Hatice Eke Gungor

Hypomorphic homozygous mutations in phosphoglucomutase 3 (PGM3) impair immunity and increase serum IgE levels

BACKGROUND Recurrent bacterial and fungal infections, eczema, and increased serum IgE levels characterize patients with the hyper-IgE syndrome (HIES). Known genetic causes for HIES are mutations in signal transducer and activator of transcription 3 (STAT3) and dedicator of cytokinesis 8 (DOCK8), which are involved in signal transduction pathways. However, glycosylation defects have not been described in patients with HIES. One crucial enzyme in the glycosylation pathway is phosphoglucomutase 3 (PGM3), which catalyzes a key step in the synthesis of uridine diphosphate N-acetylglucosamine, which is required for the biosynthesis of N-glycans. OBJECTIVE We sought to elucidate the genetic cause in patients with HIES who do not carry mutations in STAT3 or DOCK8. METHODS After establishing a linkage interval by means of SNPchip genotyping and homozygosity mapping in 2 families with HIES from Tunisia, mutational analysis was performed with selector-based, high-throughput sequencing. Protein expression was analyzed by means of Western blotting, and glycosylation was profiled by using mass spectrometry. RESULTS Mutational analysis of candidate genes in an 11.9-Mb linkage region on chromosome 6 shared by 2 multiplex families identified 2 homozygous mutations in PGM3 that segregated with disease status and followed recessive inheritance. The mutations predict amino acid changes in PGM3 (p.Glu340del and p.Leu83Ser). A third homozygous mutation (p.Asp502Tyr) and the p.Leu83Ser variant were identified in 2 other affected families, respectively. These hypomorphic mutations have an effect on the biosynthetic reactions involving uridine diphosphate N-acetylglucosamine. Glycomic analysis revealed an aberrant glycosylation pattern in leukocytes demonstrated by a reduced level of tri-antennary and tetra-antennary N-glycans. T-cell proliferation and differentiation were impaired in patients. Most patients had developmental delay, and many had psychomotor retardation. CONCLUSION Impairment of PGM3 function leads to a novel primary (inborn) error of development and immunity because biallelic hypomorphic mutations are associated with impaired glycosylation and a hyper-IgE-like phenotype.

Decreased Levels of Lipoxin A4 and Annexin A1 in Wheezy Infants

Objective: Wheezing is a common and challenging health issue in infancy and early childhood. Asthma diagnosis is frequent in patients with a history of recurrent wheezing. A relationship has been reported between asthma and anti-inflammatory mediators such as lipoxin A4 and annexin A1. However, this remains uncertain in wheezy infants. The aim of the present study was to determine lipoxin A4 and annexin A1 levels in wheezy infants. Materials and Methods: Eighty-seven patients aged 6-36 months were included in this study. Demographic characteristics, clinical features, laboratory data, clinical diagnoses, and treatments, if present, were recorded. Patients were divided into 2 groups: patients with wheezing (n = 59) and healthy controls (n = 28). Blood samples were taken and lipoxin A4 and annexin A1 levels were evaluated by ELISA. Results: Lipoxin A4 and annexin A1 levels were significantly lower in the wheezing group than in the control group (p < 0.05). A significant correlation was found between the serum total immunoglobulin E (IgE) level and the percentage and absolute number of eosinophils (p < 0.05). No significant correlation was found in terms of lipoxin A4 and annexin A1 levels, the serum total IgE level, and the percentage and absolute number of eosinophils among groups (p > 0.05). Conclusion: This is the first study to assess lipoxin A4 and annexin A1 levels in wheezy infants. The levels of lipoxin A4 and annexin A1 were found to be low in wheezy infants. We hope that these results will lead to novel therapeutic options for asthma in cases where an optimal treatment modality is lacking.

Autoimmune diseases detected in children with primary immunodeficiency diseases: results from a reference centre at middle anatolia

Primary immunodeficiency diseases (PIDs) are a heterogeneous group of disorders that genetically affect distinct components of the immune system; thus, predispose individuals to recurrent infections, allergy, autoimmunity, and malignancies. In this retrospective study, autoimmune diseases (ADs), which developed during the course of PID in children, were discussed.Twenty-five patients were included in this study. Symptoms related to ADs, such as autoimmune thyroiditis, type 1 diabetes mellitus, coeliac disease, juvenile idiopathic arthritis, dermatomyositis, autoimmune haemolytic anaemia, leukocytoclastic vasculitis, Henoch-Schonlein purpura, hypoparathyroidism, alopecia areata, Addisons disease, vitiligo and systemic lupus erythematosus were detected in these patients, who have been followed with diagnosis of PID including common variable immunodeficiency, selective and partial IgA deficiency, Wiskott-Aldrich syndrome, ataxia telangiectasia, hyperimmunoglobulin E syndrome, chronic mucocutaneous candidiasis, Griscelli syndrome, and partial C4 deficiency.Immunodeficiency and autoimmune phenomenon may concomitantly present in an individual, although they seem to be incompatible ends in the spectrum of the clinical immune response. Patients with primary immune deficiency should be closely monitored for development of autoimmune diseases.

The efficacy of Pelargonium sidoides in the treatment of upper respiratory tract infections in children with transient hypogammaglobulinemia of infancy

Transient hypogammaglobulinemia of infancy (THI), defined as prolongation of physiological hypogammaglobulinemia normally seen between the initial 3rd and 6th months of life, is one of the most common immune deficiencies of childhood. Recurrent upper respiratory tract infections (URTI) are rather common in this group of patients, and generally, antibiotic treatment is the usual choice, although viruses involved in most cases. Pelargonium sidoides extract a herbal drug with known immunmodulator, antiviral and antibacterial effects. In this randomized, placebo controlled, prospective, monocentric pilot study, 14 of 28 patients with a diagnosed THI, were given Pelargonium sidoides, while 14 were given placebo during the period of URTI. Before and after the treatment period of one week, complete blood count, prothrombin time, activated prothromboplastin time, serum alanine aminotransferase, aspartate aminotransferase, gamma glutamyl transpeptidase, total and direct bilirubin levels were measured. Mothers were asked to fill in a questionnaire for the recovery of the clinical symptoms during the treatment. The results were evaluated and compared in both group to assess the effect of Pelargonium sidoides. As a conclusion, the Pelargonium sidoides group showed increased appetite. The Pelargonium sidoides were found to beneficial for the nasal congestion, recovery of daily and nocturnal cough but not found be significant. Further studies with large number of participants are necessary to highlight the effect of Pelargonium sidoides in children with transient hypogammaglobulinemia of infancy.

Gastric signet ring carcinoma in a patient with ataxia-telangiectasia: a case report and review of the literature.

Ataxia-telangiectasia (A-T) is an autosomal recessive primary immunodeficiency disease characterized by progressive cerebellar ataxia, telangiectasia, sinopulmoner recurrent infections, and cancer susceptibility. Individuals with A-T are known to be at increased risk of certain malignancies including leukemia, lymphoma, and breast and gastric cancer. We present an 18-year-old case of A-T with Hashimoto thyroiditis who admitted with complaints of nausea, vomiting, anorexia, and weight loss. An upper endoscopic biopsy revealed gastric signet ring cell carcinoma. To the best of our knowledge, we report the first case of signet ring cell carcinoma in the patient with A-T. Our experience with occurrence of Hashimoto thyroiditis and gastric signet ring cell carcinoma in the same case of A-T underlines that the clinicians handling A-T must be vigilant about both malignancy and autoimmune disorders.

Chronic granulomatous disease with markedly elevated IgE levels mimicking hyperimmunoglobulin E syndrome

Patients with hyperimmunoglobulin E syndrome (HIES) and chronic granulomatous disease (CGD) have prominently increased immunoglobulin (Ig) E levels. We present a 9-year-old boy with medical history revealing recurrent pneumonia, suppurative lymphadenitis, diarrhea, and otitis. The patient was hospitalized with severe pneumonia. The examination showed tachypnea, crackles at the right and left base of the lung, freckles on his face, red-hair, gingivitis, a high arched palate, and retained primary dentition. Serum IgE level was markedly increased. Nevertheless, patient did not have STAT3 or DOCK8 mutation, characteristic of HIES. Neutrophil function test with dihydrorhodamine (DHR) showed X linked-CGD pattern and molecular analysis of DNAshowed a splice site mutation (c.338-1G > A) in CYBB gene. Herein, we present a case of CGD with selective IgA deficiency. Laboratory findings and elevated IgE mimic the features seen in HIES. Thus, CGD must be considered as a differential diagnosis in patients with elevated Ig E.

The association of forced expiratory volume in one second and forced expiratory flow at 50% of the vital capacity, peak expiratory flow parameters, and blood eosinophil counts in exercise-induced bronchospasm in children with mild asthma.

Background Exercise-induced bronchoconstriction (EIB), which describes acute airway narrowing that occurs as a result of exercise, is associated with eosinophilic airway inflammation, bronchial hyperresponsiveness. The forced expiratory volume in one second (FEV1) is the most commonly used spirometric test in the diagnosis of EIB in exercise challenge in asthma. Other parameters such as forced expiratory flow at 50% of the vital capacity (FEF50%) and peak expiratory flow (PEF) are used less often in the diagnosis of EIB. Objective The purpose of this study is to evaluate the association of FEV1 and FEF50%, PEF parameters, blood eosinophil counts in EIB in children with mild asthma. Methods Sixty-seven children (male: 39, female: 28) with mild asthma were included in this study. Pulmonary functions were assessed before and at 1, 5, 10, 15, and 20 minutes after exercise. The values of spirometric FEV1, FEF50%, PEF, and blood eosinophil counts were evaluated in EIB in children with mild asthma. Results There was a positive correlation between FEV1 with FEF50% and PEF values (p<0.05; FEF50%, r=0.68; PEF, r=0.65). Also, a positive correlation was found between blood eosinophil counts and the values of spirometric FEV1, FEF50%, and PEF (p<0.05; FEV1, r=0.54; FEF50%, r=0.42; PEF, r=0.26). In addition to these correlations, in the exercise negative group for FEV1, the FEF50% and PEF values decreased more than the cutoff values in 3, and 2 patients, respectively. Conclusion According to the presented study, eosinophil may play a major role in the severity of EIB in mild asthma. FEF50% and PEF values can decrease in response to exercise without changes in FEV1 in mild asthmatic patients.

Effect of montelukast on clinical score and cytokine levels of infants for clinically diagnosed acute bronchiolitis

BACKGROUND Acute bronchiolitis comprises a major cause for morbidity in infants with viral infection which induces an immune inflammatory response that may produce long lasting harmful effects. Currently, there is no effective therapy for bronchiolitis. OBJECTIVE Our aim was to investigate the efficacy of five-day montelukast therapy in acute bronchiolitis management. METHODS The study included 50 infants with acute bronchiolitis. The infants with first episode of acute bronchiolitis were randomly assigned to receive daily montelukast dose of 4mg over five days after admission or no treatment. Plasma eotaxin, IL-4, IL-8 and IFN-gamma levels were evaluated before and after treatment by ELISA method. In the present study, the primary outcome measure was change in clinical severity score, whilst secondary outcome measures were changes in plasma eotaxin, IL-4, IL-8, IFN-gamma levels. RESULTS No significant differences was found in clinical severity score with five-day montelukast treatment (p>0.05, Mann-Whitney U test). There were no significant differences in plasma eotaxin, IL-4, IL-8, IFN-gamma levels between the groups (p>0.05 Mann-Whitney U test). There was significant decrease in plasma IFN-gamma levels following five-day montelukast treatment (p=0.027, Wilcoxon). There were no significant differences in plasma IL-4, IL-8, IFN-gamma levels between the groups after five-day montelukast treatment (p>0.05, Wilcoxon). There was significant increase in eotaxin levels after five-day montelukast treatment (p=0.009, Wilcoxon). CONCLUSION Our study showed that montelukast affected plasma IFN-gamma and eotaxin levels after five days of treatment. Further studies are needed to demonstrate effects of montelukast on chemokine levels in bronchiolitis.

Hashimoto thyroiditis associated with ataxia telangiectasia.

Abstract Ataxia telangiectasia is a rare genetic disease characterized by neurological manifestations, infections, and cancers. In addition to these cardinal features, different autoimmune diseases can be seen in patients with ataxia telangiectasia. Although there were reports of positive autoimmune thyroid antibodies associated with ataxia telangiectasia, to our knowledge, we report the first cases of nodular Hashimoto thyroiditis in two patients with ataxia telangiectasia in the English medical literature. These cases illustrate that despite the rarity of nodular Hashimoto thyroiditis associated with ataxia telangiectasia, physicians should be aware of this possibility. Furthermore, thyroid examination of patient with ataxia telangiectasia is recommended for early diagnosis.

The plasma gelsolin levels in atopic dermatitis: Effect of atopy and disease severity

BACKGROUND Gelsolin is an actin-binding protein with several cellular functions including anti-apoptosis and is reported to have an anti-inflammatory effect. Apoptosis of keratinocytes has been implicated as a key mechanism of atopic dermatitis (AD). OBJECTIVE We aimed to determine plasma gelsolin (pGSN) levels in children with atopic dermatitis (AD). METHOD The diagnosis of AD was made according to Hanifin and Rajka criteria. The disease severity was scored by objective SCORAD index by the same allergist. Skin prick testing (SPT), total IgE levels, and eosinophil counts were analyzed. The pGSN levels were determined using ELISA technique. RESULTS Children aged between 0.5 and 3.0 years were included in the study. The children with AD (AD; n=84) were analyzed in two groups according to the presence (AD+/Atopy+; n=54) or absence of SPT positivity (AD+/Atopy-; n=30). The comparisons were made with a healthy control group matched for age and sex (n=81). The median (interquartile range) of pGSN levels in AD+/A+, AD+/A- and control groups were 267μg/ml (236-368), 293 (240-498) and 547 (361-695), respectively (p<0.001). The difference between the control group and AD sub-groups remained significant after Bonferroni correction (p<0.001). Correlation analysis failed to reach significance with the disease severity total IgE levels and eosinophil counts. CONCLUSION This is the first study investigating the association of pGSN levels with AD and disease severity. pGSN levels decreased in AD. These findings suggest that gelsolin may have a role in the disease process in AD patients.