PFAPA syndrome

What is PFAPA syndrome?

PFAPA is an acronym derived from periodic fever, aphthous stomatitis, pharnygitis and adenitis, the major features of this syndrome. It is the commonest cause of a recurrent fever syndrome in children.

Who gets PFAPA syndrome and why?

PFAPA syndrome predominantly affects children, with onset in the first five years, and as young as 1 month of age (mean 18 months of age).

There is no correlation with race, sex or geographic area but it has mainly been reported from Europe and America.

No genetic defect for PFAPA syndrome has yet been determined, however 14% have a positive family history so there may be an as yet unidentified genetic basis for some cases.

PFAPA syndrome is a more common cause of recurrent fever in children than monogenic periodic fevers and the age at onset is generally older than for genetically positive patients with PFAPA-like symptoms.

Clinical features of PFAPA syndrome

A child with PFAPA syndrome presents with recurrent episodes every 2-6 weeks which, in 60%, occur with clockwork regularity. The episodes last for 3-6 days and there are symptom-free intervals of 3-5 weeks. Between episodes the child is well with normal growth and development.

The major feature of an episode is fever with spikes ranging 38.5-41C.

Spontaneous remission occurs in 30% with PFAPA syndrome after 4-8 years.

How is PFAPA syndrome diagnosed?

Diagnosis of PFAPA syndrome is clinical, with exclusion of other causes. It is based on recurrent fever of early onset (<5years) and at least one of the following associated features:

• Aphthous stomatitis
• Enlarged tender lymph nodes in the neck
• Pharnygitis

In the absence of:

• Respiratory tract infections
• Cyclical neutropaenia
• Monogenic periodic fever

There are no specific tests for PFAPA syndrome, but during a febrile attack, the following blood test abnormalities may be noted:

• Mild increase in white blood cell numbers
• Elevated ESR and other acute phase reactants
• Mild elevation of IgA, IgD, IgM in some cases

White cell count and acute phase reactants are normal when symptom-free.

In a study in Italy of 210 children fulfilling the criteria for PFAPA syndrome, 43 carried diagnostic mutations for a familial fever syndrome – mevalonate kinase deficiency (33), familial Mediteranean fever (7) and TRAPS (3). The Gaslini score is useful for identifying patients who fit the PFAPA syndrome criteria and who are at low risk of carrying a mutation associated with a monogenic periodic fever.

The Gaslini score is calculated from:

• Young age at onset
• Positive family history of a periodic fever
• Chest pain/abdominal pain
• Diarrhoea
• Aphthous ulcers

Patients with a low-risk Gaslini score may be diagnosed as having PFAPA syndrome without having genetic testing. However those with a high risk score should be screened for the most likely gene depending on clinical and laboratory findings and classified as PFAPA syndrome only after negative genetic testing.

What is the treatment for PFAPA syndrome?

Options to treat PFAPA syndrome include:

• Systemic corticosteroids, e.g., prednisolone 1-2 mg/kg/d at onset of fever, which shortens the duration of the episode but also leads to shortening of the symptom-free period.
• Cimetidine, which is associated with resolution of fever in some; 30% have a reduction of attacks when taken over months but the mechanism of effect is unknown.
• Tonsillectomy/adenectomy – its role is controversial as in many cases the condition resolves sontaneously.