NORD gratefully acknowledges Dr. Hal Hoffman, Associate Professor of Pediatrics and Medicine, Division of Rheumatology, Allergy, and Immunology at the University of California at San Diego School of Medicine, for assistance in the preparation of this report.
Familial cold autoinflammatory syndrome (FCAS), also known as familial cold urticaria, is a rare, inherited inflammatory disorder characterized by intermittent episodes of rash, fever, joint pain and other signs/symptoms of systemic inflammation triggered by exposure to cold. Onset of FCAS occurs during infancy and early childhood and persists throughout the patient’s life.
FCAS is one of the cryopyrin associated periodic syndromes (CAPS) caused by mutations in the CIAS1/NLRP3 gene. These syndromes are characterized by fever, rash, and joint pain. As in other CAPS, amyloidosis can rarely develop later in life in FCAS patients. Amyloidosis is due to an abnormal accumulation of the protein amyloid in a patient’s tissues and organs such as the kidneys where it results in damage and often kidney failure if untreated.
FCAS shares symptoms, and should not be confused, with acquired cold urticaria, a more common condition mediated by different mechanisms that usually develops later in life and is rarely inherited.
Patients with FCAS experience mild to debilitating symptoms such as rash, fatigue, recurrent fever and chills, recurrent joint pain, and recurrent conjunctivitis (inflammation of the outer most layer of the eye causing redness, discomfort and discharge from the eye).
Other symptoms include profuse sweating, drowsiness, headache, extreme thirst, red eyes, blurred vision, eye pain, watering eyes and nausea
Symptoms occur within hours after exposure to cold. In most cases, a rash will occur within the first 1-2 hours, followed by a fever and joint pain. Episodes usually last for less than 24 hours.
FCAS is usually inherited in an autosomal dominant condition and is caused by a heterozygous mutation in a gene identified as CIAS1/NLRP3 that codes for the protein cryopyrin (NALP3). Mutations in this gene are hypothesized to cause increased activity of a protein complex containing cryopyrin. This protein complex is known as the inflammasome and regulates inflammation in the body. Increased inflammasome activity results in increased release of a protein known as interleukin (IL) 1ß, which leads to symptoms of inflammation such as fever and joint pain.
Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary to cause a particular disease. The abnormal gene can be inherited from either parent or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy. The risk is the same for males and females.
Since FCAS is a newly discovered condition, the actual incidence and prevalence of the disease is difficult to determine at this time.
Diagnosis of FCAS is determined through an evaluation of a patient’s symptoms. Confirmation of the diagnosis is achieved through DNA gene analysis and the identification of a CIAS1/NLRP3 mutation(4), although not all FCAS patients possess a mutation in this gene.
Some of the common criteria that distinguish FCAS from other hereditary periodic fevers and acquired cold urticaria include:
Non-steroidal anti-inflammatory drugs are often used to alleviate joint pain. High doses of corticosteroids have shown to be somewhat effective, but may cause short- and long-term side effects.
Arcalyst (Rilonacept) by Regeneron Pharmaceuticals, an interleukin-1 blocker, was approved by the FDA in 2008 for the treatment of CAPS, including FCAS and MWS, in adults and children 12 and older.
Ilaris (Canakinumab) by Novartis Pharmaceuticals, a monoclonal antibody to interleukin-1 beta,. was approved by the FDA in 2009 as a treatment for children and adults with CAPS, including FCAS and MWS.
Kineret (Anakinra) by Biovitrum pharmaceuticals, an IL-1 receptor antagonist, has been used extensively in FCAS patients with excellent clinical results. However, it is not currently approved by the FDA for the treatment of FCAS or any of the CAPS diseases.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]
For information about clinical trials sponsored by private sources, contact:
Contact for additional information about familial cold autoinflammatory syndrome:
Dr. Harold M. Hoffman
Associate Professor of Pediatrics and Medicine
Division of Rheumatology, Allergy, and Immunology
University of California at San Diego School of Medicine
RareConnect offers a safe patient-hosted online community for patients and caregivers affected by this rare disease. For more information, visit www.rareconnect.org.
Stojanov S, Kastner DL. Familial autoinflammatory diseases: genetics, pathogenesis and treatment. Current Opinion in Rheumatology. 2005;17:586-599.
Drenth JPH. van der Meer JWM. The inflammasome – a linebacker of innate defense. New England Journal of Medicine. 2006;355(7):730-732.
Hoffman, HM, Mueller, JL, et al. Mutation of a new gene encoding a putative pyrin-like protein causes familial cold autoinflammatory syndrome and Muckle-Wells syndrome. Nature. 2001;29:301-305.
Hoffman, HM, Wanderer, AA, & Broide, DH. Familial cold autoinflammatory syndrome: Phenotype and genotype of an autosomal dominant periodic fever. J Allergy Clin Immunol. 2001;108(4):615-620.
FROM THE INTERNET
Familial Cold Autoinflammatory Syndrome (FCAS). Available at: http://www.nomidalliance.net/subpage1.html. Accessed: November 21, 2006.
Hoffman, HM. Cold Autoinflammatory Syndrome, Familial. Orphanet Encyclopedia. November 2003: http://www.orpha.net/data/patho/GB/uk-FCAS.pdf
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