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Familial Cold Autoinflammatory Syndrome

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Copyright 2007, 2011

NORD is very grateful to 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.

Synonyms of Familial Cold Autoinflammatory Syndrome

Disorder Subdivisions

General Discussion

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.

Affected Populations

Since FCAS is a newly discovered condition, the actual incidence and prevalence of the disease is difficult to determine at this time.

Related Disorders

Symptoms of the following disorders can be similar to those of FCAS and there is significant phenotypic overlap. Comparisons may be useful for a differential diagnosis.

Neonatal-onset multisystem inflammatory disease (NOMID), also known as chronic infantile neurologic cutaneous articular (CINCA) syndrome, is a rare, congenital, systemic, inflammatory condition characterized by fever, abnormal joint findings, rash, and central nervous system (CNS) disease with onset during infancy. NOMID is the most severe form of the cryopyrin associated periodic syndromes (CAPS) and is often caused by mutations in the CIAS1/NLRP3 gene.

Muckle-Wells syndrome (MWS) is one of the cryopyrin associated periodic syndromes (CAPS). Individuals with MWS often have episodic fever, chills, and painful joints. Sometimes these symptoms are exacerbated by cold similar to the related condition FCAS, but can also be triggered by other stimuli. In most cases, MWS patients develop progressive hearing loss. In some MWS cases amyloidosis develops later in life, a disease in which an abnormal accumulation of the protein amyloid occurs in a patient's tissues and organs. Accumulation of amyloid in the kidneys results in damage and often kidney failure if untreated.

Standard Therapies

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:

* Recurrent, intermittent episodes of fever and rash that primarily follow exposure to cold

* Family history of the disease

* Age of onset of less than 6 months of age

* Duration of most attacks less than 24 hours

* Presence of conjunctivitis associated with attacks

* Absence of swelling of the eyes, swelling of one or more lymph nodes, and serositis (the inflammation of the serous membrane which lines and encloses several body cavities including the abdomen and the heart).

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.

Investigational Therapies

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: prpl@cc.nih.gov

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

Familial Cold Autoinflammatory Syndrome Resources

NORD offers an online community for this rare disease. RareConnect was created by EURORDIS (European Rare Disease Organisation) and NORD (National Organization for Rare Disorders) to provide a safe space where individuals and families affected by rare diseases can connect with each other, share vital experiences, and find helpful information and resources. You can view these international, rare disease communities at www.rareconnect.org.

NORD Member Organizations:

(To become a member of NORD, an organization must meet established criteria and be approved by the NORD Board of Directors. If you're interested in becoming a member, please contact Susan Olivo, Membership Manager, at solivo@rarediseases.org.)

Other Organizations:


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.

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

Report last updated: 2011/02/14 00:00:00 GMT+0