Hereditary angioedema type iii D84.9

Dewald and Bork 2006

Hereditary angioedema type III is a type of angioedema that (in contrast to angioedema types I and II) is induced by a mutation in the gene for the blood clotting factor XII (Hageman factor) (Bork K et al 2017).

Hereditary angioedema is thus known to have three subtypes of the disease, all of which follow an autosomal dominant mode of inheritance.

In patients with HAE type I and type II, the concentration and/or activity of the C1 esterase inhibitor (C1-INH) are decreased due to a mutation. C1-INH normally inhibits central factors of the kallikrein-kinin cascade, resulting in a controlled release of bradykinin. The impaired functional activity of C1-INH leads to an excessive formation of the peptide hormone bradykinin, to a dilation of blood vessels with an increased influx of fluid into the tissue (edema formation) (Deroux A et al. 2016).

The prevalence of the disease is unknown. While women and men are equally affected by angioedema attacks in HAE types I and II, type III attacks more frequently affect women (w:m=9:1 Veronez CL et al. 2018). Estrogens probably influence the expression of the Hagemann factor.

Type III of HAE (HAE-nC1) is clinically indistinguishable from HAE types I and II. However, the function of C1-INH is by definition normal (see naming). In type III, a mutation in the gene for blood clotting factor XII (Hageman factor) can be detected (Bork K et al 2017). Due to the mutation-related structural change in factor XII, there is an overproduction of bradykinin in the kinin-Kallikrein cascade and thus, as with types I and II, increased permeability of the vessel walls. This aberrant bradykinin formation is considered to be the cause of the tendency of HAE type III patients to swell.

In larger studies the mean age of onset of the disease was between 20 and 30 years (Deroux A et al. 2016) (Bouillet L et al. 2017).

The clinical symptoms of HAE type III, analogous to types I and II, are spontaneous, recurrent angioedema mainly in the face and genitals. Swelling of the tongue, pharynx and larynx is possible and potentially life-threatening. Changes in the oestrogen balance in women (puberty, pregnancy, use of oestrogen-containing contraceptives and hormone replacement therapy) favour the tendency towards angioedema. Angioedema can, however, also develop spontaneously and without a recognisable trigger.

About 50% of male mutation carriers remain asymptomatic (Veronez CL et al. 2018). Their disease symptoms are usually much less pronounced.

Laboratory diagnostics are the same as for types I and II. The C1-INH concentration is normal and C4 in plasma is not reduced.

An intake of oestrogen must be avoided at all costs. About 90% of this patient population benefits from a discontinuation of estrogens (Bork K et al 2017).

Five drugs are currently available for acute treatment of HAE: Berinert® P (C1-INH concentrate), Firazyr® (Icatibant), Ruconest™ (recombinant human C1-INH), Cinryze® (C1-INH concentrate) and fresh frozen plasma. All are suitable for the treatment of acute attacks in adults. A weighting is not possible based on the data available to date.

As a special feature of HAE type III, prophylaxis with progesterone can be helpful.

Danazol is optionally available as a long-term therapeutic agent

Not in all cases of HAE-nC1 patients a factor XII gene defect could be detected. The defect has not yet been detected in this patient group. Some patients had a missense mutation in exon 9 of the plasminogen (PLG) gene (Dewald G 2018).

1. Bork K et al (2015) Hereditary angioedema with normal C1-INH with versus without specific F12 gene mutations. Allergy 70:1004-1012. https://www.ncbi.nlm.nih.gov/pubmed/25952149
2. Bork K et al (2017) Treatment for hereditary angioedema with normal C1-INH and specific mutations in the F12 gene (HAE-FXII). Allergy 72:320-324. https://www.ncbi.nlm.nih.gov/pubmed/27905115
3. Bouillet L et al (2017) Hereditary angioedema with normal C1 inhibitor: clinical characteristics and treatment response with plasma-derived human C1 inhibitor concentrate (Berinert(®)) in a French cohort. Eur J Dermatol 27:155-159. https://www.ncbi.nlm.nih.gov/pubmed/28250922
4. Deroux A et al (2016) Hereditary angioedema with normal C1 inhibitor and factor XII mutation: a series of 57 patients from the French National Center of Reference for Angioedema. Clin Exp Immunol 185:332-337.
5. Dewald G (2018) A missense mutation in the plasminogen gene, within the plasminogen kringle 3 domain, in hereditary angioedema with normal C1 inhibitor. Biochem Biophys Res Commun 498:193-198.
6. Magerl M et al (2017) Hereditary Angioedema with Normal C1 Inhibitor: Update on Evaluation and Treatment. Immunol Allergy Clin North Am 37:571-584.
7. Veronez CL et al (2018) Hereditary Angioedema with Normal C1 Inhibitor and F12 Mutations in 42 Brazilian Families. J Allergy Clin Immunol Pract 6:1209-1216.