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CINCA Syndrome

Mendelian MONDO:0011776 Autoinflammatory diseases Cryopyrin-associated periodic syndromes
0
Mappings
0
Definitions
1
Inheritance
9
Pathophysiology
4
Histopathology
9
Phenotypes
1
Genes
4
Treatments
2
Subtypes
3
Differentials
2
Datasets
5
Trials
👪

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.
◆

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 (5 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.
+ 2 more references
⚙

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.
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 link ⚠ ABNORMAL
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 link ⚠ ABNORMAL Pyroptotic inflammatory response link ⚠ ABNORMAL
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 link ⚠ ABNORMAL
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 link Monocyte link
Neutrophil chemotaxis link ⚠ ABNORMAL Inflammatory response link ⚠ ABNORMAL
Skin of body link
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 link
Leptomeninx link Cochlea link
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 link ⚠ ABNORMAL
Epiphysis link Growth plate cartilage link
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 link
Extracellular matrix disassembly link ⚠ ABNORMAL
Synovial joint link
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 link
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.
✶

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.
⬡

Causal Graph

graph LR
    Systemic_neutrophilic_inflammation["Systemic neutrophilic inflammation"]
    Cartilage_damage_and_destructive_arthropathy["Cartilage damage and destructive arthropathy"]
    Epiphyseal_skeletal_overgrowth["Epiphyseal skeletal overgrowth"]
    Central_nervous_system_inflammation["Central nervous system inflammation"]
    Excessive_IL_18_production["Excessive IL-18 production"]
    Constitutive_NLRP3_inflammasome_activation["Constitutive NLRP3 inflammasome activation"]
    Excessive_IL_1beta_production["Excessive IL-1beta production"]
    Secondary_amyloidosis["Secondary amyloidosis"]
    NLRP3_gain_of_function_mutation["NLRP3 gain-of-function mutation"]

    NLRP3_gain_of_function_mutation --> Constitutive_NLRP3_inflammasome_activation
    Constitutive_NLRP3_inflammasome_activation --> Excessive_IL_1beta_production
    Constitutive_NLRP3_inflammasome_activation --> Excessive_IL_18_production
    Excessive_IL_1beta_production --> Systemic_neutrophilic_inflammation
    Excessive_IL_1beta_production --> Central_nervous_system_inflammation
    Excessive_IL_1beta_production --> Epiphyseal_skeletal_overgrowth
    Excessive_IL_1beta_production --> Cartilage_damage_and_destructive_arthropathy
    Excessive_IL_1beta_production --> Secondary_amyloidosis
    Excessive_IL_18_production --> Systemic_neutrophilic_inflammation

    style Systemic_neutrophilic_inflammation fill:#dbeafe
    style Cartilage_damage_and_destructive_arthropathy fill:#dbeafe
    style Epiphyseal_skeletal_overgrowth fill:#dbeafe
    style Central_nervous_system_inflammation fill:#dbeafe
    style Excessive_IL_18_production fill:#dbeafe
    style Constitutive_NLRP3_inflammasome_activation fill:#dbeafe
    style Excessive_IL_1beta_production fill:#dbeafe
    style Secondary_amyloidosis fill:#dbeafe
    style NLRP3_gain_of_function_mutation fill:#dbeafe
●

Phenotypes

9
Cardiovascular(2) Ear(1) Eye(2) Immune(1) Metabolism(1) Musculoskeletal(1) Growth(1)
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 2
Papilledema VERY_FREQUENT Papilledema (HP:0001085)
Show evidence (1 reference)
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 confirming high prevalence of ophthalmologic involvement including papilledema in severe CAPS phenotypes.
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.
Immune 1
Chronic aseptic meningitis VERY_FREQUENT Meningitis (HP:0001287)
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 1
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.
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.
🧬

Genetic Associations

1
NLRP3 (Causative)
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).
💊

Treatments

4
IL-1 inhibition with anakinra MAXO:0000058
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 ↗ Urticaria ↗
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 MAXO:0000058
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 ↗ Arthropathy ↗
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 MAXO:0000058
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 ↗
Show evidence (1 reference)
PMID:31077002 SUPPORT Other
"Investigators have taken advantage of some of these pathways to develop and apply novel targeted therapies, which have resulted in improved quality of life for patients with this orphan disease."
Review describing the development and application of IL-1 targeted therapies including rilonacept for CAPS patients.
Genetic counseling MAXO:0000079
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
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
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 Not Yet Curated 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 Not Yet Curated 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
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 ↗ Meningitis ↗ Arthropathy ↗ Papilledema ↗
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 ↗ Urticaria ↗ Meningitis ↗
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 ↗ Urticaria ↗
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 ↗ Urticaria ↗
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.
{ }

Source YAML

click to show 
name: CINCA Syndrome
creation_date: '2026-02-09T17:35:00Z'
updated_date: '2026-02-17T21:53:14Z'
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
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
    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
    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
    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
    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
    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
    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%.
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
    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
    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
    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
    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
    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
    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
    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
    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.
- 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
    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
    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.
- 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
    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
    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.
- 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
    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
    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
    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
    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
    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
    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
    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.
  context: Chronic, from neonatal period
  severity: Severe
  diagnostic: true
  phenotype_term:
    preferred_term: Meningitis
    term:
      id: HP:0001287
      label: Meningitis
  evidence:
  - reference: PMID:16899778
    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
    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
    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
    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.
  frequency: VERY_FREQUENT
  context: Secondary to chronic meningitis
  phenotype_term:
    preferred_term: Papilledema
    term:
      id: HP:0001085
      label: Papilledema
  evidence:
  - reference: PMID:37809096
    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 confirming high prevalence of
      ophthalmologic involvement including papilledema in severe CAPS
      phenotypes.
- 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
    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
    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
    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
    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
    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
    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.
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
    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
    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
    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
    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
    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
    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
  evidence:
  - reference: PMID:16899778
    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
  evidence:
  - reference: PMID:16899778
    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
    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
    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
    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
    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
    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: MAXO:0000127
      label: genetic testing
  evidence:
  - reference: PMID:37809096
    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
    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
    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
    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
    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: MAXO:0000058
      label: pharmacotherapy
    qualifiers:
    - predicate:
        preferred_term: Therapeutic Agent
        term:
          id: NCIT:C2259
          label: Therapeutic Agent
      value:
        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
    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
    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: MAXO:0000058
      label: pharmacotherapy
    qualifiers:
    - predicate:
        preferred_term: Therapeutic Agent
        term:
          id: NCIT:C2259
          label: Therapeutic Agent
      value:
        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
    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
    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: MAXO:0000058
      label: pharmacotherapy
    qualifiers:
    - predicate:
        preferred_term: Therapeutic Agent
        term:
          id: NCIT:C2259
          label: Therapeutic Agent
      value:
        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:31077002
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Investigators have taken advantage of some of these pathways to develop
      and apply novel targeted therapies, which have resulted in improved quality
      of life for patients with this orphan disease."
    explanation: Review describing the development and application of IL-1
      targeted therapies including rilonacept for CAPS patients.
- 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: MAXO:0000079
      label: genetic counseling
  evidence:
  - reference: PMID:11687797
    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
    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
    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
    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
    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
    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
    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
    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
    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
    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
    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
  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.
references:
- 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: []