Gray zone in the spectrum of autoinflammatory diseases: familial Mediterranean fever accompanying periodic fever, aphthous stomatitis, pharyngitis, and adenitis syndrome: single-center experience.

Despite the advanced knowledge concerning autoinflammatory diseases (AID), more data regarding the optimal treatment options and outcomes of the children who met the criteria of more than one AID are required. This study aimed to describe the demographic and clinical characteristics of children from familial Mediterranean fever (FMF)-endemic countries who meet both the FMF and the periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA) syndrome criteria. Moreover, we aimed to measure the response rates to colchicine and tonsillectomy and evaluate the factors affecting the colchicine response in these patients. The study was conducted at pediatric rheumatology tertiary centre. A total of 131 patients (58 females; 73 males) who met both the modified Marshall and pediatric FMF criteria were included. The median age at onset was 18 months (1-77 months), and the mean age at diagnosis was 47 ± 21.88 months. The median interval between episodes was 21 (7-90) days. The median disease duration was 46 (6-128) months. Consanguineous marriage was detected in 17 (13%) of the patients. The most common clinical finding was fever (100%), followed by exudative pharyngitis (88.5%), abdominal pain (86.3%), arthralgia (61.8%), stomatitis (51.1%), adenitis (42%), myalgia (28.7%), chest pain (16%), maculopapular rash (12.2%), arthritis (8.4%), and erysipelas-like rash (4.6%). MEFV gene variants were identified in 106 (80.9%) patients. The most common variants were M694V heterozygous (29%). We found that patients with tonsillopharyngitis, aphthous stomatitis, and PFAPA family history were more likely to be colchicine-resistant and tonsillectomy responsive, while those with exon 10 MEFV gene mutations were more prone to have a favorable response to colchicine.     Conclusion: PFAPA syndrome patients with exon 10 MEFV gene mutation, showing typical FMF symptoms, should be treated with colchicine, even after tonsillectomy. In multivariate analysis, PFAPA family history and lack of exon 10 MEFV gene mutations were independent risk factors for colchicine resistance. Thus, tonsillectomy may be recommended as a possible treatment option for these patients. It has yet to be clarified when colchicine treatment will be discontinued in patients whose attacks ceased after tonsillectomy that was performed due to colchicine unresponsiveness. What is Known: • A certain number of patients with periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA) syndrome concomitantly fulfill the familial Mediterranean fever (FMF) criteria. • While colchicine is proposed as a first treatment choice in familial Mediterranean fever (FMF), corticosteroids are recommended as a first-line treatment in PFAPA syndrome patients. What is New: • In patients with concomitant PFAPA syndrome and FMF, PFAPA family history and lack of exon 10 MEFV gene mutation are predictive factors of colchicine resistance. • The presence of exon 10 MEFV gene mutations in patients with concomitant FMF and PFAPA syndrome has a favourable effect on response to colchicine treatment.

Long-term efficacy of tonsillectomy/adenotonsillectomy in patients with periodic fever aphthous stomatitis pharyngitis adenitis syndrome with special emphasis on co-existence of familial Mediterranean fever.

Periodic fever, aphthous stomatitis, pharyngitis, adenitis (PFAPA) syndrome is one of the most common autoinflammatory fever disorders in the childhood which may co-exists with familial Mediterranean fever (FMF) causing treatment complexity. As the role of surgery in PFAPA syndrome is still controversial, in this paper, our aim is to present our results of tonsillectomy/adenotonsillectomy in the treatment of PFAPA syndrome. Archives of a tertiary care hospital were investigated for patients who underwent tonsillectomy or adenotonsillectomy due to PFAPA Syndrome between 2010 and 2020. 344 patients were found but only 281 of them were accessible. Through phone call interview and chart review methods, preoperative and postoperative the number and severity of the attacks and general satisfaction after the operation were recorded and analyzed. Also, patients with concomitant FMF were analyzed separately. A total of 281 patients were included in the study. There was no improvement in 10 (3.55%) patients. Eight (2.84%) patients showed mild improvement, 29 (10.32%) patients had moderate improvement and 234 (83.27%) patients had full recovery after tonsillectomy. There were 266 PFAPA patients without FMF. No improvement, mild improvement, moderate improvement, and full recovery in this patient group were 5 (1.9%), 6 (2.3%), 25 (9.4%) and 230 (86.5%), respectively. FMF was present in 5.33% (15/281) of the patients. In PFAPA + FMF group 5 patients had no improvement (33.3%), 2 had mild improvement (13.3%), 4 had moderate improvement (26.7%) and 4 had full recovery (26.7%). Benefit of tonsillectomy was significantly lower in the patients with concomitant FMF when compared to the patients who did not have FMF (p < 0.001). Age of diagnosis, age of operation, severity of the disease, type of operation, and gender were found to have no significant relationship with the benefit from surgery (p < 0.05). According to the findings of this study, tonsillectomy is an effective long-term treatment for PFAPA syndrome with success rate of 83.27%. Also, preoperatively FMF should be considered in these patients, which dramatically reduces surgical efficacy.

The effects of nusinersen treatment on respiratory status of children with spinal muscular atrophy.

BACKGROUND: Respiratory involvement is the main factor predicting the prognosis of spinal muscular atrophy (SMA). Significant responses in motor functions have been demonstrated with nusinersen, but pulmonary outcomes are still varied. We aimed to explore the effects of nusinersen on the respiratory functions of patients with SMA. METHODS: Patients with SMA who were receiving regular nusinersen treatment in our tertiary care hospital were enrolled in this study. We evaluated the patients in terms of the necessity to ventilatory or nutritional support, presence of motor involvement and other comorbidities related with prognosis at three consecutive assessments. RESULTS: The study group consisted of 43 patients (18 type 1, 12 type 2, and 13 type 3) with SMA with a mean age of 27.8 months at diagnosis and 60.8 months at the beginning of nusinersen treatment. The respiratory function improvements were noted in six patients at third assessment. Early initiation of nusinersen was significantly correlated with reduced hospital admissions (P = 0.026). Nutritional support and weight gain were remarkable in the ventilatory-supported group. Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders scores were significantly higher in the non-tracheostomized group in patients with SMA type 1 (P < 0.005). CONCLUSIONS: We posit that nusinersen may change the natural prognosis of SMA and improve care of children with SMA. Following up children with SMA for longer periods under nusinersen may be beneficial for understanding the effects of treatment. Results of our study need to be supported by future long-term studies to reach a consensus on nusinersen, considering the overall genetic and environmental status as well as the cost-effectiveness of the treatment.

The role of Mediterranean fever gene variants in patients with periodic fever, aphthous stomatitis, pharyngitis, and adenitis syndrome.

This study was conducted to investigate the relationship between clinic features and Mediterranean fever gene (MEFV) variants in patients with periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA) syndrome. In total, 167 patients with PFAPA syndrome were included in the study. Female:male ratio of the patients was 0.75 (72 females, 95 males). In total 59.9% of patients with PFAPA had at least one MEFV variant and the most common heterozygous variants were M694V in 29.3% of the patients (40/167), E148Q in 8.3% (14/167), and V726A in 7.1% (12/167). The median age at the disease onset was significantly higher and the median duration of the episodes was significantly lower in patient with variants in exon 10 comparing to the others (both p = 0.01). Similarly, the median age at the disease onset was significantly higher (p = 0.01) and the median duration of the episodes was significantly lower (p = 0.04) in patient with MEFV variants than in the remaining patients. There were no significant differences according to the genotypes of the patients in terms of both treatment response and the frequency of clinical findings.Conclusion: In PFAPA syndrome, MEFV variants may be a modifier for disease onset and attack duration. What is Known: • Due to periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA) syndrome having clinical findings resembling familial Mediterranean fever (FMF), it can be difficult to distinguish PFAPA syndrome and FMF especially in endemic regions for FMF. • Underlying MEFV mutations could affect the periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA) syndrome's clinical presentation and response to treatment. What is New: • Having one of the underlying MEFV variants is related to later disease onset and shorter episode duration in patients with PFAPA syndrome.

Performance of recently proposed periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome criteria in a region endemic for familial Mediterranean fever.

The periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome is an auto-inflammatory condition characterized by recurrent episodes of fever accompanied by aphthosis, cervical adenitis, and pharyngitis. Diagnosis of PFAPA could be challenging due to clinic overlap with familial Mediterranean fever (FMF). An international consensus has been established recently, to define a new set of classification criteria for PFAPA syndrome. We aimed to evaluate the performance of recently proposed PFAPA criteria, to assess their utility in FMF regions. Patients diagnosed with PFAPA syndrome, FMF, and juvenile idiopathic arthritis (JIA) were included. Two investigators blindly evaluated all of patients for the newly proposed PFAPA criteria. A total of 542 patients (322 with PFAPA syndrome, 118 FMF and 102 JIA) were evaluated. Mean age of patients was 6.6 ± 2.81, 12.75 ± 3.9, and 12.42 ± 4.8 years for PFAPA, FMF, and JIA, respectively. We found quite high sensitivity (89.7%) but insufficient specificity of newly proposed PFAPA criteria (69.5%). When applied to control patients separately, specificity was found to be 61% and 79.4% for FMF and JIA patients, respectively. Positive predictive value was 81%, while negative predictive value was 82%. Recently proposed PFAPA criteria have satisfactory sensitivity, but its specificity is still under expectation. There is a need for a distinctive criterion between PFAPA syndrome and FMF, in FMF endemic regions, e.g., cryptic tonsillitis rapidly responsive to single dose of glucocorticoids. Further studies with higher patients' number in different regions are needed.

Exploring the Influence of Concurrent Nutritional Therapy on Children with Spinal Muscular Atrophy Receiving Nusinersen Treatment.

Background This study examines spinal muscular atrophy (SMA), a neuromuscular disease associated with malnutrition. Our goals are to assess how effectively screening tools can detect malnutrition and evaluate the impact of nutritional interventions on neurological outcomes, particularly motor functions. Methods Thirty-seven genetically diagnosed SMA patients (types 1, 2, and 3) under nusinersen therapy were included in the study. The nutritional status of these patients was assessed by using anthropometric measurements, including height for age (HFA), weight for height (WFH), and body mass index (BMI) before and after the study. Additionally, the risk of malnutrition was determined using screening tools, namely the Pediatric Yorkhill Malnutrition Score (PYMS) and the Screening Tool for the Assessment of Malnutrition in Pediatrics (STAMP). Nutritional counseling followed the European Society for Paediatric Gastroenterology Hepatology and Nutrition (ESPGHAN) guidelines and considered the patients' dietary history, including content and administration method. Motor functions were assessed by validated tests: the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND) and the Hammersmith Functional Motor Scale-Expanded (HFMSE). Result The study showed an improvement in HFA, by a change from -0.95 to -0.65 (p = 0.015). Conversely, BMI scores decreased from 0.08 to -0.54 (p = 0.015), while WFH and MUAC showed no significant alterations (p = 0.135, p = 0.307). Following nutritional interventions, HFMSE demonstrated a median increase from 29.5 to 30.5 (p = 0.023). Patients identified as being at high risk for malnutrition based on PYMS and STAMP belonged to the moderate-to-severe malnutrition group (BMI Z-score ≤ -2, p = 0.001). Conclusions Use of screening tools in SMA patients is highly beneficial for the early detection of malnutrition. Future research should highlight the importance of combining nutritional management with nusinersen therapy to potentially alter the disease trajectory, especially in motor and neurological functions.

A Large Turkish Cohort of Williams Syndrome: The Evaluation of Facial, Cardiovascular, and Neuropsychiatric Features.

OBJECTIVE: Williams syndrome is caused by a microdeletion at 7q11.23 and is characterized by a distinctive face, cardiovascular disease, and intellectual disability with a specific cognitive and behavioral profile. This study aims to evaluate the clinical features and obtain important information that can guide early diagnoses and correct follow-up. MATERIALS AND METHODS: The study included 78 patients whose diagnoses were confirmed by fluorescent in situ hybridization. Facial features, anthropometric measurements, and neurocognitive, endocrine, and urinary system evaluations were obtained from the medical records, and photographs of the patients were evaluated retrospectively. RESULTS: The most common complaints at admission were cardiovascular disease and atypical face. The mean age at admission was 39 ± 4.8 months. The mean age of patients presenting with atypical face was 41 ± 5.6 months, while it was 11 ± 3.1 months in patients presenting with cardiovascular disease. Short nose/bulbous nasal type with anteverted nares and periorbital fullness, which are diagnostic facial features, were present in all patients in the infantile/ early childhood period. 80% of the patients had cardiovascular disease; supravalvular aortic stenosis (53.8%) and peripheral pulmonary artery stenosis (41%) were the most common cardiac anomalies.Intel lectu al/de velop menta l disability was present in 75.6% of the patients. Behavioral disorders including autism spectrum disorder and attention deficit hyperactivity disorder were detected in 50% of our patients. Hypersensitivity to loud and/or sudden sounds was present in all patients. CONCLUSION: We highlighted that recognition of facial findings is important for early diagnosis, especially in patients without cardiovascular disease. The frequency of cardiovascular, endocrinological, renal anomalies, and intellectual disab ility /deve lopme ntal delay was described that provide valuable information in the follow-up of patients.

Periodic Fever, Aphthous Stomatitis, Pharyngitis, and Adenitis Syndrome: A Single-Center Experience.

OBJECTIVE: The purpose of this study is to share our experience about clinical findings, natural course, and treatment response rates of a large cohort of patients with periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA) syndrome. MATERIALS AND METHODS: Medical records of patients who were diagnosed with PFAPA syndrome between January 2010 and May 2021 at Istanbul University-Cerrahpasa Cerrahpasa Medical Faculty pediatric rheumatology department were reviewed retrospectively. RESULTS: A total of 607 patients (females: 277, males: 330) with PFAPA syndrome were included. The median duration of episodes was 3 (1-15; interquartile range (IQR) 3-5) days, and the median interval between episodes was 20 days (5-120; IQR 15-30). The median age at the last attack and median disease duration were 66 (24-168; IQR 48-84) months and 40 (4-132; IQR 27.5-60) months, respectively. Fever (100%) was the most common clinical finding, followed by pharyngitis/exudative tonsillitis in 594 (97.9%), aphthous stomatitis in 308 (50.7%), cervical lymphadenopathy in 278 (45.8%), abdominal pain in 249 (41%), and arthralgia in 228 (37.6%) of the patients. Among the clinical findings, there was no statistical difference according to gender, except for cervical lymphadenitis being higher in males (P < .001). Of the patients who were given steroids during attacks, 94.6% were responsive. Colchicine was effective in 93 (63.7%) patients. The disease episodes ceased in 313 (95.4%) of patients who had tonsillectomy/adenoidectomy. CONCLUSIONS: Clinicians should be alert for additional symptoms such as abdominal pain, arthralgia, and headache apart from the cardinal signs. Although tonsillectomy is highly effective, its use is controversial. Colchicine may be a good alternative for prophylaxis.

The Correlation of Cord Arterial Blood Gas Analysis Results and Apgar Scores in Term Infants Without Fetal Distress.

OBJECTIVE: This study aimed to evaluate the necessity of cord arterial blood gas analysis in cases without fetal distress and normal Apgar score. MATERIALS AND METHODS: The cord arterial blood gas analysis and the 1- and 5-minute Apgar scores data of 1438 cases were evaluated. Newborns with fetal distress, neonates requiring cardiopulmonary resuscitation in the delivery room, congenital anomalies, severe and moderate acidemia (pH ≤7.1 at cord arterial blood gas analysis), and pre- and post-term newborns are excluded. Following cord arterial blood gas analysis, threshold values were accepted as abnormal pH <7.2, base excess ≥ -6 mmol/L, lactate ≥ 5 mmol/L, bicarbonate < 18 mmol/L, and partial pressure of carbon dioxide ≥ 50 mmHg. We evaluated the correlation between cord arterial blood gas analysis and 1- and 5-minute Apgar scores. RESULTS: There was a significant correlation between both 1- and 5-minute Apgar scores and cord arterial blood gas analysis values such as pH, lactate, and partial pressure of carbon dioxide (P < .001). In addition, a significant correlation was found between the 5-minute Apgar score of <7 and some cord arterial blood gas analysis abnormal threshold values (pH, bicarbonate, base excess) (P < .001). We found that some patients with mild acidemia had 1- and 5-minute Apgar scores of ≥7 in 1.9% and 2% of cases, respectively. CONCLUSION: The 5-minute Apgar score of 7 or higher may not be sufficient to verify the wellbeing of a newborn. Relying only on the Apgar scores may create the risk of missing some newborns with mild metabolic acidosis. The necessity of routine cord arterial blood gas analysis should be considered in prospective studies even if there are no signs of fetal distress and Apgar score ≥7.

Independent risk factors for resolution of periodic fever, aphthous stomatitis, pharyngitis, and adenitis syndrome within 4 years after the disease onset.

BACKGROUND/OBJECTIVE: Periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA) syndrome is a polygenic disease with unknown etiology. In this retrospective cohort study, we aimed to evaluate the risk factors for the resolution of PFAPA syndrome within 4 years after the onset. METHODS: In total, 466 patients with PFAPA syndrome that are being followed up our department were included into the study. Between May 2020 and September 2020, medical charts of the patients were reviewed retrospectively. RESULTS: The median age of the patients at the time of the study and at disease onset were 8.6 (2.9-20.5; IQR 6.9-10.6) years and 18 (1-84; IQR 11-31) months. On univariate analysis age at disease onset (p = 0.003), positive family history of PFAPA syndrome (p = 0.04), absence of myalgia (p = 0.04), and absence of headache (p = 0.003) were all associated with the resolution of PFAPA syndrome within 4 years after the onset. Multivariate logistic regression analysis revealed that age at disease onset (OR 1.04, 95% CI 1.01-1.07, p = 0.002), positive family history of PFAPA syndrome (OR 2.69, 95% CI 1.12-6.48, p = 0.02), and absence of headache (OR 0.2, 95% CI 0.05-0.74, p = 0.01) were independent risk factors for the resolution of PFAPA syndrome within 4 years after the onset. CONCLUSION: We report later age of disease onset, positive family history of PFAPA syndrome, and absence of headache as independent risk factors for resolution of PFAPA syndrome within 4 years after the onset. KEY POINTS: • Periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA) syndrome is a multifactorial disease with unknown etiology. • Although, PFAPA syndrome usually resolves within 3-5 years after the disease onset, it can persist for years and even continue into adulthood. With our current knowledge, there is no clue to predict which patients will have a long disease course and which patients will not. • Later age of disease onset, positive family history of PFAPA syndrome and absence of headache as independent risk factors for resolution of PFAPA syndrome within 4 years after the onset.