Unravelling the clinical heterogeneity of undefined recurrent fever over time in the European registries on Autoinflammation.

BACKGROUND: Systemic autoinflammatory disorders (SAIDs) represent a growing spectrum of diseases characterized by dysregulation of the innate immune system. The most common pediatric autoinflammatory fever syndrome, Periodic Fever, Aphthous Stomatitis, Pharyngitis, Adenitis (PFAPA), has well defined clinical diagnostic criteria, but there is a subset of patients who do not meet these criteria and are classified as undefined autoinflammatory diseases (uAID). This project, endorsed by PRES, supported by the EMERGE fellowship program, aimed to analyze the evolution of symptoms in recurrent fevers without molecular diagnosis in the context of undifferentiated AIDs, focusing on PFAPA and syndrome of undifferentiated recurrent fever (SURF), using data from European AID registries. METHODS: Data of patients with PFAPA, SURF and uSAID were collected from 3 registries including detailed epidemiological, demographic and clinical data, results of the genetic testing and additional laboratory investigations with retrospective application of the modified Marshall and PRINTO/Eurofever classification criteria on the cohort of PFAPA patients and preliminary SURF criteria on uSAID/SURF patients. RESULTS: Clinical presentation of PFAPA is variable and some patients did not fit the conventional PFAPA criteria and exhibit different symptoms. Some patients did not meet the criteria for either PFAPA or SURF, highlighting the heterogeneity within these groups. The study also explored potential overlaps between PFAPA and SURF/uAID, revealing that some patients exhibited symptoms characteristic of both conditions, emphasizing the need for more precise classification criteria. CONCLUSIONS: Patients with recurrent fevers without molecular diagnoses represent a clinically heterogeneous group. Improved classification criteria are needed for both PFAPA and SURF/uAID to accurately identify and manage these patients, ultimately improving clinical outcomes.

Intavenous immunoglobulin for the management of intractable epilepsy in a boy.

BACKGROUND: The involvement of the immune system in the pathogenesis of certain types of epilepsy has been supported in the past. The use of intravenous immunoglobulin in the treatment of neurologic diseases has shown a progressive trend over the last years. CASE REPORT: We report the case of a 9.5-year-old boy with refractory epilepsy who was admitted for investigation of his persistent seizures and severe psychomotor regression. He experienced persistent tonic-clonic over the preceding six months and long lasting atonic seizures since the age of six and did not respond to multiple anticonvulsant drugs. The administration of intravenous immunoglobulin achieved seizure control and cognitive improvement. CONCLUSION: This case underscores the efficacy of intravenous immunoglobulin in the treatment of refractory epilepsy in children. HIPPOKRATIA 2017, 21(1): 55-57.

Evaluation and management of juvenile recurrent parotitis in children from northern Greece.

BACKGROUND: Juvenile Recurrent Parotitis (JRP) is a recurrent parotid inflammation of childhood.  The aim of our study was to investigate the clinical, laboratory and imaging profile of children with JRP as well as to estimate the impact of siadendoscopy as a therapeutic tool in the clinical outcome of JRP. METHODS: Twenty-three children with JRP aged 3.5-16 years, were investigated. Twelve of them underwent sialendoscopy: seven aged <8 years under general and five aged >8 years under local anesthesia. RESULTS: The age at onset ranged from 2-15 years while the number of episodes from 2-8 per year. The autoantibody profile was negative in all patients, suggesting no evidence for autoimmune diseases.  Antibody deficiency was found in two children. The imaging studies reveal an overall parotid swelling and intraparotid lymph nodes while microabscesses were present in 31% of the patients. Twelve patients who underwent sialendoscopy had a significant improvement in their clinical outcome; the mean episodes of JRP before sialendoscopy was 3.9/year and reduced to 0.4 at the post-intervention year. CONCLUSION: Sialendoscopy represents an alternative and promising perspective in the management of JRP. Hippokratia 2015; 19 (4): 356-359.

Apelin and G212A apelin receptor gene polymorphism in obese and diabese youth.

OBJECTIVE: The apelinergic system has been previously described to participate in fluid homeostasis, cardiac contractility, blood pressure and neo-vascularization. The role of apelin in obesity and glucose metabolism has also lately gained interest; however, it still remains obscure. This study aimed to assess serum apelin levels in obese youngsters and to investigate any possible association with the G212A polymorphism of the apelin receptor (APLNR) gene. METHODS: Ninety obese individuals and 90 matched for age and gender lean controls were included. Anthropometric measurements, data of glucose metabolism, including an oral glucose tolerance test, and serum apelin levels were obtained. The presence of the G212A polymorphism of the APLNR gene was also analyzed in the obese group. RESULTS: Obese participants had significantly lower serum apelin levels as compared with controls (P = 0.011). After being grouped according to their status of glucose metabolism, only obese subjects with impaired glucose metabolism (diabese) exhibited lower apelin levels as compared with controls. The presence of the G212A polymorphism did not differ from the HapMap-reported frequencies in Caucasians (GG = 53.3%/GA = 38.9%/ΑΑ = 7.8% vs. GG = 46.9%/GA = 39.8%/ΑΑ = 13.3%, P = 0.232). The GG and GA obese subgroups had significantly lower apelin levels as compared with the AA group (P = 0.013 and P = 0.016, respectively). CONCLUSION: Obese (especially diabese) youngsters demonstrated lower serum apelin levels; the G212A polymorphism of the APLNR gene was found to exert a favourable effect on circulating apelin levels in childhood obesity.

Analysis of Btk mutations in patients with X-linked agammaglobulinaemia (XLA) and determination of carrier status in normal female relatives: a nationwide study of Btk deficiency in Greece.

Bruton's tyrosine kinase (Btk) is a nonreceptor tyrosine kinase, critical for B-cell development and function. Mutations that inactivate this kinase were found in families with X-linked agammaglobulinaemia (XLA). In this study the Btk gene was analyzed in 13 registered Greek patients with XLA phenotype originated from 12 unrelated families, in order to provide a definite diagnosis of the XLA. The structure of Btk was analyzed at the cDNA level using the recently developed method, NIRCA (Non-Isotopic-Rnase-Cleavage-Assay). Alterations were detected in all patients and sequencing analysis confirmed the results and defined six novel XLA-associated Btk mutations (three missense mutations: C337G, L346R, L452P; one nonsense mutation: Y392X, and two frameshift alterations: c1211-1212delA, c1306-1307insA). Having defined the genetic alteration in the affected males of these families, the information was used to design polymerase chain reaction (PCR) primers and the Btk segments containing the mutated sequences were amplified from peripheral blood derived genomic DNA of potential female carriers. The PCR products were directly sequenced and carrier status was determined in 12 out of 16 phenotypically normal females analyzed. This protocol can be used once the nature of the Btk mutation has been defined in one of the affected males and provides a convenient, simple and reliable way to determine the carrier status of other female family members. Molecular genetic analysis constitutes a determinative tool for the definitive diagnosis of XLA and may allow accurate carrier and prenatal diagnosis for genetic counselling.

Monitoring of two intravenous immunoglobulin. Preparations for immunoglobulin G subclasses and specific antibodies to bacterial surface antigens and relation with their levels in treated immunodeficient patients.

Patients with antibody deficiency disorders are highly susceptible to bacterial infections. Replacement therapy with intravenous immunoglobulin preparations (IVIG) has been established in such patients for two decades. The efficacy of IVIG treatment depends on the amount of functional pathogen-specific antibodies provided. The present study was undertaken to determine the levels of immunoglobulin classes, IgG subclasses, and specific antibodies to bacterial surface antigens in two different IVIG preparations (Sandoglobulin and Gamimmune) and blood sera of IVIG-treated immunodeficient patients. The levels of IgG, IgA, IgM and IgG subclasses were determined in both IVIG preparations and in patients' sera and were compared with those of healthy individuals. Sandoglobulin contained significantly higher concentrations of IgA, IgG, and IgG4 than Gamimmune. The latter contained higher concentrations of IgG1. Patients treated with Gamimmune) had significantly lower concentration of IgG4 as compared with healthy individuals and Sandoglobulin-treated patients. This finding was related to the preparation's composition. Screening of 20 lots from each preparation for antibodies to frequent clinically isolated strains of Escherichia coli, Staphylococcus aureus, S. epidermidis. Klebsiella pneumoniae and Enterococci spp. showed a high lot-to-lot variability. In order to overcome the lot-to-lot variability and correlate the observed effects with each IVIG preparation, the administered IVIG lots were selected so that their titers were in the interval of mean value +/- S.D. for each pathogen. The two tested preparations showed significant differences in their content of specific antibodies that ultimately affected the levels of these antibodies in treated patients. More specifically, Sandoglobulin contained higher levels of antibodies to E. coli and S. epidermidis strains. Infusion of this preparation maintained the respective antibodies in the recipients significantly higher than those of healthy individuals. Gamimmune infusion led to similar and comparable levels. Both IVIG preparations had comparable antibody titers towards K. pneumoniae, provided high amounts of antibodies, and kept recipients' specific IgG at levels significantly higher than those of the healthy individuals. Enterococci spp. specific antibodies were significantly higher in Gamimmune, whereas titers of antibodies towards S. aureus were comparable. Levels of antibodies against both Enterococci spp. and S. epidermidis after administration of both preparations were close to those in healthy individuals. None of the patients developed infection during the time of the study. In conclusion, most of the lots of the two IVIG preparations studied, despite some quantitative differences, provide patients with sufficient amounts of antibodies to bacterial surface antigens that protect them against infections.