New familial cold urticaria identified

Cold urticaria. Photo by: SecretName101, via Wikimedia Commons

A group of German researchers have identified a previously unknown form of familial cold urticaria. They note their findings explain why conventional treatments are ineffective in some people with the disorder, and suggest potential alternative treatments.

In a press release from Charité—Universitätsmedizin Berlin, authors of the study explain how they discovered a form of the condition—which can cause skin rash, fever and joint pain—caused by a mutation in the Factor 12 gene. The team has proposed the name ‘Factor XII-associated cold autoinflammatory syndrome,’ or FACAS, for the newly-identified hereditary disorder.

In many people, this disorder will develop suddenly, but gradually lessen and disappear again after a number of years. Why it appears at all remains unknown. A small proportion of those with cold urticaria inherit the disorder from their parents. In these people, the immune system response to cold temperatures is due to a genetic defect which, in addition to a skin rash, will cause signs of systemic inflammation, including fever and joint pain. Researchers led by Dr. Karoline Krause of the Department of Dermatology, Venereology and Allergology on Campus Charité Mitte have now discovered a new form of cold urticaria which is caused by a previously unknown mutation in the ‘Factor 12’ gene. The name proposed for this new hereditary disorder is ‘Factor XII-associated cold autoinflammatory syndrome,’ or FACAS.

“Our report relates to several members of the same family seen in our department. At least one person in each generation of this family reported identical symptoms, which they had suffered from birth,” said Dr. Krause, in the release.“These individuals all developed a burning skin rash after 30 minutes of exposure to temperatures below 15°C (59°F). The rash was exacerbated by windy weather and humid conditions, and only resolved several hours after the individual returned to a warmer room.”

The patients also reported other symptoms such as chills, fatigue, headache and joint pain. In contrast to people who develop cold urticaria spontaneously, these patients did not respond to a cold provocation test known as the ‘ice cube test.’ Their symptoms also failed to respond to antihistamines, which are normally an effective treatment for cold urticaria.

“The family’s symptoms were clearly indicative of a hereditary form of cold urticaria,” said Dr. Krause. “We therefore studied the affected individual’s genetic information, looking for mutations which are known to cause the disorder’s hereditary form, but to no avail. What we found instead was a previously unknown defect in the Factor 12 gene.”

According to the release, this gene defect leads to activation of the contact system pathway, leading to the release of inflammatory mediators which then induce urticaria.

“Interestingly, defects in the Factor 12 gene had previously been known to cause a very different condition which we refer to as hereditary angioedema,” said Dr. Krause. Hereditary angioedema is characterized by sudden attacks of severe and painful swelling in the deeper tissues.

“While the symptoms reported by FACAS patients are those of hereditary cold urticaria, the underlying mechanisms causing these symptoms are entirely different. These patients therefore qualify for treatment with drugs normally used in hereditary angioedema,” she said.

One of the FACAS patients showed an immediate response when given icatibant, a medication normally used to treat acute attacks of hereditary angioedema. Upon administration, the patient’s cold-induced symptoms resolved quickly and almost completely.

Findings from the study, published in Nature Communications (Jan. 10, 2020), could aid researchers in discovering the causes of currently unexplained cases—individuals with hereditary cold urticaria of unknown origin, in whom conventional drugs such as antihistamines are ineffective, can undergo genetic testing for FACAS.

“We also plan to conduct a small clinical study in order to test whether lanadelumab can provide long-term relief in our group of adult FACAS patients,” said Dr. Krause. Lanadelumab is a type of antibody primarily used as a preventive long-term treatment in hereditary angioedema.

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