Hereditary Angioedema with Normal C1 Inhibitor: Update on Evaluation and Treatment

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Key points

  • Clinically, hereditary angioedema with normal C1 inhibitor (HAE-nC1) is similar to hereditary angioedema caused by C1 inhibitor (C1-INH) deficiency, but not identical. About a quarter of HAE-nC1 cases are attributed to mutations in the F12 gene; in three-quarters of the cases the pathomechanism is still widely unknown.

  • Swelling attacks in patients with HAE-nC1 are thought to be caused by bradykinin.

  • As of now, there are no routine laboratory tests to confirm the diagnosis of HAE-nC1, so the

The pathophysiology of hereditary angioedema with normal C1 inhibitor

Swelling attacks in patients with HAE-C1-INH are brought about by activation of the contact system and the subsequent generation of bradykinin, which causes extravasation by activating the bradykinin 2 receptor. This pathomechanism is thought to also be involved in HAE-nC1. The contact system, a side-branch enzyme system of the coagulation system, consists of factor XII (FXII), plasma prekallikrein (PPK), and high-molecular-weight kininogen (HK). These factors generate spontaneous enzymatic

The genetics of hereditary angioedema with normal C1 inhibitor

About a quarter of HAE-nC1 cases are attributed to mutations in the F12 gene located in chromosome 5 (5q33-qter) and encoding for coagulation factor XII (Hageman factor, FXII). Up to now, four F12 mutations have been identified and are thought to be causal for HAE-nC1 based on their cosegregation patterns.39 All of them are located in the proline-rich linker peptide between the Kringle and trypsinlike serine protease (Tryp-SPc) domains of the FXII protein39; these are two distinct missense

Clinical features of hereditary angioedema with normal C1 inhibitor

Similar to HAE-C1-INH, patients with HAE-nC1 experience angioedema attacks of the skin, gastrointestinal tract, and airways. The episodes are transient and generally separated by intervals of complete remission. Individual HAE-nC1 attacks are indistinguishable from HAE-C1-INH attacks. However, HAE-nC1 is different from HAE-C1-INH in many aspects, and the subgroups of HAE-nC1, HAE-FXII, and HAE-UNK also show differences.

The mean age of onset of HAE-nC1 symptoms is reported to be 26.8 years

Diagnosis

The diagnostic work-up of HAE-C1-INH is usually straightforward. The history and pattern of signs and symptoms are typical and prompt the assessment of levels of C4 and C1-INH as well as its function. In rare cases, genetic testing may be needed to confirm the diagnosis. Nevertheless, patients with HAE-C1-INH are commonly misdiagnosed, most frequently with allergic angioedema and appendicitis, resulting in long delays in the correct diagnosis.70, 71

In contrast, the diagnosis of HAE-nC1 is more

Treatment of hereditary angioedema with normal C1 inhibitor

No prospective, randomized controlled studies have been performed so far in patients with HAE-nC1, and there are, therefore, no licensed treatments available as of now. However, several observational studies have assessed various medications for the treatment of HAE-nC1, although most of these studies do not clearly distinguish between HAE-UNK and HAE-FXII. There is consensus that angioedema attacks in patients with HAE-nC1 do not respond to corticosteroids or antihistamines, even at high doses.

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    Conflicts of interest: M. Magerl has received consultancy/honorarium fees from Shire, Viropharma, CSL Behring, and Sobi. A.E. Germenis has received research support from Shire (grant no: IIR-GRC-000905), Amgen, and Novartis; has received consultancy fees from Shire; has received lecture fees from Novartis and Amgen; and has received travel support from Shire. C. Maas is consultant to Shire, Pharming. M. Maurer has received research support, consultancy/lecture fees, and/or travel support from Biocryst, CSL Behring, and Shire/Dyax/Viropharma.

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