Alternative titles; symbols
ORPHA: 100054, 91378; DO: 0080940;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 5q35.3 | Angioedema, hereditary, 3 | 610618 | Autosomal dominant | 3 | F12 | 610619 |
A number sign (#) is used with this entry because of evidence that hereditary angioedema-3 (HAE3) is caused by heterozygous mutation in the gene encoding coagulation factor XII (F12; 610619) on chromosome 5q35.
Hereditary angioedema-3 (HAE3) is a rare disorder characterized clinically by recurrent skin swelling, abdominal pain attacks, and potentially life-threatening upper airway obstruction. The disorder occurs almost exclusively in women and is often precipitated or worsened by high estrogen levels (e.g., during pregnancy or treatment with oral contraceptives). Both concentration and function of C1 inhibitor (C1NH; 606860) are normal (summary by Dewald and Bork, 2006).
For a discussion of genetic heterogeneity of HAE, see 106100.
Binkley and Davis (2000) reported a 3-generation Italian family with a unique type of hereditary angioedema that was estrogen-dependent. The episodes were clinically indistinguishable from HAE1 and HAE2 (see 106100), but occurred only during pregnancy or with the use of exogenous estrogens. The patients were otherwise asymptomatic, except for 1 patient who had aspirin/NSAID-related angioedema later in life. There were 7 clearly affected individuals, but the status of several members in later generations was unknown. Laboratory studies of multiple complement proteins, including C1 inhibitor, as well as an assay for coagulation factor XII, were normal.
While screening a large population of patients with recurrent angioedema of the skin, Bork et al. (2000) identified 10 unrelated women with hereditary angioneurotic edema who had normal C1 inhibitor protein concentration and function, and normal C4 concentration. A more detailed study of these families identified another 26 affected members, who were also all women. Fourteen of the 26 women were studied and all were found to have normal C1 inhibitor concentration and function, and normal C4 concentration. The disease was seen in successive generations, and in offspring of affected mothers the male-to-female sex ratio was shifted to 1/1.5. Bork et al. (2000) stated that the formal genetics of this entity are suggestive of an X-linked dominant mode of inheritance. They observed the transmission of disease to children from an unaffected female in 2 kindreds. Bork et al. (2000) proposed the term 'hereditary angioedema type 3' or this disorder. The main clinical features of HAE3 include one or more of the following: recurrent skin swelling, abdominal pain attacks, and episodes of upper airway obstruction. There was no history of urticaria in the patients or any family members. Duration of the disorder extended over decades or many years, either in patients or in family members. Normal C1 inhibitor and C4 concentrations were present in plasma. There was no efficacy of antihistamines or corticosteroids on symptoms, and no treatment effect of C1 inhibitor concentrate. In some patients the onset of disease was during adolescence or after initiation of oral contraceptives. Occasional patients had symptoms only while taking oral contraceptives or when pregnant.
Kranke et al. (2000) pointed out that C1 inhibitor activity can sometimes be normal or near normal in symptom-free periods, but substantially lowered during attack. They suggested that the failure response to therapy observed by Bork et al. (2000) might be related to an underdosed therapeutic regimen.
HAE3 is an autosomal dominant disorder (Dewald and Bork, 2006; Cichon et al., 2006).
Cichon et al. (2006) performed a genomewide linkage study of 4 German families with HAE3 reported by Bork et al. (2000) and found evidence for a disease-causing gene on chromosome 5q35.2-q35.3.
In affected members of 4 German families with HAE3, 3 of which had previously been reported 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 2 reasons: factor XII proteolytic activity is involved in the generation of kinins, which increase vascular linkage and trigger edema formation, and expression of factor XII and plasma levels are known to be regulated by estrogens.
Cichon et al. (2006) reported the occurrence of the T309K mutation, which they referred to as T328K, in affected members of a French family with HAE3. Haplotype analyses with use of SNPs at the F12 locus provided evidence that the French family and 3 of the German families reported by Dewald and Bork (2006) (families 0003, 0004, 0005) shared a common founder.
In an Italian family with estrogen-dependent angioedema, Binkley and Davis (2000) excluded mutations at the C1 inhibitor locus and in the promoter region of the F12 gene. In a study of 3 affected members of the family reported by Binkley and Davis (2000), Duan et al. (2009) identified heterozygosity for the T328K mutation in the coding region of the F12 gene. These 3 patients also carried the A allele of SNP rs3788853 in the XPNPEP2 gene (300145.0001) which may have contributed to the phenotype, but this minor allele was also present in 10 unaffected family members.
Kranke et al. (2000) criticized the designation HAE III for this disorder, because Day and Good (1988) had used the designation HAE III for a type characterized by an albumin-bound C1 inhibitor protein without functional activity, which can be differentiated from the C1 inhibitor protein of HAE II by electrophoresis. Kranke et al. (2000) suggested that the type discussed by Bork et al. (2000) should be named HAE IV.
Binkley, K. E., Davis, A., III. Clinical, biochemical, and genetic characterization of a novel estrogen-dependent inherited form of angioedema. J. Allergy Clin. Immun. 106: 546-550, 2000. [PubMed: 10984376] [Full Text: https://doi.org/10.1067/mai.2000.108106]
Bork, K., Barnstedt, S.-E., Koch, P., Traupe, H. Hereditary angioedema with normal C1-inhibitor activity in women. Lancet 356: 213-217, 2000. [PubMed: 10963200] [Full Text: https://doi.org/10.1016/S0140-6736(00)02483-1]
Cichon, S., Martin, L., Hennies, H. C., Muller, F., Van Driessche, K., Karpushova, A., Stevens, W., Colombo, R., Renne, T., Drouet, C., Bork, K., Nothen, M. M. Increased activity of coagulation factor XII (Hageman factor) causes hereditary angioedema type III. Am. J. Hum. Genet. 79: 1098-1104, 2006. [PubMed: 17186468] [Full Text: https://doi.org/10.1086/509899]
Day, N. K., Good, R. A. Inherited and acquired deficiencies of C1 esterase inhibitor in man.In: Rother, K.; Till, G. O. (eds.) : The Complement System. Heidelberg: Springer-Verlag 1988.
Dewald, G., Bork, K. Missense mutations in the coagulation factor XII (Hageman factor) gene in hereditary angioedema with normal C1 inhibitor. Biochem. Biophys. Res. Commun. 343: 1286-1289, 2006. [PubMed: 16638441] [Full Text: https://doi.org/10.1016/j.bbrc.2006.03.092]
Duan, Q. L., Binkley, K., Rouleau, G. A. Genetic analysis of factor XII and bradykinin catabolic enzymes in a family with estrogen-dependent inherited angioedema. J. Allergy Clin. Immun. 123: 906-910, 2009. [PubMed: 19178938] [Full Text: https://doi.org/10.1016/j.jaci.2008.12.010]
Kranke, B., Salmhofer, W., Aberer, W. Hereditary angioedema and normal C1-inhibitor activity in women. (Letter) Lancet 356: 1440 only, 2000. [PubMed: 11052609] [Full Text: https://doi.org/10.1016/S0140-6736(05)74078-2]