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Familial Cold Urticaria
Wednesday, 16 July 2003
Sunday, 23 October 2005
Familial Cold Autoinflammatory Syndrome, Cold Hypersensitivity, Familial Polymorphous Cold Eruptio

What

Familial cold urticaria is an inherited autoimmune disorder that consists of an often painful rash, fever, and joint pain after exposure to cold. It is considered to be a periodic fever syndrome, a class which includes familial Mediterranean fever. It should be distinguished from the more commonly seen acquired cold urticaria, which presents later in life as an immediate allergic response of itchy “hives” caused by direct contact with cold and is not associated with fever or joint pain.

Who

Familial cold urticaria is very rare, with an incidence of less than one in 1,000,000. Most cases have been reported in North America and Europe, with onset at less than 6 months old, and 60% presenting at birth. It is inherited in an autosomal dominant manner, meaning that an affected individual will have two copies of the allele (gene sequence for a particular characteristic or disease), one with the mutation that causes the disease. That person can pass on either of the two alleles to his/her offspring, so each child has a 50% of inheriting the mutated allele and therefore having the disorder.

Signs and Symptoms

The following signs and symptoms occur in individuals with familial cold urticaria after exposure to cold, including weather and air conditioning:

  • Rash of tender, red, raised papules (spots) and plaques (patches) starts 1-2 hours after exposure, though it can be up to 8 hours after
  • Low-grade fever and joint pain start 4-6 hours after exposure, often affecting the hands, knees, and ankles
  • Some also have muscle aches, conjunctivitis (irritation of the eye membranes), sweating, drowsiness, headache, extreme thirst, and nausea Each episode usually lasts less than 24 hours. Patients may experience mild symptoms on a daily basis, with attacks initiated by mild temperature drops such as from air conditioning. They often have elevated white blood cells counts from 20,000 to 40,000, and an elevated erythrocyte sedimentation rate (ESR, a marker of inflammation). Less than 2% of those affected will develop AA amyloidosis, in which amyloid (a type of protein) breakdown products are deposited in the kidneys due to chronic inflammation in the body, potentially causing renal failure.

Possible Causes

Mutations on a gene called NALP3 or CIAS1 located on chromosome 1 (specifically position 1q44) have been identified in cases of familial cold urticaria. However, some patients do not have NALP3 mutations, so there are likely other genes involved. In addition, NALP3 mutations have been identified in two other diseases, believed to be in the same spectrum as familial cold urticaria. Muckle Wells syndrome has similar symptoms except cold sensitivity is absent and patient often have hearing loss. Chronic infantile neurologic cutaneous articular syndrome (CINCA, also known as neonatal-onset multisystem inflammatory disease or NOMID) presents with rash, fever, chronic meningitis, hearing loss, and deforming joint disease in infancy. The NALP3 gene normally produces a protein named cryopyrin, which is believed to play a role in the death of white blood cells involved in the early stages of inflammation. The onset of symptoms may be associated with cold temperatures activating a chain of events resulting in the inflammatory symptoms of an attack.

Diagnosis

The following criteria have been proposed to make the diagnosis, which is mainly through clinical symptoms: • Recurrent intermittent episodes of fever and rash that usually follow any generalized cold exposure • Autosomal dominant pattern of inheritance, though a spontaneous mutation may lead to the first case in a family • Age of onset less than 6 months • Duration of most attacks less than 24 hours • Conjunctivitis associated with attacks, though this is present in only 84% of patients • Absence of deafness, periorbital edema, lymphadenopathy, and serositis Testing for NALP3 gene mutation may be done but may still be negative in the affected individual. To differentiate from acquired cold urticaria, the clinician may perform an ice cube test, in which an ice cube is held on the patient’s skin to see if an urticarial rash occurs. If such a rash develops, the test is considered to be diagnostic of acquired cold urticaria and likely not the familial form.

Treatment

The most effective treatment for patients with familial cold urticaria will be to avoid the cold. After the onset of an attack, warming treatments and non-steroidal anti-inflammatories like ibuprofen may help. Others have used high dose steroids, but side effects are a major deterrent. There have been reports of a drug called anakinra (kineret), a recombinant IL-1 receptor antagonist used in rheumatoid arthritis, preventing symptoms after exposure to cold, but clinical trials have not been performed yet.

Prognosis

Life expectancy is the same as the normal population. Patients should expect to have lifelong symptoms, though they may lessen in severity with increasing age.

Connect with other parents

In the spirit of community and support, Madisons Foundation offers the unique service of connecting parents of children with rare diseases. If you would like to be connected to other parents of children with this disease, please fill out this brief form.

Weblinks

Cold Urticaria Info Island
An online support group for those with familial cold urticaria, but also includes individuals with acquired cold urticaria and other types of chronic urticaria.

FCAS Study
Call for enrollment in a study of the condition, run by Dr. Hal Hoffman, who discovered the NALP3 gene mutation seen in many patients.

Familial Cold Urticaria
Personal website of an affected individual who is attempting to collect contact information of others to form a support group.

Fire and Ice: An Altered Protein Brings Fever, Chills
Press release about the identification of NALP3 mutation as the basis for both familial cold urticaria and Muckle-Wells syndrome.

Google Search for Familial Cold Urticaria

References and Sources

Bingham, CO (2005). UpToDate: Etiology and diagnosis of urticaria. http://www.utdol.com/application/topic/print.asp?file=allergy/9917&type=P&selectedTitle=5~6 Hoffman HM (2005). Orphanet Encyclopedia: Familial cold autoinflammatory syndrome. http://www.orpha.net/data/patho/GB/uk-FCAS.pdf Simon A, van der Meer JWM, and Drenth JPH (2005). Familial autoinflammatory syndromes. Kelley’s Textbook of Rheumatology, 7th ed. Philadelphia: Elsevier. 1773-1788. Wanderer AA (2004). The spectrum of acquired and familial cold-induced urticaria/urticaria-like syndromes. Immunol Allergy Clin North Am 24(2): 259-286.