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Last updated:
8/20/2025
Years published: 2018, 2025
NORD gratefully acknowledges Gioconda Alyea, MD (FMG), MS, National Organization for Rare Disorders, Kara Mossler, MD 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.
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Autoinflammation with infantile enterocolitis (AIFEC) is a newly identified and extremely rare genetic disorder that causes chronic, damaging inflammation beginning in infancy and continuing through life.
AIFEC is caused by a change (variant) in the NLRC4 gene, which triggers excessive immune activity and widespread inflammation that harms healthy tissues without infection (autoinflammation).
Infants with AIFEC often develop enterocolitis, a severe inflammation of the digestive tract that leads to persistent diarrhea. Over time, they may experience repeated flares of macrophage activation syndrome (MAS), a serious immune reaction marked by high fevers, enlarged spleen, abnormal blood counts and risk of organ failure or death if untreated.
The combination of enterocolitis and recurring MAS episodes makes AIFEC a serious and complex condition requiring careful management and treatment.
AIFEC is characterized by a variety of symptoms related to the activation of inflammatory processes. The overactivation of the person’s immune system is destructive to the person’s own 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, many people with AIFEC also develop enterocolitis, or inflammation of the digestive tract. This enterocolitis can range in severity from mild to life-threatening. It usually causes the following symptoms:
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 cell, macrophages, appears to be particularly overactivated. MAS symptoms may include:
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, decreased ability of the blood to carry oxygen (anemia) and short height have also been observed in adults with AIFEC.
AIFEC is caused by a variant 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 a person’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 a variant in the NLRCA gene causes 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 healthy cells resulting in symptoms of AIFEC. When NLRC4 is always active in intestinal cells, it causes constant shedding of the lining of the GI tract causing diarrhea (enterocolitis). 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) are still developing.
AIFEC follows an autosomal dominant pattern of inheritance. Dominant genetic disorders occur when only a single copy of a disease-causing gene variant is necessary to cause the disease. The gene variant can be inherited from either parent or can be the result of a new (de novo) changed gene in the affected individual that is not inherited. The risk of passing the gene variant from an affected parent to a child is 50% for each pregnancy. The risk is the same for males and females.
Very few patients have been identified with the activating NLRC4 variants that cause AIFEC. As of 2025, less than 15 patients have been identified since the first patients were reported in 2014.
A diagnosis of AIFEC may be suspected based on the person’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 decreased cells in the blood (pancytopenia). Exam of the 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 doctor may biopsy them to see if inflammatory cells are present. The diagnosis is confirmed with genetic testing that shows an activating variant of the NLCR4 gene.
Treatment
AIFEC is so recently identified and so few patients have been diagnosed that no medications are currently considered standard. Treatment is often determined 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).
Tadekinig alfa is a lab-made (recombinant) protein that binds to interleukin-18 (IL-18), helping to block the harmful immune and inflammatory responses caused by excessive IL-18. In the United States, it has been granted Orphan Drug, Breakthrough Therapy, and Rare Pediatric Disease designations. It has also received Orphan Drug status in Europe. Research is ongoing to determine if this is an effective treatment for AIFEC.
Information on current clinical trials is posted on the Internet at https://clinicaltrials.gov/ All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government website.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Toll Free: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]
Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/
For information about clinical trials sponsored by private sources, contact:
https://www.centerwatch.com/
For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/
JOURNAL ARTICLES
Khalesi M, Vahedi S, Jafari S, Malek A, Kianifar HR, Vahedi M. Challenges in the Diagnosis of Infantile Enterocolitis and Rare Auto-Inflammatory Syndromes: A Case Report and Literature Review. Clin Case Rep. 2025;13(7):e70521. Published 2025 Jul 16. doi:10.1002/ccr3.70521
Asna Ashari K, Parvaneh N, Mirnia K, et al. Three cases of autoinflammatory disease with novel NLRC4 mutations, and the first mutation reported in the CARD domain of NLRC4 associated with autoinflammatory infantile enterocolitis (AIFEC). Pediatr Rheumatol Online J. 2024;22(1):90. Published 2024 Oct 18. doi:10.1186/s12969-024-01020-z
Wang Y, Gao JZ, Gurung P, et al. An animal model for autoinflammation with infantile enterocolitis. The Journal of Immunology. 2023;210, Issue Supplement_1. https://doi.org/10.4049/jimmunol.210.Supp.161.13
Canna SW, Girard C, Malle L. Life-threatening NLRC4-associated hyperinflammation successfully treated with IL-18 inhibition. J Allergy Clin Immunol. 2017 May;139(5):1698-1701. doi: 10.1016/j.jaci.2016.10.022. Epub 2016 Nov 19.
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.
Rauch I, Deets KA, JI DX, et al. NAIP-NLRC4 Inflammasomes Coordinate Intestinal Epithelial Cell Expulsion with Eicosanoid and IL-18 release via Activation of Caspase-1 and -8. Immunity. 2017;46(4)649-59.
Romberg N, Vogel TP, Canna SW. NLRC4 inflammasomopathies. Curr Opin Allergy Clin Immunol. 2017;17(6):398-404. Accessed Oct 30, 2017. doi: 10.1097/ACI.0000000000000396
Guo H, Callaway JB, Ting JP. Inflammasomes: mechanism of action, role in disease, and therapeutics. Nat Med. 2015 Jul;21(7):677-87. doi: 10.1038/nm.3893. Epub 2015 Jun 29.
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.
INTERNET
Online Mendelian Inheritance in Man (OMIM). Johns Hopkins University. Autoinflammation with Infantile Enterocolitis. Entry No:616050. Last Edited 05/16/2017. Available at: https://omim.org/entry/616050 Accessed August 14, 2025.
Aliases for NLRC4 Gene. Gene Card Human Gene Database. https://www.genecards.org/cgi-bin/carddisp.pl?gene=NLRC4 Accessed August 14, 2025.
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Learn more https://rarediseases.org/patient-assistance-programs/caregiver-respite/The information provided on this page is for informational purposes only. The National Organization for Rare Disorders (NORD) does not endorse the information presented. The content has been gathered in partnership with the MONDO Disease Ontology. Please consult with a healthcare professional for medical advice and treatment.
The Genetic and Rare Diseases Information Center (GARD) has information and resources for patients, caregivers, and families that may be helpful before and after diagnosis of this condition. GARD is a program of the National Center for Advancing Translational Sciences (NCATS), part of the National Institutes of Health (NIH).
View reportOrphanet has a summary about this condition that may include information on the diagnosis, care, and treatment as well as other resources. Some of the information and resources are available in languages other than English. The summary may include medical terms, so we encourage you to share and discuss this information with your doctor. Orphanet is the French National Institute for Health and Medical Research and the Health Programme of the European Union.
View reportOnline Mendelian Inheritance In Man (OMIM) has a summary of published research about this condition and includes references from the medical literature. The summary contains medical and scientific terms, so we encourage you to share and discuss this information with your doctor. OMIM is authored and edited at the McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine.
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