What Are Periodic Fever Syndromes?

This family of disorders causes fever without infection

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Periodic fever syndromes is the term given to a number of conditions that feature an unexplained fever that returns over and over again. Sometimes these fevers come with other symptoms, but not always. Periodic fever syndromes usually arise in childhood and may resolve before the adult years—but not always.

These conditions are rarely fatal but may result in lifelong challenges and treatments. Keep reading to learn more about the different types of periodic fever syndromes and how to manage them.

Baby having temperature taken may have a periodic fever syndrome
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Types of Periodic Fever Syndrome

Pediatric fever syndromes is an umbrella term for a number of conditions that present with a fever that wasn’t caused by a bacterial or viral illness. Most of these conditions are hereditary, passed down through families as a genetic mutation.

The most common periodic fever syndromes are listed below:

  • Familial Mediterranean fever (FMF)
  • Hyperimmunologlobulin D syndrome (HIDS)
  • Muckle-Wells syndrome and familial cold autoinflammatory syndrome
  • Neonatal onset multisystem inflammatory disease (NOMID)
  • Periodic fever, aphthous-stomatitis, pharyngitis, adenitis syndrome (PFAPA)
  • Tumor necrosis receptor associated periodic syndrome (TRAPS)

Periodic Fever Syndrome Symptoms

While the most common symptom in this family of disorders is recurrent fever without an infectious cause, there are also a range of symptoms that go along with the fevers depending on which condition you may have:

  • Familial Mediterranean fever: This is the most common of the periodic fever syndromes and includes abdominal pain, joint pain, and chest pain, in addition to fevers.
  • Tumor necrosis factor receptor associated periodic syndrome: Formerly known as familial Hibernian fever, TRAPS can cause abdominal pain, diarrhea, muscle pain, swelling around the eyes, painful skin rashes, and body pain that moves around the body in addition to episodic fevers.
  • Hyperimmunologlobulin D syndrome (HIDS): Also known as mevalonate kinase-associated periodic fever syndrome, fevers can get quite high in this condition, and you may also experience skin rashes, swollen lymph nodes, headache, loss of appetite, abdominal pain, vomiting, and diarrhea.
  • Neonatal onset multisystem inflammatory disease (NOMID): This condition often comes with fevers and a rash, but there are a number of other more serious symptoms, too. People with NOMID may also have one or more of the following symptoms: chronic meningitis, vision problems, hearing loss, other neurologic problems, bulging eyes, vomiting, delayed closure of the soft spot (anterior fontanel) of the skull in infancy, headaches, joint pain or swelling, bone or joint deformities, hand deformities, and clubbing of the fingers and/or toes.
  • Muckle-Wells syndrome and familial cold autoinflammatory syndrome: This condition can present with fevers, and sometimes skin rashes or deafness.
  • Periodic fever, aphthous-stomatitis, pharyngitis, adenitis syndrome (PFAPA): In addition to periodic fevers, people with PFAPA may have a sore throat, mouth ulcers, enlarged lymph nodes in the neck, headache, vomiting, diarrhea, abdominal pain, and joint pain.

Causes

While each of the periodic fever syndromes is unique, they are typically genetic in nature. Passed down through families and caused by a gene mutation in most cases, these disorders are considered autoinflammatory diseases.

Autoinflammatory diseases represent a sort of malfunction within the immune system. Instead of only attacking foreign threats like viruses or bacteria, gene mutations in people with these conditions cause their immune cells to attack their own bodies. This can result in a number of symptoms, including fevers.

The symptoms that present depend on what body system your immune cells are working against. In some cases, the symptoms are more limited to the mutation of a single gene. In others, the inflammation caused by the gene mutation is damaging to other organs.

Diagnosis

Diagnosis of periodic fever syndromes usually happens after months or years of unexplained fevers occur without evidence of viral or bacterial infections. These diseases usually appear in infancy or childhood but can continue into adulthood, too.

Most of these conditions are so rare that they aren’t seen by most doctors, with the exception of the more common familial Mediterranean fever (FMF).

Typically, the diagnosis will rely on family histories and the presence of certain symptoms.

Symptoms and Tests for Diagnosis

A formal diagnosis may accompany the following symptoms or tests:

  • Observed patterns of recurrent fevers without infection
  • Absence of other problems like cancers, infections, or other diseases
  • Genetic testing for known gene mutations
  • Family histories
  • Ethnicity—there is a higher prevalence of FMF in people of Mediterranean and Middle Eastern descent
  • Elevated inflammatory markers like c-reactive protein

Treatment

Once again, specific treatments will depend on the specific disease, but generally medications that reduce inflammation or suppress the immune system may be used to manage these conditions. While there are treatments to manage symptoms of these disorders—and some may resolve with age—most periodic fever disorders are not curable.

There has also been some progress in using biologics like Enbrel (etanercept), Ilaris (canakinumab), and Kineret (anakinra) that block certain immune functions to treat certain periodic fever syndromes.

These medications reprogram immune cells by targeting the mutated cell type, and disarming it, or blocking the receptors that respond to those cell types. Biologics are frequently used to manage autoimmune and auto-inflammatory disorders.

Some specific treatments, by condition, that may help are:

  • Familial Mediterranean fever (FMF): Colchicine, Ilaris
  • Hyperimmunologlobulin D syndrome (HIDS): Non-steroidal anti-inflammatory drugs, steroids
  • Muckle-Wells syndrome and familial cold autoinflammatory syndrome: Kineret
  • Neonatal onset multisystem inflammatory disease (NOMID): Non-steroidal anti-inflammatory drugs, steroids, methotrexate, Kineret
  • Periodic fever, aphthous-stomatitis, pharyngitis, adentitis syndrome (PFAPA): Steroids, cimetidine
  • Tumor necrosis receptor associated periodic syndrome (TRAPS): Anti-inflammatory agents like steroids, Enbrel

Prognosis

While recurrent fevers are not ideal, these disorders rarely cause lifelong serious problems. In PFAPA and HIDS, symptoms typically lessen throughout childhood—especially after age 10.

Mild symptoms may continue into adulthood or contribute to other conditions like arthritis. FMF is a lifelong condition that is manageable as long as colchicine treatment is continuous.

NOMID, on the other hand, often results in serious physical deformities and/or neurological damage. Many of these conditions, particularly Muckle-Wells, are also associated with a condition called amyloidosis.

Amyloidosis occurs when abnormal proteins build up in and cause damage to your organs—especially to the kidneys. This condition can even lead to kidney failure.

While these conditions can cause a range of symptoms from mild to serious, periodic fever syndromes are not fatal in most cases.

A Word From Verywell

Periodic fever syndromes are a family of disorders with recurrent fevers that aren’t caused by infections. These disorders are largely rare and are not contagious. Most of these conditions are passed through families as a genetic mutation. Symptoms can stick around for life, but anti-inflammatory medicines and new biologic treatments can help manage them.

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