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CINCA Syndrome

Neonatal-Onset Multisystem Inflammatory Disease

Chronic infantile neurological cutaneous and articular syndrome (CINCA) is characterized by a neonatal onset of rash, arthritis and central nervous system symptoms as a result of chronic inflammation. Genetic mutations that promote overstimulation of proinflammatory cytokines are the underlying cause and identification of these mutations is the key in making the diagnosis. Suppression of IL-1 by various immunomodulating drugs is the mainstay of therapy.

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Presentation

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
  • 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]
  • Anaemia and associated hepato-splenomegaly are well described in CINCA patients [ 12 ].[ped-rheum.biomedcentral.com]
  • The CINGA syndrome is a chronic inflammatory disease and the children usually have to contend with numerous flare-ups that may be associated with a fever (low grade or high spiking), splenomegaly, and adenomegaly.[healio.com]
  • Cervical lymphadenopathy is a common manifestation of HIDS, as are severe headache and splenomegaly. Pleurisy is uncommon. Amyloidosis has not been reported in patients with HIDS.[emedicine.medscape.com]
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]
  • 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]
  • In patients with elevated intracranial pressure, closure of the anterior fontanelle may be delayed, and macrocrania, frontal bossing, and saddle nose appearance are frequently noted. [ 56 ] Ancillary testing/diagnosis Patients with NOMID/CINCA usually[emedicine.medscape.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]
Fever
  • CINCA syndrome is a genetic disorder characterized by early onset of recurrent fever, rash, progressive articular and neurological involvement.[ncbi.nlm.nih.gov]
  • Clinical features include fever episodes, urticarial rash, arthralgia and arthritis, eyes and central nervous system involvement.[vestnik.szd.si]
  • Cognitive impairment, progressive hearing and vision loss, vomiting, bone pain and fever are described in these patients as well.[symptoma.com]
  • […] neurologic, cutaneous, articular (CINCA) syndrome is a rare congenital autoinflammatory disease characterized by neonatal-onset chronic meningitis, hydrocephalus, sensorineural hearing loss, persistent urticarial rash, deforming arthritis, and recurrent fever[ncbi.nlm.nih.gov]
  • In five toddlers with missense mutations in TRNT1 , indicator hints included expensive fevers, anemia, and neurologic involvement. The neonates also had dysmorphic stamps.[vxla.net]
Disability
  • 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.[ncbi.nlm.nih.gov]
  • Being well tolerated, it can be introduced already in neonates presenting clinical signs of severe CINCA syndrome in order to rapidly control inflammation and to prevent life-long disability.[ncbi.nlm.nih.gov]
  • Nowadays, the use of anti-IL-1 drugs has sensibly reduced the risk of developing main complications such as severe intellectual disability, hearing-loss and amyloidosis, if treatment is started early on.[ncbi.nlm.nih.gov]
  • This may change with successful treatment now minimising neurological disability.[dermnetnz.org]
  • Autoimmune diseases are a family of more than 100 chronic, and often disabling, illnesses that develop when underlying defects in the immune system lead the body to attack its own organs, tissues, and cells.[books.google.com]
Anemia
  • 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]
  • In five toddlers with missense mutations in TRNT1 , indicator hints included expensive fevers, anemia, and neurologic involvement. The neonates also had dysmorphic stamps.[vxla.net]
  • Anemia is frequent. 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.[en.wikipedia.org]
  • He also was found to have a mild iron deficiency anemia with a leukocytosis. At the age of 2, he was admitted with a painful swollen left knee, lymphadenopathy, and fever.[healio.com]
  • (low hematocrit, hemoglobin and microcytic anemia), High polynuclear leukocytes, and thrombocytes (on a Complete Blood Count of the White Blood Cells [WBC's]), and many other changes.[autoinflammatory.org]
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]
  • 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]
  • At the age of 2, he was admitted with a painful swollen left knee, lymphadenopathy, and fever.[healio.com]
  • Also, patients develop osteopathy and long-bone epiphyseal overgrowth, growth delay, and progressive sensory neural hearing loss, lymphadenopathy, with/or without hepatosplenomegaly.[clevelandclinicmeded.com]
Chills
  • She had no fever or neurologic or cardiorespiratory distortions, but markers of irritation were chilling and she was treated with antimicrobial deputes for 4 days without healing.[vxla.net]
  • Signs & Symptoms Patients with FCAS experience mild to debilitating symptoms such as rash, fatigue, recurrent fever and chills, recurrent joint pain, and recurrent conjunctivitis (inflammation of the outer most layer of the eye causing redness, discomfort[rarediseases.org]
  • The mildest form of CAPS is familial cold urticaria (also known as familial cold autoinflammatory syndrome, FCAS) causes flu-like symptoms with fever, chills and painful joints a few hours after exposure to cold.[gesundheitsindustrie-bw.de]
  • The main symptoms are recurrent episodes of fever typically lasting two or three weeks, associated with chills and intense muscle pain involving the trunk and the upper limbs.[my.clevelandclinic.org]
  • Episodes are often heralded by chills and headache, a rising fever, abdominal pain, nausea, and vomiting.[emedicine.medscape.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]
  • The chronic meningitis presents with the features of chronically raised intracranial pressure: headaches, vomiting, ventriculomegaly , hydrocephalus , macromegaly, cerebral atrophy , and optic atrophy .[en.wikipedia.org]
  • Some patients may also vomit repeatedly and have excessive thirst during flares, along with severe headaches, irritability and pain at the joints and spine. They have great discomfort during very frequent, almost daily flare-ups.[autoinflammatory.org]
  • Other symptoms may include: headaches, seizures , and vomiting resulting from chronic meningitis (inflammation of the tissue that covers and protects the brain and spinal cord); intellectual disability ; episodes of mild fever; and hearing and vision[rarediseases.info.nih.gov]
Hepatosplenomegaly
  • Hepatosplenomegaly was confirmed by abdominal ultrasound. A maculopapular skin rash was first observed at 11-months of age.[cags.org.ae]
  • 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]
  • The systemic form occurs in about 20% of children and may not have prominent joint symptoms, but may cause a remitting fever, hepatosplenomegaly, and abdominal pain.[healio.com]
  • […] retinal vasculitis – rare Physical appearance Prominent forehead Flattening of the nasal bridge (saddleback nose) Large head (macrocephaly) – 95% Large fontanelle Short stature Short thick extremeties Finger clubbing Other Liver and spleen enlargement ( hepatosplenomegaly[dermnetnz.org]
  • Also, patients develop osteopathy and long-bone epiphyseal overgrowth, growth delay, and progressive sensory neural hearing loss, lymphadenopathy, with/or without hepatosplenomegaly.[clevelandclinicmeded.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]
  • These syndromes were initially described as distinct clinical entities despite some clinical similarities: patients often present overlapping symptoms including fever, skin eruption appearing like hives (pseudo-urticarial) and joint involvement of varying[printo.it]
  • […] neurologic cutaneous and articular (CINCA) syndrome One of the auto-inflammatory syndromes whose onset is associated with NLRP3 gene mutation, this is a chronic inflammatory disease with immediate postnatal onset characterized by three main symptoms: dermal eruption[cira.kyoto-u.ac.jp]
Progressive Sensorineural Deafness
  • 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.[autoinflammatory.org]
  • 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]
  • MWS is characterized by progressive sensorineural deafness as well as recurrent episodes of skin rash, fever and arthralgia (1).[medicaljournals.se]
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.[autoinflammatory.org]
Arthritis
  • This primary systemic inflammatory disorder should be distinguished from juvenile rheumatoid arthritis (JRA).[ncbi.nlm.nih.gov]
  • Chronic infantile neurologic, cutaneous, articular (CINCA) syndrome is a rare congenital autoinflammatory disease characterized by neonatal-onset chronic meningitis, hydrocephalus, sensorineural hearing loss, persistent urticarial rash, deforming arthritis[ncbi.nlm.nih.gov]
  • Joint involvement may vary from minimal swelling to destructive arthritis, with inability to stand or walk.[ncbi.nlm.nih.gov]
  • Features of CINCA duvet rash, arthritis, and neurologic displays embracing attend to breakdown.[vxla.net]
  • Arthritis Rheum. 2010, 62: 258-267.[ped-rheum.biomedcentral.com]
Arthralgia
  • 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]
  • 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]
  • Clinical features include fever episodes, urticarial rash, arthralgia and arthritis, eyes and central nervous system involvement.[vestnik.szd.si]
  • MWS is characterized by progressive sensorineural deafness as well as recurrent episodes of skin rash, fever and arthralgia (1).[medicaljournals.se]
  • FCAS MWS CINCA/NOMID Cold triggered Rare cold triggered No cold triggered Recurrent episodes of fever Recurrent episodes of fever Fever Urticaria Urticaria Urticaria Arthralgia/myalgia Arthralgia/arthritis Arthralgia/arthritis/severe arthropathies Conjunctivitis[clevelandclinicmeded.com]
Myalgia
  • Myalgia is another frequent finding in patients with FMF (reported in 20% of cases).[emedicine.medscape.com]
  • FCAS MWS CINCA/NOMID Cold triggered Rare cold triggered No cold triggered Recurrent episodes of fever Recurrent episodes of fever Fever Urticaria Urticaria Urticaria Arthralgia/myalgia Arthralgia/arthritis Arthralgia/arthritis/severe arthropathies Conjunctivitis[clevelandclinicmeded.com]
  • […] cases, often with concurrent constitutional symptoms such as fatigue, malaise, mood disorders or failure to thrive), skin rash (either urticarial or maculopapular rash ; 97% of cases) especially after cold exposure, and musculoskeletal involvement ( myalgia[en.wikipedia.org]
  • […] site reaction/pain, future malignancy Rilonacept Infection, injection site reaction, hypersensitivity reaction, hyperlipidemia, possible risk of future malignancy Canakinumab Infection, injection site reaction, diarrhea, nausea, vertigo, weight gain, myalgias[clinicaladvisor.com]
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]
  • […] conjunctivitis papillitis optic atrophy can result in loss of vision – 25% of adults have major visual impairment including blindness retinal vasculitis – rare Physical appearance Prominent forehead Flattening of the nasal bridge (saddleback nose) Large head (macrocephaly[dermnetnz.org]
Joint Swelling
  • 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]
  • Usually the joint swelling resolves over 5-14 days. In about 5-10% of cases the joint involvement may become chronic. Some children report muscle pain in the legs.[my.clevelandclinic.org]
Frontal Bossing
  • From the first days of life, patients display an urticarial rash in association with chronic inflammation with a typical facies featured by frontal bossing and saddle back nose.[ncbi.nlm.nih.gov]
  • 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]
  • 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]
  • Hypertrophic arthropathy with contractures and bone deformity (frontal bossing, patellar overgrowth) is also typical of this form.[ojrd.biomedcentral.com]
Renal Impairment
  • In our cohort, two of the three children with renal impairment died, even though they were diagnosed early on in the course of this complication.[adc.bmj.com]
  • These findings suggest that even in patients with established amyloidosis, effective treatment of the underlying syndrome can lead to improved renal function and regression of amyloid, as long as renal impairment is not too advanced at time of diagnosis[ojrd.biomedcentral.com]
Headache
  • 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]
  • Headache, vomiting, altered mental state, intellectual disability, seizures, episodes of hemiplegia and chronic meningitis-like states are CNS manifestations of the disease.[symptoma.com]
  • Central nervous system involvement is revealed by chronic headaches due to chronic meningitis with granulocytes. In the severe forms, intellectual deficit can occur.[orpha.net]
  • Periodic Fevers & Flare-ups Often, NOMID syndrome causes bouts of fevers (starting in infancy), accompanied by flare-ups of the rash, increased pain in the joints, headaches, red eyes and other symptoms.[autoinflammatory.org]
  • Early chapters present differential diagnosis and management approaches to common overarching problems such as coma, headache, and elevated intracranial pressure, followed by chapters focusing on the evaluation and management of specific conditions including[books.google.de]
Seizure
  • Headache, vomiting, altered mental state, intellectual disability, seizures, episodes of hemiplegia and chronic meningitis-like states are CNS manifestations of the disease.[symptoma.com]
  • CNS symptoms include chronic meningitis, mental retardation, seizures and sensory organ dysfunction, which results in vision and hearing loss. Joint inflammation and joint and bone deformities range in severity.[rarediseases.org]
  • […] diagnosis and management approaches to common overarching problems such as coma, headache, and elevated intracranial pressure, followed by chapters focusing on the evaluation and management of specific conditions including traumatic brain injury, stroke, seizures[books.google.de]
  • The following are common symptoms of NOMID/CINCA: Fever Skin rashes Chronic meningitis Mental retardation Seizures Sensory organ dysfunction which may result in vision and hearing loss Joint inflammation and joint and bone deformities Enlargement of the[patientworthy.com]
  • Seizures occur in 25% of cases, but other manifestations are rare. Histological examination shows infiltration of the meninges with polymorphs .[en.wikipedia.org]
Altered Mental Status
  • Two patients had clinical evidence of CNS involvement with irritability and altered mental status.[adc.bmj.com]

Workup

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].

Treatment

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].

Prognosis

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.

Etiology

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].

Epidemiology

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.

Sex distribution
Age distribution

Pathophysiology

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.

Prevention

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.

Summary

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].

Patient Information

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.

References

Article

  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.
  4. de Boeck H, Scheerlinck T, Otten J. The CINCA syndrome: a rare cause of chronic arthritis and multisystem inflammatory disorders. Acta Orthop Belg. 2000;66(5):433-437.
  5. Prieur AM. A recently recognized chronic inflammatory disease of early onset characterized by the triad of rash, central nervous system involvement and arthropathy. Clin Exp Rheumatol 2001;19:103-106.
  6. Goldbach-Mansky R. Current Status of Understanding the Pathogenesis and Management of Patients With NOMID/CINCA. Curr Rheumatol Rep. 2011;13(2):123-131.
  7. Omoyinmi E, Gomes SM, Standing A, et al. Brief Report: Whole-exomesequencing revealing somatic NLRP3 mosaicism in a patient with chronic infantile neurologic, cutaneous, articular syndrome. Arthritis Rheum 2014;66:197–202.
  8. Saito M, Fujisawa A, Nishikomori R, et al. Somatic mosaicism of CIAS1 in a patient with chronic infantile neurologic,cutaneous, articular syndrome. Arthritis Rheum 2005;52:3579-3585.
  9. Tanaka N, Izawa K, Saito MK, et al. High incidence of NLRP3 somatic mosaicism in patients with chronic infantile neurologic, cutaneous, articular syndrome: results of an International Multicenter Collaborative Study. Arthritis Rheum. 2011;63:3625-3632.
  10. Feldmann J, Prieur A-M, Quartier P, et al. Chronic Infantile Neurological Cutaneous and Articular Syndrome Is Caused by Mutations in CIAS1, a Gene Highly Expressed in Polymorphonuclear Cells and Chondrocytes. Am J Hum Genet. 2002;71(1):198-203.
  11. Paccaud Y, Berthet G, Von Scheven-Gête A, et al. Neonatal treatment of CINCA syndrome. Pediatr Rheumatol Online J. 2014;12:52.
  12. Church LD, Savic S, McDermott MF. Long term management of patients with cryopyrin-associated periodic syndromes (CAPS): focus on rilonacept (IL-1 Trap). Biologics. 2008;2(4):733-742.

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Last updated: 2018-06-22 11:30