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Familial Cold Urticaria

FCU

Familial cold urticaria, also known as familial cold autoinflammatory syndrome, is a rare autosomal dominant disease in which exposure to cold temperatures trigger symptoms such as rash, fever, joint pain and conjunctivitis. Symptoms appear in early infancy and the diagnosis can be made on clinical grounds, while confirmation of NALP3 gene mutations is a definite diagnostic measure. The IL-1β antagonist, anankira, has proved to be efficient in managing symptoms.

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Presentation

Clinical presentation starts as soon as birth and virtually all patients develop symptoms within the first 6 months of life [4]. After exposure to cold temperatures or sudden drops that may be caused by air conditioning, rash, fever and arthralgia are most frequently reported [1]. The rash develops approximately 1-2 hours after cold exposure and is painful, pruritic and urticaria-like [4]. Low-grade fever and arthralgia ensue several hours after the onset of rash, while additional symptoms include sweating, headaches, nausea and extreme thirst [4]. Ocular symptoms such as conjunctivitis are frequent, while certain reports have also documented keratitis [3].

Fever
  • A painful, pruritic, urticaria-like rash that is followed by fever, joint pain, fatigue, headache and fever is the typical clinical course. Symptoms are preceded by exposure to cold temperatures by 1-2 hours, which is a hallmark of FCU.[symptoma.com]
  • Signs and symptoms may include include an itchy or burning rash; fever; and joint pain which are triggered by exposure to cold temperatures.[rarediseases.info.nih.gov]
  • NLRP3 Deletion and Duplication Analysis NLRP3 Whole Gene Sequencing Periodic Fever, 6 Gene Deletion and Duplication Panel Periodic Fever, 6 Gene NGS Panel Periodic Fever Deletion and Duplication Panel Periodic Fever NGS Panel Search Tests Search this[ddccliniclab.org]
  • Abstract Familial cold urticaria (FCU) is a rare autosomal dominant inflammatory disorder characterized by intermittent episodes of rash with fever, arthralgias, conjunctivitis, and leukocytosis.[ncbi.nlm.nih.gov]
  • Associated fever, chills, joint pains, nausea, stiffness and swelling of the hands and feet frequently occur. The symptoms are variable, ranging from mild to incapacitating. The pathogenesis of FCU remains unknown.[ncbi.nlm.nih.gov]
Chills
  • Associated fever, chills, joint pains, nausea, stiffness and swelling of the hands and feet frequently occur. The symptoms are variable, ranging from mild to incapacitating. The pathogenesis of FCU remains unknown.[ncbi.nlm.nih.gov]
  • Systemic symptoms included burning, chills, and arthralgias rather than the anaphylactic symptoms associated with acquired urticarias. Cold room challenge induced "non-urticarial" lesions after a delay of one-half to two hours.[ncbi.nlm.nih.gov]
  • FACU differs from familial cold auto-inflammatory syndrome in symptom timing and the absence of fever, chills, and joint pain. The cause is suspected to be mast cell related. Treatment of reactions is similar to that for ACU.[coldallergy.org]
  • Roughly 1-4 hours when a cold exposure rash, fever, chills, joint pains, and red eyes develop. Alternative less common symptoms embrace extreme thirst, drowsiness, nausea, and headaches. An “attack” typically lasts 24-48 hours.[aryanzherbal.com]
  • In contrast, MWS leads to progressive sensorineural deafness, amyloidosis of the kidneys and other organs, fevers, chills, rigors, malaise, and chronic recurrent urticaria.[pediatrics.aappublications.org]
Fatigue
  • Most symptoms during an episode last less than 24 hours, and can also include conjunctivitis in the eyes, sweating, fatigue, headaches, generalized pains, extreme thirst, and nausea in addition to the fever, rash and joint pains.[autoinflammatory.org]
  • A painful, pruritic, urticaria-like rash that is followed by fever, joint pain, fatigue, headache and fever is the typical clinical course. Symptoms are preceded by exposure to cold temperatures by 1-2 hours, which is a hallmark of FCU.[symptoma.com]
  • Signs & Symptoms Patients with FCAS experience mild to debilitating symptoms such as rash, fatigue, recurrent fever and chills, recurrent joint pain, and recurrent conjunctivitis (inflammation of the outer most layer of the eye causing redness, discomfort[rarediseases.org]
  • Neurologic: Some have headaches and fatigue with fever after cold exposure.[autoinflammatory-search.org]
Asymptomatic
  • The finding of the G569R mutation in an asymptomatic individual further emphasizes the importance of such modifier a gene (or genes) in determining the disease phenotype.[ncbi.nlm.nih.gov]
Nausea
  • Associated fever, chills, joint pains, nausea, stiffness and swelling of the hands and feet frequently occur. The symptoms are variable, ranging from mild to incapacitating. The pathogenesis of FCU remains unknown.[ncbi.nlm.nih.gov]
  • Alternative less common symptoms embrace extreme thirst, drowsiness, nausea, and headaches. An “attack” typically lasts 24-48 hours. The rash isn’t fretful, however is commonly delineate as painful or “burning.”[aryanzherbal.com]
  • Most symptoms during an episode last less than 24 hours, and can also include conjunctivitis in the eyes, sweating, fatigue, headaches, generalized pains, extreme thirst, and nausea in addition to the fever, rash and joint pains.[autoinflammatory.org]
  • In addition, it may appear redness of conjunctivitis, sweating, drowsiness, headache, thirst and nausea. This process is due to mutations in genes NLRP3 and NLRP12.[ivami.com]
Arthralgia
  • Abstract Familial cold urticaria (FCU) is a rare autosomal dominant inflammatory disorder characterized by intermittent episodes of rash with fever, arthralgias, conjunctivitis, and leukocytosis.[ncbi.nlm.nih.gov]
  • These rare autosomal dominant diseases are both characterized by recurrent inflammatory crises that start in childhood and that are generally associated with fever, arthralgia, and urticaria.[ncbi.nlm.nih.gov]
  • Systemic symptoms included burning, chills, and arthralgias rather than the anaphylactic symptoms associated with acquired urticarias. Cold room challenge induced "non-urticarial" lesions after a delay of one-half to two hours.[ncbi.nlm.nih.gov]
  • After exposure to cold temperatures or sudden drops that may be caused by air conditioning, rash, fever and arthralgia are most frequently reported.[symptoma.com]
  • The FCAS clinical picture includes: skin rash (100%), arthralgia (96%), fever (93%), conjunctivitis (84%), disease onset in the first 6 months of life (95%), an average time delay between cold exposure and the onset of symptoms of 2.5 hours, and an average[pediatrics.aappublications.org]
Myalgia
  • It is characterized by recurrent episodes of skin rash with arthralgias, myalgias, fever and chills.[moldiag.com]
  • FCAS causes hives, fever, chills, myalgias, headache, stiffness and swelling, among other symptoms. “It's like you're freezing from the inside out,” says Rachel Doherty. “Your whole body contracts until you warm up, which can take hours or days.”[news-medical.net]
  • […] the acute episodes of familial cold autoinflammatory syndrome can include: Fever – 93%, lasts less than 24 hours, preceding chills, associated with profuse sweating, often occur at night, settle within hours Skin rash – 100%, see below Muscle pain ( myalgia[dermnetnz.org]
  • FCAS MWS CINCA/NOMID Cold triggered Rare cold triggered No cold triggered Recurrent episodes of fever Recurrent episodes of fever Fever Urticaria Urticaria Urticaria Arthralgia/myalgia Arthralgia/arthritis Arthralgia/arthritis/severe arthropathies Conjunctivitis[clevelandclinicmeded.com]
Eruptions
  • Recently, FCAS—also known as familial cold urticaria and familial polymorphous cold eruption—has been well-described by the same authors.[pediatrics.aappublications.org]
  • It's conjointly been mentioned as cold hypersensitivity, cold pathergy, and familial cold polymorphous eruption. It's also been documented as fireplace and Ice Syndrome.[ayurvedayogashram.com]
  • Title Other Names: FCAS; Familial polymorphous cold eruption; Familial cold urticaria Categories: Familial cold autoinflammatory syndrome is a type of periodic fever syndrome .[rarediseases.info.nih.gov]
  • Familial cold autoinflammatory syndrome (FCAS, also known as familial cold urticaria, familial polymorphous cold eruption, and cold hypersensitivity) is a relatively mild febrile syndrome characterized by episodic fever, rash, and arthralgia, precipitated[centrallakesclinic.biz]
  • People who have the “acquired form,” however, erupt into hives within two to five minutes after exposure.[inverse.com]
Increased Sweating
  • Management of this condition involves avoiding exposure to cold temperatures and treatment with specific types of medications. 0012378 Fever 0001945 Hyperhidrosis Excessive sweating Increased sweating Profuse sweating Sweating Sweating profusely Sweating[rarediseases.info.nih.gov]
Hyperhidrosis
  • Management of this condition involves avoiding exposure to cold temperatures and treatment with specific types of medications. 0012378 Fever 0001945 Hyperhidrosis Excessive sweating Increased sweating Profuse sweating Sweating Sweating profusely Sweating[rarediseases.info.nih.gov]
Increased Sweating
  • Management of this condition involves avoiding exposure to cold temperatures and treatment with specific types of medications. 0012378 Fever 0001945 Hyperhidrosis Excessive sweating Increased sweating Profuse sweating Sweating Sweating profusely Sweating[rarediseases.info.nih.gov]
Headache
  • Low-grade fever and arthralgia ensue several hours after the onset of rash, while additional symptoms include sweating, headaches, nausea and extreme thirst.[symptoma.com]
  • Most symptoms during an episode last less than 24 hours, and can also include conjunctivitis in the eyes, sweating, fatigue, headaches, generalized pains, extreme thirst, and nausea in addition to the fever, rash and joint pains.[autoinflammatory.org]
  • Alternative less common symptoms embrace extreme thirst, drowsiness, nausea, and headaches. An “attack” typically lasts 24-48 hours. The rash isn’t fretful, however is commonly delineate as painful or “burning.”[aryanzherbal.com]
  • In addition, it may appear redness of conjunctivitis, sweating, drowsiness, headache, thirst and nausea. This process is due to mutations in genes NLRP3 and NLRP12.[ivami.com]
Neurologic Manifestation
  • Neurological manifestations of the Mendelian-inherited autoinflammatory syndromes. Dev Med Child Neurol 2009; 51: 420-428. Neven B, Prieur A-M, Quartier dit Maire P. Cryopyrinopathies: update on pathogenesis and treatment.[dermnetnz.org]

Workup

FCU may be established on the basis of diagnostic criteria that have been proposed in order to distinguish it from other conditions that present with similar symptoms, such as familial Mediterranean fever, hyper-IgD syndrome and acquired cold urticaria. Confirmed autosomal dominant pattern of inheritance, onset before 6 months of age, recurrent episodic appearance of fever and rash, but also conjunctivitis when exposed to cold environments, resolution of symptoms within 24 hours of their onset, together with absence of deafness, periorbital edema, serositis and lymph node involvement are hallmarks of FCU [4]. To distinguish this condition from other cryopyrinopathies, absence of neurological symptoms and presence of optic neuritis and papilledema should be evaluated (which is characteristic for CINCA) [7]. Genetic testing to establish NLRP gene mutations is a definite diagnostic measure, but because it is scarcely available, workup remains on clinical criteria.

Treatment

Initial therapeutic strategies included administration of NSAIDs, corticosteroids and body warming, but the introduction of IL-1β receptor antagonists resulted in dramatic improvement and maintenance of symptoms [4] [9]. Anakira has shown to be very effective in many patients and is given subcutaneously in doses of 0.5-1.5 mg/kg/day. Apart from injection-site reaction, which showed to be present in up to 50% of patients according to some studies [10], adverse effects are minimal and is safe for long-term use.

Prognosis

A very early onset of symptoms (< 6 months of age) and their frequent appearance may be severely debilitating for the patient, but the prognosis has drastically improved with the introduction of IL-1 receptor antagonists. Late-onset amyloidosis that involves the kidneys, a potentially life-threatening complication, is reported in less than 2% of patients [9], and is more frequently observed in other cryopyrinopathies [9]. Nevertheless, monitoring of renal function is generally recommended [4]. This condition does not pose significant risk in terms of life expectancy and it is considered to be the mildest variant of cryopyrinopathies [4].

Etiology

In the vast majority of cases, FCU develops due to mutations of cryopyrin, a protein that is coded by the NALP3 (knows as CIAS1) gene on chromosome 1q44 [2]. NALP3 gene products, including cryopyrin, belong to the group of nucleotide-binding domain and leucine-rich-repeat containing proteins (NLRs) and numerous mutations of these molecules have been identified across all diseases that are classified into cryopyrinopathies [5]. Additionally, these mutations are transmitted by an autosomal dominant pattern of inheritance, with a 50% chance for children to be born with these mutations if one of the parents is suffering from FCU.

Epidemiology

FCU is considered to be a very rare clinical entity and only about 150 cases have been documented, mainly from Europe and North America [6]. Moreover, rough incidence rates estimate that FCU develops in less than 1 in 1 million individuals [4]. Apart from genetic predisposition, risk factors for this condition have not been established.

Sex distribution
Age distribution

Pathophysiology

The pathogenesis of FCU starts with mutations in the NLRP family of genes. NALP1 belongs to this group and codes for cryopyrin, an important constituent of numerous pro-inflammatory activities exerted by the immune system. One of the pivotal roles of cryopyrin is the assembly of the inflammasome and upregulation of transcription pathways, mainly NF-κB, ultimately leading to increased cleavage of IL-1β from its inactive forms [8]. IL-1β is one of the most potent pro-inflammatory cytokines, while abnormalities in concentrations of IL-6, tumor necrosis factor alpha (TNF-α) and granulocyte-colony stimulating factor (G-CSF) have also been documented [8] [9]. On the contrary, mutations of proteins that should suppress the inflammatory response, such as monarch-1 (or NLRP12) have also been discovered [5], indicating that FCU is characterized by both overt stimulation and reduced capacity for inhibition of the inflammatory response. For unknown reasons, these mechanisms are triggered at very cold temperatures and lead to the development symptoms.

Prevention

Although specific mutations have been established, current prevention strategies do not exist. Genetic counseling for families with known mutations may be advised, as there is a 50% chance for disease transmission.

Summary

Familial cold urticaria (FCU), or familial cold autoinflammatory syndrome (FCAS), is a clinical entity that belongs to the group of cryopyrinopathies, together with Muckle Wells syndrome (MWS) and Chronic Infantile Neurological Cutaneous and Articular syndrome (CINCA) [1]. Mutations of the NALP3 gene (also known as CIAS1) on chromosome 1q44 and alterations of cryopyrin, a protein that is expressed in peripheral leukocytes and chondrocytes, are the underlying cause of symptoms in this group of diseases [2]. Cryopyrin is involved in various pro-inflammatory processes, one of them being activation of caspase 1 and nuclear transcription factor-kappa B (NF-κB), eventually causing upregulation of interleukin 1 (IL-1) production and inflammation that produces symptoms [3]. FCU has shown to have an autosomal dominant pattern of inheritance, but sporadic cases in whom de novo mutations occurred have been reported [4]. Only about 150 cases in Europe and North America have been documented in literature and incidence rates are estimated to be below 1 per 1 million individuals [4] [5]. The clinical presentation includes a very early onset, as the majority of patients develop clear symptoms within the first 6 months of life [6]. A painful, pruritic, urticaria-like rash that is followed by fever, joint pain, fatigue, headache and fever is the typical clinical course [7]. Symptoms are preceded by exposure to cold temperatures by 1-2 hours, which is a hallmark of FCU [7]. Symptoms come in attacks and the duration may vary depending severity of exposure, but in most patients, resolution is seen within 24 hours [4]. To make the diagnosis, evident appearance of symptoms after exposure to cold temperatures and a positive family history for similar complaints are highly suggestive of FCU. When symptoms are present, acute-phase reactants such as C-reactive protein as well as leukocyte count may be elevated [7]. Although identification of NALP3 mutations can confirm the diagnosis, this test is not readily available. Treatment principles have drastically changed with the introduction of anakira, an IL-1β receptor antagonist, which showed markedly better results compared to non-steroidal anti-inflammatory drugs (NSAIDs) and corticosteroids, both in terms of efficacy and severity of adverse effects [4]. When it comes to prevention, genetic counseling is advisable for families in whom NALP3 gene mutations have been established.

Patient Information

Familial cold urticaria (FCU), also known as familial cold autoinflammatory syndrome (FCAS), belongs to the group of diseases known as cryopyrinopathies, together with Muckle-Wells syndrome (MWS) and Chronic Infantile Neurological Cutaneous and Articular syndrome (CINCA). In FCU, symptoms arise due to mutations of cryopyrin, a protein that is involved in production of an inflammatory response. Namely, cryopyrin is abnormally activated and stimulates production of interleukin-1 (IL-1), one of the most potent molecules that mobilizes cells of the immune system and triggers the onset of symptoms. The condition is genetic in origin, as it is transferred from parents to children by autosomal dominant pattern of inheritance, meaning that one of the parents also suffers from this condition. Only 150 cases have been described in literature so far, mainly from Europe and the United States, with estimations that FCU is seen in less than 1 in 1 million individuals. The hallmark of FCU is the appearance of symptoms such as rash, joint pain and fever after exposure to cold temperatures. After 1-2 hours, a rash that is itchy, painful and resembles urticaria (seen in allergies) develops, followed by low-grade fever, joint pain, conjunctivitis, headaches, drowsiness and extreme thirst. These complaints usually resolve within 24 hours after their appearance and recur practically every day. To distinguish FCU from other diseases that belong in the same group, the onset of symptoms before 6 months of age (some may even present at birth) and absence of neurological and hearing symptoms may be useful. To make the diagnosis, signs and symptoms together with patient history should suffice, while genetic testing may serve as a definite measure, but it is not commercially available. Treatment is focused on alleviation of symptoms through administration of drugs that suppress inflammation, such as non-steroidal anti-inflammatory drugs (NSAIDs) and corticosterodis, but the introduction of anakira, an interleukin-1 receptor antagonist, has significantly improved management of patients. Complications of FCU are rare and minimal compared to Muckle Wells syndrome and CINCA and life expectancy is normal compared to the general population, but an early diagnosis may significantly reduce the burden this condition may have on the quality of life.

References

Article

  1. Gattorno M, Federici S, Pelagatti MA, Caorsi R, Brisca G, Malattia C, Martini A: Diagnosis and management of autoinflammatory diseases in childhood. J Clin Immunol. 2008;28:73-83.
  2. Hoffman HM, Mueller JL, Broide DH, et al. Mutation of a new gene encoding a putative pyrin-like protein causes familial cold autoinflammatory syndrome and Muckle-Wells syndrome. Nat Genet. 2001;29(3):301–305.
  3. Espandar L, Boehlke CS, Kelly MP. First report of keratitis in familial cold autoinflammatory syndrome. Can J Ophthalmol. 2014;49(3):304-306.
  4. Hoffman HM, Wanderer AA, Broide DH. Familial cold autoinflammatory syndrome: phenotype and genotype of an autosomal dominant periodic fever. J Allergy Clin Immunol. 2001;108(4):615-620.
  5. Borghini S, Tassi S, Chiesa S, et al. Clinical Presentation and Pathogenesis of Cold-Induced Autoinflammatory Disease in a Family With Recurrence of an NLRP12 Mutation. Arthritis Rheum. 2011;63(3):830-839.
  6. Goldfinger S. The Inherited Autoinflammatory Syndrome: A Decade of Discovery. Trans Am Clin Climatol Assoc. 2009;120:413-418.
  7. Neven B, Prieur AM, Quartier dit Maire P. Cryopyrinopathies: update on pathogenesis and treatment. Nat Clin Pract Rheumatol. 2008;4,481-489.
  8. Hedrich CM, Bruck N, Paul D, Hahn G, Gahr M, Rösen-Wolff A. "Mutation negative" familial cold autoinflammatory syndrome (FCAS) in an 8-year-old boy: clinical course and functional studies. Rheumatol Int. 2012;32(9):2629-2636.
  9. Hoffman HM, Wright FA, Broide DH, et al. Identification of a locus on chromosome 1q44 for familial cold urticaria. Am J Hum Genet. 2000;66:1693-1698.
  10. Ross JB, Finlayson LA, Klotz PJ, et al. Use of anakinra (Kineret) in the treatment of familial cold autoinflammatory syndrome with a 16-month follow-up. Journal of cutaneous medicine and surgery. 2010;12(1):8–16.

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Last updated: 2018-06-21 23:23