Evaluation of Clinical and Immunological Alterations Associated with ICF Syndrome.

PURPOSE: Immunodeficiency with centromeric instability and facial anomalies (ICF) syndrome is a rare autosomal recessive combined immunodeficiency. The detailed immune responses are not explored widely. We investigated known and novel immune alterations in lymphocyte subpopulations and their association with clinical symptoms in a well-defined ICF cohort. METHODS: We recruited the clinical findings from twelve ICF1 and ICF2 patients. We performed detailed immunological evaluation, including lymphocyte subset analyses, upregulation, and proliferation of T cells. We also determined the frequency of circulating T follicular helper (cTFH) and regulatory T (Treg) cells and their subtypes by flow cytometry. RESULTS: There were ten ICF1 and two ICF2 patients. We identified two novel homozygous missense mutations in the ZBTB24 gene. Respiratory tract infections were the most common recurrent infections among the patients. Gastrointestinal system (GIS) involvements were observed in seven patients. All patients received intravenous immunoglobulin replacement therapy and antibacterial prophylaxis; two died during the follow-up period. Immunologically, CD4+ T-cell counts, percentages of recent thymic emigrant T cells, and naive CD4+ T decreased in two, five, and four patients, respectively. Impaired T-cell proliferation and reduced CD25 upregulation were detected in all patients. These changes were more prominent in CD8+ T cells. GIS involvements negatively correlated with CD3+ T-, CD3+CD4+ T-, CD16+CD56+ NK-cell counts, and CD4+/CD8+ T-cell ratios. Further, we observed expanded cTFH cells and reduced Treg and follicular regulatory T cells with a skewing to a TH2-like phenotype in all tested subpopulations. CONCLUSION: The ICF syndrome encompasses various manifestations affecting multiple end organs. Perturbed T-cell responses with increased cTFH and decreased Treg cells may provide further insight into the immune aberrations observed in ICF syndrome.

Evaluation of red meat allergy patients and review of the literature.

BACKGROUND: It was reported that prevalence of red meat allergy in children was higher in our country than in western populations. However, the diagnosis of these patients is often delayed. The aim of the study was to present the clinical and laboratory characteristics of our red meat allergy patients. METHODS: The data were collected retrospectively from the files of children with red meat allergy. Also, 6 adults with red meat allergies were recorded in the families of the children. Patients with symptoms associated with red meat allergy and sensitive to beef or mutton in prick-to-prick tests were recorded. RESULTS: The median age of the 43 patients was 12 years (2-37), and 51% were male. Most of the patients were children (n=37, 86%). The median age was 10 years in children (2-17), and 54% were male. All of the children had dermatologic manifestations, 51% had respiratory symptoms, and 64% had anaphylaxis upon exposure to red meat. The anaphylaxis history was not associated with demographic, clinical and laboratory data. A total of 63% children had additional allergic diseases, and 75% of them were sensitive to both mutton and beef in prickto- prick tests. The median total IgE level of the children was 327 (20-3550) IU/mL, median eosinophil count was 210/mm < sup > 3 < /sup > (40-990) and mean vitamin D was 13.1 ± 1.2 mcg/L (n=27). Anaphylaxis occurred in 3 of 9 patients who received the open oral food challenge (OFC) test. After OFC, 3 patients continued to eat red meat without issues, and 1 patient was recommended to eat alternatives to red meat. CONCLUSIONS: Clinical and laboratory findings were heterogeneous in children with red meat allergy. Anaphylaxis risk seems to be higher than other food allergies. OFC test is more helpful in both diagnosis and alternative red meat selection compared to laboratory findings.

Multiplex PCR-Based Newborn Screening for Severe T and B-Cell Lymphopenia: The first Pilot Study in Turkey.

Objectives: Severe combined immunodeficiency disease (SCID), non-SCID T-cell lymphopenia, and other primary immunodeficiency diseases with T-cell and B-cell lymphopenia have low the T-cell-receptor-excision circles (TRECs) and κ-deleting-recombination-excision circles (KRECs) levels that can be measured in dried blood spots (DBS) of the newborn. The incidence of SCID and non-SCID T-cell lymphopenia in Western societies has been reported by TREC screening of newborns as 1: 58,000 and 1: 7300, respectively. Since there is no similar study in our country, we aimed to perform the first pilot study of TREC and KREC screening of newborn for SCID and non-SCID T-cell lymphopenia in Turkey. Methods: The heel blood samples of newborns born between 1st October 2015 and 31st December 2016 at two major hospitals in our city were included in this study. TREC and KREC copies were determined by a multiplex quantitative PCR-based method from newborn DBS. Cutoff levels were used as 7 copies per DBS for TRECs and KRECs, 1000 copies for ACTB (internal control). Failed samples or abnormal results in measurements were tested the second time. An immunologist evaluated data of newborns with low TREC and KREC copies clinically and through the laboratory. Results: A total of 1960 DBS were tested. The results of 1856 newborns were evaluated. The low TRECs and/or KRECs levels were detected in 71 newborns (3.8 %). The low TRECs rate was 1.1 %. Preterm newborns have lower levels of TRECs and KRECs than term newborns (both p <0.0001). As a result of immunological research, we did not detect any SCID, but we detected 2 newborns with non-SCID T-cell lymphopenia (1:928). These 2 newborns were found to have frequent and severe infectious diseases or hypogammaglobulinemia in their clinical follow-up, although they did not have absolute lymphopenia. Conclusion: Non-SCID T-cell lymphopenia is common in our country than in western societies. TRECs and KRECs assay should be considered for routine NBS programs in our country. Studies involving more newborns should be conducted to detect SCID.

Abatacept as a Long-Term Targeted Therapy for LRBA Deficiency.

BACKGROUND: LPS-responsive beige-like anchor (LRBA) deficiency presents with susceptibility to infections, autoimmunity, and lymphoproliferation. The long-term efficacy of cytotoxic T-lymphocyte-associated antigen 4-immunoglobulin (abatacept) as targeted therapy for its immune dysregulatory features remains to be established. OBJECTIVE: To determine the clinical and immunologic features of LRBA deficiency and long-term efficacy of abatacept treatment in controlling the different disease manifestations. METHODS: Twenty-two LRBA-deficient patients were recruited from different immunology centers and followed prospectively. Eighteen patients on abatacept were evaluated every 3 months for long-term clinical and immunologic responses. LRBA expression, lymphocyte subpopulations, and circulating T follicular helper cells were determined by flow cytometry. RESULTS: The mean age of the patients was 13.4 ± 7.9 years, and the follow-up period was 3.4 ± 2.3 years. Recurrent infections (n = 19 [86.4%]), immune dysregulation (n = 18 [81.8%]), and lymphoproliferation (n = 16 [72.7%]) were common clinical features. The long-term benefits of abatacept in 16 patients were demonstrated by complete control of lymphoproliferation and chronic diarrhea followed by immune dysregulation, most notably autoimmune cytopenias. Weekly or every other week administration of abatacept gave better disease control compared with every 4 weeks. There were no serious side effects related to the abatacept therapy. Circulating T follicular helper cell frequencies were found to be a reliable biomarker of disease activity, which decreased on abatacept therapy in most subjects. However, high circulating T follicular helper cell frequencies persisted in 2 patients who had a more severe disease phenotype that was relatively resistant to abatacept therapy. CONCLUSIONS: Long-term abatacept therapy is effective in most patients with LRBA deficiency.

Comparison of practical application steps of the previously used adrenaline auto injector in Turkey (EpiPen) and the currently available adrenaline auto injector (Penepin): a multi-center study.

AIM: It has been shown by a great number of studies that the correct use of adrenaline auto injectors prescribed to patients with anaphylaxis is associated with the design of the auto injector, in addition to training. The aim of this study was to compare the skills of adults in using two different auto injectors prescribed to patients with anaphylaxis. MATERIAL AND METHODS: Parents of patients aged between 1 and 18 years who referred to allergy outpatients were included in the study. RESULTS: A total of 630 volunteers from nine centers were included in the study. Four hundred fifty-seven (72.5%) of the participants were females and 235 (37.3%) were undergraduates. The rate of showing all the steps of auto injector trainers correctly by the participants was found as (60.2%) (n=379) for EpiPen and 42.9% (n=270) for Penepin (p<0.001). The most frequent mistake with both auto injector trainers was the step of "place appropriate injection tip into outer thigh/press the trigger so it clicks." When the preferences of the volunteers were asked after training and application, 527 (83.7%) chose EpiPen, stating that it was easier and simpler to use. CONCLUSIONS: Our study showed that the correct usage rates of both adrenaline auto injectors were much lower than expected and there could be mistakes in the application of both. It could be appropriate to make improvements in the design of Penepin, which is still the only available adrenaline auto injector in Turkey, such that its application steps will be simpler and quicker.

Seven chronic granulomatous disease cases in a single-center experience and a review of the literature.

BACKGROUND: Chronic granulomatous disease (CGD) is a rare primary immunodeficiency caused by defects in the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase enzyme system. This disease causes the disordered functioning of phagocytic cells. It is characterized by life-threatening and/or recurrent infections by bacteria and fungi. CGD has both an X-linked recessive (X-CGD) and autosomal recessive (AR-CGD) phenotypes. AR form have four subtypes including defects with one of these NADPH oxidase components (p22, p40, p47 and p67phox). OBJECTIVES: To report the clinical and laboratory characteristics of seven CGD patients based on their genetic characteristics. METHODS: Seven boys with CGD were reviewed based on clinical findings and genetic results. Dihydrorhodamine-1,2,3 (DHR) assay was used as a diagnostic test. Genetic analysis was conducted to establish moleculer diagnoses in all patients. RESULTS: The age of diagnosis varied between 1.5 years and 15 years. The most frequent clinical presentation was pneumonia, and two patients had BCG-itis. Four patients had the AR-CGD phenotype, and three patients had the X-CGD phenotype. Severe invasive infections due to Aspergillus, Staphylococcus, and Serratia species were reported. Frequent lung and lymph node involvement was observed during follow-up of the cases. CONCLUSIONS: CGD is life-threatening disease that involves deep-seated infection. In our patients, the most commonly affected organs were the lungs and lymph nodes. Phagocytic disorders should be considered in cases of recurrent infectious diseases, invasive fungal diseases, BCG complications that are not self-limiting, unexplained lymphadenitis or osteomyelitis, and chronic inflammatory disorders.

An evaluation of vitamin D levels in children with seasonal allergic rhinitis during pollen season.

BACKGROUND: Serum vitamin D levels have not been studied in children with seasonal allergic rhinitis (SAR). The aim of this study was to evaluate the vitamin D levels of children with SAR and to compare them to levels in healthy children during pollen season. METHODS: This study was conducted in 100 children with SAR and 100 healthy controls. Clinical and laboratory evaluations and vitamin D analyses of all the participants were performed between the months of April and July. Pollen sensitization was detected in the patient group using a skin prick test. 25(OH)D3 levels were compared between the patient and control groups. Associations among the patient 25(OH)D3 levels and their demographic, clinical, and laboratory characteristics were analyzed. RESULTS: Overall, 72% of the patients were male, the median age was 12.35 years (range: 6-17.8 years), and the median body mass index value was 19.15 (range: 13.6-27.8). There were no differences between the patients and healthy controls in terms of gender, age, or body mass index. The mean levels of 25(OH)D3 (20.78±6) in patients were higher than those of the controls (17.92±4). In the patient group, no associations were found among 25(OH)D3 levels, demographic characteristics, atopy test results, atopy history, severity of rhinitis, and the total four symptoms score (all P>.05). CONCLUSIONS: During pollen season, children with SAR may have higher vitamin D levels than healthy controls. The presence of asthma and/or atopic dermatitis in addition to SAR did not change this result.

Vesicourethral reflux-induced renal failure in a patient with ICF syndrome due to a novel DNMT3B mutation.

ICF syndrome is a primary immunodeficiency disease characterized by hypo- or agammaglobulinemia, centromeric instability mainly on chromosomes 1, 9, and 16 and facial anomalies. ICF syndrome presents with frequent respiratory tract infections in infancy. A 20-month-old female patient was referred to our clinic due to frequent lower respiratory tract infections. ICF syndrome was considered because of comorbidity of hypogammaglobulinemia, facial anomalies, and neuromotor growth retardation. Metaphase chromosome analysis revealed centromeric instability on chromosomes 1, 9, and 16 and through Sanger a previously unreported homozygous missense mutation (c.1805T>C; [p.V602A]) was identified in the DNMT3B, confirming ICF1. The patient was found to have a breakdown in renal function 1 year later; the urinary system was examined and bilateral vesicoureteral reflux was found, warranting the need for dialysis in time. This report expands the mutation spectrum of ICF1 and is the first to describe bilateral vesicoureteral reflux accompanying ICF syndrome. © 2016 Wiley Periodicals, Inc.

Evaluation of olfactory function in children with allergic rhinitis and nonallergic rhinitis.

OBJECTIVES: Allergic rhinitis (AR) occurs when the symptoms of rhinitis arise as a result of allergen-induced nasal mucosal inflammation. In the presence of rhinitis symptoms without infection or an allergic reaction in the nose, non-allergic rhinitis (NAR) is considered. Adults with these diseases have increased frequency of olfactory dysfunction. The aim of the present study is to assess olfactory function in children with AR and NAR. METHODS: A total of 77 children (aged six to 18 years) with AR and NAR were included in the study. The control group consisted of 45 healthy children. Sniffin' Sticks test was applied to both groups. The association between odor scores and demographic, clinical, and laboratory results was investigated. RESULTS: Forty two patients had allergic rhinitis. No significant difference was observed between patients with rhinitis and healthy controls with respect to odor scores. No association was observed between odor scores and the severity of rhinitis and the laboratory results of the patient groups. Odor identification and total odor scores of the patients with rhinitis lasting for longer than three years were significantly lower than those in the patient group with rhinitis lasting for one to three years. In the AR and control groups, the odor scores were found to increase with age. CONCLUSIONS: When compared with healthy children, children with allergic rhinitis and non-allergic rhinitis were not found to have reduced olfactory function. The duration of rhinitis may be associated with the olfactory dysfunction in children with rhinitis.

Gender Identity and Gender Role in DSD Patients Raised as Females: A Preliminary Outcome Study.

Gender identity and gender role are expected to be consistent with gender assignment for optimal DSD management outcome. To our knowledge, our study is the first to attempt evaluation of gender related outcomes in Turkish DSD patients. After receiving institutional ethical board approval and subject (or parent) informed consent, subjects with DSD raised as girls (22 patients 46 XX DSD, 11 patients 46 XY DSD) answered 566 questions of the Minnesota Multiphasic Personality Inventory (MMPI) questionnaire including 60-item Masculinity-Femininity (MF) subscale which was the focus in this study. Controls (n: 50) were females similar to the probands in age, level of education, relationship status, and having a job or not also answered all questions. The answers were evaluated by a trained psychologist (Derya Inceoglu) on MMPI. For statistical purposes, seven findings were obtained from the data related to the MF subscale from the patients and controls. Of these seven findings (S1-S7), two were associated with masculinity (S3-S4) and another two were associated with femininity (S5-S6). In DSD patients, the percentages of masculinity findings were significantly higher when compared to controls (p < 0.001 and p < 0.001 for S3 and S4, respectively). In controls, the percentages of femininity findings were significantly higher when compared to DSD females (p < 0.001 and p < 0.001 for S5 and S6 respectively). There was no significant difference between 46 XX DSD patients and 46 XY DSD patients with respect to the percentage of any of the seven findings. Two patients requested gender change to male; only these two patients had the finding stating that sexual impulses could come to existence as actions (S7). In conclusion efforts to identify modifiable factors with negative impact and thus modifying them, and professional guidance may be important in minimizing the encountered gender related problems in DSD patients.

Outcome for patients with isolated atrial septal defects in the oval fossa diagnosed in infancy.

OBJECTIVE: Our aim was to investigate the change in diameter of holes within the oval fossa, and the role of aneurismal formation in reducing the size of the hole, in patients diagnosed during infancy with isolated defects in the floor of the fossa. PATIENTS: In a retrospective study, we included 100 patients diagnosed during the first year of life with an isolated defect in the floor of the oval fossa who had subsequently been observed for at least 5 years. There were 56 females and 44 males. They had been admitted to hospital because of a murmur in 65, heart failure in 9, and other reasons in 17. The remaining 9 patients were referred from other institutions with an established diagnosis of defects within the oval fossa. Patients were grouped according to the size of the deficiency in the floor of the fossa. Defects of diameter less than 5 mm were considered to be small, and 20 patients had such defects. Medium sized defects were judged to be between 5 and 8 mm, with 26 patients fulfilling this criterion, with the other 54 patients having large defects with diameters greater than 8 mm. RESULTS: The overall spontaneous rate of closure was 27%. Of those with medium defects, half closed spontaneously, but only 7.5% of those with large defects showed such closure. Of the patients who were diagnosed with heart failure, 9 had defects measuring 7 mm, and of these, 6 required surgical closure, 1 patient had spontaneous closure, while the defect became smaller in the remaining 2. On the other hand, in 9 out of 10 patients who had aneurysms, the diameter of the defect was between 7 and 15 mm. Amongst these patients, the defect closed spontaneously in 3, and reduced in size in the others. CONCLUSION: When holes within the oval fossa measure 8 mm or below, the majority of patients with experience either spontaneous closure or show decrease in size of the defect. In those with larger defects, the size usually increases, and surgery is needed for closure. If there is aneurismal formation, however, even when the defect measures more than 8 mm, the defect usually closes on its own or gets smaller.

Systemic lupus erythematosus due to Epstein-Barr virus or Epstein-Barr virus infection provocating acute exacerbation of systemic lupus erythematosus?

Systemic lupus erythematosus (SLE) is a rheumatologic disease characterized by an inflammatory destruction of the target organ systems of the body in an unknown way by autoantibodies formed against self-antigens. Infectious agents like Epstein-Barr virus (EBV), cytomegalovirus and parvovirus B19 may have a role in the occurrence or the exacerbation of the SLE. In this report, the clinical follow-up of a 14-year-old girl diagnosed with SLE following an EBV infection with bicytopenia, lymphadenomegaly and hepatomegaly is discussed. This case could support the role of viral infections in the etiology of SLE.