Neither hereditary periodic fever nor periodic fever, aphthae, pharingitis, adenitis: Undifferentiated periodic fever in a tertiary pediatric center

AIM To describe the frequency and clinical characteristics of patients with undifferentiated periodic fever(UPF) and to investigate whether a clinical classification of UPF based on the PRINTO-Eurofever score can help predicting the response to treatment and the outcome at follow-up.METHODS Clinical and therapeutic information of patients with recurrent fever who presented at a single pediatric rheumatology center from January 2006 through April 2016 were retrospectively collected. Patients with a clinical suspicion of hereditary periodic fever(HPF) syndrome and patients with clinical picture of periodic fever, aphthae, pharingitis, adenitis(PFAPA) who were refractory to tonsillectomy underwent molecular analysis of five HPF-related genes: MEFV(NM_000243.2), MVK(NM_000431.3), TNFRSF1 A(NM_001065.3), NLRP3(NM_001079821.2), NLRP12(NM_001277126.1). All patients who had a negative genetic result were defined as UPF and further investigated. PRINTO-Eurofever score for clinical diagnosis of HPF was calculated in all cases. RESULTS Of the 221 patients evaluated for periodic fever, twelve subjects with a clinical picture of PFAPA who were refractory to tonsillectomy and 22 subjects with a clinical suspicion of HPF underwent genetic analysis. Twenty-three patients(10.4%) resulted negative and were classified as UPF. The median age at presentation of patients with UPF was 9.5 mo(IQR 4-24). Patients with UPF had a higher frequency of aphthae(52.2% vs 0%, P = 0.0026) and musculoskeletal pain(65.2% vs 18.2%, P = 0.0255) than patients with genetic confirmed HPF. Also, patients with UPF had a higher frequency of aphthous stomatitis(52.2% vs 10.7%, P < 0.0001), musculoskeletal pain(65.2% vs 8,0%, P < 0.0001), and abdominal pain(52.2% vs 4.8%, P < 0.0001) and a lower frequency of pharyngitis(56.6% vs 81.3%, P = 0.0127) compared with typical PFAPA in the same cohort. Twenty-one of 23 patients with UPF(91.3%) received steroids, being effective in 16; 13(56.2%) were given colchicine, which was effective in 6. Symptoms resolution occurred in 2 patients with UPF at last follow-up. Classification according to the PRINTOEurofever score did not correlate with treatment response and prognosis. CONCLUSION UPF is not a rare diagnosis among patients with periodic fever. Clinical presentation place UPF half way on a clinical spectrum between PFAPA and HPF. The PRINTOEurofever score is not useful to predict clinical outcome and treatment response in these patients.