Periodic fever, aphthous stomatitis, pharyngitis and adenitis
Synonyms and keywords: Marshalls syndrome, PFAPA syndrome

# Overview
Periodic fever, aphthous stomatitis, pharyngitis and adenitis (PFAPA) syndrome is a medical condition, typically starting in young children, in which high fever occurs periodically at intervals of about 3-5 weeks, frequently accompanied by aphthous ulcers, pharyngitis and/or adenitis. The syndrome was described in 1987 and named two years later.

# Historical Perspective
- Periodic fever, aphthous stomatitis, pharyngitis and adenitis was first discribed by Dr. Marshall in 1987.
- Initially it was named fever, aphthous stomatitis, pharyngitis and adenitis (FAPA) syndrome, later was changed to periodic fever, aphthous stomatitis, pharyngitis and adenitis (PFAPA) syndrome to further emphasize on its periodic nature, the main feature of this disorder.

# Classification
- There is no established system for the classification of periodic fever, aphthous stomatitis, pharyngitis and adenitis.

# Pathophysiology
- The exact pathogenesis of periodic fever, aphthous stomatitis, pharyngitis and adenitis is not fully understood.
- Dysregulated innate immune response, as well as inappropriate T cell activity, have been proposed theoretically as the possible pathogenesis.
- Consistent data with abnormal activity of T cells include increased levels of Th1 inflammatory response cytokines such as TNF, INF-, IL-6, and IP-10 in blood samples of PFAPA patients.
- Elevated IL-1 production has also been observed in  PFAPA patients which is consistent with abnormal innate immune response.
- Studies trying to find a gene mutation associated with PFAPA syndrome resulted in controversy.

# Causes
- PFAPA is frequently discussed together with other periodic fever syndromes, but it is unknown whether the cause is primarily genetic or due to an initial infection.

# Differentiating Periodic fever, aphthous stomatitis, pharyngitis and adenitis from Other Diseases
- Periodic fever, aphthous stomatitis, pharyngitis and adenitis must be differentiated from cyclic neutropenia, familial mediterranean fever (FMF), familial Hibernian fever (FHF), and hyperglobulinemia D syndrome.
- For more information on PFAPA syndrome differential diagnosis please click here.

# Epidemiology and Demographics
- The incidence of PFAPA syndrome is approximately 23 per 100,000 children up to 5 years of age worldwide.
- The exact prevalence of PFAPA syndrome is not known, however it appears to be more frequent than other autoinflammatory disorders.
- PFAPA syndrome more commonly affects children of 2-5 years of age.
- There is also reports of adult onset PFAPA syndrome.
- There is no racial predilection to PFAPA syndrome.
- PFAPA syndrome affects men and women equally.

# Risk Factors
- There are no established risk factors for PFAPA syndrome.

# Screening
- There is insufficient evidence to recommend routine screening for PFAPA syndrome.

# Natural History, Complications, and Prognosis
- Patients with PFAPA syndrome develop the manifestations early in childhood, between 2-5 years of age.
- It manifests with periods of high fevers  lasting for 3 to 6 days along with aphthous ulcers and non-infectious, exudative pharyngitis.
- Symptoms usually occur every 21 to 28 days.
- In between episodes, and even during the episodes, the children appear healthy.
- According to present research, PFAPA does not lead to other diseases and spontaneously resolves as the child gets older, with no long term effects.

# Diagnosis

## Diagnostic Study of Choice
- The diagnosis of PFAPA syndrome is made when the following diagnostic criteria are met:
- Diagnosis of PFAPA syndrome also requires exclusion of possible infection, immunodeficiency, monogenic auto-inflammatory disorders, and cyclic neutropenia.

## History and Symptoms
- The key symptoms of PFAPA are those in its name: periodic high fever, aphthous ulcers, pharyngitis and/or adenitis.
- Other less frequent symptoms are abdominal pain, diarrhea, headache, skin rash, and arthralgia.

## Physical Examination
- Physical examination of patients with PFAPA syndrome may show high fever, exudative pharyngitis, aphthous ulcers, and cervical lymphadenopathy.

## Laboratory Findings
- Laboratory findings of patients with PFAPA syndrome may include leukocytosis (with a preponderance of neutrophils), increases of the inflammatory markers (ESR and CRP) during febrile episodes, normal inflammatory markers in between episodes of fever.
Quantitative immunoglobulin levels have been demonstrated to be normal or near normal.
At the very onset of fever, the inflammatory markers may be normal.
- Quantitative immunoglobulin levels have been demonstrated to be normal or near normal.
- At the very onset of fever, the inflammatory markers may be normal.
- CD64 and CXCL10 has been proposed as potential specific bio-markers of PFAPA syndrome. However, more studies are needed to confirm this association.

## Electrocardiogram
- There are no ECG findings associated with PFAPA syndrome.

## X-ray
- There are no x-ray findings associated with PFAPA syndrome.

## Echocardiography or Ultrasound
- There are no echocardiography/ultrasound findings associated with PFAPA syndrome.

## CT Scan
- There are no CT scan findings associated with PFAPA syndrome.

## MRI
- There are no MRI findings associated with PFAPA syndrome.

## Other Imaging Findings
- There are no other imaging findings associated with PFAPA syndrome.

## Other Diagnostic Studies
- There are no other diagnostic studies associated with PFAPA syndrome.

# Treatment

## Medical Therapy
- There is no treatment for PFAPA syndrome; the mainstay of therapy is supportive care.
- A possible treatment for PFAPA is a single dose of prednisone (2 mg per kg body mass) at the beginning of each fever episode.
- The single-dose usually terminates the fever within several hours. However, in some children, prednisone causes fever episodes to occur more frequently (and more regularly).
- Daily administration of colchicine has been associated with decreased frequency of episodes.
- IL-1 blockade with drugs, such as anakinra, rilonacept, and canakinumab have also indicated promising results.
Implication of these medications have resulted in the shortened course of the disease as well as a complete resolution of symptoms in some cases.
- Implication of these medications have resulted in the shortened course of the disease as well as a complete resolution of symptoms in some cases.

## Surgery
- Adenotonsillectomy is recommended for patients with PFAPA syndrome who failed to response to medical treatment.
- However, recent studies reported the moderate quality of evidence which supports the role of surgery in the management of these patients. This report suggests evaluation of risks and benefits before performing the surgery.

## Primary Prevention
- There are no established measures for the primary prevention of PFAPA syndrome.

## Secondary Prevention
- There are no established measures for the secondary prevention of PFAPA syndrome.