Familial cold autoinflammatory syndrome is a type of periodic fever syndrome. Signs and symptoms may include include an itchy or burning rash; fever; and joint pain which are triggered by exposure to cold temperatures. It is inherited in an autosomal dominant manner and can be caused by mutations in the NLRP3 or NLRP12 genes. Management of this condition involves avoiding exposure to cold temperatures and treatment with specific types of medications.

NLRP3 or NLRP12. These genes normally provide instructions for making proteins involved in the immune system, helping to regulate the process of inflammation. Changes in these genes impair the body's mechanisms for controlling inflammation, resulting in the signs and symptoms of this condition. It remains unclear why episodes are triggered by cold exposure.

Normal Function

The NLRP3 gene provides instructions for making a protein called cryopyrin. Cryopyrin is a member of a family of proteins called intracellular "NOD-like" receptor (NLR) proteins. Cryopyrin is found mainly in white blood cells and in cartilage-forming cells (chondrocytes).

NLR proteins are involved in the immune system, helping to start and regulate the immune system's response to injury, toxins, or foreign invaders. NLR proteins recognize specific molecules and respond by helping to turn on (activate) certain parts of the immune system. Cryopyrin recognizes bacteria; chemicals such as asbestos, silica, and uric acid crystals; and compounds released by injured cells.

Cryopyrin molecules assemble themselves, along with other proteins, into structures called inflammasomes, which help trigger the process of inflammation. Inflammation occurs when the immune system sends signaling molecules as well as white blood cells to a site of injury or disease to fight foreign invaders and help repair damaged tissues. Once the threat is over, the body stops (inhibits) the inflammatory response, to prevent damage to its own cells and tissues.

Health Conditions Related to Genetic Changes

Cryopyrin-associated periodic syndromes

Several variants (also known as mutations) in the NLRP3 gene have been found to cause cryopyrin-associated periodic syndromes (CAPS). CAPS are a group of conditions that have overlapping signs and symptoms. The conditions are generally characterized by periodic episodes of skin rash, fever, and joint pain. CAPS include three conditions known as familial cold autoinflammatory syndrome type 1 (FCAS1), Muckle-Wells syndrome (MWS), and neonatal-onset multisystem inflammatory disorder (NOMID). These conditions were once thought to be distinct disorders but are now considered to be part of the same condition spectrum. FCAS1 is the least severe form of CAPS, MWS is intermediate in severity, and NOMID is the most severe form.

Many of the variants that cause CAPS are in a region of the NLRP3 gene known as exon 3. All of the variants likely result in the cryopyrin protein being overactive. Inflammasomes made with abnormal cryopyrin proteins trigger inflammatory responses even when there is no injury or disease. Impairment of the body's mechanisms for controlling inflammation results in episodes of fever and widespread damage to the body’s cells and tissues.

While the CAPS spectrum shares similar signs and symptoms, it is unclear why variants in different parts of the NLRP3 gene cause the patterns of features that distinguish FCAS1, MWS, and NOMID.

Other Names for This Gene

• AII/AVP
• AII/AVP receptor-like
• angiotensin/vasopressin receptor AII/AVP-like
• AVP
• C1orf7
• CIAS1
• CLR1.1
• cryopyrin
• NACHT domain-, leucine-rich repeat-, and PYD-containing protein 3
• NACHT, LRR and PYD containing protein 3
• NALP3_HUMAN
• NLR family, pyrin domain containing 3
• nucleotide-binding oligomerization domain, leucine rich repeat and pyrin domain containing 3
• PYPAF1
• PYRIN-containing APAF1-like protein 1

Genomic Location

The NLRP3 gene is found on chromosome 1.

Normal Function

The NLRP12 gene provides instructions for making a protein called monarch-1. Monarch-1 is a member of a family of proteins called intracellular "NOD-like" receptor (NLR) proteins. Monarch-1 is found mainly in certain types of white blood cells.

NLR proteins are involved in the immune system, helping to control the immune system's response to injury, toxins, or foreign invaders. The monarch-1 protein is involved in an immune process known as inflammation. Inflammation occurs when the immune system sends signaling molecules and white blood cells to a site of injury or disease to fight foreign invaders and help with tissue repair. After this has been accomplished, stopping the inflammatory response helps to prevent damage to the body's own cells and tissues.

Monarch-1 primarily stops (inhibits) inflammation by blocking the release of specific molecules that are involved in the process. However, monarch-1 can also promote the production of proteins that trigger inflammation when certain molecules are present.

Health Conditions Related to Genetic Changes

Familial cold autoinflammatory syndrome type 2

At least 20 variants (also known as mutations) in the NLRP12 gene have been found to cause familial cold autoinflammatory syndrome type 2. This condition causes episodes of fever, skin rash, and joint pain, often in response to cold temperatures.

Many of the NLRP12 gene variants that cause familial cold autoinflammatory syndrome type 2 are in a region of the gene known as exon 3. Most NLRP12 gene variants appear to reduce the ability of the monarch-1 protein to inhibit inflammation, resulting in an unusually long inflammatory response. However, research shows that other variants increase the protein's ability to trigger inflammatory responses, even when there is no injury or disease.

Impairment of the body's mechanisms for controlling inflammation results in the episodes of skin rash, fever, and joint pain seen in familial cold autoinflammatory syndrome type 2. It is unclear why episodes can be triggered by cold exposure in this disorder.

Additional changes in the NLRP12 gene or changes in other genes may influence the severity of familial cold autoinflammatory syndrome type 2, but little is known about how these changes contribute to the condition.

In some families, individuals with an NLRP12 gene variant may develop familial cold autoinflammatory syndrome type 2 but others with the mutation do not, which is a situation known as reduced penetrance.

Other Names for This Gene

• monarch 1
• Monarch1
• NACHT, leucine rich repeat and PYD containing 12
• NACHT, LRR and PYD containing protein 12
• NALP12
• NLR family, pyrin domain containing 12
• nucleotide-binding oligomerization domain, leucine rich repeat and pyrin domain containing 12
• PAN6
• PYPAF7
• PYRIN-containing APAF1-like protein 7

Genomic Location

The NLRP12 gene is found on chromosome 19.

There have been reported cases of this condition occurring in individuals with no history of the condition in the family; in these cases, the condition was not inherited from a parent, but occurred for the first time in the affected individual.

Signs and symptoms of familial cold autoinflammatory syndrome may include rash, fever, and joint pain triggered by exposure to cold temperatures. The rash often begins on exposed arms and legs and extends to the remainder of the body. The rash may consist of red macules and plaques, hives (urticaria), and petechiae. The skin rash can cause burning or itching. Conjuctivitis during a fever episode is also common. Other symptoms can include swelling, muscle pain, profuse sweating, drowsiness, headache, extreme thirst, and nausea.Symptoms may begin anywhere between 10 minutes to 8 hours after cold exposure. Fever attacks may last a few hours up to three days. Most people with familial cold autoinflammatory syndrome experience their first fever attack within the first year of life, many within the first day of life. Episodes continue to occur throughout life.

Individuals with familial cold autoinflammatory syndrome (FCAS) are generally advised to avoid exposure to cold temperatures. Bed rest, warmth and corticosteroids can be used to treat an acute attack. Treatment may include the use of biologic agents (drugs derived from living material) which can control the symptoms of FCAS by blocking interleukin-1; they are called selective recombinant interleukin-1 receptor agonists. Examples of these agents are rilonacept, anakinra, and canakinumab. These agents reportedly have a significant beneficial effect on quality of life for individuals with FCAS.

Symptoms of familial cold autoinflammatory syndrome continue throughout one's lifetime, but may improve with treatment. Rare complications that have been reported in individuals with this disorder include amyloidosis and kidney failure.