F12 – Hereditary Angioedema Type III

Hereditary angioedema (HAE) type III is an estrogen-dependent form of HAE characterized by recurrent angioedema attacks without urticaria and normal C1-inhibitor levels and function. Variants in the coagulation factor XII gene, F12, have been implicated in this subtype of hereditary angioedema. Clinical cohorts and familial segregation studies have identified gain-of-function missense mutations, notably c.983C>A (p.Thr328Lys), in multiple unrelated families ([PMID:19178407], [PMID:16638441]).

Inheritance is autosomal dominant with variable penetrance and marked female bias, likely reflecting transcriptional upregulation of F12 by estrogens. Index cases and their relatives carrying p.Thr328Lys present with recurrent facial, laryngeal, and abdominal angioedema often triggered by high-estrogen states such as pregnancy or oral contraceptive use ([PMID:19178407]). Co-segregation in at least one family with three additional affected relatives supports pathogenicity.

Genetic screening of 20 unrelated HAE type III patients revealed two recurrent missense changes at F12 codon 328: c.983C>A (p.Thr328Lys) in 17 patients and c.983C>G (p.Thr328Arg) in 3 patients, absent in healthy controls ([PMID:16638441]). These variants account for the majority of F12-related HAE cases, and no loss-of-function or splice variants have been associated with this phenotype.

Functional assays show that p.Thr328Lys is a gain-of-function mutation resulting in markedly increased FXII amidolytic activity without alteration of plasma FXII levels. Enhanced FXII enzymatic activity in female carriers leads to excessive bradykinin generation via the contact system, underpinning angioedema attacks ([PMID:17186468]). Estrogen-mediated upregulation of F12 transcription likely explains the female predominance.

Therapeutically, acute attacks respond poorly to histamines or corticosteroids but improve with C1-INH concentrate or bradykinin B2-receptor antagonists. Long-term prophylaxis with tranexamic acid or androgenic agents reduces attack frequency. Genetic testing for F12 should be considered in women with recurrent angioedema, normal C1-INH, and estrogen sensitivity.

Key Take-home: F12 gain-of-function variants (especially c.983C>A (p.Thr328Lys)) cause autosomal dominant, estrogen-triggered HAE type III; genetic diagnosis enables targeted prophylaxis and acute management.

References

• American Journal of Human Genetics • 2006 • Increased activity of coagulation factor XII (Hageman factor) causes hereditary angioedema type III PMID:17186468
• Allergy • 2009 • Missense mutation Thr309Lys in the coagulation factor XII gene in a Spanish family with hereditary angioedema type III PMID:19178407
• Biochemical and Biophysical Research Communications • 2006 • Missense mutations in the coagulation factor XII (Hageman factor) gene in hereditary angioedema with normal C1 inhibitor PMID:16638441

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