The clinical presentation involves a myriad of symptoms, but the triad of skin, joint and central nervous system defects is the hallmark of this condition. Firstly, an urticaria-like non-pruritic rash that develops during the neonatal period is observed [5]. Headache, vomiting, altered mental state, intellectual disability, seizures, episodes of hemiplegia and chronic meningitis-like states are CNS manifestations of the disease [5] [6]. In terms of joint involvement, recurrent flares that may be accompanied with overgrowth of the patella are most frequently reported, together with arthralgia that can be severe and changes in the epiphysis and metaphysis [6] [10]. Joint pain and symptoms appear in symmetric fashion, while synovial fluid effusion is commonly observed [5]. Additional symptoms include optic nerve damage and potential loss of vision, hearing impairment, chronic anterior uveitis and fever [5] [6].

• Splenomegaly

  Nausea, vomiting and abdominal pain with flares, or with elevated intracranial pressure (ICP). [6] Lymphatic: Splenomegaly. [autoinflammatory-search.org]

  […] rash in varying degrees during the course of the disease.Nine of them had obvious arthritis.Nine children had central nervous system involvement.There were 8 cases of binaural nervous deafness,7 cases of binocular optic neuritis,and 6 cases of hepato-splenomegaly [pesquisa.bvsalud.org]

  The course was that of a chronic inflammatory disease with numerous flare-ups associating fever, splenomegaly and adenomegaly. [pubmed.ncbi.nlm.nih.gov]

  Failure to thrive, mild splenomegaly, and refractory iron-deficiency anemia, without a detectable source of infection, led to no definitive diagnosis, and an extensive investigation for autoantibodies and complement defects was negative. [jrheum.org]

• Generalized Lymphadenopathy

  Nevertheless, many other manifestations are described, including fever, generalized lymphadenopathy, hepatosplenomegaly, developmental retardation, hydrocephalus, cerebral atrophy, ocular involvement in the form of uveitis and papilitis, and perceptive [digital.csic.es]

  These attacks were accompanied with a low grade fever and an almost persistent skin rash and generalized lymphadenopathy. Upon evaluation at 8-years of age, his height, weight and head circumference were below normal. [cags.org.ae]

• Fever

  This category includes the hereditary periodic fever syndromes, namely, familial Mediterranean fever (FMF), tumour necrosis factor receptor-associated periodic fever syndrome (TRAPS), hyperimmunoglobulinaemia D with periodic fever syndrome and cryopyrinopathies [medicaljournals.se]

  Still syndrome; periodic fever syndromes of other genesis. Therapy This section has been translated automatically. Non-steroidal anti-inflammatory drugs and corticoids. [altmeyers.org]

  They are characterized by intermittent episodes of fever, urticarial rash, arthralgias, and abdominal pain. In FCAS, the symptoms are precipitated by exposure to cold. [genedx.com]

  The other periodic fevers differ in the severity of clinical manifestations. No formal recommended treatment guidelines exist. Non-steroidal anti-inflammatory drugs and corticosteroids offer temporary relief for pain, fever and joint mobility. [indianpediatrics.net]

  All of these syndromes are characterized by fever, rash, and musculoskeletal pain. [rarediseases.org]

• Disability

  This may change with successful treatment now minimising neurological disability. [dermnetnz.org]

  Surgical interventions by soft tissue release and hemiepiphysiodesis improved the contracture and the deformity, and IL-1 receptor antagonist dramatically controlled systemic inflammation, and the patient lives without any disabilities. [tandfonline.com]

  The disability seen in NOMID patients relates to the duration, extent, and severity of the inflammation. [periodicfevers.com]

• Anemia

  irritability, anemia Recurrent fever, anemia Nervous system Development delay, frontal bossing, intracranial hypertension, CSF pleiocytosis Development delay, frontal bossing, dilated CSF spaces, CSF pleiocytosis Frequent headaches, frontal bossing, [onlinelibrary.wiley.com]

  Extremely elevated inflammatory parameters (BSG, CRP, leukocytosis), anemia, polyclonal stimulation of IgM and IgG, and increased circulating IgM and IgG immune complexes. Histology This section has been translated automatically. [altmeyers.org]

  Relevant laboratory findings included mild leukocytosis, iron resistants hypochromic anemia of chronic disease, elevated ESR and no detectable autoimmune profile. Radiograph revealed abnormalities of metaphysis of both distal femurs. [jacionline.org]

  Laboratory findings show leucocytosis, anemia, elevation of CRP levels and acceleration of ESR. The syndrome is associated with CIAS1 gene and its encoding protein cryopyrin. [jstage.jst.go.jp]

  Secondary amyloidosis in <2% pts. [1], [6] Abnormal labs: Chronically high: ESR, CRP, SAA, anemia, granulocytic leukocytosis. [autoinflammatory-search.org]

• Lymphadenopathy

  These attacks were accompanied with a low grade fever and an almost persistent skin rash and generalized lymphadenopathy. Upon evaluation at 8-years of age, his height, weight and head circumference were below normal. [cags.org.ae]

  Rapidly changing maculo-papular or urticarial exanthema, arthropathy, neurological disorders due to chronic aseptic menitis, lymphadenopathy and hepatosplenomegaly (see below fever syndromes, hereditary, periodic). [altmeyers.org]

  Nevertheless, many other manifestations are described, including fever, generalized lymphadenopathy, hepatosplenomegaly, developmental retardation, hydrocephalus, cerebral atrophy, ocular involvement in the form of uveitis and papilitis, and perceptive [digital.csic.es]

  We describe a 23-year-old Caucasian woman who had developed urticarial skin lesions, lymphadenopathy, and recurrent febrile episodes within the first week after birth. [jrheum.org]

• Short Stature

  stature/skeletal dysplasia (99.9% **) WES skin disorders¹ (99.9% **) ** % of the coding region of this gene has a coverage of >20x. [order.radboudumc.nl]

  Some have frontal bossing of the forehead, saddleback nose, contractures, and/or have clubbing of the fingers. [1] Short stature, growth delays, failure to thrive, arthritis, and osteopenia are often noted.[1],[26] <50% of patients knees or joints have [autoinflammatory-search.org]

  Some studies mentioned short stature as a symptom of CINCA syndrome.13 Our patient had a short stature despite normal serum growth hormone (GH) level. If untreated, CINCA patients develop permanent CNS damage. [journals.sagepub.com]

  Common morphological features characterized these patients with short stature, head enlargement, saddle back nose and short and thick extremities with clubbing of fingers. [pubmed.ncbi.nlm.nih.gov]

  Short stature, frontal bossing of the skull, characteristic flattening of the nasal bridge, clubbing of the fingers and delayed closure of the fontanelles (at age 10 years) contributed to the clinical picture. [jrheum.org]

• Saddle Nose

  The principal clinical signs in our child with CINC syndrome clockwise. (1) Clubbing (2) Skin rash (3) Saddle nose (4) Patellar overgrowth. Fig. 2. Fundus findings: Retinal vasculitis. [indianpediatrics.net]

  On physical examination she had frontal bossing, saddle nose, nystagmus, swelling of bilateral knees and ankles (Fig. 1a) and high APR (CRP: 299mg/L, ESR: 140mm/h). [reumatologiaclinica.org]

  However, when we met the patient we noticed a dysmorphic facial appearance characterized by frontal bossing of the skull, saddle nose, micrognathia and clubbing of the fingers. [academic.oup.com]

  At the patient’s initial visit, a clinical examination confirmed the presence of a rash on her body with a saddle nose and clubbed fingers. [joii-journal.springeropen.com]

• Clubbed Finger

  At the patient’s initial visit, a clinical examination confirmed the presence of a rash on her body with a saddle nose and clubbed fingers. [joii-journal.springeropen.com]

• Vomiting

  Five key symptoms were included in the primary variable DSSS: fever, headache, rash, joint pain, and vomiting. Each of the diary variables was evaluated as a mean value for a period preceding the visits. [clinicaltrials.gov]

  Cognitive impairment, progressive hearing and vision loss, vomiting, bone pain and fever are described in these patients as well. [symptoma.com]

  Individuals with NOMID may also have chronic meningitis (inflammation of the membranes surrounding the brain), which may lead to headaches, seizures, and vomiting. Hearing loss, vision loss, and intellectual disability, may also occur. [rarediseases.info.nih.gov]

• Failure to Thrive

  Disease was characterized by high spiking fever and permanent rash, failure to thrive, progressive arthropathy and bony appearance with partial response to NSAID ans steroid. Conclusion A syndrome of neonatal onset can be recognized. [jacionline.org]

  Some have frontal bossing of the forehead, saddleback nose, contractures, and/or have clubbing of the fingers. [1] Short stature, growth delays, failure to thrive, arthritis, and osteopenia are often noted.[1],[26] <50% of patients knees or joints have [autoinflammatory-search.org]

  However, some patients may have a progressive course with continued failure to thrive and dyslipidemia, and a few may develop chronic or fatal liver disease. Markedly elevated plasma citrulline is the hallmark of these disorders. [medlink.com]

  Clinical characteristics of the patients with NOMID/CINCA syndrome* Characteristic Patient 1 Patient 2 Patient 3 Sex/age, years M/4 F/10 F/8 Age at onset Birth Birth Birth General Recurrent fever, irritability, anemia Failure to thrive, recurrent fever [onlinelibrary.wiley.com]

  Failure to thrive was observed in six subjects; four patients (P5, P7, P9, P11) were adults (aged >18 yrs) with a final height under the genetic target. In 10 patients, the age of onset was in the first month of life. [academic.oup.com]

• Hepatosplenomegaly

  Hepatosplenomegaly was confirmed by abdominal ultrasound. A maculopapular skin rash was first observed at 11-months of age. [cags.org.ae]

  Rapidly changing maculo-papular or urticarial exanthema, arthropathy, neurological disorders due to chronic aseptic menitis, lymphadenopathy and hepatosplenomegaly (see below fever syndromes, hereditary, periodic). [altmeyers.org]

  Nevertheless, many other manifestations are described, including fever, generalized lymphadenopathy, hepatosplenomegaly, developmental retardation, hydrocephalus, cerebral atrophy, ocular involvement in the form of uveitis and papilitis, and perceptive [digital.csic.es]

• Hepatomegaly

  Some with retinal scarring, corneal haze or vision loss. [6], [26] Cardiopulmonary: Some may have a pericardial effusion, or pericarditis. [1] Abdominal: Some patients have hepatomegaly, splenomegaly, or hepatosplenomegaly. [autoinflammatory-search.org]

  […] abnormalities 0001872 Anemia Low number of red blood cells or hemoglobin 0001903 Delayed closure of the anterior fontanelle Later than typical closing of soft spot of skull 0001476 Edema Fluid retention Water retention [ more ] 0000969 Frontal bossing 0002007 Hepatomegaly [rarediseases.info.nih.gov]

• Visual Impairment

  Consequences of secondary amyloidosis, deafness, visual impairment, mental retardation or existing developmental delay can or do persist, remaining stable or showing further progression. Proteinuria may improve but kidney impairment may be stable. [dermnetnz.org]

  However, it is progressive neurologic, auditory, and visual impairment that determines long‐term disability in this disorder (5). It is uncertain whether these complications can be avoided by treatment with anakinra. Joost Frenkel MD*, Nico M. [onlinelibrary.wiley.com]

  She developed bilateral chronic uveitis with secondary band keratopathy (Figure 1A) and optic neuritis, which led to a significant visual impairment with optic nerve atrophy. [jrheum.org]

• Skin Rash

  […] months Urticarial rash + ND ND ND + ND – ND FCAS 31 years/F 2 years Skin rash + ND + + + ND ND ND Yamashita et al. 1987 (17) FCAS 3 years/M 2 months Skin rash + ND + – + ND ND ND CINCA 14 years/M At birth Skin rash ND ND + + ND ND ND + Inamo et al. 1994 [medicaljournals.se]

  A maculopapular skin rash was first observed at 11-months of age. Bone marrow biopsy was consistent with chronic infection or inflammation, although serological studies for several viruses and bacteria were negative. [cags.org.ae]

  From Wikidata Jump to navigation Jump to search Chronic Infantile Neurological, Cutaneous, and Articular (CINCA) syndrome is characterised by skin rash, joint involvement, chronic meningitis with granulocytes and, in some cases, sensorineural hearing [wikidata.org]

  Mother notice erythematous skin rash soon after birth which increasing and decreasing but never fading. [medcraveonline.com]

• Eruptions

  The syndrome is characterized by a generalized, wandering palpable rash eruption of neonatal onset, chronic arthropathy characterized by abnormal proliferation of cartilage and an abnormal ossification, and a progressive neurological impairment as the [digital.csic.es]

  Three main manifestations of CINCA syndrome are cutaneous signs, including maculopapular urticarial eruptions, commonly observed in the infantile period, joint involvement of variable severity, and CNS involvement. [cags.org.ae]

• Maculopapular Skin Rash

  A maculopapular skin rash was first observed at 11-months of age. Bone marrow biopsy was consistent with chronic infection or inflammation, although serological studies for several viruses and bacteria were negative. [cags.org.ae]

  The most common findings that distinguish this syndrome are: Persistent Rash from Infancy Most NOMID/CINCA infants have a maculopapular skin rash. The rash appears shortly after birth, or within the first few days or weeks of life. [nomidalliance.org]

• Hearing Impairment

  NLRP3 - CINCA syndrome This test is available for the following conditions: Conditions > Immunological, hereditary > CINCA syndrome This product is also part of the following panels: WES hearing impairment (99.9% **) WES Mendelian inherited disorders [order.radboudumc.nl]

  Hearing loss, vision loss, and intellectual disability, may also occur. [rarediseases.info.nih.gov]

• Progressive Hearing Loss

  Owing to the unknown pathogenesis of the progressive hearing loss seen in CINCA syndrome and the limited effectiveness of anakinra in reversing the progressive hearing loss, we suggest that cochlear implantation is the modality of choice in rehabilitating [ncbi.nlm.nih.gov]

  In addition, affected patients often show other features, including fever, lymphadenopathy, hepatosplenomegaly, progressive hearing loss, eye involvement (conjunctivitis, uveitis, papilledema, and optic nerve atrophy), abnormal crabiofacial features, [cags.org.ae]

  hearing loss and amyloidosis. [rarediseases.org]

• Progressive Sensorineural Deafness

  MWS is characterized by progressive sensorineural deafness as well as recurrent episodes of skin rash, fever and arthralgia (1). [medicaljournals.se]

  This type is characterized by retinitis pigmentosa and progressive sensorineural deafness. ( Arch Otolaryngol 105:353-354, 1979) Full Text Download PDF Full Text Cite This Citation Gorlin RJ, Tilsner TJ, Feinstein S, Duvall AJ. [jamanetwork.com]

  Hearing Loss Progressive sensorineural deafness (often related to chronic pressure in the brain from constant inflammation) can occur in many children with NOMID/CINCA, so hearing tests need to be done by audiologists. [nomidalliance.org]

• Hearing Problem

  The basic "pre-school hearing tests" will not usually catch the complex array of hearing problems early enough, but it may help to find those children with very profound hearing losses. [nomidalliance.org]

• Arthritis

  LLD is often found in young patients with unilateral arthritis [13], and valgus deformity of the knee is found in patients with general arthritis. [docksci.com]

  Differential diagnosis includes other hereditary febrile diseases, congenital infections and systemic onset of juvenile idiopathic arthritis (SOJIA). [indianpediatrics.net]

  Arthritis Rheum. 2010 Apr;62(4):1158-66. doi: 10.1002/art.27342. Arthritis Rheum. 2010. PMID: 20131270 Publication types MeSH terms Substances LinkOut - more resources Full Text Sources Ediciones Doyma, S.L. [pubmed.ncbi.nlm.nih.gov]

  Arthritis Rheum. 2010, 62: 258-267. [springermedizin.de]

  On day six she developed arthritis in small joints of hands (Figure 3) and feet. Arthritis, together with the rash and the persisting elevated inflammation markers led to the diagnosis of CINCA syndrome. [ncbi.nlm.nih.gov]

• Arthralgia

  MWS is characterized by progressive sensorineural deafness as well as recurrent episodes of skin rash, fever and arthralgia (1). [medicaljournals.se]

  They are characterized by intermittent episodes of fever, urticarial rash, arthralgias, and abdominal pain. In FCAS, the symptoms are precipitated by exposure to cold. [genedx.com]

  Familial Cold Autoinflammatory Syndrome (FCAS) This syndrome is characterized by: - Cold-induced attacks of fever - Urticaria-like rash (after cold exposure) - Arthralgia - Conjunctivitis - Fevers typically last less than 24 hours. [immunodeficiencysearch.com]

  Articular manifestations vary from arthralgia to transient swelling without effusion to severe deforming arthropathy. [indianpediatrics.net]

  In terms of joint involvement, recurrent flares that may be accompanied with overgrowth of the patella are most frequently reported, together with arthralgia that can be severe and changes in the epiphysis and metaphysis. [symptoma.com]

• Myalgia

  Tendinopathies occured in 12 (16%) of the patients and myalgia in 26 (35%). Conclusions Articular symptoms are frequent in patients with CAPS and considered as invalidating in 20% but they are poorly investigated by radiographs. [ard.bmj.com]

  Myalgia is another frequent finding in patients with FMF (reported in 20% of cases). [emedicine.medscape.com]

  It is characterized by recurrent and self-limited episodes of fever, urticaria, arthralgia, myalgia and conjunctivitis since childhood, which are related to exposure to cold temperatures. Lately, progressive sensorineural hearing loss occurs. [scielo.br]

  The rash was waxing and waning spontaneously but sometimes was getting worse with accompanying myalgia, red eyes and subtle fever for a few days. [reumatologiaclinica.org]

• Macrocephaly

  Craniofacial abnormalities include macrocephaly with frontal bossing, saddle-back nose, and delayed closure of the anterior fontanel. CINCA syndrome is extremely rare, with only close to 100 patients having been reported in medical literature. [cags.org.ae]

  Other findings that have been reported include macrocephaly (95%), large fontanelle, prominent forehead, flattening of the nasal bridge (saddleback nose), short and thick extremities, and finger clubbing. The liver and/or spleen may be enlarged. [en.wikipedia.org]

• Joint Swelling

  At 20 months of age, she developed knee joint swelling with limited ROM resulting in problems with standing and walking. [ped-rheum.biomedcentral.com]

  Patients may have joint tenderness on exam, however, joint swelling is rare. An urticaria-like rash marked by migratory non-pruritic raised erythematous wheals with well-defined borders and a smooth surface may be present. [rheumatologyadvisor.com]

  Articular manifestations involving the knees (Figure 1), ankles, feet, elbows, wrists, and hands range from joint swelling occurring during flare-ups to severe bone changes with unique radiological features12 (Figure 2). [jamanetwork.com]

  In some children, the sole finding of the disease may be episodes of joint pain and swelling, which is misdiagnosed as acute rheumatic fever, or juvenile idiopathic arthritis. Usually, the joint swelling resolves over five to 14 days. [my.clevelandclinic.org]

• Frontal Bossing

  He had frontal bossing, no wrinkling of palms and soles, a maculopapular skin rash, injected conjunctivae, hepatosplenomegaly, and clubbing. Tests ruled out the possibility of lipid storage diseases and oligosaccharidosis. [cags.org.ae]

  bossing, intracranial hypertension, CSF pleiocytosis Development delay, frontal bossing, dilated CSF spaces, CSF pleiocytosis Frequent headaches, frontal bossing, intracranial hypertension, CSF pleiocytosis Eyes Normal Uveitis Papilledema, uveitis Ears [onlinelibrary.wiley.com]

  Some have frontal bossing of the forehead, saddleback nose, contractures, and/or have clubbing of the fingers. [1] Short stature, growth delays, failure to thrive, arthritis, and osteopenia are often noted.[1],[26] <50% of patients knees or joints have [autoinflammatory-search.org]

• Headache

  We report a case of 16 years old girl with CINCA syndrome with history of recurrent headaches & fever. She had a de novo F309S mutation in exon 3 of CIAS1 gene on chromosome 1. [worldwidejournals.com]

  Migraine headache Migraine headaches [ more ] 0002076 Myalgia Muscle ache Muscle pain [ more ] 0003326 Nausea and vomiting 0002017 Papule 0200034 Pseudopapilledema 0000538 Sensorineural hearing impairment 0000407 Urticaria Hives 0001025 Uveitis 0000554 [rarediseases.info.nih.gov]

• Seizure

  Affected infants appear normal at birth, but as ammonia builds up in the body they present symptoms such as lethargy, poor feeding, vomiting, seizures and loss of consciousness. [malacards.org]

  A few have seizures. Strokes are rare. [6] Auditory: Many have increased sensorineural hearing loss, starting in infancy/early childhood. [1], [6] Ophthalamic: Papilledema, uveitis, iritis, conjunctivitis. [autoinflammatory-search.org]

  Headache, vomiting, altered mental state, intellectual disability, seizures, episodes of hemiplegia and chronic meningitis-like states are CNS manifestations of the disease. [symptoma.com]

  She presented seizures at 6 months-old… CONTINUE READING [semanticscholar.org]

  Early treatment helps to prevent or reduce serious and life-threatening health problems such as: learning delays speech delays co-ordination problems enlarged liver metabolic crisis seizures [newbornscreening.on.ca]

• Papilledema

  Gallen (CH) A unilateral vision loss with papilledema is seldom seen during childhood. Possible causes are an optic neuritis, a cns-tumor in the orbital region or a vasculitis. [thieme-connect.com]

  Papilledema is common. Many have mental delay and/or cognitive delay, impairments, or intellectual disability. A few have seizures. [autoinflammatory-search.org]

  In addition, affected patients often show other features, including fever, lymphadenopathy, hepatosplenomegaly, progressive hearing loss, eye involvement (conjunctivitis, uveitis, papilledema, and optic nerve atrophy), abnormal crabiofacial features, [cags.org.ae]

  Miller SJHSanders MDFfytche TJ Fluorescein fundus photography in the detection of early papilledema and its differentiation from pseudo-papilledema. Lancet. 1965;2651- 654Google ScholarCrossref 21. [jamanetwork.com]

  Progressive pressure in the brain, and chronic CNS inflammation in most NOMID/CINCA patients often causes varying degrees of chronic papilledema in the eyes (bulging out of the optic discs in the back of the eyes.) [nomidalliance.org]

• Altered Mental Status

  Two patients had clinical evidence of CNS involvement with irritability and altered mental status. [adc.bmj.com]

To make the diagnosis, a thorough workup must be performed. Physical examination that reveals typical symptoms at a very early age can suggest CINCA syndrome and is the most important tool in making initial suspicion [11]. Laboratory findings reveal slight elevations of inflammatory parameters such as C-reactive protein and erythrocyte sedimentation rate (ESR), together with anemia and leukocytosis [5]. Radiography often reveals bony overgrowth, especially of the patella, while sensorineural deafness and optic atrophy may be diagnosed during physical examination. To confirm CINCA syndrome, genetic testing for NLRP3 mutation is necessary. Standard genetic testing, however, reveals mutations in only 50% of patients, primarily because a significant number of individuals have developed CINCA syndrome as a result of somatic NLRP3 mosaicism, which is significantly harder to identify [8]. In fact, between 10-69% of patients were shown to be mutation-negative, which is why whole-exome sequencing, a more powerful method of detection, is becoming more frequently used [8].

Initial treatment principles attempted to reduce inflammatory effects through the use of corticosteroids, non-steroidal anti-inflammatory drugs (NSAIDs) and anti-rheumatic drugs, but without major success [5]. Fortunately, the creation of drugs that target IL-1β have produced much better survival rates and significantly improved the quality of life. Anankira is an IL-1β receptor antagonist and is considered as first-line therapy in patients with CINCA syndrome. It is administered in the form of subcutaneous injections on a daily basis, as symptoms rapidly appear after its withdrawal [12]. Canakinumab is an IgG monoclonal antibody that has recently been approved for use in this patient group and its effects are similar to anankira, while rilonacept, the first drug to be used in patients with IL-1β abnormalities, acts by destroying formed IL-1 in the circulation before reaching target tissues [12].

The prognosis of patients suffering from CINCA syndrome almost solely depends on the time of diagnosis and initiation of appropriate treatment. The course of disease is chronic, with recurrent bouts of fever, arthralgia and other accompanying symptoms, while numerous complications eventually arise, such as severe bony deformities, IQ reduction, blindness and in up to 25% of patients, amyloidosis [5]. With the use of directed therapy, however, complications and mortality rates are substantially lower.

CINCA is caused by mutations of the nucleotide-binding oligomerization domain-like receptor (NLRP3) gene that is responsible for signal transduction in the innate immune system and eventual activation of IL-1β [9]. These mutations appear de novo in most cases, but autosomal dominant pattern of inheritance was also shown to be present [1]. So far, more than 80 mutations that trigger this disease have been discovered, but some patients may develop somatic NLRP3 mosaicism that cannot be detected on standard genetic testing [7]. Although certain studies have brought an early onset of symptoms and infectious pathogens into connection, attempts to deem any kind of microorganism as responsible have been unsuccessful [5].

CINCA belongs to the group of Cryopyrin-associated periodic syndrome (CAPS), together with familial cold-induced autoinflammatory syndrome (FCAS) and Muckle Wells syndrome (MWS) and they are considered to be quite rare in medical practice. Prevalence rates suggest that this entire group of disorders affects approximately 1 in 1 million individuals [2], while only about 100 cases of CINCA have been described in literature. Apart from positive family history, risk factors for this disease are currently not established, nor is gender or ethnic predilection.

The NLRP3 genes provide important information about the production of cryopyrin (NLRP3 protein), which belongs to the group of danger-signaling receptors, for ex. presence of a microbial pathogen or tissue damage and is an important constituent of the innate immune system [9]. Normally, this protein binds with several other molecules, including procaspase 1 to create the inflammasome, a key step in formation of active caspase 1 that eventually leads to production of IL-1β [6]. IL-1β initiates a pro-inflammatory cascade that provides an adequate response to the stimulus that is recognized as harmful. In the case of CINCA, however, NLRP3 genes are mutated and upregulated, leading to increased production of cryopyrin, inflammasome and eventually IL-1β. Persistent inflammation in the body occurs and leads to development of severe symptoms.

Although gene mutations that are responsible for development of CINCA syndrome, preventive strategies currently do not exist and the focus of reducing the burden of this condition remains on an early diagnosis.

Chronic infantile neurological cutaneous and articular syndrome (CINCA) is a very rare but severe and chronic inflammatory disorder that belongs to the group of Cryopyrin-associated periodic syndrome (CAPS) [1]. Together with familial cold autoinflammatory syndrome (FCAS) and Muckle Wells syndrome (MWS), CAPS occur in approximately 1 in 1 million individuals and only 100 cases have been described in literature so far [2]. In North America, CINCA is known as neonatal onset multisystemic inflammatory disease (NOMID). It arises due to either familial or de novo mutations in genes that regulate the production of interleukin-1β (IL-1β), one of the most important proinflammatory cytokines [1]. Under physiological circumstances, IL-1β secretion by polymorphonuclear (PMN) cells is triggered as a response to a harmful stimuli, such as lipopolisaccharide (LPS), but in patients suffering from CINCA, a constant production of this cytokine is observed without an obvious stimuli [3]. This overproduction stems from mutations in the NLRP3 protein (cryopyrin), a constituent of the IL-1β, whose mutations are found in up to 60% of patients when using standard genetic testing [2]. This pathophysiological process leads to a specific triad of symptoms that develop during the neonatal period - generalized rash, chronic aseptic meningitis and arthritis [4]. Rash is described as a non-pruritic urticaria that persists throughout childhood and into adulthood, whereas meningeal irritation manifests with headaches, transient episodes of hemiplegia and seizures [5]. The extent of joint involvement significantly varies from patient to patient and may range from mild arthralgia to severe complaints that occur due to patellar overgrowth and changes in both epiphyseal and metaphyseal plates, together with effusion of the synovial fluid [5]. Cognitive impairment, progressive hearing and vision loss, vomiting, bone pain and fever are described in these patients as well [6]. To make the diagnosis, a thorough clinical examination is necessary to asses the signs and symptoms and exclude other more common causes of rash, joint pain and meningitis. The ultimate diagnostic tool in a patient with a clinical suspicion toward CINCA is genetic testing for NLRP3 mutation [7]. Standard testing, however, does not reveal mutations in all patients, which is why whole-exome sequencing, an expensive but very accurate diagnostic method, is used to detect mutations that developed as a result of mosaicism [8]. Treatment focuses on reducing the activity of IL-1β, mainly through long-term administration of anankira, an IL-1β receptor antagonist [1]. Rilonacept, an inhibitor of IL-1β, and Canakinumab, an IgG monoclonal antibody, were recently approved for use, but their long-term effects remain to be seen [1]. Treatment, however, is only effective if the diagnosis is made early on, as damage caused by inflammatory changes may be irreversible and permanent. Growth retardation, brain atrophy, amyloidosis, retinal scarring and many other systemic complications may occur and can significantly impair the quality of life [6].

Chronic infantile neurological cutaneous and articular syndrome (CINCA) belongs to a group of disorders called Cryopyrin-associated periodic syndrome (CAPS), which are caused by mutations of genes that code for several molecules of the immune system. The exact cause of these mutations remain unknown, but they lead to overproduction of a molecule called interleukin-1 beta (IL-1β), a protein that is involved in generation of inflammation and stimulation of various immune cells, resulting in significant damage across different tissues. CINCA is very rare, as the entire group of disorders is seen in approximately 1 in 1 million individuals. CINCA syndrome is distinguished by its characteristic clinical presentation that involves the skin, joints and central nervous system changes. A rash usually develops in early neonatal period and resembles urticaria that is observed in allergies, while joint pain and bone overgrowth, especially of the patella is frequently observed. Headaches, seizures, vomiting and intellectual disability occur as a result of central nervous system involvement, while vision and hearing loss accompanied with fever are also reported. Usually, clinical findings seen during physical examination can be sufficient to make an initial diagnosis and is confirmed by genetic testing. Identification of NLRP3 gene mutations on both standard and advanced genetic evaluation is necessary to establish CINCA as the cause of symptoms. Until recently, therapeutic principles yielded slim results, but the introduction of IL-1β directed therapy has revolutionized the outcome of patients suffering from this condition. Anankira is an IL-1β antagonist, Canakinumab is an antibody that binds to IL-1β receptors, while rilonacept is a drug that destroys already produced IL-1β in the circulation. Regardless of the mechanism of action, the goal of therapy is to reduce the activity of this pro-inflammatory molecule and thus suppress the damage caused by profound inflammation. Treatment efficacy, however, significantly depends on the time of diagnosis, since early initiation of therapy may prevent irreversible damage to various organs, including the bones and the brain.

1. Neven B, Marvillet I, Terrada C, et al. Long-term efficacy of the interleukin-1 receptor antagonist anakinra in ten patients with neonatal-onset multisystem inflammatory disease/chronic infantile neurologic, cutaneous, articular syndrome. Arthritis Rheum. 2010;62:258-267.
2. Kone Paut I, Lachmann HJ, Kuemmerle Deschner JB, et al. Sustained remission of symptoms and improved health-related quality of life in patients with cryopyrin-associated periodic syndrome treated with canakinumab: results of a double-blind placebo-controlled randomized withdrawal study. Arthritis Res Ther. 2011;13:R202-10.
3. Tanaka T, Takahashi K, Yamane M, Tomida S, Nakamura S, Oshima K, et al. Induced pluripotent stem cells from CINCA syndrome patients as a model for dissecting somatic mosaicism and drug discovery. Blood. 2012;120(6):1299-1308.
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