Recurrent Fever Syndromes (Formerly Known as Periodic Fever Syndromes)

What are periodic fever syndromes (now known as recurrent fever syndromes)?

Recurrent fever syndromes, formerly known as periodic fever syndromes, are a group of disorders that cause recurrent fevers that don’t have an infectious (virus, bacteria) cause. The syndromes are considered autoinflammatory diseases, which means an abnormality or regulation problem in your child’s natural (innate) immune system causes the condition. Recurrent fever syndrome isn’t an autoimmune disease, in which your child’s acquired (adaptive) immune system malfunctions and mistakenly attacks healthy tissue.

Recurrent fever syndromes typically (but not always) start when your child is a baby or toddler. Your child will experience episodes, or attacks, that cause fevers and other symptoms. Children may not have symptoms between episodes. Most of these syndromes are passed down (hereditary) and result from a genetic change (mutation).

Many of these syndromes have a specific treatment, often based on understanding the issue that the genetic mutation causes. If left untreated, periodic fever syndrome can be dangerous because of injury caused by recurrent or ongoing inflammation.

Is recurrent fever syndrome common?

There are several different types of recurrent fever syndrome. For some types, the frequency (how often someone has the condition) is unknown. For others, the frequency is increasing because researchers have discovered a variety of mutations that cause the syndromes. Most are very rare, but some are more common than others. For instance, tumor necrosis factor receptor-associated periodic syndrome (TRAPS) affects 1 in 1 million people. But familial Mediterranean fever affects approximately 1 in 200 people of Mediterranean and Middle Eastern descent.

What are some of the different types of recurrent fever syndrome?

Familial Mediterranean fever (FMF)

Familial Mediterranean fever (FMF) is the most common genetically diagnosed recurrent fever syndrome. It causes recurrent fevers and may cause painful inflammation in your child’s abdomen, chest and joints. With FMF, the attacks typically begin in childhood. As your child ages, the frequency and severity of their attacks may become less intense.

Periodic fever, aphthous-stomatitis, pharyngitis, adenitis (PFAPA)

Periodic fever, aphthous-stomatitis, pharyngitis, adenitis (PFAPA) includes periodic fevers with mouth sores (aphthous stomatitis), sore throat (pharyngitis) and swollen lymph nodes (adenitis) in your child’s neck. PFAPA affects children in early childhood, usually starting before 4 years old. Episodes usually decrease in frequency and resolve after age 10.

Tumor necrosis factor receptor-associated periodic syndrome (TRAPS)

Apart from episodes of fever, tumor necrosis factor receptor-associated periodic syndrome (TRAPS) may cause abdominal pain, diarrhea, spreading skin rashes, muscle pain and swelling around your child’s eyes. TRAPS may first appear during early to late childhood or into adulthood. The former name of this syndrome was familial Hibernian fever.

Hyperimmunoglobulin D syndrome (HIDS)

Hyperimmunoglobulin D syndrome (HIDS) causes episodic high fevers with skin rashes, swollen neck lymph nodes, abdominal pain, arthritis and/or vomiting and diarrhea. The disease typically starts before 1 year of age. The name of this disease comes from the fact that most babies produce very high amounts of immunoglobulin type D (but this isn’t important diagnostically or clinically). Immunoglobulins are proteins that are part of your child’s immune system.

Neonatal onset multisystem inflammatory disease (NOMID)

Neonatal onset multisystem inflammatory disease (NOMID) causes episodes of fever and skin rash. The symptoms of this condition start at birth or within the first weeks of life. The same gene mutation causes two other diseases (Muckle-Wells syndrome and familial cold autoinflammatory syndrome). These three diseases are called cryopyrin-associated autoinflammatory diseases.

What causes recurrent fever syndrome?

Most recurrent fever syndromes are genetic diseases. A mutation in a certain gene causes each syndrome. The types of recurrent fever syndrome and their genetic causes are in the chart below:

What are the symptoms of recurrent fever syndrome?

Recurrent fever syndrome symptoms typically start during childhood. Less than 10% of recurrent fever syndrome cases develop in adults. People generally may feel well and have no symptoms between attacks. The most common symptom of the condition is a periodic (episodic) fever. Each type of recurrent fever syndrome may produce different symptoms:

• FMF may cause inflammation and severe pain in your child’s joints. A rash may develop in your child’s lower legs or ankles.
• PFAPA may cause a sore throat, mouth sores and swollen lymph nodes in your child’s neck.
• TRAPS may cause chills and muscle pain in your child’s trunk and arms. They may develop a painful red rash that moves from their arms and legs to their trunk.
• HIDS may cause chills, headaches, abdominal pain, loss of appetite and flu-like symptoms.
• NOMID may cause premature birth in some infants. Your newborn may have a fever and a rash that looks like hives but doesn’t itch.

Is recurrent fever syndrome contagious?

No. Recurrent fever syndromes are genetic conditions, and the fever caused by them isn’t contagious.

How do you diagnose recurrent fever syndrome?

Your child’s healthcare provider will use several factors to diagnose recurrent fever syndrome. They’ll ask about your child’s symptoms and their biological family history. Your child’s provider may suspect recurrent fever syndrome if your child:

• Frequently get fevers.
• Has a family history of periodic fevers.
• Comes from an ethnicity where periodic fevers are more common.

Your healthcare provider may recommend several tests to make a diagnosis. These may include:

• Laboratory tests: Laboratory tests, such as a C-reactive protein (CRP) or a complete blood count (CBC), can show signs of inflammation. These types of tests become positive during an attack and return to normal or nearly normal after an attack.
• Urine test: A urine protein test checks for high levels of protein in your urine. For HIDS, a urine test for organic acid (acids in your child’s body that contain a carbon atom) will show high levels of mevalonic acid.
• Genetic testing: Genetic testing can look for genetic mutations. However, in some children with periodic fever syndromes, detectable gene mutations aren’t found, so test results may come back negative.

How do you treat recurrent fever syndrome?

Recurrent fever syndrome treatment depends on the type. The diseases aren’t curable, but you can usually manage your child’s symptoms with medication:

• FMF: You can control FMF with a medication called colchicine, which helps reduce inflammation. Colchicine prevents FMF attacks in many children with the condition and partially prevents attacks in the remainder of cases.
• PFAPA: You can shorten episodes of PFAPA with a single dose of steroids (usually prednisone) timed when symptoms first appear. The medication may end an episode. In some children, a medicine used to treat stomach ulcers (cimetidine) may prevent or minimize symptoms of some attacks.
• TRAPS: Canakinumab, a biologic type of medication prescribed monthly, is often an effective treatment. You can also help relieve symptoms of TRAPS with nonspecific anti-inflammatory agents including steroids.
• HIDS: Canakinumab is an effective option for treatment. During an episode, nonsteroidal anti-inflammatory drugs (NSAIDs) — such as ibuprofen and naproxen — or steroids may be helpful.
• NOMID: Canakinumab treats NOMID effectively.

How can I prevent recurrent fever syndrome?

You can’t prevent recurrent fever syndrome because genetic mutations cause the condition. If you plan on becoming pregnant, talk to your healthcare provider about genetic counseling. Genetic counseling can help you understand your risk of having a baby with a genetic condition.

Does recurrent fever syndrome go away?

Some recurrent fever syndromes are lifelong conditions. Others may last several years and then go away with age. Some conditions are lifelong disorders but episodes will get milder and less frequent over time. Your child’s healthcare provider can provide specific details about your child’s condition.

A note from Cleveland Clinic

Recurrent fever syndromes are genetic conditions that cause episodic fevers. If your child has a biological family history of the condition or they’re experiencing recurring fevers, reach out to your healthcare provider. It’s important that your child gets a proper diagnosis so they can receive the correct treatment. For some syndromes, your child can take medication to manage their symptoms and even prevent attacks.