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NOMID/CINCA syndrome

NOMID and CINCA are alternative acronyms for the same disorder.

What is NOMID/CINCA?

NOMID/CINCA (MIM 607115) is the most severe and rarest form of cryopyrin-associated periodic syndrome (CAPS). Although usually due to a single gene mutation, it is rarely, if ever, inherited as it causes major 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 USA.

Who gets NOMID/CINCA and why?

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

NOMID/CINCA is an autosomal dominant condition meaning only a single copy of the defective gene is required to cause the clinical syndrome. The child of a sufferer would have a 50% chance of inheriting the condition. However, it is not usually familial as it is either fatal before adult life or results in severe disabilities. Therefore nearly all reported cases have resulted from spontaneous mutations. This may change with successful treatment now minimising neurological disability.

Molecular biology and genetics

Mutations in the NLRP3 gene are commonly identified in NOMID/CINCA, therefore linking it with 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 observed in patients with Muckle-Wells syndrome. Different overlap features can be seen even within one 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) condition as 40% of cases do not have an identifiable mutation in the NLRP3 gene. There is, however, no difference in response to treatment with anakinra between those with or without the NLRP3 mutations. The mechanism of disease development is likely to involve overstimulation of the interleukin-1beta receptor in all cases.

Clinical features of NOMID/CINCA

The clinical features of NOMID/CINCA that differentiate it from the other forms of CAPS include presentation at birth or soon after, severe unique joint changes and chronic aseptic meningitis which results in profound developmental delay and significant disability. As in all forms of CAPS, symptoms include skin rash, fever and inflammation of the eyes.

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

Symptom Description
Fever
  • Short episodes
  • Recurrent/intermittent
  • May be absent or very mild
Skin rash
  • 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 disease flare
  • non-itchy, urticarial, migratory, red plaques
  • maculopapular rashes – can be locally persistent
Joint changes Early onset in the first year after birth:
  • affects 33-50%
  • associated with severe disease
  • severe ‘overgrowth’ arthropathy
  • joint enlargement – eg giant kneecap is characteristic
  • knees commonest, followed by ankles, elbows, wrists
  • small joints in hands and feet can also be involved
  • usually bilateral
  • painful
  • contractures cause limited range of movement – an important cause of disability
  • characteristic unique x-ray changes
  • due to uncontrolled overgrowth of the knee cap and ends of long bones with large abnormal bony masses in the joints
Later onset:
  • half to two-thirds
  • mild non-destructive arthropathy
  • mild transient swelling during a disease flare
Neurological Chronic aseptic meningitis:
  • from infancy
  • almost all patients
  • can present at birth or in utero as hydrocephalus or ventriculomegaly
  • results in chronically raised intracranial pressure – chronic headaches, vomiting, ventriculomegaly, hydrocephalus, macromegaly, cerebral atrophy, optic atrophy
  • mental and developmental retardation (50%)
  • seizures (25%)
  • spasticity of the legs – rare
  • hypotonia – rare
  • transient hemiplegia – rare
Hearing loss:
  • affects 75%
  • begins in late childhood
  • progressive
  • bilateral
  • perceptive 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 (anterior 50%, posterior 20%)
  • conjunctivitis
  • papillitis
  • optic atrophy can result in loss of vision – 25% of adults have major visual impairment including blindness
  • retinal vasculitis – rare
Physical appearance
  • Prominent forehead
  • Flattening of the nasal bridge (saddleback nose)
  • Large head (macrocephaly) – 95%
  • Large fontanelle
  • Short stature
  • Short thick extremeties
  • Finger clubbing
Other
  • Liver and spleen enlargement (hepatosplenomegaly)
  • Lymph node enlargement (adenopathy)
  • Umbilical cord anomalies – occasional
  • Delayed puberty and secondary amenorrhoea
  • Hoarseness – due to inflammation of the laryngeal cartilage
  • Secondary amyloidosis can develop with age

20% die before reaching adult life, due to infection, vasculitis and amyloidosis.

How is NOMID/CINCA diagnosed?

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

Clinical clues that should raise particular suspicion of the diagnosis in a child are:

The table below describes the results of investigations.

Test Findings
Blood tests
  • increased white blood cells (leukocytosis) – mild neutrophilia
  • elevated markers of inflammation: erythrocyte sedimentation rate (ESR) C-reactive protein (CRP) serum amyloid A (SAA)
X-rays
  • characteristic and unique to this syndrome
  • bony overgrowth due to premature ossification of the patella (knee cap) and the long bone epiphyses
  • in very young children, bowing of long bones with widening and shortening periosteal reaction
CSF
  • increased pressure increased protein and inflammatory cells (neutrophils 20-70% eosinophils 0-30%) AND;
  • no evidence of infection with viruses, bacteria, mycobacteria, yeasts or fungi
Skin biopsy
  • neutrophilic perivascular dermal infiltrate
Audiometry
  • perceptive deafness
Ophthalmologic assessment
  • visual impairment due to optic atrophy
  • Visual field – retinal blind spot enlargement
CT scan
  • can be normal
  • show mild cerebral atrophy – mild enlargement of ventricles and subdural spaces
MRI with gadolinium
  • enhancement of leptomeninges and cochlea
EEG
  • slow waves and spike discharges

Treatment of NOMID/CINCA

Anakinra is a biologic agent. It is is a recombinant interleukin-1 receptor antagonist and the treatment of choice for NOMID/CINCA. It is given as a daily subcutaneous injection, dose range 1-10mg/kg/d. Very young children appear to require a much higher dose per kg (6-10mg/kg/d) to control symptoms and inflammatory markers than older children or adults (1-3 mg/kg/d). It should be started as early in life as possible to minimise irreversible neurological complications. It is likely treatment will be continued for life. So far studies have been reported with up to 42 months of continuous treatment. Treatment has been started as young as 3 months of age.

Two large prospective case series have been reported, one involving 18 patients and the second 10, including two infants.

Improvement has been reported in:

But no improvement is seen in the bone changes which can continue to progress. Consequences of secondary amyloidosis, deafness, visual impairment, mental retardation or existing developmental delay can or do persist, remaining stable or showing further progression. Proteinuria may improve but kidney impairment may be stable. Evidence of persistent CNS inflammation may be detected in CSF as increased protein and/or white cells and on MRI. Approximately one-third showed partial improvement in existing hearing loss on audiograms, but deterioration was noted in 17% in one series.

In the first series, all 18 patients showed clearance of the rash within 3 days, and complete remission of inflammatory changes within 6 months. Relapse occurred within 5 days of ceasing anakinra. In the more recent series, all 10 patients had complete clinical remission of fever, rash, joint and muscle pain within 24 hours of the first injection. Improvement was, in all but one patient, maintained throughout treatment over 2-3.5 years. The two very young patients (treatment started at 3 and 4 months of age) however showed recurrence of symptoms 6-8 hours after low-dose (1mg/kg/d) injection and required escalating split doses. One continued to develop occasional skin rashes associated with viral infections despite a dose of 10mg/kg/d. Persistence of headaches correlated with the presence of papilloedema and responded to increased dosages.

In the prospective study of 18 patients with NOMID/CINCA, local injection site reactions were the commonest adverse event, with an increase in upper respiratory tract infections. In the second series of 10 patients, injection site reactions only were reported. Very young chldren are at risk of developing pneumococcal infection due to the very high doses required and their poor immune response to encapsulated bacteria. All patients should be immunised against Streptococcus pneumoniae and Haemophilus influenzae before starting therapy and is is suggested very young children should be prescribed prophylactic antibiotics.

Anakinra has a major beneficial impact on the quality of life of patients with NOMID/CINCA. If started early in life, anakinra may prevent the disability caused by joint changes and neurological inflammation, however longer followup is required to confirm this impression.

Note: anakinra is not registered or subsidised in New Zealand (March 2011). In other countries such as the USA and Europe, its registered indication is rheumatoid arthritis.

Draft 4 March 2011

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Author: Dr Delwyn Dyall-Smith FACD, Dermatologist.

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