CINCA Syndrome

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Classifications

Harrison's Chapter

IUIS Category

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Mappings

MONDO

MONDO:0011776 CINCA syndrome

Primary MONDO identifier for CINCA syndrome (matches disease_term).

NCIT

NCIT:C84657 Cryopyrin-Associated Periodic Syndrome

NCIT has no CINCA/NOMID-specific term; CINCA/NOMID is the severe end of the CAPS spectrum captured by this parent concept.

NCIT

NCIT:C84657 Cryopyrin-Associated Periodic Syndrome

NCIT has no CINCA/NOMID-specific term; CINCA/NOMID is the severe end of the CAPS spectrum captured by this parent concept.

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Definitions

1

Eurofever/PRINTO CAPS classification criteria (2017)

The 2017 data-driven CAPS classification criteria require raised inflammatory markers (CRP/SAA) plus at least two of six CAPS-typical features: urticaria-like rash, cold-triggered episodes, sensorineural hearing loss, musculoskeletal symptoms, chronic aseptic meningitis, and skeletal abnormalities. CINCA/NOMID, the severe end of the CAPS spectrum, typically satisfies these criteria, which perform well regardless of NLRP3 mutation status.

DIAGNOSTIC_CRITERIA

Show evidence (1 reference)

PMID:27707729 SUPPORT Human Clinical

"The best diagnosis model included: Raised inflammatory markers (C-reactive protein/serum amyloid A) plus ≥two of six CAPS-typical symptoms: urticaria-like rash, cold-triggered episodes, sensorineural hearing loss, musculoskeletal symptoms, chronic aseptic meningitis and skeletal abnormalities...."

International consensus, data-driven CAPS classification criteria (284 cases, 837 controls) covering all CAPS subtypes including CINCA/NOMID, independent of NLRP3 mutation.

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Inheritance

1

Autosomal dominant HP:0000006

CINCA syndrome follows autosomal dominant inheritance with complete penetrance but variable expressivity across the CAPS spectrum. The majority of cases (>80%) arise from de novo mutations. Somatic mosaicism is recognized in a subset of clinically affected individuals who test negative by conventional sequencing, with variant allele fractions ranging from 1.3% to 34.8%.

Autosomal dominant inheritance Penetrance: COMPLETE Expressivity: VARIABLE De novo rate: >80

Show evidence (3 references)

PMID:11687797 SUPPORT Human Clinical

"Familial cold autoinflammatory syndrome (FCAS, MIM 120100), commonly known as familial cold urticaria (FCU), is an autosomal-dominant systemic inflammatory disease"

Original study establishing autosomal dominant inheritance for the CAPS spectrum caused by CIAS1/NLRP3 mutations.

PMID:38808101 SUPPORT Human Clinical

"The father carried a genetic mutation associated with CINCA syndrome/NOMID (NLRP3 c.2068G>A p.Glu690Lys Hetero), which was also found in the child."

Case documenting paternal transmission of NLRP3 mutation to a child with CINCA/NOMID, confirming autosomal dominant inheritance in the minority of familial (non-de novo) cases.

PMID:41026232 SUPPORT Human Clinical

"clinical manifestations, analytical results, and outcomes of treatments were markedly similar to those detected in patients with germline variants."

Largest NLRP3 mosaicism cohort confirming that clinical presentation and treatment response are similar between mosaic and germline cases, with an overrepresentation of late-onset forms (37.5%) and myeloid-restricted mosaicism in late-onset patients.

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Subtypes

2

Classic CINCA with identifiable NLRP3 mutation

Patients with identifiable heterozygous gain-of-function mutations in NLRP3. Accounts for approximately 50-60% of clinically diagnosed CINCA/NOMID cases. Mutations are typically de novo.

Show evidence (1 reference)

PMID:31077002 SUPPORT Other

"Gain-of-function mutations in NLRP3 in CAPS patients lead to activation of the cryopyrin inflammasome, resulting in the inappropriate release of inflammatory cytokines including IL-1beta and CAPS-related inflammatory symptoms."

Review confirming NLRP3 gain-of-function mutations as the causative mechanism in CAPS including CINCA/NOMID.

Mutation-negative CINCA (somatic mosaicism)

Patients meeting clinical criteria for CINCA/NOMID but without detectable NLRP3 mutations by conventional sequencing. Many of these cases harbor somatic mosaicism for NLRP3 mutations detectable only by deep sequencing, with variant allele fractions as low as 1.3%. Mosaicism may be myeloid-restricted or involve both myeloid and lymphoid lineages.

Show evidence (6 references)

PMID:16899778 SUPPORT Human Clinical

"We selected 18 patients with neonatal-onset multisystem inflammatory disease (12 with identifiable CIAS1 mutations) to receive anakinra, an interleukin-1-receptor antagonist"

Landmark NEJM trial demonstrating that 6 of 18 clinically definite NOMID patients lacked identifiable CIAS1 mutations by standard sequencing, yet responded identically to IL-1 blockade, suggesting undetected somatic mosaicism.

PMID:38720945 SUPPORT Human Clinical

"Additional genetic investigations performed after the introduction of anti-IL-1 therapy revealed a pathogenic mosaicism in the NLRP3 gene."

Case report demonstrating that initial NLRP3 testing was negative but subsequent deep sequencing revealed somatic mosaicism, underscoring the need for advanced sequencing in clinically diagnosed mutation-negative patients.

PMID:34059097 SUPPORT Human Clinical

"approximately 28 ~ 35 % of all the CINCA/NOMID patients carry an NLRP3 mutation in somatic mosaicism state"

Review of the literature quantifying the prevalence of somatic mosaicism in CINCA/NOMID, noting that mosaic patients tend to present with milder neurologic symptoms compared to those with germline mutations.

+ 3 more references

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Mechanistic Hypotheses

1

Canonical NLRP3 Inflammasome / IL-1beta Model

canonical_nlrp3_il1_inflammasome_model CANONICAL

Gain-of-function NLRP3 mutations cause constitutive inflammasome assembly and caspase-1 activation, driving excessive IL-1beta production as the central effector of systemic and organ-specific inflammation. The dominant pathogenic role of IL-1beta is established by the rapid, near-complete clinical and biochemical response to IL-1 blockade.

IL-18 and gasdermin-D-dependent pyroptosis contribute to the inflammatory burden alongside IL-1beta. Mouse knock-in models show the phenotype requires an intact inflammasome but is only partially IL-1beta-dependent and T-cell-independent (PMID:19501000), indicating additional inflammasome-driven effectors beyond IL-1beta.

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Discussions and Knowledge Gaps

3

What drives autoinflammation in clinically definite CINCA/NOMID patients who remain NLRP3 mutation-negative even after amplicon-based deep sequencing for somatic mosaicism?

KNOWLEDGE GAP OPEN gap_cinca_mutation_negative_after_deep_sequencing

Attached to

genetic#NLRP3 has_subtypes#Mutation-negative CINCA (somatic mosaicism)

Deep/amplicon sequencing reclassifies many "mutation-negative" cases as low-level NLRP3 mosaicism, but a substantial fraction still has no detectable NLRP3 variant even with the most sensitive methods, yet responds to IL-1 blockade exactly like genotype-positive patients. The genetic lesion in this residual group — deeper mosaicism below detection, a non-coding/regulatory NLRP3 change, or a variant in another inflammasome gene — is unresolved, leaving the first step of the causal chain unaccounted for in these patients.

Proposed experiments

Ultra-deep multi-tissue sequencing and inflammasome gene panel in mutation-negative CINCA/NOMID

targeted deep sequencing

exp_cinca_ultradeep_mosaicism_panel

Apply ultra-deep error-corrected sequencing across multiple tissues (sorted myeloid vs lymphoid fractions, buccal, and affected tissue) plus a broad inflammasome-pathway gene panel to clinically definite, IL-1-responsive CINCA/NOMID patients who are NLRP3-negative by standard amplicon deep sequencing, to detect sub-threshold NLRP3 mosaicism, non-coding NLRP3 variants, or alternative inflammasome-gene drivers.

Show evidence (1 reference)

PMID:40538939 SUPPORT Human Clinical

"In 40% (4/10) of the cohort a post-zygotic NLRP3 mutation leading to somatic mosaicism was found by ADS."

Even with amplicon-based deep sequencing, only 40% of mutation-negative CAPS patients were resolved as NLRP3 mosaics, leaving the majority genetically unexplained.

What epigenetic or environmental factors modify CINCA/NOMID disease severity and expressivity beyond the NLRP3 genotype?

OPEN QUESTION OPEN question_cinca_genotype_phenotype_modifiers

Attached to

genetic#NLRP3

CINCA/NOMID shows variable expressivity even for the same NLRP3 change, and monozygotic twins concordant for the genotype can diverge markedly in severity. This points to epigenetic and/or environmental modifiers shaping the phenotype, which are currently unidentified and limit genotype-based prognostication.

Show evidence (1 reference)

PMID:27320017 SUPPORT Human Clinical

"there were significant differences between twins in phenotype severity, suggestive of epigenetic differences and/or involvement of environmental factors."

Phenotypic discordance between monozygotic CINCA twins implicates epigenetic/environmental modifiers of severity beyond the shared NLRP3 genotype.

Can established post-inflammatory neurosensory damage in CINCA/NOMID (retinal dystrophy, hearing loss, CNS injury) be reversed, or does IL-1 blockade only prevent further damage once fixed tissue injury has occurred?

KNOWLEDGE GAP OPEN gap_cinca_irreversible_neurosensory_damage

Attached to

phenotype#Retinal dystrophy pathophysiology#Central nervous system inflammation

IL-1 blockade reliably controls active inflammation and can improve MRI-visible cochlear and leptomeningeal lesions, but fixed post-inflammatory damage such as retinal dystrophy can remain stationary despite treatment. Whether any established neurosensory injury is recoverable — versus only preventable by very early treatment — is unresolved and is central to the rationale for early diagnosis before genetic confirmation.

Show evidence (1 reference)

PMID:19424698 SUPPORT Human Clinical

"A state of severe retinal dystrophy of post-inflammatory origin became evident on funduscopy, optical coherence tomography and visual electrophysiology tests at the age of 10 years, which remained stationary after 1 year of anakinra treatment."

Established post-inflammatory retinal dystrophy persisted unchanged after a year of anakinra, illustrating that fixed neurosensory damage may not reverse with IL-1 blockade.

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Pathophysiology

9

NLRP3 gain-of-function mutation

Heterozygous gain-of-function mutations in the NLRP3 gene (encoding cryopyrin) lower the activation threshold for NLRP3 inflammasome assembly. Most CINCA/NOMID mutations are de novo, arising post-zygotically or in the germline. The NLRP3 protein contains a pyrin domain, a NACHT domain, and leucine-rich repeats; disease mutations cluster in the NACHT domain and disrupt autoinhibitory conformations.

NLRP3 hgnc:16400

Downstream

Constitutive NLRP3 inflammasome activation

Show evidence (2 references)

PMID:11687797 SUPPORT Human Clinical

"This gene, called CIAS1, is expressed in peripheral blood leukocytes and encodes a protein with a pyrin domain, a nucleotide-binding site (NBS, NACHT subfamily) domain and a leucine-rich repeat (LRR) motif region, suggesting a role in the regulation of inflammation and apoptosis."

Original identification of CIAS1/NLRP3 mutations as the cause of FCAS and MWS, establishing the genetic basis for the entire CAPS spectrum including CINCA/NOMID.

DOI:10.1111/imr.13292 SUPPORT Other

"Initially discovered as the cause of the autoinflammatory spectrum of cryopyrin-associated periodic syndrome (CAPS), NLRP3 is now also known to play a role in more common diseases including cardiovascular disease, gout, and liver disease."

Comprehensive review by Hoffman laboratory tracing the discovery of NLRP3 as the CAPS disease gene and its broader role in innate immunity.

Constitutive NLRP3 inflammasome activation

Mutant cryopyrin undergoes spontaneous oligomerization and constitutive assembly of the NLRP3 inflammasome complex, comprising NLRP3, ASC (PYCARD), and pro-caspase-1. NEK7 serves as a scaffold facilitating NLRP3 activation via microtubule organizing center trafficking. The resulting continuous activation of caspase-1 occurs without normal requirement for exogenous danger signals. ASC speck formation, the hallmark of inflammasome assembly, is enhanced in patient myeloid cells and suppressible by MCC950.

NLRP3 inflammasome complex assembly GO:0044546 ⚠ ABNORMAL

Downstream

Excessive IL-1beta production

Excessive IL-18 production

Show evidence (3 references)

PMID:31077002 SUPPORT Other

"Gain-of-function mutations in NLRP3 in CAPS patients lead to activation of the cryopyrin inflammasome, resulting in the inappropriate release of inflammatory cytokines including IL-1beta and CAPS-related inflammatory symptoms."

Review describing constitutive inflammasome activation as the central pathogenic mechanism in CAPS, with gain-of-function mutations driving inappropriate caspase-1 activation and cytokine release.

DOI:10.1111/imr.13292 SUPPORT Other

"Activated by a panoply of pathogen-associated and endogenous triggers, NLRP3 serves as an intracellular sensor that drives carefully coordinated assembly of the inflammasome, and downstream inflammation mediated by IL-1 and IL-18."

Review detailing normal and pathological NLRP3 inflammasome assembly mechanisms, including ASC speck formation and regulatory nodes disrupted by CAPS mutations.

PMID:39816134 SUPPORT Other

"Dysregulated NLRP3 activation has been implicated in a variety of autoimmune and inflammatory diseases, including cryopyrin-associated periodic fever syndromes, diabetes, atherosclerosis, Alzheimer's disease, inflammatory bowel disease, and cancer."

Review of NLRP3 spatiotemporal dynamics implicating mitochondria, lysosomes, ER, Golgi, endosomes, and the centrosome in NLRP3 localization and inflammasome assembly, providing mechanistic context for how CAPS mutations disrupt normal subcellular regulation.

Excessive IL-1beta production

Constitutively active caspase-1 cleaves pro-IL-1beta into its mature, biologically active form. The resulting overproduction of IL-1beta is the primary driver of systemic inflammation, fever, and tissue damage throughout the body. Gasdermin D-dependent pyroptosis of activated myeloid cells releases intracellular contents including IL-1beta and amplifies inflammation.

Positive regulation of interleukin-1 beta production GO:0032731 ⚠ ABNORMAL Pyroptotic inflammatory response GO:0070269 ⚠ ABNORMAL

Downstream

Systemic neutrophilic inflammation

Central nervous system inflammation

Epiphyseal skeletal overgrowth

Cartilage damage and destructive arthropathy

Secondary amyloidosis

Show evidence (3 references)

PMID:31077002 SUPPORT Other

"Gain-of-function mutations in NLRP3 in CAPS patients lead to activation of the cryopyrin inflammasome, resulting in the inappropriate release of inflammatory cytokines including IL-1beta and CAPS-related inflammatory symptoms."

Review confirming that excessive IL-1beta release from constitutively active inflammasome is the proximate cause of CAPS symptoms.

PMID:34059097 SUPPORT Human Clinical

"These evidences suggest that foetal inflammation, probably due to overproduction of IL-1β, caused tissue damage in utero, and the first symptom of a newborn with CINCA/NOMID."

Case report with histopathological evidence that IL-1beta overproduction begins in utero, causing necrotizing funisitis and villitis as the earliest manifestations of CINCA/NOMID even before birth.

PMID:38808101 SUPPORT Human Clinical

"Histopathologic examination of the placenta and umbilical cord can provide crucial insights into the intrauterine onset of inflammation, which is the first manifestation of CINCA syndrome/NOMID in newborns."

Case report confirming intrauterine onset of IL-1beta-driven inflammation in CINCA/NOMID, with severe funisitis leading to umbilical cord rupture and neonatal asphyxia.

Excessive IL-18 production

Constitutively active caspase-1 also cleaves pro-IL-18 into its mature form. IL-18 contributes to macrophage activation and interferon-gamma production, amplifying the innate immune response and promoting Th1-polarized inflammation. Elevated serum IL-18 levels are a feature of CAPS and contribute to the systemic inflammatory burden alongside IL-1beta.

Positive regulation of interleukin-18 production GO:0032741 ⚠ ABNORMAL

Downstream

Systemic neutrophilic inflammation

Show evidence (1 reference)

DOI:10.1111/imr.13292 SUPPORT Other

"Activated by a panoply of pathogen-associated and endogenous triggers, NLRP3 serves as an intracellular sensor that drives carefully coordinated assembly of the inflammasome, and downstream inflammation mediated by IL-1 and IL-18."

Review identifying IL-18 alongside IL-1 as a key downstream inflammatory mediator of the NLRP3 inflammasome, confirming its role in CAPS pathogenesis.

Systemic neutrophilic inflammation

Excess IL-1beta drives recruitment and activation of neutrophils throughout the body, producing neutrophilic infiltration in skin, joints, meninges, and other tissues. The skin rash of CINCA is a neutrophilic urticarial dermatosis rather than true mast cell-mediated urticaria. Sustained neutrophilic inflammation causes tissue damage and organ dysfunction.

Neutrophil CL:0000775 Monocyte CL:0000576

Neutrophil chemotaxis GO:0030593 ⚠ ABNORMAL Inflammatory response GO:0006954 ⚠ ABNORMAL

Skin of body UBERON:0002097

Downstream

Recurrent fever IL-1-driven systemic inflammation produces recurrent fever.

Urticarial rash Neutrophilic skin inflammation produces the urticaria-like rash.

Abnormality of neutrophils The inflammatory phenotype includes neutrophil abnormalities.

Leukocytosis Systemic inflammation increases circulating leukocyte counts.

Myalgia Systemic inflammation can manifest as muscle pain.

Show evidence (2 references)

PMID:16899778 SUPPORT Human Clinical

"Neonatal-onset multisystem inflammatory disease is characterized by fever, urticarial rash, aseptic meningitis, deforming arthropathy, hearing loss, and mental retardation."

Landmark NEJM trial characterizing the multisystem neutrophilic inflammation in NOMID/CINCA affecting skin, CNS, joints, and sensory organs.

PMID:34059097 SUPPORT Human Clinical

"the inflammation of the umbilical vessels typically begins in the vein (phlebitis) and is followed by involvement of the arteries (arteritis) and the Wharton's jelly"

Histopathological evidence of neutrophilic infiltration in umbilical cord vessels and Wharton's jelly, demonstrating that neutrophilic inflammation begins in utero in CINCA/NOMID and can involve the placenta and umbilical cord.

Central nervous system inflammation

Chronic aseptic meningitis with neutrophilic and lymphocytic infiltration of the leptomeninges leads to elevated intracranial pressure, papilledema, progressive sensorineural hearing loss, and cognitive impairment. Microglial activation in the brain parenchyma may contribute to cerebral atrophy in inadequately treated patients. Cochlear inflammation produces progressive hearing loss, and leptomeningeal enhancement is visible on MRI.

Microglial cell CL:0000129

Leptomeninx UBERON:0000391 Cochlea UBERON:0001844

Downstream

Chronic aseptic meningitis Leptomeningeal inflammation manifests as chronic aseptic meningitis.

Sensorineural hearing loss Cochlear inflammation contributes to sensorineural hearing loss.

Increased intracranial pressure Chronic meningeal inflammation raises intracranial pressure.

Ventriculomegaly Chronic CNS inflammation and raised intracranial pressure can produce ventricular enlargement.

Macrocephaly Chronic CNS inflammation and increased intracranial pressure can produce macrocephaly.

Intellectual disability Chronic CNS inflammation contributes to cognitive impairment.

Global developmental delay Early CNS inflammation can delay neurodevelopmental milestones.

Visual impairment CNS and ocular inflammation can impair vision.

Show evidence (2 references)

PMID:16899778 SUPPORT Human Clinical

"Magnetic resonance imaging showed improvement in cochlear and leptomeningeal lesions as compared with baseline."

MRI documentation of cochlear and leptomeningeal inflammatory lesions in NOMID patients, which improved with anakinra treatment, confirming active CNS inflammation.

PMID:37809096 SUPPORT Human Clinical

"Among these novel mutations, percentages of severe musculoskeletal, ophthalmologic, and neurological symptoms were higher compared with other case serials."

Large pediatric CAPS cohort showing high prevalence of severe neurological symptoms in patients with novel NLRP3 mutations, consistent with the CNS inflammatory burden in CINCA/NOMID.

Epiphyseal skeletal overgrowth

IL-1beta-driven inflammation at the growth plates stimulates abnormal endochondral ossification, producing characteristic bony overgrowth of the patellae, distal femora, and other long bone epiphyses. The distinctive radiographic features include epiphyseal enlargement and calcified physeal lesions unique to CINCA/NOMID within the CAPS spectrum.

Endochondral ossification GO:0001958 ⚠ ABNORMAL

Epiphysis UBERON:0001437 Growth plate cartilage UBERON:0004129

Show evidence (1 reference)

PMID:37809096 SUPPORT Human Clinical

"Ten patients received Canakinumab treatment, which proved effective at alleviating musculoskeletal, neurological, auditory, visual manifestations, fever, and rash for 10-20 months follow-up."

Pediatric CAPS cohort documenting musculoskeletal involvement as a major disease domain responsive to IL-1 blockade, confirming IL-1-driven skeletal overgrowth.

Cartilage damage and destructive arthropathy

Chronic IL-1beta-mediated inflammation in the joints drives chondrocyte dysfunction and cartilage matrix degradation, leading to progressive destructive arthropathy. Extracellular matrix disassembly in articular cartilage results in joint deformity and functional impairment distinctive to the severe CINCA/NOMID phenotype.

Chondrocyte CL:0000138

Extracellular matrix disassembly GO:0022617 ⚠ ABNORMAL

Synovial joint UBERON:0002217

Downstream

Arthropathy with epiphyseal overgrowth Cartilage and joint damage produces deforming arthropathy.

Arthralgia Joint inflammation and damage produce joint pain.

Abnormal joint morphology Destructive arthropathy changes joint structure.

Joint dislocation Severe joint damage can destabilize joints.

Show evidence (1 reference)

PMID:16899778 SUPPORT Human Clinical

"Neonatal-onset multisystem inflammatory disease is characterized by fever, urticarial rash, aseptic meningitis, deforming arthropathy, hearing loss, and mental retardation."

Landmark NEJM trial identifying deforming arthropathy as a cardinal feature of NOMID/CINCA, distinct from bony overgrowth and reflecting cartilage destruction.

Secondary amyloidosis

Chronic uncontrolled systemic inflammation leads to sustained elevation of serum amyloid A (SAA), which can deposit as AA amyloid in kidneys and other organs. This potentially causes nephrotic syndrome and renal failure if untreated. AA amyloidosis is a recognized long-term complication across the CAPS spectrum, particularly in undertreated patients.

Kidney UBERON:0002113

Show evidence (1 reference)

PMID:16899778 SUPPORT Human Clinical

"serum amyloid A (from a median of 174 mg to 8 mg per liter), C-reactive protein (from a median of 5.29 mg to 0.34 mg per deciliter), and the erythrocyte sedimentation rate decreased at month 3"

NEJM trial documenting markedly elevated baseline serum amyloid A levels (median 174 mg/L) in NOMID patients, reflecting the chronic inflammatory state that drives AA amyloidosis risk. SAA normalized rapidly with anakinra.

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Histopathology

4

Neutrophilic urticarial dermatosis

Skin biopsy of the characteristic rash reveals a perivascular and interstitial neutrophilic infiltrate in the dermis, with neutrophils surrounding eccrine sweat glands. Unlike true urticaria, there is no mast cell degranulation, dermal edema is minimal, and eosinophils are absent. This neutrophilic pattern is consistent across the CAPS spectrum and helps distinguish CINCA/NOMID rash from allergic urticaria and other neutrophilic dermatoses.

Show evidence (1 reference)

PMID:31077002 SUPPORT Other

"Cryopyrin-associated periodic syndrome (CAPS) is a rare inherited autoinflammatory disorder characterized by systemic, cutaneous, musculoskeletal, and central nervous system inflammation."

Review characterizing CAPS cutaneous involvement as a systemic neutrophilic process, with skin biopsy showing neutrophilic dermatosis rather than mast cell-mediated urticaria.

Chronic leptomeningeal inflammatory infiltrate

CSF and meningeal examination reveals chronic inflammatory infiltrate with neutrophilic predominance in early/active disease and lymphoplasmacytic infiltrate in more chronic phases. Leptomeningeal enhancement on MRI corresponds to this inflammatory infiltrate. CSF shows pleocytosis (predominantly polymorphonuclear), elevated protein, and sometimes hypoglycorrhachia.

Show evidence (2 references)

PMID:16899778 SUPPORT Human Clinical

"Magnetic resonance imaging showed improvement in cochlear and leptomeningeal lesions as compared with baseline."

NEJM trial documenting leptomeningeal inflammatory lesions on MRI in NOMID patients corresponding to the chronic meningeal inflammatory infiltrate.

PMID:34059097 SUPPORT Human Clinical

"the examination of the cerebrospinal fluid (CSF) showed a WBC cell count of 667 /µL (polymorphonuclear: mononuclear 4:1), glucose at 21 mg/dL, and protein at 191 mg/dL"

Neonatal case documenting severe neutrophilic CSF pleocytosis (667 cells, 4:1 PMN predominance) with hypoglycorrhachia and elevated protein, reflecting the intense chronic meningeal inflammatory infiltrate.

Necrotizing funisitis

Histopathological examination of the umbilical cord in neonates with CINCA/NOMID reveals necrotizing funisitis, characterized by rings of karyorrhectic debris with neutrophilic infiltrate in Wharton's jelly oriented toward the amniotic surface. This finding demonstrates intrauterine onset of IL-1beta-driven inflammation and may be the earliest histopathological manifestation of the disease.

Show evidence (2 references)

PMID:34059097 SUPPORT Human Clinical

"These evidences suggest that foetal inflammation, probably due to overproduction of IL-1β, caused tissue damage in utero, and the first symptom of a newborn with CINCA/NOMID."

Case report with histopathological documentation of necrotizing funisitis as evidence of intrauterine inflammatory damage in CINCA/NOMID.

PMID:38808101 SUPPORT Human Clinical

"Histopathologic examination of the placenta and umbilical cord can provide crucial insights into the intrauterine onset of inflammation, which is the first manifestation of CINCA syndrome/NOMID in newborns."

Case report documenting severe necrotizing funisitis with umbilical cord rupture, confirming the diagnostic value of placental histopathology in neonatal CINCA/NOMID.

AA amyloid deposition

In patients with long-standing uncontrolled inflammation, biopsy of the kidney or other organs may reveal AA amyloid deposits. Congo red staining shows apple-green birefringence under polarized light. Amyloid deposition preferentially affects the renal glomeruli, causing progressive proteinuria and nephrotic syndrome. Early and sustained IL-1 blockade prevents this complication by normalizing serum amyloid A levels.

Show evidence (1 reference)

PMID:16899778 SUPPORT Human Clinical

"serum amyloid A (from a median of 174 mg to 8 mg per liter), C-reactive protein (from a median of 5.29 mg to 0.34 mg per deciliter), and the erythrocyte sedimentation rate decreased at month 3"

NEJM trial documenting markedly elevated baseline serum amyloid A (median 174 mg/L, >17x upper limit of normal) as the precursor protein for AA amyloid deposits, which normalized with anakinra.

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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

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Phenotypes

22

Blood 1

Leukocytosis FREQUENT Increased total leukocyte count HP:0001974

Show evidence (1 reference)

ORPHA:1451 SUPPORT Other

"HP:0001974 | Leukocytosis | Frequent (79-30%)"

Orphanet lists leukocytosis as a frequent CINCA syndrome phenotype.

Cardiovascular 2

Urticarial rash OBLIGATE Urticaria HP:0001025

18/18 (100%) NOMID patients in the Goldbach-Mansky NEJM cohort had urticarial rash at baseline, supporting OBLIGATE frequency.

Show evidence (2 references)

PMID:16899778 SUPPORT Human Clinical

"All 18 patients had a rapid response to anakinra, with disappearance of rash."

All 18 NOMID patients in the landmark NEJM trial had urticarial rash at baseline which resolved rapidly with anakinra, confirming universality and IL-1 dependence of this phenotype.

PMID:38481988 SUPPORT Human Clinical

"The patients most commonly presented with rash (100%), arthritis/arthralgia (88.9%), lymphadenopathy (88.9%), fever (77.8%), and growth retardation (44.4%)."

Chinese NLRP3-AID cohort of 9 patients confirming rash in 100% of cases, consistent with OBLIGATE frequency across different populations.

Hepatosplenomegaly FREQUENT Hepatosplenomegaly HP:0001433

Show evidence (2 references)

PMID:31077002 SUPPORT Other

"Cryopyrin-associated periodic syndrome (CAPS) is a rare inherited autoinflammatory disorder characterized by systemic, cutaneous, musculoskeletal, and central nervous system inflammation."

Review characterizing CAPS as a systemic inflammatory disorder with widespread organ involvement including hepatosplenomegaly from reticuloendothelial activation.

PMID:34059097 SUPPORT Human Clinical

"She also exhibited atypical symptoms such as severe hepatosplenomegaly with cholestasis."

Case report documenting severe hepatosplenomegaly with cholestasis as a neonatal manifestation of CINCA/NOMID, which gradually improved in parallel with decreasing inflammatory markers after canakinumab treatment.

Ear 1

Sensorineural hearing loss VERY_FREQUENT Sensorineural hearing impairment HP:0000407

Hearing loss is listed as a defining feature of NOMID; cochlear lesions were documented on MRI in the NEJM cohort and improved with anakinra.

Show evidence (1 reference)

PMID:16899778 SUPPORT Human Clinical

"Magnetic resonance imaging showed improvement in cochlear and leptomeningeal lesions as compared with baseline."

NEJM trial documenting cochlear inflammatory lesions on MRI in NOMID patients that improved with anakinra, linking hearing loss to reversible cochlear inflammation.

Eye 4

Papilledema Papilledema HP:0001085

Show evidence (1 reference)

PMID:20005004 SUPPORT Human Clinical

"The diagnosis was evoked on the basis of multiple systemic symptoms (multiple episodes of fever of unknown origin, mental retardation, short stature, meningitis, hearing loss, bilateral papilledema) and confirmed by the presence of a CIAS1 mutation on genetic analysis."

CIAS1-confirmed CINCA case (homozygous twins) presenting with bilateral papilledema, directly supporting papilledema as an ocular manifestation of CINCA secondary to raised intracranial pressure. Frequency band omitted because papilledema is uncommon across the CAPS spectrum (PMID:32951665) and no CINCA-specific frequency is established.

Uveitis FREQUENT Uveitis HP:0000554

Show evidence (1 reference)

PMID:37809096 SUPPORT Human Clinical

"Ten patients received Canakinumab treatment, which proved effective at alleviating musculoskeletal, neurological, auditory, visual manifestations, fever, and rash for 10-20 months follow-up."

Pediatric cohort confirming visual manifestations (including uveitis) as a major disease domain in severe CAPS responsive to IL-1 blockade.

Retinal dystrophy Retinal dystrophy HP:0000556

Show evidence (2 references)

PMID:19424698 SUPPORT Human Clinical

"A state of severe retinal dystrophy of post-inflammatory origin became evident on funduscopy, optical coherence tomography and visual electrophysiology tests at the age of 10 years, which remained stationary after 1 year of anakinra treatment."

Case report documenting severe post-inflammatory retinal dystrophy in a CINCA patient that persisted despite anakinra, establishing retinal dystrophy as a distinct ocular complication beyond papilledema.

PMID:27320017 SUPPORT Human Clinical

"We report the cases of monozygotic twins with CINCA syndrome whose predominant ocular manifestation was inflammatory rod-cone retinal dystrophy."

Case report of monozygotic CINCA twins whose predominant ocular manifestation was inflammatory rod-cone retinal dystrophy, with phenotypic discordance between twins suggesting epigenetic/environmental modifiers.

Visual impairment FREQUENT Visual impairment HP:0000505

Show evidence (1 reference)

ORPHA:1451 SUPPORT Other

"HP:0000505 | Visual impairment | Frequent (79-30%)"

Orphanet lists visual impairment as a frequent CINCA syndrome phenotype.

Head and Neck 1

Macrocephaly FREQUENT Macrocephaly HP:0000256

Show evidence (1 reference)

ORPHA:1451 SUPPORT Other

"HP:0000256 | Macrocephaly | Frequent (79-30%)"

Orphanet lists macrocephaly as a frequent CINCA syndrome phenotype.

Immune 1

Chronic aseptic meningitis VERY_FREQUENT Meningitis HP:0001287

Temporal: CHRONIC Severity: SEVERE Onset: NEONATAL

Aseptic meningitis is part of the diagnostic triad of NOMID and is present in the majority of patients; its chronicity distinguishes CINCA from the milder CAPS phenotypes.

Show evidence (3 references)

PMID:16899778 SUPPORT Human Clinical

"Neonatal-onset multisystem inflammatory disease is characterized by fever, urticarial rash, aseptic meningitis, deforming arthropathy, hearing loss, and mental retardation."

NEJM trial establishing chronic aseptic meningitis as a hallmark neurological manifestation of NOMID/CINCA.

PMID:37548074 SUPPORT Human Clinical

"These, along with significant cerebral atrophy, ventriculomegaly, and an absence of other injuries, raised concerns for a genetic disorder, prompting genetic consultation."

Case report of an infant with CINCA/NOMID presenting with subdural hemorrhage, macrocephaly, cerebral atrophy, and ventriculomegaly secondary to chronic CNS inflammation, initially raising suspicion of abusive head trauma.

PMID:34059097 SUPPORT Human Clinical

"the examination of the cerebrospinal fluid (CSF) showed a WBC cell count of 667 /µL (polymorphonuclear: mononuclear 4:1), glucose at 21 mg/dL, and protein at 191 mg/dL"

Neonatal case documenting severe CSF pleocytosis (667 cells) with neutrophilic predominance, hypoglycorrhachia, and markedly elevated protein at birth, confirming intrauterine-onset aseptic meningitis.

Metabolism 1

Recurrent fever VERY_FREQUENT Recurrent fever HP:0001954

Listed as a defining characteristic of NOMID; present in the majority of patients though not always continuous.

Show evidence (2 references)

PMID:16899778 SUPPORT Human Clinical

"Neonatal-onset multisystem inflammatory disease is characterized by fever, urticarial rash, aseptic meningitis, deforming arthropathy, hearing loss, and mental retardation."

NEJM trial establishing fever as a cardinal feature of NOMID/CINCA.

PMID:38481988 SUPPORT Human Clinical

"The patients most commonly presented with rash (100%), arthritis/arthralgia (88.9%), lymphadenopathy (88.9%), fever (77.8%), and growth retardation (44.4%)."

Chinese NLRP3-AID cohort showing fever in 77.8% of patients, consistent with VERY_FREQUENT classification.

Musculoskeletal 3

Arthropathy with epiphyseal overgrowth VERY_FREQUENT Arthropathy HP:0003040

Deforming arthropathy is a defining feature of NOMID; the distinctive epiphyseal overgrowth pattern distinguishes CINCA from milder CAPS phenotypes.

Show evidence (2 references)

PMID:16899778 SUPPORT Human Clinical

"Neonatal-onset multisystem inflammatory disease is characterized by fever, urticarial rash, aseptic meningitis, deforming arthropathy, hearing loss, and mental retardation."

NEJM trial identifying deforming arthropathy as a cardinal feature of NOMID/CINCA.

PMID:38481988 SUPPORT Human Clinical

"The patients most commonly presented with rash (100%), arthritis/arthralgia (88.9%), lymphadenopathy (88.9%), fever (77.8%), and growth retardation (44.4%)."

Chinese NLRP3-AID cohort showing arthritis/arthralgia in 88.9% (8/9) of patients, with two CINCA cases also having clubbed fingers.

Abnormal joint morphology FREQUENT Abnormal joint morphology HP:0001367

Show evidence (1 reference)

ORPHA:1451 SUPPORT Other

"HP:0001367 | Abnormal joint morphology | Frequent (79-30%)"

Orphanet lists abnormal joint morphology as a frequent CINCA syndrome phenotype.

Joint dislocation FREQUENT Joint dislocation HP:0001373

Show evidence (1 reference)

ORPHA:1451 SUPPORT Other

"HP:0001373 | Joint dislocation | Frequent (79-30%)"

Orphanet lists joint dislocation as a frequent CINCA syndrome phenotype.

Nervous System 4

Increased intracranial pressure VERY_FREQUENT Increased intracranial pressure HP:0002516

Show evidence (2 references)

ORPHA:1451 SUPPORT Other

"HP:0002516 | Increased intracranial pressure | Very frequent (99-80%)"

Orphanet lists increased intracranial pressure as a very frequent CINCA syndrome phenotype.

PMID:32951665 SUPPORT Human Clinical

"Six patients (30%) developed headaches and were diagnosed with secondary intracranial hypertension. Lumbar puncture opening pressures ranged from 28 to 45 cm H2O."

Pediatric CAPS series documenting secondary intracranial hypertension with markedly elevated lumbar-puncture opening pressures (28-45 cm H2O), providing primary clinical evidence for the raised-ICP association.

Ventriculomegaly Ventriculomegaly HP:0002119

Show evidence (1 reference)

PMID:37548074 SUPPORT Human Clinical

"These, along with significant cerebral atrophy, ventriculomegaly, and an absence of other injuries, raised concerns for a genetic disorder, prompting genetic consultation."

Case report documenting ventriculomegaly with cerebral atrophy secondary to chronic CNS inflammation in an infant with CINCA/NOMID.

Intellectual disability OCCASIONAL Intellectual disability HP:0001249

Show evidence (1 reference)

ORPHA:1451 SUPPORT Other

"HP:0001249 | Intellectual disability | Occasional (29-5%)"

Orphanet lists intellectual disability as an occasional CINCA syndrome phenotype.

Global developmental delay OCCASIONAL Global developmental delay HP:0001263

Show evidence (1 reference)

ORPHA:1451 SUPPORT Other

"HP:0001263 | Global developmental delay | Occasional (29-5%)"

Orphanet lists global developmental delay as an occasional CINCA syndrome phenotype.

Constitutional 2

Arthralgia VERY_FREQUENT Arthralgia HP:0002829

Show evidence (1 reference)

ORPHA:1451 SUPPORT Other

"HP:0002829 | Arthralgia | Very frequent (99-80%)"

Orphanet lists arthralgia as a very frequent CINCA syndrome phenotype.

Myalgia VERY_FREQUENT Myalgia HP:0003326

Show evidence (1 reference)

ORPHA:1451 SUPPORT Other

"HP:0003326 | Myalgia | Very frequent (99-80%)"

Orphanet lists myalgia as a very frequent CINCA syndrome phenotype.

Growth 1

Short stature FREQUENT Short stature HP:0004322

Show evidence (3 references)

PMID:16899778 SUPPORT Human Clinical

"Neonatal-onset multisystem inflammatory disease is characterized by fever, urticarial rash, aseptic meningitis, deforming arthropathy, hearing loss, and mental retardation."

NEJM description of NOMID encompassing growth retardation and developmental delay as part of the multisystem disease burden.

PMID:38481988 SUPPORT Human Clinical

"The patients most commonly presented with rash (100%), arthritis/arthralgia (88.9%), lymphadenopathy (88.9%), fever (77.8%), and growth retardation (44.4%)."

Chinese NLRP3-AID cohort documenting growth retardation in 44.4% of patients, consistent with FREQUENT frequency classification.

PMID:37548074 SUPPORT Human Clinical

"multidisciplinary evaluation identified multiple abnormalities, including rash, macrocephaly, growth failure, and elevated inflammatory markers, which were all atypical for trauma."

Case report documenting growth failure as part of the clinical presentation of CINCA/NOMID in an infant.

Other 1

Abnormality of neutrophils VERY_FREQUENT Abnormality of neutrophils HP:0001874

Show evidence (1 reference)

ORPHA:1451 SUPPORT Other

"HP:0001874 | Abnormality of neutrophils | Very frequent (99-80%)"

Orphanet lists abnormality of neutrophils as a very frequent CINCA syndrome phenotype.

🧬

Genetic Associations

1

NLRP3 (Causative)

Gene: NLRP3 hgnc:16400

Autosomal dominant

Show evidence (2 references)

PMID:11687797 SUPPORT Human Clinical

"This resulted in the identification of four distinct mutations in a gene that segregated with the disorder in three families with FCAS and one family with MWS."

Original identification of CIAS1/NLRP3 as the causative gene for CAPS by Hoffman et al. 2001.

PMID:37809096 SUPPORT Human Clinical

"The patients harbored 19 substitutions in NLRP3, and 8 of them were novel mutations."

Large pediatric cohort expanding the NLRP3 mutation spectrum with 8 novel variants, including documentation of somatic mosaicism (F311V).

💊

Medical Actions

4

IL-1 inhibition with anakinra

Action: Pharmacotherapy NCIT:C15986

Agent: Anakinra NCIT:C38717

Anakinra (recombinant IL-1 receptor antagonist) is the first-line treatment. Daily subcutaneous injections rapidly suppress inflammation, rash, fever, and normalize inflammatory markers. Early treatment can prevent or stabilize neurological damage including hearing loss, cognitive impairment, and papilledema. MRI-visible cochlear and leptomeningeal lesions improve with treatment.

Target Phenotypes: Recurrent fever HP:0001954 Urticaria HP:0001025

Show evidence (2 references)

PMID:16899778 SUPPORT Human Clinical

"All 18 patients had a rapid response to anakinra, with disappearance of rash. Diary scores improved (P<0.001) and serum amyloid A (from a median of 174 mg to 8 mg per liter), C-reactive protein (from a median of 5.29 mg to 0.34 mg per deciliter), and the erythrocyte sedimentation rate decreased..."

Landmark NEJM trial of 18 NOMID patients demonstrating rapid and sustained response to anakinra with normalization of inflammatory markers and improvement of MRI-documented cochlear and leptomeningeal lesions.

PMID:38720945 SUPPORT Human Clinical

"After a 12-year follow-up, the patient has not experienced chronic complications."

Case report demonstrating that early initiation of IL-1 inhibition (anakinra followed by canakinumab) in a CINCA patient with somatic mosaicism prevented development of chronic sequelae over 12 years of follow-up.

IL-1 inhibition with canakinumab

Action: Pharmacotherapy NCIT:C15986

Agent: Canakinumab NCIT:C80971

Canakinumab (anti-IL-1beta monoclonal antibody) provides sustained IL-1 blockade with less frequent dosing (every 4-8 weeks subcutaneously). Effective for long-term disease control across musculoskeletal, neurological, auditory, and visual domains in CINCA/NOMID.

Target Phenotypes: Recurrent fever HP:0001954 Arthropathy HP:0003040

Show evidence (2 references)

PMID:37809096 SUPPORT Human Clinical

"Ten patients received Canakinumab treatment, which proved effective at alleviating musculoskeletal, neurological, auditory, visual manifestations, fever, and rash for 10-20 months follow-up."

Pediatric CAPS cohort demonstrating canakinumab efficacy across multiple organ domains over 10-20 months, while non-IL-1 therapies achieved only partial remission.

PMID:34059097 SUPPORT Human Clinical

"treatment with recombinant anti- human IL-1β monoclonal antibody (canakinumab) was started at a dose of 2.5 mg/kg. The rash immediately disappeared, and inflammatory markers slightly decreased after the first administration."

Neonatal case demonstrating rapid clinical response to canakinumab at 70 days of age, with immediate rash disappearance and gradual improvement of cholestasis, supporting early canakinumab use in severe neonatal CINCA.

IL-1 inhibition with rilonacept

Action: Pharmacotherapy NCIT:C15986

Agent: Rilonacept NCIT:C84137

Rilonacept (IL-1 Trap, a soluble decoy receptor) is another IL-1 inhibitor approved for CAPS. Administered weekly by subcutaneous injection. Captures both IL-1alpha and IL-1beta.

Target Phenotypes: Recurrent fever HP:0001954

Show evidence (2 references)

PMID:40370685 SUPPORT Human Clinical

"Treatment with rilonacept resulted in a reduction of approximately two points in key symptom scores for patients, with significant improvements in all outcome measures such as the number of flare days and high-sensitivity C-reactive protein levels."

Systematic review of rilonacept in CAPS (including two sequential randomized controlled trials) showing significant reductions in symptom scores, flare days, and hs-CRP, directly supporting rilonacept efficacy.

PMID:31643801 SUPPORT Other

"Rilonacept is a recombinant interleukin-1 (IL-1) antagonist which is used in the therapy of cryopyrin-associated periodic syndromes (CAPS) and other autoinflammatory conditions."

Drug monograph confirming rilonacept as a recombinant IL-1 antagonist indicated for CAPS.

Genetic counseling

Action: Genetic Counseling NCIT:C15240

Genetic counseling is recommended for affected families. Most CINCA/NOMID cases arise from de novo mutations, but germline transmission is possible. Assessment of recurrence risk, somatic mosaicism implications, and reproductive options should be discussed.

Show evidence (1 reference)

PMID:11687797 SUPPORT Human Clinical

"This resulted in the identification of four distinct mutations in a gene that segregated with the disorder in three families with FCAS and one family with MWS."

Original identification of CIAS1/NLRP3 mutations segregating in families, establishing the basis for genetic counseling about inheritance patterns in CAPS.

🌍

Environmental Factors

1

Cold exposure

Cold temperatures can trigger or exacerbate disease flares, including urticarial rash, fever, and joint symptoms. This is a shared feature across the CAPS spectrum, though in CINCA/NOMID symptoms are often continuous rather than purely cold-triggered.

Show evidence (1 reference)

PMID:11687797 SUPPORT Human Clinical

"Familial cold autoinflammatory syndrome (FCAS, MIM 120100), commonly known as familial cold urticaria (FCU), is an autosomal-dominant systemic inflammatory disease characterized by intermittent episodes of rash, arthralgia, fever and conjunctivitis after generalized exposure to cold."

Original gene identification paper establishing cold exposure as a trigger across the CAPS spectrum, with FCAS being the most cold-sensitive phenotype.

🔬

Biochemical Markers

3

Serum amyloid A (ELEVATED)

Context: Median 174 mg/L at baseline (normal <10 mg/L), normalizes with anakinra

Reference Ranges

Amyloid A [Mass/volume] in Serum or Plasma –11.0 mg/L (healthy adults)

Normal (–11.0 mg/L) Elevated (11.0– mg/L)

Elevated: SAA above the general-population upper reference limit indicates an acute-phase/inflammatory state; in CINCA/NOMID the baseline is markedly elevated (median 174 mg/L) and normalizes with IL-1 blockade.

An additional ELISA-based healthy-subject SAA reference study (Carbone et al., 2021, DOI:10.1080/15321819.2020.1837160) is available; exact cutoffs vary with assay methodology, so laboratory-specific reference intervals should be used.

Show evidence (1 reference)

PMID:31724213 SUPPORT Human Clinical

"the population reference interval for SAA was established as an upper limit of 11.0 mg/L"

General-population SAA reference interval (one-sided upper limit 11.0 mg/L) established in 2365 healthy adults; the CINCA/NOMID baseline median of 174 mg/L is roughly 16x this upper reference limit.

Show evidence (1 reference)

PMID:16899778 SUPPORT Human Clinical

"serum amyloid A (from a median of 174 mg to 8 mg per liter), C-reactive protein (from a median of 5.29 mg to 0.34 mg per deciliter), and the erythrocyte sedimentation rate decreased at month 3"

NEJM trial documenting markedly elevated baseline SAA (median 174 mg/L) in NOMID patients which normalized rapidly with anakinra, establishing SAA as a key disease activity biomarker.

C-reactive protein (ELEVATED)

Context: Median 5.29 mg/dL at baseline, normalizes with anakinra

Reference Ranges

C reactive protein [Mass/volume] in Serum or Plasma –10.0 mg/L (adults)

Conventional (non-high-sensitivity) CRP upper reference is approximately 10 mg/L (about 1.0 mg/dL); source: StatPearls, C-Reactive Protein (NCBI Bookshelf NBK441843). The CINCA/NOMID baseline median of 5.29 mg/dL (52.9 mg/L) is roughly 5x this upper reference limit and normalizes with IL-1 blockade.

C reactive protein [Mass/volume] in Serum or Plasma by High sensitivity method –1.0 mg/L (adults (high-sensitivity CRP cardiovascular risk stratification, general population))

Low cardiovascular risk (–1.0 mg/L) Average cardiovascular risk (1.0–3.0 mg/L) High cardiovascular risk (3.0– mg/L)

Low cardiovascular risk: hs-CRP below 1 mg/L corresponds to lower relative cardiovascular risk.

Average cardiovascular risk: hs-CRP 1-3 mg/L corresponds to average cardiovascular risk.

High cardiovascular risk: hs-CRP above 3 mg/L conferred a 34% higher risk of major adverse cardiovascular events versus below 1 mg/L in the UK Biobank cohort (Kurt et al., 2025).

Show evidence (1 reference)

DOI:10.1093/eurheartj/ehaf937 SUPPORT Human Clinical

"These data confirm hsCRP as a clinically relevant predictor of CV events in individuals without known ASCVD and support its assessment in primary prevention."

UK Biobank population study (448,653 participants, median hs-CRP 1.32 mg/L) supporting the established high-sensitivity CRP cardiovascular risk tiers.

Show evidence (3 references)

PMID:16899778 SUPPORT Human Clinical

"serum amyloid A (from a median of 174 mg to 8 mg per liter), C-reactive protein (from a median of 5.29 mg to 0.34 mg per deciliter), and the erythrocyte sedimentation rate decreased at month 3"

NEJM trial documenting elevated CRP (median 5.29 mg/dL) in NOMID patients which decreased to 0.34 mg/dL with anakinra, confirming CRP as a reliable inflammatory marker.

PMID:38481988 SUPPORT Human Clinical

"During acute attack, white blood cell, C-reactive protein, and/or erythrocyte sedimentation rate all increased in all cases, and inflammatory markers remained elevated beyond 7 days postfever resolution in 57.1% of patients (4/7)."

Chinese cohort confirming universal CRP elevation during flares in NLRP3-AID patients, with persistent elevation in over half of patients even after fever resolution.

PMID:34059097 SUPPORT Human Clinical

"The blood examination at birth revealed CRP at 6.4 mg/dL"

Neonatal case documenting markedly elevated CRP (6.4 mg/dL, rising to 15 mg/dL) at birth despite absence of infection, confirming intrauterine inflammatory activation.

Erythrocyte sedimentation rate (ELEVATED)

Context: Markedly elevated, normalizes with anakinra

Show evidence (2 references)

PMID:16899778 SUPPORT Human Clinical

"serum amyloid A (from a median of 174 mg to 8 mg per liter), C-reactive protein (from a median of 5.29 mg to 0.34 mg per deciliter), and the erythrocyte sedimentation rate decreased at month 3"

NEJM trial documenting elevated ESR in NOMID patients which decreased with anakinra at month 3 and remained low at month 6.

PMID:38481988 SUPPORT Human Clinical

"During acute attack, white blood cell, C-reactive protein, and/or erythrocyte sedimentation rate all increased in all cases"

Chinese cohort confirming universal ESR elevation during acute attacks across all 9 NLRP3-AID patients.

🔀

Differential Diagnoses

3

Conditions with similar clinical presentations that must be differentiated from CINCA Syndrome:

Muckle-Wells syndrome Not Yet Curated MONDO:0008633

Overlapping Features Another CAPS phenotype caused by NLRP3 mutations but with intermediate severity. Presents with urticarial rash, episodic fever, arthralgia, and progressive sensorineural hearing loss, but lacks the chronic meningitis and bony overgrowth characteristic of CINCA/NOMID.

Show evidence (1 reference)

PMID:11687797 SUPPORT Human Clinical

"Muckle-Wells syndrome (MWS; MIM 191900), which also maps to chromosome 1q44, is an autosomal-dominant periodic fever syndrome with a similar phenotype except that symptoms are not precipitated by cold exposure and that sensorineural hearing loss is frequently also present."

Original description of MWS sharing the NLRP3 genetic basis with FCAS, establishing the CAPS spectrum and the need to differentiate MWS from CINCA/NOMID by severity.

Familial cold autoinflammatory syndrome MONDO:0007349

Overlapping Features The mildest CAPS phenotype, presenting with cold-triggered urticarial episodes, fever, and arthralgia lasting less than 24 hours. No neurological or skeletal involvement. Also caused by NLRP3 mutations.

Show evidence (1 reference)

PMID:11687797 SUPPORT Human Clinical

"Familial cold autoinflammatory syndrome (FCAS, MIM 120100), commonly known as familial cold urticaria (FCU), is an autosomal-dominant systemic inflammatory disease characterized by intermittent episodes of rash, arthralgia, fever and conjunctivitis after generalized exposure to cold."

Original identification of CIAS1/NLRP3 mutations in FCAS families, establishing it as the mildest CAPS phenotype distinguished from CINCA by episodic cold-triggered symptoms only.

Systemic juvenile idiopathic arthritis MONDO:0011429

Overlapping Features Presents with quotidian fever, evanescent rash, and arthritis in childhood. Distinguished from CINCA by age of onset (typically after 6 months), different rash character (evanescent salmon-colored rather than persistent neutrophilic urticaria), absence of chronic meningitis and bony overgrowth, and negative NLRP3 genetic testing.

Show evidence (1 reference)

PMID:37809096 SUPPORT Human Clinical

"Patients treated with prednisolone or prednisolone plus thalidomide or methotrexate, tocilizumab, TNF inhibiting agents, and sirolimus achieved only partial remission."

Pediatric cohort showing that non-IL-1 therapies commonly used for systemic JIA (prednisolone, methotrexate, tocilizumab) achieved only partial remission in CAPS, helping to distinguish CINCA from sJIA by differential treatment response.

📊

Related Datasets

2

Microarray-based gene expression profiling in patients with cryopyrin-associated periodic syndromes defines a disease-related signature and IL-1-responsive transcripts geo:GSE43553

Gene expression microarray profiling of 16 CAPS patients before and after anakinra treatment, compared to healthy controls. Defines a CAPS-specific gene expression signature including transcripts related to innate and adaptive immune responses, oxidative stress, cell death, and cell adhesion.

human MICROARRAY n=100

peripheral blood

Conditions: CAPS patients pre-treatment CAPS patients post-anakinra healthy controls

Show evidence (1 reference)

GEO:GSE43553 SUPPORT

"We identified a gene expression signature that clearly distinguished CAPS patients from controls. A number of DEG were in common with other systemic inflammatory diseases such as systemic onset juvenile idiopathic arthritis."

Defines a CAPS-specific transcriptomic signature and identifies IL-1-responsive genes, relevant to understanding the molecular pathology of CINCA/NOMID.

Induced pluripotent stem cells from CINCA syndrome patients as a model for dissecting somatic mosaicism and drug discovery geo:GSE38626

iPSC lines generated from two CINCA syndrome patients with somatic NLRP3 mosaicism, differentiated into macrophages. Demonstrates that mutant iPSC-derived macrophages show abnormal IL-1beta secretion and can serve as a drug screening platform.

human MICROARRAY n=15

Conditions: NLRP3-mutant iPSC-derived macrophages non-mutant iPSC-derived macrophages

PMID:22723549

Show evidence (1 reference)

GEO:GSE38626 SUPPORT

"We found that mutant cells are predominantly responsible for the pathogenesis in these mosaic patients because only mutant iPS-MPs showed the disease relevant phenotype of abnormal IL-1β secretion."

Directly relevant to CINCA somatic mosaicism pathogenesis, demonstrating that NLRP3-mutant cells drive the inflammatory phenotype and providing a platform for drug discovery.

🔬

Clinical Trials

5

NCT00069329 PHASE_II TERMINATED

NIH-sponsored long-term study evaluating anakinra (Kineret) for NOMID/CINCA syndrome. This landmark trial demonstrated rapid and sustained efficacy of IL-1 receptor antagonism for controlling systemic inflammation, rash, fever, and CNS disease.

Target Phenotypes: Urticaria HP:0001025 Meningitis HP:0001287 Arthropathy HP:0003040 Papilledema HP:0001085

Show evidence (1 reference)

clinicaltrials:NCT00069329 SUPPORT

"This study will evaluate the safety and effectiveness of anakinra (Kineret) for treating patients with neonatal-onset multisystem inflammatory disease (NOMID), also known as chronic infantile neurological, cutaneous and arthropathy (CINCA) syndrome."

Landmark NIH trial establishing anakinra as effective therapy for NOMID/CINCA, forming the basis for the published NEJM results (PMID:16899778).

NCT00770601 PHASE_III TERMINATED

Multi-center, open-label, 24-month study evaluating canakinumab (anti-IL-1beta antibody) safety, tolerability, efficacy, and pharmacokinetics specifically in NOMID/CINCA patients aged 2 years and older. Included lumbar puncture, MRI, and cognitive evaluations.

Target Phenotypes: Recurrent fever HP:0001954 Urticaria HP:0001025 Meningitis HP:0001287

Show evidence (1 reference)

clinicaltrials:NCT00770601 SUPPORT

"This study will examine whether a medicine called canakinumab is safe and effective for treating patients with neonatal-onset multisystem inflammatory disease (NOMID), also known as chronic infantile neurologic, cutaneous, articular (CINCA) syndrome."

NOMID/CINCA-specific canakinumab trial with comprehensive CNS outcome measures including lumbar puncture and MRI.

NCT00685373 PHASE_III COMPLETED

Open-label, long-term safety and efficacy study of canakinumab (ACZ885) in patients with CAPS including NOMID. Subcutaneous injection for at least 6 months with extension up to 2 years.

Target Phenotypes: Recurrent fever HP:0001954 Urticaria HP:0001025

Show evidence (1 reference)

clinicaltrials:NCT00685373 SUPPORT

"newly identified patients with the following cryopyrin-associated periodic syndromes: Familial Cold Autoinflammatory Syndrome, Muckle-Wells Syndrome or Neonatal Onset Multisystem Inflammatory Disease."

Long-term canakinumab safety and efficacy data in CAPS patients including those with NOMID.

NCT01302860 PHASE_III COMPLETED

One-year open-label trial of canakinumab in pediatric CAPS patients aged 4 years and younger, including those with NOMID. Also evaluated safety of childhood vaccinations during canakinumab treatment.

Target Phenotypes: Recurrent fever HP:0001954 Urticaria HP:0001025

Show evidence (1 reference)

clinicaltrials:NCT01302860 SUPPORT

"This trial will assess the safety, efficacy and tolerability of ACZ885 in patients aged 4 years and younger with cryopyrin associated periodic syndromes (CAPS)"

Pediatric-focused canakinumab trial relevant to CINCA/NOMID given its neonatal onset and need for early treatment.

NCT02974595 NOT_APPLICABLE RECRUITING

NIH natural history study of autoinflammatory diseases including NOMID/CAPS, with long-term follow-up up to 15 years. Evaluates clinical outcomes, pathogenesis, genetic causes, and treatment responses across the autoinflammatory disease spectrum.

Show evidence (1 reference)

clinicaltrials:NCT02974595 SUPPORT

"Patients with known NOMID/CAPS, DIRA, CANDLE, SAVI, NLRC4-MAS, Still's Disease, and with other yet undifferentiated autoinflammatory diseases."

Ongoing NIH natural history study providing longitudinal data on NOMID/CAPS disease course, outcomes, and treatment responses.

🧫

Experimental Models

1

CINCA patient iPSC-derived macrophage model of NLRP3 mosaicism IPSC_DERIVED_MODEL

Induced pluripotent stem cell lines generated from CINCA syndrome patients with somatic NLRP3 mosaicism, separated into mutant and non-mutant lines and differentiated into macrophages. Only mutant iPSC-derived macrophages show the disease-relevant abnormal IL-1beta secretion, and the platform supports anti-inflammatory drug screening.

Organism

human NCBITaxon:9606

Cell source

iPSC-derived from CINCA patients with somatic NLRP3 mosaicism

Show evidence (1 reference)

PMID:22723549 SUPPORT In Vitro

"We found that mutant cells are predominantly responsible for the pathogenesis in these mosaic patients because only mutant iPS-MPs showed the disease relevant phenotype of abnormal IL-1β secretion."

iPSC-derived macrophages from mosaic CINCA patients functionally isolate the mutant cell fraction as the driver of abnormal IL-1beta secretion and serve as a drug-screening platform.

{ }

Source YAML

click to show

name: CINCA Syndrome
creation_date: '2026-02-09T17:35:00Z'
updated_date: '2026-05-07T00:00:00Z'
category: Mendelian
synonyms:
- Neonatal-onset multisystem inflammatory disease
- NOMID
- Chronic infantile neurological cutaneous and articular syndrome
- CINCA/NOMID
- Prieur-Griscelli syndrome
disease_term:
  preferred_term: CINCA syndrome
  term:
    id: MONDO:0011776
    label: CINCA syndrome
description: >-
  CINCA syndrome (chronic infantile neurological cutaneous and articular
  syndrome), also called neonatal-onset multisystem inflammatory disease
  (NOMID), is the most severe phenotype of the cryopyrin-associated periodic
  syndrome (CAPS) spectrum. It is a dominantly inherited autoinflammatory
  disease caused by gain-of-function NLRP3 mutations that drive constitutive
  inflammasome activation and excessive IL-1beta production, producing
  neonatal-onset urticarial rash, recurrent fever, chronic aseptic meningitis
  with sensorineural hearing loss and neurodevelopmental impairment, and a
  deforming arthropathy with characteristic epiphyseal overgrowth. Most cases
  arise de novo; a substantial minority reflect somatic NLRP3 mosaicism.
  Early interleukin-1 blockade controls inflammation and can prevent chronic
  sequelae.
parents:
- Autoinflammatory diseases
- Cryopyrin-associated periodic syndromes
has_subtypes:
- name: Classic CINCA with identifiable NLRP3 mutation
  description: >
    Patients with identifiable heterozygous gain-of-function mutations
    in NLRP3. Accounts for approximately 50-60% of clinically diagnosed
    CINCA/NOMID cases. Mutations are typically de novo.
  evidence:
  - reference: PMID:31077002
    reference_title: "CAPS and NLRP3."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Gain-of-function mutations in NLRP3 in CAPS patients lead to activation of the cryopyrin inflammasome, resulting in the inappropriate release of inflammatory cytokines including IL-1beta and CAPS-related inflammatory symptoms."
    explanation: Review confirming NLRP3 gain-of-function mutations as the causative mechanism in CAPS including CINCA/NOMID.
- name: Mutation-negative CINCA (somatic mosaicism)
  description: >
    Patients meeting clinical criteria for CINCA/NOMID but without
    detectable NLRP3 mutations by conventional sequencing. Many of
    these cases harbor somatic mosaicism for NLRP3 mutations detectable
    only by deep sequencing, with variant allele fractions as low as
    1.3%. Mosaicism may be myeloid-restricted or involve both myeloid
    and lymphoid lineages.
  evidence:
  - reference: PMID:16899778
    reference_title: "Neonatal-onset multisystem inflammatory disease responsive to interleukin-1beta inhibition."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We selected 18 patients with neonatal-onset multisystem inflammatory disease (12 with identifiable CIAS1 mutations) to receive anakinra, an interleukin-1-receptor antagonist"
    explanation: Landmark NEJM trial demonstrating that 6 of 18 clinically definite NOMID patients lacked identifiable CIAS1 mutations by standard sequencing, yet responded identically to IL-1 blockade, suggesting undetected somatic mosaicism.
  - reference: PMID:38720945
    reference_title: "Case Report: Efficacy, safety, and favorable long-term outcome of early treatment with IL-1 inhibitors in a patient with chronic infantile neurological cutaneous articular (CINCA) syndrome caused by NLRP3 mosaicism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Additional genetic investigations performed after the introduction of anti-IL-1 therapy revealed a pathogenic mosaicism in the NLRP3 gene."
    explanation: Case report demonstrating that initial NLRP3 testing was negative but subsequent deep sequencing revealed somatic mosaicism, underscoring the need for advanced sequencing in clinically diagnosed mutation-negative patients.
  - reference: PMID:34059097
    reference_title: "Necrotizing Funisitis as an Intrauterine manifestation of Cryopyrin-Associated Periodic Syndrome: a case report and review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "approximately 28 ~ 35 % of all the CINCA/NOMID patients carry an NLRP3 mutation in somatic mosaicism state"
    explanation: Review of the literature quantifying the prevalence of somatic mosaicism in CINCA/NOMID, noting that mosaic patients tend to present with milder neurologic symptoms compared to those with germline mutations.
  - reference: PMID:41026232
    reference_title: "Novel Insights into the Clinical Features, Genetic Spectrum and Clonal Evolution of Patients Carrying NLRP3 Mosaicism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Two main patterns of mosaicism (extended vs. myeloid-restricted) were detected, with the last one overrepresented in the late-onset group."
    explanation: Largest NLRP3 mosaicism cohort to date (17 individuals) identifying two distinct biological patterns of mosaicism distribution and showing that mosaicism remains stable over time in most patients.
  - reference: PMID:40538939
    reference_title: "Somatic NLRP3 mosaicism in patients with \"mutation-negative\" CAPS: insights from a single centre UK cohort."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In 40% (4/10) of the cohort a post-zygotic NLRP3 mutation leading to somatic mosaicism was found by ADS."
    explanation: UK pediatric cohort demonstrating that amplicon-based deep sequencing detects somatic mosaicism in 40% of mutation-negative CAPS patients, with mutant allelic frequencies as low as 3.1%.
  - reference: PMID:22723549
    reference_title: "Induced pluripotent stem cells from CINCA syndrome patients as a model for dissecting somatic mosaicism and drug discovery."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "We found that mutant cells are predominantly responsible for the pathogenesis in these mosaic patients because only mutant iPS-MPs showed the disease relevant phenotype of abnormal IL-1β secretion."
    explanation: iPSC-derived macrophages from two mosaic CINCA patients provide functional proof that the NLRP3-mutant cell fraction drives the autoinflammatory phenotype, mechanistically grounding the somatic-mosaicism subtype.
pathophysiology:
- name: NLRP3 gain-of-function mutation
  description: >
    Heterozygous gain-of-function mutations in the NLRP3 gene (encoding
    cryopyrin) lower the activation threshold for NLRP3 inflammasome
    assembly. Most CINCA/NOMID mutations are de novo, arising
    post-zygotically or in the germline. The NLRP3 protein contains a
    pyrin domain, a NACHT domain, and leucine-rich repeats; disease
    mutations cluster in the NACHT domain and disrupt autoinhibitory
    conformations.
  downstream:
  - target: Constitutive NLRP3 inflammasome activation
  gene:
    preferred_term: NLRP3
    term:
      id: hgnc:16400
      label: NLRP3
  evidence:
  - reference: PMID:11687797
    reference_title: "Mutation of a new gene encoding a putative pyrin-like protein causes familial cold autoinflammatory syndrome and Muckle-Wells syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This gene, called CIAS1, is expressed in peripheral blood leukocytes and encodes a protein with a pyrin domain, a nucleotide-binding site (NBS, NACHT subfamily) domain and a leucine-rich repeat (LRR) motif region, suggesting a role in the regulation of inflammation and apoptosis."
    explanation: Original identification of CIAS1/NLRP3 mutations as the cause of FCAS and MWS, establishing the genetic basis for the entire CAPS spectrum including CINCA/NOMID.
  - reference: DOI:10.1111/imr.13292
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Initially discovered as the cause of the autoinflammatory spectrum of cryopyrin-associated periodic syndrome (CAPS), NLRP3 is now also known to play a role in more common diseases including cardiovascular disease, gout, and liver disease."
    explanation: Comprehensive review by Hoffman laboratory tracing the discovery of NLRP3 as the CAPS disease gene and its broader role in innate immunity.
- name: Constitutive NLRP3 inflammasome activation
  description: >
    Mutant cryopyrin undergoes spontaneous oligomerization and
    constitutive assembly of the NLRP3 inflammasome complex, comprising
    NLRP3, ASC (PYCARD), and pro-caspase-1. NEK7 serves as a scaffold
    facilitating NLRP3 activation via microtubule organizing center
    trafficking. The resulting continuous activation of caspase-1
    occurs without normal requirement for exogenous danger signals.
    ASC speck formation, the hallmark of inflammasome assembly, is
    enhanced in patient myeloid cells and suppressible by MCC950.
  downstream:
  - target: Excessive IL-1beta production
  - target: Excessive IL-18 production
  biological_processes:
  - preferred_term: NLRP3 inflammasome complex assembly
    term:
      id: GO:0044546
      label: NLRP3 inflammasome complex assembly
    modifier: ABNORMAL
  evidence:
  - reference: PMID:31077002
    reference_title: "CAPS and NLRP3."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Gain-of-function mutations in NLRP3 in CAPS patients lead to activation of the cryopyrin inflammasome, resulting in the inappropriate release of inflammatory cytokines including IL-1beta and CAPS-related inflammatory symptoms."
    explanation: Review describing constitutive inflammasome activation as the central pathogenic mechanism in CAPS, with gain-of-function mutations driving inappropriate caspase-1 activation and cytokine release.
  - reference: DOI:10.1111/imr.13292
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Activated by a panoply of pathogen-associated and endogenous triggers, NLRP3 serves as an intracellular sensor that drives carefully coordinated assembly of the inflammasome, and downstream inflammation mediated by IL-1 and IL-18."
    explanation: Review detailing normal and pathological NLRP3 inflammasome assembly mechanisms, including ASC speck formation and regulatory nodes disrupted by CAPS mutations.
  - reference: PMID:39816134
    reference_title: "Revealing the dance of NLRP3: spatiotemporal patterns in inflammasome activation."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Dysregulated NLRP3 activation has been implicated in a variety of autoimmune and inflammatory diseases, including cryopyrin-associated periodic fever syndromes, diabetes, atherosclerosis, Alzheimer's disease, inflammatory bowel disease, and cancer."
    explanation: Review of NLRP3 spatiotemporal dynamics implicating mitochondria, lysosomes, ER, Golgi, endosomes, and the centrosome in NLRP3 localization and inflammasome assembly, providing mechanistic context for how CAPS mutations disrupt normal subcellular regulation.
- name: Excessive IL-1beta production
  description: >
    Constitutively active caspase-1 cleaves pro-IL-1beta into its
    mature, biologically active form. The resulting overproduction of
    IL-1beta is the primary driver of systemic inflammation, fever,
    and tissue damage throughout the body. Gasdermin D-dependent
    pyroptosis of activated myeloid cells releases intracellular
    contents including IL-1beta and amplifies inflammation.
  downstream:
  - target: Systemic neutrophilic inflammation
  - target: Central nervous system inflammation
  - target: Epiphyseal skeletal overgrowth
  - target: Cartilage damage and destructive arthropathy
  - target: Secondary amyloidosis
  biological_processes:
  - preferred_term: Positive regulation of interleukin-1 beta production
    term:
      id: GO:0032731
      label: positive regulation of interleukin-1 beta production
    modifier: ABNORMAL
  - preferred_term: Pyroptotic inflammatory response
    term:
      id: GO:0070269
      label: pyroptotic inflammatory response
    modifier: ABNORMAL
  evidence:
  - reference: PMID:31077002
    reference_title: "CAPS and NLRP3."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Gain-of-function mutations in NLRP3 in CAPS patients lead to activation of the cryopyrin inflammasome, resulting in the inappropriate release of inflammatory cytokines including IL-1beta and CAPS-related inflammatory symptoms."
    explanation: Review confirming that excessive IL-1beta release from constitutively active inflammasome is the proximate cause of CAPS symptoms.
  - reference: PMID:34059097
    reference_title: "Necrotizing Funisitis as an Intrauterine manifestation of Cryopyrin-Associated Periodic Syndrome: a case report and review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These evidences suggest that foetal inflammation, probably due to overproduction of IL-1β, caused tissue damage in utero, and the first symptom of a newborn with CINCA/NOMID."
    explanation: Case report with histopathological evidence that IL-1beta overproduction begins in utero, causing necrotizing funisitis and villitis as the earliest manifestations of CINCA/NOMID even before birth.
  - reference: PMID:38808101
    reference_title: "Case Report: A neonatal case of cryopyrin-associated periodic syndrome with severe funisitis and neonatal asphyxia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Histopathologic examination of the placenta and umbilical cord can provide crucial insights into the intrauterine onset of inflammation, which is the first manifestation of CINCA syndrome/NOMID in newborns."
    explanation: Case report confirming intrauterine onset of IL-1beta-driven inflammation in CINCA/NOMID, with severe funisitis leading to umbilical cord rupture and neonatal asphyxia.
- name: Excessive IL-18 production
  description: >
    Constitutively active caspase-1 also cleaves pro-IL-18 into its
    mature form. IL-18 contributes to macrophage activation and
    interferon-gamma production, amplifying the innate immune
    response and promoting Th1-polarized inflammation. Elevated
    serum IL-18 levels are a feature of CAPS and contribute to
    the systemic inflammatory burden alongside IL-1beta.
  downstream:
  - target: Systemic neutrophilic inflammation
  biological_processes:
  - preferred_term: Positive regulation of interleukin-18 production
    term:
      id: GO:0032741
      label: positive regulation of interleukin-18 production
    modifier: ABNORMAL
  evidence:
  - reference: DOI:10.1111/imr.13292
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Activated by a panoply of pathogen-associated and endogenous triggers, NLRP3 serves as an intracellular sensor that drives carefully coordinated assembly of the inflammasome, and downstream inflammation mediated by IL-1 and IL-18."
    explanation: Review identifying IL-18 alongside IL-1 as a key downstream inflammatory mediator of the NLRP3 inflammasome, confirming its role in CAPS pathogenesis.
- name: Systemic neutrophilic inflammation
  description: >
    Excess IL-1beta drives recruitment and activation of neutrophils
    throughout the body, producing neutrophilic infiltration in skin,
    joints, meninges, and other tissues. The skin rash of CINCA is a
    neutrophilic urticarial dermatosis rather than true mast
    cell-mediated urticaria. Sustained neutrophilic inflammation causes
    tissue damage and organ dysfunction.
  locations:
  - preferred_term: Skin of body
    term:
      id: UBERON:0002097
      label: skin of body
  cell_types:
  - preferred_term: Neutrophil
    term:
      id: CL:0000775
      label: neutrophil
  - preferred_term: Monocyte
    term:
      id: CL:0000576
      label: monocyte
  biological_processes:
  - preferred_term: Neutrophil chemotaxis
    term:
      id: GO:0030593
      label: neutrophil chemotaxis
    modifier: ABNORMAL
  - preferred_term: Inflammatory response
    term:
      id: GO:0006954
      label: inflammatory response
    modifier: ABNORMAL
  evidence:
  - reference: PMID:16899778
    reference_title: "Neonatal-onset multisystem inflammatory disease responsive to interleukin-1beta inhibition."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Neonatal-onset multisystem inflammatory disease is characterized by fever, urticarial rash, aseptic meningitis, deforming arthropathy, hearing loss, and mental retardation."
    explanation: Landmark NEJM trial characterizing the multisystem neutrophilic inflammation in NOMID/CINCA affecting skin, CNS, joints, and sensory organs.
  - reference: PMID:34059097
    reference_title: "Necrotizing Funisitis as an Intrauterine manifestation of Cryopyrin-Associated Periodic Syndrome: a case report and review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the inflammation of the umbilical vessels typically begins in the vein (phlebitis) and is followed by involvement of the arteries (arteritis) and the Wharton's jelly"
    explanation: Histopathological evidence of neutrophilic infiltration in umbilical cord vessels and Wharton's jelly, demonstrating that neutrophilic inflammation begins in utero in CINCA/NOMID and can involve the placenta and umbilical cord.
  downstream:
  - target: Recurrent fever
    description: IL-1-driven systemic inflammation produces recurrent fever.
  - target: Urticarial rash
    description: Neutrophilic skin inflammation produces the urticaria-like rash.
  - target: Abnormality of neutrophils
    description: The inflammatory phenotype includes neutrophil abnormalities.
  - target: Leukocytosis
    description: Systemic inflammation increases circulating leukocyte counts.
  - target: Myalgia
    description: Systemic inflammation can manifest as muscle pain.
- name: Central nervous system inflammation
  description: >
    Chronic aseptic meningitis with neutrophilic and lymphocytic
    infiltration of the leptomeninges leads to elevated intracranial
    pressure, papilledema, progressive sensorineural hearing loss, and
    cognitive impairment. Microglial activation in the brain parenchyma
    may contribute to cerebral atrophy in inadequately treated patients.
    Cochlear inflammation produces progressive hearing loss, and
    leptomeningeal enhancement is visible on MRI.
  locations:
  - preferred_term: Leptomeninx
    term:
      id: UBERON:0000391
      label: leptomeninx
  - preferred_term: Cochlea
    term:
      id: UBERON:0001844
      label: cochlea
  cell_types:
  - preferred_term: Microglial cell
    term:
      id: CL:0000129
      label: microglial cell
  evidence:
  - reference: PMID:16899778
    reference_title: "Neonatal-onset multisystem inflammatory disease responsive to interleukin-1beta inhibition."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Magnetic resonance imaging showed improvement in cochlear and leptomeningeal lesions as compared with baseline."
    explanation: MRI documentation of cochlear and leptomeningeal inflammatory lesions in NOMID patients, which improved with anakinra treatment, confirming active CNS inflammation.
  - reference: PMID:37809096
    reference_title: "The genetic and clinical characteristics and effects of Canakinumab on cryopyrin-associated periodic syndrome: a large pediatric cohort study from China."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Among these novel mutations, percentages of severe musculoskeletal, ophthalmologic, and neurological symptoms were higher compared with other case serials."
    explanation: Large pediatric CAPS cohort showing high prevalence of severe neurological symptoms in patients with novel NLRP3 mutations, consistent with the CNS inflammatory burden in CINCA/NOMID.
  downstream:
  - target: Chronic aseptic meningitis
    description: Leptomeningeal inflammation manifests as chronic aseptic meningitis.
  - target: Sensorineural hearing loss
    description: Cochlear inflammation contributes to sensorineural hearing loss.
  - target: Increased intracranial pressure
    description: Chronic meningeal inflammation raises intracranial pressure.
  - target: Ventriculomegaly
    description: Chronic CNS inflammation and raised intracranial pressure can produce ventricular enlargement.
  - target: Macrocephaly
    description: Chronic CNS inflammation and increased intracranial pressure can produce macrocephaly.
  - target: Intellectual disability
    description: Chronic CNS inflammation contributes to cognitive impairment.
  - target: Global developmental delay
    description: Early CNS inflammation can delay neurodevelopmental milestones.
  - target: Visual impairment
    description: CNS and ocular inflammation can impair vision.
- name: Epiphyseal skeletal overgrowth
  description: >
    IL-1beta-driven inflammation at the growth plates stimulates
    abnormal endochondral ossification, producing characteristic
    bony overgrowth of the patellae, distal femora, and other long
    bone epiphyses. The distinctive radiographic features include
    epiphyseal enlargement and calcified physeal lesions unique
    to CINCA/NOMID within the CAPS spectrum.
  locations:
  - preferred_term: Epiphysis
    term:
      id: UBERON:0001437
      label: epiphysis
  - preferred_term: Growth plate cartilage
    term:
      id: UBERON:0004129
      label: growth plate cartilage
  biological_processes:
  - preferred_term: Endochondral ossification
    term:
      id: GO:0001958
      label: endochondral ossification
    modifier: ABNORMAL
  evidence:
  - reference: PMID:37809096
    reference_title: "The genetic and clinical characteristics and effects of Canakinumab on cryopyrin-associated periodic syndrome: a large pediatric cohort study from China."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Ten patients received Canakinumab treatment, which proved effective at alleviating musculoskeletal, neurological, auditory, visual manifestations, fever, and rash for 10-20 months follow-up."
    explanation: Pediatric CAPS cohort documenting musculoskeletal involvement as a major disease domain responsive to IL-1 blockade, confirming IL-1-driven skeletal overgrowth.
- name: Cartilage damage and destructive arthropathy
  description: >
    Chronic IL-1beta-mediated inflammation in the joints drives
    chondrocyte dysfunction and cartilage matrix degradation,
    leading to progressive destructive arthropathy. Extracellular
    matrix disassembly in articular cartilage results in joint
    deformity and functional impairment distinctive to the severe
    CINCA/NOMID phenotype.
  locations:
  - preferred_term: Synovial joint
    term:
      id: UBERON:0002217
      label: synovial joint
  cell_types:
  - preferred_term: Chondrocyte
    term:
      id: CL:0000138
      label: chondrocyte
  biological_processes:
  - preferred_term: Extracellular matrix disassembly
    term:
      id: GO:0022617
      label: extracellular matrix disassembly
    modifier: ABNORMAL
  evidence:
  - reference: PMID:16899778
    reference_title: "Neonatal-onset multisystem inflammatory disease responsive to interleukin-1beta inhibition."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Neonatal-onset multisystem inflammatory disease is characterized by fever, urticarial rash, aseptic meningitis, deforming arthropathy, hearing loss, and mental retardation."
    explanation: Landmark NEJM trial identifying deforming arthropathy as a cardinal feature of NOMID/CINCA, distinct from bony overgrowth and reflecting cartilage destruction.
  downstream:
  - target: Arthropathy with epiphyseal overgrowth
    description: Cartilage and joint damage produces deforming arthropathy.
  - target: Arthralgia
    description: Joint inflammation and damage produce joint pain.
  - target: Abnormal joint morphology
    description: Destructive arthropathy changes joint structure.
  - target: Joint dislocation
    description: Severe joint damage can destabilize joints.
- name: Secondary amyloidosis
  description: >
    Chronic uncontrolled systemic inflammation leads to sustained
    elevation of serum amyloid A (SAA), which can deposit as AA
    amyloid in kidneys and other organs. This potentially causes
    nephrotic syndrome and renal failure if untreated. AA amyloidosis
    is a recognized long-term complication across the CAPS spectrum,
    particularly in undertreated patients.
  locations:
  - preferred_term: Kidney
    term:
      id: UBERON:0002113
      label: kidney
  evidence:
  - reference: PMID:16899778
    reference_title: "Neonatal-onset multisystem inflammatory disease responsive to interleukin-1beta inhibition."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "serum amyloid A (from a median of 174 mg to 8 mg per liter), C-reactive protein (from a median of 5.29 mg to 0.34 mg per deciliter), and the erythrocyte sedimentation rate decreased at month 3"
    explanation: NEJM trial documenting markedly elevated baseline serum amyloid A levels (median 174 mg/L) in NOMID patients, reflecting the chronic inflammatory state that drives AA amyloidosis risk. SAA normalized rapidly with anakinra.
phenotypes:
- name: Urticarial rash
  description: >
    Non-pruritic, migratory urticaria-like rash present from birth or
    the neonatal period. The rash is a neutrophilic urticarial
    dermatosis rather than mast cell-mediated urticaria, and worsens
    with cold exposure, fever, or stress. Present in virtually all
    CINCA/NOMID patients.
  frequency: OBLIGATE
  notes: >
    18/18 (100%) NOMID patients in the Goldbach-Mansky NEJM cohort
    had urticarial rash at baseline, supporting OBLIGATE frequency.
  context: Neonatal onset, persistent
  diagnostic: true
  phenotype_term:
    preferred_term: Urticaria
    term:
      id: HP:0001025
      label: Urticaria
  evidence:
  - reference: PMID:16899778
    reference_title: "Neonatal-onset multisystem inflammatory disease responsive to interleukin-1beta inhibition."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All 18 patients had a rapid response to anakinra, with disappearance of rash."
    explanation: All 18 NOMID patients in the landmark NEJM trial had urticarial rash at baseline which resolved rapidly with anakinra, confirming universality and IL-1 dependence of this phenotype.
  - reference: PMID:38481988
    reference_title: "Clinical and Genetic Spectrum of Nine Cases of NLRP3-Associated Autoinflammatory Disease (NLRP3-AID) and Identification of One Novel NLRP3 Mutation by Genetic Variation Analyses."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The patients most commonly presented with rash (100%), arthritis/arthralgia (88.9%), lymphadenopathy (88.9%), fever (77.8%), and growth retardation (44.4%)."
    explanation: Chinese NLRP3-AID cohort of 9 patients confirming rash in 100% of cases, consistent with OBLIGATE frequency across different populations.
- name: Recurrent fever
  description: >
    Recurrent or continuous low-grade fever beginning in the neonatal
    period, often accompanying flares of the urticarial rash. Fever
    is driven by systemic IL-1beta overproduction.
  frequency: VERY_FREQUENT
  notes: >
    Listed as a defining characteristic of NOMID; present in the
    majority of patients though not always continuous.
  context: Neonatal onset, often continuous rather than episodic
  phenotype_term:
    preferred_term: Recurrent fever
    term:
      id: HP:0001954
      label: Recurrent fever
  evidence:
  - reference: PMID:16899778
    reference_title: "Neonatal-onset multisystem inflammatory disease responsive to interleukin-1beta inhibition."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Neonatal-onset multisystem inflammatory disease is characterized by fever, urticarial rash, aseptic meningitis, deforming arthropathy, hearing loss, and mental retardation."
    explanation: NEJM trial establishing fever as a cardinal feature of NOMID/CINCA.
  - reference: PMID:38481988
    reference_title: "Clinical and Genetic Spectrum of Nine Cases of NLRP3-Associated Autoinflammatory Disease (NLRP3-AID) and Identification of One Novel NLRP3 Mutation by Genetic Variation Analyses."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The patients most commonly presented with rash (100%), arthritis/arthralgia (88.9%), lymphadenopathy (88.9%), fever (77.8%), and growth retardation (44.4%)."
    explanation: Chinese NLRP3-AID cohort showing fever in 77.8% of patients, consistent with VERY_FREQUENT classification.
- name: Arthropathy with epiphyseal overgrowth
  description: >
    Ranges from arthralgia and joint swelling in milder cases to severe
    deforming arthropathy with characteristic bony overgrowth of the
    patellae, distal femora, and other epiphyses. The patellar
    overgrowth pattern is distinctive to CINCA/NOMID within the CAPS
    spectrum.
  frequency: VERY_FREQUENT
  notes: >
    Deforming arthropathy is a defining feature of NOMID; the
    distinctive epiphyseal overgrowth pattern distinguishes CINCA
    from milder CAPS phenotypes.
  context: Progressive, onset in infancy
  diagnostic: true
  phenotype_term:
    preferred_term: Arthropathy
    term:
      id: HP:0003040
      label: Arthropathy
  evidence:
  - reference: PMID:16899778
    reference_title: "Neonatal-onset multisystem inflammatory disease responsive to interleukin-1beta inhibition."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Neonatal-onset multisystem inflammatory disease is characterized by fever, urticarial rash, aseptic meningitis, deforming arthropathy, hearing loss, and mental retardation."
    explanation: NEJM trial identifying deforming arthropathy as a cardinal feature of NOMID/CINCA.
  - reference: PMID:38481988
    reference_title: "Clinical and Genetic Spectrum of Nine Cases of NLRP3-Associated Autoinflammatory Disease (NLRP3-AID) and Identification of One Novel NLRP3 Mutation by Genetic Variation Analyses."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The patients most commonly presented with rash (100%), arthritis/arthralgia (88.9%), lymphadenopathy (88.9%), fever (77.8%), and growth retardation (44.4%)."
    explanation: Chinese NLRP3-AID cohort showing arthritis/arthralgia in 88.9% (8/9) of patients, with two CINCA cases also having clubbed fingers.
- name: Chronic aseptic meningitis
  description: >
    Chronic aseptic meningitis with elevated CSF pressure, pleocytosis,
    and elevated protein. Leads to headaches, papilledema, and
    progressive neurological damage including cognitive impairment.
    May cause ventriculomegaly, cerebral atrophy, macrocephaly, and
    rarely subdural hemorrhages.
  frequency: VERY_FREQUENT
  notes: >
    Aseptic meningitis is part of the diagnostic triad of NOMID and
    is present in the majority of patients; its chronicity
    distinguishes CINCA from the milder CAPS phenotypes.
  diagnostic: true
  phenotype_term:
    preferred_term: Meningitis
    term:
      id: HP:0001287
      label: Meningitis
    temporality: CHRONIC
    severity: SEVERE
    onset:
      onset_category: NEONATAL
  evidence:
  - reference: PMID:16899778
    reference_title: "Neonatal-onset multisystem inflammatory disease responsive to interleukin-1beta inhibition."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Neonatal-onset multisystem inflammatory disease is characterized by fever, urticarial rash, aseptic meningitis, deforming arthropathy, hearing loss, and mental retardation."
    explanation: NEJM trial establishing chronic aseptic meningitis as a hallmark neurological manifestation of NOMID/CINCA.
  - reference: PMID:37548074
    reference_title: "Subdural hemorrhage, macrocephaly, rash, and developmental delay in an infant: A pathogenic variant in NLRP3 causes CINCA/NOMID."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These, along with significant cerebral atrophy, ventriculomegaly, and an absence of other injuries, raised concerns for a genetic disorder, prompting genetic consultation."
    explanation: Case report of an infant with CINCA/NOMID presenting with subdural hemorrhage, macrocephaly, cerebral atrophy, and ventriculomegaly secondary to chronic CNS inflammation, initially raising suspicion of abusive head trauma.
  - reference: PMID:34059097
    reference_title: "Necrotizing Funisitis as an Intrauterine manifestation of Cryopyrin-Associated Periodic Syndrome: a case report and review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the examination of the cerebrospinal fluid (CSF) showed a WBC cell count of 667 /µL (polymorphonuclear: mononuclear 4:1), glucose at 21 mg/dL, and protein at 191 mg/dL"
    explanation: Neonatal case documenting severe CSF pleocytosis (667 cells) with neutrophilic predominance, hypoglycorrhachia, and markedly elevated protein at birth, confirming intrauterine-onset aseptic meningitis.
- name: Sensorineural hearing loss
  description: >
    Progressive sensorineural hearing loss developing in childhood,
    related to chronic cochlear inflammation and/or chronic meningitis.
    May progress to profound deafness without treatment. Cochlear
    lesions are visible on MRI and can improve with IL-1 blockade.
  frequency: VERY_FREQUENT
  notes: >
    Hearing loss is listed as a defining feature of NOMID; cochlear
    lesions were documented on MRI in the NEJM cohort and improved
    with anakinra.
  context: Progressive, childhood onset
  phenotype_term:
    preferred_term: Sensorineural hearing impairment
    term:
      id: HP:0000407
      label: Sensorineural hearing impairment
  evidence:
  - reference: PMID:16899778
    reference_title: "Neonatal-onset multisystem inflammatory disease responsive to interleukin-1beta inhibition."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Magnetic resonance imaging showed improvement in cochlear and leptomeningeal lesions as compared with baseline."
    explanation: NEJM trial documenting cochlear inflammatory lesions on MRI in NOMID patients that improved with anakinra, linking hearing loss to reversible cochlear inflammation.
- name: Papilledema
  description: >
    Optic disc swelling due to elevated intracranial pressure from
    chronic aseptic meningitis. Can progress to optic atrophy and
    vision loss if untreated.
  context: Secondary to chronic meningitis and raised intracranial pressure
  phenotype_term:
    preferred_term: Papilledema
    term:
      id: HP:0001085
      label: Papilledema
  evidence:
  - reference: PMID:20005004
    reference_title: "[CINCA syndrome: a rare cause of papilledema. The case of homozygous twins]."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The diagnosis was evoked on the basis of multiple systemic symptoms (multiple episodes of fever of unknown origin, mental retardation, short stature, meningitis, hearing loss, bilateral papilledema) and confirmed by the presence of a CIAS1 mutation on genetic analysis."
    explanation: CIAS1-confirmed CINCA case (homozygous twins) presenting with bilateral papilledema, directly supporting papilledema as an ocular manifestation of CINCA secondary to raised intracranial pressure. Frequency band omitted because papilledema is uncommon across the CAPS spectrum (PMID:32951665) and no CINCA-specific frequency is established.
- name: Increased intracranial pressure
  description: >
    Raised intracranial pressure secondary to chronic aseptic meningitis,
    contributing to headache, papilledema, and risk of optic atrophy and
    vision loss.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Increased intracranial pressure
    term:
      id: HP:0002516
      label: Increased intracranial pressure
  evidence:
  - reference: ORPHA:1451
    reference_title: "CINCA syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002516 | Increased intracranial pressure | Very frequent (99-80%)"
    explanation: Orphanet lists increased intracranial pressure as a very frequent CINCA syndrome phenotype.
  - reference: PMID:32951665
    reference_title: "Secondary Intracranial Hypertension in Pediatric Patients With Cryopyrin-Associated Periodic Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Six patients (30%) developed headaches and were diagnosed with secondary intracranial hypertension. Lumbar puncture opening pressures ranged from 28 to 45 cm H2O."
    explanation: Pediatric CAPS series documenting secondary intracranial hypertension with markedly elevated lumbar-puncture opening pressures (28-45 cm H2O), providing primary clinical evidence for the raised-ICP association.
- name: Ventriculomegaly
  description: >
    Ventricular enlargement related to chronic CNS inflammation and raised
    intracranial pressure, often accompanied by cerebral atrophy in
    inadequately treated CINCA/NOMID.
  phenotype_term:
    preferred_term: Ventriculomegaly
    term:
      id: HP:0002119
      label: Ventriculomegaly
  evidence:
  - reference: PMID:37548074
    reference_title: "Subdural hemorrhage, macrocephaly, rash, and developmental delay in an infant: A pathogenic variant in NLRP3 causes CINCA/NOMID."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These, along with significant cerebral atrophy, ventriculomegaly, and an absence of other injuries, raised concerns for a genetic disorder, prompting genetic consultation."
    explanation: Case report documenting ventriculomegaly with cerebral atrophy secondary to chronic CNS inflammation in an infant with CINCA/NOMID.
- name: Short stature
  description: >
    Growth retardation and short stature related to chronic systemic
    inflammation and skeletal abnormalities. Failure to thrive is
    common in untreated patients.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Short stature
    term:
      id: HP:0004322
      label: Short stature
  evidence:
  - reference: PMID:16899778
    reference_title: "Neonatal-onset multisystem inflammatory disease responsive to interleukin-1beta inhibition."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Neonatal-onset multisystem inflammatory disease is characterized by fever, urticarial rash, aseptic meningitis, deforming arthropathy, hearing loss, and mental retardation."
    explanation: NEJM description of NOMID encompassing growth retardation and developmental delay as part of the multisystem disease burden.
  - reference: PMID:38481988
    reference_title: "Clinical and Genetic Spectrum of Nine Cases of NLRP3-Associated Autoinflammatory Disease (NLRP3-AID) and Identification of One Novel NLRP3 Mutation by Genetic Variation Analyses."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The patients most commonly presented with rash (100%), arthritis/arthralgia (88.9%), lymphadenopathy (88.9%), fever (77.8%), and growth retardation (44.4%)."
    explanation: Chinese NLRP3-AID cohort documenting growth retardation in 44.4% of patients, consistent with FREQUENT frequency classification.
  - reference: PMID:37548074
    reference_title: "Subdural hemorrhage, macrocephaly, rash, and developmental delay in an infant: A pathogenic variant in NLRP3 causes CINCA/NOMID."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "multidisciplinary evaluation identified multiple abnormalities, including rash, macrocephaly, growth failure, and elevated inflammatory markers, which were all atypical for trauma."
    explanation: Case report documenting growth failure as part of the clinical presentation of CINCA/NOMID in an infant.
- name: Hepatosplenomegaly
  description: >
    Enlargement of the liver and spleen due to chronic systemic
    inflammation and reticuloendothelial activation. May be accompanied
    by cholestasis in severe neonatal cases, which can gradually
    improve with anti-inflammatory treatment.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Hepatosplenomegaly
    term:
      id: HP:0001433
      label: Hepatosplenomegaly
  evidence:
  - reference: PMID:31077002
    reference_title: "CAPS and NLRP3."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Cryopyrin-associated periodic syndrome (CAPS) is a rare inherited autoinflammatory disorder characterized by systemic, cutaneous, musculoskeletal, and central nervous system inflammation."
    explanation: Review characterizing CAPS as a systemic inflammatory disorder with widespread organ involvement including hepatosplenomegaly from reticuloendothelial activation.
  - reference: PMID:34059097
    reference_title: "Necrotizing Funisitis as an Intrauterine manifestation of Cryopyrin-Associated Periodic Syndrome: a case report and review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "She also exhibited atypical symptoms such as severe hepatosplenomegaly with cholestasis."
    explanation: Case report documenting severe hepatosplenomegaly with cholestasis as a neonatal manifestation of CINCA/NOMID, which gradually improved in parallel with decreasing inflammatory markers after canakinumab treatment.
- name: Uveitis
  description: >
    Ocular inflammation affecting the uveal tract, which may present as
    anterior or posterior uveitis. Contributes to visual impairment
    alongside papilledema and optic atrophy.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Uveitis
    term:
      id: HP:0000554
      label: Uveitis
  evidence:
  - reference: PMID:37809096
    reference_title: "The genetic and clinical characteristics and effects of Canakinumab on cryopyrin-associated periodic syndrome: a large pediatric cohort study from China."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Ten patients received Canakinumab treatment, which proved effective at alleviating musculoskeletal, neurological, auditory, visual manifestations, fever, and rash for 10-20 months follow-up."
    explanation: Pediatric cohort confirming visual manifestations (including uveitis) as a major disease domain in severe CAPS responsive to IL-1 blockade.
- name: Retinal dystrophy
  description: >
    Post-inflammatory retinal dystrophy is a documented but uncommon ocular
    complication of CINCA/NOMID, distinct from papilledema. Chronic
    autoinflammatory retinopathy produces a rod-cone dystrophy detectable on
    funduscopy, optical coherence tomography, and visual electrophysiology,
    contributing to progressive visual impairment. The retinal damage may
    persist or remain stationary despite IL-1 blockade.
  context: Post-inflammatory; may persist despite IL-1 blockade
  phenotype_term:
    preferred_term: Post-inflammatory retinal dystrophy
    term:
      id: HP:0000556
      label: Retinal dystrophy
  evidence:
  - reference: PMID:19424698
    reference_title: "Post-inflammatory retinal dystrophy in CINCA syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A state of severe retinal dystrophy of post-inflammatory origin became evident on funduscopy, optical coherence tomography and visual electrophysiology tests at the age of 10 years, which remained stationary after 1 year of anakinra treatment."
    explanation: Case report documenting severe post-inflammatory retinal dystrophy in a CINCA patient that persisted despite anakinra, establishing retinal dystrophy as a distinct ocular complication beyond papilledema.
  - reference: PMID:27320017
    reference_title: "Autoinflammatory retinopathy in chronic infantile neurological cutaneous and articular (CINCA) syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We report the cases of monozygotic twins with CINCA syndrome whose predominant ocular manifestation was inflammatory rod-cone retinal dystrophy."
    explanation: Case report of monozygotic CINCA twins whose predominant ocular manifestation was inflammatory rod-cone retinal dystrophy, with phenotypic discordance between twins suggesting epigenetic/environmental modifiers.
- name: Macrocephaly
  description: >
    Macrocephaly is a frequent neurologic/head-size manifestation of CINCA/NOMID.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Macrocephaly
    term:
      id: HP:0000256
      label: Macrocephaly
  evidence:
  - reference: ORPHA:1451
    reference_title: "CINCA syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000256 | Macrocephaly | Frequent (79-30%)"
    explanation: Orphanet lists macrocephaly as a frequent CINCA syndrome phenotype.
- name: Visual impairment
  description: >
    Visual impairment is a frequent consequence of ocular and CNS inflammation in
    CINCA/NOMID.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Visual impairment
    term:
      id: HP:0000505
      label: Visual impairment
  evidence:
  - reference: ORPHA:1451
    reference_title: "CINCA syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000505 | Visual impairment | Frequent (79-30%)"
    explanation: Orphanet lists visual impairment as a frequent CINCA syndrome phenotype.
- name: Intellectual disability
  description: >
    Intellectual disability is an occasional neurologic outcome in CINCA/NOMID.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  evidence:
  - reference: ORPHA:1451
    reference_title: "CINCA syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001249 | Intellectual disability | Occasional (29-5%)"
    explanation: Orphanet lists intellectual disability as an occasional CINCA syndrome phenotype.
- name: Global developmental delay
  description: >
    Global developmental delay is an occasional neurodevelopmental phenotype in
    CINCA/NOMID.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: ORPHA:1451
    reference_title: "CINCA syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001263 | Global developmental delay | Occasional (29-5%)"
    explanation: Orphanet lists global developmental delay as an occasional CINCA syndrome phenotype.
- name: Abnormal joint morphology
  description: >
    Abnormal joint morphology is a frequent musculoskeletal phenotype reflecting
    destructive CINCA/NOMID arthropathy.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Abnormal joint morphology
    term:
      id: HP:0001367
      label: Abnormal joint morphology
  evidence:
  - reference: ORPHA:1451
    reference_title: "CINCA syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001367 | Abnormal joint morphology | Frequent (79-30%)"
    explanation: Orphanet lists abnormal joint morphology as a frequent CINCA syndrome phenotype.
- name: Joint dislocation
  description: >
    Joint dislocation is a frequent severe joint manifestation in CINCA/NOMID.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Joint dislocation
    term:
      id: HP:0001373
      label: Joint dislocation
  evidence:
  - reference: ORPHA:1451
    reference_title: "CINCA syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001373 | Joint dislocation | Frequent (79-30%)"
    explanation: Orphanet lists joint dislocation as a frequent CINCA syndrome phenotype.
- name: Abnormality of neutrophils
  description: >
    Abnormality of neutrophils is a very frequent cellular inflammatory phenotype.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Abnormality of neutrophils
    term:
      id: HP:0001874
      label: Abnormality of neutrophils
  evidence:
  - reference: ORPHA:1451
    reference_title: "CINCA syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001874 | Abnormality of neutrophils | Very frequent (99-80%)"
    explanation: Orphanet lists abnormality of neutrophils as a very frequent CINCA syndrome phenotype.
- name: Leukocytosis
  description: >
    Leukocytosis is a frequent blood inflammatory phenotype in CINCA/NOMID.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Leukocytosis
    term:
      id: HP:0001974
      label: Increased total leukocyte count
  evidence:
  - reference: ORPHA:1451
    reference_title: "CINCA syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001974 | Leukocytosis | Frequent (79-30%)"
    explanation: Orphanet lists leukocytosis as a frequent CINCA syndrome phenotype.
- name: Arthralgia
  description: >
    Arthralgia is a very frequent joint-pain manifestation of CINCA/NOMID.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Arthralgia
    term:
      id: HP:0002829
      label: Arthralgia
  evidence:
  - reference: ORPHA:1451
    reference_title: "CINCA syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002829 | Arthralgia | Very frequent (99-80%)"
    explanation: Orphanet lists arthralgia as a very frequent CINCA syndrome phenotype.
- name: Myalgia
  description: >
    Myalgia is a very frequent systemic pain manifestation of CINCA/NOMID.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Myalgia
    term:
      id: HP:0003326
      label: Myalgia
  evidence:
  - reference: ORPHA:1451
    reference_title: "CINCA syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0003326 | Myalgia | Very frequent (99-80%)"
    explanation: Orphanet lists myalgia as a very frequent CINCA syndrome phenotype.
histopathology:
- name: Neutrophilic urticarial dermatosis
  description: >
    Skin biopsy of the characteristic rash reveals a perivascular and
    interstitial neutrophilic infiltrate in the dermis, with neutrophils
    surrounding eccrine sweat glands. Unlike true urticaria, there is no
    mast cell degranulation, dermal edema is minimal, and eosinophils
    are absent. This neutrophilic pattern is consistent across the CAPS
    spectrum and helps distinguish CINCA/NOMID rash from allergic
    urticaria and other neutrophilic dermatoses.
  finding_term:
    preferred_term: Intramucosal Neutrophilic Infiltrate
    term:
      id: NCIT:C96187
      label: Intramucosal Neutrophilic Infiltrate
  diagnostic: true
  evidence:
  - reference: PMID:31077002
    reference_title: "CAPS and NLRP3."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Cryopyrin-associated periodic syndrome (CAPS) is a rare inherited autoinflammatory disorder characterized by systemic, cutaneous, musculoskeletal, and central nervous system inflammation."
    explanation: Review characterizing CAPS cutaneous involvement as a systemic neutrophilic process, with skin biopsy showing neutrophilic dermatosis rather than mast cell-mediated urticaria.
- name: Chronic leptomeningeal inflammatory infiltrate
  description: >
    CSF and meningeal examination reveals chronic inflammatory
    infiltrate with neutrophilic predominance in early/active disease
    and lymphoplasmacytic infiltrate in more chronic phases.
    Leptomeningeal enhancement on MRI corresponds to this
    inflammatory infiltrate. CSF shows pleocytosis (predominantly
    polymorphonuclear), elevated protein, and sometimes
    hypoglycorrhachia.
  finding_term:
    preferred_term: Chronic Inflammatory Infiltrate
    term:
      id: NCIT:C35980
      label: Chronic Inflammatory Infiltrate
  evidence:
  - reference: PMID:16899778
    reference_title: "Neonatal-onset multisystem inflammatory disease responsive to interleukin-1beta inhibition."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Magnetic resonance imaging showed improvement in cochlear and leptomeningeal lesions as compared with baseline."
    explanation: NEJM trial documenting leptomeningeal inflammatory lesions on MRI in NOMID patients corresponding to the chronic meningeal inflammatory infiltrate.
  - reference: PMID:34059097
    reference_title: "Necrotizing Funisitis as an Intrauterine manifestation of Cryopyrin-Associated Periodic Syndrome: a case report and review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the examination of the cerebrospinal fluid (CSF) showed a WBC cell count of 667 /µL (polymorphonuclear: mononuclear 4:1), glucose at 21 mg/dL, and protein at 191 mg/dL"
    explanation: Neonatal case documenting severe neutrophilic CSF pleocytosis (667 cells, 4:1 PMN predominance) with hypoglycorrhachia and elevated protein, reflecting the intense chronic meningeal inflammatory infiltrate.
- name: Necrotizing funisitis
  description: >
    Histopathological examination of the umbilical cord in neonates
    with CINCA/NOMID reveals necrotizing funisitis, characterized by
    rings of karyorrhectic debris with neutrophilic infiltrate in
    Wharton's jelly oriented toward the amniotic surface. This
    finding demonstrates intrauterine onset of IL-1beta-driven
    inflammation and may be the earliest histopathological
    manifestation of the disease.
  finding_term:
    preferred_term: Necrotic Lesion
    term:
      id: NCIT:C36123
      label: Necrotic Lesion
  context: Umbilical cord and placenta at birth
  evidence:
  - reference: PMID:34059097
    reference_title: "Necrotizing Funisitis as an Intrauterine manifestation of Cryopyrin-Associated Periodic Syndrome: a case report and review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These evidences suggest that foetal inflammation, probably due to overproduction of IL-1β, caused tissue damage in utero, and the first symptom of a newborn with CINCA/NOMID."
    explanation: Case report with histopathological documentation of necrotizing funisitis as evidence of intrauterine inflammatory damage in CINCA/NOMID.
  - reference: PMID:38808101
    reference_title: "Case Report: A neonatal case of cryopyrin-associated periodic syndrome with severe funisitis and neonatal asphyxia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Histopathologic examination of the placenta and umbilical cord can provide crucial insights into the intrauterine onset of inflammation, which is the first manifestation of CINCA syndrome/NOMID in newborns."
    explanation: Case report documenting severe necrotizing funisitis with umbilical cord rupture, confirming the diagnostic value of placental histopathology in neonatal CINCA/NOMID.
- name: AA amyloid deposition
  description: >
    In patients with long-standing uncontrolled inflammation, biopsy
    of the kidney or other organs may reveal AA amyloid deposits.
    Congo red staining shows apple-green birefringence under
    polarized light. Amyloid deposition preferentially affects the
    renal glomeruli, causing progressive proteinuria and nephrotic
    syndrome. Early and sustained IL-1 blockade prevents this
    complication by normalizing serum amyloid A levels.
  finding_term:
    preferred_term: Amyloid Deposition
    term:
      id: NCIT:C54018
      label: Amyloid Deposition
  context: Kidney, gastrointestinal tract, and other organs in undertreated patients
  evidence:
  - reference: PMID:16899778
    reference_title: "Neonatal-onset multisystem inflammatory disease responsive to interleukin-1beta inhibition."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "serum amyloid A (from a median of 174 mg to 8 mg per liter), C-reactive protein (from a median of 5.29 mg to 0.34 mg per deciliter), and the erythrocyte sedimentation rate decreased at month 3"
    explanation: NEJM trial documenting markedly elevated baseline serum amyloid A (median 174 mg/L, >17x upper limit of normal) as the precursor protein for AA amyloid deposits, which normalized with anakinra.
biochemical:
- name: Serum amyloid A
  presence: ELEVATED
  context: Median 174 mg/L at baseline (normal <10 mg/L), normalizes with anakinra
  biomarker_term:
    preferred_term: Serum Amyloid A
    term:
      id: NCIT:C105940
      label: Serum Amyloid A
  reference_ranges:
  - loinc_term:
      id: LOINC:48498-0
      label: Amyloid A [Mass/volume] in Serum or Plasma
    upper_bound: 11.0
    unit: mg/L
    population: healthy adults
    evidence:
    - reference: PMID:31724213
      reference_title: "Distribution of serum amyloid A and establishment of reference intervals in healthy adults."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "the population reference interval for SAA was established as an upper limit of 11.0 mg/L"
      explanation: General-population SAA reference interval (one-sided upper limit 11.0 mg/L) established in 2365 healthy adults; the CINCA/NOMID baseline median of 174 mg/L is roughly 16x this upper reference limit.
    notes: "An additional ELISA-based healthy-subject SAA reference study (Carbone et al., 2021, DOI:10.1080/15321819.2020.1837160) is available; exact cutoffs vary with assay methodology, so laboratory-specific reference intervals should be used."
    interpretation_bands:
    - name: Normal
      upper_bound: 11.0
      unit: mg/L
      abnormal_flag: NORMAL
    - name: Elevated
      lower_bound: 11.0
      unit: mg/L
      abnormal_flag: HIGH
      interpretation: SAA above the general-population upper reference limit indicates an acute-phase/inflammatory state; in CINCA/NOMID the baseline is markedly elevated (median 174 mg/L) and normalizes with IL-1 blockade.
  evidence:
  - reference: PMID:16899778
    reference_title: "Neonatal-onset multisystem inflammatory disease responsive to interleukin-1beta inhibition."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "serum amyloid A (from a median of 174 mg to 8 mg per liter), C-reactive protein (from a median of 5.29 mg to 0.34 mg per deciliter), and the erythrocyte sedimentation rate decreased at month 3"
    explanation: NEJM trial documenting markedly elevated baseline SAA (median 174 mg/L) in NOMID patients which normalized rapidly with anakinra, establishing SAA as a key disease activity biomarker.
- name: C-reactive protein
  presence: ELEVATED
  context: Median 5.29 mg/dL at baseline, normalizes with anakinra
  biomarker_term:
    preferred_term: C-Reactive Protein
    term:
      id: NCIT:C60651
      label: C-Reactive Protein
  reference_ranges:
  - loinc_term:
      id: LOINC:1988-5
      label: C reactive protein [Mass/volume] in Serum or Plasma
    upper_bound: 10.0
    unit: mg/L
    population: adults
    notes: "Conventional (non-high-sensitivity) CRP upper reference is approximately 10 mg/L (about 1.0 mg/dL); source: StatPearls, C-Reactive Protein (NCBI Bookshelf NBK441843). The CINCA/NOMID baseline median of 5.29 mg/dL (52.9 mg/L) is roughly 5x this upper reference limit and normalizes with IL-1 blockade."
  - loinc_term:
      id: LOINC:30522-7
      label: C reactive protein [Mass/volume] in Serum or Plasma by High sensitivity method
    upper_bound: 1.0
    unit: mg/L
    population: adults (high-sensitivity CRP cardiovascular risk stratification, general population)
    evidence:
    - reference: DOI:10.1093/eurheartj/ehaf937
      reference_title: "C-reactive protein and cardiovascular risk in the general population"
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "These data confirm hsCRP as a clinically relevant predictor of CV events in individuals without known ASCVD and support its assessment in primary prevention."
      explanation: UK Biobank population study (448,653 participants, median hs-CRP 1.32 mg/L) supporting the established high-sensitivity CRP cardiovascular risk tiers.
    interpretation_bands:
    - name: Low cardiovascular risk
      upper_bound: 1.0
      unit: mg/L
      abnormal_flag: NORMAL
      interpretation: hs-CRP below 1 mg/L corresponds to lower relative cardiovascular risk.
    - name: Average cardiovascular risk
      lower_bound: 1.0
      upper_bound: 3.0
      unit: mg/L
      abnormal_flag: HIGH
      severity: MILD
      interpretation: hs-CRP 1-3 mg/L corresponds to average cardiovascular risk.
    - name: High cardiovascular risk
      lower_bound: 3.0
      unit: mg/L
      abnormal_flag: HIGH
      severity: MODERATE
      interpretation: hs-CRP above 3 mg/L conferred a 34% higher risk of major adverse cardiovascular events versus below 1 mg/L in the UK Biobank cohort (Kurt et al., 2025).
  evidence:
  - reference: PMID:16899778
    reference_title: "Neonatal-onset multisystem inflammatory disease responsive to interleukin-1beta inhibition."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "serum amyloid A (from a median of 174 mg to 8 mg per liter), C-reactive protein (from a median of 5.29 mg to 0.34 mg per deciliter), and the erythrocyte sedimentation rate decreased at month 3"
    explanation: NEJM trial documenting elevated CRP (median 5.29 mg/dL) in NOMID patients which decreased to 0.34 mg/dL with anakinra, confirming CRP as a reliable inflammatory marker.
  - reference: PMID:38481988
    reference_title: "Clinical and Genetic Spectrum of Nine Cases of NLRP3-Associated Autoinflammatory Disease (NLRP3-AID) and Identification of One Novel NLRP3 Mutation by Genetic Variation Analyses."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "During acute attack, white blood cell, C-reactive protein, and/or erythrocyte sedimentation rate all increased in all cases, and inflammatory markers remained elevated beyond 7 days postfever resolution in 57.1% of patients (4/7)."
    explanation: Chinese cohort confirming universal CRP elevation during flares in NLRP3-AID patients, with persistent elevation in over half of patients even after fever resolution.
  - reference: PMID:34059097
    reference_title: "Necrotizing Funisitis as an Intrauterine manifestation of Cryopyrin-Associated Periodic Syndrome: a case report and review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The blood examination at birth revealed CRP at 6.4 mg/dL"
    explanation: Neonatal case documenting markedly elevated CRP (6.4 mg/dL, rising to 15 mg/dL) at birth despite absence of infection, confirming intrauterine inflammatory activation.
- name: Erythrocyte sedimentation rate
  presence: ELEVATED
  context: Markedly elevated, normalizes with anakinra
  biomarker_term:
    preferred_term: Erythrocyte Sedimentation Rate Measurement
    term:
      id: NCIT:C74611
      label: Erythrocyte Sedimentation Rate Measurement
  evidence:
  - reference: PMID:16899778
    reference_title: "Neonatal-onset multisystem inflammatory disease responsive to interleukin-1beta inhibition."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "serum amyloid A (from a median of 174 mg to 8 mg per liter), C-reactive protein (from a median of 5.29 mg to 0.34 mg per deciliter), and the erythrocyte sedimentation rate decreased at month 3"
    explanation: NEJM trial documenting elevated ESR in NOMID patients which decreased with anakinra at month 3 and remained low at month 6.
  - reference: PMID:38481988
    reference_title: "Clinical and Genetic Spectrum of Nine Cases of NLRP3-Associated Autoinflammatory Disease (NLRP3-AID) and Identification of One Novel NLRP3 Mutation by Genetic Variation Analyses."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "During acute attack, white blood cell, C-reactive protein, and/or erythrocyte sedimentation rate all increased in all cases"
    explanation: Chinese cohort confirming universal ESR elevation during acute attacks across all 9 NLRP3-AID patients.
diagnosis:
- name: Clinical assessment
  description: >
    Diagnosis is suspected based on the triad of neonatal-onset
    urticarial rash, chronic meningitis, and arthropathy. Elevated
    acute phase reactants (ESR, CRP, serum amyloid A) and
    leukocytosis with neutrophilia support the diagnosis. CSF
    analysis shows aseptic meningitis with pleocytosis.
  evidence:
  - reference: PMID:16899778
    reference_title: "Neonatal-onset multisystem inflammatory disease responsive to interleukin-1beta inhibition."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Diary scores improved (P<0.001) and serum amyloid A (from a median of 174 mg to 8 mg per liter), C-reactive protein (from a median of 5.29 mg to 0.34 mg per deciliter), and the erythrocyte sedimentation rate decreased at month 3"
    explanation: NEJM trial quantifying the characteristic laboratory abnormalities in NOMID (markedly elevated SAA, CRP, ESR) that support clinical diagnosis and serve as biomarkers for disease activity.
- name: Genetic testing for NLRP3 mutations
  description: >
    Confirmatory diagnosis by identification of heterozygous
    gain-of-function NLRP3 mutations. Standard Sanger sequencing
    detects mutations in approximately 50-60% of cases. Deep
    sequencing or next-generation sequencing can detect somatic
    mosaicism with variant allele fractions as low as 1.3% in
    some mutation-negative cases. Clinical diagnosis should not be
    delayed pending genetic confirmation when the clinical picture
    is highly suggestive.
  diagnosis_term:
    preferred_term: genetic testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  evidence:
  - reference: PMID:37809096
    reference_title: "The genetic and clinical characteristics and effects of Canakinumab on cryopyrin-associated periodic syndrome: a large pediatric cohort study from China."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The patients harbored 19 substitutions in NLRP3, and 8 of them were novel mutations."
    explanation: Large pediatric CAPS cohort identifying 19 NLRP3 variants including 8 novel mutations through genetic testing, with functional confirmation via inflammasome activation assays.
  - reference: PMID:11687797
    reference_title: "Mutation of a new gene encoding a putative pyrin-like protein causes familial cold autoinflammatory syndrome and Muckle-Wells syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we screened exons in the 1q44 region for mutations by direct sequencing of genomic DNA from affected individuals and controls. This resulted in the identification of four distinct mutations in a gene that segregated with the disorder"
    explanation: Original gene identification study establishing sequencing of CIAS1/NLRP3 as the definitive diagnostic test for CAPS.
  - reference: PMID:38720945
    reference_title: "Case Report: Efficacy, safety, and favorable long-term outcome of early treatment with IL-1 inhibitors in a patient with chronic infantile neurological cutaneous articular (CINCA) syndrome caused by NLRP3 mosaicism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "this case highlights the importance of early diagnosis of CINCA patients when the clinical and laboratory picture is highly suggestive in order to start the appropriate anti-cytokine treatment even in the absence of a genetic confirmation."
    explanation: Case report emphasizing that treatment should not be withheld pending genetic confirmation, as initial testing may miss somatic mosaicism detectable only by advanced sequencing.
  - reference: PMID:37548074
    reference_title: "Subdural hemorrhage, macrocephaly, rash, and developmental delay in an infant: A pathogenic variant in NLRP3 causes CINCA/NOMID."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Clinical trio exome sequencing identified a de novo likely pathogenic variant in NLRP3, which is associated with chronic infantile neurological, cutaneous, and articular (CINCA) syndrome"
    explanation: Case illustrating the diagnostic utility of trio exome sequencing in identifying de novo NLRP3 variants, especially when clinical presentation initially mimics other conditions such as abusive head trauma.
  - reference: PMID:40538939
    reference_title: "Somatic NLRP3 mosaicism in patients with \"mutation-negative\" CAPS: insights from a single centre UK cohort."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "TGPs identified 4/4 cases of mosaicism whilst WES detected only 1/3."
    explanation: UK cohort demonstrating that targeted gene panels outperform whole-exome sequencing for detecting somatic mosaicism, and that amplicon-based deep sequencing is the most sensitive method for low-level mosaicism (MAF 3.1-14.5%).
treatments:
- name: IL-1 inhibition with anakinra
  description: >
    Anakinra (recombinant IL-1 receptor antagonist) is the first-line
    treatment. Daily subcutaneous injections rapidly suppress
    inflammation, rash, fever, and normalize inflammatory markers.
    Early treatment can prevent or stabilize neurological damage
    including hearing loss, cognitive impairment, and papilledema.
    MRI-visible cochlear and leptomeningeal lesions improve with
    treatment.
  context: First-line therapy
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: Anakinra
      term:
        id: NCIT:C38717
        label: Anakinra
  target_phenotypes:
  - preferred_term: Recurrent fever
    term:
      id: HP:0001954
      label: Recurrent fever
  - preferred_term: Urticaria
    term:
      id: HP:0001025
      label: Urticaria
  evidence:
  - reference: PMID:16899778
    reference_title: "Neonatal-onset multisystem inflammatory disease responsive to interleukin-1beta inhibition."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All 18 patients had a rapid response to anakinra, with disappearance of rash. Diary scores improved (P<0.001) and serum amyloid A (from a median of 174 mg to 8 mg per liter), C-reactive protein (from a median of 5.29 mg to 0.34 mg per deciliter), and the erythrocyte sedimentation rate decreased at month 3 (all P<0.001), and remained low at month 6."
    explanation: Landmark NEJM trial of 18 NOMID patients demonstrating rapid and sustained response to anakinra with normalization of inflammatory markers and improvement of MRI-documented cochlear and leptomeningeal lesions.
  - reference: PMID:38720945
    reference_title: "Case Report: Efficacy, safety, and favorable long-term outcome of early treatment with IL-1 inhibitors in a patient with chronic infantile neurological cutaneous articular (CINCA) syndrome caused by NLRP3 mosaicism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "After a 12-year follow-up, the patient has not experienced chronic complications."
    explanation: Case report demonstrating that early initiation of IL-1 inhibition (anakinra followed by canakinumab) in a CINCA patient with somatic mosaicism prevented development of chronic sequelae over 12 years of follow-up.
- name: IL-1 inhibition with canakinumab
  description: >
    Canakinumab (anti-IL-1beta monoclonal antibody) provides sustained
    IL-1 blockade with less frequent dosing (every 4-8 weeks
    subcutaneously). Effective for long-term disease control across
    musculoskeletal, neurological, auditory, and visual domains in
    CINCA/NOMID.
  context: Long-acting IL-1 blockade
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: Canakinumab
      term:
        id: NCIT:C80971
        label: Canakinumab
  target_phenotypes:
  - preferred_term: Recurrent fever
    term:
      id: HP:0001954
      label: Recurrent fever
  - preferred_term: Arthropathy
    term:
      id: HP:0003040
      label: Arthropathy
  evidence:
  - reference: PMID:37809096
    reference_title: "The genetic and clinical characteristics and effects of Canakinumab on cryopyrin-associated periodic syndrome: a large pediatric cohort study from China."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Ten patients received Canakinumab treatment, which proved effective at alleviating musculoskeletal, neurological, auditory, visual manifestations, fever, and rash for 10-20 months follow-up."
    explanation: Pediatric CAPS cohort demonstrating canakinumab efficacy across multiple organ domains over 10-20 months, while non-IL-1 therapies achieved only partial remission.
  - reference: PMID:34059097
    reference_title: "Necrotizing Funisitis as an Intrauterine manifestation of Cryopyrin-Associated Periodic Syndrome: a case report and review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "treatment with recombinant anti- human IL-1β monoclonal antibody (canakinumab) was started at a dose of 2.5 mg/kg. The rash immediately disappeared, and inflammatory markers slightly decreased after the first administration."
    explanation: Neonatal case demonstrating rapid clinical response to canakinumab at 70 days of age, with immediate rash disappearance and gradual improvement of cholestasis, supporting early canakinumab use in severe neonatal CINCA.
- name: IL-1 inhibition with rilonacept
  description: >
    Rilonacept (IL-1 Trap, a soluble decoy receptor) is another IL-1
    inhibitor approved for CAPS. Administered weekly by subcutaneous
    injection. Captures both IL-1alpha and IL-1beta.
  context: Alternative IL-1 blockade
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: Rilonacept
      term:
        id: NCIT:C84137
        label: Rilonacept
  target_phenotypes:
  - preferred_term: Recurrent fever
    term:
      id: HP:0001954
      label: Recurrent fever
  evidence:
  - reference: PMID:40370685
    reference_title: "Comprehensive Clinical Analysis of Rilonacept in the Treatment of Cryopyrin-Associated Periodic Syndromes: A Systematic Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Treatment with rilonacept resulted in a reduction of approximately two points in key symptom scores for patients, with significant improvements in all outcome measures such as the number of flare days and high-sensitivity C-reactive protein levels."
    explanation: Systematic review of rilonacept in CAPS (including two sequential randomized controlled trials) showing significant reductions in symptom scores, flare days, and hs-CRP, directly supporting rilonacept efficacy.
  - reference: PMID:31643801
    reference_title: "Rilonacept."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Rilonacept is a recombinant interleukin-1 (IL-1) antagonist which is used in the therapy of cryopyrin-associated periodic syndromes (CAPS) and other autoinflammatory conditions."
    explanation: Drug monograph confirming rilonacept as a recombinant IL-1 antagonist indicated for CAPS.
- name: Genetic counseling
  description: >
    Genetic counseling is recommended for affected families. Most
    CINCA/NOMID cases arise from de novo mutations, but germline
    transmission is possible. Assessment of recurrence risk, somatic
    mosaicism implications, and reproductive options should be
    discussed.
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:11687797
    reference_title: "Mutation of a new gene encoding a putative pyrin-like protein causes familial cold autoinflammatory syndrome and Muckle-Wells syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This resulted in the identification of four distinct mutations in a gene that segregated with the disorder in three families with FCAS and one family with MWS."
    explanation: Original identification of CIAS1/NLRP3 mutations segregating in families, establishing the basis for genetic counseling about inheritance patterns in CAPS.
prevalence:
- population: General population
  notes: >
    CINCA/NOMID is extremely rare, with an estimated prevalence of
    less than 1 per 1,000,000. It is the most severe phenotype within
    the CAPS spectrum.
  evidence:
  - reference: PMID:31077002
    reference_title: "CAPS and NLRP3."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Cryopyrin-associated periodic syndrome (CAPS) is a rare inherited autoinflammatory disorder characterized by systemic, cutaneous, musculoskeletal, and central nervous system inflammation."
    explanation: Review establishing CAPS as a rare inherited disorder, with CINCA/NOMID representing the most severe and rarest end of the spectrum.
genetic:
- name: NLRP3
  gene_term:
    preferred_term: NLRP3
    term:
      id: hgnc:16400
      label: NLRP3
  association: Causative
  notes: >
    Caused by heterozygous gain-of-function mutations in NLRP3 (also
    known as CIAS1 or NALP3), encoding cryopyrin. Over 170
    disease-associated NLRP3 variants have been reported across the
    CAPS spectrum. Most CINCA mutations are de novo. Somatic mosaicism
    with variant allele fractions as low as 1.3% is present in a
    subset of mutation-negative cases.
  presence: PRESENT
  inheritance:
  - name: Autosomal dominant
  evidence:
  - reference: PMID:11687797
    reference_title: "Mutation of a new gene encoding a putative pyrin-like protein causes familial cold autoinflammatory syndrome and Muckle-Wells syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This resulted in the identification of four distinct mutations in a gene that segregated with the disorder in three families with FCAS and one family with MWS."
    explanation: Original identification of CIAS1/NLRP3 as the causative gene for CAPS by Hoffman et al. 2001.
  - reference: PMID:37809096
    reference_title: "The genetic and clinical characteristics and effects of Canakinumab on cryopyrin-associated periodic syndrome: a large pediatric cohort study from China."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The patients harbored 19 substitutions in NLRP3, and 8 of them were novel mutations."
    explanation: Large pediatric cohort expanding the NLRP3 mutation spectrum with 8 novel variants, including documentation of somatic mosaicism (F311V).
inheritance:
- name: Autosomal dominant
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  penetrance: COMPLETE
  expressivity: VARIABLE
  de_novo_rate: ">80"
  description: >
    CINCA syndrome follows autosomal dominant inheritance with
    complete penetrance but variable expressivity across the CAPS
    spectrum. The majority of cases (>80%) arise from de novo
    mutations. Somatic mosaicism is recognized in a subset of
    clinically affected individuals who test negative by
    conventional sequencing, with variant allele fractions ranging
    from 1.3% to 34.8%.
  evidence:
  - reference: PMID:11687797
    reference_title: "Mutation of a new gene encoding a putative pyrin-like protein causes familial cold autoinflammatory syndrome and Muckle-Wells syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Familial cold autoinflammatory syndrome (FCAS, MIM 120100), commonly known as familial cold urticaria (FCU), is an autosomal-dominant systemic inflammatory disease"
    explanation: Original study establishing autosomal dominant inheritance for the CAPS spectrum caused by CIAS1/NLRP3 mutations.
  - reference: PMID:38808101
    reference_title: "Case Report: A neonatal case of cryopyrin-associated periodic syndrome with severe funisitis and neonatal asphyxia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The father carried a genetic mutation associated with CINCA syndrome/NOMID (NLRP3 c.2068G>A p.Glu690Lys Hetero), which was also found in the child."
    explanation: Case documenting paternal transmission of NLRP3 mutation to a child with CINCA/NOMID, confirming autosomal dominant inheritance in the minority of familial (non-de novo) cases.
  - reference: PMID:41026232
    reference_title: "Novel Insights into the Clinical Features, Genetic Spectrum and Clonal Evolution of Patients Carrying NLRP3 Mosaicism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "clinical manifestations, analytical results, and outcomes of treatments were markedly similar to those detected in patients with germline variants."
    explanation: Largest NLRP3 mosaicism cohort confirming that clinical presentation and treatment response are similar between mosaic and germline cases, with an overrepresentation of late-onset forms (37.5%) and myeloid-restricted mosaicism in late-onset patients.
environmental:
- name: Cold exposure
  description: >
    Cold temperatures can trigger or exacerbate disease flares,
    including urticarial rash, fever, and joint symptoms. This is
    a shared feature across the CAPS spectrum, though in CINCA/NOMID
    symptoms are often continuous rather than purely cold-triggered.
  effect: TRIGGERING
  evidence:
  - reference: PMID:11687797
    reference_title: "Mutation of a new gene encoding a putative pyrin-like protein causes familial cold autoinflammatory syndrome and Muckle-Wells syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Familial cold autoinflammatory syndrome (FCAS, MIM 120100), commonly known as familial cold urticaria (FCU), is an autosomal-dominant systemic inflammatory disease characterized by intermittent episodes of rash, arthralgia, fever and conjunctivitis after generalized exposure to cold."
    explanation: Original gene identification paper establishing cold exposure as a trigger across the CAPS spectrum, with FCAS being the most cold-sensitive phenotype.
differential_diagnoses:
- name: Muckle-Wells syndrome
  description: >
    Another CAPS phenotype caused by NLRP3 mutations but with
    intermediate severity. Presents with urticarial rash, episodic
    fever, arthralgia, and progressive sensorineural hearing loss,
    but lacks the chronic meningitis and bony overgrowth
    characteristic of CINCA/NOMID.
  disease_term:
    preferred_term: Muckle-Wells syndrome
    term:
      id: MONDO:0008633
      label: Muckle-Wells syndrome
  evidence:
  - reference: PMID:11687797
    reference_title: "Mutation of a new gene encoding a putative pyrin-like protein causes familial cold autoinflammatory syndrome and Muckle-Wells syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Muckle-Wells syndrome (MWS; MIM 191900), which also maps to chromosome 1q44, is an autosomal-dominant periodic fever syndrome with a similar phenotype except that symptoms are not precipitated by cold exposure and that sensorineural hearing loss is frequently also present."
    explanation: Original description of MWS sharing the NLRP3 genetic basis with FCAS, establishing the CAPS spectrum and the need to differentiate MWS from CINCA/NOMID by severity.
- name: Familial cold autoinflammatory syndrome
  description: >
    The mildest CAPS phenotype, presenting with cold-triggered
    urticarial episodes, fever, and arthralgia lasting less than 24
    hours. No neurological or skeletal involvement. Also caused by
    NLRP3 mutations.
  disease_term:
    preferred_term: Familial cold autoinflammatory syndrome 1
    term:
      id: MONDO:0007349
      label: familial cold autoinflammatory syndrome 1
  evidence:
  - reference: PMID:11687797
    reference_title: "Mutation of a new gene encoding a putative pyrin-like protein causes familial cold autoinflammatory syndrome and Muckle-Wells syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Familial cold autoinflammatory syndrome (FCAS, MIM 120100), commonly known as familial cold urticaria (FCU), is an autosomal-dominant systemic inflammatory disease characterized by intermittent episodes of rash, arthralgia, fever and conjunctivitis after generalized exposure to cold."
    explanation: Original identification of CIAS1/NLRP3 mutations in FCAS families, establishing it as the mildest CAPS phenotype distinguished from CINCA by episodic cold-triggered symptoms only.
- name: Systemic juvenile idiopathic arthritis
  description: >
    Presents with quotidian fever, evanescent rash, and arthritis in
    childhood. Distinguished from CINCA by age of onset (typically
    after 6 months), different rash character (evanescent
    salmon-colored rather than persistent neutrophilic urticaria),
    absence of chronic meningitis and bony overgrowth, and negative
    NLRP3 genetic testing.
  disease_term:
    preferred_term: Juvenile idiopathic arthritis
    term:
      id: MONDO:0011429
      label: juvenile idiopathic arthritis
  evidence:
  - reference: PMID:37809096
    reference_title: "The genetic and clinical characteristics and effects of Canakinumab on cryopyrin-associated periodic syndrome: a large pediatric cohort study from China."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients treated with prednisolone or prednisolone plus thalidomide or methotrexate, tocilizumab, TNF inhibiting agents, and sirolimus achieved only partial remission."
    explanation: Pediatric cohort showing that non-IL-1 therapies commonly used for systemic JIA (prednisolone, methotrexate, tocilizumab) achieved only partial remission in CAPS, helping to distinguish CINCA from sJIA by differential treatment response.
datasets:
- accession: geo:GSE43553
  title: >
    Microarray-based gene expression profiling in patients with
    cryopyrin-associated periodic syndromes defines a disease-related
    signature and IL-1-responsive transcripts
  description: >-
    Gene expression microarray profiling of 16 CAPS patients before
    and after anakinra treatment, compared to healthy controls. Defines
    a CAPS-specific gene expression signature including transcripts
    related to innate and adaptive immune responses, oxidative stress,
    cell death, and cell adhesion.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: MICROARRAY
  sample_types:
  - preferred_term: peripheral blood
    tissue_term:
      preferred_term: blood
      term:
        id: UBERON:0000178
        label: blood
  sample_count: 100
  conditions:
  - CAPS patients pre-treatment
  - CAPS patients post-anakinra
  - healthy controls
  evidence:
  - reference: GEO:GSE43553
    supports: SUPPORT
    snippet: "We identified a gene expression signature that clearly distinguished CAPS patients from controls. A number of DEG were in common with other systemic inflammatory diseases such as systemic onset juvenile idiopathic arthritis."
    explanation: Defines a CAPS-specific transcriptomic signature and identifies IL-1-responsive genes, relevant to understanding the molecular pathology of CINCA/NOMID.
- accession: geo:GSE38626
  title: >
    Induced pluripotent stem cells from CINCA syndrome patients as a
    model for dissecting somatic mosaicism and drug discovery
  description: >-
    iPSC lines generated from two CINCA syndrome patients with somatic
    NLRP3 mosaicism, differentiated into macrophages. Demonstrates
    that mutant iPSC-derived macrophages show abnormal IL-1beta
    secretion and can serve as a drug screening platform.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: MICROARRAY
  publication: PMID:22723549
  sample_count: 15
  conditions:
  - NLRP3-mutant iPSC-derived macrophages
  - non-mutant iPSC-derived macrophages
  evidence:
  - reference: GEO:GSE38626
    supports: SUPPORT
    snippet: "We found that mutant cells are predominantly responsible for the pathogenesis in these mosaic patients because only mutant iPS-MPs showed the disease relevant phenotype of abnormal IL-1β secretion."
    explanation: Directly relevant to CINCA somatic mosaicism pathogenesis, demonstrating that NLRP3-mutant cells drive the inflammatory phenotype and providing a platform for drug discovery.
clinical_trials:
- name: NCT00069329
  description: >
    NIH-sponsored long-term study evaluating anakinra (Kineret) for
    NOMID/CINCA syndrome. This landmark trial demonstrated rapid and
    sustained efficacy of IL-1 receptor antagonism for controlling
    systemic inflammation, rash, fever, and CNS disease.
  phase: PHASE_II
  status: TERMINATED
  target_phenotypes:
  - preferred_term: Urticaria
    term:
      id: HP:0001025
      label: Urticaria
  - preferred_term: Meningitis
    term:
      id: HP:0001287
      label: Meningitis
  - preferred_term: Arthropathy
    term:
      id: HP:0003040
      label: Arthropathy
  - preferred_term: Papilledema
    term:
      id: HP:0001085
      label: Papilledema
  evidence:
  - reference: clinicaltrials:NCT00069329
    supports: SUPPORT
    snippet: "This study will evaluate the safety and effectiveness of anakinra (Kineret) for treating patients with neonatal-onset multisystem inflammatory disease (NOMID), also known as chronic infantile neurological, cutaneous and arthropathy (CINCA) syndrome."
    explanation: Landmark NIH trial establishing anakinra as effective therapy for NOMID/CINCA, forming the basis for the published NEJM results (PMID:16899778).
- name: NCT00770601
  description: >
    Multi-center, open-label, 24-month study evaluating canakinumab
    (anti-IL-1beta antibody) safety, tolerability, efficacy, and
    pharmacokinetics specifically in NOMID/CINCA patients aged 2 years
    and older. Included lumbar puncture, MRI, and cognitive evaluations.
  phase: PHASE_III
  status: TERMINATED
  target_phenotypes:
  - preferred_term: Recurrent fever
    term:
      id: HP:0001954
      label: Recurrent fever
  - preferred_term: Urticaria
    term:
      id: HP:0001025
      label: Urticaria
  - preferred_term: Meningitis
    term:
      id: HP:0001287
      label: Meningitis
  evidence:
  - reference: clinicaltrials:NCT00770601
    supports: SUPPORT
    snippet: "This study will examine whether a medicine called canakinumab is safe and effective for treating patients with neonatal-onset multisystem inflammatory disease (NOMID), also known as chronic infantile neurologic, cutaneous, articular (CINCA) syndrome."
    explanation: NOMID/CINCA-specific canakinumab trial with comprehensive CNS outcome measures including lumbar puncture and MRI.
- name: NCT00685373
  description: >
    Open-label, long-term safety and efficacy study of canakinumab
    (ACZ885) in patients with CAPS including NOMID. Subcutaneous
    injection for at least 6 months with extension up to 2 years.
  phase: PHASE_III
  status: COMPLETED
  target_phenotypes:
  - preferred_term: Recurrent fever
    term:
      id: HP:0001954
      label: Recurrent fever
  - preferred_term: Urticaria
    term:
      id: HP:0001025
      label: Urticaria
  evidence:
  - reference: clinicaltrials:NCT00685373
    supports: SUPPORT
    snippet: "newly identified patients with the following cryopyrin-associated periodic syndromes: Familial Cold Autoinflammatory Syndrome, Muckle-Wells Syndrome or Neonatal Onset Multisystem Inflammatory Disease."
    explanation: Long-term canakinumab safety and efficacy data in CAPS patients including those with NOMID.
- name: NCT01302860
  description: >
    One-year open-label trial of canakinumab in pediatric CAPS
    patients aged 4 years and younger, including those with NOMID.
    Also evaluated safety of childhood vaccinations during canakinumab
    treatment.
  phase: PHASE_III
  status: COMPLETED
  target_phenotypes:
  - preferred_term: Recurrent fever
    term:
      id: HP:0001954
      label: Recurrent fever
  - preferred_term: Urticaria
    term:
      id: HP:0001025
      label: Urticaria
  evidence:
  - reference: clinicaltrials:NCT01302860
    supports: SUPPORT
    snippet: "This trial will assess the safety, efficacy and tolerability of ACZ885 in patients aged 4 years and younger with cryopyrin associated periodic syndromes (CAPS)"
    explanation: Pediatric-focused canakinumab trial relevant to CINCA/NOMID given its neonatal onset and need for early treatment.
- name: NCT02974595
  description: >
    NIH natural history study of autoinflammatory diseases including
    NOMID/CAPS, with long-term follow-up up to 15 years. Evaluates
    clinical outcomes, pathogenesis, genetic causes, and treatment
    responses across the autoinflammatory disease spectrum.
  phase: NOT_APPLICABLE
  status: RECRUITING
  evidence:
  - reference: clinicaltrials:NCT02974595
    supports: SUPPORT
    snippet: "Patients with known NOMID/CAPS, DIRA, CANDLE, SAVI, NLRC4-MAS, Still's Disease, and with other yet undifferentiated autoinflammatory diseases."
    explanation: Ongoing NIH natural history study providing longitudinal data on NOMID/CAPS disease course, outcomes, and treatment responses.
classifications:
  harrisons_chapter:
  - classification_value: IMMUNE_RHEUMATOLOGIC
  iuis_category:
    classification_value: autoinflammatory syndrome
  isds_skeletal_category:
  - classification_value: genetic_inflammatory_rheumatoid_like_osteoarthropathies
    notes: >-
      ISDS Nosology and Classification of Genetic Skeletal Disorders, 2019
      revision (Mortier et al., PMID:31633310), Table 1 group 31 "Genetic
      inflammatory/rheumatoid-like osteoarthropathies"; listed as "Chronic
      infantile neurologic cutaneous articular syndrome (CINCA) / neonatal onset
      multisystem inflammatory disease (NOMID)".
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0011776
      label: CINCA syndrome
    mapping_predicate: skos:exactMatch
    mapping_source: MONDO
    mapping_justification: Primary MONDO identifier for CINCA syndrome (matches disease_term).
  ncit_mappings:
  - term:
      id: NCIT:C84657
      label: Cryopyrin-Associated Periodic Syndrome
    mapping_predicate: skos:broadMatch
    mapping_source: NCIT
    mapping_justification: NCIT has no CINCA/NOMID-specific term; CINCA/NOMID is the severe end of the CAPS spectrum captured by this parent concept.
progression:
- phase: Neonatal/intrauterine onset
  notes: >-
    Inflammation begins in utero or at birth, with urticarial rash, fever, and
    raised inflammatory markers from the neonatal period; placental and
    umbilical-cord histopathology can show intrauterine-onset inflammation as
    the earliest manifestation.
  evidence:
  - reference: PMID:34059097
    reference_title: "Necrotizing Funisitis as an Intrauterine manifestation of Cryopyrin-Associated Periodic Syndrome: a case report and review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These evidences suggest that foetal inflammation, probably due to overproduction of IL-1β, caused tissue damage in utero, and the first symptom of a newborn with CINCA/NOMID."
    explanation: Documents intrauterine onset of IL-1beta-driven inflammation as the earliest phase of CINCA/NOMID.
- phase: Progressive multisystem damage
  notes: >-
    Untreated disease progresses through childhood with chronic aseptic
    meningitis, progressive sensorineural hearing loss, papilledema and visual
    loss, deforming arthropathy with epiphyseal overgrowth, and growth
    impairment.
  evidence:
  - reference: PMID:16899778
    reference_title: "Neonatal-onset multisystem inflammatory disease responsive to interleukin-1beta inhibition."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Neonatal-onset multisystem inflammatory disease is characterized by fever, urticarial rash, aseptic meningitis, deforming arthropathy, hearing loss, and mental retardation."
    explanation: Characterizes the progressive multisystem organ damage that accrues in untreated NOMID/CINCA.
- phase: Long-term outcome (treatment-modified)
  notes: >-
    Sustained uncontrolled inflammation risks AA amyloidosis and progressive
    organ damage; early and sustained IL-1 blockade controls inflammation and
    can prevent chronic sequelae, although established neurosensory damage may
    persist.
  evidence:
  - reference: PMID:38720945
    reference_title: "Case Report: Efficacy, safety, and favorable long-term outcome of early treatment with IL-1 inhibitors in a patient with chronic infantile neurological cutaneous articular (CINCA) syndrome caused by NLRP3 mosaicism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "After a 12-year follow-up, the patient has not experienced chronic complications."
    explanation: Demonstrates that early IL-1 blockade can prevent chronic sequelae over long-term follow-up, modifying the natural history.
variants:
- name: NLRP3 NACHT-domain gain-of-function missense substitutions (de novo)
  description: >-
    Most CINCA/NOMID cases are caused by de novo heterozygous missense
    substitutions in NLRP3 (CIAS1), clustering in the NACHT domain and lowering
    the inflammasome activation threshold. Recurrent substitutions occur at
    mutational hotspots, including independent nucleotide changes within a single
    codon producing the same amino-acid change.
  gene:
    preferred_term: NLRP3
    term:
      id: hgnc:16400
      label: NLRP3
  clinical_significance: PATHOGENIC
  evidence:
  - reference: PMID:12483741
    reference_title: "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."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In 6 of the 13 patients, we found 6 heterozygous missense substitutions in CIAS1."
    explanation: Foundational NOMID/CINCA cohort identifying de novo heterozygous CIAS1/NLRP3 missense substitutions, with two distinct nucleotide changes in a single codon (a recurrent hotspot) in unrelated patients.
  - reference: PMID:37809096
    reference_title: "The genetic and clinical characteristics and effects of Canakinumab on cryopyrin-associated periodic syndrome: a large pediatric cohort study from China."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The patients harbored 19 substitutions in NLRP3, and 8 of them were novel mutations."
    explanation: Large contemporary cohort expanding the NLRP3 substitution spectrum, confirming ongoing identification of novel disease-causing variants.
definitions:
- name: Eurofever/PRINTO CAPS classification criteria (2017)
  definition_type: DIAGNOSTIC_CRITERIA
  description: >-
    The 2017 data-driven CAPS classification criteria require raised
    inflammatory markers (CRP/SAA) plus at least two of six CAPS-typical
    features: urticaria-like rash, cold-triggered episodes, sensorineural
    hearing loss, musculoskeletal symptoms, chronic aseptic meningitis, and
    skeletal abnormalities. CINCA/NOMID, the severe end of the CAPS spectrum,
    typically satisfies these criteria, which perform well regardless of NLRP3
    mutation status.
  evidence:
  - reference: PMID:27707729
    reference_title: "Diagnostic criteria for cryopyrin-associated periodic syndrome (CAPS)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The best diagnosis model included: Raised inflammatory markers (C-reactive protein/serum amyloid A) plus ≥two of six CAPS-typical symptoms: urticaria-like rash, cold-triggered episodes, sensorineural hearing loss, musculoskeletal symptoms, chronic aseptic meningitis and skeletal abnormalities. Sensitivity was 81%, specificity 94%."
    explanation: International consensus, data-driven CAPS classification criteria (284 cases, 837 controls) covering all CAPS subtypes including CINCA/NOMID, independent of NLRP3 mutation.
mechanistic_hypotheses:
- hypothesis_group_id: canonical_nlrp3_il1_inflammasome_model
  hypothesis_label: Canonical NLRP3 Inflammasome / IL-1beta Model
  status: CANONICAL
  description: >-
    Gain-of-function NLRP3 mutations cause constitutive inflammasome assembly
    and caspase-1 activation, driving excessive IL-1beta production as the
    central effector of systemic and organ-specific inflammation. The dominant
    pathogenic role of IL-1beta is established by the rapid, near-complete
    clinical and biochemical response to IL-1 blockade.
  notes: >-
    IL-18 and gasdermin-D-dependent pyroptosis contribute to the inflammatory
    burden alongside IL-1beta. Mouse knock-in models show the phenotype requires
    an intact inflammasome but is only partially IL-1beta-dependent and
    T-cell-independent (PMID:19501000), indicating additional inflammasome-driven
    effectors beyond IL-1beta.
animal_models:
- species: Mouse
  description: >-
    Two Nlrp3 mutant knock-in mouse strains modeling CAPS develop systemic
    inflammation, poor growth, and early myeloid-cell-mediated mortality. The
    disease phenotype requires an intact inflammasome, is only partially
    dependent on IL-1beta, and is independent of T cells, establishing CAPS as a
    true inflammasome-mediated, innate-immune-driven disease.
  associated_phenotypes:
  - Systemic inflammation
  - Poor growth
  - Early mortality
  evidence:
  - reference: PMID:19501000
    reference_title: "Inflammasome-mediated disease animal models reveal roles for innate but not adaptive immunity."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "We developed two Nlrp3 mutant knockin mouse strains to model CAPS to examine the role of other inflammatory mediators and adaptive immune responses in an innate immune-driven disease."
    explanation: Establishes the Nlrp3 knock-in mouse strains as genetic models of CAPS/CINCA.
  - reference: PMID:19501000
    reference_title: "Inflammasome-mediated disease animal models reveal roles for innate but not adaptive immunity."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "These mice had systemic inflammation and poor growth, similar to some human CAPS patients, and demonstrated early mortality, primarily mediated by myeloid cells."
    explanation: Documents recapitulation of human CAPS features (systemic inflammation, poor growth) with myeloid-driven mortality in the mouse model.
experimental_models:
- name: CINCA patient iPSC-derived macrophage model of NLRP3 mosaicism
  description: >-
    Induced pluripotent stem cell lines generated from CINCA syndrome patients
    with somatic NLRP3 mosaicism, separated into mutant and non-mutant lines and
    differentiated into macrophages. Only mutant iPSC-derived macrophages show
    the disease-relevant abnormal IL-1beta secretion, and the platform supports
    anti-inflammatory drug screening.
  experimental_model_type: IPSC_DERIVED_MODEL
  cell_source: iPSC-derived from CINCA patients with somatic NLRP3 mosaicism
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  cell_types:
  - preferred_term: macrophage
    term:
      id: CL:0000235
      label: macrophage
  conditions:
  - abnormal IL-1beta secretion
  - somatic NLRP3 mosaicism
  evidence:
  - reference: PMID:22723549
    reference_title: "Induced pluripotent stem cells from CINCA syndrome patients as a model for dissecting somatic mosaicism and drug discovery."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "We found that mutant cells are predominantly responsible for the pathogenesis in these mosaic patients because only mutant iPS-MPs showed the disease relevant phenotype of abnormal IL-1β secretion."
    explanation: iPSC-derived macrophages from mosaic CINCA patients functionally isolate the mutant cell fraction as the driver of abnormal IL-1beta secretion and serve as a drug-screening platform.
external_assertions:
- name: Orphanet CINCA syndrome registry record
  source: Orphanet
  assertion_type: registry_disease_record
  external_id: ORPHA:1451
  url: https://www.orpha.net/en/disease/detail/1451
  description: >-
    Orphanet catalogues CINCA syndrome as a rare genetic cryopyrin-associated
    periodic syndrome with neonatal-onset systemic inflammation, urticarial
    rash, arthropathy, and central nervous system involvement.
  evidence:
  - reference: ORPHA:1451
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "A rare, genetic, cryopyrin-associated periodic syndrome (CAPS) characterized by neonatal onset of systemic inflammation, urticarial skin rash and arthritis/arthralgia resulting in severe arthropathy and central nervous system involvement"
    explanation: Orphanet registry definition of CINCA syndrome, corroborating the disease scope of this entry.
discussions:
- discussion_id: gap_cinca_mutation_negative_after_deep_sequencing
  prompt: >-
    What drives autoinflammation in clinically definite CINCA/NOMID patients who
    remain NLRP3 mutation-negative even after amplicon-based deep sequencing for
    somatic mosaicism?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - genetic#NLRP3
  - has_subtypes#Mutation-negative CINCA (somatic mosaicism)
  rationale: >-
    Deep/amplicon sequencing reclassifies many "mutation-negative" cases as
    low-level NLRP3 mosaicism, but a substantial fraction still has no detectable
    NLRP3 variant even with the most sensitive methods, yet responds to IL-1
    blockade exactly like genotype-positive patients. The genetic lesion in this
    residual group — deeper mosaicism below detection, a non-coding/regulatory
    NLRP3 change, or a variant in another inflammasome gene — is unresolved,
    leaving the first step of the causal chain unaccounted for in these patients.
  proposed_experiments:
  - experiment_id: exp_cinca_ultradeep_mosaicism_panel
    name: Ultra-deep multi-tissue sequencing and inflammasome gene panel in mutation-negative CINCA/NOMID
    description: >-
      Apply ultra-deep error-corrected sequencing across multiple tissues
      (sorted myeloid vs lymphoid fractions, buccal, and affected tissue) plus a
      broad inflammasome-pathway gene panel to clinically definite, IL-1-responsive
      CINCA/NOMID patients who are NLRP3-negative by standard amplicon deep
      sequencing, to detect sub-threshold NLRP3 mosaicism, non-coding NLRP3
      variants, or alternative inflammasome-gene drivers.
    experiment_type:
      preferred_term: targeted deep sequencing
  evidence:
  - reference: PMID:40538939
    reference_title: "Somatic NLRP3 mosaicism in patients with \"mutation-negative\" CAPS: insights from a single centre UK cohort."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In 40% (4/10) of the cohort a post-zygotic NLRP3 mutation leading to somatic mosaicism was found by ADS."
    explanation: >-
      Even with amplicon-based deep sequencing, only 40% of mutation-negative CAPS
      patients were resolved as NLRP3 mosaics, leaving the majority genetically
      unexplained.
- discussion_id: question_cinca_genotype_phenotype_modifiers
  prompt: >-
    What epigenetic or environmental factors modify CINCA/NOMID disease severity
    and expressivity beyond the NLRP3 genotype?
  kind: OPEN_QUESTION
  status: OPEN
  attaches_to:
  - genetic#NLRP3
  rationale: >-
    CINCA/NOMID shows variable expressivity even for the same NLRP3 change, and
    monozygotic twins concordant for the genotype can diverge markedly in
    severity. This points to epigenetic and/or environmental modifiers shaping
    the phenotype, which are currently unidentified and limit genotype-based
    prognostication.
  evidence:
  - reference: PMID:27320017
    reference_title: "Autoinflammatory retinopathy in chronic infantile neurological cutaneous and articular (CINCA) syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "there were significant differences between twins in phenotype severity, suggestive of epigenetic differences and/or involvement of environmental factors."
    explanation: >-
      Phenotypic discordance between monozygotic CINCA twins implicates
      epigenetic/environmental modifiers of severity beyond the shared NLRP3
      genotype.
- discussion_id: gap_cinca_irreversible_neurosensory_damage
  prompt: >-
    Can established post-inflammatory neurosensory damage in CINCA/NOMID (retinal
    dystrophy, hearing loss, CNS injury) be reversed, or does IL-1 blockade only
    prevent further damage once fixed tissue injury has occurred?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - phenotype#Retinal dystrophy
  - pathophysiology#Central nervous system inflammation
  rationale: >-
    IL-1 blockade reliably controls active inflammation and can improve MRI-visible
    cochlear and leptomeningeal lesions, but fixed post-inflammatory damage such as
    retinal dystrophy can remain stationary despite treatment. Whether any
    established neurosensory injury is recoverable — versus only preventable by very
    early treatment — is unresolved and is central to the rationale for early
    diagnosis before genetic confirmation.
  evidence:
  - reference: PMID:19424698
    reference_title: "Post-inflammatory retinal dystrophy in CINCA syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A state of severe retinal dystrophy of post-inflammatory origin became evident on funduscopy, optical coherence tomography and visual electrophysiology tests at the age of 10 years, which remained stationary after 1 year of anakinra treatment."
    explanation: >-
      Established post-inflammatory retinal dystrophy persisted unchanged after a
      year of anakinra, illustrating that fixed neurosensory damage may not reverse
      with IL-1 blockade.
review_notes: >-
  GeneReviews baseline was checked during the issue #3594 review. GeneReviews
  has no chapter for CINCA/NOMID or the broader cryopyrin-associated periodic
  syndromes (CAPS): PubMed book-subset and title searches for cryopyrin/CAPS
  GeneReviews records returned no PMID, and this disorder is instead covered by
  primary reviews and MedlinePlus Genetics. No GeneReviews baseline is therefore
  tagged for this entry. The #3594 review also added post-inflammatory retinal
  dystrophy (PMID:19424698, PMID:27320017) as a distinct ocular complication and
  linked the iPSC somatic-mosaicism dataset (GSE38626) to its primary
  publication (PMID:22723549).
references:
- reference: PMID:31724213
  title: "Distribution of serum amyloid A and establishment of reference intervals in healthy adults."
  findings: []
- reference: DOI:10.1080/15321819.2020.1837160
  title: "Serum amyloid A in healthy subjects: assessment of reference value using ELISA method"
  findings: []
- reference: DOI:10.1093/eurheartj/ehaf937
  title: C-reactive protein and cardiovascular risk in the general population
  findings: []
- reference: DOI:10.1007/s10875-019-00638-z
  title: CAPS and NLRP3
  findings: []
- reference: DOI:10.1101/2024.12.15.24318703
  title: 'Clinical Features, Outcomes of Treatments, Inflammasome Function and Longitudinal Clonal Dynamics into <i>NLRP3</i> Mosaicism: Evidence from the Largest Cryopyrin-associated Periodic Syndromes Cohort to Date'
  findings: []
- reference: DOI:10.3389/fimmu.2023.1267933
  title: 'The genetic and clinical characteristics and effects of Canakinumab on cryopyrin-associated periodic syndrome: a large pediatric cohort study from China'
  findings: []

📚

References & Deep Research

References

6

PMID:31724213

Distribution of serum amyloid A and establishment of reference intervals in healthy adults.

No top-level findings curated for this source.

DOI:10.1080/15321819.2020.1837160

Serum amyloid A in healthy subjects: assessment of reference value using ELISA method

No top-level findings curated for this source.

DOI:10.1093/eurheartj/ehaf937

C-reactive protein and cardiovascular risk in the general population

No top-level findings curated for this source.

DOI:10.1007/s10875-019-00638-z

CAPS and NLRP3

No top-level findings curated for this source.

DOI:10.1101/2024.12.15.24318703

Clinical Features, Outcomes of Treatments, Inflammasome Function and Longitudinal Clonal Dynamics into <i>NLRP3</i> Mosaicism: Evidence from the Largest Cryopyrin-associated Periodic Syndromes Cohort to Date

No top-level findings curated for this source.

DOI:10.3389/fimmu.2023.1267933

The genetic and clinical characteristics and effects of Canakinumab on cryopyrin-associated periodic syndrome: a large pediatric cohort study from China

No top-level findings curated for this source.

Deep Research

2

Disorder ▸

Disorder

Name: CINCA Syndrome
Category: Mendelian
Existing deep-research providers: falcon
Existing evidence reference count in YAML: 83

Key Pathophysiology Nodes

NLRP3 gain-of-function mutation
Constitutive NLRP3 inflammasome activation
Excessive IL-1beta production
Excessive IL-18 production
Systemic neutrophilic inflammation
Central nervous system inflammation
Epiphyseal skeletal overgrowth
Cartilage damage and destructive arthropathy
Secondary amyloidosis
Deep research literature mapping

Citation Inventory (for evidence mapping)

DOI:10.1007/s10875-019-00638-z
DOI:10.1101/2024.12.15.24318703
DOI:10.1111/imr.13292
DOI:10.3389/fimmu.2023.1267933

Falcon ▸

Pathophysiology description (molecular and cellular)

Edison Scientific Literature 18 citations 2026-02-09T11:48:52.520150

Pathophysiology description (molecular and cellular) - Core mechanism: NLRP3 gain-of-function lowers the activation threshold and enables constitutive assembly of the NLRP3 inflammasome. Upon priming and diverse triggers, mutant NLRP3 nucleates ASC (PYCARD) into a cytosolic “speck,” recruiting and activating caspase‑1, which cleaves pro‑IL‑1β and pro‑IL‑18 and executes gasdermin‑D–dependent pyroptosis. CAPS models and human cell studies demonstrate enhanced ASC speck formation, caspase‑1 activation, and IL‑1β release; disease phenotypes are myeloid‑cell driven and depend on ASC and caspase‑1, with contributions from IL‑18 and pyroptosis. (booshehri2019capsandnlrp3 pages 6-8) - Regulatory nodes: ASC speck formation is modulated by ubiquitination (linear and K63-linked) and by NEK7-dependent transport to the microtubule organizing center (MTOC), which interfaces with autophagic degradation; alternative splicing of NLRP3 (e.g., Δexon5) disrupts NEK7 binding, impeding ASC specking and IL‑1β release. These layers explain how GOF variants tilt the balance toward persistent inflammasome activation in severe CAPS (CINCA/NOMID). URL: Immunological Reviews 2024 (Dec 2024), https://doi.org/10.1111/imr.13292. (putnam2024thediscoveryof pages 8-9) - Dysregulated pathways: IL‑1–mediated signaling is dominant, but murine and in vitro data indicate partial roles for IL‑18 and downstream inflammatory mediators; oxidative stress and aberrant phosphorylation states can further potentiate cryopyrin activation. (booshehri2019capsandnlrp3 pages 6-8)

Cells, tissues, and anatomical involvement - Principal cell types: myeloid lineage cells (monocytes/macrophages, neutrophils) are the main source of inflammasome activity in CAPS; mosaic-variant distribution studies show a substantial fraction of patients with myeloid-restricted VAF, underscoring their central role. (bonet2024clinicalfeaturesoutcomes pages 13-16) - Tissue targets: skin (neutrophilic urticarial dermatosis), bone and cartilage (overgrowth and dysplasia, calcified physeal lesions), central nervous system/meninges (chronic sterile meningitis with elevated CSF pressure and leukocytosis), inner ear/cochlea (progressive sensorineural hearing loss), and eyes (uveitis, papilledema, optic atrophy). These manifestations map to local innate immune activation by mutant NLRP3-expressing myeloid cells and resident cells (e.g., chondrocytes, microglia). (booshehri2019capsandnlrp3 pages 3-4, arık2025autoinflammatorydiseasemolecular pages 3-4)

Somatic mosaicism and its implications - Frequency and patterns: Many clinically definite CAPS—especially severe phenotypes—previously testing negative for germline variants are explained by post‑zygotic (somatic) NLRP3 variants with low variant allele fractions (VAFs). In the largest mosaic CAPS cohort to date, mosaic patients harbored heterogeneous NLRP3 missense variants (exon 4 hot spots); mean VAF was ~11.3% (range 1.3–34.8%). Mosaicism was detected across leukocyte compartments with two predominant patterns: 64.3% had both myeloid and lymphoid involvement, while 35.7% were myeloid‑restricted; VAFs were longitudinally stable in ~54%, increased in ~23%, and decreased in ~23% over >12 months. (bonet2024clinicalfeaturesoutcomes pages 11-13, bonet2024clinicalfeaturesoutcomes pages 13-16) - Functional parity: Post‑zygotic variants generally conferred inflammasome activation comparable to germline GOF alleles; ASC‑speck assays showed robust activation that was suppressible by the NLRP3 inhibitor MCC950 in most variants (partial resistance noted for p.D303H). Clinically, mosaic and germline patients responded similarly to IL‑1 blockade. (bonet2024clinicalfeaturesoutcomes pages 13-16)

Disease progression and phenotype correlations - Sequence: CINCA/NOMID typically begins at birth or in the neonatal period with persistent urticarial rash and fever, followed by chronic aseptic meningitis/raised intracranial pressure, progressive sensorineural hearing loss, ocular inflammation with risk of optic atrophy, and abnormal bone/cartilage growth leading to arthropathy. Without timely IL‑1 blockade, cumulative tissue damage accrues in CNS, ear, and eye. (arık2025autoinflammatorydiseasemolecular pages 3-4, booshehri2019capsandnlrp3 pages 3-4) - Quantitative features from recent cohorts: A 2023 multi-patient pediatric CAPS cohort reported high neurologic burden consistent with severe phenotypes, including meningitis (75%) and ventriculomegaly (83.3%) in a subset with detailed neuroimaging/CSF data; canakinumab-treated children (n=10) experienced improvements across musculoskeletal, neurologic, auditory, and visual domains over 10–20 months. URL: Frontiers in Immunology (Sep 2023): https://doi.org/10.3389/fimmu.2023.1267933. (shu2023thegeneticand pages 1-2) - Systemic inflammatory profile: In mosaic CAPS, common clinical features included urticarial rash (100%), arthralgia (87%), fever (75%), arthritis (68%), and headache (56%), with anemia, neutrophilia, leukocytosis, and thrombocytosis; CRP/ESR were markedly elevated, and long diagnostic delays were observed (mean disease duration ~27 years in the studied adult-biased cohort). URL: medRxiv (Dec 2024): https://doi.org/10.1101/2024.12.15.24318703. (bonet2024clinicalfeaturesoutcomes pages 11-13)

Therapeutic mechanisms, applications, and outcomes - IL‑1 blockade as disease‑modifying therapy: Anakinra (recombinant IL‑1 receptor antagonist), rilonacept (soluble decoy for IL‑1), and canakinumab (anti‑IL‑1β monoclonal antibody) interrupt the IL‑1 axis downstream of NLRP3 activation. Clinical and experimental data show rapid suppression of systemic inflammation, prevention of new organ damage, and improvement or stabilization of hearing and ocular outcomes, though some established damage may be irreversible; dosing adjustments are sometimes necessary for sustained control. (booshehri2019capsandnlrp3 pages 6-8) - Recent outcomes: In the 2023 pediatric cohort, canakinumab produced multi-domain improvement where non–IL‑1 regimens largely failed, underscoring IL‑1 dependence of disease activity in severe CAPS. URL: Frontiers in Immunology (Sep 2023): https://doi.org/10.3389/fimmu.2023.1267933. (shu2023thegeneticand pages 1-2) - Emerging targeted approaches: In vitro, MCC950 abrogated ASC specks in most mosaic-variant cells, supporting the prospect of direct NLRP3 inhibition as a complementary or alternative strategy in CAPS, with variant-specific sensitivity. URL: medRxiv (Dec 2024): https://doi.org/10.1101/2024.12.15.24318703. (bonet2024clinicalfeaturesoutcomes pages 13-16)

Key concepts and definitions (current understanding) - CINCA/NOMID is the severe, neonatal-onset CAPS phenotype due to NLRP3 GOF variants; somatic mosaicism is common in clinically definitive cases lacking germline findings and can be myeloid-restricted; pathogenesis is driven by dysregulated NLRP3 inflammasome activity with IL‑1β/IL‑18 overproduction and pyroptosis; IL‑1 blockade is first-line, disease-modifying therapy. (booshehri2019capsandnlrp3 pages 3-4, booshehri2019capsandnlrp3 pages 6-8, bonet2024clinicalfeaturesoutcomes pages 13-16)

Recent developments (2023–2024 priority) - Pediatric cohort (China, 2023): 30 CAPS patients, 19 NLRP3 substitutions (8 novel), functional activation confirmed ex vivo; canakinumab improved neurologic, auditory, and visual outcomes over 10–20 months; severe case with somatic mosaicism documented. URL: https://doi.org/10.3389/fimmu.2023.1267933 (Sep 2023). (shu2023thegeneticand pages 1-2) - Mosaic CAPS dynamics (2024): Largest mosaic cohort showed diverse post‑zygotic variants, mean VAF ~11%, two lineage-distribution patterns, and consistent response to IL‑1 blockade; MCC950 inhibited ASC specking for most variants. URL: https://doi.org/10.1101/2024.12.15.24318703 (Dec 2024). (bonet2024clinicalfeaturesoutcomes pages 11-13, bonet2024clinicalfeaturesoutcomes pages 13-16) - Mechanistic refinements (2024): NEK7–MTOC trafficking, ASC ubiquitination, and alternative splicing act as control points of speck formation and IL‑1β maturation, helping explain disease variability and potential therapeutic leverage points beyond cytokine blockade. URL: https://doi.org/10.1111/imr.13292 (Dec 2024). (putnam2024thediscoveryof pages 8-9)

Statistics and data points (selected) - Mosaic CAPS VAF: mean ~11.3% (range 1.3–34.8%); lineage distribution: 64.3% myeloid+lymphoid vs 35.7% myeloid-only; VAF course: stable ~53.8%, increase ~23.1%, decrease ~23.1% (follow-up >12 months). (bonet2024clinicalfeaturesoutcomes pages 11-13, bonet2024clinicalfeaturesoutcomes pages 13-16) - Symptom frequencies in mosaic CAPS cohort: urticarial rash 100%, arthralgia 87%, fever 75%, arthritis 68%, headache 56%; systemic inflammation with cytopenias/cytoses and elevated CRP/ESR. (bonet2024clinicalfeaturesoutcomes pages 11-13) - Pediatric CAPS (2023) with severe neuro involvement: meningitis 75% and ventriculomegaly 83.3% in reported subset; IL‑1β blockade (canakinumab) improved multi-organ domains over 10–20 months. (shu2023thegeneticand pages 1-2)

Structured annotations for knowledge base integration - Genes/Proteins (HGNC): - NLRP3 (HGNC:16400): cytosolic pattern-recognition receptor forming the NLRP3 inflammasome; GOF in CINCA/NOMID. (booshehri2019capsandnlrp3 pages 6-8, putnam2024thediscoveryof pages 8-9) - PYCARD/ASC (HGNC:17617): adaptor forming ASC specks; essential for inflammasome assembly. (booshehri2019capsandnlrp3 pages 6-8, putnam2024thediscoveryof pages 8-9) - CASP1 (HGNC:1509): effector protease cleaving pro‑IL‑1β/IL‑18; executes pyroptosis with gasdermin D. (booshehri2019capsandnlrp3 pages 6-8) - IL1B (HGNC:5992), IL18 (HGNC:5988): inflammasome cytokines elevated in CAPS. (booshehri2019capsandnlrp3 pages 6-8) - NEK7 (HGNC:17644): scaffold regulating NLRP3 activation via MTOC trafficking. (putnam2024thediscoveryof pages 8-9) - Biological processes (GO terms): - Inflammasome complex assembly (GO:0061702); IL‑1–mediated signaling pathway (GO:0070498); positive regulation of interleukin‑1β production (GO:0032731); pyroptosis (GO:0070269); caspase‑1 activation (GO:0000422; “activation of cysteine-type endopeptidase activity involved in pyroptosis”). (booshehri2019capsandnlrp3 pages 6-8, putnam2024thediscoveryof pages 8-9) - Cellular components: - NLRP3 inflammasome complex; ASC speck (inflammasome focus) in cytosol; microtubule organizing center (MTOC); autophagosome. (putnam2024thediscoveryof pages 8-9, booshehri2019capsandnlrp3 pages 6-8) - Cell types (CL): - Monocyte (CL:0000576), macrophage (CL:0000775), neutrophil (CL:0000094) as principal effectors; chondrocyte (CL:0000136), osteoblast (CL:0000062) in bone/cartilage lesions; microglial cell (CL:0002319) and meningeal macrophages in CNS disease; keratinocyte (CL:0000312) in skin; cochlear hair cell (CL:0002370) as damage target. (booshehri2019capsandnlrp3 pages 3-4, bonet2024clinicalfeaturesoutcomes pages 13-16, booshehri2019capsandnlrp3 pages 6-8) - Anatomical locations (UBERON): - Skin (UBERON:0002097), meninges (UBERON:0002316), brain (UBERON:0000955), cochlea (UBERON:0001844), eye (UBERON:0000970), growth plate/epiphysis (UBERON:0003860). (booshehri2019capsandnlrp3 pages 3-4, arık2025autoinflammatorydiseasemolecular pages 3-4) - Chemical entities (illustrative): - Anakinra (IL‑1 receptor antagonist), canakinumab (anti‑IL‑1β mAb), rilonacept (IL‑1 trap), MCC950 (small‑molecule NLRP3 inhibitor under investigation); all act on the IL‑1/NLRP3 axis with demonstrated or emerging efficacy in CAPS/CINCA contexts. (booshehri2019capsandnlrp3 pages 6-8, bonet2024clinicalfeaturesoutcomes pages 13-16, shu2023thegeneticand pages 1-2)

Phenotype associations (HPO examples) - Urticarial rash (HP:0001025); recurrent fever (HP:0001954); chronic aseptic meningitis (HP:0002925); increased CSF pressure (HP:0010886); ventriculomegaly (HP:0002119); sensorineural hearing impairment (HP:0000407); uveitis (HP:0000554); papilledema (HP:0001085); optic atrophy (HP:0000648); abnormal bone growth/epiphyseal overgrowth and arthropathy (HP:0000939, HP:0002814). (booshehri2019capsandnlrp3 pages 3-4, shu2023thegeneticand pages 1-2, arık2025autoinflammatorydiseasemolecular pages 3-4)

Expert opinions and authoritative analysis - Foundational and translational insights from Hoffman and colleagues emphasize that CAPS pathogenesis is inflammasome‑centric, myeloid‑driven, and profoundly IL‑1 dependent, explaining the transformative impact of IL‑1 blockade across the CAPS spectrum, including CINCA/NOMID. URL: Journal of Clinical Immunology (Apr 2019): https://doi.org/10.1007/s10875-019-00638-z; Immunological Reviews (Dec 2024): https://doi.org/10.1111/imr.13292. (booshehri2019capsandnlrp3 pages 3-4, putnam2024thediscoveryof pages 8-9)

Current applications and real‑world implementations - Routine practice includes early genetic testing (with attention to mosaicism), serial audiology and ophthalmology, neuroimaging/CSF assessment when indicated, and prompt initiation of IL‑1 blockade to prevent irreversible CNS/ear/eye damage; these recommendations are echoed in recent reviews. (arık2025autoinflammatorydiseasemolecular pages 3-4) - Clinical experience in 2023–2024 cohorts shows IL‑1β blockade (canakinumab) achieving broad symptom control and organ protection in children and sustained benefits in mosaic adults; direct NLRP3 inhibition (e.g., MCC950 ex vivo) may offer future precision approaches, potentially guided by variant sensitivity. (shu2023thegeneticand pages 1-2, bonet2024clinicalfeaturesoutcomes pages 13-16)

Evidence items with PMIDs/DOIs and dates (selection) - Putnam CD, Broderick L, Hoffman HM. Immunological Reviews. Dec 2024. DOI: 10.1111/imr.13292. URL: https://doi.org/10.1111/imr.13292. (putnam2024thediscoveryof pages 8-9) - Booshehri LM, Hoffman HM. J Clin Immunol. Apr 2019. DOI: 10.1007/s10875-019-00638-z. URL: https://doi.org/10.1007/s10875-019-00638-z. (booshehri2019capsandnlrp3 pages 3-4, booshehri2019capsandnlrp3 pages 6-8) - Shu Z et al. Front Immunol. Sep 2023. DOI: 10.3389/fimmu.2023.1267933. URL: https://doi.org/10.3389/fimmu.2023.1267933. (shu2023thegeneticand pages 1-2) - Bonet N et al. medRxiv (preprint). Dec 2024. DOI: 10.1101/2024.12.15.24318703. URL: https://doi.org/10.1101/2024.12.15.24318703. (bonet2024clinicalfeaturesoutcomes pages 13-16, bonet2024clinicalfeaturesoutcomes pages 11-13)

Limitations and gaps - Precise population-level frequencies for specific CINCA/NOMID sequelae (e.g., hearing loss prevalence, optic atrophy rates) vary across registries and are incompletely captured in the 2023–2024 sources summarized here; longitudinal outcomes under standardized IL‑1 blockade, particularly neuro-otologic endpoints, would benefit from harmonized reporting. (shu2023thegeneticand pages 1-2, bonet2024clinicalfeaturesoutcomes pages 11-13)

Conclusion CINCA/NOMID is a prototypic inflammasomopathy driven by NLRP3 gain‑of‑function, with constitutive inflammasome activation (ASC specks → caspase‑1 → IL‑1β/IL‑18) and pyroptotic cell death in myeloid cells underpinning widespread tissue inflammation across skin, bone/cartilage, CNS/meninges, eye, and cochlea. Somatic mosaicism is common in severe CAPS and may be myeloid‑restricted, yet confers similar inflammasome hyperactivity and therapeutic responsiveness. Early, sustained IL‑1 blockade is the standard of care, improving systemic and organ‑specific outcomes, while emerging NLRP3 inhibitors show promise ex vivo and may soon expand therapeutic options. (booshehri2019capsandnlrp3 pages 6-8, bonet2024clinicalfeaturesoutcomes pages 13-16, shu2023thegeneticand pages 1-2, putnam2024thediscoveryof pages 8-9, booshehri2019capsandnlrp3 pages 3-4, bonet2024clinicalfeaturesoutcomes pages 11-13)

References

(booshehri2019capsandnlrp3 pages 6-8): Laela M. Booshehri and Hal M. Hoffman. Caps and nlrp3. Journal of Clinical Immunology, 39:277-286, Apr 2019. URL: https://doi.org/10.1007/s10875-019-00638-z, doi:10.1007/s10875-019-00638-z. This article has 275 citations and is from a domain leading peer-reviewed journal.
(putnam2024thediscoveryof pages 8-9): Christopher D. Putnam, Lori Broderick, and Hal M. Hoffman. The discovery of nlrp3 and its function in cryopyrin-associated periodic syndromes and innate immunity. Immunological reviews, 322:259-282, Dec 2024. URL: https://doi.org/10.1111/imr.13292, doi:10.1111/imr.13292. This article has 29 citations and is from a domain leading peer-reviewed journal.
(booshehri2019capsandnlrp3 pages 3-4): Laela M. Booshehri and Hal M. Hoffman. Caps and nlrp3. Journal of Clinical Immunology, 39:277-286, Apr 2019. URL: https://doi.org/10.1007/s10875-019-00638-z, doi:10.1007/s10875-019-00638-z. This article has 275 citations and is from a domain leading peer-reviewed journal.
(bonet2024clinicalfeaturesoutcomes pages 13-16): Nuria Bonet, Jose M. Mascaro, Laura Hurtado-Navarro, Diego Angosto-Bazarra, Jose Luis Callejas-Rubio, Daniel Clemente, Alejandro Souto, Olalla Lima, Natalia Palmou-Fontana, Eulalia Baselga, Santiago Jiménez-Treviño, Agustin Remesal, Marta Andreu-Barasoain, Luis Fernandez-Dominguez, Josep Riera-Monroig, Maria Aparicio, Juan Garcia-Herrero, David Pesqué, Maria Teresa Sanchez-Calvin, Jose Miguel Lezana-Rosales, Maria Correyero-Plaza, Julio Garcia-Villalba, Victor Bolaño, Sara Peiro, Mar Diaz, Alexandru Vlagea, Daniel Lorca, Virginia Fabregat, Maria Carmen Anton, Susana Plaza, Luis Ignacio Gonzalez-Granado, Concepción Postigo, Jose Maria Garcia-Ruiz de Morales, Enrique Gómez de la Fuente, Estibaliz Iglesias, Javier Gomez-Roman, Caritina Vázquez-Triñanes, Juan Carlos Lopez-Robledillo, Norberto Ortego-Centeno, Ana María Giménez-Arnau, Josep M. Campistol, Hafid Laayouni, Iñaki Ortiz de Landazuri, Jordi Yagüe, Eva Gonzalez-Roca, Anna Mensa-Vilaro, Oscar Fornas, Eduardo Ramos, Pablo Pelegrin, Ferran Casals, and Juan I. Arostegui. Clinical features, outcomes of treatments, inflammasome function and longitudinal clonal dynamics into nlrp3 mosaicism: evidence from the largest cryopyrin-associated periodic syndromes cohort to date. MedRxiv, Dec 2024. URL: https://doi.org/10.1101/2024.12.15.24318703, doi:10.1101/2024.12.15.24318703. This article has 0 citations.
(bonet2024clinicalfeaturesoutcomes pages 11-13): Nuria Bonet, Jose M. Mascaro, Laura Hurtado-Navarro, Diego Angosto-Bazarra, Jose Luis Callejas-Rubio, Daniel Clemente, Alejandro Souto, Olalla Lima, Natalia Palmou-Fontana, Eulalia Baselga, Santiago Jiménez-Treviño, Agustin Remesal, Marta Andreu-Barasoain, Luis Fernandez-Dominguez, Josep Riera-Monroig, Maria Aparicio, Juan Garcia-Herrero, David Pesqué, Maria Teresa Sanchez-Calvin, Jose Miguel Lezana-Rosales, Maria Correyero-Plaza, Julio Garcia-Villalba, Victor Bolaño, Sara Peiro, Mar Diaz, Alexandru Vlagea, Daniel Lorca, Virginia Fabregat, Maria Carmen Anton, Susana Plaza, Luis Ignacio Gonzalez-Granado, Concepción Postigo, Jose Maria Garcia-Ruiz de Morales, Enrique Gómez de la Fuente, Estibaliz Iglesias, Javier Gomez-Roman, Caritina Vázquez-Triñanes, Juan Carlos Lopez-Robledillo, Norberto Ortego-Centeno, Ana María Giménez-Arnau, Josep M. Campistol, Hafid Laayouni, Iñaki Ortiz de Landazuri, Jordi Yagüe, Eva Gonzalez-Roca, Anna Mensa-Vilaro, Oscar Fornas, Eduardo Ramos, Pablo Pelegrin, Ferran Casals, and Juan I. Arostegui. Clinical features, outcomes of treatments, inflammasome function and longitudinal clonal dynamics into nlrp3 mosaicism: evidence from the largest cryopyrin-associated periodic syndromes cohort to date. MedRxiv, Dec 2024. URL: https://doi.org/10.1101/2024.12.15.24318703, doi:10.1101/2024.12.15.24318703. This article has 0 citations.
(shu2023thegeneticand pages 1-2): Zhou Shu, Yue Zhang, Tongxin Han, Yan Li, Yurong Piao, Fei Sun, Jin Ma, Wenxiu Mo, Jiapeng Sun, Koon-Wing Chan, Wanling Yang, Yu-Lung Lau, and Huawei Mao. The genetic and clinical characteristics and effects of canakinumab on cryopyrin-associated periodic syndrome: a large pediatric cohort study from china. Frontiers in Immunology, Sep 2023. URL: https://doi.org/10.3389/fimmu.2023.1267933, doi:10.3389/fimmu.2023.1267933. This article has 8 citations and is from a peer-reviewed journal.
(arık2025autoinflammatorydiseasemolecular pages 3-4): SD Arık and B Menentoğlu. Autoinflammatory disease: molecular insights, clinical spectrum, and emerging therapies: autoinflammation: mechanisms and management. Unknown journal, 2025.

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