What is NOMID/CINCA?

NOMID is the commonly used acronym for: Neonatal Onset Multisystem(ic) Inflammatory disease. This syndrome is also known in Europe as CINCA, which is the acronym for: Chronic Infantile Neurological, Cutaneous and Articular Syndrome. NOMID/CINCA is a very rare syndrome, with varying degrees of severity. In approximately 60% of patients, NOMID has shown to be caused by a genetic mutation in chromosome 1q44 of the CIAS1 gene, in the cryopyrin protein region. Muckle-Wells Syndrome (MWS), and Familial Cold Autoinflammatory Syndrome (FCAS/FCU) are other slightly more common, but less severe syndromes that have been found to have mutations in the same genetic region of the CIAS1 gene. NOMID/CINCA is the most devastating of these cryopyrin-related syndromes.

Symptoms of NOMID/CINCA

NOMID/CINCA symptoms are generally present at birth. Due to the effects of the gentic mutation causing this syndrome, there is a chance of some inflammation developing while the baby is still in the mother's womb. Most NOMID patients are born with uneventful deliveries or pregnancies, but at birth or shortly after in the neonatal period develop severe NOMID symptoms, usually starting with the rash. A few infants with NOMID have been born premature, and some have had placental anomolies showing inflammation present on the placenta and umbilical cord. The most common findings that distinguish this syndrome are:

Persistent Rash from Infancy

1. At birth, most NOMID/CINCA infants have a maculopapular skin rash present at birth, or the rash appears shortly after birth-usually within the first few weeks or months of age. The rash generally resembles hives, and varies in severity and presence, depending on the time or day, and intensifies with increased flare-ups of inflammation throughout the body. Generally the rash is not iritating, but there are some that complain that it is itchy. There are common skin biopsy findings related to this syndrome, but can be missed if the pathologist is not familiar with this syndrome. Some of these findings include an increased number of neutrophils at the eccrine coils. (see Syndrome Photos for an example of a NOMID rash.)

Joint & Orthopedic Symptoms

2. Articular (joint) affects of variable degree, including periodic swelling without damage between flare ups of inflammation are generally present. There can also be disfiguring and uncontrolled anomolous changes to the growth cartilage, often at the knees, suggestive of a pseudo-tumor growth. Many people that have developed this have enormously enlarged kneecaps (patellas) and other bony overgrowth. This can occur in approximately 50% of people with NOMID. Often, biopsy findings show disorganized cartilage with no inflammatory cells present. In the past, physicians thought that the bony overgrowth was a necessary characteristic in order to diagnose someone with NOMID/CINCA, but now, it is clear that not all people with this syndrome develop the irreverible, disfiguring and debilitating damage to the joints. There is a great degree of variance in inflammation, deformity and pain in the joints with NOMID/CINCA. Often, many patients have other musculoskeletal problems, including decreased muscle tone, lax muscles, knee valguses, and the need for orthotic devices to assist or correct for problems. Some patients are unable to walk, or bear weight on their legs, due to joint damage, and/or pain. See the CRI website for photos of some joint manifestations in NOMID (Warning,: Some images show some very severe cases.)

Central Nervous System Inflammation

3. Central Nervous System (CNS=Brain, spinal cord, and nervous system) involvement, and damage is common to varying degrees in almost all patients with this syndrome, but a lucky few do not develop damage from CNS inflammation. In the past, it was believed that you must show profound CNS involvement to have NOMID/CINCA, but there are a few patients that do not have these symptoms, or present with extremely mild CNS involvement that may be difficult to detect at times. However, these symptoms can develop at any time in the patient's life, and should be assessed regularly. CNS inflammation is one of the most debilitating symptoms, with a great degree of variance between patients, and may include: Headaches, neck and spinal pain with nausea and vomiting, elevated spinal fluid pressures (sometimes requiring shunts to relieve the pressure), vision changes or light sensitivity, chronic aseptic meningitis (non-infectious brain inflammation) with neutrophils, and occasionally eosinophils present in the cerebro-spinal fluid. A few children have even suffered from strokes and epileptic seizures due to the CNS inflammation. The majority children with NOMID/CINCA have significant cognitive and mental deficits, and/or learning disabilities. However, there are a few that have been spared from any mental or cognitive effects, despite having notable CNS inflammation. CNS inflammation can also cause damage to vision and hearing in many people. Increased CNS symptoms can vary with the degree of inflammation, and can intensify during flare ups of the syndrome.

Periodic Fevers & Flare-ups

4. Often, NOMID syndrome causes bouts of fevers (starting in infancy), accompanied by flare ups of the rash, increased pain in the joints, head and elsewhere. Some also vomit repeatedly with excessive thirst, are very irritable, and have great discomfort during flare ups that can be very frequent-even almost daily. The recurrent flares of symptoms is why NOMID/CINCA and the other CAPS syndromes are considered to be autoinflammatory periodic syndromes. Flare episodes are very debilitating, and may even require medical assistance. Often, these flare ups are misdiagnosed as bouts of illness, or allergic reactions, until more symptoms develop over time.

Eye Inflammation

5. At birth, and during inflammatory flare-up episodes, many people with NOMID/CINCA suffer from conjunctivitis (reddened whites of the eye, NOT caused by infection). Progressive pressure in the brain, and inflammation often causes varying degrees of chronic papilledema in the eyes (bulging out of the optic discs in the eyes), that can lead to serious loss of vision. In some patients, inflammation can cause sudden, and potentially damaging conjunctivitis, iritis and uveitis. 50% of patients that develop uveitis do not respond to conventional treatment, and can have permanent damage to their vision. It is very important to have a complete opthaltmology exam of the eyes in all patients with this syndrome, or those suspected of having it. For infants and children that are too uncooperative (due to age or developmental issues), an eye exam under anesthesia can help in the diagnosis and treatment of these patients. It is imperitave to have a good view of the optic discs in the eye, and other features to evaluate inflammation.

Hearing Loss

6. Progressive sensoneurial deafness (often related to chronic pressure in the brain from inflammation) can occur in many children with this syndrome, so hearing tests need to be done by audiologists. The basic "pre-school hearing tests" will not usually catch the complex array of hearing problems with this syndrome, but may help to only find those children with very profound hearing losses. Therefore, a full audiology evaluation of any patient suspected of having NOMID or one of the other periodic syndromes should be mandatory. Hearing aids can help some patients, depending on the degree of hearing loss present.

Abnormal Labs

7. Laboratory tests often reveal signs of non-specific inflammatory markers, even at birth, such as: elevated ESR (Erythrocyte Sedimentation Rate), high C-Reactive Protein (high sensitivity CRP test, or CRP test), Elevated serum AA (Amyloid), anemia (low hematocrit, hemoglobin and microcytic anemia), High polynuclear leukocytes, and thrombocytes (on a Complete Blood Count of the White Blood Cells (WBC's)), and many other changes. Many other irregularities are often present, including variances in IgG, Ig A, IgM, and elevated platelets. No antibodies or immune deficiencies in lab findings have been noted, but often, these children do seem to get sick easier than unaffected children. There is a significant risk for Amyloidosis if prolonged buildup of serum AA is allowed to occur. There is a genetic test for CAPS syndromes available, but there are afew patients with all the clinical symptoms and features of CPAS that do not have the gene mutation present in the CIAS1 gene. However, genetic testing is helpful, and should be done for all patients suspected to have CAPS, but should not be the only basis of diagnosis. As advances in genetics and the study of these syndromes continue over time, perhaps more genetic clues will come forward regarding these syndromes.

Other Symptoms

Some patients with NOMID/CINCA have been found to have unique facial characteristics, such as a saddle back noses (scooped nose with very little nasal bridge between the eye area), or frontal bossing (rounded, protruding forehead) but these features are not present in all patients, and are NOT essential criteria for the diagnosis of CAPS patients. Some also have narrowed, smaller teeth and other dental anomolies. Amyloidosis can develop in some patients after years of chronic inflammation with elevated serum amyloid, and some have enlarged livers and spleens.

Treatments

Currently, the best treatments found to help the many of sufferers of NOMID/CINCA have been the use of various Interleukin-1 blocking, trapping or otherwise attacking drugs to prevent the cellular uptake of Interleukin-1ß in CAPS patients. (See orpha.net Research Findings section to read about a study with one of these medications from the August 10, 2006 New England Journal of Medicine). Often, dramatic improvement is seen within days to weeks of starting these medications, but more research in this area is needed. References for this information include Dr. Anne-Marie Prieur's posting on orpha.net