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Familial cold autoinflammatory syndrome 3(FCAS3)

MedGen UID:
482544
Concept ID:
C3280914
Disease or Syndrome
Synonyms: ANTIBODY DEFICIENCY AND IMMUNE DYSREGULATION, PLCG2-ASSOCIATED; FAMILIAL ATYPICAL COLD URTICARIA; FCAS3
Modes of inheritance:
Autosomal dominant inheritance
MedGen UID:
141047
Concept ID:
C0443147
Intellectual Product
Source: Orphanet
A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in heterozygotes. In the context of medical genetics, an autosomal dominant disorder is caused when a single copy of the mutant allele is present. Males and females are affected equally, and can both transmit the disorder with a risk of 50% for each child of inheriting the mutant allele.
 
Gene (location): PLCG2 (16q23.3)
 
Monarch Initiative: MONDO:0013766
OMIM®: 614468
Orphanet: ORPHA300359

Definition

Familial cold autoinflammatory syndrome-3 is an autosomal dominant immune disorder characterized by the development of cutaneous urticaria, erythema, and pruritus in response to cold exposure. Affected individuals have variable additional immunologic defects, including antibody deficiency, decreased numbers of B cells, defective B cells, increased susceptibility to infection, and increased risk of autoimmune disorders (summary by Ombrello et al., 2012). For a discussion of genetic heterogeneity of FCAS, see FCAS1 (120100). [from OMIM]

Additional description

From MedlinePlus Genetics
PLCG2-associated antibody deficiency and immune dysregulation (PLAID) is an immune system disorder characterized by an allergic reaction to cold temperatures. Other immune system problems can also occur. The hallmark feature of PLAID is the development of a red, itchy rash (hives) when the skin is exposed to cool temperatures, which is known as cold urticaria. In PLAID, the hives typically develop in response to evaporative cooling, such as when a cool breeze or air conditioning blows on damp or sweaty skin. Being in a cold swimming pool can also trigger hives. In contrast, people with PLAID do not have a reaction when they touch a cold object, like an ice cube. (The ice cube test is a common test for a cold allergy; it triggers a reaction in people with other forms of cold urticaria, which usually begin later in life than PLAID.) However, some people with PLAID do experience a burning sensation in their throats when they eat cold foods, like ice cream. In PLAID, the hives go away once the skin warms up. Prolonged exposure to cold can lead to loss of consciousness or a serious allergic reaction known as anaphylaxis.

Other skin problems can also occur in PLAID. A small number of affected individuals develop a blistering rash on the tip of their nose, ears, and fingers shortly after birth. The rash usually heals on its own in infancy, although in rare cases, it worsens over time. After the initial rash goes away, a different rash sometimes develops on the torso and limbs later in life. This rash, called a granuloma, can affect small patches of skin or be widespread. In people with PLAID, the granulomas do not occur in warm regions of the body, such as the armpits and other skin folds.

In many people with PLAID, immune system function is reduced, leading to recurrent infections such as frequent colds, ear infections, or bouts of pneumonia. The infections are likely related to lower-than-normal levels of special proteins called antibodies or immunoglobulins, particularly immunoglobulin M (IgM) or immunoglobulin G (IgG). Antibodies attach to specific foreign particles and germs, marking them for destruction. The number of immune system cells called natural killer (NK) cells may also be reduced.

Autoimmune disorders, which occur when the immune system malfunctions and attacks the body's own tissues and organs, can also occur. Autoimmune disorders associated with PLAID include autoimmune thyroiditis and vitiligo. Autoimmune thyroiditis results from damage to the butterfly-shaped, hormone-producing gland in the lower neck (the thyroid). Vitiligo is caused by attacks on the pigment cells in the skin, resulting in a patchy loss of skin coloration. Most people with PLAID have abnormal antibodies called autoantibodies in their blood. One such antibody common in people with PLAID is known as antinuclear antibody (ANA). Autoantibodies attach to normal proteins and can trigger an immune attack against the body's own tissues. However, not everyone with these abnormal antibodies has an autoimmune disease.  https://medlineplus.gov/genetics/condition/plcg2-associated-antibody-deficiency-and-immune-dysregulation

Clinical features

From HPO
Presyncope
MedGen UID:
148578
Concept ID:
C0700200
Sign or Symptom
Presyncope is a state of lightheadedness, muscular weakness, blurred vision, and feeling faint. Presyncope is most often cardiovascular in cause.
Recurrent sinopulmonary infections
MedGen UID:
339549
Concept ID:
C1846546
Finding
An increased susceptibility to infections involving both the paranasal sinuses and the lungs, as manifested by a history of recurrent sinopulmonary infections.
Asthma
MedGen UID:
2109
Concept ID:
C0004096
Disease or Syndrome
Asthma is characterized by increased responsiveness of the tracheobronchial tree to multiple stimuli, leading to narrowing of the air passages with resultant dyspnea, cough, and wheezing.
Allergy
MedGen UID:
9370
Concept ID:
C0020517
Pathologic Function
An allergy is an immune response or reaction to substances that are usually not harmful.
Onychomycosis
MedGen UID:
11825
Concept ID:
C0040261
Disease or Syndrome
A fungal infection of the toenails or fingernails that tends to cause the nails to thicken, discolor, disfigure, and split.
Antinuclear antibody positivity
MedGen UID:
101792
Concept ID:
C0151480
Laboratory or Test Result
The presence of autoantibodies in the serum that react against nuclei or nuclear components.
Hashimoto thyroiditis
MedGen UID:
151769
Concept ID:
C0677607
Disease or Syndrome
Hashimoto's disease is a condition that affects the function of the thyroid, which is a butterfly-shaped gland in the lower neck. The thyroid makes hormones that help regulate a wide variety of critical body functions. For example, thyroid hormones influence growth and development, body temperature, heart rate, menstrual cycles, and weight. Hashimoto's disease is a form of chronic inflammation that can damage the thyroid, reducing its ability to produce hormones.\n\nOne of the first signs of Hashimoto's disease is an enlargement of the thyroid called a goiter. Depending on its size, the enlarged thyroid can cause the neck to look swollen and may interfere with breathing and swallowing. As damage to the thyroid continues, the gland can shrink over a period of years and the goiter may eventually disappear.\n\nOther signs and symptoms resulting from an underactive thyroid can include excessive tiredness (fatigue), weight gain or difficulty losing weight, hair that is thin and dry, a slow heart rate, joint or muscle pain, and constipation. People with Hashimoto's disease may also have a pale, puffy face and feel cold even when others around them are warm. Affected women can have heavy or irregular menstrual periods and difficulty conceiving a child (impaired fertility). Difficulty concentrating and depression can also be signs of a shortage of thyroid hormones.\n\nHashimoto's disease usually appears in mid-adulthood, although it can occur earlier or later in life. Its signs and symptoms tend to develop gradually over months or years.
Recurrent otitis media
MedGen UID:
155436
Concept ID:
C0747085
Disease or Syndrome
Increased susceptibility to otitis media, as manifested by recurrent episodes of otitis media.
Allergic rhinitis
MedGen UID:
382012
Concept ID:
C2607914
Disease or Syndrome
It is characterized by one or more symptoms including sneezing, itching, nasal congestion, and rhinorrhea.
Angioedema
MedGen UID:
1543
Concept ID:
C0002994
Pathologic Function
Rapid swelling (edema) of the dermis, subcutaneous tissue, mucosa and submucosal tissues of the skin of the face, normally around the mouth, and the mucosa of the mouth and/or throat, as well as the tongue during a period of minutes to several hours. The swelling can also occur elsewhere, typically in the hands. Angioedema is similar to urticaria, but the swelling is subcutaneous rather than on the epidermis.
Pruritus
MedGen UID:
19534
Concept ID:
C0033774
Sign or Symptom
Pruritus is an itch or a sensation that makes a person want to scratch. This term refers to an abnormally increased disposition to experience pruritus.
Erythema
MedGen UID:
11999
Concept ID:
C0041834
Disease or Syndrome
Redness of the skin, caused by hyperemia of the capillaries in the lower layers of the skin.
Vitiligo
MedGen UID:
22677
Concept ID:
C0042900
Disease or Syndrome
Generalized well circumscribed patches of leukoderma that are generally distributed over symmetric body locations and is due to autoimmune destruction of melanocytes.
Cold urticaria
MedGen UID:
472942
Concept ID:
C0221207
Disease or Syndrome
Urticaria may be caused by cold temperatures.
Dermatographic urticaria
MedGen UID:
488854
Concept ID:
C0343065
Disease or Syndrome
An exaggerated whealing tendency when the skin is stroked, that is, formation of red, itchy bumps and lines on the skin as a result of pressure on the skin (for instance, stroking the skin with a pen or tongue depressor).

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
Follow this link to review classifications for Familial cold autoinflammatory syndrome 3 in Orphanet.

Professional guidelines

PubMed

Gattorno M, Hofer M, Federici S, Vanoni F, Bovis F, Aksentijevich I, Anton J, Arostegui JI, Barron K, Ben-Cherit E, Brogan PA, Cantarini L, Ceccherini I, De Benedetti F, Dedeoglu F, Demirkaya E, Frenkel J, Goldbach-Mansky R, Gul A, Hentgen V, Hoffman H, Kallinich T, Kone-Paut I, Kuemmerle-Deschner J, Lachmann HJ, Laxer RM, Livneh A, Obici L, Ozen S, Rowczenio D, Russo R, Shinar Y, Simon A, Toplak N, Touitou I, Uziel Y, van Gijn M, Foell D, Garassino C, Kastner D, Martini A, Sormani MP, Ruperto N; Eurofever Registry and the Paediatric Rheumatology International Trials Organisation (PRINTO)
Ann Rheum Dis 2019 Aug;78(8):1025-1032. Epub 2019 Apr 24 doi: 10.1136/annrheumdis-2019-215048. PMID: 31018962
Landmann EC, Walker UA
Expert Rev Clin Pharmacol 2017 Aug;10(8):855-864. Epub 2017 Jun 20 doi: 10.1080/17512433.2017.1338946. PMID: 28586272
Coll RC, Robertson AA, Chae JJ, Higgins SC, Muñoz-Planillo R, Inserra MC, Vetter I, Dungan LS, Monks BG, Stutz A, Croker DE, Butler MS, Haneklaus M, Sutton CE, Núñez G, Latz E, Kastner DL, Mills KH, Masters SL, Schroder K, Cooper MA, O'Neill LA
Nat Med 2015 Mar;21(3):248-55. Epub 2015 Feb 16 doi: 10.1038/nm.3806. PMID: 25686105Free PMC Article

Recent clinical studies

Etiology

Tartey S, Kanneganti TD
J Leukoc Biol 2020 Mar;107(3):379-391. Epub 2019 Oct 14 doi: 10.1002/JLB.3MIR0919-191R. PMID: 31608507Free PMC Article
Kacar M, Pathak S, Savic S
Rheumatology (Oxford) 2019 Nov 1;58(Suppl 6):vi31-vi43. doi: 10.1093/rheumatology/kez448. PMID: 31769858Free PMC Article
Gattorno M, Hofer M, Federici S, Vanoni F, Bovis F, Aksentijevich I, Anton J, Arostegui JI, Barron K, Ben-Cherit E, Brogan PA, Cantarini L, Ceccherini I, De Benedetti F, Dedeoglu F, Demirkaya E, Frenkel J, Goldbach-Mansky R, Gul A, Hentgen V, Hoffman H, Kallinich T, Kone-Paut I, Kuemmerle-Deschner J, Lachmann HJ, Laxer RM, Livneh A, Obici L, Ozen S, Rowczenio D, Russo R, Shinar Y, Simon A, Toplak N, Touitou I, Uziel Y, van Gijn M, Foell D, Garassino C, Kastner D, Martini A, Sormani MP, Ruperto N; Eurofever Registry and the Paediatric Rheumatology International Trials Organisation (PRINTO)
Ann Rheum Dis 2019 Aug;78(8):1025-1032. Epub 2019 Apr 24 doi: 10.1136/annrheumdis-2019-215048. PMID: 31018962
Ginsberg S, Rosner I, Rozenbaum M, Slobodin G, Zilber K, Boulman N, Kaly L, Awisat A, Jiries N, Beyar-Katz O, Rimar D
Semin Arthritis Rheum 2016 Dec;46(3):367-371. Epub 2016 Jul 20 doi: 10.1016/j.semarthrit.2016.07.007. PMID: 27612399
McDermott MF, Aksentijevich I
Curr Opin Allergy Clin Immunol 2002 Dec;2(6):511-6. doi: 10.1097/00130832-200212000-00006. PMID: 14752334

Diagnosis

Kacar M, Pathak S, Savic S
Rheumatology (Oxford) 2019 Nov 1;58(Suppl 6):vi31-vi43. doi: 10.1093/rheumatology/kez448. PMID: 31769858Free PMC Article
Gattorno M, Hofer M, Federici S, Vanoni F, Bovis F, Aksentijevich I, Anton J, Arostegui JI, Barron K, Ben-Cherit E, Brogan PA, Cantarini L, Ceccherini I, De Benedetti F, Dedeoglu F, Demirkaya E, Frenkel J, Goldbach-Mansky R, Gul A, Hentgen V, Hoffman H, Kallinich T, Kone-Paut I, Kuemmerle-Deschner J, Lachmann HJ, Laxer RM, Livneh A, Obici L, Ozen S, Rowczenio D, Russo R, Shinar Y, Simon A, Toplak N, Touitou I, Uziel Y, van Gijn M, Foell D, Garassino C, Kastner D, Martini A, Sormani MP, Ruperto N; Eurofever Registry and the Paediatric Rheumatology International Trials Organisation (PRINTO)
Ann Rheum Dis 2019 Aug;78(8):1025-1032. Epub 2019 Apr 24 doi: 10.1136/annrheumdis-2019-215048. PMID: 31018962
Davis MDP, van der Hilst JCH
J Allergy Clin Immunol Pract 2018 Jul-Aug;6(4):1162-1170. Epub 2018 Jun 2 doi: 10.1016/j.jaip.2018.05.006. PMID: 29871797
Ginsberg S, Rosner I, Rozenbaum M, Slobodin G, Zilber K, Boulman N, Kaly L, Awisat A, Jiries N, Beyar-Katz O, Rimar D
Semin Arthritis Rheum 2016 Dec;46(3):367-371. Epub 2016 Jul 20 doi: 10.1016/j.semarthrit.2016.07.007. PMID: 27612399
Hausmann JS, Dedeoglu F
Dermatol Clin 2013 Jul;31(3):481-94. Epub 2013 Jun 2 doi: 10.1016/j.det.2013.04.003. PMID: 23827250

Therapy

Moltrasio C, Romagnuolo M, Marzano AV
Front Immunol 2022;13:1007705. Epub 2022 Oct 6 doi: 10.3389/fimmu.2022.1007705. PMID: 36275641Free PMC Article
Gattorno M, Hofer M, Federici S, Vanoni F, Bovis F, Aksentijevich I, Anton J, Arostegui JI, Barron K, Ben-Cherit E, Brogan PA, Cantarini L, Ceccherini I, De Benedetti F, Dedeoglu F, Demirkaya E, Frenkel J, Goldbach-Mansky R, Gul A, Hentgen V, Hoffman H, Kallinich T, Kone-Paut I, Kuemmerle-Deschner J, Lachmann HJ, Laxer RM, Livneh A, Obici L, Ozen S, Rowczenio D, Russo R, Shinar Y, Simon A, Toplak N, Touitou I, Uziel Y, van Gijn M, Foell D, Garassino C, Kastner D, Martini A, Sormani MP, Ruperto N; Eurofever Registry and the Paediatric Rheumatology International Trials Organisation (PRINTO)
Ann Rheum Dis 2019 Aug;78(8):1025-1032. Epub 2019 Apr 24 doi: 10.1136/annrheumdis-2019-215048. PMID: 31018962
Coll RC, Robertson AA, Chae JJ, Higgins SC, Muñoz-Planillo R, Inserra MC, Vetter I, Dungan LS, Monks BG, Stutz A, Croker DE, Butler MS, Haneklaus M, Sutton CE, Núñez G, Latz E, Kastner DL, Mills KH, Masters SL, Schroder K, Cooper MA, O'Neill LA
Nat Med 2015 Mar;21(3):248-55. Epub 2015 Feb 16 doi: 10.1038/nm.3806. PMID: 25686105Free PMC Article
Hausmann JS, Dedeoglu F
Dermatol Clin 2013 Jul;31(3):481-94. Epub 2013 Jun 2 doi: 10.1016/j.det.2013.04.003. PMID: 23827250
Dhimolea E
MAbs 2010 Jan-Feb;2(1):3-13. Epub 2010 Jan 15 doi: 10.4161/mabs.2.1.10328. PMID: 20065636Free PMC Article

Prognosis

Matsuda T, Takimoto-Ito R, Lipsker D, Kambe N
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Kacar M, Pathak S, Savic S
Rheumatology (Oxford) 2019 Nov 1;58(Suppl 6):vi31-vi43. doi: 10.1093/rheumatology/kez448. PMID: 31769858Free PMC Article
Finetti M, Omenetti A, Federici S, Caorsi R, Gattorno M
Orphanet J Rare Dis 2016 Dec 7;11(1):167. doi: 10.1186/s13023-016-0542-8. PMID: 27927236Free PMC Article
Kanazawa N
J Dermatol Sci 2012 Jun;66(3):183-9. Epub 2012 Jan 18 doi: 10.1016/j.jdermsci.2012.01.004. PMID: 22336993
Miyamae T
Paediatr Drugs 2012 Apr 1;14(2):109-17. doi: 10.2165/11595040-000000000-00000. PMID: 22335455

Clinical prediction guides

Paim-Marques LB, Cavalcante A, Castro C, Muskardin TLW, de Oliveira JB, Niewold TB, Appenzeller S
Rheumatol Int 2021 Jan;41(1):219-225. Epub 2020 Aug 19 doi: 10.1007/s00296-020-04683-5. PMID: 32813153
Landmann EC, Walker UA
Expert Rev Clin Pharmacol 2017 Aug;10(8):855-864. Epub 2017 Jun 20 doi: 10.1080/17512433.2017.1338946. PMID: 28586272
Finetti M, Omenetti A, Federici S, Caorsi R, Gattorno M
Orphanet J Rare Dis 2016 Dec 7;11(1):167. doi: 10.1186/s13023-016-0542-8. PMID: 27927236Free PMC Article
Hernández-Rodríguez J, Ruíz-Ortiz E, Tomé A, Espinosa G, González-Roca E, Mensa-Vilaró A, Prieto-González S, Espígol-Frigolé G, Mensa J, Cardellach F, Grau JM, Cid MC, Yagüe J, Aróstegui JI, Cervera R
Autoimmun Rev 2016 Jan;15(1):9-15. Epub 2015 Aug 21 doi: 10.1016/j.autrev.2015.08.008. PMID: 26299986
Kanazawa N
J Dermatol Sci 2012 Jun;66(3):183-9. Epub 2012 Jan 18 doi: 10.1016/j.jdermsci.2012.01.004. PMID: 22336993

Recent systematic reviews

Rodrigues F, Cuisset L, Cador-Rousseau B, Giurgea I, Neven B, Buob D, Quartier P, Hachulla E, Lequerré T, Cam G, Boursier G, Hervieu V, Grateau G, Georgin-Lavialle S
Rheumatology (Oxford) 2022 Nov 28;61(12):4827-4834. doi: 10.1093/rheumatology/keac145. PMID: 35262642
Kuemmerle-Deschner JB, Gautam R, George AT, Raza S, Lomax KG, Hur P
RMD Open 2020 Jul;6(2) doi: 10.1136/rmdopen-2020-001227. PMID: 32723831Free PMC Article

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