CINCA syndrome

CINCA syndrome in short

• A rare genetic disorder classified under cryopyrin-associated periodic syndromes (CAPS), this condition is characterized by systemic inflammation beginning in the neonatal period.
• Key features include a persistent urticarial skin rash, arthritis or arthralgia leading to progressive joint damage, and involvement of the central nervous system—manifesting as chronic aseptic meningitis, brain atrophy, and sensorineural hearing loss.

Synonyms

• IOMID syndrome
• Infantile-onset multisystem inflammatory disease
• NOMID syndrome
• Neonatal-onset multisystem inflammatory disease
• Prieur-Griscelli syndrome
• Chronic infantile neurological cutaneous and articular syndrome

Inheritance: Autosomal dominant, Not applicable

Age of onset: Infancy, Neonatal

How common is CINCA syndrome?

• The exact prevalence of chronic infantile neurological, cutaneous, and articular (CINCA) syndrome remains unknown; however, the overall prevalence of cryopyrin-associated periodic syndromes (CAPS) is estimated at approximately 1 in 360,000 in France, with CINCA representing the rarest and most severe form.
• Data from the Eurofever registry, which includes information on over 250 individuals with NLRP3 mutations, indicate that around 25% of these patients exhibit the severe CINCA phenotype.

What are the symptoms of CINCA syndrome?

Very Frequent Symptoms

• Abnormality of granulocytes
• Abnormality of neutrophils
• Arthralgia
• Brachydactyly
• Elevated circulating C-reactive protein concentration
• Elevated erythrocyte sedimentation rate
• Fatigue 
• Fever
• Hearing impairment
• Increased intracranial pressure
• Inflammatory abnormality of the eye
• Meningitis
• Migraine
• Myalgia
• Nausea and vomiting
• Papule
• Pseudopapilledema
• Sensorineural hearing impairment
• Urticaria
• Uveitis

Frequent Symptoms

• Abnormal joint morphology
• Abnormality of thrombocytes
• Anemia
• Delayed closure of the anterior fontanelle
• Edema
• Frontal bossing
• Hepatomegaly
• Joint dislocation
• Leukocytosis
• Lymphadenopathy
• Macrocephaly
• Proptosis
• Skeletal dysplasia
• Splenomegaly
• Visual impairment 

Occasional symptoms

• Blindness
• EEG abnormality
• Global developmental delay
• Growth delay
• Intellectual disability
• Premature birth
• Purpura
• Reduced bone mineral density
• Retrobulbar optic neuritis

Clinical description

• The disease typically presents within the first few hours to days of life, marked by an urticarial skin rash, persistently elevated acute phase reactants, and intermittent fever, which may be mild or even absent.
• Characteristic facial features include frontal bossing and a saddle-shaped nasal bridge. The rash is usually non-itchy, migratory in nature throughout the day, and lacks signs of vasculitis. Central nervous system involvement includes chronic aseptic meningitis, which, if untreated, can result in brain atrophy, severe intellectual disability, and sensorineural hearing loss.
• Common neurological symptoms include chronic irritability, headaches, early morning nausea and vomiting, and, less commonly, seizures. Ocular involvement may present as conjunctivitis, papilledema, optic atrophy, and progressive visual impairment. Early-onset degenerative arthropathy, typically affecting large joints, leads to deformities and contractures.

What causes this condition?

• Mutations in the NLRP3 gene (located on chromosome 1q44) are found in the majority of individuals with the condition, typically arising de novo. However, 30–35% of affected individuals do not have a detectable germline mutation; many of these cases are due to somatic mosaicism for NLRP3.
• This gene plays a crucial role in innate immune responses by encoding a key component of the NLRP3 inflammasome. Gain-of-function mutations result in excessive production of interleukin-1β (IL-1β), driving systemic inflammation.

How is this condition diagnosed?

• The diagnosis of CINCA is primarily clinical, based on characteristic symptoms and presentation. Laboratory findings typically reveal a nonspecific inflammatory profile, including anemia, granulocytic leukocytosis, elevated erythrocyte sedimentation rate (ESR), and increased C-reactive protein (CRP) levels. Autoantibodies and immune deficiencies are generally absent.
• Skin biopsy commonly shows a neutrophilic dermatosis, characterized by dense perivascular neutrophil infiltration without evidence of vasculitis. Brain MRI often demonstrates signs of chronic meningitis, with possible inflammatory involvement of the inner ear.
• Ophthalmologic evaluation may reveal papilledema. Although genetic testing frequently identifies de novo NLRP3 mutations, it is not required for diagnosis. In cases with negative standard genetic results, somatic mosaicism for NLRP3 should be considered.

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 condition follows an autosomal dominant inheritance pattern. Individuals with a germline mutation have a 50% chance of passing the disorder on to each offspring. In cases involving somatic mosaicism, the recurrence risk depends on whether the somatic mutation is present in the parental germ cells.

Management and treatment – How is CINCA syndrome treated?

• Various therapeutic strategies using anti-inflammatory and immunosuppressive agents have shown limited effectiveness. While corticosteroids may offer partial symptom relief, their use is often associated with significant toxicity.
• Targeted treatments such as anakinra (an interleukin-1 receptor antagonist) and canakinumab (a monoclonal antibody against IL-1β) have demonstrated notable efficacy in reducing inflammatory symptoms, intracranial hypertension, and hearing loss.

What is the prognosis of CINCA syndrome?

• Without prompt and appropriate treatment, quality of life is generally poor.
• The severity of the syndrome varies widely, and long-term functional outcomes largely depend on the extent of neurological involvement—particularly intellectual disability and hearing loss—as well as the presence of tendon contractures.