CINCA syndrome (ORPHA:1451)
A rare, genetic, cryopyrin-associated periodic syndrome (CAPS) characterized by neonatal onset of systemic inflammation, urticarial skin rash and arthritis/arthralgia resulting in severe arthropathy and central nervous system involvement (including chronic aseptic meningitis, brain atrophy and sensorineural hearing loss).
Epidemiology
Whilst the exact prevalence of chronic infantile neurological, cutaneous, and articular (CINCA) syndrome is unknown, it is estimated that the whole spectrum of CAPS has a prevalence of 1/360,000 in France, CINCA being the less common form. In the Eurofever registry, collecting information on over 250 patients with NLRP3 mutation, about 25% of the patients present the most severe CINCA phenotype.
Clinical description
Disease onset typically occurs within the first hours/days of life with an urticarial rash, persistent elevation of acute phase reactants, and intermittent fever (which may be low-grade or absent). Typical facial features include frontal bossing and saddle back nose. The rash is typically non-pruritic and changes distribution during the day, without vasculitic alterations. Central nervous system manifestations include chronic aseptic meningitis, which, if left untreated, leads to brain atrophy, severe intellectual disability and sensorineural hearing loss. Typical neurological symptoms include chronic irritability, headache, early morning nausea, vomiting and, rarely, seizures. Ocular manifestations may include conjunctivitis, papilledema, optic nerve atrophy and progressive vision loss. Early degenerative arthropathy frequently involves large joints and causes deformities and contractures.
Etiology
Mutations (usually de novo ) in the NLRP3 gene (chromosome 1q44) are identified in the majority of patients; however 30-35% of affected individuals lack a detectable mutation. Most of these patients display a somatic mosaicism for NLRP3. The NLRP3 gene plays a key role in innate immunity, encoding a component of the NLRP3-inflammasome, with gain of function mutations leading to overproduction of interleukin 1beta (IL-1beta).
Diagnostic methods
The general consensus is that the clinical picture of CINCA is sufficient for diagnosis. Laboratory analyses document a nonspecific inflammatory syndrome with anemia, granulocyte hyperleukocytosis, elevated erythrocyte sedimentation rate (ESR) and elevated concentrations of C reactive protein. No autoantibodies or immune deficiencies are detected. Skin biopsy shows a neutrophilc dermatosis with massive perivascular neutrophil infiltration without signs of vasculitis. Brain MRI shows evident signs of meningitis with a possible inflammatory involvement of the inner ear. Ophthalmological examination may reveal papilledema. Genetic testing usually detects de-novo NLRP3 mutations but is not obligatory for diagnosis. In the absence of a positive standard genetic test, NLRP3 somatic mosaicism should be investigated
Differential diagnosis
An infectious disease is often suspected at disease onset. CINCA should be differentiated from similar monogenic or multifactorial autoinflammatory diseases, including, systemic onset juvenile idiopathic arthritis, tumor necrosis factor receptor 1 associated periodic syndrome, and the severe form of mevalonate kinase deficiency, CANDLE syndrome as well as the milder phenotype associated to mutations of NLRP3 (familial cold urticarial and Muckle-Wells syndrome).
Genetic counseling
The pattern of inheritance is autosomal dominant. Affected patients carrying a germinal mutation have a 50% risk of transmitting the disease to each child. In case of somatic mosaicism, risk depends on the possible presence of somatic mutations in reproductive organs of the parents.
Management and treatment
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 (a receptor antagonist of interleukin-1) and canakinumab (a monoclonal antibody against IL-1beta) have proved to be efficient against inflammatory signs, as well as against intracranial hypertension and hearing loss.
Prognosis
Without adequate and timely treatment, quality of life is often poor. Syndrome severity is wide-ranging and the functional prognosis depends on the degree of neurological manifestations (such as intellectual disability and hearing loss) and the occurrence of tendinous retractions.

                            Last update: 
                            February 2020


                            - Expert reviewer(s): 
                            Dr Marco GATTORNO