Familial Cold Autoinflammatory Syndrome 4

A number sign (#) is used with this entry because of evidence that familial cold autoinflammatory syndrome-4 (FCAS4) is caused by heterozygous mutation in the NLRC4 gene (606831) on chromosome 2p22. One such family has been reported.

For a phenotypic description and a discussion of genetic heterogeneity of familial cold autoinflammatory syndrome, see FCAS1 (120100).

Clinical Features

Kitamura et al. (2014) reported a 3-generation Japanese family in which multiple individuals had an autoinflammatory disorder characterized by onset of episodic high fevers, urticaria-like rash, and arthralgias beginning at 2 to 3 months of age. The symptoms were often induced by exposure to cold stimuli. The rash was not accompanied by itching, and the patients did not have splenomegaly or bone erosions. The symptoms resolved without treatment in most cases, although some patients took nonsteroidal antiinflammatory drugs to reduce joint pain.

Inheritance

The transmission pattern of FCAS4 in the family reported by Kitamura et al. (2014) was consistent with autosomal dominant inheritance.

Molecular Genetics

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, which was found by whole-exome sequencing, segregated with the disorder in the family. In vitro cellular functional expression studies showed that the H443P mutation increased oligomerization of NLRC4 and resulted in hyperactivation of caspase-1 (CASP1; 147678) with an increase in secretion of IL1B (147720).

Animal Model

Kitamura et al. (2014) found that expression of the murine equivalent of the human NLRC4 H443P mutation in mouse spleen caused dermatitis and swollen joints beginning at 3 weeks of age. Mutant mice developed splenomegaly with inflammatory cell infiltration and bone erosion. Splenocytes derived from mutant mice showed increased Il1b secretion, and serum levels of Il1b, Il17a (603149), and Gcsf (CSF3; 138970) were increased in mutant mice compared to controls. Most of the cells that produced Il17a in mutant mice were neutrophils, not T cells, and depletion of these cells and/or antibodies against Il1b and Il17a decreased footpad swelling. Exposure to cold stimuli increased the autoinflammation in mutant mice, similar to that observed in affected members of a Japanese family with the mutation.