Hereditary angioedema with normal C1-INH with versus without specific F12 gene mutations

Allergy. 2015 Aug;70(8):1004-12. doi: 10.1111/all.12648. Epub 2015 May 22.

Abstract

Background: Hereditary angioedema with normal C1-INH may be linked to specific mutations in the coagulation factor 12 (FXII) gene (HAE-FXII) or mutations in genes that are still unknown (HAE-unknown). To assess the differences in transmission and inheritance, clinical features, and laboratory parameters between patients with HAE-FXII and HAE-unknown.

Methods: Sixty-nine patients with HAE-FXII from 23 unrelated families and 196 patients with HAE-unknown from 65 unrelated families were studied.

Results: Both HAE-FXII and HAE-unknown are inherited as autosomal-dominant traits with incomplete penetrance. The male to female ratio was 1 : 68 in HAE-FXII and 1 : 6.3 in HAE-unknown. The maternal to paternal transmission ratio was 35 : 14 for HAE-FXII and 109 : 12 for HAE-unknown. Mean age at onset of clinical symptoms was 20.3 years in patients with HAE-FXII and 29.6 years in patients with HAE-unknown. The incidence of asphyxiation due to angioedema was similar for HAE-FXII and HAE-unknown. Oral contraceptives and pregnancies had a significantly higher impact on HAE-FXII than on HAE-unknown. Slightly decreased C1-INH activity and C4 concentration were observed in more patients with HAE-FXII than HAE-unknown. Tests for FXI and FXII activity, plasminogen activator inhibitor 1, and activated partial thromboplastin time showed variability but no significant differences between the groups. No abnormalities were found for C1-INH protein, C1q, alpha2-macroglobulin, antithrombin III, and angiotensin-converting enzyme. In families with HAE-FXII, the number of female offspring with F12 mutations was significantly increased and that of male offspring was significantly decreased.

Conclusions: HAE-FXII and HAE-unknown differ in various respects, including gender distribution, genetics, symptoms, and estrogen impact.

Keywords: Angioedema; coagulation factor XII; hereditary angioedema type III; hereditary angioedema with normal C1 inhibitor; specific mutations in the F12 gene.

Publication types

  • Comparative Study

MeSH terms

  • Adult
  • Age Distribution
  • Age of Onset
  • Angioedemas, Hereditary / diagnosis
  • Angioedemas, Hereditary / epidemiology*
  • Angioedemas, Hereditary / genetics*
  • Cohort Studies
  • Complement C1 Inhibitor Protein / genetics*
  • Databases, Factual
  • Factor XII / genetics*
  • Female
  • Humans
  • Incidence
  • Male
  • Middle Aged
  • Mutation*
  • Pedigree
  • Phenotype
  • Prognosis
  • Recombinant Proteins / genetics
  • Retrospective Studies
  • Severity of Illness Index
  • Sex Distribution
  • Young Adult

Substances

  • Complement C1 Inhibitor Protein
  • Recombinant Proteins
  • conestat alfa
  • Factor XII