Clinical features of genetically characterized types of hereditary angioedema with normal C1 inhibitor: a systematic review of qualitative evidence

Abstract

Background: Hereditary angioedema (HAE) with normal C1 inhibitor (C1-INH) (HAEnCI) is associated with skin swellings, abdominal attacks, and the risk of asphyxia due to upper airway obstruction. Several different gene mutations linked to the HAE phenotype have been identified. Our aim was to qualitatively assess and describe the clinical differentiators of these genetically identified HAEnCI types. To achieve this, we performed a systematic literature review of patients with angioedema symptoms and a genetically confirmed diagnosis of an HAEnCI type.

Results: A systematic literature search, conducted in March 2020, returned 132 records, 43 of which describe patients with symptoms of angioedema and a genetically confirmed diagnosis of an HAEnCI type. Overall, this included 602 patient cases from 220 families. HAEnCI with a mutation in the coagulation factor XII gene (F12) (HAE-FXII) was diagnosed in 446 patients from 185 families (male:female ratio = 1:10). Estrogens (oral contraceptives, hormonal replacement therapy, and pregnancy) negatively impacted the course of disease in most female patients (252 of 277). Asphyxia occurred in 2 of 446 patients. On-demand and/or long-term prophylaxis treatment included C1-INH concentrates, icatibant, progestins, and tranexamic acid. HAEnCI with a specific mutation in the plasminogen gene (HAE-PLG) was diagnosed in 146 patients from 33 families (male:female ratio = 1:3). Estrogens had a negative influence on the course of disease in the minority of female patients (14 of 62). Tongue swelling was an important clinical feature. Asphyxia occurred in 3 of 146 patients. On-demand treatment with icatibant and C1-INH concentrate and long-term prophylaxis with progestins and tranexamic acid were effective. HAEnCI with a specific mutation in the angiopoietin-1 gene (HAE-ANGPT1) was diagnosed in 4 patients from 1 family and HAEnCI with a specific mutation in the kininogen-1 gene (HAE-KNG1) in 6 patients from 1 family.

Conclusions: A number of clinical differentiators for the different types of HAEnCI have been identified which may support clinicians to narrow down the correct diagnosis of HAEnCI prior to genetic testing and thereby guide appropriate treatment and management decisions. However, confirmation of the causative gene mutation by genetic testing will always be required.

Keywords: Asphyxia; Clinical features; HAE with a specific mutation in the F12 gene; HAE with a specific mutation in the angiopoietin-1 gene; HAE with a specific mutation in the kininogen-1 gene; HAE with a specific mutation in the myoferlin gene; HAE with a specific mutation in the plasminogen gene; Hereditary angioedema; Hereditary angioedema with normal C1 inhibitor; Tongue swelling.

Fig. 1

Mutations linked to various types of HAEnCI and its impact on the various proteases and protease inhibitors of the fibrinolytic and kallikrein-kinin systems. ANGPT1 = angiopoietin-1 gene, B2R = bradykinin-2 receptor, C1-INH = C1 esterase inhibitor, FXII = coagulation factor XII gene, HMWK = high molecular weight kininogen, KNG1 = kininogen-1 gene, MYOF = myoferlin gene, PAI = plasminogen activator inhibitor, PLG = plasminogen gene, TIE2 = tyrosine-protein kinase, tPA = tissue plasminogen activator, scuPA = single-chain urokinase-type plasminogen activator, uPA = urokinase-type plasminogen activator, VEGF = vascular endothelial growth factor

Fig. 2

QUOROM flow-chart shows the number of publications screened and included in the systematic review for qualitative evidence. HAE-ANGPT1 = hereditary angioedema with a specific mutations in the angiopoietin-1 gene, HAE-FXII = hereditary angioedema with specific mutations in the factor XII gene, HAE-KNG-1 = hereditary angioedema with a specific mutation in the kininogen-1 gene, HAE-PLG = hereditary angioedema with a specific mutation in the plasminogen gene, HMWK = high molecular weight kininogen, HAEnCI = hereditary angioedema with normal C1 esterase inhibitor, MeSH = medical subject headings, N = number of records. *("complement c1 inhibitor protein"[MeSH Term] AND ("angioedema, hereditary" [MeSH Term]) search for a period from 1 January 2006 to 1 March 2020