Neonatal Onset Multisystem Inflammatory disease

Alternate names

Chronic Infantile Neurological Cutaneous Articular syndrome; CINCA syndrome; CINCA; Infantile Onset Multisystem Inflammatory Disease; IOMID; NOMID; Multisystem inflammatory disease, neonatal-onset; Prieur Griscelli syndrome

Definition

Neonatal onset multisystem inflammatory disease (NOMID) is an inflammatory disorder present from birth (congenital) characterized by tissue damage of the nervous system, skin, and joints. Individuals with NOMID have a skin rash that is present from birth and persists throughout life.

Summary

• Affected individuals often have headaches, seizures, and vomiting resulting from chronic meningitis, which is inflammation of the tissue that covers and protects the brain and spinal cord (meninges).
• Intellectual disability may occur in some people with this disorder.
• Hearing and vision problems may result from nerve damage and inflammation in various tissues of the eyes.
• People with NOMID experience joint inflammation, swelling, and cartilage overgrowth, causing characteristic prominent knees and other skeletal abnormalities that worsen over time.
• Joint deformities called contractures may restrict the movement of certain joints.
• Other features of this disorder include short stature with shortening of the lower legs and forearms, and characteristic facial features such as a prominent forehead and protruding eyes. Abnormal deposits of a protein called amyloid (amyloidosis) may cause progressive kidney damage.

Cause

Mutations in the NLRP3 gene (also known as CIAS1) cause NOMID. The NLRP3 gene provides instructions for making a protein called cryopyrin.

Cryopyrin belongs to a family of proteins called nucleotide-binding domain and leucine-rich repeat containing (NLR) proteins. These proteins are involved in the immune system, helping to regulate the process of inflammation. Inflammation occurs when the immune system sends signaling molecules and white blood cells to a site of injury or disease to fight microbial invaders and facilitate tissue repair. When this has been accomplished, the body stops (inhibits) the inflammatory response to prevent damage to its own cells and tissues.

Cryopyrin is involved in the assembly of a molecular complex called an inflammasome, which helps trigger the inflammatory process. Researchers believe that NLRP3 mutations that cause NOMID result in a hyperactive cryopyrin protein and an inappropriate inflammatory response. Impairment of the body's mechanisms for controlling inflammation results in the episodes of fever and widespread inflammatory damage to the body's cells and tissues seen in NOMID.

In about 50 percent of individuals diagnosed with NOMID, no mutations in the NLRP3 gene have been identified. The cause of NOMID in these individuals is unknown.

Inheritance

Autosomal dominant pattern, a 50/50 chance.

This condition is inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder.

In almost all cases, NOMID results from new mutations. These cases occur in people with no history of the disorder in their family. A few cases have been reported in which an affected person has inherited the mutation from one affected parent.

Symptoms

The first symptoms are usually a skin rash and fever. Individuals with NOMID may also have chronic meningitis (inflammation of the membranes surrounding the brain), which may lead to headaches, seizures, and vomiting. Hearing loss, vision loss, and intellectual disability, may also occur. For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed. 80%-99% of people have these symptoms

• Abnormality of neutrophils
• Arthralgia(Joint pain)
• Brachydactyly(Short fingers or toes)
• Elevated C-reactive protein level
• Elevated erythrocyte sedimentation rate(High ESR)
• Fatigue(Tired)
• Fever
• Increased intracranial pressure(Rise in pressure inside skull)
• Meningitis
• Migraine(Intermittent migraine headaches)
• Myalgia(Muscle ache)
• Nausea and vomiting
• Papule
• Pseudopapilledema
• Sensorineural hearing impairment
• Urticaria(Hives)
• Uveitis

30%-79% of people have these symptoms

• Abnormal thrombocyte morphology(Platelet abnormalities)
• Anemia(Low number of red blood cells or hemoglobin)
• Delayed closure of the anterior fontanelle(Later than typical closing of soft spot of skull)
• Edema(Fluid retention)
• Frontal bossing
• Hepatomegaly(Enlarged liver)
• Joint dislocation(Joint dislocations)
• Leukocytosis(Elevated white blood count)
• Lymphadenopathy(Swollen lymph nodes)
• Macrocephaly(Increased size of skull)
• Proptosis(Bulging eye)
• Skeletal dysplasia
• Splenomegaly(Increased spleen size)

5%-29% of people have these symptoms

• Blindness
• EEG abnormality
• Global developmental delay
• Growth delay(Delayed growth)
• Intellectual disability(Mental deficiency)
• Premature birth(Premature delivery of affected infants)
• Purpura(Red or purple spots on the skin)
• Reduced bone mineral density(Low solidness and mass of the bones)
• Retrobulbar optic neuritis

Diagnosis

A few blood tests help, by showing signs of long standing inflammation. There is no specific test for the disease, though now that the gene that causes the disease is known, that may change.

Routine laboratory investigations are non specific: anaemia, increased numbers of polymorphs, an elevated erythrocyte sedimentation rate and elevated concentrations of C-reactive protein are typically all the abnormalities found. Lumbar puncture shows elevated levels of polymorphs (20-70% of cases) and occasionally raised eosinophil counts (0-30% of cases).CSF neopterin may be elevated.

The X ray changes are unique and characteristic of this syndrome. These changes include bony overgrowth due to premature ossification of the patella and the long bone epiphyses in very young children and bowing of long bones with widening and shortening periosteal reaction in older ones.

Audiometry shows a progressive sensineural deafness. Visual examination shows optic atrophy and an increase in the blind spot. CT is usually normal but may show enlargement of the ventricles. MRI with contrast may show enhancement of leptomeninges and cochlea consistent with chronic meningitis. EEG shows a non-specific pattern with slow waves and spike discharges.

Polymorphs tend to show increased expression of CD10.

Treatment

There have been attempts to control the inflammation using drugs that work in other conditions where inflammation is a problem. The most successful of these are steroids, but they have side effects when used long term. Other medications, including methotrexate, colchicine and canakinumab, have been tried with some success. Otherwise, the treatment is supportive, or aimed solely at controlling symptoms and maximizing function.

The medication(s) listed below have been approved by the Food and Drug Administration (FDA) as orphan products for treatment of this condition.

• Rilonacept (Brand name: Arcalyst) rilonacept (Arcalyst) was approved for treatment of cryopyrin-assisted periodic syndromes (CAPS).
• Anakinra (Brand name: Kineret)anakinra (Kineret) was approved for the treatment of neonatal-onset multisystem inflammatory disease (NOMID).

Prognosis

Overall, the prognosis for patients with NOMID is not good, though many (80%) live into adulthood, and a few appear to do relatively well. They are at risk for leukemia, infections, and some develop deposits of protein aggregated called amyloid, which can lead to kidney failure and other problems. The neurologic problems are most troubling. The finding that other diseases are related and a better understanding of where the disease comes from may lead to more effective treatments.

Epidemiology

NOMID is a very rare disorder; approximately 100 affected individuals have been reported worldwide.

NIH genetic and rare disease info

• NIH info on Neonatal Onset Multisystem Inflammatory disease

Neonatal Onset Multisystem Inflammatory disease is a rare disease.

Neonatal Onset Multisystem Inflammatory disease Resources
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