Mystery Fevers and Hidden Inflammation – Could It Be Autoinflammatory Disease?

Fever is a natural response to infection. But what if a child has recurring fevers—without any sign of infection? What if the fever comes back again and again, sometimes with a rash or joint pain, and no clear explanation?

In these cases, doctors may consider a group of rare conditions called autoinflammatory syndromes—diseases where the body’s innate immune system causes inflammation without infection or autoimmune triggers.

⚠️ Important: Recurrent fevers that follow a pattern, especially if accompanied by skin rashes, joint or abdominal pain, eye inflammation, or mouth ulcers, should be evaluated by a specialist. Some of these syndromes are genetic and can cause long-term damage if left untreated.

What Are Autoinflammatory Syndromes?

Autoinflammatory syndromes are caused by abnormalities in the innate immune system, leading to repeated episodes of inflammation. Unlike autoimmune diseases, they do not involve autoantibodies, and symptoms often start in early childhood.

These conditions are rare, but early diagnosis can make a huge difference in quality of life.

Common Conditions Include:

• Familial Mediterranean Fever (FMF)

• Mevalonate Kinase Deficiency (MKD)

• Tumor Necrosis Factor Receptor-Associated Periodic Syndrome (TRAPS)

• Cryopyrin-Associated Periodic Syndromes (CAPS)

• PFAPA syndrome (Periodic Fever, Aphthous stomatitis, Pharyngitis, Adenitis)

• Blau syndrome, DIRA, Majeed, CANDLE, PAPA, and others

Some are monogenic, meaning they are caused by mutations in a single gene.

What Are the Symptoms?

Although each syndrome is different, common features include:

• Recurrent high fevers, often without infection

• Skin rashes

• Joint pain or swelling

• Abdominal or chest pain

• Mouth ulcers

• Eye inflammation (e.g. conjunctivitis or uveitis)

• Growth delay or fatigue

• In some cases, long-term complications such as amyloidosis

The episodes can last from a few hours to several days, and may repeat in regular patterns.

How Is Diagnosis Made?

Because symptoms can mimic many infections or autoimmune diseases, diagnosis is often delayed. Evaluation may include:

• Detailed symptom diary (to spot patterns)

• Blood tests during and between fever episodes

• Genetic testing for known mutations

• Exclusion of infections, malignancies, and autoimmune diseases

Pediatric rheumatologists often lead the diagnostic process.

How Are These Conditions Treated?

Treatment depends on the specific syndrome and its severity. Options include:

• Colchicine (especially for FMF)

• Corticosteroids for flares

• Biologic therapies, such as:

• IL-1 inhibitors (anakinra, canakinumab)

• TNF inhibitors (etanercept)

• IL-6 or IL-18 blockers (in research or specific indications)

Early treatment can reduce symptoms, prevent organ damage, and improve daily functioning.

Can Children Live a Normal Life?

Yes—with proper diagnosis and modern therapies, many children with autoinflammatory diseases live full, active lives. Long-term care and regular follow-up are essential, especially for those with more severe or persistent disease.

Genetic counseling may also be helpful for families.

Learn More

PRINTO offers a detailed leaflet explaining autoinflammatory diseases, their symptoms, and the different syndromes.

🔗 Read more on PRINTO:

Autoinflammatory Diseases – PRINTO Patient Leaflet

All rights and content remain with PRINTO, and the original resources can be found at:

https://www.printo.it/pediatric-rheumatology/GB/info/GB