Pathophysiology of Hereditary Angioedema (HAE) Beyond the SERPING1 Gene

Clin Rev Allergy Immunol. 2021 Jun;60(3):305-315. doi: 10.1007/s12016-021-08835-8. Epub 2021 Jan 14.


Hereditary Angioedema (HAE) is an autosomal dominant disorder characterized clinically by recurrent episodes of swelling involving subcutaneous tissues, gastrointestinal tract, and oro-pharyngeal area. Gene mutations are the most common genetic cause of HAE and observed in more than 90% of patients. More than 700 mutation variants have been described so far. Patients with angioedema who have no mutations in the gene for C1-INH and normal levels and activity of this inhibitor are labelled: normal C1 inhibitor HAE. These include genetic mutations in factor 12 gene, plasminogen gene, angiopoietin gene, kininogen 1, and myoferlin genes. The clinical manifestations of patients with these mutations are similar to with patients with C1-INH gene mutations. However, a later age of onset, oro-pharyngeal involvement, and higher female preponderance have been reported in these rare subtypes of hereditary angioedema. With the advent and increased accessibility of whole-exome sequencing, it is expected that new genetic defects and novel pathophysiological pathways will be identified in families with HAE of unknown cause or normal C1-INH angioedema. This review covers some of the recent advances in the field of HAE. The review focuses on pathophysiology of HAE beyond the well-known C1-INH deficiency phenotypes, including various biomarkers that can serve the diagnosis and management of these rare disorders.

Keywords: Angioedema; Angiopoietin; Factor XII; Hereditary; Kininogen; Myoferlin; Plasminogen.

Publication types

  • Review

MeSH terms

  • Angioedemas, Hereditary* / diagnosis
  • Angioedemas, Hereditary* / genetics
  • Complement C1 Inhibitor Protein / genetics
  • Factor XII / genetics
  • Female
  • Humans
  • Phenotype


  • Complement C1 Inhibitor Protein
  • SERPING1 protein, human
  • Factor XII