Genetic analysis reveals recurrent HAE with normal C1-INH: Study

Testing can show disease in previously asymptomatic family members

Steve Bryson, PhD avatar

by Steve Bryson, PhD |

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A genetic analysis revealed hereditary angioedema (HAE) was hidden among people with chronic, recurring swelling, but without an apparent family history and normal C1-inhibitor (C1-INH) levels, a study reported.

Searching for mutations in patients with chronic, recurring angioedema with an inherited component may detect asymptomatic family members at risk of developing the condition.

“Based on our results, we recommend that patients with long-standing recurrent angioedema that is not responding to antihistamines, and who are solitary in their families, should be investigated for mutations linked to hereditary angioedema with normal C1-INH,” the researchers wrote in the study, “Gene mutations linked with hereditary angioedema in solitary angioedema patients with normal C1-INH,” which was published in the Journal of Allergy and Clinical Immunology: In Practice.

Types of angioedema

Angioedema is marked by swelling in the deep layers of the skin or mucous membranes and is classified into different types based on the underlying cause or causes.

Acute allergic angioedema, the most common type, is triggered by an allergic reaction to infections, certain medications, or foods. Nonallergic angioedema, also called drug-induced angioedema, is caused by medication side effects, particularly to ACE inhibitors that treat high blood pressure.

Inherited mutations are mainly associated with HAE, but genetic defects can occur spontaneously with no family history.

HAE type 1 and 2 are caused by mutations in the SERPING1 gene, leading to a deficiency in C1-INH. This protein normally blocks the activity of two other proteins, plasma kallikrein and coagulation factor 12, both of which stimulate the production of bradykinin, a molecule that promotes inflammation and swelling.

HAE type 3 is rarer form of the condition, also known as HAE-nC1-INH, where functional C1-INH levels are within the normal range. It can be caused by mutations in other genes, such as the F12 gene that contains instructions for making coagulation factor 12.

Lastly, idiopathic angioedema refers to a broad class of angioedema with no apparent cause, a feature of which is chronic, relapsing swelling. Reports have identified people with chronic, relapsing angioedema (CRA) without wheals, whose disease failed to respond to antihistamines, or so-called non-histaminergic idiopathic angioedema.

In some cases, however, patients have normal C1-INH levels with symptoms similar to those with HAE-nC1-INH, but without an obvious family history.

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Analysis of patients with normal C1-INH

Researchers in Germany conducted a genetic analysis of 132 unrelated patients, all reporting no family history of angioedema, but having chronic, relapsing swelling without wheals, that was unresponsive to antihistamines. C1-INH levels were normal in all of them.

Genes associated with HAE-nC1-INH, including F12, PLG, ANGPT1, KNG1, MYOF, and HS3ST6 were examined.

Among the participants, 10 (7.6%) had an HAE-nC1-INH-specific mutation in the F12 gene, called c.983C>A, while six (4.5%) had a PLG gene mutation, known as c.988A>G. In the remaining 116 (87.9%) patients with recurrent angioedema, none of the six HAE-nC1-INH-linked mutations were found.

Although participants reported no family history, a more detailed examination revealed two of the F12 mutation carriers and all those with the PLG mutation had deceased relatives with HAE symptoms.

Among the 10 patients with F12 mutations, eight had 26 available first-degree relatives (parent, sibling, or child) who’d never had HAE symptoms. Ten of these 26 were carriers of the c.983C>A mutation. One of the asymptomatic five first-degree relatives of those with the PLG mutation carried the c.988A>G mutation.

Complete information was available for 15 of the 16 participants who tested positive for an HAE-nC1-INH-specific mutation. Fourteen of them had family members who were either mutation carriers or who had clinical symptoms of HAE-nC1-INH. In contrast, for the 116 patients without HAE-linked mutations, the detailed family history didn’t reveal any affected relatives.

Clinical features of patients

All those with F12 mutations were women, as were 83.3% of the patients with PLG mutations and 69.9% of those without HAE-linked mutations. The mean age of symptom onset was 17 for those with F12 mutations, 35.7 for those with PLG mutations, and 38.9 in those without HAE-specific mutations.

Across the whole study population, 121 reported skin swelling; 41, abdominal attacks; 64, tongue swelling; and 36 had throat swelling. Except for abdominal attacks, differences with and without mutations didn’t reach statistical significance.

Angioedema was triggered by estrogen in all 10 women with F12 mutations, in two of the three with PLG mutations who received estrogens (67%), and in 21 of the 42 (50%) women without HAE-specific mutations who were also given estrogens. In three of six PLG mutation patients, swelling was caused by ACE inhibitors.

The “search for [HAE-nC1-INH]-linked mutations in patients with solitary CRA may lead to the detection of patients and families with [HAE-nC1-INH],” the researchers wrote. “This is important because further and previously asymptomatic family members at risk for developing potentially life-threatening angioedema can be identified.”

“Without genetic investigation, the risk of a [HAE-nC1-INH] would have remained undetected in these patients and asymptomatic relatives,” they wrote.