April 23, 2019
Years published: 2007, 2011, 2019
NORD gratefully acknowledges Onyinye Kammelu, NORD Editorial Intern from the Massachusetts College of Pharmacy and Health Sciences, and Dr. Hal Hoffman, Professor of Pediatrics and Medicine, Division of Rheumatology, Allergy, and Immunology at the University of California at San Diego School of Medicine, for assistance in the preparation of this report.
Neonatal-onset multisystem inflammatory disease (NOMID), also known as chronic infantile neurologic cutaneous articular (CINCA) syndrome, is a rare, systemic, inflammatory condition characterized by fever, rash, joint symptoms, and central nervous system (CNS) symptoms. The hallmark of NOMID is onset during early infancy, usually before six months of age. The severity of NOMID varies from child to child. Early diagnosis and prompt treatment with specific medications is important for preventing severe complications of the disease and improving life expectancy.
NOMID is the least common and most severe form of the cryopyrin associated periodic syndromes (CAPS) caused by mutations in the CIAS1/NLRP3 gene. All of these syndromes are characterized by fever, rash, and musculoskeletal pain.
In addition to fever, symptoms of NOMID involve the skin, CNS and joints. Skin rashes occur in all patients within the first six weeks of life and persist throughout their lives. CNS symptoms include inflammation around the brain (chronic aseptic meningitis), cognitive/mental deficits/learning disabilities, and seizures and sensory organ dysfunction, which can result in vision and hearing loss. Joint inflammation and joint and bone deformities range in severity. Enlargement of the bones around the knee is also characteristic of NOMID.
Other clinical features include stunted growth, enlargement of the liver and spleen, an abnormal increase in the number of white blood cells, an elevation in blood levels of the protein amyloid A, C-reactive protein, and erythrocyte sedimentation rate (blood tests used to measure elevations of these markers can detect or grade inflammation). In addition, abnormal facial features, narrowed smaller teeth and other dental abnormalities can sometimes be seen.
NOMID shares symptoms, and should not be confused, with juvenile idiopathic arthritis (JIA). High recurrent fevers, joint pain, deforming joint disease and rash are symptoms of both NOMID and JIA. However, NOMID is differentiated by the onset of skin disease at birth and a persistent rash. In addition, many patients with NOMID have nonspecific joint pain and enlargement of the knees, while patients with JIA present with inflamed synovial joints, such as the shoulder or knee, increased production of fluid in the synovial joints and warm, swollen, stiff joints.
NOMID patients suffer from frequent, almost daily flare-up episodes which cause great discomfort, can be very debilitating, and may require medical assistance during the episodes. Some patients are unable to walk or bear weight on their legs due to joint damage and/or pain. Many children with NOMID have cognitive and mental deficits and/or learning disabilities as well as vision and hearing loss.
About 50-60 percent of those who are diagnosed with NOMID have an alteration (mutation) in the CIAS1/NLRP3 gene that codes for the protein cryopyrin (NALP3). Most of the NOMID patients originally described without identifiable mutations were later found to be have somatic mutations a small percentage of their white blood cells (somatic mosaics). Mutations in this gene result in increased activity of a protein complex containing cryopyrin known as the inflammasome, which regulates inflammation in the body. Increased inflammasome activity leads to an increased release of a protein known as interleukin (IL-1ß), which leads to symptoms of inflammation such as fever and joint pain.
NOMID follows an autosomal dominant inheritance pattern. Dominant genetic disorders occur when only a single copy of an altered gene is necessary to cause a particular disease. The altered gene can be inherited from either parent or can be the result of a new mutation in the affected individual. The risk of passing the altered gene from affected parent to offspring is 50% for each pregnancy. The risk is the same for males and females.
NOMID is a very rare disorder; approximately 100 affected individuals with different ethnic backgrounds have been widely reported. Males and females are equally affected.
Symptoms of the following disorders can be similar to those of NOMID, and there is significant phenotypic overlap. Comparisons may be useful for a differential diagnosis.
Familial cold autoinflammatory syndrome (FCAS), also known as familial cold urticaria, is another condition in the CAPS category, caused by mutations in the CIAS1/NLRP3 gene. It is a rare, inherited inflammatory disorder characterized by intermittent episodes of a similar rash, fever, chills, joint pain and other signs/symptoms of systemic inflammation triggered by exposure to cold. Onset of FCAS presents during infancy and early childhood and persists throughout the patient’s life. (For more information on this condition, chose “FCAS” as your search term in the Rare Disease Database.)
Muckle-Wells syndrome (MWS) is another condition in the CAPS category, caused by mutations in the CIAS1/NLRP3 gene. Individuals with MWS often have episodic fever, chills, and painful joints. Sometimes these symptoms are exacerbated by cold similar to the related condition FCAS, but can also be triggered by other stimuli or have no apparent cause. Most MWS patients develop progressive hearing loss. In some MWS patients, amyloidosis develops later in life, a disease in which an abnormal accumulation of the protein amyloid occurs in a patient’s tissues and organs. Accumulation of amyloid in the kidneys results in damage and often kidney failure if untreated. (For more information on this condition, chose “Muckle-Wells” as your search term in the Rare Disease Database.)
Diagnosis of NOMID is determined through an evaluation of a patient’s symptoms and medical history. Diagnosis includes: skin biopsy, eye exam, hearing test, brain MRI, joint x-rays and cerebrospinal fluid test (detects aseptic meningitis or high white blood counts in the spinal fluid). The diagnosis can be confirmed through genetic testing, but almost half of all NOMID patients do not have an easily identifiable mutation in the CIAS1/NLRP3 gene.
Therapies that suppress inflammation, including high-dose corticosteroids and disease-modifying antirheumatic drugs have been used to treat NOMID.
Anakinra (Kineret) marketed by Sobi, Inc. was approved by the U.S. Food and Drug Administration (FDA) in 2013 to treat patients with NOMID, and is the only medication that is FDA approved to treat these patients.
Canakinumab (Ilaris) by Novartis Pharmaceuticals, a monoclonal antibody to interleukin-1 beta, was approved by the FDA in 2009 as a treatment for adults and children 4 years and older with familial cold autoinflammatory syndrome (FCAS) and Muckle-Wells syndrome (MWS). Ilaris has been used to successfully treat NOMID patients and is approved in Europe, although higher than standard doses are often required and it is not FDA approved for NOMID at this time.
Rilonacept (Arcalyst) by Regeneron Pharmaceuticals, an interleukin-1 blocker, was approved by the FDA in 2008 for the treatment of CAPS, including FCAS and MWS, in adults and children 12 years and older, but it is not approved for NOMID and there is limited clinical experience in NOMID patients.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
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:
For information about clinical trials sponsored by private sources, contact:
For more information about clinical trials conducted in Europe, contact:
Contact for additional information about NOMID:
Dr. Hal M. Hoffman
Associate Professor of Pediatrics and Medicine
Division of Rheumatology, Allergy, and Immunology
University of California at San Diego School of Medicine
RareConnect offers a safe patient-hosted online community for patients and caregivers affected by this rare disease. For more information, visit www.rareconnect.org.
Finetti M, Omenetti A, Federici S, Caorsi R, Gattorno M. Chronic Infantile Neurological Cutaneous and Articular (CINCA) syndrome: a review. Orphanet Journal of Rare Diseases. 2016;11:167. https://ojrd.biomedcentral.com/track/pdf/10.1186/s13023-016-0542-8
Caroli F, Pontillo A, D’Osualdo A, et al. Clinical and genetic characterization of Italian patients affected by CINCA syndrome. Rheumatology. 2007;46(3):473-8.
Goldbach-Mansky R, et al. Neonatal-onset multisystem inflammatory disease responsive to interleukin-1ß inhibition. New England Journal of Medicine. 2006;355(6):581-592.
Kilcline C, Shinkai K, Bree A, et al. Neonatal-onset multisystem inflammatory disorder. Archives of Dermatology. 2005;141:248-253.
Lovell D J, et al. Interleuken-1 blockade by Anakinra improves clinical symptoms in patients with neonatal-onset multisystem inflammatory disease. Arthritis & Rheumatism. 2005;52(4):1283-1286.
Chronic Infantile Neurological Cutaneous Articular syndrome. Genetic and Rare Diseases Information Center. Last updated: 10/25/2016. https://rarediseases.info.nih.gov/diseases/1356/chronic-infantile-neurological-cutaneous-articular-syndrome Accessed March 11, 2019.
Neonatal onset multisystem inflammatory disease. Genetics Home Reference. Reviewed: September 2008. https://ghr.nlm.nih.gov/condition/neonatal-onset-multisystem-inflammatory-disease Accessed March 11, 2019.
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