Periodic fever, aphthous stomatitis, pharyngitis and adenitis syndrome is a medical condition, typically occurring in young children, in which high

fever Fever, also referred to as pyrexia, is defined as having a body temperature, temperature above the human body temperature, normal range due to an increase in the body's temperature Human body temperature#Fever, set point. There is not a single ...

occurs periodically at intervals of about 3-5 weeks, frequently accompanied by aphthous-like ulcers,

pharyngitis Pharyngitis is inflammation of the back of the throat, known as the pharynx. It typically results in a sore throat and fever. Other symptoms may include a runny nose, cough, headache, difficulty swallowing, swollen lymph nodes, and a hoarse voice ...

and/or cervical adenitis ( cervical lymphadenopathy). The syndrome was described in 1987 and named two years later.

Signs and symptoms

The key symptoms of PFAPA are those in its name: periodic high

at intervals of about 3–5 weeks, as well as

aphthous ulcer Aphthous stomatitis, or recurrent aphthous stomatitis (RAS), is a common condition characterized by the repeated formation of benign and non-contagious mouth ulcers (aphthae) in otherwise healthy individuals. The informal term ''canker sore'' i ...

and/or

adenitis Adenitis is a general term for an inflammation of a gland. Often it is used to refer to lymphadenitis which is the inflammation of a lymph node. Classification Lymph node adenitis ''Lymph adenitis'' or ''lymph node adenitis'' is caused by infec ...

. In between episodes, and even during the episodes, the children appear healthy. At least 6 months of episodes. Diagnosis requires recurrent negative throat cultures and that other causes (such as EBV, CMV, FMF) be excluded.

Cause

The cause of PFAPA is unknown. It is frequently discussed together with other

periodic fever syndrome Periodic fever syndromes are a set of disorders characterized by recurrent episodes of systemic and organ-specific inflammation. Unlike autoimmune disorders such as systemic lupus erythematosus, in which the disease is caused by abnormalities of ...

s. Possible causes include primarily

gene In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a ba ...

tic factors or it may be due to an initial

infection An infection is the invasion of tissues by pathogens, their multiplication, and the reaction of host tissues to the infectious agent and the toxins they produce. An infectious disease, also known as a transmissible disease or communicable dise ...

. The condition appears to be the result of a disturbance of innate immunity. The changes in the immune system are complex and include increased expression of complement related genes (C1QB, C2, SERPING1), interleukin-1-related genes (interleukin-1B, interleukin 1 RN, CASP1, interleukin 18 RAP) and

interferon Interferons (IFNs, ) are a group of signaling proteins made and released by host cells in response to the presence of several viruses. In a typical scenario, a virus-infected cell will release interferons causing nearby cells to heighten the ...

induced (AIM2, IP-10/CXCL10) genes.

T cell A T cell is a type of lymphocyte. T cells are one of the important white blood cells of the immune system and play a central role in the adaptive immune response. T cells can be distinguished from other lymphocytes by the presence of a T-cell r ...

associated

s ( CD3, CD8B) are down regulated. Flares are accompanied by increased serum levels of activated T lymphocyte chemokines (IP-10/CXCL10, MIG/CXCL9), G-CSF and proinflammatory

cytokine Cytokines are a broad and loose category of small proteins (~5–25 kDa) important in cell signaling. Cytokines are peptides and cannot cross the lipid bilayer of cells to enter the cytoplasm. Cytokines have been shown to be involved in autocrin ...

s (interleukin 6, interleukin 18). Flares also manifest with a relative lymphopenia. Activated CD4(+)/

CD25 Interleukin-2 receptor alpha chain (also called CD25) is the human protein encoded by the ''IL2RA'' gene. The interleukin 2 (IL2) receptor alpha (IL2RA) and beta (IL2RB) chains, together with the common gamma chain (IL2RG), constitute the high-a ...

(+) T-lymphocyte counts correlated negatively with serum concentrations of IP-10/CXCL10, whereas CD4(+)/HLA-DR(+) T lymphocyte counts correlated positively with serum concentrations of the counterregulatory IL-1 receptor antagonist.

Diagnosis

Treatment

PFAPA syndrome typically resolves spontaneously. Treatment options are used to lessen the severity of episodes. These treatments are either medical or surgical: One treatment often used is a dose of a

corticosteroid Corticosteroids are a class of steroid hormones that are produced in the adrenal cortex of vertebrates, as well as the synthetic analogues of these hormones. Two main classes of corticosteroids, glucocorticoids and mineralocorticoids, are involv ...

at the beginning of each fever episode. A single dose usually ends the fever within several hours. However, in some children, they can cause the fever episodes to occur more frequently.

Interleukin-1 The Interleukin-1 family (IL-1 family) is a group of 11 cytokines that plays a central role in the regulation of immune and inflammatory responses to infections or sterile insults. Discovery Discovery of these cytokines began with studies on t ...

inhibition appears to be effective in treating this condition. There has been some evidence for the use of medications to reduce the frequency of flare-ups, including

colchicine Colchicine is a medication used to treat gout and Behçet's disease. In gout, it is less preferred to NSAIDs or steroids. Other uses for colchicine include the management of pericarditis and familial Mediterranean fever. Colchicine is taken ...

and

cimetidine Cimetidine, sold under the brand name Tagamet among others, is a histamine H2 receptor antagonist that inhibits stomach acid production. It is mainly used in the treatment of heartburn and peptic ulcers. The development of longer-acting H2 rec ...

Surgical removal of the tonsils appears to be beneficial compared to no surgery in symptom resolution and number of future episodes. The evidence to support surgery is; however, of moderate quality. Children with PFAPA have an impaired quality of life, which may be treated via individual

counseling Counseling is the professional guidance of the individual by utilizing psychological methods especially in collecting case history data, using various techniques of the personal interview, and testing interests and aptitudes. This is a list of co ...

Prognosis

According to present research, PFAPA does not lead to other diseases and spontaneously resolves as the child gets older, with no long term physical effects. However, PFAPA has been found in adults and may not spontaneously resolve. Children with PFAPA experience lower physical, emotional, and psychosocial functioning. Their performance in school is also substantially impacted.

References

External links

{{General symptoms and signs Fever Pediatrics Autoinflammatory syndromes