Familial cold autoinflammatory syndrome type 2 is a condition that causes episodes of fever, skin rash, and joint pain. These episodes can be triggered by exposure to cold temperatures, or they may arise without warning, and they can last a few hours to several days. These episodes typically begin in childhood and persist throughout life.

Episodes typically occur after an hour or more of cold exposure in affected individuals who are sensitive to cold; however only a few minutes of cold exposure is required in some individuals.

In people with familial cold autoinflammatory syndrome type 2, the most common symptom that occurs during an episode is a fever. Other common features are an itchy rash and joint and muscle pain.

Additional features of familial cold autoinflammatory syndrome type 2 include abdominal pain, diarrhea, headache, and nausea. Some affected individuals develop hearing loss (sensorineural deafness) due to chronic inflammation.

Familial cold autoinflammatory syndrome type 2 is caused by variants (also known as mutations) in the NLRP12 gene. The NLRP12 gene provides instructions for making the protein monarch-1. Monarch-1 belongs to a family of proteins called intracellular "NOD-like" receptor (NLR) proteins. These proteins are involved in the immune system, helping to regulate the process of inflammation. Inflammation occurs when the immune system sends signaling molecules and white blood cells to a site of injury or disease to fight microbial invaders and facilitate tissue repair. When this has been accomplished, the body stops (inhibits) the inflammatory response to prevent damage to its own cells and tissues. The monarch-1 protein is primarily involved in stopping the inflammatory response, but it can trigger inflammation in certain situations.

Most variants in the NLRP12 gene appear to reduce the ability of the monarch-1 protein to stop inflammation, resulting in an unusually long inflammatory response. 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.

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

In most cases, familial cold autoinflammatory syndrome type 2 is inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder. Most affected individuals have one parent with the condition.

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

In rare cases, familial cold autoinflammatory syndrome type 2 is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have variants. The parents of an individual with an autosomal recessive condition each carry one copy of the altered gene, but they typically do not show signs and symptoms of the condition.

Familial cold autoinflammatory syndrome type 2 is a very rare condition. More than 60 cases of this condition have been reported in the scientific literature.