Chronic infantile neuro-cutaneo-articular syndrome (CINCA syndrome) is an autoinflammatory disorder that causes a spurious inflammatory response in the body. The syndrome manifests itself in infancy, including fever, pain, and neurological symptoms. Treatment is with the help of drugs that reduce the protein interleukin-1β.
What is CINCA syndrome?
The term chronic infantile neuro-cutaneo-articular syndrome (CINCA syndrome) refers to a form of cryopyrin-associated periodic syndrome. Medical science groups several autoinflammatory diseases under this term; Muckle-Wells syndrome and Familial Cold-Induced Autoinflammatory Syndrome (FCAS) also belong to this group. In an autoinflammatory disease, the body reacts as if to inflammation – however, in reality, the inflammation is not present. Autoinflammatory diseases are thus similar to autoimmune diseases, but in which the body turns against its own immune system. All three forms of cryopyrin-associated periodic syndrome share their genetic basis: a gene defect interferes with the normal inflammatory response and triggers it, even though there is no actual cause. CINCA syndrome first appears in infancy.
Causes
CINCA syndrome is an inherited disease for which the NLRP3 gene is responsible. The NLRP3 gene is located on chromosome 1 and is dominant. This means that a single mutated allele is already sufficient for CINCA syndrome to manifest in the affected individual. However, whether an affected parent passes the disease to a child depends largely on chance; the probability of inheritance is 50 percent. The NLRP3 gene encodes the protein cryopyrin, which transmits inflammatory signals. In addition, cryopyrin also plays a role in cell self-destruction (apoptosis) – ensuring that damaged cells disappear and do no harm to the body. Cryopyrin stimulates the synthesis of interleukin-1β. This is a messenger substance that promotes inflammation. Interleukin-1β stimulates liver cells to produce serum amyloid A protein (SAA). Three different variants of acute-phase SAAs exist, which are known to medicine today. These SAAs are responsible for the acute inflammatory response and trigger the symptoms of CINCA syndrome. SAA-1 and SAA-2 are involved in the inflammatory reaction of the liver. In studies, medical researchers also found SAA-3 in other tissues; it appears to trigger the inflammatory responses there.
Symptoms, complaints, and signs
The symptoms of CINCA syndrome are more severe than those of the other two forms of cryopyrin-associated periodic syndrome. In CINCA syndrome, symptoms may present in episodes or continuously. Typical symptoms include fever, rash or hives, hearing loss, joint pain (arthralgia), and muscle pain (myalgia). These signs of disease may also manifest in other autoinflammatory disorders. However, CINCA syndrome is distinguished from them by, among other things, its early onset: Infants can already develop the disease. In addition to the general symptoms of cryopyrin-associated periodic syndromes, other complaints occur. CINCA syndrome can affect the central nervous system (CNS) and lead to meningitis, which is chronic. Furthermore, the disease potentially causes seizures and increases incranial pressure. This is the pressure that exists in the brain. Normally, it is 5 to 15 mm Hg. If the incranial pressure increases, affected individuals initially experience symptoms such as nausea, vomiting, fatigue, restlessness, bradycardia, headache and vigilance problems. Advanced signs of intracranial pressure include quantitative disorders of consciousness such as somnolence, which manifests primarily as severe drowsiness and unusual sleepiness. In stupor, affected individuals are difficult to awaken and respond only to strong painful stimuli. CINCA syndrome can also cause the most severe quantitative disorder of consciousness: coma. The disease also potentially causes lymph node swelling, kidney damage, and blindness.
Diagnosis and course
CINCA syndrome begins in infancy. For this reason, medicine refers to it as neonatal-onset inflammatory systemic disease.During diagnosis, doctors detect inflammatory markers in the blood that form a specific pattern. Based on this pattern, they can distinguish CINCA syndrome from other inflammatory diseases.
Complications
Various symptoms occur as a result of CINCA syndrome. These may occur mainly in episodes, so that the affected person has no particular symptoms in between. In most cases, there is a skin rash and fever. Furthermore, there is also pain in the muscles and extremities, which complicates the daily life of the affected person. The joints may also hurt and there is hearing loss. In the worst case, this hearing loss leads to complete hearing loss. Without treatment, CINCA syndrome leads to meningitis, which can cause paralysis and other sensory disturbances. Convulsions and epileptic seizures also occur. The affected person generally feels tired and exhausted and no longer takes an active part in life. Due to the constant pain and discomfort, it is not uncommon for psychological upsets and depression to occur. Furthermore, blindness or renal insufficiency may occur if CINCA syndrome is not treated. The treatment itself does not lead to further complications and can relieve the symptoms. However, treatment usually needs to be repeated more often.
When should you see a doctor?
If CINCA syndrome is suspected, the doctor should be consulted immediately. Typical warning signs that require medical evaluation include fever, skin rash, joint and muscle pain, and hives and hearing loss. Anyone who notices one or more of these symptoms should seek medical advice immediately. If signs of meningitis appear, the hospital should be sought. Seizures, severe headaches and impaired consciousness must also be clarified immediately and treated if necessary. In the event of stupor or coma, emergency medical assistance is required. If possible, the affected person should be given first aid and then treated immediately by a specialist. A longer hospital stay is necessary in any case after such a severe course. Depending on the subsequent symptoms, other physicians may need to be consulted. In case of hearing loss, an ear specialist must be consulted, while blindness must be treated by an eye specialist and later by an ophthalmologist. If psychological upsets and depression occur, a visit to a therapist is recommended.
Treatment and therapy
Because drugs and other therapies cannot affect the triggering mutation in the NLRP3 gene, treatment of CINCA syndrome is directed against the chain reaction that causes the inflammatory symptoms. Anakinra is frequently used in this context. This drug is a receptor antagonist of interleukin-1 and affects both interleukin-1α and interleukin-1β. Anakinra can relieve hearing loss as well as normalize the erythrocyte sedimentation rate and the amount of C-reactive protein in the blood. It is taken at about the same time each day. Affected individuals can inject it themselves. Another drug that may be used in CINCA syndrome is canakinumab. This is an agent that targets only the protein interleukin-1β, making it more specific. In contrast to anakinra, those affected only have to repeat the canakinumab injection at longer intervals. As a rule, there are several weeks between two injections. Doctors sometimes treat acute inflammatory symptoms of CINCA syndrome with cortisone-containing drugs. It is often necessary for affected individuals to take pain medications for joint and muscle discomfort.
Outlook and prognosis
In general, treatment for CINCA syndrome is always directed against the inflammation, with the goal being to limit the chain reaction of inflammation. Causal treatment is not possible in this syndrome. However, with the help of medication, the symptoms can be limited relatively well. Hearing loss is also alleviated, since it does not occur as a result of damage to the ear. There are also no particular complications, although those affected are dependent on lifelong therapy in order to permanently alleviate the symptoms.In CINCA syndrome, the pain in the muscles and joints is relieved with the help of painkillers, although no causal therapy is possible either and patients are dependent on permanent treatment. If no treatment of CINCA syndrome occurs, the inflammations spread over the entire body of the patient and can lead to severe complications and, in the worst case, to the death of the affected person. Treatment is therefore necessary from infancy for the child to survive. However, it cannot be predicted whether CINCA syndrome will negatively affect life expectancy if treated.
Prevention
Currently, there is no effective way to causally prevent genetic diseases such as CINCA syndrome. Because the condition appears in infancy, there is less room for measures that affect general health. Healthy eating and good stress management may help limit complications. Recognized relaxation techniques such as progressive muscle relaxation or autogenic training potentially reduce individual symptoms such as pain. Children can learn such techniques starting around preschool age. Because CINCA syndrome is a severe chronic disease that drastically affects lifestyle, children often benefit from psychosocial interventions as well.
Follow-up
In most cases, patients with CINCA syndrome have no options for follow-up care. This condition is a congenital disease and therefore cannot be treated causally, only symptomatically. If the person affected by CINCA syndrome wishes to have children, genetic counseling can be performed beforehand to prevent the syndrome from being passed on to the children. As a rule, the syndrome itself is treated with the help of medication. No particular complications occur and the symptoms can be relatively well alleviated. However, the affected person is dependent on the regular intake of these medications. Furthermore, the interactions with other medications should also be taken into account. It is not uncommon for CINCA syndrome to lead to psychological complaints or depressive moods. If these complaints also occur, discussions with friends or with one’s own family can also be very helpful. In case of severe psychological complaints, however, a visit to a psychologist is essential. Furthermore, contact with other patients of CINCA syndrome can often prove to be very useful, as this often leads to an exchange of information. The patient’s life expectancy is not negatively affected by CINCA syndrome.
Here’s what you can do yourself
Individuals who have CINCA syndrome usually suffer from a variety of symptoms. The most important self-help measure is to take the prescribed medications regularly and to carry out the therapeutic measures prescribed by the physician. Accompanying this, therapeutic counseling is useful. Particularly in the case of severe disorders, it can help to talk to a specialist who may also be able to put you in touch with other sufferers. Furthermore, the diet must be changed in the case of CINCA syndrome. To prevent typical symptoms such as skin rash, joint pain, hives and fever, an individual diet is necessary. For this purpose, patients are best advised to consult a specialist physician or a nutritionist. Lastly, patients need plenty of bed rest and sparing. The disease places an enormous strain on the entire body, and major exertion and stress should therefore be avoided. Moderate exercise and coordinated occupational therapy are permitted, which is also best implemented together with a professionally trained physician. CINCA syndrome also always requires close medical monitoring. Especially in case of unusual symptoms or acute complaints, the responsible medical professional should be consulted promptly.
