ABSTRACT
Objective
Periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome is a periodic fever syndrome that onsets in early childhood. The precise roles of medical treatments in symptom control have not yet been clarified. This study aimed to evaluate the clinical characteristics, treatment responses, and genetic findings of children diagnosed with PFAPA.
Method
Patients who were followed with a diagnosis of PFAPA between January 2021 and January 2025 were included in the study. Demographic data, clinical and laboratory findings, results of genetic analyses, and responses to corticosteroids, colchicine, and tonsillectomy were retrospectively evaluated.
Results
A total of 22 patients with a mean age of 77.6 months (male cases: 50%) were included in the study. The median duration of attacks was 4 days [interquartile range (IQR): 3-6], and the median interval between attacks was 30 days (IQR: 25-41.3). Mediterranean fever (MEFV) gene mutations were detected in 36.4% (n=8) of the patients. All patients benefited from corticosteroid therapy during attacks; however, an increase in attack frequency was observed in 45.5% of cases. A decrease in attack frequency was observed in 57.1% (4/7) of the patients using colchicine. Tonsillectomy was performed in 63.6% (n=14) of the patients, and no postoperative complications were observed, while complete recovery was achieved in all cases.
Conclusion
Our findings demonstrate that tonsillectomy is an effective treatment method for controlling febrile attacks in PFAPA.
INTRODUCTION
Periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome was first described by Marshall et al.(1) in 1987. The most characteristic feature of this syndrome is the regular periodicity of febrile episodes(2). These febrile attacks usually last 3-6 days and recur at remarkably regular intervals of 3-8 weeks(3).
PFAPA symptoms most often become manifest before the age of 5 years, and the annual incidence in children under 5 years has been reported as 2.3-2.6 per 10,000(4). Although the pathogenesis of the syndrome has not been fully elucidated, the involvement of palatine tonsils is thought to play a central role(3).
The main goal in the management of PFAPA is to control acute febrile episodes, prevent recurrences, or at least reduce the severity and frequency of attacks(5). Non-steroidal anti-inflammatory drugs and corticosteroids are the main symptomatic pharmaceutical treatment options, while colchicine and cimetidine are the principal prophylactic medical alternatives(2, 5). However, the precise role of these treatments in symptom control remains uncertain and further research is needed.
The beneficial effect of tonsillectomy on the clinical course of PFAPA was first demonstrated by Abramson et al.(6). During the following years, several studies reported varying complete clinical remission rates after tonsillectomy(5). In a long-term follow-up study, Lantto et al.(7) reported that tonsillectomy resulted in complete resolution of febrile episodes in most children with PFAPA. Moberg et al.(3) noted that although tonsillectomy had relieved febrile episodes in the majority of children, some patients continued to experience febrile attacks or other PFAPA-related symptoms.
In this retrospective study, we have aimed to evaluate the clinical characteristics, treatment approaches, and genetic features of children diagnosed with PFAPA who were followed at a tertiary pediatric hospital in Türkiye. In addition, we sought to clarify the efficacy of tonsillectomy and the potential effects of Mediterranean fever (MEFV) gene mutations on the disease phenotype.
MATERIALS and METHODS
This retrospective, cross-sectional study was conducted at University of Health Sciences Türkiye, Dr. Behçet Uz Pediatric Diseases and Surgery Training and Research Hospital. All consecutive patients younger than 18 years of age who were diagnosed with PFAPA syndrome and followed in our clinic between January 2021 and January 2025 were screened in terms of eligibility criteria for inclusion in the study. The diagnosis of PFAPA was based on the modified Marshall criteria proposed by Thomas et al.(8). Patients were included if they fulfilled these diagnostic criteria and had attained regular follow-up visits in our clinic. Patients with incomplete medical records or with an alternative diagnosis that could explain recurrent febrile episodes (such as infectious, autoimmune, or other autoinflammatory diseases) were excluded. The inclusion of consecutive patients during the study period was intended to reduce potential selection bias.
Ethical approval was obtained from the Local Ethics Committee of University of Health Sciences Türkiye, Dr. Behçet Uz Pediatric Diseases and Surgery Training and Research Hospital (decision no: 2025/10-04, date: 29.05.2025). Written informed consent was obtained from the parents of all patients. Data collected from medical records included the demographic characteristics, age at symptom onset, and at the time of diagnosis of PFAPA was made, comorbidities, clinical features during attacks, duration of attacks, and attack intervals. Remarkable laboratory findings detected during attacks [white blood cell (WBC) count, C-reactive protein (CRP), erythrocyte sedimentation rate (ESR)] were also recorded.
Treatment-related data were collected, concerning the use of corticosteroids during attacks, prophylactic colchicine therapy, and surgical interventions (tonsillectomy with or without adenoidectomy) performed. In addition, the type of tonsillectomy, age at surgery, time interval between diagnosis and surgery, duration of postoperative follow-up, complications, and outcomes were documented. Parental satisfaction with treatment outcomes was also noted.
Results of MEFV gene analysis were recorded for patients who underwent testing. According to the results, patients were divided into heterozygous mutation- positive and mutation-negative groups. Clinical findings, laboratory parameters, treatment responses, and surgical outcomes were compared according to genetic mutation status.
Statistical Analysis
Statistical analyses were performed using SPSS version 25.0 software program (IBM Corp., Armonk, NY, USA). Continuous variables were presented as mean ± standard deviation or median values and interquartile range (IQR), depending on their distribution patterns. Categorical variables were expressed as numbers and percentages. Comparisons of categorical variables were performed using the chi-square test, while non-normally distributed continuous variables were compared using the Mann-Whitney U test. A two-sided p-value<0.05 was considered statistically significant.
RESULTS
A total of 22 cases comprising 11 (50.0%) female and 11 (50.0%). Male patients diagnosed with PFAPA syndrome were included in the study. The mean age of the patients at the time of evaluation was 77.6±27.4 months. The median age at symptom onset was 21.0 months (IQR: 13.5-36.0), while the mean age at diagnosis was 46.8±22.0 months. A comorbid condition was observed in only one patient (4.5%), who had chronic urticaria. Heterozygous MEFV gene mutations were identified in 8 (36.4%) patients. The distribution of mutations was as follows: M694V in 3 (13.6%), E148Q in 3 (13.6%), R202Q in 1 (4.5%), and V726A in 1 (4.5%) patient, respectively. The demographic and clinical characteristics of the patients are summarized in Table 1.
During attacks, all patients presented with fever. The most frequent accompanying findings were tonsillar exudate in 20 (90.9%), pharyngitis in 15 (68.2%), oral aphthae in 8 (36.4%), and cervical lymphadenopathy in 17 (77.3%) patients. Abdominal pain was reported for 5 (22.7%) and arthralgia for 3 (13.6%) patients, while none of them experienced arthritis or headache. The median duration of attacks was 4 days (IQR: 3-6), and the median interval between attacks was 30.0 days (IQR: 25.0-41.3). Laboratory investigations performed during attacks revealed a mean WBC count of 8461.4±2924.9/mm3, a mean CRP level of 58.0±26.5 mg/L, and a median ESR of 22.5 mm/h (IQR: 13.8-34.0).
All patients received corticosteroid treatment during attacks, and improvement in clinical findings was observed in all cases. However, despite this acute response, 10 (45.5%) patients experienced an increased frequency of subsequent attacks after corticosteroid treatment, which led to repeated corticosteroid use during recurrent attacks. Colchicine was used by 7 (31.8%) patients of whom 4 (57.1%) showed a reduction in attack frequency. None of the patients experienced colchicine-related adverse effects. Tonsillectomy was performed in 14 (63.6%) patients with a median age of 51.5 months (IQR: 46.5-60.8) at surgery and a median interval between diagnosis and surgery was 4.0 months (IQR: 2.0-8.5). Among these, 13 (92.9%) patients underwent total tonsillectomy, while 1 (7.1%) had partial tonsillectomy. Concurrent adenoidectomy was performed in 6 (42.9%) patients. No postoperative complications were observed, and all patients achieved complete recovery following tonsillectomy. An overview of the therapeutic interventions and clinical responses of the patients is provided in Table 2.
The clinical and genetic characteristics of the patients undergoing tonsillectomy are detailed in Table 3. Among these 14 patients, MEFV gene mutations were identified in 5 cases, including heterozygous M694V (n=2), R202Q (n=1), V726A (n=1), and E148Q (n=1) mutations. Regardless of age at tonsillectomy, gender, type of tonsillectomy, concurrent adenoidectomy, or MEFV status, complete recovery was achieved in all patients following surgery. During the postoperative follow-up period, which ranged from 6 to 40 months, none of the patients required corticosteroid therapy, and no attacks were observed within the last 6 months. Moreover, all parents reported a reduction in school or daycare absenteeism and expressed overall satisfaction with the surgical outcomes.
A total of 16 patients underwent MEFV gene analysis, of whom 8 had heterozygous mutations and 8 were mutation-negative. The age at symptom onset did not differ significantly between the heterozygous mutation-positive (22 months, IQR: 18-42) and mutation-negative (21 months, IQR: 12-39.8) groups (p>0.05). Similarly, intervals between attacks were comparable (30 days, IQR: 22.5-37.8 vs. 30 days, IQR: 25-30; p>0.05). During attacks, WBC counts (9086.3±3354.7 vs. 7272.5±2060.8/mm3; p>0.05) and ESR levels (23.5 mm/h, IQR: 22.0-34.0 vs. 21.5 mm/h, IQR: 13.8-33.0; p>0.05) were also comparable between the groups. However, CRP levels were significantly higher in the heterozygous mutation group (76.8±19.5 vs. 47.3±25.1 mg/L; p=0.020). Although an increase in attack frequency following corticosteroid use was observed in 62.5% of heterozygous-mutation and 37.5% of mutation-negative patients, this difference was not statistically significant (p>0.05). Response to colchicine was also comparable, with improvement observed in 50.0% of heterozygous-mutation and 66.7% of mutation-negative patients (p>0.05).
DISCUSSION
Our study has focused on evaluating the clinical, laboratory, and genetic characteristics, as well as the outcomes of therapeutic approaches in patients followed up at a pediatric diseases and surgery training and research hospital with the diagnosis of PFAPA syndrome. Heterozygous MEFV mutations were detected in 36.4% of patients, and this rate increased to 50% in the subgroup who underwent genetic testing. This finding suggests that genetic factors may play a role in the susceptibility to this disease, the pathogenesis of which has not yet been fully elucidated. Corticosteroids, commonly used in the management of PFAPA syndrome were found to increase attack frequency in 45.5% of cases. In addition, tonsillectomy was performed in 63.6% of patients, with no complications reported during follow-up, and complete resolution of febrile attacks was observed.
PFAPA is an autoinflammatory syndrome of unknown etiology, with symptoms typically become manifest during the early childhood(9). In our study, the median age at symptom onset was 21 months, consistent with the literature data(3). The attacks exhibit a periodicity that can be easily recognized by parents; however, no standardized treatment protocol exists for their management. Corticosteroids represent the main medical option for relieving symptoms during attacks and have been reported to be effective in 85-95% of the cases(2, 5). In our cohort, all patients received corticosteroid therapy during attacks and showed a clinical response. Although this dramatic response is considered an important finding supporting the diagnosis of PFAPA, corticosteroids do not prevent the emergence of new episodes(5, 10). Furthermore, in 45.5% of our study patients an increased frequency of flare-ups was observed following corticosteroid therapy.
Colchicine has been investigated as a potential prophylactic treatment option in PFAPA patients to reduce corticosteroid use and the frequency of febrile attacks(5). In the literature, response rates to colchicine treatment have been reported to range between 45% and 95.1%(11). In our study, a reduction in frequency of attacks was observed in 57.1% of patients receiving colchicine. The treatment was well tolerated, and no colchicine-related adverse effects were detected in our study. In contrast, Welzel et al.(12) reported adverse effects associated with colchicine therapy in PFAPA patients which had not necessitated discontinuation of therapy including mild to moderate gastrointestinal symptoms, asymptomatic mild elevations of transaminases, and leukopenia.
In the Turkish population, the prevalence of MEFV gene mutations is approximately 20%, whereas in our study, its prevalence rate (50%) among PFAPA patients who underwent genetic testing was markedly higher than observed in the general population(13). The impact of MEFV mutations on the disease phenotype in PFAPA, particularly with regard to treatment response, has been investigated(11). Pehlivan et al.(14) reported that PFAPA patients carrying MEFV mutations exhibited a better response to colchicine, whereas Otar Yener et al.(15) found no significant association between MEFV mutation status and treatment response. Özaslan et al.(11) suggested that M694V carriage was the only predictor of colchicine responsiveness. In our study, patients with MEFV mutations did not differ in terms of age at disease onset or attack frequency. CRP levels during attacks were significantly higher in patients with MEFV mutations; however, this finding did not translate into a distinct disease phenotype. Although an increase in attack frequency following corticosteroid use was observed more frequently in patients with heterozygous MEFV mutations relative to those without, but the difference in incidence rates was not statistically significant. Similarly, no differences were found between groups in terms of response to colchicine therapy.
Although PFAPA is considered a self-limiting disease, it has a substantial negative impact on the health status of both children and their caregivers(5). Rydenman et al.(4) demonstrated that health-related quality of life deteriorates during febrile episodes and that this effect persists even during afebrile periods. In our study, the median interval between PFAPA diagnosis and tonsillectomy was 4 months, reflecting parents’ desire to achieve a curative treatment as soon as possible despite its potential surgical risks. A Cochrane review published in 2019 reported that children may benefit from tonsillectomy; however, only moderate level of evidence has favoured surgical intervention(9).
To date, only two randomized controlled trials have evaluated the efficacy of tonsillectomy in PFAPA(9). In the first study, complete resolution of postoperative febrile attacks was reported in 63% of patients (12/19), while in the second study, all 14 patients (100%) had achieved remission(16, 17). In other series, rates of complete clinical remission have been reported to range between 74% and 97%(3, 14, 18-20). In our study, tonsillectomy alone was performed in 8 patients, while 6 patients underwent concurrent adenoidectomy. Regardless of the type of tonsillectomy, and concurrent adenoidectomy performed, or MEFV mutation status, complete recovery was achieved in all patients following surgery.
Study Limitations
The main limitations of our study are its retrospective design and its single-center design. In addition, MEFV genetic mutation analysis was not performed in all patients. The relatively rare occurrence of PFAPA limited the sample size, thereby restricting the generalizability of the findings, particularly with regard to surgical complications.
CONCLUSION
In conclusion, this study demonstrates that tonsillectomy per se or in combination with adenoidectomy, is an effective treatment for controlling febrile attacks in children with PFAPA. Nevertheless, the potential risks of surgery should be carefully communicated to families. Furthermore, the detection of a high frequency of MEFV mutations among the analyzed patients strengthens our view that advances in genetics may contribute to elucidating the pathogenesis of this syndrome.
