What should I do if my child develops a fever and rash after a brief exposure to cold?

Immediately move the child to a warm environment, remove any wet clothing, and apply a cool (not cold) compress to the rash if it is uncomfortable. Give an antipyretic such as acetaminophen for fever, and contact your rheumatologist or primary care provider within a few hours, especially if symptoms are severe or involve joint swelling.

How can I reduce the frequency of cold‑triggered attacks without completely avoiding normal daily activities?

Wear layered, moisture‑wicking clothing, use gloves and hats even indoors if the ambient temperature is low, and keep indoor heating at a comfortable level (≥20 °C). Pre‑emptive use of a short course of NSAIDs (e.g., ibuprofen) 30 minutes before known cold exposure has helped some patients, but discuss dosing with your physician.

Is there a specific medication that can prevent episodes long‑term, and what are the common side effects?

Colchicine, anakinra (IL‑1 receptor antagonist), and canakinumab (IL‑1β monoclonal antibody) have been used to suppress inflammation in NLRP12‑related disease. Colchicine may cause gastrointestinal upset and, rarely, blood‑count changes; anakinra can cause injection‑site reactions and mild infections; canakinumab carries a risk of upper‑respiratory infections. Treatment choice is individualized based on severity and response.

If genetic testing confirms an NLRP12 variant, what are the implications for family planning?

NLRP12 mutations are inherited in an autosomal‑dominant pattern, meaning each child has a 50 % chance of inheriting the variant. Discuss options such as prenatal diagnostic testing (chorionic villus sampling or amniocentesis) or pre‑implantation genetic diagnosis (PGD) with a genetic counselor to make informed reproductive decisions.

Familial cold autoinflammatory syndrome type 2

A rare genetic disorder caused by NLRP12 variants that leads to fever, rash, and joint pain episodes often triggered by cold exposure.

Overview

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. The 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.

Symptoms

During an episode, the most common symptom is a fever. Other common features include:

Itchy rash
Joint and muscle pain
Abdominal pain
Diarrhea
Headache
Nausea
Sensorineural hearing loss (due to chronic inflammation in some individuals)

Frequency

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.

Causes & Risk Factors

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.

Learn more about the gene associated with Familial cold autoinflammatory syndrome type 2

NLRP12

Inheritance

In most cases, familial cold autoinflammatory syndrome type 2 is inherited in an , 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 , 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.

Other Names

Familial cold‑induced autoinflammatory syndrome type 2
FCAS2

Additional Information & Resources

Genetic Testing Information

Genetic Testing Registry: Familial cold autoinflammatory syndrome 2

Genetic and Rare Diseases Information Center

Familial cold urticaria

Patient Support and Advocacy Resources

National Organization for Rare Disorders (NORD)

Catalog of Genes and Diseases from OMIM

FAMILIAL COLD AUTOINFLAMMATORY SYNDROME 2; FCAS2

Scientific Articles on PubMed

PubMed

References

Ayla AY, Eren H, Zare J, Calhan SS, Karacan I, Seven M, Ugurlu S. A rare case of an NLRP12-associated autoinflammatory disease. Eur J Med Genet. 2021 Apr;64(4):104168. doi: 10.1016/j.ejmg.2021.104168. Epub 2021 Mar 3. Citation on PubMed
Del Porto F, Cifani N, Proietta M, Verrecchia E, Di Rosa R, Manna R, Chiurazzi P. NLRP12 gene mutations and auto‑inflammatory diseases: ever‑changing evidence. Rheumatology (Oxford). 2020 Nov 1;59(11):3129-3136. doi: 10.1093/rheumatology/keaa304. Citation on PubMed
Jeru I, Duquesnoy P, Fernandes‑Alnemri T, Cochet E, Yu JW, Lackmy‑Port‑Lis M, Grimprel E, Landman‑Parker J, Hentgen V, Marlin S, McElreavey K, Sarkisian T, Grateau G, Alnemri ES, Amselem S. Mutations in NALP12 cause hereditary periodic fever syndromes. Proc Natl Acad Sci U S A. 2008 Feb 5;105(5):1614-9. doi: 10.1073/pnas.0708616105. Epub 2008 Jan 29. Citation on PubMed or Free article on PubMed Central
Wang W, Zhou Y, Zhong LQ, Li Z, Jian S, Tang XY, Song HM. The clinical phenotype and genotype of NLRP12‑autoinflammatory disease: a Chinese case series with literature review. World J Pediatr. 2020 Oct;16(5):514-519. doi: 10.1007/s12519-019-00294-8. Epub 2019 Dec 9. Citation on PubMed

Understanding Genetics

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What are the different ways a genetic condition can be inherited?
How are genetic conditions treated or managed?