The gene mutation “factor XII”, which is hereditary, would explain the presence of cold-induced hives in some people, which cannot be cured by antihistamines.
Exposure to cold can lead to hives on the skin, with headache and joint pain associated with a previously unknown genetic disease. This is the result of a recent study by the Department of Dermatology and Allergy at Charité — Universitätsmedizin Berlin published in Nature Communications. The symptoms of skin rashes, as well as head and joint pain in patients with hereditary hives, develop when exposed to temperatures below 15°C, which was previously unknown.
According to the team, it is a new form of this inflammatory skin disease. Through their research, they also succeeded in understanding why conventional treatments were ineffective in treating this disease. According to the researchers, people suffering from this condition develop mild symptoms and it takes several years for the disease to subside and disappear.
Inherited genetic defect
The researchers did not understand why it occurred, but they found that a small number of people with this disease inherited the disease from their parents. In these people, the immune system’s reaction to cold is due to a genetic defect that causes systemic inflammation, including fever and joint pain, in addition to skin rashes.
The research team led by Dr. Karoline Krause from the Department of Dermatology, Venerology, and Allergology at Charité Mitte has discovered a new form of an urticarial rash, which they believe is caused by a previously unknown mutation of the “Factor XII” gene.
“Our report includes several members of the same family seen in our department. At least one person from each generation of this family reported identical symptoms they had suffered from since birth,” explains Karoline Krause. All these people developed a burning rash after being exposed to temperatures below 15°C for 30 minutes. The rash was aggravated by wind and humidity and did not disappear until several hours after the person had returned to a warmer room.
The ineffectiveness of antihistamines
Many of the patients with this disease reported headaches and joint pain as well as other symptoms such as chills and tiredness. The research team also found that these people do not respond to the cold challenge test known as the “ice cube test”, while people who develop cold hives respond spontaneously to these tests. They also do not respond to antihistamines, which are given to patients to treat hives.
According to Karoline Krause, “the family symptoms clearly indicated a hereditary form of hives,” explains the dermatologist. So we examined the genetic information of the affected person and looked for mutations that are known to cause the hereditary form of the disease, but in vain. What we found instead was a previously unknown defect in the factor 12 gene”.
The genetic defect also activates the contact system pathway that was demonstrated in the research, where it was found that hives are actually created by the subsequent release of inflammatory mediators.
“Strangely enough, it was previously known that defects in the Factor 12 gene caused a completely different condition, which we call hereditary angioedema. Although the symptoms reported by FXII-associated cold autoinflammatory syndrome (FACAS) patients are the symptoms of a hereditary cold-induced urticarial rash, the underlying mechanisms that cause these symptoms are completely different,” says Caroline Krause. These patients can, therefore, benefit from treatment with drugs that are usually used for hereditary angioedema.
Interestingly, one of the patients with FACAS showed an immediate response when given Icatibant, a drug commonly used to treat acute attacks of hereditary angioedema. After administration, the patient’s cold-related symptoms were quickly and almost completely resolved.