Familial Cold Autoinflammatory Syndrome 2
A number sign (#) is used with this entry because of evidence that familial cold autoinflammatory syndrome-2 (FCAS2) is caused by heterozygous mutation in the NLRP12 gene (609648) on chromosome 19q13.
DescriptionFamilial cold autoinflammatory syndrome-2 (FCAS2) is an autosomal dominant autoinflammatory disorder characterized by episodic and recurrent rash, urticaria, arthralgia, myalgia, and headache. In most patients, these episodes are accompanied by fever and serologic evidence of inflammation. Most, but not all, patients report exposure to cold as a trigger for the episodes. Additional features may include abdominal pain, thoracic pain, and sensorineural deafness. The age at onset is variable, ranging from the first year of life to middle age, and the severity and clinical manifestations are heterogeneous (summary by Shen et al., 2017).
For a phenotypic description and a discussion of genetic heterogeneity of familial cold autoinflammatory syndrome, see FCAS1 (120100).
Clinical FeaturesJeru et al. (2008) reported 2 unrelated families from Guadeloupe with a periodic fever syndrome. Inheritance was autosomal dominant. Affected 10-year-old twin boys in one family had onset in the first days of life of episodic fever, arthralgia, and myalgia. Episodes developed after generalized exposure to cold. Urticaria was observed 2 times in each patient, and both had bilateral sensorineural hearing loss. Headache and lower limb pain occurred during and between episodes. Serum C-reactive protein (CRP; 123260) and IgD were normal. The affected father had attacks lasting 2 to 3 days during childhood, and had episodes of fever and urticaria triggered by mild physical activity as an adult. His audiogram was normal. The proband of the second family was a 9-year-old girl with episodic fever since the first year of life. Episodes were triggered by cold exposure and associated with abdominal pain, vomiting, arthralgia, buccal aphthous ulcers, and lymphadenopathy. Serum CRP was found to be increased during attacks. Her father had attacks from age 5 to 12 years.
Borghini et al. (2011) reported an Italian family in which 4 individuals had variable manifestations of FCAS2. The proband was a 32-year-old woman who experienced recurrent episodes of urticarial rash on the face, arms, and trunk associated with fever, arthralgias, myalgia, and headache since age 20 years. The clinical manifestations occurred exclusively during winter; she had complete well-being during the warm season. Fever episodes were associated with elevations in the levels of acute-phase reactants. She had a good response to steroid and antihistamine administration. Her father and paternal aunt had a similar phenotype with onset of features in childhood or infancy, although the father did not have episodes of fever, and the aunt developed optic neuritis. Both the father and aunt were treated with NSAIDs and occasionally steroids. The fourth patient, a 67-year-old paternal uncle of the proband, reported an urticarial-like rash in conjunction with episodes of fever, which he believed were associated with intercurrent viral or bacterial infections. He denied ever having any cold-induced features, and had no musculoskeletal or ocular manifestations.
Jeru et al. (2011) reported 2 unrelated patients, from Armenia and Italy, respectively, with FCAS2. Both patients had onset of recurrent and episodic cold-induced myalgia, abdominal pain, and fever in the first years of life. The Italian patient also had associated adenopathy, malar rash, and buccal aphthosis, as well as increased CRP during the episodes, consistent with autoinflammation. Laboratory studies of CRP from the other patient were not available. Notably, neither patient had urticaria.
Vitale et al. (2013) reported 6 unrelated Italian probands with FCAS2. The age of symptom onset ranged from 2 to 36 years, and the features included recurrent episodes of fever and cold-induced symptoms. Symptoms were variable, but included rash, urticaria, lymphadenopathy, headache, arthralgia, arthritis, myalgia, and fatigue. One patient had sensorineural hearing loss, and several showed increased acute phase response proteins. The patients showed a response to steroid treatment. Two patients had affected relatives with the mutation, but there were also unaffected mutation carriers in some families, consistent with incomplete penetrance.
Xia et al. (2016) reported a 4-generation Chinese family in which 5 individuals had FCAS2. One older patient was deceased. The patients developed cold-associated urticarial rashes on the limbs and trunk in the first year of life. The symptomatic periods in these patients lasted for 12 to 24 hours and appeared a few hours after exposure to cold. The episodes were accompanied by fever and often by joint pain. Hearing loss, mental retardation, and renal disturbance were not observed in any of the affected individuals. Laboratory studies showed increased erythrocyte sedimentation rates and CRP levels in all 4 living patients.
Shen et al. (2017) reported 3 unrelated Han Chinese patients with onset of features of FCAS2 in their thirties or forties. They had recurrent fever associated with headache, arthralgia, and myalgia, with skin involvement manifest as erythema nodosa or urticaria. Some patients had lymphadenopathy or splenomegaly. Laboratory studies showed increased ESR, CRP, and leukocytosis during the attacks, all of which normalized between episodes. Only 1 patient reported triggering of the episodes by cold. The episodes occurred every few months and lasted for several weeks. Treatment with prednisone resulted in resolution of symptoms. None had a family history of the disorder and none had sensorineural deafness.
InheritanceThe transmission pattern of FCAS2 in the family reported by Borghini et al. (2011) was consistent with autosomal dominant inheritance and incomplete penetrance.
Molecular GeneticsIn affected members of 2 unrelated families with FCAS2, Jeru et al. (2008) identified heterozygous mutations in the NLRP12 gene (R284X; 609648.0001 and a splice site mutation 609648.0002). Both mutations were predicted to result in a loss of function. In vitro functional expression studies showed that both mutations reduced inhibitory action against NF-kappa-B (164011) compared to wildtype NLRP12.
In 4 affected members of an Italian family with variable manifestations of FCAS2, Borghini et al. (2011) identified a heterozygous missense mutation in the NLRP12 gene (D294E; 609648.0003). The mutation, which was found by direct sequencing of exon 3 of the NLRP12 gene in 50 patients with a similar disorder, segregated with the disorder in the family. In vitro functional expression studies in HEK293 cells showed that the D294E mutation did not result in decreased inhibitory action against NF-kappa-B, but rather showed similar inhibitory activity as the wildtype protein. Patient-derived monocytes did not show increased quantitative secretion of IL1B (147720) compared to controls when stimulated with pathogen-associated molecular patterns (PAMPs). However, patient cells showed altered kinetics of IL1B secretion, with significant acceleration of IL1B secretion compared to controls in a given time frame. Patient cells also showed increased production of reactive oxygen species and upregulation of antioxidant systems, resulting in rapid exhaustion of the antioxidant systems compared to controls. These changes were most apparent in the more severely affected individual and less apparent in the least affected individual.
In 2 unrelated patients with FCAS2, Jeru et al. (2011) identified a heterozygous missense mutation in the NLRP12 gene (R352C; 609648.0004). The mutation, which was found by direct sequencing of the NLRP12 gene, occurred at a CpG dinucleotide and thus could correspond to a hotspot. In vitro functional expression studies in HEK293 cells showed that the mutant protein did not affect the NF-kappa-B inhibitory activity of NRLP12. However, the R352C mutant showed enhanced ability to induce the processing of caspase-1 (CASP1; 147678) compared to wildtype, consistent with a gain-of-function effect. Transfected cells also showed significantly more speck formation compared to controls. Specks represent intracellular aggregates reflecting activation of the caspase 1/IL1B pathway. Although IL1B levels were not ascertained in these patients, the findings suggested that the R352C mutant protein leads to increased CASP1 processing, which would result in increased IL1B secretion and a hyperinflammatory state.
Vitale et al. (2013) identified a heterozygous F402L variant in the NLRP12 gene (F402L; 609648.0005) in 5 unrelated Italian probands with FACS2. The variant showed a high frequency (up to 5%) in various databases, as well as incomplete penetrance in some of the family members studied, and Vitale et al. (2013) suggested that it may be a low-penetrance mutation. Functional studies of the variant and studies of patient cells were not performed.
Shen et al. (2017) identified a heterozygous F402L mutation in 3 unrelated Han Chinese patients with adult-onset FACS2 and no family history of the disorder. The mutations were found by whole-genome sequencing of periodic fever genes and confirmed by Sanger sequencing. Functional studies of the variant and studies of patient cells were not performed.