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.
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