What Is Familial Cold Autoinflammatory Syndrome?

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Familial cold autoinflammatory syndrome (FCAS) is an autoinflammatory disease that causes episodes of fever, skin rash, and joint pain after exposure to cold temperatures. FCAS usually begins in infancy and continues throughout a person’s life.

As an autoinflammatory disease, FCAS falls under a group of conditions called cryopyrin-associated periodic syndromes (CAPS). These syndromes are characterized by fever, rash, and joint pain and are caused by gene mutations.

FCAS is a genetic condition and runs in families. It is not unusual to find multiple members of the same family afflicted with the condition. Here is what you need to know about FCAS, including symptoms, causes, diagnosis, and treatment.

Fever
Luis Alvarez / Getty Images.

FCAS Symptoms

A person with FCAS can go long periods without any signs of the condition. When there is an attack or flare-up of FCAS, symptoms can show up within minutes or after several hours after exposure to cold temperatures.

Cold temperature triggers include decreases in outside temperature and exposure to air conditioning. Flare-ups of FCAS can last up to 12 hours or they may continue for days.

The most common symptoms of FCAS are skin rash, fever, joint pain, and eye problems.

Skin Rash

FCAS can cause the skin to break out in hives. The skin may burn and itch. A person with FCAS may experience areas of inflamed skin called patches or plaques. Tiny purple-brown spots called petechiae may also appear on the skin. Rashes appear on the arms and legs after cold exposure and may spread to the rest of the body.

Skin inflammation may also cause other body areas to become inflamed and swollen. FCAS may cause recurring skin issues outside of disease flares.

Fever

Fevers associated with FCAS can last a few hours or a few days. A person experiencing an FCAS episode may also experience chills.

Joint Pain

Joint pain can occur several hours after cold exposure. It can affect the hands, knees, and ankles.

Eye Problems

FCAS affects the white parts of the eyes—the sclera—and causes redness and irritation in the form of a condition called conjunctivitis (pink eye). FCAS can also cause eye pain, excess tear production, and blurry vision.

Additional Symptoms

Additional symptoms of FCAS include muscle pain, nausea, fatigue, headache, extreme thirst, and excess sweating.

While rare, FCAS can cause amyloid A (AA) amyloidosis. This is where inflammation causes a protein called amyloid A to buildup in the organs, causing the organs to thicken and lose function. AA amyloidosis is also called autoimmune amyloidosis or secondary amyloidosis.

The organs most commonly affected by AA amyloidosis are the kidneys. Your doctor will want to check how well your kidneys are functioning as FCAS progresses.

Causes

FCAS is an autoinflammatory condition, and it is extremely rare, affecting 1 out of every 1 million people. It has mostly been reported in Europe and North America. The risk of developing FCAS is the same for both males and females.

FCAS is part of a group of newly categorized diseases resulting from gene mutations that affect the innate part of the immune system. The innate immune system includes the skin, gastrointestinal and respiratory tracts, nasopharynx, cilia, eyelashes, and other body hair. It is the body’s first line of defense against bacteria and other pathogens. 

The innate immune system will use white blood cells and short-term inflammation to attack a pathogen. Sometimes, that response becomes chronic and leads to frequent fevers, rashes, joint and muscle pain, and all-over inflammation, as is the case with conditions like FCAS.

Researchers believe FCAS occurs when there is a gene mutation of the NLRP3 gene. This is the gene that gives your body instructions on how to use cryopyrin—a protein mainly found in white blood cells and cells responsible for building cartilage.

The NLPR3 gene also regulates inflammation in the body. With a gene mutation of NLPR3, there will be an increase in the release of inflammatory proteins responsible for fever and joint pain.

You can get FCAS by inheriting a mutated NLRP3 gene from one of your parents. It is also possible to acquire a new gene mutation during fetal development that eventually causes FCAS to develop. Because FCAS is usually inherited in an autosomal dominant manner, there is a 50% chance you can pass the condition on to your child.

Diagnosis

To make a diagnosis of FCAS, your healthcare provider will give you a physical exam and ask you about your medical history, including symptoms experienced. To confirm FCAS, your healthcare provider will rely on common criteria to distinguish FCAS from other autoinflammatory disorders.

The criteria include:

  • Repeat episodes of fever and rash after exposure to cold
  • A family history of FCAS
  • Episodes that started before age 6 months
  • Symptoms that go away within 24 hours
  • Eye redness (conjunctivitis) during FCAS flare-ups
  • Absence of eye swelling, lymph node swelling, or serositis—inflammation of the serous membranes that line and enclose internal body cavities like the heart and abdomen

Your healthcare provider may also request bloodwork and genetic testing:

  • Bloodwork: Your doctor will want to check C-reactive protein (inflammatory protein) and/or amyloid A protein levels. These tend to be higher in people with autoinflammatory diseases like FCAS.
  • Genetic testing: Genetic testing for FCAS involves checking the blood for changes in the NLRP3 gene. Blood tests can be helpful in confirming a diagnosis.

Treatment

Treatment for FCAS usually involves medications to prevent or ease symptoms. Your doctor may also suggest you avoid the cold as much as possible.

Avoid cold: Cold situations can trigger FCAS symptoms and include outside temperatures, cold air blasts, damp rain, cold air from your refrigerator, and air conditioning.

Biologics: Biologic drugs—sometimes called biologics—can help to prevent or reduce symptoms of FCAS. These drugs are usually given by injection under the skin and will work to block the inflammatory proteins responsible for the symptoms of FCAS.

Common biologics prescribed to manage FCAS include Arcalyst (rilonacept), Ilaris (canakinumab), and Kineret (anakinra).

Other medications: Drug therapies used to manage FCAS include nonsteroidal anti-inflammatory drugs (NSAIDs) and corticosteroids. NSAIDs can help ease joint pain, fever, and inflammation. Corticosteroids are given for short periods to slow down the immune system.

Corticosteroid drugs are known for causing severe side effects, especially when taken for long periods. Discuss with your doctor the pros and cons of treating FCAS with steroids.

A Word From Verywell

Familial cold autoinflammatory syndrome is a life-long condition. It is important to rest and stay warm during flare-ups of the condition and to avoid triggering disease episodes.

Let your doctor know if FCAS symptoms are not under control. There are plenty of treatment options. If your regular doctor can’t help you, it is OK to ask for a referral to a rheumatologist or immunologist.

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  6. Medline Plus. NLRP3 gene. Updated August 18, 2020.