PFAPA syndrome and Behçet’s disease: a comparison of two medical entities based on the clinical interviews performed by three different specialists

Abstract

The pediatric syndrome characterized by periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) and adult Behçet's disease share some clinical manifestations and are both polygenic autoinflammatory disorders with interleukin-1β showing to play a pivotal role. However, the diagnosis is mostly clinical and we hypothesize that specific criteria may be addressed differently by different physicians. To determine the diagnostic variability, we compared the answers of 80 patients with a definite diagnosis of Behçet's disease (age 42.1 ± 13.7 years) obtained by separate telephone interviews conducted by a rheumatologist, a pediatrician, and an internist working largely in the field of autoinflammatory disorders. Questions were related to the age of symptom onset, the occurrence of recurrent fevers during childhood, and the association with oral aphthosis, cervical adenitis and/or pharyngitis, previous treatments, possible growth impairment, the time lapse between PFAPA-like symptoms and the onset of Behçet's disease, and the occurrence of Behçet-related manifestation during childhood. The rheumatologist identified 30 % of patients with Behçet's disease fulfilling PFAPA syndrome diagnostic criteria, compared to the pediatrician and the internist identifying 10 and 7.5 %, respectively. Most of the patients suffered from recurrent oral aphthosis in childhood also without fever (50, 39, and 48 % with each interviewer), yet no patient fulfilled the Behçet's disease diagnostic criteria. Our data suggest that physician awareness and expertise are central to the diagnosis of autoinflammatory disorders through an accurate collection of the medical history.

Hints for Genetic and Clinical Differentiation of Adult-Onset Monogenic Autoinflammatory Diseases

“…Skin lesions are identified in more than two thirds of patients with MKD: they are variable and nonspecific, including maculopapular, morbilliform, erythematous, and purpuric rashes [156,163,164]. Oral and/or genital aphthosis can be seen in about half of MKD patients, requiring differential diagnosis with BD, PFAPA syndrome, and FMF [136,149,165,166].…”

Basic Characteristics of Adults with Periodic Fever, Aphthous Stomatitis, Pharyngitis, and Adenopathy Syndrome in Comparison with the Typical Pediatric Expression of Disease

“…This could suggest either that a common immune imbalance might underlie both diseases or that PFAPA syndrome may predispose to the development of BD [ 81 , 82 ]. Of note, these are very preliminary and retrospective data that need to be confirmed on larger numbers; nonetheless they indicate that BD should be ruled out in a patient with PFAPA-like phenotype, particularly in the pediatric age [ 83 ].…”

Periodic Fever with Aphthous Stomatitis, Pharyngitis, and Cervical Adenitis Syndrome Is Associated with a CARD8 Variant Unable To Bind the NLRP3 Inflammasome

“…eriodic fever with aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome is characterized by recurrent fever flares accompanied by pharyngitis, adenitis, and/or aphthous stomatitis without evidence of infection, relatively asymptomatic intervals between the flares, and normal growth and development. Onset before the age of 5 y used to be considered a criterion based on the first patients described; however, observations of classical PFAPA phenotype with later disease onset suggest that relying on age at onset to confirm the diagnosis might not be appropriate (1)(2)(3).…”

“…Therefore, we screened for variants of genes involved in pathways associated with autoinflammatory conditions, such as familial Mediterranean fever (gene MEFV), TNFR-associated periodic syndrome (gene TNFRSF1A), and hyper-IgD syndrome (gene MVK). We also extended our screening to inflammasomerelated genes, such as NLRPs (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14), and some regulator genes to gain fundamental insights into genetic alterations that are potential predisposing factors for PFAPA.…”