Neonatal-onset multisystem inflammatory disease

Neonatal-onset multisystem inflammatory disease is a rare genetic periodic fever syndrome which causes uncontrolled inflammation in multiple parts of the body starting in the newborn period. Symptoms include skin rashes, severe arthritis, and chronic meningitis leading to neurologic damage. It is one of the cryopyrin-associated periodic syndromes.

NOMID can result from a mutation in the CIAS1 gene (also known as NLRP3 gene), which helps control inflammation. Mutations in this gene also cause familial cold urticaria and Muckle–Wells syndrome. NOMID has been successfully treated with the drug anakinra.

This syndrome is also known as the Prieur–Griscelli syndrome as it was first described by these authors in 1981.^[2]

The age of onset is almost always before 3 months of age. Many infants are born preterm (1/3 cases) and dysmature. The babies are frequently small for dates. The placenta may be abnormal with non-specific inflammation on histology. Umbilical cord anomalies have occasionally been reported. In severe cases, signs in the brain may be detected on prenatal ultrasound.

The disease manifests in many forms, making the diagnosis difficult, but the most common features of this disease involve the skin, joints, and central nervous system.

All have a maculopapular urticarial skin rash that is often present at birth (75% cases). It is probably more correctly described as an urticarial-like rash. The presence of the rash varies with time, and biopsy of these skin lesions shows a perivascular inflammatory infiltrate including granulocytes.

In about 35–65% of cases, arthritis occurs. Joint signs are variably expressed and can lead to transient swelling without sequelae between crises, or to unpredictable anomalies of growth cartilage and long bones epiphyses suggestive of a pseudo-tumour. Biopsies reveal hypertrophiccartilage without inflammatory cells. This most commonly affects the large joints (knees, ankles, elbows, and wrists) but may also involve the small joints of the hands and feet. It is usually bilateral and painful. A common and characteristic feature is giant kneecaps. Severe cases may result in contractures (joint deformities).

Most patients eventually have neurological problems. These manifest themselves in three principal ways: chronic meningitis, involvement of both the optic tract and eye, and sensorineural hearing loss. The chronic meningitis presents with the features of chronically raised intracranial pressure: headaches, vomiting, ventriculomegaly, hydrocephalus, macromegaly, cerebral atrophy, and optic atrophy. Some of these features may be evidenced on prenatal ultrasound. In 50% of cases, intellectual deficit occurs. Seizures occur in 25% of cases, but other manifestations are rare. Histological examination shows infiltration of the meninges with polymorphs.

Ocular manifestations occur in 80% of cases and include uveitis (70%), papillary involvement, conjunctivitis, and optical neuritis. If untreated, these may result in blindness (25%). The sensorineural hearing loss occurs in 75%, and tends to be progressive leading to deafness in 20% of cases.

Almost all children are remarkably short and have growth delay. Fever is extremely common but inconstant and is most often mild. Anemia is frequent. Other findings that have been reported include macrocephaly (95%), large fontanelle, prominent forehead, flattening of the nasal bridge (saddleback nose), short and thick extremities, and finger clubbing. The liver and spleen may be enlarged. Lymph node enlargement may also be present.

Later in life, secondary amyloidosis may occur. Delayed puberty and secondary amenorrhoea are not uncommon. Hoarseness due to inflammation of the laryngeal cartilage has also been reported.

En el 60% de los casos, la enfermedad se debe a una mutación en el gen CIAS1, que se sabe que está implicado en otros síndromes de apariencia similar, como el síndrome de Muckle-Wells y la urticaria por frío familiar . En muchos pacientes, los padres no presentan la misma mutación, lo que indica que el problema no es hereditario, a pesar de tratarse de una enfermedad genética. El gen CIAS1 interviene en el control del sistema inmunitario, por lo que la mutación provoca una inflamación descontrolada.

El diagnóstico se basa en la observación del paciente y la identificación del conjunto de síntomas y signos descritos anteriormente. Algunos análisis de sangre son útiles, ya que muestran signos de inflamación crónica. No existe una prueba específica para la enfermedad, aunque ahora que se conoce el gen que la causa, esto podría cambiar.

Las pruebas de laboratorio rutinarias no son específicas: anemia , aumento del número de polimorfonucleares, velocidad de sedimentación globular elevada y concentraciones elevadas de proteína C reactiva son las anomalías que suelen encontrarse. La punción lumbar muestra niveles elevados de polimorfonucleares (20-70% de los casos) y, ocasionalmente, recuentos elevados de eosinófilos (0-30% de los casos). La neopterina en el líquido cefalorraquídeo puede estar elevada. Las anomalías radiográficas son únicas y características de este síndrome. Estos cambios incluyen un crecimiento óseo excesivo debido a la osificación prematura de la rótula y las epífisis de los huesos largos en niños muy pequeños, y arqueamiento de los huesos largos con ensanchamiento y acortamiento de la reacción perióstica en niños mayores.

La audiometría muestra una sordera neurosensorial progresiva . El examen visual revela atrofia óptica y un aumento del punto ciego . La tomografía computarizada suele ser normal, pero puede mostrar dilatación de los ventrículos. La resonancia magnética con contraste puede mostrar realce de las leptomeninges y la cóclea, compatible con meningitis crónica. El electroencefalograma muestra un patrón inespecífico con ondas lentas y descargas de espigas.

Los polimorfos tienden a mostrar una mayor expresión de CD10 .

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.

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.

This is a rare condition with an incidence estimated to be less than 1 in a million live births. About 100 cases have been reported worldwide. The bulk of cases are sporadic but familial forms with autosomal dominant transmission have also been described.

• Deficiency of the interleukin-1–receptor antagonist (DIRA)
• Familial cold urticaria, a similar disease
• List of cutaneous conditions
• Muckle–Wells syndrome, a similar disease

• Online Mendelian Inheritance in Man (OMIM): 607115
• Goldbach-Mansky, R. et al. Neonatal-Onset Multisystem Inflammatory Disease Responsive to Interleukin-1{beta} Inhibition N Engl J Med 2006 355: 581–592.