Istanbul University

Attention-Deficit/Hyperactivity Disorder Symptoms in School-Aged Children with a History of Periodic Fever, Aphthous Stomatitis, Pharyngitis, and Cervical Denitis Syndrome: A Comparative Evaluation with Healthy Peers.

Periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome is the most common periodic fever syndrome of childhood, and growing evidence links early-life inflammation to neurodevelopment, but whether PFAPA affects attention and behavior at school age is unknown. This study compared parent-reported attention-deficit/hyperactivity disorder (ADHD) symptoms in school-aged children with a preschool PFAPA diagnosis with those of healthy peers and examined associations with PFAPA-related clinical characteristics. This cross-sectional study included 96 children (mean age 10.84 ± 1.64 years) diagnosed with PFAPA during the preschool years and followed at a pediatric rheumatology clinic and 81 healthy controls (10.40 ± 1.88 years) without chronic disease or tonsillectomy. Attention-deficit/hyperactivity disorder symptoms were assessed with the Revised Conners' Parent Rating Scale-Short Form (CPRS-R:S). The groups did not differ in age or sex. No significant between-group difference was found on any CPRS-R:S subscale. Within the PFAPA group, an earlier age at symptom onset was weakly but significantly correlated with a higher ADHD Index (ρ = -0.317, P = .002), and this association remained significant after false discovery rate correction (false discovery rate-adjusted P value [pFDR] = 0.048) and multivariable adjustment (β = -0.295, P = .004); subgroup analyses by comorbidity, tonsillectomy, and medication use showed no differences. Children with a preschool diagnosis of PFAPA did not show increased parentreported ADHD symptoms at school age. The weak association with earlier onset warrants cautious interpretation. These findings suggest that the immune-neurodevelopment relationship should be considered in a disease-specific manner, distinguishing PFAPA's benign, episodic course from chronic autoinflammatory diseases.

Phenotypes of patients with more than one autoinflammatory disease-associated gene variant: overlapping and mixed autoinflammatory disorders.

Genetic screening for systemic autoinflammatory disorders (SAIDs) often does not yield a definite diagnosis based on pathogenic variants. Instead, many patients are found to carry combinations of variants of uncertain significance (VUS), either in isolation or alongside pathogenic or likely pathogenic variants. We herein aimed to investigate the relationship between clinical phenotypes and genotypes in patients identified as carriers of variants in ≥2 autoinflammatory genes. We conducted a retrospective analysis of patients who underwent genetic screening for SAIDs. Inclusion criteria were the presence of variants in ≥2 autoinflammatory genes, including both VUS and pathogenic/likely pathogenic variants. Clinical features were reviewed and compared across genetic profiles. Forty-four (29.5%) of 149 referred patients were identified as having ≥2 gene variants. Fifteen (36.3%) were classified as familial Mediterranean fever (FMF), and some had non-FMF findings in association with additional variants. An additional five patients were diagnosed with VEXAS syndrome (n = 1), deficiency of adenosine deaminase 2 (DADA2, n = 2), A20 haploinsufficiency (HA20, n = 1), DADA2 and HA20 overlap (n = 1). The remaining patients were grouped as having NLRP1-AID (n = 1), NLRC4-AID (n = 1), NLRP1 and NLRC4-AID (n = 1) overlap, PFAPA-like (n = 2), and Behçet disease-like (n = 7) disorder according to their dominant phenotype. Twelve (27.2%) patients could not be classified into any groups. The presence of multiple variants in autoinflammatory genes is a common finding in patients with SAID-like symptoms but does not always correlate with a known diagnosis. Follow-up of this group of patients with so-called 'mixed autoinflammatory disorder' (MAID) is necessary for the evaluation of their clinical course and long-term prognosis.

Syndrome of undifferentiated recurrent fever (SURF): a multicenter real-world experience from Türkiye.

Syndrome of undifferentiated recurrent fever (SURF) is an autoinflammatory disorder that is recognised in an increasing number of patients. In this study, we aimed to assess the data of SURF patients from the main reference centres in our country. Data for this retrospective multicentre observational cohort study were obtained from the records of SURF patients aged 0-18 years who were followed up in 10 pediatric rheumatology clinics in Türkiye between 2010 and June 2023. Patients with recurrent fever that could not be explained by periodic fever, aphthous stomatitis, pharyngitis and adenopathy (PFAPA) and hereditary recurrent fevers and had no other cause were included in the study. Of the 134 patients included in the study, 74 (55.2%) were male. The median age at diagnosis was 67 months. The most common symptom was abdominal pain in 98 (73.1%), arthralgia in 82 (61.2%), malaise in 77 (57.5%). The age at symptom onset was ≤ 5 years in 109 patients (81.3%). Pharyngitis was more common symptom in children aged ≤ 5 years (p = 0.008), headache, arthralgia, chest pain were more common findings in children > 5 years (p = 0.008, p = 0.032, p = 0.045). There were 113 patients receiving colchicine alone or in combination therapy and 74.3% of them achieved complete or partial remission. The presence of abdominal pain (p = 0.021, OR = 0.254) increased the remission rate with colchicine. SURF patients present with a wide range of clinical manifestations. Distinguishing between SURF and PFAPA is not concrete. Further omics studies will enlighten whether there is a true group of SURF. Key Points • SURF is an autoinflammatory disease that is becoming increasingly recognised. • The clinical manifestations of SURF are quite heterogeneous. • Colchicine and anti-IL-1 treatment is effective in most SURF patients. • It is controversial whether it should be called SURF or PFAPA-like syndrome, especially in children aged ≤ 5 years.

Exploring factors for predicting colchicine responsiveness in children with PFAPA.

Periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis syndrome (PFAPA) are the most common autoinflammatory syndromes in children. This study aimed to evaluate the clinical and laboratory parameters that may predict colchicine responsiveness.This retrospective, multicenter, cross-sectional study involved nine pediatric rheumatology centers from our country., The patients diagnosed with PFAPA were compared on the basis of their responses to colchicine. In the 806 (42.3% female 57.7% male) patients, the most common clinical findings were fever (100%), exudative tonsillitis (86.5%), pharyngitis (80.9%), and aphthous stomatitis (50.5%). The mean attack frequency was 13.5 ± 6.8 attacks per year lasting for a mean of 3.9 ± 1.1 days. Colchicine treatment was attempted in 519 (64.4%) patients, with 419 (80.7%) showing a favorable response. In patients who underwent MEFV gene analysis (70.8%), the most common variant was M694V heterozygous (16.8%). The presence of pharyngitis (p = 0.03, 95% CI 0.885 to 0.994), the presence of arthralgia (p = 0.04, 95% CI 0.169 to 0.958), and having more frequent attacks (p = 0.001, 95% CI 0.028 to 0.748) were found to be associated with colchicine unresponsiveness, whereas the carriage of the M694V variant (p = 0.001, 95% CI 0.065 to 0.242) was associated with colchicine responsiveness. This study identified the presence of pharyngitis, arthralgia, and increased attack frequency in patients with PFAPA as factors predicting colchicine unresponsiveness, whereas the carriage of the M694V variant emerged as a predictor of colchicine responsiveness. Predicting colchicine response at disease onset may facilitate a more effective management of PFAPA. • Colchicine treatment can be used in the prophylaxis of PFAPA disease. • Having the MEFV variant is the most commonly known factor in predicting response to colchicine. • The presence of pharyngitis or arthralgia, and more frequent attacks in PFAPA disease were found to be independently associated with colchicine unresponsiveness. • Carrying the M694V variant was identified as the sole factor predicting colchicine responsiveness.

Mevalonate kinase deficiency/Hyperimmunoglobulin D syndrome (MVK/HIDS) in a Differential Diagnosis of Periodic Fever, Aphthous Stomatitis, Pharyngitis, and Cervical Adenitis (PFAPA) Syndrome and Familial Mediterranean Fever (FMF): A Case Report.

Increased Frequency of Febrile Seizures in Two Periodic Fever Syndromes: Familial Mediterranean Fever and PFAPA Syndrome.

Our aim in this study is to reveal the frequency of febrile seizures in patients with Familial Mediterranean Fever and Periodic Fever, Aphthous stomatitis, Pharyngitis, cervical Adenitis syndrome and to compare it to normal population. Patients with Familial Mediterranean Fever and Periodic Fever, Aphthous stomatitis, Pharyngitis, cervical Adenitis syndrome, who were diagnosed accord- ing to Turkish pediatric Familial Mediterranean Fever diagnostic criteria and Marshall criteria, were enrolled to the study. A form containing questions about febrile seizures history was pre- pared for Familial Mediterranean Fever and Periodic Fever, Aphthous stomatitis, Pharyngitis, cervical Adenitis syndrome patients. Demographic data and febrile seizures history of Periodic Fever, Aphthous stomatitis, Pharyngitis, cervical Adenitis patients were obtained by calling the parents by phone. Familial Mediterranean Fever patients were randomly selected during their routine follow-up. The frequency of febrile seizures in both disease groups was compared with the prevalence of previous febrile seizures studies in the general population in Turkey. A total of 417 Familial Mediterranean Fever and 152 Periodic Fever, Aphthous stomati- tis, Pharyngitis, cervical Adenitis subjects were recruited to the study. The frequency of febrile seizures in Familial Mediterranean Fever and Periodic Fever, Aphthous stomatitis, Pharyngitis, cervical Adenitis syndrome was similar (8.4% vs. 8.6%; P > .05). The frequency of febrile seizures in Familial Mediterranean Fever and Periodic Fever, Aphthous stomatitis, Pharyngitis, cervical Adenitis syndrome patients was found to be significantly higher than the frequency in general population (8.4% vs. 4.4%) [P < .0001, OR: 1.99 (CI: 1.4-2.8)]; (8.6% vs. 4.4%) [P < .01, OR: 2.03 (CI: 1.1-3.6)], respectively. The frequency of febrile seizures in patients with Familial Mediterranean Fever and Periodic Fever, Aphthous stomatitis, Pharyngitis, cervical Adenitis syndrome was found to be significantly higher than in the general population. This increased frequency of febrile seizures in both periodic syndromes seems to be a result of recurrent fever.

Pre- and postoperative quality of life and emotional/behavioural problems in children with PFAPA.

This study aimed to evaluate the effects of surgical intervention on quality of life, emotional/behavioural problems and school absenteeism in children with periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis (PFAPA.) METHOD: A total of 56 children aged between 4 and 12 years, diagnosed with PFAPA and undergoing tonsillectomy with/without adenoidectomy at a tertiary hospital were included in the study. The Questionnaire for Quality of Life Assessment for Children and Adolescents Parent Form (Kid-KINDL) and the Strengths and Difficulties Questionnaires (SDQ) were used to evaluate quality of life and emotional/behavioural problems, respectively. The cases were assessed before and three months after surgery. The mean (SD) age of the children was 6.64 (3.03) years, and 58.9% (n = 33) were boys. The numbers of pre- and post-operative periodic fever episodes were 3.0 (1.7) and 0.6 (0.9) (p < 0.001), those for school absenteeism were 10.28 (5.53) and 2.85 (2.95) days (p < 0.001) and those for hospital presentations were 3.8 (2.5) and 1.1 (1.1) (p < 0.001), respectively, all of which were significantly lower in children with PFAPA at three months after the operation. The surgical procedures were effective in improving quality of life and emotional/behavioural problems, as evidenced by the significant differences between the pre- and post-treatment scores in outcome measures, including SDQ and Kid-KINDL (p < 0.001). This study demonstrated that the surgical approach exhibited positive effects in terms of improving quality of life and reducing emotional/behavioural problems and school absenteeism in children with PFAPA.

Familial Mediterranean fever and periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA) syndrome: shared features and main differences.

Autoinflammatory diseases are characterized by fever attacks of varying durations, associated with variety of symptoms including abdominal pain, lymphadenopathy, polyserositis, arthritis, etc. Despite the diversity of the clinical presentation, there are some common features that make the differential diagnosis of the autoinflammatory diseases challenging. Familial Mediterranean fever (FMF) is the most commonly seen autoinflammatory conditions, followed by syndrome associated with periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA). In this review, we aim to evaluate disease characteristics that make a diagnosis of FMF and PFAPA challenging, especially in a regions endemic for FMF. The ethnicity of patient, the regularity of the disease attacks, and the involvement of the upper respiratory systems and symphonies could be helpful in differential diagnosis. Current data from the literature suggest the use of biological agents as an alternative for patients with FMF and PFAPA who are non-responder classic treatment options. More controlled studies are needed to evaluate the efficacy and safety of this strategy.

Classification criteria for autoinflammatory recurrent fevers.

Different diagnostic and classification criteria are available for hereditary recurrent fevers (HRF)-familial Mediterranean fever (FMF), tumour necrosis factor receptor-associated periodic fever syndrome (TRAPS), mevalonate kinase deficiency (MKD) and cryopyrin-associated periodic syndromes (CAPS)-and for the non-hereditary, periodic fever, aphthosis, pharyngitis and adenitis (PFAPA). We aimed to develop and validate new evidence-based classification criteria for HRF/PFAPA. Step 1: selection of clinical, laboratory and genetic candidate variables; step 2: classification of 360 random patients from the Eurofever Registry by a panel of 25 clinicians and 8 geneticists blinded to patients' diagnosis (consensus ≥80%); step 3: statistical analysis for the selection of the best candidate classification criteria; step 4: nominal group technique consensus conference with 33 panellists for the discussion and selection of the final classification criteria; step 5: cross-sectional validation of the novel criteria. The panellists achieved consensus to classify 281 of 360 (78%) patients (32 CAPS, 36 FMF, 56 MKD, 37 PFAPA, 39 TRAPS, 81 undefined recurrent fever). Consensus was reached for two sets of criteria for each HRF, one including genetic and clinical variables, the other with clinical variables only, plus new criteria for PFAPA. The four HRF criteria demonstrated sensitivity of 0.94-1 and specificity of 0.95-1; for PFAPA, criteria sensitivity and specificity were 0.97 and 0.93, respectively. Validation of these criteria in an independent data set of 1018 patients shows a high accuracy (from 0.81 to 0.98). Eurofever proposes a novel set of validated classification criteria for HRF and PFAPA with high sensitivity and specificity.

PFAPA Syndrome in a Population with Endemic Familial Mediterranean Fever.

We reviewed the medical records of patients with periodic fever, aphthosis, pharyngitis, and adenitis (PFAPA) to investigate the clinical course, treatment response, and association with MEFV gene mutation. Familial Mediterranean fever should be considered in patients with PFAPA who do not respond to adenotonsillectomy.

A novel assessment tool for clinical care of patients with autoinflammatory disease: juvenile autoinflammatory disease multidimensional assessment report.

To develop and test a new multidimensional questionnaire for assessment of children with auto-inflammatory disease (AID) such as FMF, PFAPA, HIDS, TRAPS in standard clinical care. The juvenile auto-inflammatory disease multidimensional assessment report (JAIMAR) includes 16 parent or patient-centered measures and four dimensions that assess functional status, pain, therapeutic compliance and health-related quality of life (physical, social, school, emotional status) with disease outcome. It is proposed for use as both a proxy-report and a patient self-report, with the suggested age range of 8-18 years for use as a self-report. 250 children with FMF were included in the study. Total of 179 forms were filled up by parents and patients, and 71 forms were filled up by parents having children less than 8 years. Completing and scoring the JAIMAR can be done in 15 minutes. For the JAIMAR's dimensions, the Cronbach's alpha coefficient for internal consistency was between 0.507-0.998. There was a significant and a positive correlation between the test-retest scale scores (ICC=0.607-0.966). Concerning construct validity, all factors loadings were above 0.30. For the criterion validity, the correlation level between each dimension and the related scale ranged from medium (r=0.329, p<0.0001) to large (r=0.894, p<0.0001). The parents' proxy-reported and children's self-reported data were outstandingly concordant (r=0.770-0.989). The development of the JAIMAR introduces a new and multi-dimensional approach in paediatric rheumatology practice. It is a new tool for children with auto-inflammatory dis-ease and it may help enhance their quality of care.