Original Article
Hereditary Angioedema with Normal C1 Inhibitor and F12 Mutations in 42 Brazilian Families

https://doi.org/10.1016/j.jaip.2017.09.025Get rights and content

Background

Hereditary angioedema (HAE) with normal C1 inhibitor (C1-INH) is a rare condition with clinical features similar to those of HAE with C1-INH deficiency. Mutations in the F12 gene have been identified in subsets of patients with HAE with normal C1-INH, mostly within families of European descent.

Objectives

Our aim was to describe clinical characteristics observed in Brazilians from 42 families with HAE and F12 gene mutations (FXII-HAE), and to compare these findings with those from other populations.

Methods

We evaluated a group of 195 individuals, which included 102 patients clinically diagnosed with FXII-HAE and their 93 asymptomatic relatives.

Results

Genetic analysis revealed that of the 195 subjects, 134 individuals (77.6% females) carried a pathogenic mutation in F12. The T328K substitution was found in 132 individuals, and the c.971_1018+24del72 deletion was found in 2 patients. The mean age at onset of symptoms in patients with FXII-HAE was 21.1 years. The most common symptoms were subcutaneous edema (85.8% of patients), abdominal pain attacks (69.7%), and upper airway edema (32.3%). Of male individuals carrying F12 mutations, 53.3% (16 of 30) were symptomatic. Compared with reports from Europe, fewer female patients (68.6%) reported an influence of estrogen on symptoms.

Conclusions

Our study included a large number of patients with FXII-HAE, and, as the first such study conducted in a South American population, it highlighted significant differences between this and other study populations. The high number of symptomatic males and patients with estrogen-independent FXII-HAE found here suggests that male sex and the absence of a hormonal influence should not discourage clinicians from searching for F12 mutations in cases of HAE with normal C1-INH.

Section snippets

Subjects

After genetic testing, 102 Brazilian patients with recurrent episodes of subcutaneous edema without wheals, normal quantitative and/or functional C1-INH plasma levels, and no clinical response to high doses of antihistamines according to the criteria established by Cicardi et al1 were included in this study. All patients who showed mutations in the F12 gene known to be related to HAE were characterized as having FXII-HAE, a criterion for entering the study. Family history was a relevant factor

Genetic analyses

We performed genetic analyses of 195 individuals belonging to 42 unrelated families. One hundred two were symptomatic patients (86 females, 16 males) who presented pathogenic mutations in the F12 gene that were previously associated with HAE, and 32 were asymptomatic relatives (18 females, 14 males) who were carriers of F12 mutations. One hundred thirty-two patients (103 females, 29 males), distributed in 41 families, presented the pathogenic T328K mutation in the F12 gene (Figure 1). Two

HAE treatment

Management of patients with FXII-HAE focused on the discontinuation of potential trigger factors, including eOCs, HRT, or ACEI, and providing drug therapy, as recently reported by Bork et al.26 eOC was discontinued in 44 female patients who reported worsening of symptoms with these medications, and 27 switched to progestin as a contraceptive medication and/or were prescribed progestin as a treatment. In 1 patient who had symptoms that began after HRT was initiated, withdrawal of this medication

Discussion

In the present study, we described the clinical features of Brazilian patients with FXII-HAE from 42 families, who were evaluated at 9 HAE reference centers coordinated by the Brazilian Study Group on Hereditary Angioedema (GEBRAEH). Since the first report of this disease in Germany, several families presenting FXII-HAE have been identified in France, Spain, Italy, the United Kingdom, Luxemburg, Turkey, Australia, and Morocco,27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38 with T328K as the most

Acknowledgements

We thank Eduardo Costa, MD, PhD, from the Allergy and Immunology Division at the State University of Rio de Janeiro for providing blood samples from patients with HAE. We are grateful to Priscila Amorin Nicolicht from the Department of Biophysics at Universidade Federal de São Paulo (UNIFESP) and Mrs Marina Mendonça Dias from Ribeirão Preto Medical School, University of São Paulo, for technical assistance.

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    This work was supported by the São Paulo Research Foundation (FAPESP) (grant nos. 2011/24142-3, 2011/23439-2, 2013/02661-4, and 2014/27198-8). A.S.G. was supported by the Shire Research Program for Investigators.

    Conflicts of interest: S. R. Valle is on the boards for Novartis, Sanofi, and CSL Behring and has received lecture fees from Novartis and Takeda. E. Mansour has received research and travel support from Shire; is on the CSL Behring board; and has received research support from Shire and CSL Behring. A. S. Grumach has received research support from São Paulo Research Foundation (FAPESP) (grant nos. 2011/24142-3, 2011/23439-2, 2013/02661-4, and 2014/27198-8) and Shire; has received travel support from Shire, CSL, Pharming, and Baxalta; is on the advisory boards for Shire, CSL, and LASID; has received consultancy fees from Shire, CSL, Pharming, Baxalta, and Viropharma; has received lecture fees from Shire, CSL, and Baxalta; and has received payment for developing educational presentations from Shire and CSL. The rest of the authors declare that they have no relevant conflicts of interest.

    These authors contributed equally to this work.

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