What is the history of Marshall syndrome - PFAPA?

Marshall syndrome, also known as PFAPA (Periodic Fever, Aphthous stomatitis, Pharyngitis, and Adenitis) syndrome, was first clinically described in 1987 by Dr. Gary S. Marshall and colleagues. The condition has evolved from being initially misdiagnosed as recurrent viral infections or streptococcal pharyngitis to being recognized today as a distinct autoinflammatory disorder of childhood.

When and how was Marshall syndrome (PFAPA) first described?

The medical community officially recognized Marshall syndrome (PFAPA) in 1987 when Dr. Gary S. Marshall and his team at the University of Rochester published a landmark paper in The Journal of Pediatrics. They identified 12 children who suffered from a specific, recurring pattern of high fevers, mouth ulcers (aphthous stomatitis), sore throats (pharyngitis), and swollen lymph nodes (adenitis). Before this identification, these children were often subjected to unnecessary, repeated rounds of antibiotics, as physicians assumed they were dealing with chronic infections, specifically recurrent Group A beta-hemolytic streptococcal infections.

How has our understanding of Marshall syndrome (PFAPA) evolved?

For decades, the medical community struggled to categorize Marshall syndrome (PFAPA). Early researchers were puzzled by the fact that despite the severe symptoms, children appeared completely healthy between episodes. As clinical research progressed, it became clear that this was not an infectious disease, but rather an autoinflammatory condition—a dysregulation of the innate immune system. Unlike autoimmune diseases, where the body attacks its own tissues, Marshall syndrome (PFAPA) involves the body’s immune system triggering an inflammatory response without an external pathogen.

What were the major milestones in treatment and diagnosis?

The management of Marshall syndrome (PFAPA) has seen significant shifts, moving from aggressive surgical intervention to targeted pharmacological control. Key milestones include:

• The move away from tonsillectomy: In the late 20th century, tonsillectomy was frequently performed to stop the symptoms, though its efficacy was debated.


• Corticosteroid intervention: The discovery that a single dose of corticosteroids could abort an episode significantly improved the quality of life for patients.


• Colchicine and Cimetidine: The off-label use of these medications was introduced to help prevent the frequency of flares in patients who do not respond to or cannot tolerate steroids.


• Recognition of "Periodic Fever Syndromes": The inclusion of Marshall syndrome (PFAPA) within the broader category of periodic fever syndromes helped clinicians distinguish it from more severe genetic conditions like Familial Mediterranean Fever (FMF).

How have technology and genetics changed our perspective?

While Marshall syndrome (PFAPA) is still primarily a clinical diagnosis based on the Marshall criteria, modern genetic sequencing has helped researchers rule out other hereditary autoinflammatory disorders. Although no single "PFAPA gene" has been identified, the use of high-throughput genetic testing allows doctors to exclude monogenic fever syndromes, providing peace of mind to families. Today, the 7 members of the DiseaseMaps community with Marshall syndrome (PFAPA) can leverage this knowledge to advocate for more accurate, timely diagnoses, avoiding the "diagnostic odyssey" that many families faced in the 1980s and 90s.

Next steps

• Consult a pediatric rheumatologist or an immunologist to confirm the diagnosis using established clinical criteria.


• Keep a detailed fever diary documenting the timing and duration of episodes to share with your healthcare team.


• Join the DiseaseMaps.org community to connect with other families navigating the challenges of Marshall syndrome (PFAPA).


• Discuss the risks and benefits of corticosteroids and prophylactic medications with your specialist.

Medical disclaimer: This content is for informational purposes only and does not constitute professional medical advice, diagnosis, or treatment; always seek the advice of your physician or other qualified health provider.

References

• Marshall GS, et al. "Periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA) syndrome." The Journal of Pediatrics, 1987.


• NIH Genetic and Rare Diseases Information Center (GARD) - PFAPA Syndrome.


• Orphanet: Periodic fever-aphthous stomatitis-pharyngitis-cervical adenitis syndrome.


• OMIM (Online Mendelian Inheritance in Man) database regarding autoinflammatory periodic fevers.