On Jun. 8, 2020, researchers at the National Human Genome Research Institute announced they had discovered clues to the possible cause of recurring, non-contagious fevers and sores that affect only children. Several genes have been implicated with the syndrome, known as PFAPA syndrome (Periodic Fever, Aphthous Stomatitis, Pharyngitis, Adenitis), which could lead to new treatments. The results were published in the journal PNAS.

The findings were made possible by the realization of commonalities with other chronic inflammatory conditions that also involved sores on the body, including the common canker sore. The study illustrates how long-standing health mysteries may now be solved when researchers discover new biological connections with the help of increasing amounts of genomic data.

In 1987, researchers first described a syndrome seen in 12 children, which was marked by recurrent fever, painful canker sores, sore throat and inflamed lymph nodes. The condition starts at an early age, between the ages of 1 and 5. The first sign is fever, accompanied by sore throat with redness and other symptoms.

“PFAPA syndrome is the most periodic of periodic fevers, with many children having an episode every month lasting three to five days,” said Kalpana Manthiram, M.D., Clinical Fellow at NHGRI and lead author of the study. “That is an immense burden on families since these kids cannot go to school and may be bedridden for days during flares.”

While PFAPA syndrome has become the most common recurring fever syndrome in children from Western countries, diagnosis and treatment methods have remained largely primitive and insufficient. The episodes usually spontaneously stop in pre-adolescence.

Because of the nature of the disease, researchers have long thought that answers may lie in genomics. After ruling out the possibility that the syndrome is caused by mutations in a single gene, they considered the possibility that multiple genes are involved.

“But the biggest issue is that there is still no diagnostic test for detecting PFAPA syndrome, which means the disease is usually underdiagnosed,” said Daniel Kastner, M.D., Ph.D., senior author of the paper and NHGRI scientific director. “Identifying the disease has been mostly based on clinical history and depends on parents and doctors recognizing it. We know its time to do better than that, and consider that this study will create the scope for more accurate diagnosis of the syndrome.”