Rare genetic variant may help explain recurring angioedema attacks

A rare genetic variant may help explain recurrent angioedema attacks in a woman whose levels and function of a protein called C1-esterase inhibitor (C1-INH) were normal, according to a case report.

The 51-year-old woman had experienced swelling episodes for 13 years despite trying several treatments. Her symptoms and responses to treatment suggested that her angioedema was driven by bradykinin, a molecule involved in triggering swelling, even though her C1-INH levels and activity were normal.

To investigate the possible cause, researchers performed genetic testing and identified a rare variant in a gene called MYOF. The variant, classified as being of uncertain significance, may make blood vessels unusually sensitive to bradykinin, the researchers suspect.

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Understanding angioedema with normal C1-INH

Although further studies are needed to confirm the variant’s role, the findings may offer clues about what causes angioedema in people with normal C1-INH levels and function.

The study, “Bradykinin-Mediated Angioedema with Normal C1 Inhibitor Associated with a MYOF Variant: Therapeutic and Structural Insights,” was published in the Annals of Allergy, Asthma & Immunology.

Angioedema causes sudden swelling in the deeper layers of the skin or mucous membranes, often affecting the face, lips, tongue, or throat. In hereditary angioedema (HAE), acquired angioedema (AAE), and some cases of idiopathic (of unknown cause) angioedema, swelling is driven by bradykinin. This molecule makes blood vessels leakier, allowing fluid to escape into nearby tissues.

In the two most common forms of HAE, types 1 and 2, genetic mutations cause low levels or reduced activity of C1-INH, a protein that helps control bradykinin production. In a rarer form, known as type 3 HAE or HAE with normal C1-INH, both C1-INH levels and function remain normal. Variants in several other genes, including MYOF, have been linked to this form, although their roles remain poorly understood.

In AAE, abnormally low C1-INH levels or activity are commonly caused by another illness, such as cancer or an autoimmune disease. In bradykinin-mediated idiopathic angioedema, however, the cause of abnormal bradykinin signaling remains unknown.

The researchers described the woman’s 13-year history of recurrent swelling affecting her face, arms, legs, and genital area, sometimes accompanied by severe abdominal pain. Each episode lasted two to three days.

She occasionally developed hives, which commonly accompany allergic angioedema, but they usually occurred separately from her swelling episodes.

Swelling attacks persist despite allergy treatments

However, antihistamines, the allergy and asthma medication omalizumab (sold as Xolair), and immunosuppressants such as cyclosporine and corticosteroids failed to control her swelling. This suggested that histamine, a chemical involved in allergic reactions, was unlikely to be driving her angioedema.

Blood tests showed normal C1-INH levels and activity, and an extensive evaluation for autoimmune disease was negative. The researchers noted that some forms of HAE with normal C1-INH can develop later in life and that neither the onset of the woman’s symptoms nor subsequent episodes were linked to hormonal changes or medications.

Doctors suspected bradykinin-mediated angioedema and started therapeutic plasma exchange (TPE) in 2021, based on earlier reports of its use for severe angioedema with normal C1-INH. The procedure, commonly used to treat certain autoimmune and blood disorders, removes and replaces plasma, the liquid portion of blood, to help clear substances that may contribute to disease.

With TPE every four weeks, her swelling episodes decreased from two or three per month to one every one or two months, and her hives disappeared. However, episodes returned when catheter problems interrupted treatment, and TPE was discontinued after three years.

In February 2025, weekly infusions of plasma-derived C1-INH concentrate completely stopped her swelling, but episodes returned within two weeks after treatment ended.

She then started Orladeyo (berotralstat) in December 2025. The oral medication, approved for preventing swelling attacks in children and adults with HAE, blocks plasma kallikrein, an enzyme involved in bradykinin production. Over eight months of follow-up, she remained free of swelling attacks.

Rare genetic variant may affect blood vessel function

To investigate the possible genetic basis of the woman’s condition, researchers performed genetic testing. They found no variants classified as disease-causing or likely disease-causing in genes already known to be associated with angioedema. However, they identified a rare variant, called N267D, in MYOF, which provides instructions for making myoferlin, a protein involved in blood vessel function. The variant was also found in several relatives who had no symptoms of angioedema. The researchers said further laboratory studies are needed to determine whether the variant affects blood vessel function.

Examinations revealed fewer tiny blood vessels around her fingernails and signs of new vessel growth, similar to abnormalities previously reported in people with HAE carrying a different MYOF variant. Her blood level of VEGF-A, a protein involved in blood vessel growth, was also higher than the average measured in a small group of healthy people.

Computer-based modeling suggested that the variant may alter how myoferlin interacts with cell membranes and how certain receptors are recycled in endothelial cells, which line the inside of blood vessels. The researchers proposed that these changes could make blood vessels more sensitive to bradykinin, allowing fluid to leak more easily into surrounding tissues.

“This case integrates converging clinical, therapeutic, vascular, genetic, and structural evidence supporting a bradykinin-mediated endothelial disorder,” the researchers wrote. “Functional studies are now required to determine whether this variant directly alters myoferlin-dependent membrane trafficking and endothelial barrier regulation.”