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].

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.

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.

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].

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.

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.

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.

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.

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.

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.

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