NORD gratefully acknowledges Kara Mossler, MD Candidate, Georgetown University School of Medicine, and Scott W. Canna, MD, Assistant Professor of Pediatrics and of Immunology, Division of Pediatric Rheumatology, University of Pittsburgh School of Medicine, for the preparation of this report.
Autoinflammation with infantile enterocolitis (AIFEC) is a newly identified and extremely rare inflammatory disorder that manifests early in infancy and affects patients throughout adulthood. AIFEC is caused by a change (mutation) in the NLRC4 gene, resulting in increased inflammation and damage to healthy tissues (autoinflammation). Patients with NLRC4 mutations present with enterocolitis (inflammation of the digestive tract causing diarrhea) in infancy and flares of severe and sometimes life-threatening autoinflammation throughout life. Macrophage activation syndrome (MAS), the type of autoinflammation seen in AIFEC, causes fevers, enlarged spleen, blood disturbances, and can progress to organ damage and death if not treated.
AIFEC is characterized by a variety of symptoms related to the activation of inflammatory processes. The overactivation of the patient’s immune system is destructive to the patient’s healthy tissues and may be life-threatening. Symptoms often occur in flares alternating with largely symptom-free periods. The exact cause of the flares is not completely understood, but may be linked to emotional stress, physical stress, and/or stresses on the immune system such as viral or bacterial infections.
Though fever and flu-like symptoms are the most common symptoms in AIFEC patients, many patients also develop enterocolitis, or inflammation of the digestive tract. This enterocolitis can range in severity from mild to life-threatening in AIFEC patients. It usually causes a severe watery diarrhea, and may also cause vomiting. This diarrhea usually occurs only in infancy and resolves after the child is about 1-year-old. Patients with severe diarrhea may need extra nutrition in the hospital in the form of fluid provided into a vein (total parenteral nutrition, TPN). The other inflammatory symptoms usually persist into adulthood.
The type of autoinflammation seen in AIFEC is sometimes called macrophage activation syndrome (but MAS is not only found in AIFEC) because one kind of immune cells, macrophages, appear to be particularly overactivated. MAS can cause fever, fast heart rate, decreased numbers of cells in the blood, clotting problems, increased fats in the blood, changes in iron handling, large spleen, and other blood abnormalities that indicate inflammation. Less commonly, organ-specific symptoms can include spotted, bumpy, and/or itchy rashes, loss of consciousness, seizures, breathing problems, and liver dysfunction. Without treatment, symptoms may progress to severe blood clotting problems (DIC), organ failure, and death. Muscle pain, joint pain, anemia (decreased ability for the blood to carry oxygen), and short height have also been observed in adults with AIFEC.
AIFEC is caused by a mutation in the NLCR4 gene resulting in activation of the NLRC4 protein, an important component of the immune system in healthy individuals. Proteins found on the surface of certain bacteria such as Salmonella and Pseudomonas are normally recognized by a receptor (NAIP) found on the patient’s immune system and intestinal cells – this is a way for the human body to recognize foreign bacteria so that it can begin to fight them off. When the NAIP receptor senses bacteria, it then activates NLRC4. Once activated, NLRC4 quickly works with other proteins to form a complex called the NLRC4 inflammasome. This inflammasome complex works inside cells of the immune system (including macrophages) to generate inflammatory cytokines, like IL-1 and IL-18, and to trigger cells infected with the bacteria to die. The activated immune system can also cause intestinal cells infected with the bacteria to be shed into the gut lumen. This causes diarrhea, but also prevents the bacteria from crossing over from the gut into the rest of the body where they could cause more damage.
When mutations cause the NLRC4 protein to always be active, it results in widespread activation of the immune system even when bacteria are not present. This uncontrolled activation causes damage to the patient’s healthy cells resulting in the symptoms of AIFEC. When NLRC4 is always active in intestinal cells, it causes constant shedding of the lining of the GI tract causing enterocolitis (diarrhea). It is not yet understood why diarrhea is present only in infancy, but it may relate to the fact that an infant’s gut bacteria (microbiota) is still developing.
AIFEC follows an autosomal dominant pattern of inheritance. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary to cause a particular disease. The abnormal gene can be inherited from either parent or can be the result of a mutated gene in the affected individual. The risk of passing the abnormal gene from an affected parent to an offspring is 50% for each pregnancy. The risk is the same for males and females. AIFEC has been observed in some patients due to somatic mutations, meaning the mutation isn’t even present in all of the patient’s cells.
Very few patients have been identified with the activating NLRC4 mutations that cause AIFEC. Seven patients have been identified since the first patients were diagnosed in 2014. Due to the low number of patients, it is so far unclear what puts patients at increased risk of acquiring the disease-causing mutation other than having a parent with the disease.
The physician will first perform a clinical evaluation based on the patient’s symptoms. Blood tests will likely show a variety of blood abnormalities including: markers of inflammation (high CRP, high ferritin, high IL2R), signs of overactive NLRC4 (high IL18), as well as pancytopenia (decreased cells in the blood). Exam of the patient’s gastrointestinal tract (endoscopy or colonoscopy), including intestinal biopsies, may show intestinal lesions/injuries and inflammation in infants. A bone marrow biopsy may show signs that overactive immune cells are targeting healthy cells. If skin lesions are present, the physician may biopsy them to see if inflammatory cells are present. Eventually genetic tests will show an activating mutation of the NLCR4 gene.
AIFEC is so recently identified and so few patients have been diagnosed that no medications are currently considered standard. Treatment is often by trial and error because one patient may respond differently to a drug than another patient. Some of the drugs that have been used with varying success are general anti-inflammatory drugs like corticosteroids, cyclosporine, and IVIg. Some more specific therapies targeted to the patient’s overactive immune system include IL1 inhibitor (anakinra), TNF inhibitor (infliximab), and integrin-inhibitors (vedolizumab).
One of the most promising investigational therapies currently in clinical trials (NCT03113760) is IL-18BP (IL-18 binding protein), which has been shown to dramatically reduce IL-18 activity in the blood and thereby reduce some of the symptoms caused by overactive NLRC4.
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Liang J, Alfano DN, Squires JE, et al. Novel NLRC4 mutation causes a syndrome of perinatal autoinflammation. Pediatr Dev Pathol. 2017;20(6):498-505.
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Romberg N, Al Moussawi K, Nelson-Williams C, et al. Mutation of NLRC4 causes a syndrome of enterocolitis and autoinflammation. Nature Genet. 2014;46: 1135-1139.
Canna SW, de Jesus AA, Gouni S, et al. An activating NLRC4 inflammasome mutation causes autoinflammation with recurrent macrophage activation syndrome. Nature Genet. 2014;46: 1140-1146.
Online Mendelian Inheritance in Man (OMIM). The Johns Hopkins University.Autoinflammation with Infantile Enterocolitis. Entry No:616050. Last Edited 05/16/2017. Available at: https://www.omim.org/entry/616050 Accessed July 12, 2018.
NLRC4 Gene. Genetics Home Reference. https://ghr.nlm.nih.gov/gene/NLRC4#conditions Accessed July 17, 2018.
Aliases for NLRC4 Gene. Gene Card Human Gene Database. https://www.genecards.org/cgi-bin/carddisp.pl?gene=NLRC4 Accessed July 17, 2018.
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