Familial cold autoinflammatory syndrome 4 L50.2

Familial cold-induced autoinflammatory syndrome 4, FCAS4 for short, is associated with a heterozygous mutation in the NLRC4 gene (606831) on chromosome 2p22. The inheritance pattern of FCAS4 in the family reported by Kitamura et al. (2014) corresponded to an autosomal dominant inheritance.

Like other entities in this family, FACS used to be subsumed under the term"cold urticaria". It has since been recognized that this group of diseases belongs to the hereditary periodic fever syndromes. All these entities are characterized by cold-provoked itchy, burning or slightly painful exanthema (usually limited to the site of contact), which can be accompanied by fever attacks and other signs of inflammation. To date, 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 entities belong to this family:

• "Cold-induced autoinflammatory syndrome, familial " (FCAS1) 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). The autosomal dominant inherited syndrome 2 is caused by heterozygous mutations in the NLRP12 gene (609648).
• The autosomal dominant 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 " (FACS4).

NLRC4 mutant mice developed splenomegaly with inflammatory cell infiltration and bone erosion. Splenocytes derived from mutant mice showed increased Il-1b secretion, and serum levels of Il-1b, Il-17a (603149), and GCSF (CSF3; 138970) were increased in mutant mice compared with controls. Most of the cells that produced Il17a in the mutant mice were neutrophilic granulocytes. Cold stimuli increased autoinflammation in the mutant mice.

First manifestations appeared from the age of 2 to 3 months.

Kitamura et al (2014) reported on a third-generation Japanese family in which several individuals had an, autosomal-dominant, autoinflammatory disease characterized by the cold-induced, onset of episodic high fever, nonpruritic urticarial exanthema, and arthralgias. The symptoms disappeared in most cases without treatment.

In affected members of a Japanese family with FCAS4, Kitamura et al. (2014) identified a heterozygous missense mutation in the NLRC4 gene (H443P; 606831.0003). The mutation, found by whole-exome sequencing, segregated with the disorder in the family. Cellular functional in vitro expression studies showed that the H443P mutation increases oligomerization of NLRC4 and leads to hyperactivation of caspase-1 (CASP1; 147678) with increased secretion of IL1Beta (147720, see IL1B gene below) (Kitamura A et al. 2014) .

1. Andrade WA et al (2020) NLRC4 biology in immunity and inflammation. J Leukoc Biol 108:1117-1127.
2. Bauer R et al (2020) The NAIP/NLRC4 inflammasome in infection and pathology. Mol Aspects Med 76:100863.
3. Duncan JA et al (2018) The NLRC4 inflammasome. Immunol Rev 281:115-123.
4. Kitamura A et al (2014) An inherited mutation in NLRC4 causes autoinflammation in human and mice. J Exp Med 211: 2385-2396.