Understanding PFAPA Syndrome: A Brief Guide for Physicians

Introduction

PFAPA (Periodic Fever, Aphthous stomatitis, Pharyngitis, and Adenitis) syndrome is an uncommon but increasingly recognized autoinflammatory disorder that primarily affects children, although it can also be diagnosed in adults. Despite being the most common periodic fever syndrome, PFAPA remains underdiagnosed, leading to prolonged suffering and unnecessary treatments for patients. To avoid this, physicians should be familiar with this condition, to ensure timely recognition and optimal management. 

Etiology

The exact cause of PFAPA remains unknown, but it is classified as an autoinflammatory disorder, likely stemming from abnormalities in proteins related to the innate immune system. Current understanding suggests PFAPA arises from a blend of environmental factors and polygenic inheritance involving various genes associated with innate immunity. While some cases appear familial and follow autosomal-dominant inheritance, genomic analyses on these have not revealed rare variants in a single common gene, and most patients do not have mutations in genes previously implicated in monogenic periodic fever syndromes. Some studies propose a localized abnormal immune response in the palatine tonsils, as evidenced by resolution following tonsillectomy in most cases. Additionally, others have suggested that Behçet syndrome, PFAPA and recurrent aphthous stomatitis may represent a continuum of the same entity.

Epidemiology

PFAPA syndrome is considered a relatively uncommon condition, with an estimated incidence of 2.6 per 10 000 children < 5 years of age. However, recent studies suggest that it may be more common than previously thought, indicating a need for greater awareness among healthcare providers. In most pediatric studies, PFAPA syndrome shows a slight male predilection and occurs across diverse ethnic backgrounds.

Clinical Presentation

Figure 1. Atypical clinical features in PFAPA syndrome

PFAPA syndrome typically manifests in children under the age of five (mean age of three), although some cases have been reported in older children and even adults. The hallmark features of PFAPA syndrome include recurrent episodes of fever (every 2-8 weeks) that begin abruptly and usually last for 3-7 days, accompanied by one or more of the following symptoms: aphthous stomatitis, pharyngitis, and cervical adenitis. During episodes, children may also experience malaise, headache, abdominal pain (more frequent but not severe enough to warrant surgical consultation), vomiting and arthralgia. The presence of several atypical symptoms (figure 1) should make us consider other autoinflammatory disorders.

Diagnosis

Figure 3. Eurofever/PRINTO clinical classification criteria for PFAPA. Adapted from Gattorno M, Hofer M, Federici S for the Eurofever Registry and the Paediatric Rheumatology International Trials Organisation (PRINTO), et al. Classification criteria for autoinflammatory recurrent fevers Annals of the Rheumatic Diseases 2019;78:1025-1032

Figure 2. Modified Marshall’s criteria for PFAPA Syndrome (1999).

Diagnosing PFAPA syndrome can be challenging due to its nonspecific symptoms and overlap with other conditions, such as recurrent infections and autoimmune disorders. However, several key clinical criteria can aid in diagnosis, including regular and predictable fever episodes, absence of upper respiratory symptoms during episodes, and prompt resolution of symptoms with oral corticosteroids. Laboratory tests may reveal elevated inflammatory markers during episodes, but these are nonspecific and not required for diagnosis. Ultimately, the diagnosis of PFAPA syndrome is clinical and based on the characteristic pattern of symptoms. Modified Marshall’s criteria (Figure 2 above) and the Eurofever/PRINTO clinical classification criteria (Figure 3-> right) may establish diagnosis.

Treatment

The management of PFAPA syndrome mainly focuses on alleviating symptoms and improving the quality of life for affected children and their families.

The cornerstone of treatment is corticosteroids, which can rapidly resolve fever episodes and associated symptoms. Prednisone or prednisolone (1, sometimes 2 doses) administered at the onset of symptoms typically leads to prompt resolution of the episode. However, long-term corticosteroid use is not recommended due to potential adverse effects and the possibility of shortening the intervals between crises.

Alternative treatment options for attack prevention include tonsillectomy, which has been shown to provide sustained remission in most cases, as well as non-surgical therapeutic options such as colchicine and probiotics. For severe and refractory cases, an IL-1 inhibitor like anakinra can be considered. A concise algorithm for the treatment of PFAPA can be found in figure 4.

Figure 4. Treatment algorithm Adapted from Batu ED. Periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome: main features and an algorithm for clinical practice. Rheumatol Int. 2019;39(6):957-970. doi:10.1007/s00296-019-04257-0

Prognosis

PFAPA is mostly a benign and self-limited condition and it usually resolves in most patients before the age of 10 years, with mean duration of attacks ranging from 4.5 to 8 years. Affected children tend to grow and develop normally without any long-term sequelae. In rare cases, symptomatic persistence into adulthood may be observed in some patients.

Conclusion

In conclusion, PFAPA syndrome is a relatively common but often underdiagnosed autoinflammatory disorder in children. By familiarizing themselves with the epidemiology, clinical presentation, diagnostic/classification criteria, and treatment options for PFAPA syndrome, physicians can improve recognition and management of this condition, leading to better outcomes and quality of life for affected children and their families. Continued research and collaboration in the field of autoinflammatory diseases are essential to further our understanding of PFAPA syndrome and optimize patient care.

Always keep in mind, as doctors we can only diagnose what we know about, and during history-taking and physical examinations, we only search for what we're familiar with.

by Ricardo Craveiro da Costa- JIR CliPS, WG PFAPA/SURF

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