Rare Pediatrics News

Disease Profile

Familial cold autoinflammatory syndrome

Prevalence
Prevalence estimates on Rare Medical Network websites are calculated based on data available from numerous sources, including US and European government statistics, the NIH, Orphanet, and published epidemiologic studies. Rare disease population data is recognized to be highly variable, and based on a wide variety of source data and methodologies, so the prevalence data on this site should be assumed to be estimated and cannot be considered to be absolutely correct.

Unknown

US Estimated

Europe Estimated

Age of onset

Infancy

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ICD-10

L50.2

Inheritance

Autosomal dominant A pathogenic variant in only one gene copy in each cell is sufficient to cause an autosomal dominant disease.

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Autosomal recessive Pathogenic variants in both copies of each gene of the chromosome are needed to cause an autosomal recessive disease and observe the mutant phenotype.

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X-linked
dominant X-linked dominant inheritance, sometimes referred to as X-linked dominance, is a mode of genetic inheritance by which a dominant gene is carried on the X chromosome.

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X-linked
recessive Pathogenic variants in both copies of a gene on the X chromosome cause an X-linked recessive disorder.

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Mitochondrial or multigenic Mitochondrial genetic disorders can be caused by changes (mutations) in either the mitochondrial DNA or nuclear DNA that lead to dysfunction of the mitochondria and inadequate production of energy.

Multigenic or multifactor Inheritance involving many factors, of which at least one is genetic but none is of overwhelming importance, as in the causation of a disease by multiple genetic and environmental factors.

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Not applicable

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Other names (AKA)

FCAS; Familial polymorphous cold eruption; Familial cold urticaria

Categories

Congenital and Genetic Diseases; Immune System Diseases; Musculoskeletal Diseases;

Summary

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.[1][2]

Symptoms

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.[1]

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.[1]

This table lists symptoms that people with this disease may have. For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed. This information comes from a database called the Human Phenotype Ontology (HPO) . The HPO collects information on symptoms that have been described in medical resources. The HPO is updated regularly. Use the HPO ID to access more in-depth information about a symptom.

Medical Terms Other Names
Learn More:
HPO ID
80%-99% of people have these symptoms
Arthritis
Joint inflammation
0001369
Dysesthesia
0012534
Erythema
0010783
Fatigue
Tired
Tiredness

[ more ]

 0012378
Fever
0001945
Hyperhidrosis
Excessive sweating
Increased sweating
Profuse sweating
Sweating
Sweating profusely
Sweating, increased

[ more ]

 0000975
Myalgia
Muscle ache
Muscle pain

[ more ]

 0003326
Pruritus
Itching
Itchy skin
Skin itching

[ more ]

 0000989
Urticaria
Hives
0001025
30%-79% of people have these symptoms
Headache
Headaches
0002315
Nausea and vomiting
0002017
5%-29% of people have these symptoms
Abdominal pain
Pain in stomach
Stomach pain

[ more ]

 0002027
Arthralgia
Joint pain
0002829
Conjunctivitis
Pink eye
0000509
Dehydration
0001944
Polydipsia
Extreme thirst
0001959
Sensorineural hearing impairment
0000407
1%-4% of people have these symptoms
Aphthous ulcer
Canker sore
0032154
Elevated C-reactive protein level
0011227
Renal amyloidosis
0001917
Uveitis
0000554
Percent of people who have these symptoms is not available through HPO
Autosomal dominant inheritance
0000006
Chills
0025143
Infantile onset
Onset in first year of life
Onset in infancy

[ more ]

 0003593
Leukocytosis
Elevated white blood count
High white blood count
Increased blood leukocyte number

[ more ]

 0001974
Recurrent fever
Episodic fever
Increased body temperature, episodic
Intermittent fever

[ more ]

 0001954
Skin rash
0000988
Do you have updated information on this disease? We want to hear from you.

Cause

Familial cold autoinflammatory syndrome is caused by changes (mutations) in either one of two genes: 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.[2]

Diagnosis

Familial cold autoinflammatory syndrome (FCAS) is primarily a clinical diagnosis, meaning that it is mostly based on the presence or absence of specific of signs and symptoms as well as family history.[3] Diagnostic criteria have been proposed in order to distinguish FCAS from acquired cold urticaria and other periodic fever disorders. The criteria include: recurring episodes of fever and rash that primarily follow cold exposures; autosomal dominant pattern of disease inheritance in a family; age of onset younger than 6 months; duration of most attacks less than 24 hours; conjunctivitis in association with attacks; and absence of deafness, swelling around the eyes, enlarged lymph nodes, and serositis.[1][3] Having four of six of the criteria strongly suggests a diagnosis of FCAS. A diagnosis of FCAS may also be confirmed in some affected individuals by genetic testing.[3]

Testing Resources

  • The Genetic Testing Registry (GTR) provides information about the genetic tests for this condition. The intended audience for the GTR is health care providers and researchers. Patients and consumers with specific questions about a genetic test should contact a health care provider or a genetics professional.

    Treatment

    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.[4] 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.[5][4] These agents reportedly have a significant beneficial effect on quality of life for individuals with FCAS.[4]

    FDA-Approved Treatments

    The medication(s) listed below have been approved by the Food and Drug Administration (FDA) as orphan products for treatment of this condition. Learn more orphan products.

    • Rilonacept(Brand name: Arcalyst) Manufactured by Regeneron Pharmaceuticals, Inc.
      FDA-approved indication: February 2008, rilonacept (Arcalyst) was approved for treatment of cryopyrin-assisted periodic syndromes (CAPS).
      National Library of Medicine Drug Information Portal
    • Canakinumab(Brand name: Ilaris) Manufactured by Novartis Pharmaceuticals Corporation
      FDA-approved indication: June 2009, canakinumab (Ilaris) was approved for the treatment of cryopyrin-associated periodic syndromes (CAPS), in adults and children 4 years of age and older. In May 2013, it was also approved for the treatment of active Systemic Juvenile Idiopathic Arthritis (SJIA) in patients aged 2 through 16 years.
      National Library of Medicine Drug Information Portal

    Organizations

    Support and advocacy groups can help you connect with other patients and families, and they can provide valuable services. Many develop patient-centered information and are the driving force behind research for better treatments and possible cures. They can direct you to research, resources, and services. Many organizations also have experts who serve as medical advisors or provide lists of doctors/clinics. Visit the group’s website or contact them to learn about the services they offer. Inclusion on this list is not an endorsement by GARD.

    Organizations Supporting this Disease

      Social Networking Websites

      • RareConnect has an online community for patients and families with this condition so they can connect with others and share their experiences living with a rare disease. The project is a joint collaboration between EURORDIS (European Rare Disease Organisation) and NORD (National Organization for Rare Disorders).

        Organizations Providing General Support

          Learn more

          These resources provide more information about this condition or associated symptoms. The in-depth resources contain medical and scientific language that may be hard to understand. You may want to review these resources with a medical professional.

          Where to Start

          • The Cleveland Clinic provides an overview of the different types of periodic fever syndromes.
          • DermNet NZ is an online resource about skin diseases developed by the New Zealand Dermatological Society Incorporated. DermNet NZ provides information about this condition.
          • Genetics Home Reference (GHR) contains information on Familial cold autoinflammatory syndrome. This website is maintained by the National Library of Medicine.
          • The National Organization for Rare Disorders (NORD) has a report for patients and families about this condition. NORD is a patient advocacy organization for individuals with rare diseases and the organizations that serve them.

            In-Depth Information

            • Medscape Reference provides information on this topic. You may need to register to view the medical textbook, but registration is free.
            • The Monarch Initiative brings together data about this condition from humans and other species to help physicians and biomedical researchers. Monarch’s tools are designed to make it easier to compare the signs and symptoms (phenotypes) of different diseases and discover common features. This initiative is a collaboration between several academic institutions across the world and is funded by the National Institutes of Health. Visit the website to explore the biology of this condition.
            • Online Mendelian Inheritance in Man (OMIM) is a catalog of human genes and genetic disorders. Each entry has a summary of related medical articles. It is meant for health care professionals and researchers. OMIM is maintained by Johns Hopkins University School of Medicine. 
            • Orphanet is a European reference portal for information on rare diseases and orphan drugs. Access to this database is free of charge.
            • PubMed is a searchable database of medical literature and lists journal articles that discuss Familial cold autoinflammatory syndrome. Click on the link to view a sample search on this topic.

              Selected Full-Text Journal Articles

                References

                1. Simon A, Van Der Meer S, Drenth J. Familial autoinflammatory syndromes. In: Harris et al.,. Harris: Kelley's Textbook of Rheumatology, 7th ed. Philadelphia, PA: Saunders; 2005;
                2. Familial cold autoinflammatory syndrome. Genetics Home Reference. September 2008; https://ghr.nlm.nih.gov/condition/familial-cold-autoinflammatory-syndrome. Accessed 10/28/2013.
                3. Hoffman HM. Familial Cold Autoinflammatory Syndrome. Orphanet Encyclopedia. February 2005; https://www.orpha.net/data/patho/GB/uk-FCAS.pdf.
                4. Delwyn Dyall-Smith. Familial cold autoinflammatory syndrome. DermNet NZ. March 2011; https://www.dermnetnz.org/systemic/fcas.html. Accessed 10/30/2013.
                5. Marwan Shinawi. Hereditary Periodic Fever Syndromes. Medscape Reference. January 11, 2013; https://emedicine.medscape.com/article/952254-overview#aw2aab6b7. Accessed 12/12/2016.
                6. Familial cold autoinflammatory syndrome. Genetics Home Reference. September 2008; https://ghr.nlm.nih.gov/condition=familialcoldautoinflammatorysyndrome.

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