**4. Historical review (from C1 inhibitor to coagulation factor XII)**

In 1986, the *C1NH* gene was identified (Gene Bank X54486; Swiss-Prot P05155), which encodes the C1INH protein, also called *SERPING1*, located on chromosome 11 subregion q11-q13.1 [57–59]. Although the possible relationship between AE and estrogens in women was described as early as 1986 [60], it was not until the first decade of the twenty-first century when several series of patients with HAE were described with normal levels of the fractions of the complement system [61, 62]. It was originally called HAE type III [62]. Finally, a mutation was found

Initially, C2-kinin, a vasoactive peptide generated by cleavage of the C2b fragment was

In 1998, there was growing support for another hypothesis in the generation of AE. It argued that BK was the most important mediator in the development of AE [67] and had been proven through clinical, *in vitro* studies and experiments in an experimental model of C1INHdeficient transgenic mice [68]. In 2002, a transgenic mouse with C1 inhibitor deficiency was

thought to be involved in angioedema formation in C1-INH-HAE [66].

in *F12* gene in some of the families [63–65].

212 A Comprehensive Review of Urticaria and Angioedema

**Figure 3.** Historical review of angioedema due to C1-inhibitor deficiency.

developed by Professor Davis [69].

In hereditary angioedema (HAE) with mutation in *F12* gene (FXII-HAE), symptoms are similar to C1-INH-HAE, there are no abnormalities in the *C1NH* gene and antigenic and functional C1INH, C1q and C4 are usually within the normal range [91]. The final common mediator is thought to be bradykinin (BK). The history of the description of nC1-INH-HAE can be seen in **Figure 4**.

**Figure 4.** Historical review of angioedema type III.

In 2000, Binkley et al. [92] analyzed the family tree of eight women from three different generations noting that AE episodes were triggered by estrogen treatment (OCPs, hormone replacement therapy in menopause) or by pregnancies, the onset being at 14–21 days after conception, and at 7–14 days after the initiation of hormone replacement therapy. Börk et al. [93] described simultaneously a series of 36 women with angioedema with functionality conserved in the different fractions of the complement system (including C1 inhibitor), and who worsened in relation to situations of increased estrogens. Bork et al. [93] proposed to call this new AE type as HAE type III. Simultaneously, Marcos et al. [94] described in the XXII National SEAIC Congress the first family case in Spain, data that would be extended over the years [95]. One year later, Martin et al. [96] contributed data regarding the transmission of "HAE type III" in France.

Boulliet et al. [97] reported that increased levels of estrogen in healthy women have produced a reduction of C1INH, which entailed an increase in amidolytic FXII activity. Dewald et al. analyzed 20 unrelated women with HAE without C1INH deficiency, finding two mutations in the *F12* gene in the second position of the ACG codon, corresponding to the residual amino acid 309; mutation I (five patients) 1032C>A; Thr309Lys; and mutation II (1 patient) 1032C>G; Thr309Arg (**Figure 4**). This mutation was not found in 145 healthy controls. Later, these authors extended the study to five families with 20 symptomatic patients and 10 asymptomatic family members (eight men and two women), which showed the presence of one of the two mutations [98]. Cichon et al. [99] studied a family proving that the increased amidolytic enzymatic activity of FXII in women produced an increase in the production of kinins. A year later, Martin et al. [100] studied four generations of one family with eight members who were carriers of the *F12* gene 1032C>A mutation (four symptomatic and four asymptomatic), noting that in women symptoms were triggered or exacerbated by estrogens, whereas in men the symptoms were milder.

Börk et al. [101] described 35 symptomatic women from 13 different families with FXII-HAE (with proven mutations p.Thr309Lys/p.Thr309Arg). Triggers were taking OCPs (17 women) and pregnancy (3 women). A symptomatic exacerbation occurred after taking OCPs (8 women), pregnancy (7 women), hormone replacement therapy with estrogen (3 women), taking ACE inhibitors (2 women) and taking type 1 ACE receptor blocker (1 woman). pdC1INH was effective as the treatment of acute AE attacks (6 women) and progestogens (8 women), danazol (2 women), and tranexamic acid (1 woman) were used as prophylactic treatment.

Börk et al. proposed to use FXII-HAE to name those cases of nC1-INH-HAE with a mutation in *F12* gene and unknown-HAE (U-HAE) to those without a known mutation [101].

The series with the largest number of hereditary (related to estrogen) (HAE type III) corresponds to Börk et al., who described 69 patients from 23 unrelated families with HAE-FXII, and 196 patients with U-HAE [102].

An increase in FXII amidolytic activity was initially described as the cause of activation of contact system and the final release of bradykinin with the consequent angioedema in FXII-HAE [99], although other authors could not confirm this. Recently, another study has shown

**Figure 4.** Historical review of angioedema type III.

214 A Comprehensive Review of Urticaria and Angioedema

that the different mutations in exon 9 of *F12* gene found in FXII-HAE produce an increase in FXII activability by plasmin [103].

In Spain, several studies have been published focusing on FXIII-HAE: Serrano et al. [104] (six cases; two of them women from the same family) and Prieto et al. [105] (four generations of the same family with mutation 1032C>A; Thr309Lys; three symptomatic women, one male asymptomatic carrier).

Baeza et al. [106] described a nonatopic 27-year-old Arab woman from Morocco with a clinical diagnosis of hereditary angioedema type III and the p.Thr328Lys mutation. Icatibant acetate was prescribed for compassionate use.

Gómez-Traseira et al. [107] describes 20 cases (11 females and 9 males on a large 3-generation Spanish family). The p.Thr309Lys mutation was detected in five female patients who had a phenotypic variant in which AE was exclusively precipitated by high estrogen levels and in six asymptomatic relatives.

Piñero-Saavedra et al. [108] described p.Thr309Lys mutation in 35 individuals (80% females) from 9 unrelated families. In this prospective observational cohort study, 16 females (44% estrogen dependent, 56% estrogen sensitive) were clearly symptomatic. Also, two polymorphisms (XPNPEP2 c-2399A and the ACE insertion/deletion) were detected in 17% of patients.

The University Hospital in Grenoble is a reference center for the study of FXII-HAE in France. As a result of this, Vitrat-Hincky et al. [109] published a retrospective analysis (for the years 2000–2009) with 26 patients, which included four symptomatic men).

Duan et al. [110] not only confirmed the *F12* gene mutation (gene-codifying coagulation factor XII) in women of the same family but also provide certain polymorphisms in the genes encoding aminopeptidase P (APP) and angiotensin-converting enzyme (ACE). It highlights the role of the BK-catabolizing enzymes in the pathogenesis of angioedema.

Börk et al. [111] described a new mutation in the *F12* gene (deletion of 72 base pairs c.971\_1018+24del72\*). More recently, Kiss et al. [112] described a new mutation consisting in the duplication of 18 base pairs (c.892\_909dup) causing the repeated presence of 6 aa (p.298- 303) in the same region of FXII to those described above.

Grumach et al. [113] report two Brazilian FXII-HAE families segregating the mutation c.983 C>A (p.Thr328Lys). In each family, one patient with a homozygous mutation was found. The homozygous FXII-HAE mutation status leads to a severe phenotype in females and males, and to an increased risk of manifest symptoms in the latter.

In terms of treatment, there is no approved drug for the treatment of nC1-INH-HAE, either FXII-HAE or U-HAE. The pdhC1INH has been used in the acute attack of AE in some cases of FXII-HAE [102, 114, 115]. More recently, icatibant acetate was effective but also used off-label as this indication is not reflected in the product's prescribing information [115].
