**Author details**

that the different mutations in exon 9 of *F12* gene found in FXII-HAE produce an increase in

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

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

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

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

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

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

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-

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,

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 informa-

2000–2009) with 26 patients, which included four symptomatic men).

of the BK-catabolizing enzymes in the pathogenesis of angioedema.

303) in the same region of FXII to those described above.

and to an increased risk of manifest symptoms in the latter.

FXII activability by plasmin [103].

216 A Comprehensive Review of Urticaria and Angioedema

was prescribed for compassionate use.

asymptomatic carrier).

six asymptomatic relatives.

patients.

tion [115].

Jesús Jurado-Palomo1,2\*, Irina Diana Bobolea3,4, Alexandru Daniel Vlagea5 and Teresa Caballero2,6,7

\*Address all correspondence to: h72jupaj@yahoo.es

1 Department of Allergology, Nuestra Señora del Prado University General Hospital, Talavera de la Reina, Spain

2 Spanish Study Group on Bradykinin-Induced Angioedema (SGBA), Spanish Society of Allergology and Clinical Immunology (SEAIC), Madrid, Spain

3 Department of Allergology, Hospital Doce de Octubre Institute for Health Research (i+12), Madrid, Spain

4 Highly-specialized Severe Asthma Unit, Hospital Doce de Octubre Institute for Health Research (i+12), Madrid, Spain

5 Department of Immunology, Central Laboratory of Madrid Community—BRSalud, San Sebastián de los Reyes, Madrid, Spain

6 Department of Allergology, Hospital La Paz Institute for Health Research (IdiPAZ), Madrid, Spain

7 Biomedical Research Network on Rare Diseases, CIBERER (U754), Madrid, Spain
