scopus (54) Google Scholar,8Bork K. Wulff K. Möhl B.S. Steinmüller-Magin L. Witzke G. Hardt J. et al.Novel hereditary angioedema linked with a heparan sulfate 3-O-sulfotransferase 6 gene mutation.J Allergy Clin Immunol. 2021; 148: 1041-1048Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar And the newly identified mutant 3-OST-6 affects cell surface interactions of key players in the formation of angioedema.8Bork K. Wulff K. Möhl B.S. Steinmüller-Magin L. Witzke G. Hardt J. et al.Novel hereditary angioedema linked with a heparan sulfate 3-O-sulfotransferase 6 gene mutation.J Allergy Clin Immunol. 2021; 148: 1041-1048Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar The classification of a medical condition requires knowledge of its unique cause, the effects that it has on the body, the symptoms that it produces, and other factors. With regard to HAE and its current subtypes, the symptom of swelling is the common denominator, whereas all of the other criteria may differ. Thus, the descriptive name HAE seems to be a unifying umbrella term for a group of orphan diseases.5Cicardi M. Aberer W. Banerji A. Bas M. Bernstein J.A. Bork K. et al.Classification, diagnosis, and approach to treatment for angioedema: consensus report from the Hereditary Angioedema International Working Group.Allergy. 2014; 69: 602-616Crossref PubMed Scopus (446) Google Scholar But 2 final and critical questions may be allowed: (1) is it wise, is it appropriate, and is it legitimate to summarize diseases with a different cause, divergent pathogenesis, and heterogeneous treatment response just because of phenotypic similarity? and (2) is it academically acceptable, and/or is it clinically helpful to the affected patient? Reliable biomarkers are required to monitor disease activity as well as response to therapy.10Kaplan AP, Maas C. The search for biomarkers in hereditary angioedema. Front Med (Lausanne) https://doi.org/10.3389/fmed.2017.00206. Accessed November 22, 2017.Google Scholar But also essential is a correct disease classification, which demands flexibility from the similar phenotypic to the divergent molecular level. Novel hereditary angioedema linked with a heparan sulfate 3-O-sulfotransferase 6 gene mutationJournal of Allergy and Clinical ImmunologyVol. 148Issue 4PreviewHereditary angioedema (HAE) is a potentially fatal disorder resulting in recurrent attacks of severe swelling. It may be associated with a genetic deficiency of functional C1 inhibitor or with normal C1 inhibitor (HAEnCI). In families with HAEnCI, HAE-linked mutations in the F12, PLG, KNG1, ANGPT1, or MYOF genes have been identified. In many families with HAEnCI the genetic cause of the disease is currently unknown. Full-Text PDF