Evaluating the Genetics and Immunology of Periodic Fever, Aphthous Stomatitis, Pharyngitis, and Cervical Adenitis (PFAPA) Syndrome and Other Tonsil Disorders

Study Overview
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Brief Summary
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Background: Periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) is the most common periodic fever syndrome of childhood. Symptoms can include swelling of the glands in the throat, mouth ulcers, and tonsillitis. Removal of the tonsils can stop the periodic flareups. But researchers do not know how PFAPA develops. In this natural history study, researchers will collect specimens and data from people with PFAPA to see what they might have in common. Objective: To collect blood and other specimens from people with PFAPA to learn more about the illness. Eligibility: People aged 1 month or older with symptoms of PFAPA or another tonsil disorder. Design: Participants will be screened. Their medical records will be reviewed. Researchers will ask about a family history of PFAPA. The following specimens may be collected: Blood. Blood will be drawn either from a needle inserted into a vein or from a prick in the finger or heel. Mucus and cells. A stick with soft padding on the tip may be rubbed inside the nostrils or mouth. Stool. Saliva. Tissue samples may be taken if participants are having surgery to remove the tonsils or adenoids. Participants having surgery may also have a nasopharyngeal wash; salt water will be squirted into the back of the throat and then sucked back out with a syringe. Most participants will provide specimens only once. They can do this in person at the clinic; they can also have their local health providers send specimens to the researchers. Some participants may have optional follow-up visits over 10 years.

Detailed Description
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Study Description: The purpose of this multisite study is to collect specimens and data from patients with periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome and other tonsil disorders for genetic, immunologic, cellular, molecular, and microbial research into the pathogenesis of these conditions. Specimens include blood, saliva, buccal swabs, oropharyngeal swabs, nasopharyngeal swabs, nasopharyngeal wash, and/or stool. If a participant is scheduled to undergo a clinically indicated tonsillectomy and/or adenoidectomy, then leftover clinical specimens will also be collected for research. Participants may either be seen in person at the study sites or may be seen remotely via telehealth and provide send-in samples collected locally. Primary Objective: To collect samples to understand the immunologic mechanisms and genetic and microbial risk factors for PFAPA and other tonsil disorders. Primary Endpoints: Identify genetic risk variants for PFAPA and other tonsil disorders. Characterize immune cell populations, gene expression (including at the single-cell level), epigenetic features, and protein expression ex vivo in blood, tissue, washes, or swabs from people with PFAPA and other tonsil disorders. Characterize the tonsillar/adenoid, oral, nasal and/or stool microbiota in people with PFAPA and other tonsil disorders. Characterize clinical outcomes following tonsillectomy and other clinically indicated treatments. Secondary Objective: To understand the characteristics and function of unique cell populations in the pharyngeal lymphoid tissues (tonsils and adenoids) and how immune responses to antigens are generated in these tissues. Secondary Endpoints: Study responses to antigens and infection in the mucosal lymphoid tissue and peripheral blood. Characterize unique immune cell populations present in the mucosal tissue. Characterize immunologic and molecular pathways in the tissue cells.

Official Title
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Evaluating the Genetics and Immunology of Periodic Fever, Aphthous Stomatitis, Pharyngitis, and Cervical Adenitis (PFAPA) Syndrome and Other Tonsil Disorders

Conditions
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Periodic Fever, Aphthous Stomatitis, Pharyngitis, And Cervical Adenitis (Pfapa), Obstructive Sleep Apnea, Tonsillitis, Tonsil Disorder, Sleep Disordered Breathing

Participation Criteria
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Eligibility Criteria
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INCLUSION CRITERIA: Participants must meet all the following inclusion criteria to be eligible for this study: Aged >=1 month. To be seen at the NIH CC, participants must be >=3 years of age. Diagnosed with PFAPA or another tonsil disorder, or has symptoms consistent with these conditions, as determined by the investigator. Able to provide informed consent (for ages >=18 years) or has a parent or guardian who can provide informed consent on their behalf (for ages <18 years). Willing to allow specimens and data to be stored for future research. Willing to allow genetic testing on their biospecimens. EXCLUSION CRITERIA: An individual who has any condition that, in the judgment of the investigator, may put them at undue risk or make them unsuitable for participation in the study will be excluded.

Ages Eligible for Study
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Minimum Age: 1 Month
Maximum Age: 99 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Patients<br>Patients with periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome and other tonsil disorders. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Identify genetic risk variants for PFAPA and other tonsil disorders | To collect samples to understand the immunologic mechanisms and genetic and microbial risk factors for PFAPA and other tonsil disorders | Throughout study | 
| Characterize clinical outcomes following tonsillectomy and other clinically indicated treatments. | To collect samples to understand the immunologic mechanisms and genetic and microbial risk factors for PFAPA and other tonsil disorders | Throughout study | 
| Characterize the tonsillar/adenoid, oral, nasal and/or stool microbiota in people with PFAPA and other tonsil disorders | To collect samples to understand the immunologic mechanisms and genetic and microbial risk factors for PFAPA and other tonsil disorders | Throughout study | 
| Characterize immune cell populations, gene expression including at the single cell level, epigenetic features, and protein expression ex vivo in blood, tissue, washes, or swabs from people with PFAPA and other tonsil disorders | To collect samples to understand the immunologic mechanisms and genetic and microbial risk factors for PFAPA and other tonsil disorders | Throughout study | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Characterize immunologic and molecular pathways in the tissue cells. | To understand the characteristics and function of unique cell populations in the pharyngeal lymphoid tissues (tonsils and adenoids) and how immune responses to antigens are generated in these tissues | Throughout study | 
| Study responses to antigens and infection in the mucosal lymphoid tissue and peripheral blood. | To understand the characteristics and function of unique cell populations in the pharyngeal lymphoid tissues(tonsils and adenoids) and how immune responses to antigens are generated in these tissues | Throughout study | 
| Characterize unique cell populations and the immunologic and molecular pathways in the tissue cells | To understand the characteristics and function of unique cell populations in the pharyngeal lymphoid tissues (tonsils and adenoids) and how immune responses to antigens are generated in these tissues | Throughout study | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Genome-Wide Association Study (Gwas), Immunology, Autoinflammation, Tonsillitis, Obstructive Sleep Apnea, Sleep Disordered Breathing, Natural History