Familial cold-induced autoinflammatory syndrome 2 L50.2

Jeru I et al. (2008)

The autosomal-dominantly inherited cold-induced autoinflammatory syndrome 2, familial form (also called FCAS2 or NLRP12-associated systemic autoinflammatory disease), is a systemic, autoinflammatory disease characterized by episodic and recurrent exanthema after exposure to cold.

Like other entities in this family, FACS used to be subsumed under the term "cold urticaria". In the meantime, this group of diseases has been classified as systemic hereditary periodic fever syndromes (SAIDs). All these variants are characterized by cold-provoked itchy, burning or slightly painful exanthema (usually limited to the contact site), which can be accompanied by fever attacks and other signs of inflammation. So far, 4 genotypes with slightly different phenotypes have been described, which are now referred to as "cold-induced autoinflammatory syndromes, familial form 1-4". The following genetically defined and differentiated variants belong to this family:

• "Cold-induced autoinflammatory syndrome 1, familial " (FCAS21) is a hereditary autoinflammatory syndrome caused by a heterozygous mutation in the NLRP3 gene (1q44). FCAS1 is clinically characterized by recurrent episodes (with repeated exposure) of urticarial exanthema associated with arthralgias, myalgias, fever and chills as well as swelling of the extremities after exposure to cold. In rare cases, patients can also develop late-onset renal amyloidosis after decades of progression
• The"cold-induced autoinflammatory syndrome 2, familial" (FCAS2; OMIM: 609648)/ heterozygous mutations in the NLRP12 gene). Mutations in NLRP12 lead to"NLRP12-associated systemic autoinflammatory disease (NLRP12-AID), a rare autosomal dominant autoinflammatory systemic disease (SAID) that usually occurs in childhood. An NLRP12-AID variant is also known as familial cold autoinflammatory syndrome 2 ( FCAS2). Data from <100 patients are available worldwide (Wang HF 2022). In NLRP12-AID, > 20 different mutation types are known. Clinically, the disease is characterized by periodic fever accompanied by inflammatory damage throughout the system.
• The autosomal-dominantly inherited"cold-induced autoinflammatory syndrome 3, familial" (FCAS3), also known as PLCG2-associated antibody deficiency and immune dysregulation (PLAID), is caused by heterozygous deletions in the PLCG2 gene on chromosome 16q23.
• The " cold-induced autoinflammatory syndrome 4, familial " or FCAS4 for short, is associated with a heterozygous mutation in the NLRC4 gene (606831) on chromosome 2p22.

Autosomal dominant familial cold-induced auto-inflammatory syndrome 2 is caused by hetrozygous mutations in the NLRP12 gene (609648). To date, 21 different types of NLRP12 mutations have been discovered, including 16 missense mutations (76%), 2 nonsense mutations (10%) and 3 frameshift mutations (14%). Most of the mutation sites are located in its functional domains (Fig. 2), which may impair the anti-inflammatory function of NLRP12 and lead to an inflammatory pattern (Wang HF 2022).

Remarkably, NLRP12 mutations have also been detected in many cases in first-degree relatives, but no corresponding suspicious clinical symptoms have been reported, suggesting that NLRP12 mutations in combination with other genetic and environmental factors may be the cause of this disease.

In affected members of two 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 presumably lead to a loss of function of the encoded protein. Jeru et al. (2011) found a heterozygous missense mutation in the NLRP12 gene (R352C; 609648.0004). Shen et al. (2017) identified a heterozygous F402L mutation in three unrelated Han Chinese patients with FACS2 in adulthood. The mutations were found by whole genome sequencing of the periodic fever genes and confirmed by Sanger sequencing.

The molecular mechanism ultimately involves excessive release of inflammatory cytokines such as interleukin-1beta caused by attenuated inhibition of the nuclear factor kappa B (NF-κB) signaling pathway due to the decreased functional activity of mutant NLRP12. Due to the genetic mutation, most cases occur in early childhood (Wang HF 2022).

Apparently, a mutated functional domain in NLRP12 not only reduces the inhibitory effect on NF-kappa, but also simultaneously increases caspase-1 activity, which eventually leads to excessive production of various inflammatory cytokines such as IL-1beta. IL-1beta, an "alarm cytokine", has a strong pro-inflammatory effect on innate immunity. The cytokine can stimulate and even induce the production of other inflammatory cytokines (such as IL-6 and TNF-alpha). As a potent endogenous pyrogen, IL-1beta can increase body temperature and cooperate with other inflammatory cytokines (such as TNF, inducible nitric oxide synthase (iNOS), cyclooxygenase (COX) 2 and prostaglandin E2 (PGE2)). Jéru et al. demonstrated that intracellular IL-1beta and IL-6 levels were 80-175 times and 43-110 times higher, respectively, in children with NLRP12-AID than in control children. After further stimulation of peripheral blood mononuclear cells (PBMCs) with lipopolysaccharides, IL-1beta levels in pediatric NLRP12-AID patients were still 5-10 times higher than in the control group, and similar results were obtained for intereleukin-1Ra, intereleukin-6, and TNFalpha.

The age at diagnosis was between 2 months and 17 years. Of the children whose gender was known, 11 (35%) were male and 20 (65%) were female. Four patients (22%) had a positive family history and 10 cases (30%) were clearly induced by cold stimulation. The most common clinical symptom was periodic fever of varying duration (100%) (Wang HF 2022).

Dermatologically, itchy, cold-induced urticaria (which can be triggered after a general cooling of the body, but not by localized cold contact), arthralgias, myalgias, colicky abdominal pain and headaches are characteristic. In most patients, these episodes are accompanied by fever and serologic evidence of inflammation. Most, but not all, patients report cold as a trigger for the episodes.

Other clinical signs include inflammatory granulomatous plaques in cold-sensitive skin areas and cutis laxa-like skin lesions.

Other clinical features may include chest pain and sensorineural numbness (Shen et al. 2017).

De novo mutations have been described.

Jeru et al (2008) reported 2 unrelated families from Guadeloupe with an autosomal-dominant inherited periodic fever syndrome in one family combined with sensorineural hearing loss. Affected 10-year-old twins in one family experienced episodic fever, arthralgia, and myalgia in the first days of life. The episodes occurred after generalized exposure to cold. Spontaneous urticaria was observed several times in both patients. Headache and arthralgia of the lower limbs 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 in childhood and febrile episodes and urticaria triggered by light physical activity as an adult. His audiogram was normal.

The 9-year-old girl in the 2nd family suffered from febrile episodes since the age of 1 year. The febrile episodes were triggered by cold exposure and were associated with abdominal pain, vomiting, arthralgia, aphthous ulcers around the mouth, and lymphadenopathy. Serum CRP was found to be elevated during the attacks. An analogous one was detectable in her father between the ages of 5 and 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 had suffered recurrent episodes of urticarial rash on the face, arms, and trunk associated with fever, arthralgias, myalgias, and headache since the age of 20. The clinical manifestations occurred exclusively in winter; she was perfectly well in the warm season. The febrile episodes were associated with elevated levels of acute phase proteins. She responded well to the administration of steroids and antihistamines. Her father and paternal aunt had a similar phenotype with symptom onset in infancy or childhood. Both the father and aunt were treated with NSAIDs and occasionally steroids.

Jeru et al (2011) reported two unrelated patients from Armenia and Italy, respectively, with FCAS2. Both patients had recurrent and episodic cold-related myalgias, abdominal pain, and fever during the first years of life, and buccal aphthosis. Lab.: elevated CRP level during episodes. No urticaria.

Vitale et al (2013) reported 6 unrelated Italian subjects with FCAS2. Age at onset of symptoms ranged from 2 to 36 years, and features included recurrent febrile episodes and cold-related symptoms. Symptoms varied but included rash, urticaria, lymphadenopathy, headache, arthralgia, arthritis, myalgia, and fatigue. One patient had sensorineural hearing loss, and several showed elevated acute phase proteins.

Xia et al (2016) reported on a fourth-generation Chinese family in which five individuals suffered from FCAS2. The patients developed cold-associated urticarial exanthema on the limbs and trunk during the first year of life. The exanthem episodes lasted 12 to 24 hours in these patients and occurred after a latency of several hours after cold exposure. Episodes were accompanied by fever and often joint pain. Hearing loss, mental retardation, and renal dysfunction were not observed in any of the affected individuals. Laboratory tests showed elevated erythrocyte sedimentation rates and CRP levels in all 4 live patients.

1. Borghini S et al. Clinical presentation and pathogenesis of cold-induced autoinflammatory disease in a family with recurrence of an NLRP12 mutation. Arthritis Rheum. 63: 830-839.
2. Jeru I et al. (2008) Mutations in NALP12 cause hereditary periodic fever syndromes. Proc Nat Acad Sci 105: 1614-1619.
3. Jeru I et al. (2011) Identification and functional consequences of a recurrent NLRP12 missense mutation in periodic fever syndromes. Arthritis Rheum 63: 1459-1464.
4. Shen M et al. (2017) NLRP12 autoinflammatory disease: a Chinese case series and literature review. Clin Rheum 36: 1661-1667.
5. Vitale A et al. (2013) Rare NLRP12 variants associated with the NLRP12-autoinflammatory disorder phenotype: an Italian case series. Clin Exp Rheum 31: 155-156.

6. Wang HF (2022) NLRP12-associated systemic autoinflammatory diseases in children. Pediatric Rheumatology 20: 9 https://doi.org/10.1186/s12969-022-00669-8

7. Xia X et al. (2016) Identification of a novel NLRP12 nonsense mutation (Trp408X) in the extremely rare disease FCAS by exome sequencing. PLoS One 11: e0156981