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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
Sources: HPO, OMIM, 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.
Autosomal dominant inheritance (HPO, OMIM, Orphanet)
 
Gene (location): PLCG2 (16q23.3)
OMIM®: 614468

Definition

Familial cold autoinflammatory syndrome-2 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 GHR
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://ghr.nlm.nih.gov/condition/plcg2-associated-antibody-deficiency-and-immune-dysregulation

Clinical features

From HPO
Erythema
MedGen UID:
11999
Concept ID:
C0041834
Disease or Syndrome
Red discoloration of the skin caused by infectious agents, inflammation, drug hypersensitivity, or underlying disease.
Urticaria
MedGen UID:
22587
Concept ID:
C0042109
Disease or Syndrome
A raised, erythematous papule or cutaneous plaque, usually representing short-lived dermal edema
Asthma
MedGen UID:
2109
Concept ID:
C0004096
Disease or Syndrome
A chronic respiratory disease manifested as difficulty breathing due to the narrowing of bronchial passageways.
Asthma
MedGen UID:
2109
Concept ID:
C0004096
Disease or Syndrome
A chronic respiratory disease manifested as difficulty breathing due to the narrowing of bronchial passageways.
Recurrent infections
MedGen UID:
65998
Concept ID:
C0239998
Finding
Increased susceptibility to infections.
Hashimoto thyroiditis
MedGen UID:
151769
Concept ID:
C0677607
Disease or Syndrome
Hashimoto thyroiditis 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 thyroiditis is a form of chronic inflammation that can damage the thyroid, reducing its ability to produce hormones.One of the first signs of Hashimoto thyroiditis 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.Other 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 this condition 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.Hashimoto thyroiditis 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.
Immune dysregulation
MedGen UID:
335001
Concept ID:
C1844666
Finding
Altered immune function characterized by lymphoid proliferation, immune activation, and excessive autoreactivity often leading to autoimmune/inflammatory complications.
Allergic rhinitis
MedGen UID:
382012
Concept ID:
C2607914
Disease or Syndrome
An inflammation of the NASAL MUCOSA triggered by ALLERGENS.
Allergic rhinitis
MedGen UID:
382012
Concept ID:
C2607914
Disease or Syndrome
An inflammation of the NASAL MUCOSA triggered by ALLERGENS.
Erythema
MedGen UID:
11999
Concept ID:
C0041834
Disease or Syndrome
Red discoloration of the skin caused by infectious agents, inflammation, drug hypersensitivity, or underlying disease.
Urticaria
MedGen UID:
22587
Concept ID:
C0042109
Disease or Syndrome
A raised, erythematous papule or cutaneous plaque, usually representing short-lived dermal edema
Vitiligo
MedGen UID:
479331
Concept ID:
C3277701
Finding
Vitiligo is a condition that causes patchy loss of skin coloring (pigmentation). The average age of onset of vitiligo is in the mid-twenties, but it can appear at any age. It tends to progress over time, with larger areas of the skin losing pigment. Some people with vitiligo also have patches of pigment loss affecting the hair on their scalp or body.Researchers have identified several forms of vitiligo. Generalized vitiligo (also called nonsegmental vitiligo), which is the most common form, involves loss of pigment (depigmentation) in patches of skin all over the body. Depigmentation typically occurs on the face, neck, and scalp, and around body openings such as the mouth and genitals. Sometimes pigment is lost in mucous membranes, such as the lips. Loss of pigmentation is also frequently seen in areas that tend to experience rubbing, impact, or other trauma, such as the hands, arms, and places where bones are close to the skin surface (bony prominences). Another form called segmental vitiligo is associated with smaller patches of depigmented skin that appear on one side of the body in a limited area; this occurs in about 10 percent of affected individuals.Vitiligo is generally considered to be an autoimmune disorder. Autoimmune disorders occur when the immune system attacks the body's own tissues and organs. In people with vitiligo the immune system appears to attack the pigment cells (melanocytes) in the skin. About 15 to 25 percent of people with vitiligo are also affected by at least one other autoimmune disorder, particularly autoimmune thyroid disease, rheumatoid arthritis, type 1 diabetes, psoriasis, pernicious anemia, Addison disease, or systemic lupus erythematosus.In the absence of other autoimmune conditions, vitiligo does not affect general health or physical functioning. However, concerns about appearance and ethnic identity are significant issues for many affected individuals.
Hashimoto thyroiditis
MedGen UID:
151769
Concept ID:
C0677607
Disease or Syndrome
Hashimoto thyroiditis 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 thyroiditis is a form of chronic inflammation that can damage the thyroid, reducing its ability to produce hormones.One of the first signs of Hashimoto thyroiditis 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.Other 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 this condition 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.Hashimoto thyroiditis 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.

Recent clinical studies

Etiology

Kilic H, Sahin S, Duman C, Adrovic A, Barut K, Turanli ET, Yildirim SR, Kizilkilic O, Kasapcopur O, Saltik S
Eur J Paediatr Neurol 2019 May;23(3):466-472. Epub 2019 Mar 28 doi: 10.1016/j.ejpn.2019.03.006. PMID: 30967326
Jaeger VK, Hoffman HM, van der Poll T, Tilson H, Seibert J, Speziale A, Junge G, Franke K, Vritzali E, Hawkins PN, Kuemmerle-Deschner J, Walker UA
Rheumatology (Oxford) 2017 Sep 1;56(9):1484-1491. doi: 10.1093/rheumatology/kex185. PMID: 28482054
Houx L, Hachulla E, Kone-Paut I, Quartier P, Touitou I, Guennoc X, Grateau G, Hamidou M, Neven B, Berthelot JM, Lequerré T, Pillet P, Lemelle I, Fischbach M, Duquesne A, Le Blay P, Le Jeunne C, Stirnemann J, Bonnet C, Gaillard D, Alix L, Touraine R, Garcier F, Bedane C, Jurquet AL, Duffau P, Smail A, Frances C, Grall-Lerosey M, Cathebras P, Tran TA, Morell-Dubois S, Pagnier A, Richez C, Cuisset L, Devauchelle-Pensec V
Arthritis Rheumatol 2015 Nov;67(11):3027-36. doi: 10.1002/art.39292. PMID: 26245507
Nakagawa K, Gonzalez-Roca E, Souto A, Kawai T, Umebayashi H, Campistol JM, Cañellas J, Takei S, Kobayashi N, Callejas-Rubio JL, Ortego-Centeno N, Ruiz-Ortiz E, Rius F, Anton J, Iglesias E, Jimenez-Treviño S, Vargas C, Fernandez-Martin J, Calvo I, Hernández-Rodríguez J, Mendez M, Dordal MT, Basagaña M, Bujan S, Yashiro M, Kubota T, Koike R, Akuta N, Shimoyama K, Iwata N, Saito MK, Ohara O, Kambe N, Yasumi T, Izawa K, Kawai T, Heike T, Yagüe J, Nishikomori R, Aróstegui JI
Ann Rheum Dis 2015 Mar;74(3):603-10. Epub 2013 Dec 10 doi: 10.1136/annrheumdis-2013-204361. PMID: 24326009
Miyamae T
Paediatr Drugs 2012 Apr 1;14(2):109-17. doi: 10.2165/11595040-000000000-00000. PMID: 22335455

Diagnosis

Nakamichi S, Origuchi T, Fukui S, Yoda A, Matsubara H, Nagaura Y, Nishikomori R, Abe K, Migita K, Sakamoto N, Kawakami A, Ozono Y, Maeda T
Intern Med 2019 Apr 1;58(7):1017-1022. Epub 2018 Dec 18 doi: 10.2169/internalmedicine.1401-18. PMID: 30568124Free PMC Article
Houx L, Hachulla E, Kone-Paut I, Quartier P, Touitou I, Guennoc X, Grateau G, Hamidou M, Neven B, Berthelot JM, Lequerré T, Pillet P, Lemelle I, Fischbach M, Duquesne A, Le Blay P, Le Jeunne C, Stirnemann J, Bonnet C, Gaillard D, Alix L, Touraine R, Garcier F, Bedane C, Jurquet AL, Duffau P, Smail A, Frances C, Grall-Lerosey M, Cathebras P, Tran TA, Morell-Dubois S, Pagnier A, Richez C, Cuisset L, Devauchelle-Pensec V
Arthritis Rheumatol 2015 Nov;67(11):3027-36. doi: 10.1002/art.39292. PMID: 26245507
Nakagawa K, Gonzalez-Roca E, Souto A, Kawai T, Umebayashi H, Campistol JM, Cañellas J, Takei S, Kobayashi N, Callejas-Rubio JL, Ortego-Centeno N, Ruiz-Ortiz E, Rius F, Anton J, Iglesias E, Jimenez-Treviño S, Vargas C, Fernandez-Martin J, Calvo I, Hernández-Rodríguez J, Mendez M, Dordal MT, Basagaña M, Bujan S, Yashiro M, Kubota T, Koike R, Akuta N, Shimoyama K, Iwata N, Saito MK, Ohara O, Kambe N, Yasumi T, Izawa K, Kawai T, Heike T, Yagüe J, Nishikomori R, Aróstegui JI
Ann Rheum Dis 2015 Mar;74(3):603-10. Epub 2013 Dec 10 doi: 10.1136/annrheumdis-2013-204361. PMID: 24326009
Espandar L, Boehlke CS, Kelly MP
Can J Ophthalmol 2014 Jun;49(3):304-6. doi: 10.1016/j.jcjo.2014.01.007. PMID: 24862780
Miyamae T
Paediatr Drugs 2012 Apr 1;14(2):109-17. doi: 10.2165/11595040-000000000-00000. PMID: 22335455

Therapy

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
Jaeger VK, Hoffman HM, van der Poll T, Tilson H, Seibert J, Speziale A, Junge G, Franke K, Vritzali E, Hawkins PN, Kuemmerle-Deschner J, Walker UA
Rheumatology (Oxford) 2017 Sep 1;56(9):1484-1491. doi: 10.1093/rheumatology/kex185. PMID: 28482054
Espandar L, Boehlke CS, Kelly MP
Can J Ophthalmol 2014 Jun;49(3):304-6. doi: 10.1016/j.jcjo.2014.01.007. PMID: 24862780
Miyamae T
Paediatr Drugs 2012 Apr 1;14(2):109-17. doi: 10.2165/11595040-000000000-00000. PMID: 22335455
Hedrich CM, Bruck N, Paul D, Hahn G, Gahr M, Rösen-Wolff A
Rheumatol Int 2012 Sep;32(9):2629-36. Epub 2011 Jul 22 doi: 10.1007/s00296-011-2019-3. PMID: 21833523

Prognosis

Kilic H, Sahin S, Duman C, Adrovic A, Barut K, Turanli ET, Yildirim SR, Kizilkilic O, Kasapcopur O, Saltik S
Eur J Paediatr Neurol 2019 May;23(3):466-472. Epub 2019 Mar 28 doi: 10.1016/j.ejpn.2019.03.006. PMID: 30967326
Bujan-Rivas S, Basagaña M, Sena F, Méndez M, Dordal MT, Gonzalez-Roca E, Ruiz-Ortiz E, Mensa-Vilaró A, Plaza S, Modesto C, Ordi-Ros J, Yagüe J, Martínez-Valle F, Aróstegui JI
Clin Exp Rheumatol 2017 Nov-Dec;35 Suppl 108(6):27-31. Epub 2017 Jan 9 PMID: 28079503
Miyamae T
Paediatr Drugs 2012 Apr 1;14(2):109-17. doi: 10.2165/11595040-000000000-00000. PMID: 22335455
Hedrich CM, Bruck N, Paul D, Hahn G, Gahr M, Rösen-Wolff A
Rheumatol Int 2012 Sep;32(9):2629-36. Epub 2011 Jul 22 doi: 10.1007/s00296-011-2019-3. PMID: 21833523
Ahmadi N, Brewer CC, Zalewski C, King KA, Butman JA, Plass N, Henderson C, Goldbach-Mansky R, Kim HJ
Otolaryngol Head Neck Surg 2011 Aug;145(2):295-302. doi: 10.1177/0194599811402296. PMID: 21493283Free PMC Article

Clinical prediction guides

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
Jaeger VK, Hoffman HM, van der Poll T, Tilson H, Seibert J, Speziale A, Junge G, Franke K, Vritzali E, Hawkins PN, Kuemmerle-Deschner J, Walker UA
Rheumatology (Oxford) 2017 Sep 1;56(9):1484-1491. doi: 10.1093/rheumatology/kex185. PMID: 28482054
Sobolewska B, Angermair E, Deuter C, Doycheva D, Kuemmerle-Deschner J, Zierhut M
J Rheumatol 2016 Jun;43(6):1101-6. Epub 2016 May 1 doi: 10.3899/jrheum.150681. PMID: 27134254
Yadlapati S, Efthimiou P
Mod Rheumatol 2016;26(1):3-8. Epub 2015 Aug 3 doi: 10.3109/14397595.2015.1069459. PMID: 26140469
Anton J, Calvo I, Fernández-Martin J, Gamir ML, Merino R, Jimenez-Treviño S, Sevilla B, Cabades F, Bou R, Arostegui JI
Clin Exp Rheumatol 2015 Nov-Dec;33(6 Suppl 94):S67-71. Epub 2015 Aug 5 PMID: 26243511

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