HistoryThis section has been translated automatically.
Comment: Knowledge of rare genetic diseases such as hereditary angioedema (HAE) has evolved in parallel with the development of new molecular tools. C1 inhibitor (C1-INH) deficiency has been recognized as the major cause of HAE (HAE-C1-INH) since the 1960s. Discovery of the broad spectrum of mutations affecting the C1-INH gene (SERPING1) was not possible until the late 1980s, when Sanger sequencing became available and more readily accessible worldwide.
However, the involvement of other genes in HAE was not discovered until 2006 with the description of mutations in the F12 gene in patients with HAE and normal C1-INH. The knowledge gained through the new era of genomics has been crucial for the discovery of mutations in additional genes, improving or explaining the understanding of the complex pathogenesis of this phenotypically largely identical disease. In the last three years, advanced next-generation sequencing techniques have enabled the identification of mutations in five additional novel genes associated with hereditary angioedema variants with normal C1-INH (nC1-INH-HAE): ANGPT1 (angiopoietin-1), PLG (plasminogen), KNG1 (kininogen), MYOF (myoferlin), and HS3ST6 (heparan sulfate glucosamine 3-O-sulfotransferase 6).
DefinitionThis section has been translated automatically.
Hereditary angioedema with mutation in F12 also called hereditary angioedema-3 or HAE3 (HAE III), is a very rare, autosomal dominant (X-linked dominant?) inherited (Dewald and Bork 2006; Cichon et al. 2006), recurrent disorder clinically characterized by recurrent skin swelling, abdominal pain episodes, and potentially life-threatening upper airway obstruction. Hereditary angioedema type III is caused by a heterozygous mutation in the gene encoding coagulation factor XII (Hageman factor; OMIM:610619/ Cichon et al. 2006).
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Occurrence/EpidemiologyThis section has been translated automatically.
The disease is very rare. Incidence figures are not available because very few cases have been described (mainly patients of French, German or British origin).
EtiopathogenesisThis section has been translated automatically.
One of the possible causes is activating mutations in the F12 gene (5q33-qter) for coagulation factor XII (Hageman factor). As a consequence of the increased factor XII activity (with normal serum levels and normal activity of the C1 inhibitor), increased bradykinin is formed.
ManifestationThis section has been translated automatically.
Unlike HAE types 1 and 2, HAE 3 occurs predominantly in women. In some patients, the disease started during puberty or after taking oral contraceptives. Occasionally, symptoms occurred only while taking oral contraceptives or during pregnancy.
Clinical featuresThis section has been translated automatically.
The main clinical features of HAE3 include: recurrent skin swelling, abdominal pain attacks and episodes of upper airway obstruction. There is no history of urticaria. The duration of the disease spans many years to decades in the few larger collectives. Antihistamines or corticosteroids have no effect on symptoms; neither do C1 inhibitor concentrates.
LaboratoryThis section has been translated automatically.
Both the concentration and function of C1 inhibitor (C1NH; 606860) are normal (summary by Dewald and Bork, 2006). So are C4 concentrations. However, in some patients, markedly lowered C1 inhibitor concentrations were measured during attacks.
In affected members of four German families with HAE3, three of which had already been described by Bork et al. (2000), Dewald and Bork (2006) identified a heterozygous missense mutation in the F12 gene (T309K; 610619.0006). Dewald and Bork (2006) also found another missense mutation at the same codon in another German family (610619.0007). The F12 gene was considered a strong candidate for HAE III for two reasons: factor XII proteolytic activity is involved in the formation of kinins that increase vascular binding and trigger edema formation, and factor XII expression and plasma levels are known to be regulated by estrogens.
In an Italian family with estrogen-dependent angioedema, Duan et al (2009) identified heterozygosity for the T328K mutation in the coding region of the F12 gene. These three patients also carried the A allele of the SNP rs3788853 in the XPNPEP2 gene (300145.0001), which may have contributed to the phenotype.
Case report(s)This section has been translated automatically.
Binkley and Davis (2000) reported a third-generation Italian family with hereditary angioedema that was estrogen-dependent. The episodes were clinically indistinguishable from HAE type I and HAE type II (106100) but occurred only during pregnancy or when exogenous estrogens were taken. Patients were otherwise asymptomatic, except for 1 patient who had aspirin/NSAID-related angioedema later in life. Laboratory tests of several complement proteins, including C1 inhibitor, and a coagulation factor XII test were normal.
Bork et al (2000), screening a larger population of patients with recurrent angioedema, identified 10 unrelated women with hereditary angioneurotic edema who had normal C1 inhibitor protein concentration and function and normal C4 concentration. A more detailed examination of these families identified an additional 26 affected members, all of whom were also women. Fourteen of the 26 women were examined and all had normal C1 inhibitor concentration and function and normal C4 concentration.
LiteratureThis section has been translated automatically.
- Binkley KE et al (2000) Clinical, biochemical, and genetic characterization of a novel estrogen-dependent inherited form of angioedema. J Allergy Clin Immun 106: 546-550.
- Bork K et al (2000) Hereditary angioedema with normal C1-inhibitor activity in women. Lancet 356: 213-217.
- Cichon S et al (2006) Increased activity of coagulation factor XII (Hageman factor) causes hereditary angioedema type III. Am J Hum Genet 79: 1098-1104.
- Dewald G et al (2006) Missense mutations in the coagulation factor XII (Hageman factor) gene in hereditary angioedema with normal C1 inhibitor. Biochem Biophys Res Commun 343: 1286-1289.
- Duan QL et al (2009) Genetic analysis of factor XII and bradykinin catabolic enzymes in a family with estrogen-dependent inherited angioedema. J Allergy Clin Immun 123: 906-910.
- Kranke B et al (2000) Hereditary angioedema and normal C1-inhibitor activity in women. (Letter) Lancet 356: 1440.
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