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.

Differences and Similarities in the Mechanisms and Clinical Expression of Bradykinin-Mediated vs. Mast Cell–Mediated Angioedema

“…Involvement of the tongue, including isolated tongue swellings, is frequent in MCM-AE but also in most forms of nC1-INH-HAE, especially PLG-HAE, and in ACEi-AE. Isolated AE of the tongue is relatively rare in C1-INH-HAE and C1-INH-AAE [33,[46][47][48]. Clinical experience suggests that there is benefit in asking patients whether lip or tongue swellings begin unilaterally, as a unilateral onset of lip or tongue angioedema is more likely to occur in ACEi-AE and MCM-AE rather than in C1-INH-HAE or C1-INH-AAE.…”

“…Abdominal attacks, i.e., painful episodes of angioedema of the gut walls, are seen in almost all patients with C1-INH-HAE and are associated with severe pains lasting for many hours to several days [53]. In nC1-INH-HAE, the occurrence of abdominal angioedema attacks varies between the different types and appears to be more frequent in FXII-HAE and rather rare in PLG-HAE [33]. A small number of reports describe abdominal swellings as a rare and unusual feature of ACEi-AE [47,55,56].…”

Treatment of Hereditary Angioedema

“…C1-INH-HAE is caused by mutations in the SERPING1 gene (also known as the C1NH gene) [2,3]. Mutations in other genes (F12, FXII-HAE; plasminogen, PLG-HAE; angiopoietin 1, ANGPT1-HAE; kininogen 1, KNG1-HAE; and myoferlin, MYOF-HAE) have been reported to cause nC1-INH-HAE [4,5]. When no mutation is detected in families with nC1-INH-HAE, the disease is known as HAE of unknown origin (U-HAE) [2].…”

Novel hereditary angioedema linked with a heparan sulfate 3-O-sulfotransferase 6 gene mutation

“…Up until now, 186 families with a total of 452 patients with HAE-FXII have been reported, as have 33 families with a total of 146 patients with mutation in PT: Prothrombin time WES: Whole exome sequencing the PLG gene encoding plasminogen and 1 family each with a mutation in the ANGPT1 gene encoding angiopoietin-1 (4 patients), a mutation in the gene encoding KNG1 (6 patients), and a mutation recently identified in the MYOF gene encoding for myoferlin (3 patients). 10,11 There are further families with HAE who have presented with HAEnCI but in whom the genetic cause of the disease is still unknown. Those patients have normal C1 INH activity in plasma, and known HAEnCI mutations have been excluded (''HAE-unknown'').…”