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.
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 . Headache, vomiting, altered mental state, intellectual disability, seizures, episodes of hemiplegia and chronic meningitis-like states are CNS manifestations of the disease  . 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  . Joint pain and symptoms appear in symmetric fashion, while synovial fluid effusion is commonly observed . Additional symptoms include optic nerve damage and potential loss of vision, hearing impairment, chronic anterior uveitis and fever  .
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 . Laboratory findings reveal slight elevations of inflammatory parameters such as C-reactive protein and erythrocyte sedimentation rate (ESR), together with anemia and leukocytosis . 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 . 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 .
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 . 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 . 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 .
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 . 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 . These mutations appear de novo in most cases, but autosomal dominant pattern of inheritance was also shown to be present . 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 . 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 .
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 , 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 . 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 . 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) . 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 . 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 . 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 . 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 . This pathophysiological process leads to a specific triad of symptoms that develop during the neonatal period - generalized rash, chronic aseptic meningitis and arthritis . 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 . 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 . Cognitive impairment, progressive hearing and vision loss, vomiting, bone pain and fever are described in these patients as well . 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 . 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 . Treatment focuses on reducing the activity of IL-1β, mainly through long-term administration of anankira, an IL-1β receptor antagonist . 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 . 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 .
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.