What are the other Names for this Condition?  (Also known as/Synonyms)

• Familial Cold Urticaria (FCU)
• Familial Polymorphous Cold Eruption
• FCAS (Familial Cold Autoinflammatory Syndrome)

What is Familial Cold Autoinflammatory Syndrome? (Definition/Background Information)

• Familial Cold Autoinflammatory Syndrome (FCAS) is a rare systemic disorder in which a cold environment triggers fever, a hive-like rash, malaise, headache, conjunctivitis, and joint pain
• These may improve after sufficient time in a warm environment. Repeat exposure to the cold causes return of the signs and symptoms. The condition may be mistaken for cold urticaria due to similar signs and symptoms
• Familial Cold Autoinflammatory Syndrome is a genetic disorder with autosomal dominant inheritance. It is caused by mutations in the CIAS1/NLRP3 gene
• FCAS is a lifelong condition that may lead to complications, such as amyloidosis, in rare cases. However, with adequate symptomatic treatment and avoidance of cold environments, the outcomes are excellent

Who gets Familial Cold Autoinflammatory Syndrome? (Age and Sex Distribution)

• Familial Cold Autoinflammatory Syndrome (FCAS) is a rare congenital disorder, and the onset of signs and symptoms are most often noted at birth or infancy (usually within the first 6 months)
• In rare cases, the onset may occur during young adulthood
• FCAS is seen equally in males and females
• Most cases of Familial Cold Autoinflammatory Syndrome are of European ancestry

What are the Risk Factors for Familial Cold Autoinflammatory Syndrome? (Predisposing Factors)

• The greatest risk factor for Familial Cold Autoinflammatory Syndrome (FCAS) is having a family history of the syndrome
• Some spontaneous mutations have been reported

It is important to note that having a risk factor does not mean that one will get the condition. A risk factor increases one’s chances of getting a condition compared to an individual without the risk factors. Some risk factors are more important than others.

Also, not having a risk factor does not mean that an individual will not get the condition. It is always important to discuss the effect of risk factors with your healthcare provider.

What are the Causes of Familial Cold Autoinflammatory Syndrome? (Etiology)

• Familial Cold Autoinflammatory Syndrome (FCAS) results from a defect in the CIAS1/NLRP3 genetic site. It is inherited in an autosomal dominant manner
• This mutation is thought to cause an increase in cryopyrin, a cold-induced  inflammatory signal complex, which then increases Interleukin-1beta
  • Interleukin-1beta is a potent agent integral to many inflammatory pathways
  • Increased Interleukin-1beta is the cause of all the signs and symptoms seen in individuals with FCAS

Autosomal dominant: Autosomal dominant conditions are traits or disorders that are present when only one copy of the mutation is inherited on a non-sex chromosome. In these types of conditions, the individual has one normal copy and one mutant copy of the gene. The abnormal gene dominates, masking the effects of the correctly function gene. If an individual has an autosomal dominant condition, the chance of passing the abnormal gene on to their offspring is 50%. Children, who do not inherit the abnormal gene, will not develop the condition, or pass it on to their offspring.

What are the Signs and Symptoms of Familial Cold Autoinflammatory Syndrome?

The signs and symptoms of Familial Cold Autoinflammatory Syndrome (FCAS) can have their onset from birth or in childhood. The flare-ups may worsen with advancing age.

• Most episodes include rash, fever and chills, fatigue, joint pain, and conjunctivitis
• The rashes may be itchy or induce stinging/burning sensation
• Blurred vision, watering, and pain of the eyes due to conjunctivitis can also occur in FCAS
• Lethargy, headache, muscle pain, drowsiness, profuse sweating and thirst, which can be extreme, can also be seen
• Episodes usually occur within a few hours of cold exposure, with the hive-like rash appearing first, and other symptoms later; most cases peak within 2-6 hours of generalized cold exposure
• Most episodes resolve after 24 hours
• The signs and symptoms may be mild or severe and debilitating in some cases

How is Familial Cold Autoinflammatory Syndrome Diagnosed?

The constellation of signs and symptoms in response to cold exposure is a key to the diagnosis of Familial Cold Autoinflammatory Syndrome (FCAS).

• As a condition with autosomal dominant inheritance, children born to a parent known to have FCAS will be monitored for signs and symptoms 
• Most cases are found in large family clusters with known FCAS, simplifying the diagnosis
• Genetic testing: Mutations are also known to arise in some patients without a family history of the condition
• During disease flares, elevated white blood cell count (WBC), C-reactive protein (CRP), and erythrocyte sedimentation rate (ESR) are noted
• If a skin biopsy is done of the rash, neutrophils (a WBC type) are seen near the sweat glands

A differential diagnosis may be considered to eliminate certain skin conditions, prior to arriving at a definitive diagnosis.

Many clinical conditions may have similar signs and symptoms. Your healthcare provider may perform additional tests to rule out other clinical conditions to arrive at a definitive diagnosis.

What are the possible Complications of Familial Cold Autoinflammatory Syndrome?

• In rare instances, the protein amyloid can accumulate in the kidneys of Familial Cold Autoinflammatory Syndrome (FCAS) patients, leading to impairment or failure of kidney function
• The lifelong frequent intermittent episodes of inflammation and the need to alter activities can lead to feelings of isolation or depression

How is Familial Cold Autoinflammatory Syndrome Treated?

The treatment of Familial Cold Autoinflammatory Syndrome (FCAS) may involve:

• Lifestyle changes: Avoidance of a cold environment and appropriate clothing when exposed can mitigate the disease flares
• Adequate bed rest and keeping the patient warm
• Non-steroidal anti-inflammatory drugs (NSAIDs) are often used to control fever and joint pain
• Systemic corticosteroids can control the entire syndrome complex. As a chronic condition, frequent use of corticosteroids in FCAS can lead to significant side effects
• Patient education in understanding the condition is beneficial
• Before FDA approval of any medications for FCAS, a drug which was known to decrease Interleukin-1beta in other diseases was successfully used in Familial Cold Autoinflammatory Syndrome
• Two FDA-approved medications are currently available for treatment of FCAS

The healthcare provider may discuss the planned course of treatment with the patients and help them in understanding the benefits and potential side effects of some of the medications used in treating FCAS.

How can Familial Cold Autoinflammatory Syndrome be Prevented?

Familial Cold Autoinflammatory Syndrome (FCAS) may not be preventable since these genetic disorders are diagnosed at or following the birth of the child.

• Genetic testing of the expecting parents (and related family members) and prenatal diagnosis (molecular testing of the fetus during pregnancy) may help in understanding the risks better during pregnancy
• If there is a family history of the condition, then genetic counseling will help assess risks, before planning for a child
• Active research is currently being performed to explore the possibilities for treatment and prevention of inherited and acquired genetic disorders

Patients affected by FCAS can try to limit their exposure to cold environments (cold weather or air-conditioned rooms) to minimize the frequency of future episodes.

What is the Prognosis of Familial Cold Autoinflammatory Syndrome? (Outcomes/Resolutions)

Familial Cold Autoinflammatory Syndrome (FCAS) is a lifelong condition.

• The prognosis of FCAS is excellent, with few reports of serious complications of the syndrome
• With successful treatment, the disability from the febrile episodes and other signs and symptoms can be diminished

Additional and Relevant Useful Information for Familial Cold Autoinflammatory Syndrome:

Familial Cold Autoinflammatory Syndrome (FCAS) is associated with Muckle-Wells syndrome and neonatal-onset multisystem inflammatory disease (NOMID), or chronic infantile neurologic cutaneous articular (CINCA) syndrome, as a cryopyrin-associated periodic syndrome (CAPS).