NIH researchers uncover genes linked to common recurrent fever in children

June 9, 2020

Researchers at the National Human Genome Research Institute (NHGRI), part of the National Institutes of Health (NIH), have 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 Proceedings of the National Academy of Sciences (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.

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.

To see which genes (if any) were involved in the disease, the research team searched for commonalities in symptoms between PFAPA syndrome and two other inflammatory diseases: Behçet's disease, which causes inflammation of blood vessels, and canker sores.

Each illness presented itself with one common symptom: canker sores.

The group looked into whether the gene variants known to be associated with those diseases were also present in people with PFAPA syndrome by comparing patients with the disorder from European-American and Turkish ancestries with the general U.S. population. They performed more detailed analyses of six genes that are strongly linked to Behçet's disease and canker sores.

The strongest association was with the gene IL12A, which encodes an inflammation-related protein that is used by the immune system. The IL12A protein acts as an alarm for the immune system and prompts an inflammatory response by activating various white blood cells. Other genes involved in the immune system also showed increased expression in patients, such as STAT4, IL10, and CCR1-CCR3.

Due to genomic similarities between PFAPA syndrome, Behçet's and canker sores, the researchers proposed naming them Behçet's spectrum disorders. On the severity scale, canker sores would be on the mild end, Behçet's disease on the severe end, and PFAPA syndrome between the two.

This spectrum is clinically important because a number of patients may have symptoms that are shared between the three diseases, which could make it difficult for doctors to isolate their specific condition. According to the researchers, those patients would be better served if they were referred to having Behçet's spectrum disorders.

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