Familial cold autoinflammatory syndrome 2 is a rare autoinflammatory disorder caused by mutations in the NLRP12 gene, characterized by recurrent fever, arthralgia and rash triggered by cold exposure. This case report presents a 9-year-old boy with intellectual disability, microcephaly and skin lesions, where genetic testing revealed heterozygous pathogenic variants in both KIF11 (NM_004523.4:c.2304_2305del) and NLRP12 (NM_144687.4:c.770del) genes. While the KIF11 variant has been previously documented, the NLRP12 variant is novel and classified as likely pathogenic. This study also includes a systematic review analysing 28 studies and 100 patients with NLRP12 mutations, revealing a phenotypic spectrum ranging from classic symptoms like fever and rash to rarer features such as hypogonadism, hypothyroidism and neurological abnormalities. A significant concentration of variants was noted in Exon 3 of NLRP12, but no clear genotype-phenotype correlation was established. These findings underscore the utility of next-generation sequencing in diagnosing rare genetic conditions, particularly in patients presenting with seemingly minor symptoms. The coexistence of mutations in KIF11 and NLRP12 highlights potential interactions between distinct genetic pathways, emphasizing the need for further research. Including NLRP12 in diagnostic panels and updating databases like the Human Phenotype Ontology are crucial for improving diagnosis, understanding phenotypic diversity and optimizing patient management.

NLRP12 encodes the nucleotide-binding leucine-rich repeat-containing receptor 12 protein and has been linked to familial cold autoinflammatory syndrome 2 (FCAS2). Previous studies have reported that NLRP12 protein can dampen inflammatory responses in DSS-induced mice colitis. To date, only four alterations in the NLRP12 gene have been associated with Crohn's disease (CD). Here, we reported a novel heterozygous NLRP12 frameshift mutation (c.2188dupG, p.Val730Glyfs∗41) identified by whole-exome sequencing in the proband with CD. The Sanger sequencing confirmed that his sister and father also carried this NLRP12 mutation, which cosegregated well with the CD phenotype. In silico analysis predicted this mutation to be disease-causing. Patients heterozygous for this mutation exhibited decreased NLRP12 protein levels in the peripheral blood and colon. Functional assays showed that mutant NLRP12 plasmid-transfected HEK293T cells exhibited significantly lower NLRP12 mRNA and protein levels than wild-type plasmid-transfected cells. The nonsense-mediated decay inhibitor NMDI14 significantly increased NLRP12 mRNA and protein levels in mutant plasmid-transfected cells. Overall, our results demonstrated that this heterozygous NLRP12 mutation (c.2188dupG) resulted in decreased NLRP12 expression, which might contribute to the mechanism underlying CD.

NLRP12-associated autoinflammatory disease (NLRP12-AID) is a rarely seen periodic fever syndrome also known as familial cold autoinflammatory syndrome-2 (FCAS2), caused by autosomal dominant inherited mutations in the NLRP12 gene. We aimed to present our clinical experience constituting one of the largest paediatric NLRP12-AID cohort. The patients with preliminary diagnosis of systemic autoinflammatory disease (SAID) other than familial Mediterranean fever (FMF) and PFAPA syndrome were evaluated with the next-generation-sequence (NGS) genetic-panel analysis between January-2016 and January-2022. Among children carrying NLRP12-variant, patients with recurrent episodes of autoinflammatory disease manifestations were diagnosed with NLRP12-AID. Demographic, clinical and laboratory data, treatments and outcomes of patients were presented. Seventeen patients were diagnosed with NLRP12-AID. The mean age at diagnosis was 114.7±69.5 months. The most frequently seen clinical manifestations were respectively; fever (100%), arthritis/arthralgia (58.8%), rash (52.9%), abdominal pain (52.9%), diarrhoea (41.2%), myalgia/fatigue (53.2%) and, conjunctivitis (11.7%). Clinical manifestations were triggered by cold exposure in three patients (17.6%). Seven patients had pathogenic, one had likely pathogenic, seven had VUS, and two had novel heterozygous variants. The most common defined variant in the NLRP12 gene was R352C. Complete response was achieved in 5 patients and partial response was in 6 with colchicine treatment. Attacks were prevented with anti-IL-1 treatments in 6 patients unresponsive to colchicine. In conclusion, the disease can cause effects on various tissues, especially the musculoskeletal and gastrointestinal systems, apart from FCAS symptoms. We think that a patient who can be defined as syndrome of undifferentiated recurrent fever should also be evaluated genetically in terms of NLRP12 previously.

Systemic autoinflammatory diseases (SAIDs) are a group of monogenic diseases characterized by disordered innate immunity, which causes excessive activation of inflammatory pathways. Nucleotide-binding leucine-rich repeat-containing receptor 12-related autoinflammatory disease (NLRP12-AID) is a newly identified SAID and a rare autosomal dominant disorder caused by mutations in the NLRP12 gene, which is also known as familial cold autoinflammatory syndrome 2 (FCAS2) and mostly occurs in childhood. A total of 33 cases of NLRP12-AID in children and 21 different mutation types have been reported to date. The disease is mainly characterized by periodic fever, accompanied by multisystem inflammatory damage. NLRP12-AID is diagnosed through early clinical identification and genetic detection. Emerging drugs targeting interleukin-1-related inflammatory pathways are expected to change the treatment options and improve the quality of life of pediatric patients. This article aims to summarize the characteristics and pathogenesis of reported NLRP12-AID cases in children and provide ideas for clinical diagnosis and treatment.