Man treated for rare hereditary angioedema with normal C1-INH

A genetic analysis of patient revealed no disease-causing mutations

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by Andrea Lobo |

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In this case study illustration, one clinician holds a gigantic magnifying glass in front of a patient's head and chest while another takes notes on a clipboard.

The case of a man with a rare form of hereditary angioedema (HAE) where the levels of the C1-inhibitor (C1-INH) protein were normal, referred to as HAE-nl-C1INH, was described by researchers in Japan.

While this form of HAE is most commonly seen in women and is usually associated with hormonal changes during pregnancy or birth control or hormone replacement medications, “a few male cases have been reported globally,” said researchers who described the man’s case in “Hereditary angioedema with a normal C1 inhibitor in Japanese man,” which was published in The Journal of Dermatology as a letter to the editor. “To the best of our knowledge, this is the first male patient with HAE-nl-C1INH in Japan.”

HAE is often caused by mutations in the SERPING1 gene that impair the production or activity of C1-INH, which normally blocks the activity of other proteins that promote the production of bradykinin, a signaling molecule that causes blood vessels to widen and become more permeable. When produced excessively, it can drive the swelling attacks in HAE by causing fluid to leak from blood vessels and pool into nearby tissues.

In HAE, low C1-INH activity usually causes the levels of C4 to fall. Another protein, C4 is part of the complement cascade, which is part of the immune system.

In rare cases, patients may also have a form of HAE where C1-INH is within the normal range.

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Normal C1-INH levels

“The prevalence, etiology [causes], and pathophysiology [disease mechanisms] of HAE-nl-C1INH are not well understood,” wrote the researchers, who described the case of a man in his early 60s with swelling episodes in his lips and tongue that happened several times a month. Occasionally, he also had swelling in his forearm. His first attack happened when he was 42, without any previous signs or symptoms.

The disease developed before he started taking medications for high blood pressure and continued after he stopped taking them.

Tests showed the man’s C1-INH activity and C4 levels were normal, and his symptoms didn’t ease after treatment with tranexamic acid, which is sometimes used off-label to prevent or treat HAE attacks, along with antihistamines and corticosteroids.

A genetic analysis didn’t reveal any disease-causing mutations. The man was diagnosed with HAE-nl-C1INH based on his recurrent angioedema symptoms, which his mother and eldest son also had.

To manage his swelling attacks, he started treatment with icatibant, which is sold as Firazyr with generic forms available, and Takhzyro (lanadelumab), administered every two weeks, to prevent attacks. These treatments reduced the attacks’ frequency and severity.

While HAE-nl-C1INH occurs more frequently in women, some cases have been reported in men.

“According to new postulates, normal C1 inhibitor-induced hereditary angioedema has at least two distinct forms, one limited to women and the other affecting both sexes,” the researchers wrote.