Periodic fever syndrome does not refer to a single disease, nor is it a specific diagnosis, but rather a general term, a classification of a group of diseases.
The term “periodic fever syndrome” refers to several different autoinflammatory diseases that have similar symptoms–the primary symptom being a recurrent fever for which no infectious cause can be found. The patient just keeps getting fevers, often accompanied other inflammatory symptoms.
These are primarily genetic conditions and are not contagious. Autoinflammatory diseases are caused by a malfunction in the innate immune system that leads to an over active immune system. This over activation causes severe systemic inflammation throughout the body.
The periodic fever syndromes include, but are not limited to:
- The Cryopryin-Associated Periodic syndromes (CAPS): Familial Cold Autoinflammatory Syndrome (FCAS), Muckle-Wells Syndrome (MWS), and Neonatal-Onset Multisystem Inflammatory Disease (NOMID or CINCA)
- Familial Mediterranean Fever (FMF)
- Tumour Necrosis Factor (TNF)-Associated Periodic Syndrome (TRAPS)
- Mevalonate Kinase Deficiencies: Hyper-IgD with Periodic Fever Syndrome (HIDS), and Mevoalonate Aciduria (MA)
- Periodic Fever, Aphthous Stomatitis, Pharyngitis, & Cervical Adenitis (PFAPA syndrome)
- Familial Behcet’s-like autoinflammatory syndrome
- And several others. Click here to see a full list.
Common Periodic Fever Syndrome Symptoms
Many autoinflammatory diseases (these are NOT autoimmune – click here for more) tend to have frequent recurring fevers as the most obvious symptom. The fevers are often cyclic in nature, coming and going in some cases erratically and in some cases more predictably. However much more is going on than just a fever inside the body. These diseases cause the rapid onset of intense episodes of systemic inflammation that can affect multiple organs and tissues. Which body systems are most affected depends on the specific syndrome.
These are some of the most common symptoms that may be noted during disease flares in various periodic fever syndromes:
- Fever (recurrent, and accompanied by some of the following symptoms)*
- Mouth ulcers
- Swollen lymph nodes
- Abdominal pain
- Joint pains, or arthritis
- Abnormal blood test results during flares of symptoms, including: high white blood count (WBC) and high inflammatory markers CRP and ESR
- Serositis (pericarditis, pleurisy)
*Some will have on-going symptoms listed above without a fever.
Age of Onset
Most patients start presenting with symptoms in childhood before the age of 5. However, some patients may not develop their first symptoms until they are older (school age or adolescence) or even as adults.
Like the symptoms, the prognosis for someone living with a periodic fever syndrome often depends on which syndrome he or she has. For some, like those with PFAPA, the prognosis is considered good, as PFAPA is typically outgrown. For most others, these are lifelong conditions that must be managed with medication to prevent serious complications from the disease. In some cases, the disease may go into remission for months to years at a time.
Getting a Specific Diagnosis for a Periodic Fever Syndrome
Many of the periodic fever syndromes are also referred to as “hereditary periodic fever syndromes,” because they are caused by genetic mutations. Some mutations are dominantly inherited (meaning you only need one mutation to cause disease), and others are recessively inherited (where you need to inherit two mutations to develop the disease.)
Once a patient is suspected of having a periodic fever syndrome, it is necessary for the doctors to first do a clinical evaluation to try to determine which syndrome(s) could be a possibility. This includes an evaluation of the patient’s most common symptoms, blood tests (during flares of symptoms, and during times with no obvious symptoms), and genetic testing for these diseases. If the patient has a rash, a skin biopsy by a dermatologist should be done as well.
For some conditions, a genetic test is not yet available, such as for PFAPA. However, it is ideal to rule out the known hereditary periodic fever syndromes, such as FMF, MWS, HA20, and HIDS, when diagnosing PFAPA, since these diseases have similar symptoms. PFAPA is too often diagnosed without a full attempt to rule out the other autoinflammatory diseases, and therefore too often misdiagnosed. A misdiagnosis of PFAPA, if the patient has another periodic fever syndrome, can delay starting medications that are most effective and can prevent risks and complications of their disease. Other autoinflammatory diseases can share the same symptoms as PFAPA, but need different treatments to manage the disease and reduce the risk of serious complications.
Classic PFAPA patients are considered to be symptom-free without signs of chronic inflammation in between attacks of the fever. They also do not have elevated inflammatory labs when they are not having the fever flares. However, this can also occur in some patients with other autoinflammatory conditions such as HIDS.
If a patient has signs of enduring symptoms between times of the fever, or elevated inflammatory markers on lab tests when they are not flaring, or additional symptoms beyond the list above, other autoinflammatory diseases beyond PFAPA must be considered. Concerning symptoms of chronic inflammation include: an enlarged liver and/or spleen, progressive hearing loss, inflammation in the eyes, growth delays, neuro-cognitive deficits, persistent rashes, vasculitis, or an other unusual, chronic signs of inflammation.
Conditions Similar to Periodic Fever Syndromes
When patients have recurring fevers and other inflammatory symptoms, doctors will consider several differential diagnosis for conditions that can have similar symptoms. These include immune deficiencies, autoimmune diseases, mast cell activation syndrome (MCAS) just to name a few. The larger and cost-effective immune dysregulation genetic panels include many of these differential diagnosis along with autoinflammatory genes.
Do you have recurring fevers and need help? Follow the links below for more help.
The Autoinflammatory Alliance is a nonprofit organization dedicated to helping those with autoinflammatory diseases.