Chronic infantile neurologic cutaneous and articular syndrome

Overview

Chronic Infantile Neurologic Cutaneous and Articular (CINCA) syndrome, also known as Neonatal-Onset Multisystem Inflammatory Disease (NOMID), is a rare and severe autoinflammatory disorder that typically begins in infancy. It is part of a group of disorders called Cryopyrin-Associated Periodic Syndromes (CAPS), which are caused by mutations affecting the innate immune system. CINCA syndrome involves persistent systemic inflammation affecting the nervous system, skin, and joints. Without appropriate treatment, it can lead to significant developmental issues, chronic pain, and organ damage.

Causes

CINCA syndrome is caused by mutations in the NLRP3 gene (previously called CIAS1), which provides instructions for making a protein involved in inflammation regulation. Mutations in this gene lead to overproduction of interleukin-1β (IL-1β), a pro-inflammatory cytokine. This excessive immune response results in chronic inflammation throughout the body. The condition is usually caused by a de novo (new) mutation and is inherited in an autosomal dominant pattern, though most cases occur sporadically without a family history.

Symptoms

Symptoms of CINCA syndrome typically appear within the first weeks of life and involve a triad of neurological, cutaneous (skin), and articular (joint) manifestations:

• Neurological symptoms:

  • Chronic aseptic meningitis (non-infectious inflammation of the meninges)

  • Headaches, vomiting, and irritability

  • Hydrocephalus and increased intracranial pressure

  • Developmental delays and cognitive impairment

  • Sensorineural hearing loss

• Cutaneous symptoms:

  • Persistent, non-itchy urticarial (hive-like) rash

  • Skin lesions often present from birth or early infancy

• Articular symptoms:

  • Joint swelling, pain, and stiffness

  • Overgrowth of cartilage and bone (epiphyseal and patellar enlargement)

  • Reduced joint mobility and potential deformity

• Other possible features: Fatigue, low-grade fever, enlarged liver or spleen, and eye inflammation (e.g., uveitis)

Diagnosis

Diagnosis of CINCA syndrome is based on clinical evaluation, imaging studies, laboratory tests, and genetic analysis. Key steps include:

• Clinical history and examination: Identification of early-onset inflammation affecting skin, joints, and nervous system

• Laboratory tests:

  • Elevated inflammatory markers such as C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR)

  • Normal or slightly elevated white blood cell count

• Lumbar puncture: To detect chronic aseptic meningitis (increased white cells without infection)

• Imaging studies: Brain MRI may show hydrocephalus or meningeal enhancement; X-rays may reveal joint damage

• Genetic testing: Confirmation of mutations in the NLRP3 gene

Treatment

Management of CINCA syndrome focuses on controlling inflammation and preventing long-term complications. The primary treatment approach involves the use of interleukin-1 (IL-1) inhibitors. Options include:

• Anakinra: A daily injectable IL-1 receptor antagonist, often the first-line treatment

• Canakinumab: A long-acting monoclonal antibody that neutralizes IL-1β; administered every 4–8 weeks

• Rilonacept: A fusion protein that blocks IL-1 activity (less commonly used in CINCA)

• Supportive care:

  • Physical therapy for joint function

  • Management of hearing loss with hearing aids or cochlear implants

  • Regular monitoring of vision, growth, and development

Early treatment with IL-1 blockers has been shown to dramatically reduce symptoms and systemic inflammation, improving long-term outcomes.

Prognosis

The prognosis of CINCA syndrome has significantly improved with the introduction of IL-1 targeted therapies. Early diagnosis and intervention are critical for preventing irreversible damage to the brain, joints, and other organs. Without treatment, the condition can lead to progressive neurological decline, joint deformities, and disability. With proper management, many patients experience substantial symptom relief, improved growth, and better quality of life, although lifelong treatment and monitoring are usually necessary.