X-linked agammaglobulinemia: investigation of clinical and laboratory findings, novel gene mutations and prevention of infective complications in long-term follow-up.

Introduction-Objective: X-linked agammaglobulinemia (XLA) is a primary immunodeficiency disease predominantly with antibody deficiency and characterized by recurrent pyogenic infections, absence of B cells and agammaglobulinemia. In this study, it is aimed to review the demographic data of our XLA patients and examine the frequency of severe bacterial and mild infections and benefits of immunoglobulin replacement therapies to reduce the rate of infections. In addition, correlations between genotypic results and clinical and laboratory findings were searched. PATIENTS AND METHODS: In this study, 20 patients who were followed-up between 1995-2019 and diagnosed with XLA by flow cytometric and genetic tests were included. Demographic data, symptoms at admission and follow-up, laboratory data and radiologic imaging findings, previous infections, immunoglobulin replacement treatments, and genetic analysis results of the patients were recorded. RESULTS: All patients in the study were male and the mean age of onset of symptoms was 60 months. The mean age at diagnosis was 72 months. A total of 19 different mutations were identified in the Bruton-tyrosine kinase gene, six of them were novel. Our eldest patient was 34 years old and the longest follow-up period was 24 years. Respiratory tract infections were the most common in the patients, only 35% of the causative agents were found in sputum cultures and H. influenzae type b (57.8%) was isolated most frequently. Both intravenous and subcutaneous immunoglobulin replacement therapies significantly reduced the number of severe bacterial infections and other mild infections. CONCLUSION: XLA is a rare pediatric primary immunodeficiency disease and affected individuals require lifelong immunoglobulin replacement therapy. Immunoglobulin replacement prevents life-threatening infections and dramatically increases survival rates. The patients with regular treatment and follow-up, reach adulthood and has a high quality of life.

Early diagnosis effects the prognosis in children with atypical wheeze.

AIM: Recurrent wheezing is a common problem in preschool children.It is classified into two groups because there can be many reasons for wheeze: typical and atypical. The aim of this study was to identify the general features of atypical wheezy children. MATERIAL AND METHODS: Three hundred two children who presented to our clinic between 2000 and 2015 for three or more wheezing attacks and were diagnosed as having an underlying disease such as bronchiectasis, foreign body aspiration, recurrent aspiration pneumonia, cystic fibrosis, bronchopulmonary dysplasia, congenital anomalies, and tuberculosis, were included in the study. RESULTS: In this study, 127 (42.1%) girls and 175 (57.9%) boys were evaluated. The diagnostic distribution of the patients was as follows: bronchopulmonary dysplasia (21.9%), bronchiolitis obliterans (16.6%), bronchiectasis (14.5%), bronchiolitis obliterans + primary immunodeficiency (12.3%), cystic fibrosis (10.3%), bronchiectasis + primary immunodeficiency (7.9%), recurrent aspiration pneumonia (3.6%) and foreign body aspiration (3.3%), and other diseases (9.6%). Mosaic oligemia, bronchiectasis, atelectasis, bronchiolectasis, and small airway disease were the most distinct findings on high-resolution lung tomography. When the patients were evaluated clinically, radiologically, and according to pulmonary functions after an average period of 40 months, it was seen that 9.2% deteriorated, 33.9% regressed, and 56.7% remained stable. Presentation to hospital after the first attack occurred earlier in patients with bronchopulmonary dysplasia, bronchiolitis obliterans and bronchiolitis obliterans + primary immunodeficiency compared with patients with bronchiectasis, bronchiectasis + primary immunodeficiency, and cystic fibrosis. When presentation time and outcomes were evaluated, it was found that 63.4% of patients who presented to hospital early (0-6 months) and 7.5% of patients who presented late (after 5 years) had regression. CONCLUSION: Recurrent wheezy children must be promptly evaluated for an underlying disease. Early diagnosis and treatment influence the prognosis.

Structural Characteristics in the γ Chain Variants Associated with Fibrinogen Storage Disease Suggest the Underlying Pathogenic Mechanism.

Particular fibrinogen γ chain mutations occurring in the γ-module induce changes that hamper γ-γ dimerization and provoke intracellular aggregation of the mutant fibrinogen, defective export and plasma deficiency. The hepatic storage predisposes to the development of liver disease. This condition has been termed hereditary hypofibrinogenemia with hepatic storage (HHHS). So far, seven of such mutations in the fibrinogen γ chain have been detected. We are reporting on an additional mutation occurring in a 3.5-year-old Turkish child undergoing a needle liver biopsy because of the concomitance of transaminase elevation of unknown origin and low plasma fibrinogen level. The liver biopsy showed an intra-hepatocytic storage of fibrinogen. The molecular analysis of the three fibrinogen genes revealed a mutation (Fibrinogen Trabzon Thr371Ile) at exon 9 of the γ chain in the child and his father, while the mother and the brother were normal. Fibrinogen Trabzon represents a new fibrinogen γ chain mutation fulfilling the criteria for HHHS. Its occurrence in a Turkish child confirms that HHHS can present in early childhood and provides relevant epidemiological information on the worldwide distribution of the fibrinogen γ chain mutations causing this disease. By analyzing fibrinogen crystal structures and calculating the folding free energy change (ΔΔG) to infer how the variants can affect the conformation and function, we propose a mechanism for the intracellular aggregation of Fibrinogen Trabzon and other γ-module mutations causing HHHS.

Familial inheritance and screening of first-degree relatives in common variable immunodeficiency and immunoglobulin A deficiency patients.

Common variable immunodeficiency (CVID) and immunoglobulin A deficiency (IgAD) are the most prevalent primary immunodeficiency disorders. High rates of familial inheritance have been described in CVID and IgAD, but it is unknown in different ethnic populations. We aimed to determine the prevalence of familial cases and whether they showed more severe clinical characteristics than sporadic ones in Turkish patients. A total of 40 CVID and 70 IgAD patients and their 251 first-degree relatives (FDRs) were evaluated. Demographic, clinical, and laboratory data were reviewed. A familial case was defined as a patient with at least one affected FDR (A-FDR). The rate of parental consanguinity was 19.1%. There were 37 familial cases (37/110) (33.6%) with at least one A-FDR. There were 48 A-FDRs who had immunoglobulins lower than age-related normals (48/251) (19.1%). Pulmonary infections were significantly higher in familial cases. To our knowledge, this study includes the highest number of CVID/IgAD patients and their FDRs in literature. Familial cases are at least 30% of the IgAD and CVID patients, and they have more frequent lower respiratory tract infections than sporadic ones, so these patients have to be evaluated depending on their being familial or sporadic for better management. The risk of carrying any immunologic alterations in relatives of patients with IgAD and CVID is approximately 20%. Although most A-FDRs are asymptomatic, considering the risk of progression to CVID by age, we highly recommend routine screening for FDRs.