Familial Cold Autoinflammatory Syndrome (FCAS)

FCAS is the acronym for: Familial Cold Autoinflammatory Syndrome, also known as Familial Cold Urticaria (FCU). This syndrome is also characterized by autosomal dominant inheritied genetic mutation on the CIAS1 gene which codes the protein cryopyrin. (See Muckle-Wells Syndrome for more information.) This an extremely rare syndrome that is present in certain families primarily of North American and European decent, and is estimated to occur at a rate of 1:1,000,000 in these continents. Over 300 people are known to have been diagnosed so far in America alone. Most people with FCAS are able to lead a normal life, with an average life expectancy, and often have married and had children (which is how some affected families share a the same type of CIAS1 genetic mutation for this syndrome). However, mutations can also occur spontaneously at conception, as it can with NOMID and MWS. There can occasionally be an overlap of symptoms with MWS and FCAS. This has made many investigators conclude that FCAS, MWS, and NOMID/CINCA are just differing degrees of severity within the same genetic periodic fever syndrome-CAPS (Cryopyrin Associated Periodic Fever Syndrome). Diagnosis of FCAS/FCU requires the presence of at least FOUR of the following six criteria:

Fever & Rash After Cold Exposure

1. Recurrent, intermittent episodes of fever, accompanied by a rash that usually develops 1-2 hours AFTER exposure to natural, experimental, or any kind of generalized cold temperature exposure. The start of flares of rash, with the fever and other symptoms starts in early infancy, or rarely, early childhood in all FCAS sufferers (which is the case witH NOMID and MWS as well.) Many FCAS patients have some evidence of the rash almost daily, but intense attacks of symptoms occur after exposure to cold temperature, or even very cold air conditioned rooms. The rash is first to come out, usually within 1-2 hours after exposure, followed by a low-grade fever, and arthralgias (joint aches) about 4-6 hours after the exposure. Most symptoms during an episode last less than 24 hours, and can also incude conjunctivitis in the eyes, sweating, fatigue, headaches, genralized pains, extreme thirst, and nausea in addition to the fever, rash and joint pains. FCAS must NOT be confused with Aquired Cold Urticaria (ACU) also known as Cold Urticaria(CU), which is a common, non-genetic kind of allergic reaction to cold temperatures that develops later in life, and presents with symptoms of rash and allergic symptoms within minutes of cold exposure.

Genetic Mutation In the CAPS (CIAS1) Gene

2. Autosomal dominant inheritance leads to the passing on of the CAPS genetic mutation to offspring, and then through family groups. (This means that you can inherit the genetics to cause this syndrome even if only one parent has it). The genetic mutation is in the CIAS1 region of the cryopryin domain. This is the orgin of the "Familial" part of the syndrome, however people can also spontaneously develop a mutation in the CIAS1 region (It had to start somewhere!). Since FCAS does not commonly cause major permanent damage to the body, as in the other cryopyrin-related syndromes, many people have been able to marry and have children, and have passed FCAS genetics on throughout their family for generations. There are a few large family groups with FCAS, but there are varying degrees of suffering from symptoms within these groups. (See the "Cold Urticaria Info Island" support group link in the FCAS part of our Links Page for an extensive list of FCAS family group geneology.)

Onset During Infancy

3. The age of onset of symptoms is under 6 months of age, but most patients have the rash present at birth, or within the first few months of life. This is common to all the cryopyrin-related syndromes, however FCAS symptoms are induced by cold exposure, whereas the MWS and NOMID generally have flare ups of inflammation at random, and often with great frequency. The knowledge of onset at infancy for FCAS is helpful for diagnosis, to rule out other cold-induced syndromes (see Aquired Cold Urticaria, ACU).

Duration Under 24 Hours
	4. The duration of the majority of the attacks with FCAS is less than 24 hours from the first signs of symptoms after cold exposure, but in that time, the person suffers greatly from many symptoms, which may include: rash, fevers, fatigue, chills, joint and other pain, conjunctivitis (redness of the whites of the eyes, extreme sweating, headaches, excessive thirst, blurred vision, and nausea.

Conjunctivitis
	5. The presence of conjunctivitis (irritation and redness in the white area of the eye) with attacks or flares of FCAS. This can also occur during flares with NOMID/CINCA and Muckle-Wells Syndrome, but people with FCAS do NOT generally have the other persistent eye inflammation issues present, as seen in NOMID patients.

Absence of More Severe Symptoms

6. In FCAS patients, there is NO evidence of periorbital edema (swelling around the eye orbit), lymphadenopahty (enlarged lymph nodes), or inflammation of the pleural, peritoneal or pericardial cavities in the body(serositis). It is uncommon to have hearing los, and unknown if it is caused by CAPS or other causes. Kidney disease from AA amyloidosis is uncommon in FCAS, and occurs in less than 2% of patients (see MWS about Amyloidosis, and links page).

Treatment

Until a few years ago, people with FCAS had to treat their symptoms with warming treatments, along with non-steroidial anti-inflammatory drugs (such as Naproxen, Ibuprofen,etc.) High doses of corticosteroids are effective, but most patients would rather avoid the short and long term side effects of those drugs, in comparison to the symptoms of FCAS. Currently, great success has been seen in clinical trials with the use of the interleukin-1 blocking,trapping or otherwise Il-1 attacking drugs, which has been able to block the development of symptoms in controlled cold exposure challenge experiments. Hopefully soon, there will be some FDA approved Interleukin-1 blocking drugs with FDA labeling as a recommended treatment for FCAS, and the other CAPS syndromes. Please look at the section about other CAPS syndromes, and how they compare to FCAS, which will help you to understand this syndrome even better. References for this information include the Orphanet article by Dr. Hal M.Hoffman, and expert on FCAS, and other cryopyrin genetic mutation syndromes. (See the links section for this article)