Periodic Fever, Aphthous stomatitis, Pharyngitis, and cervical Adenitis (PFAPA) syndrome is the most common non-hereditary cause of recurrent fever in childhood, but its frequency in the general population is not widely known. The condition presents a distinct clinical picture that helps differentiate it from common childhood infections and rare autoinflammatory disorders.
Understanding PFAPA Syndrome
PFAPA is an acronym for its four defining symptoms: Periodic Fever, Aphthous stomatitis (mouth sores), Pharyngitis (sore throat), and cervical Adenitis (swollen neck glands). The syndrome involves recurrent episodes of high fever (38.5°C to 41°C) that appear with predictable regularity, typically every three to six weeks. These febrile attacks generally last for three to seven days.
Between episodes, children are completely asymptomatic and exhibit normal growth and development. PFAPA is an autoinflammatory disease, involving an abnormal activation of the innate immune system that causes inflammation without an external infectious trigger. It is not contagious or caused by an infection, which is a key distinction from conditions like recurrent strep throat. The syndrome is generally self-limiting, tending to resolve on its own, usually by the second decade of life.
Quantifying Rarity: Incidence and Prevalence Data
The rarity of a condition is measured using incidence (the rate of new cases over time) and prevalence (the total number of existing cases). Precise, universal figures for PFAPA syndrome are difficult to establish, but localized population-based studies offer current estimates.
A study from western Sweden estimated the mean annual incidence of PFAPA at 2.6 new cases per 10,000 children under five years old. A similar population-based study in Norway found an incidence of 2.3 new cases per 10,000 children up to five years old. When considering all children under 18, the Swedish study estimated the rate at approximately 0.86 new cases per 10,000 children per year.
These numbers place PFAPA firmly within the category of rare diseases when compared to common childhood illnesses like the common cold or seasonal influenza. An incidence of 2.6 per 10,000 children translates to roughly 1 in 3,850 children under five developing the condition annually in those regions. Although PFAPA is the most frequently identified autoinflammatory syndrome, its occurrence in the general population is low. Prevalence figures are elusive, but the low incidence rate suggests a relatively small number of individuals live with the syndrome at any one time.
Diagnostic Obstacles and Underreporting
The actual occurrence of PFAPA may be higher than reported due to significant diagnostic obstacles and underreporting. There is no definitive laboratory test or specific biomarker to confirm the diagnosis. Instead, diagnosis relies on clinical criteria, such as the modified Marshall criteria. These criteria require recurrent fever, at least one of the three cardinal symptoms, and the exclusion of other conditions.
This reliance on clinical observation means PFAPA is often mistaken for more common conditions, particularly recurrent bacterial or viral infections like strep throat. Lack of awareness among general practitioners and the need to rule out other periodic fever syndromes contribute to diagnostic delays. Patients frequently undergo multiple rounds of ineffective antibiotic treatments before the correct diagnosis is considered.
The consequence of this clinical ambiguity is that many cases may go undiagnosed for years or are simply misattributed to frequent infections, leading to an underestimation in epidemiological tracking. The lack of a validated, evidence-based classification system further complicates the consistent identification of the syndrome across different healthcare systems. Therefore, the reported rarity is likely a reflection of detection difficulty rather than the true frequency of the condition.
Demographics and Affected Populations
PFAPA syndrome predominantly affects children, which is reflected in the rarity statistics focused on the pediatric population. The typical age of onset is early childhood, with most patients experiencing their first symptoms between two and five years old. Almost 90% of children with the syndrome show symptoms before the age of five, with the average age of onset reported as early as 18 months.
Although traditionally considered a childhood condition, a small number of adult-onset cases are increasingly recognized, with the mean age of onset ranging from 25 to 33 years. Within the pediatric population, the syndrome is observed in both sexes, though some studies suggest a slight male predominance (e.g., a 54% to 46% boy-to-girl ratio). Other reports indicate a relatively equal distribution, suggesting that gender is not a strong predictive factor.
Geographic variations in reported rates exist, with most epidemiological data originating from Europe and North America. This uneven reporting likely reflects differences in awareness and tracking rather than true biological differences in occurrence.