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

fever Fever or pyrexia in humans is a symptom of an anti-infection defense mechanism that appears with Human body temperature, body temperature exceeding the normal range caused by an increase in the body's temperature Human body temperature#Fever, s ...

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 vo ...

and cervical adenitis (

cervical lymphadenopathy Cervical lymphadenopathy refers to lymphadenopathy of the cervical lymph nodes (the glands in the neck). The term ''lymphadenopathy'' strictly speaking refers to disease of the lymph nodes, though it is often used to describe the enlargement of th ...

). 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), commonly referred to as a canker sore or salt blister, is a common condition characterized by the repeated formation of benignity, benign and non-contagious disease, contagious mouth ...

and

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.

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 has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...

tic factors or it may be due to an initial

infection An infection is the invasion of tissue (biology), tissues by pathogens, their multiplication, and the reaction of host (biology), host tissues to the infectious agent and the toxins they produce. An infectious disease, also known as a transmis ...

. 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-1β, interleukin 1 RN,

CASP1 Caspase-1/Interleukin-1 converting enzyme (ICE) is an evolutionarily conserved enzyme that proteolytically cleaves other proteins, such as the precursors of the inflammatory cytokines interleukin 1β and interleukin 18 as well as the pyroptosis ...

, 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 ...

induced (

AIM2 Interferon-inducible protein AIM2 also known as absent in melanoma 2 or simply AIM2 is a protein that in humans is encoded by the ''AIM2'' gene. AIM2 is a cytoplasmic sensor found in hematopoietic cells that recognizes the presence of double-str ...

, IP-10/

CXCL10 C-X-C motif chemokine ligand 10 (CXCL10) also known as Interferon gamma-induced protein 10 (IP-10) or small-inducible cytokine B10 is an 8.7 kDa protein that in humans is encoded by the ''CXCL10'' gene. C-X-C motif chemokine 10 is a small cytokin ...

) genes.

T cell T cells (also known as T lymphocytes) are an important part 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 receptor (TCR) on their cell ...

associated

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

CXCL9 Chemokine (C-X-C motif) ligand 9 (CXCL9) is a small cytokine belonging to the CXC chemokine family that is also known as monokine induced by gamma interferon (MIG). The CXCL9 is one of the chemokine which plays role to induce chemotaxis, promote ...

G-CSF Granulocyte colony-stimulating factor (G-CSF or GCSF), also known as colony-stimulating factor 3 (CSF 3), is a glycoprotein that stimulates the bone marrow to produce granulocytes and stem cells and release them into the bloodstream. Function ...

and proinflammatory

cytokine Cytokines () are a broad and loose category of small proteins (~5–25 kDa) important in cell signaling. Cytokines are produced by a broad range of cells, including immune cells like macrophages, B cell, B lymphocytes, T cell, T lymphocytes ...

s (

interleukin 6 Interleukin 6 (IL-6) is an interleukin that acts as both a pro-inflammatory cytokine and an anti-inflammatory myokine. In humans, it is encoded by the ''IL6'' gene. In addition, osteoblasts secrete IL-6 to stimulate osteoclast formation. Smoo ...

interleukin 18 Interleukin-18 (IL-18), also known as interferon-gamma inducing factor is a protein which in humans is encoded by the ''IL18'' gene. The protein encoded by this gene is a proinflammatory cytokine. Many cell types, both hematopoietic cells and n ...

). Flares also manifest with a relative

lymphopenia Lymphocytopenia is the condition of having an abnormally low level of lymphocytes in the blood. Lymphocytes are a white blood cell with important functions in the immune system. It is also called lymphopenia. The opposite is lymphocytosis, which r ...

. Activated

CD4 In molecular biology, CD4 (cluster of differentiation 4) is a glycoprotein that serves as a co-receptor for the T-cell receptor (TCR). CD4 is found on the surface of immune cells such as helper T cells, monocytes, macrophages, and dendritic c ...

⁺/

CD25 The interleukin-2 receptor alpha chain (also called Tac antigen, P55, and mainly CD25) is a protein involved in the assembly of the high-affinity interleukin-2 receptor, consisting of alpha (''IL2RA''), beta ('' IL2RB'') and the common gamma cha ...

⁺ T-lymphocyte counts correlated negatively with serum concentrations of IP-10/CXCL10, whereas CD4⁺/

HLA-DR HLA-DR is an MHC class II cell surface receptor encoded by the human leukocyte antigen complex on chromosome 6 region 6p21.31. The complex of HLA-DR (Human Leukocyte Antigen – DR isotype) and peptide, generally between 9 and 30 amino acids in l ...

⁺ T lymphocyte counts correlated positively with serum concentrations of the counterregulatory IL-1 receptor antagonist.

Diagnosis

Diagnosis requires recurrent negative throat cultures and that other causes (such as EBV, CMV, FMF) be excluded.

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 invo ...

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 prevent and treat gout, to treat familial Mediterranean fever and Behçet's disease, and to reduce the risk of myocardial infarction. The American College of Rheumatology recommends colchicine, nonstero ...

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. With the development of proton pump ...

. Surgical removal of the tonsils appears to be beneficial compared to no surgery in symptom resolution and number of future episodes. However, the evidence to support surgery is 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 c ...

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 Otorhinolaryngology