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CINCA syndrome

Orpha number ORPHA1451
Synonym(s) Chronic infantile neurological cutaneous articular syndrome
IOMID syndrome
Infantile-onset multisystem inflammatory disease
NOMID syndrome
Neonatal-onset multisystem inflammatory disease
Prieur-Griscelli syndrome
Prevalence <1 / 1 000 000
Inheritance
  • Autosomal dominant
  • Sporadic
Age of onset Neonatal/infancy
ICD-10
  • E85.0
OMIM
UMLS -
MeSH -
MedDRA -
SNOMED CT
  • 239826001

Summary

Chronic Infantile Neurological, Cutaneous, and Articular (CINCA) syndrome is characterised by skin rash, joint involvement, chronic meningitis with granulocytes and, in some cases, sensorineural hearing loss and ocular signs.

Although only a hundred cases have been reported worldwide, this syndrome is increasingly recognised by paediatricians.

The maculopapular urticarial skin rash is very often present at birth but varies with time. This rash is more correctly described as urticarial-like, with a perivascular inflammatory infiltrate including granulocytes. Fever is inconstant and most often mild. 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, which, when biopsied, reveal hypertrophic cartilage without inflammatory cells. Central nervous system involvement is revealed by chronic headaches due to chronic meningitis with granulocytes. In the severe forms, intellectual deficit can occur. Sensorineural involvement includes inflammatory ocular manifestations (uveitis, papillary involvement and optical neuritis, which can lead to blindness) and often progressive sensorineural hearing loss. The syndrome progresses in a context of chronic inflammation. Growth delay can be observed and some infants are born preterm and dysmature. Secondary amyloidosis can appear.

Mutations in the CIAS1 gene have been identified in 60% of patients with either the sporadic or familial forms. This gene is highly expressed in cells of the innate immune system, especially in granulocytes and monocytes. It codes for the cryopyrin protein, which plays an important role in the control of the immune response, especially the innate immune response. Mutations of this gene are also involved in familial cold urticaria and Muckle-Wells syndrome, two phenotypically related diseases (see these terms). These three syndromes correspond to a continuum of diseases of increasing severity: familial cold urticaria being the most benign form, CINCA the most severe, and Muckle-Wells corresponding to an intermediate phenotype.

Laboratory analyses document a nonspecific inflammatory syndrome with anaemia, granulocyte hyperleucocytosis, elevated erythrocyte sedimentation rate (ESR) and elevated concentrations of C reactive protein. No autoantibodies or immune deficiency are detected. Diagnosis is based on clinical observation and is confirmed by genetic analyses.

The differential diagnosis should include systemic auto-inflammatory disorders.

Most of the cases are sporadic. However, familial forms with autosomal dominant transmission have been described.

Therapeutic approaches using numerous anti-inflammatory drugs and immunosuppressants have provided disappointing results. Corticosteroids can partially improve the symptoms but at the cost of high toxicity. Anakinra, an antagonist of the interleukin-1 beta receptor has proved to be efficient against the inflammatory signs, as well as against intracranial hypertension and hearing loss (if it is not too long-standing). However, there is no effect on the hypertrophic joint involvement.

There is a wide range of variation in the severity of the syndrome. Some patients present with the full early-onset pathognomonic clinical picture, with central nervous system involvement and early onset arthropathies. Their quality of life is often poor and the functional prognosis depends on the occurrence of tendinous retractions resulting from the arthropathies. Some patients present with a milder clinical picture and better quality of life.

Expert reviewer(s)

  • Dr Bénédicte NEVEN

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Detailed information

Summary information
Clinical practice guidelines
  • FR (2013,pdf)
Guidance for genetic testing
  • EN (2012,pdf)
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