NLRP3 – Chronic Infantile Neurologic Cutaneous and Articular (CINCA) Syndrome

NLRP3 encodes cryopyrin, a component of the inflammasome that regulates caspase-1 activation and IL-1β processing. Heterozygous gain-of-function variants in NLRP3 cause CINCA syndrome, a severe neonatal autoinflammatory disease characterized by urticarial rash, recurrent fever, chronic meningitis, and arthropathy (HP:0000988, HP:0001945, HP:0001287). Inheritance is autosomal dominant, with both de novo and familial cases.

Initial genetic studies identified distinct missense mutations in seven unrelated CINCA probands (PMID:12032915) and in 13 additional patients (PMID:12483741). Subsequent larger cohorts, including a Chinese neonatal series, documented over 100 molecularly confirmed cases (PMID:38250066), with de novo variants in more than 20 patients and segregation in multiple pedigrees.

Variant spectrum is dominated by missense changes in the NACHT domain, including hotspot codons Asp303 and Met406. One representative pathogenic allele is c.515T>C (p.Ile172Thr). Somatic mosaicism accounts for disease in 69% of conventionally mutation-negative patients (18/26) (PMID:21702021), highlighting low-level mosaicism as a key pathogenic mechanism.

Functional assays demonstrate that disease-associated cryopyrin mutants bind ASC constitutively, trigger spontaneous caspase-1 activation, and drive excessive IL-1β/IL-18 secretion in monocytic cells (PMID:15020601). Mutant cryopyrin also induces cathepsin B–dependent monocyte necrosis and NF-κB activation, and knock-in mouse models recapitulate the human inflammatory phenotype and respond to IL-1 blockade.

Approximately 40% of clinically diagnosed CINCA patients lack germline NLRP3 mutations by conventional sequencing, but deep sequencing and iPSC-derived macrophage studies reveal somatic mosaicism and confirm NLRP3 inflammasome hyperactivation. IL-1 receptor antagonists (anakinra, canakinumab) produce rapid and sustained remission, preventing irreversible neurologic and skeletal sequelae.

Integration of extensive genetic, segregation, and functional data supports a definitive association between NLRP3 and CINCA syndrome. Early genetic diagnosis enables prompt IL-1–targeted therapy and improves long-term outcomes. Key take-home: NLRP3 gain-of-function variants drive CINCA syndrome via inflammasome hyperactivation, defining a clinically actionable diagnostic and therapeutic paradigm.

References

• American Journal of Human Genetics | 2002 | Chronic infantile neurological cutaneous and articular syndrome is caused by mutations in CIAS1, a gene highly expressed in polymorphonuclear cells and chondrocytes. PMID:12032915
• Arthritis and rheumatism | 2002 | De novo CIAS1 mutations, cytokine activation, and evidence for genetic heterogeneity in patients with neonatal-onset multisystem inflammatory disease (NOMID): a new member of the expanding family of pyrin-associated autoinflammatory diseases. PMID:12483741
• Frontiers in immunology | 2023 | Clinical characteristics of Chinese neonates with neonatal-onset multisystem inflammatory disease: a case report and literature review. PMID:38250066
• Arthritis and rheumatism | 2011 | High incidence of NLRP3 somatic mosaicism in patients with chronic infantile neurologic, cutaneous, articular syndrome: results of an International Multicenter Collaborative Study. PMID:21702021
• The Journal of Biological Chemistry | 2004 | Cryopyrin-induced interleukin 1beta secretion in monocytic cells: enhanced activity of disease-associated mutants and requirement for ASC. PMID:15020601

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