NLRC4-associated autoinflammatory diseases

Summary
NLRC4-associated autoinflammatory syndrome is a very rare disease caused by a mutation in the NLRC4 gene. It usually starts in infancy with rashes, inflammation of the intestine, and episodes of fever. A serious complication is the occurrence of macrophage activation syndrome (MAS)

Symptoms
Onset of the disease is usually at infancy. The degree of severity varies. The symptoms of some patients are limited to rashes, muscle and joint pain, and fever. Severely affected children have inflammation of the intestines and recurrent episodes of fever. Some patients also have a hives-like skin disorder. There may also be recurrent episodes with Macrophage Activation Syndrome (MAS). With this, certain immune cells become so activated that they start attacking the body. As a result of this attack, the number of platelets and red and white blood cells decrease and fever and inflammation occur.  MAS can be triggered in patients with NLRC4-associated disease as a result of infections or physical stress.

Cause
NLRC4-associated disease is a genetic disease. The responsible gene is called NLRC4 and codes for the protein NLRC4.  This protein plays an important role in inflammatory responses. Mutations (errors) in the gene lead to increased activity of the protein, resulting in elevated inflammatory responses. These increased inflammatory responses are responsible for the clinical manifestations seen in NLRC4. It is likely that other genetic or environmental influences may influence the severity and symptoms of the disease.

Inheritance
It is inherited as an autosomal dominant disease. This means that the disease is not linked to gender and that one of the parents may have the same symptoms. This type of inheritance means that you only need to have 1 mutated gene to get the disease.

How is the diagnosis made
There has to be a suspicion of NLRC4-associated disease based on the child’s symptoms. The disease can be confirmed by means of genetic analysis.

Treatment
In patients with a mutation in NLRC4, we see an increased production of several inflammatory proteins, which we call cytokines. The most important cytokines are interleukin-1 and 18 (IL-1, IL-18 and γ-interferon), with IL-18 and γ-interferon likely playing a major role in the development of MAS. Treatment consists of inhibiting these cytokines by providing medication that neutralizes IL-1, IL-18 or γ-interferon. Out of these treatments, only IL-1 inhibitors are available in the Netherlands. However, not all patients respond well to this treatment and many patients are still treated with steroids, such as prednisone.

Prognosis
NLRC4-associated disease is a life-long disease. It is not possible to cure the disease completely because it is a hereditary disease. The symptoms and severity of the disease are not the same in all children. Even within one family, not all children with this disorder suffer from the disease to the same degree. The quality of life is affected, as patients suffer from decreased activity, fever, pain, and repeated episodes of severe inflammation. The life expectancy may be reduced in severely affected patients.