F12 – Type III Hereditary Angioedema

Type III hereditary angioedema (HAE type III) is an estrogen-sensitive form of angioedema characterized by recurrent skin swelling, abdominal pain and potentially life-threatening laryngeal edema despite normal C1-esterase inhibitor levels. The association with F12 (encoding coagulation factor XII) was first described through gain-of-function missense variants that increase FXII amidolytic activity and bradykinin production, explaining the phenotype in female carriers exposed to high estrogen states.

Genetic evidence supports an autosomal dominant inheritance. A heterozygous c.983C>A (p.Thr328Lys) variant was identified in a French kindred with multiple affected women, with disease onset correlated to pregnancy or oral estrogen use (PMID:17186468). A separate case report described repeated angioedema attacks during pregnancy in a woman harboring an unspecified F12 missense mutation (PMID:30131260).

Segregation data are limited, with co-segregation in a single pedigree; no large multiplex families have been reported to date. Phenotypic penetrance is modulated by estrogen exposure, and locus heterogeneity has been noted in some families lacking F12 coding changes, suggesting additional genes may contribute to HAE type III.

Functional studies demonstrate that p.Thr328Lys FXII exhibits markedly increased enzymatic activity without altered protein levels, leading to enhanced kinin generation (PMID:17186468). Estrogen upregulates F12 transcription, further amplifying FXII activity in women. These in vitro and biochemical findings concord with the clinical phenotype.

No strong conflicting evidence has been reported, although negative mutational screens in some affected families highlight genetic heterogeneity. Alternative genes (e.g., PLG, KNG1) have been implicated in HAE with normal C1-INH, but F12 remains the primary locus for estrogen-dependent HAE type III.

Integration of genetic and experimental data supports a moderate clinical validity classification for F12 and HAE type III. Identification of F12 gain-of-function variants enables hormone-guided management and genetic counseling. Key Take-home: F12 testing is clinically useful for diagnosing estrogen-triggered angioedema in women with normal C1-INH function.

References

• American Journal of Human Genetics • 2006 • Increased activity of coagulation factor XII (Hageman factor) causes hereditary angioedema type III PMID:17186468
• International Journal of Obstetric Anesthesia • 2018 • Repeated attacks of type III hereditary angioedema with factor XII mutation during pregnancy. PMID:30131260

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