Cryopyrin-Associated Periodic Syndromes — Structured Data

Key Statistics

Total reported cases

Unknown

Mean onset age

1 years

Onset range

0–50 years

Sex ratio (M:F)

1:1

Diagnostic delay

~10 years

Discovered

1940 (Kile & Rusk (FCAS, 1940); Muckle & Wells (MWS, 1962); Prieur & Griscelli (CINCA, 1981); Hoffman et al. (NLRP3 gene, 2001))

Prevalence

<1/1,000,000

Classification

autoinflammatory, monogenic, inflammasomopathy

Pathophysiology

well understood

Treatment status

effective treatment available

Genetic basis

well characterized

Aliases

CAPS, Cryopyrinopathies, NLRP3-associated autoinflammatory disease, Familial cold autoinflammatory syndrome, FCAS, Muckle-Wells syndrome, MWS, Neonatal-onset multisystem inflammatory disease, NOMID, Chronic infantile neurological cutaneous and articular syndrome, CINCA

Symptoms (16)

Molecular Pathway (11 molecules)

Genetic Findings (6)

Treatment Evidence Matrix (6 treatments)

Diagnostic Criteria

Differential Diagnoses (7)

Hypotheses (6)

Open Questions (6)

1. Why do patients with the same NLRP3 mutation develop different CAPS subtypes (FCAS vs MWS vs NOMID)?
   The same amino acid substitution can produce mild episodic disease or severe chronic multisystem inflammation. Modifier genes, epigenetics, and environmental factors are suspected but none conclusively identified.
2. What drives disease in mutation-negative CAPS patients who also lack detectable somatic mosaicism?
   Even with deep sequencing, a substantial proportion of clinically diagnosed CAPS patients remain genetically unexplained. Other inflammasome genes, epigenetic modifications, or post-translational mechanisms may be involved.
3. Can direct NLRP3 inhibition with oral small molecules replace lifelong injectable IL-1 blockade?
   Dapansutrile is in Phase 2a clinical trials. If effective, it would fundamentally change CAPS treatment from chronic injectable biologics to an oral pill. MCC950 failed due to hepatotoxicity.
4. What is the optimal timing for initiating IL-1 blockade to prevent irreversible hearing loss in MWS?
   Early treatment can partially reverse hearing loss, but once cochlear damage is established, it is irreversible. The critical window for intervention is unknown.
5. What is the long-term safety profile of lifelong IL-1 blockade started in infancy?
   Current safety data extends to 5-6 years. CAPS patients require lifelong treatment, and many are treated from early infancy. Decades-long safety data for infection risk, immunogenicity, and organ effects are unavailable.
6. Does IL-18 represent a viable therapeutic target for CAPS patients with incomplete response to IL-1 blockade?
   Mouse models show IL-18 drives skin disease independently of IL-1β. Some CAPS patients have persistent skin symptoms despite IL-1 blockade. No IL-18-targeted therapies have been tested in CAPS.

Complications (6)

Sources (43)

Pathophysiology Narrative

CAPS is caused by gain-of-function mutations in NLRP3 (cryopyrin), the sensor component of the NLRP3 inflammasome. Over 250 pathogenic variants have been identified, predominantly in exon 3 encoding the NACHT (nucleotide-binding oligomerization) domain.

In health, NLRP3 inflammasome activation requires two signals: a priming signal (NF-κB activation via TLR/cytokine receptors) and an activation signal (K+ efflux, ROS, lysosomal damage). CAPS mutations bypass the requirement for signal 2, causing constitutive or hyper-responsive inflammasome assembly.

The activated NLRP3 recruits the adaptor protein ASC (PYCARD), which forms large oligomeric structures called ASC specks. These specks recruit and activate caspase-1 through proximity-induced auto-proteolysis. Active caspase-1 cleaves pro-IL-1β and pro-IL-18 into their mature, secreted forms, and also cleaves gasdermin D.

Cleaved gasdermin D forms pores in the plasma membrane, enabling non-conventional secretion of IL-1β and IL-18 and, at high levels, triggering pyroptotic cell death. In CAPS monocytes, spontaneous ASC speck formation and constitutive gasdermin D cleavage occur without exogenous stimulation.

IL-1β is the central disease mediator, driving fever (hypothalamic prostaglandin E2), neutrophilic urticaria (neutrophil recruitment to skin), arthralgia, and hepatic acute phase response (CRP, SAA via IL-6 induction). Chronic SAA elevation leads to AA amyloid deposition.

IL-18, while less studied in CAPS, independently drives skin inflammation in mouse knock-in models, diverging from the IL-1β pathway. This may explain residual skin symptoms in some patients on IL-1 blockade.

NF-κB is constitutively activated in CAPS, creating a feed-forward loop: NF-κB drives transcription of pro-IL-1β and NLRP3 itself, amplifying the inflammatory signal.

Recent work has shown that FCAS-associated NLRP3 mutants form cryo-sensitive aggregates at lower temperatures, providing a mechanistic explanation for cold-triggered flares in FCAS. This temperature-dependent aggregation scaffolds inflammasome assembly specifically in FCAS variants.

Neutrophils, rather than macrophages, have been identified as the primary cellular source of pathogenic IL-1β in CAPS through neutrophil-specific knock-in mouse models, challenging the traditional monocyte-centric view of inflammasome biology.

Genetic Basis Narrative

CAPS is caused by heterozygous gain-of-function mutations in NLRP3 (formerly CIAS1), located on chromosome 1q44. The gene encodes cryopyrin, a 1036-amino acid protein containing three domains: an N-terminal pyrin domain (PYD), a central NACHT domain (nucleotide-binding and oligomerization), and C-terminal leucine-rich repeats (LRRs).

Over 250 pathogenic variants have been catalogued, with the vast majority located in exon 3 encoding the NACHT domain. Common variants include R260W (frequent in MWS), T348M (associated with severe CAPS), and A439V (variable phenotype). Genotype-phenotype correlations exist but are imperfect — the same mutation can produce FCAS, MWS, or NOMID in different individuals, suggesting modifier genes or epigenetic factors influence severity.

Inheritance is autosomal dominant with high penetrance for most variants. However, approximately 50–60% of NOMID cases arise from de novo mutations, making family history unreliable for excluding the diagnosis in severe phenotypes.

A critical advance has been the recognition of somatic mosaicism. Standard Sanger sequencing detects germline mutations in only 50–70% of clinically diagnosed CAPS patients. Amplicon-based deep sequencing reveals somatic NLRP3 mosaicism in approximately 40% of previously 'mutation-negative' cases, with variant allele frequencies as low as 1.9%. Somatic mosaicism can cause late adult-onset CAPS and may increase in allele frequency over time, potentially explaining phenotypic progression.

Despite these advances, a subset of clinically diagnosed CAPS patients remain genetically unexplained even with deep sequencing. Whether these cases involve mutations in other inflammasome genes, epigenetic mechanisms, or post-translational NLRP3 modifications remains an open question.