Síndrome de NOMID / CINCA - Hoogstra

Contents

NOMID and CINCA are alternative acronyms for the same disorder.

NOMID: Neonatalmulti-system boot inflammatory disease
CINCA Chronic child neurological cutaneous and articulate syndrome

What is NOMID/CINCA?

NOMID/CINCA (MIM 607115) is the most severe and rare form of cryopyrin-associated periodic syndrome (CAPS). Although it is generally due to a single gene mutation, rarely, if ever, inherited, as it causes significant disabilities and is often fatal before adult life. It is called CINCA in Europe (where the syndrome was first described and studied in detail) and NOMID in the US.

Who receives NOMID/CINCA and why?

NOMID/CINCA is very rare autoinflammatory syndrome, which occurs on or within days of birth. Signs can be detected in the brain in prenatal ultrasound before birth in severe cases. Birth is premature in a third of cases, and birth weight may be small for the dates.

NOMID/CINCA is a autosomal dominant condition, meaning that only a single copy of the defective gene is required to cause the clinical syndrome. A victim's child would have a 50% chance of inheriting the condition. However, it is not usually family as it is fatal before adulthood or results in severe disabilities. Therefore, almost all reported cases are the result of spontaneous mutations. This can change with successful treatment that now minimizes neurological disability.

Molecular biology and genetics

Mutations in the NLRP3 gene are commonly identified in NOMID/CINCA, therefore linking it to Muckle-Wells syndrome and familial cold-associated syndrome. Some mutations, such as Y570C, Y570F, F309S, and F523L, are unique to severe NOMID/CINCA. Mild clinical features of NOMID/CINCA are sometimes seen in patients with Muckle-Wells syndrome. Different overlapping characteristics can be seen even within a family. However, the severe clinical features of NOMID/CINCA have never been reported in families with milder forms of CAPS.

NOMID/CINCA is likely to be a heterogeneous (i.e. due to more than one genetic defect) such as 40% cases do not have an identifiable mutation in the NLRP3 gene. However, there is no difference in response to anakinra treatment between those with or without NLRP3 mutations. It is likely that the mechanism of disease development involves overstimulation of interleukin-1beta receiver in all cases.

Clinical Features of NOMID/CINCA

Clinical features of NOMID/CINCA that differentiate it from the other forms of CAPS include presentation at birth or soon after, severe single joint changes, and chronic aseptic. meningitis resulting in profound developmental delay and significant disability. As with all forms of CAPS, symptoms include skin eruption, fever and inflammation of the eyes

NOMID/CINCA symptoms tend to be constant, rather than episodic, with intermittent flares in activity. The clinical characteristics of NOMID/CINCA are shown in the table below.

Symptom	Description
Fever	short episodes Recurrent/intermittent May be absent or very mild
Acne	Affects 100% often the presenting feature usually present at birth – 75% varies during the day, but tends to be always present varies between patients and with severity of the disease outbreak no itch urticarialred migratory plates maculopapular rashes: may be locally persistent
Joint changes	Early onset in the first year after birth: affects 33-50% associated with serious illness severe “overgrowth” arthropathy enlargement of joints, for example, giant kneecap is characteristic most common knees, followed by ankles, elbows, wrists small joints in the hands and feet may also be involved generally bilateral painful contractures cause limited range of motion – a major cause of disability Unique X-ray characteristic changes due to uncontrolled overgrowth of the kneecap and the tips of the long bones with large abnormal bone masses in the joints
Joint changes	Later start: half to two thirds mild non-destructive arthropathy mild transient swelling during an illness flare
Neurological	Chronic aseptic meningitis: since childhood almost all patients can occur at birth or in the womb how hydrocephalus or ventriculomegaly results in chronically elevated intracranial pressure – chronic headaches, vomiting, ventriculomegaly, hydrocephalus, macromegaly, cerebral atrophy, optic atrophy mental and developmental delay (50%) seizures (25%) leg spasticity – rare hypotonia - queer transient hemiplegia – rare
	Hearing loss: affects 75% begins in late childhood progressive bilateral perceptual sensorineural deafness 20%
	Eye problems: affected in at least 80% incidence of eye problems increases with age average age of onset 4.5 years uveitis (previous 50% later 20%) conjunctivitis papillitis optic atrophy can lead to vision loss: 25% in adults has significant visual impairment, including blindness retinal vasculitis - queer
Physical appearance	Prominent forehead Flattening of the nasal bridge (saddled nose) Big head (macrocephaly) – 95% large fontanelle Short stature Short and thick limbs Finger clubbing
Other	Enlarged liver and spleen (hepatosplenomegaly) Lymph node enlargement (adenopathy) Umbilical cable occasional anomalies Delayed and secondary puberty amenorrhea Hoarseness: due to inflammation of the laryngeal cartilage Secondary amyloidosis can develop with age.

20% dies before reaching adulthood, due to infection, vasculitis and amyloidosis.

How is NOMID/CINCA diagnosed?

NOMID-CINCA is characterized by the clinical triad of skin, joint, and neurological inflammation that occurs at or around the time of birth.

The clinical clues that should generate particular suspicions of the diagnosis in a child are:

hydrocephalus or ventriculomegaly in a child with a normal number of chromosomes and no history of birth asphyxia
posterior uveitis or optic disc edema
youth arthritis.

The following table describes the results of the investigations.

Proof	recommendations
Blood test	increased white blood cells (leukocytosis) – mild neutrophilia elevated markers of inflammation: erythrocytes sedimentation rate (ESR) C-reactive protein (CRP) serum amyloid A (SAA)
X-rays	characteristic and exclusive of this syndrome bone overgrowth due to premature ossification of the kneecap (patella) and epiphyses of the long bones in very young children, bowing of long bones with periosteal reaction of widening and shortening
CSF	increased pressure increased proteins and inflammatory cells (neutrophils 20-70% eosinophils 0-30%) AND; no evidence of virus infection, bacteria, mycobacteria, yeasts or fungi
Skin biopsy	neutrophilic perivascular dermal infiltrate
Audiometry	perceptual deafness
Ophthalmological evaluation	visual impairment due to optic atrophy Visual field – enlargement of the blind spot of the retina
Connecticut scan	can be normal show mild cerebral atrophy – mild enlargement of the ventricles and subdural spaces
Magnetic resonance with gadolinium	improvement of leptomeninges and cochlea
EEG	slow waves and punctual discharges

NOMID/CINCA Treatment

Anakinra is a biological agent. It is a recombinant interleukin-1 receptor antagonist and the treatment of choice for NOMID/CINCA. It is administered daily. subcutaneous inyección, rango de dosis 1-10mg / kg / d. Los niños muy pequeños parecen requerir una dosis mucho más alta por kg (6-10mg / kg / d) para control síntomas y marcadores inflamatorios que los niños mayores o adultos (1-3 mg / kg / d). Debe iniciarse lo antes posible en la vida para minimizar las complicaciones neurológicas irreversibles. Es probable que el tratamiento continúe de por vida. Hasta ahora se han informado estudios con hasta 42 meses de tratamiento continuo. El tratamiento se inició a partir de los 3 meses de edad.

Se han informado dos grandes series de casos prospectivos, uno con 18 pacientes y el segundo con 10 bebés, incluidos dos.

Se ha informado de mejoras en:

Síntomas clínicos
Marcadores inflamatorios
Crecimiento: aumento de altura y peso si es prepuberal
La pubertad tardía y la amenorrea secundaria respondieron dentro de los 6 meses de tratamiento
Quality of life
Visión y audición
Presión intracraneal
Cambios de resonancia magnética en el oído (inflamación coclear) y leptomeninges (leptomeningitis)

Pero no se observa mejoría en los cambios óseos que pueden continuar progresando. Las consecuencias de la amiloidosis secundaria, la sordera, la discapacidad visual, el retraso mental o el retraso del desarrollo existente pueden o persisten, permanecen estables o muestran una mayor progresión. La proteinuria puede mejorar, pero la insuficiencia renal puede ser estable. Evidencia de persistencia CNS La inflamación puede detectarse en el LCR como un aumento de proteínas y / o glóbulos blancos y en la resonancia magnética. Aproximadamente un tercio mostró una mejora parcial en la pérdida auditiva existente en los audiogramas, pero se observó deterioro en el 17% en una serie.

En la primera serie, los 18 pacientes mostraron eliminación de la erupción en 3 días, y completaron remission de cambios inflamatorios dentro de los 6 meses. Relapse ocurrió dentro de los 5 días posteriores al cese de la anakinra. En la serie más reciente, los 10 pacientes tuvieron una remisión clínica completa de fiebre, erupción cutánea, dolor articular y muscular dentro de las 24 horas posteriores a la primera inyección. La mejora se mantuvo, en todos los pacientes menos uno, durante todo el tratamiento durante 2-3.5 años. Sin embargo, los dos pacientes muy jóvenes (el tratamiento comenzó a los 3 y 4 meses de edad) mostraron reappearance de síntomas 6-8 horas después de la inyección de dosis baja (1mg / kg / d) y requirió dosis divididas crecientes. Uno continuó desarrollando erupciones cutáneas ocasionales asociadas con infecciones virales a pesar de una dosis de 10 mg / kg / día. La persistencia de dolores de cabeza se correlacionó con la presencia de papiledema y respondió al aumento de las dosis.

En el estudio prospectivo de 18 pacientes con NOMID / CINCA, las reacciones locales en el lugar de la inyección fueron las más comunes. adverse event, con un aumento de las infecciones del tracto respiratorio superior. En la segunda serie de 10 pacientes, solo se informaron reacciones en el lugar de la inyección. Los niños muy pequeños corren el riesgo de desarrollar infección neumocócica debido a las dosis muy altas requeridas y su pobre respuesta inmune a encapsulated bacterias Todos los pacientes deben ser inmunizados contra Streptococcus pneumoniae y Haemophilus influenzae antes de comenzar la terapia y se sugiere que se recete a niños muy pequeños. prophylactic antibiotics

Anakinra tiene un gran impacto beneficioso en la calidad de vida de los pacientes con NOMID / CINCA. Si se comienza temprano en la vida, la anakinra puede prevenir la discapacidad causada por los cambios en las articulaciones y la inflamación neurológica, sin embargo, se requiere un seguimiento más prolongado para confirmar esta impresión.

Nota: anakinra no está registrada ni subsidiada en Nueva Zelanda (marzo de 2011). En otros países, como los EE. UU. Y Europa, su indicación registrada es la artritis reumatoide.

NOMID / CINCA syndrome