Familial cold autoinflammatory syndrome

Title

Other Names:

FCAS; Familial polymorphous cold eruption; Familial cold urticaria

Categories:

Congenital and Genetic Diseases; Immune System Diseases; Musculoskeletal Diseases; Congenital and Genetic Diseases; Immune System Diseases; Musculoskeletal Diseases; Skin Diseases See More

Summary 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]

Last updated: 10/30/2013

Symptoms 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]

Last updated: 11/1/2013

The Human Phenotype Ontology (HPO) provides the following list of features that have been reported in people with this condition. Much of the information in the HPO comes from Orphanet, a European rare disease database. If available, the list includes a rough estimate of how common a feature is (its frequency). Frequencies are based on a specific study and may not be representative of all studies. You can use the MedlinePlus Medical Dictionary for definitions of the terms below.

Signs and Symptoms	Approximate number of patients (when available)
Arthritis	Very frequent (present in 80%-99% of cases)
Dysesthesia	Very frequent (present in 80%-99% of cases)
Erythema	Very frequent (present in 80%-99% of cases)
Fatigue	Very frequent (present in 80%-99% of cases)
Fever	Very frequent (present in 80%-99% of cases)
Hyperhidrosis	Very frequent (present in 80%-99% of cases)
Myalgia	Very frequent (present in 80%-99% of cases)
Pruritus	Very frequent (present in 80%-99% of cases)
Urticaria	Very frequent (present in 80%-99% of cases)
Headache	Frequent (present in 30%-79% of cases)
Nausea and vomiting	Frequent (present in 30%-79% of cases)
Arthralgia	Occasional (present in 5%-29% of cases)
Conjunctivitis	Occasional (present in 5%-29% of cases)
Dehydration	Occasional (present in 5%-29% of cases)
Polydipsia	Occasional (present in 5%-29% of cases)
Renal amyloidosis	Occasional (present in 5%-29% of cases)
Sensorineural hearing impairment	Occasional (present in 5%-29% of cases)
Autosomal dominant inheritance	-
Episodic fever	-
Infantile onset	-
Leukocytosis	-

Last updated: 9/1/2017

Cause 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]

Last updated: 11/1/2013

Inheritance Inheritance

Familial cold autoinflammatory syndrome is inherited in an autosomal dominant manner.^[2] This means that a mutation in only one of the two copies of the responsible gene is sufficient to cause signs and symptoms of the condition. When an individual with an autosomal dominant condition has children, each child has a 50% (1 in 2) risk to inherit the mutated copy of the gene. This also means that each child has a 50% risk to not inherit the mutated copy of the gene and therefore be unaffected.

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.^[1]

Last updated: 11/1/2013

Diagnosis 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]

Last updated: 11/1/2013

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 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]

Last updated: 11/14/2013

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: Treatment of Cryopyrin-Assisted Periodic Syndromes (CAPS)
National Library of Medicine Drug Information Portal

Prognosis Prognosis

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.^[1]^[5]

Last updated: 12/12/2016

Do you have updated information on this condition? Let us know.

Research Research

Research helps us better understand diseases and can lead to advances in diagnosis and treatment. This section provides resources to help you learn about medical research and ways to get involved.

Clinical Research Resources

ClinicalTrials.gov lists trials that are studying or have studied Familial cold autoinflammatory syndrome. Click on the link to go to ClinicalTrials.gov to read descriptions of these studies.

Please note: Studies listed on the ClinicalTrials.gov website are listed for informational purposes only; being listed does not reflect an endorsement by GARD or the NIH. We strongly recommend that you talk with a trusted healthcare provider before choosing to participate in any clinical study.
The National Institute of Allergy and Infectious Diseases (NIAID) study, Pathogenesis of Physical Induced Urticarial Syndromes is currently recruiting participants. The study aims to investigate mechanisms that may cause physical hives or urticaria and to reproduce urticaria through challenge testing (procedures to test the skin for a reaction to a stimulus), followed by mast cell studies, measurement of IL-1, genetic studies, and other molecular studies to lead to a better understanding of urticaria and to design safe and more effective treatments.

Organizations 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

Autoinflammatory Alliance
P.O. Box 590354
San Francisco, CA 94118
Telephone: 415-831-8782
E-mail: karen@autoinflammatory.org
Website: http://www.autoinflammatory.org/

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

American Autoimmune Related Diseases Association (AARDA)
22100 Gratiot Avenue
Eastpointe, MI 48021
Toll-free: 800-598-4668
Telephone: 586-776-3900
Fax: 586-776-3903
E-mail: aarda@aarda.org
Website: https://www.aarda.org/

Do you know of an organization? Send us your suggestions.

Living With Living With

Living with a genetic or rare disease can impact the daily lives of patients and families. These resources can help families navigate various aspects of living with a rare disease.

Genetics Resources

To find a medical professional who specializes in genetics, you can ask your doctor for a referral or you can search for one yourself. Online directories are provided by GeneTests, the American College of Medical Genetics, and the National Society of Genetic Counselors. If you need additional help, contact a GARD Information Specialist. You can also learn more about genetic consultations from Genetics Home Reference.

Learn More 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 Autoinflammatory Alliance, a non-profit advocacy organization, offers information on Familial cold autoinflammatory syndrome
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

Leigh D Church, Sinisa Savic, and Michael F McDermott; Long term management of patients with cryopyrin-associated periodic syndromes (CAPS): focus on rilonacept (IL-1 Trap), Biologics. 2008 December; 2(4): 733–742.

News & Events News & Events

News

Don’t Miss the NCATS Toolkit for Patient-Focused Therapy Development Event
August 31, 2017
Funding Opportunities Now Available for the Undiagnosed Diseases Network (UDN) Phase II
August 30, 2017
IRDiRC Goals 2017-2027: New Rare Disease Research Goals for the Next Decade
August 10, 2017
Young Investigator Initiative Career Development and Grant Mentoring Program
June 21, 2016

NCATS Co-Sponsored Conferences

Autoinflammation 2013: The Seventh International Congress of FMF and Autoinflammatory Diseases Wednesday, May 22, 2013 - Sunday, May 26, 2013
Location: Lausanne, Switzerland
Description: The goals of this meeting include the exchange of clinical and scientific information regarding the autoinflammatory diseases. This is likely to result in improvements in the diagnosis and treatment of these diseases. Past Congresses have resulted in new scientific collaborations, development of registries for patients with specific autoinflammatory disorders, and the initiation of multicenter clinical trials.

Contact: Daniel Kastner, M.D., Ph.D., 301-496-8364kastnerd@nih.gov

Co-funding Institute(s): National Human Genome Research Institute, Office of Rare Diseases Research

GARD Answers GARD Answers

Questions sent to GARD may be posted here if the information could be helpful to others. We remove all identifying information when posting a question to protect your privacy. If you do not want your question posted, please let us know. Submit a new question

I have the syndrome, as did my mother, my second brother, and his oldest son. I had biopsies taken of the so-called hives and were told that they were neutrophiles from the blood. Is it common to have so many in one family to have this syndrome? Also, how often does it skip a generation? See answer

Have a question? Contact a GARD Information Specialist.

References References

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;
Familial cold autoinflammatory syndrome. Genetics Home Reference. September 2008; http://ghr.nlm.nih.gov/condition/familial-cold-autoinflammatory-syndrome. Accessed 10/28/2013.
Hoffman HM. Familial Cold Autoinflammatory Syndrome. Orphanet Encyclopedia. February 2005; https://www.orpha.net/data/patho/GB/uk-FCAS.pdf.
Delwyn Dyall-Smith. Familial cold autoinflammatory syndrome. DermNet NZ. March 2011; http://www.dermnetnz.org/systemic/fcas.html. Accessed 10/30/2013.
Marwan Shinawi. Hereditary Periodic Fever Syndromes. Medscape Reference. January 11, 2013; http://emedicine.medscape.com/article/952254-overview#aw2aab6b7. Accessed 12/12/2016.
Familial cold autoinflammatory syndrome. Genetics Home Reference. September 2008; http://ghr.nlm.nih.gov/condition=familialcoldautoinflammatorysyndrome.