Familial cold autoinflammatory syndrome

Overview

Familial Cold Autoinflammatory Syndrome (FCAS) is a rare, inherited autoinflammatory disorder characterized by recurrent episodes of fever, rash, and joint pain triggered by exposure to cold temperatures. It is part of a group of disorders known as Cryopyrin-Associated Periodic Syndromes (CAPS), which also includes Muckle-Wells syndrome and Neonatal-Onset Multisystem Inflammatory Disease (NOMID). FCAS is usually present from infancy or early childhood and persists throughout life, although symptoms can vary in severity.

Causes

FCAS is caused by mutations in the NLRP3 gene (also known as CIAS1), which encodes a protein called cryopyrin. This protein plays a key role in regulating the body’s inflammatory response. Mutations in the gene lead to uncontrolled activation of an inflammatory pathway, resulting in the release of pro-inflammatory cytokines like interleukin-1β (IL-1β). The condition is inherited in an autosomal dominant pattern, meaning only one copy of the mutated gene is sufficient to cause the disorder.

Symptoms

Symptoms of FCAS typically begin in infancy or early childhood and are triggered by exposure to cold environments. Common clinical features include:

• Fever: Usually low-grade, occurring shortly after cold exposure.

• Urticarial rash: Itchy, red rash resembling hives that typically appears on the limbs and trunk.

• Joint pain and swelling: Arthralgia or arthritis, particularly in large joints.

• Fatigue: General tiredness and malaise during flare-ups.

• Conjunctivitis: Inflammation of the eyes during episodes.

• Chills and headaches: Frequently reported during attacks.

Diagnosis

Diagnosis of FCAS is based on clinical presentation, family history, and genetic testing. Diagnostic steps may include:

• Clinical evaluation: Identifying patterns of symptoms related to cold exposure.

• Family history: A history of similar symptoms in close relatives supports the diagnosis.

• Genetic testing: Detection of mutations in the NLRP3 gene confirms the diagnosis.

• Laboratory tests: Elevated inflammatory markers such as ESR, CRP, and serum amyloid A (SAA) during flare-ups.

Treatment

Treatment of FCAS focuses on controlling inflammation and preventing flare-ups. Options include:

• Cold avoidance: Preventing exposure to cold environments to reduce symptom triggers.

• IL-1 inhibitors: Medications like anakinra, canakinumab, or rilonacept block the action of interleukin-1 and are highly effective in controlling symptoms.

• NSAIDs: May be used for mild symptom relief during flares.

• Monitoring and support: Regular follow-up with a rheumatologist or immunologist is recommended.

Prognosis

The prognosis for individuals with FCAS is generally favorable, especially with appropriate treatment. IL-1 inhibitors can significantly improve quality of life by reducing the frequency and severity of flare-ups. However, untreated or poorly managed FCAS may lead to complications such as amyloidosis, a condition where protein deposits accumulate in organs and cause damage. Early diagnosis and ongoing management are essential to prevent long-term complications and ensure optimal outcomes.