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BACKGROUND: The inborn errors of immunity (IEIs) are a group of heterogeneous disorders mainly characterized by severe and recurrent infections besides other complications including autoimmune and inflammatory diseases. In this study, we aim to evaluate clinical, immunological, and molecular data of monogenic IEI patients with and without autoimmune manifestations. METHODS: We have retrospectively screened cases of monogenic IEI in the Iranian PID registry for the occurrence of autoimmunity and immune dysregulation. A questionnaire was filled for all qualified patients with monogenic defects to evaluate demographic, laboratory, clinical, and molecular data. RESULTS: A total of 461 monogenic IEI patients (290 male and 171 female) with a median (IQR) age of 11.0 (6.0-20.0) years were enrolled in this study. Overall, 331 patients (72.1) were born to consanguineous parents. At the time of the study, 330 individuals (75.7) were alive and 106 (24.3) were deceased. Autoimmunity was reported in 92 (20.0) patients with a median (IQR) age at autoimmune diagnosis of 4.0 (2.0-7.0) years. Sixteen patients (3.5) showed autoimmune complications (mostly autoimmune cytopenia) as the first presentation of the disease. Most of the patients with autoimmunity were diagnosed clinically with common variable immunodeficiency (42.4). The frequency of sinusitis and splenomegaly was significantly higher in patients with autoimmunity than patients without autoimmunity. In patients with autoimmunity, the most common pathogenic variants were identified in LRBA (in 21 patients, 23.0), ATM (in 13 patients, 14.0), and BTK (in 9 patients, 10.0) genes. In the evaluation of autoimmunity by different genes, 4 of 4 IL10RB (100), 3 of 3 AIRE (100), 21 of 30 LRBA (70.0) mutated genes had the highest prevalence of autoimmunity. CONCLUSIONS: Autoimmune phenomena are common features among patients with monogenic IEI and are associated with a more complicated course of the disease. Therefore, when encountering autoimmune disorders especially in the setting of dysgammaglobulinemia, it would be appropriate to conduct next generation sequencing (due to phenocopies of IEI genes) to discover responsible genes for the immune dysregulation at an early stage of the disease.

Protein kinase C is a family of serine/threonine kinases that play a key role in the adaptive immune cell signaling, as well as regulation of growth, apoptosis, and differentiation of a variety of cell types. Patients homozygous for a null mutation of the Protein Kinase C DeltaThe data were collected by direct interview and examining the patient's clinical record. Whole-exome sequencing was performed to detect the underlying genetic mutation in the patient. We also conducted electronic searches for ALPS-like reported patients in PubMed, Web of Science, and Scopus databases.In this study, we reported a 13-year-old boy who presented with autoimmunity, lymphoproliferation, recurrent pneumonia, cardiomyopathy, and dermatological manifestations. An elevation of double-negative T cells, CD8PRKCD should be considered in the context of ALPS clinical manifestations with prominent dermatological involvements.

Asthma, as the most common chronic disease in children, encompasses substantial health and socioeconomic burden worldwide. This study aimed to evaluate the prevalence, severity, and management of asthma in adolescents aged 13-14 years. This cross-sectional study, which was part of the Global Asthma Network (GAN) 2020 survey, was conducted in early 2020 in Yazd, Iran. A total of 48 schools in Yazd city were selected by cluster sampling. In this study, 5141 students, including 3069 (59.7%) females and 2072 (40.3%) males participated. Prevalence of ever and current wheezing was 19% and 9% respectively. The former was significantly higher in males than females (p

Background: Common variable immunodeficiency (CVID) is the most frequent primary immunodeficiency disorder mainly characterized by recurrent bacterial infections besides other immunological defects including loss of or dysfunction of B cells and decreased immunoglobulin levels. In this study, our aim is to evaluate clinical, immunological, and molecular data of patients with a primary clinical diagnosis of CVID and autoimmune phenotype with a confirmed genetic diagnosis. Methods: Among 297 patients with CVID, who were registered in the Iranian Primary Immunodeficiency Registry at Children’s Medical Center Hospital in Iran, 83 patients have been genetically examined and 27 patients with autoimmunity and confirmed genetic mutations were selected for analysis. Whole-exome sequencing and confirmatory Sanger sequencing methods were used for the study population. A questionnaire was retrospectively filled for all patients to evaluate demographic, laboratory, clinical, and genetic data. Results: In the 27 studied patients, 11 different genetic defects were identified, and the most common mutated gene was LRBA, reported in 17 (63.0%) patients. Two patients (7.7%) showed autoimmune complications as the first presentation of immunodeficiency. Eleven patients (40.7%) developed one type of autoimmunity, and 16 patients (59.3%) progressed to poly-autoimmunity. Most of the patients with mono-autoimmunity (n = 9, 90.0%) primarily developed infectious complications, while in patients with poly-autoimmunity, the most common first presentation was enteropathy (n = 6, 37.6%). In 13 patients (61.9%), the diagnosis of autoimmune disorders preceded the diagnosis of primary immunodeficiency. The most frequent autoimmune manifestations were hematologic (40.7%), gastrointestinal (48.1%), rheumatologic (25.9%), and dermatologic (22.2%) disorders. Patients with poly-autoimmunity had lower regulatory T cells than patients with mono-autoimmunity. Conclusion: In our cohort, the diagnosis of autoimmune disorders preceded the diagnosis of primary immunodeficiency in most patients. This association highlights the fact that patients referring with autoimmune manifestations should be evaluated for humoral immunity.

The number of inherited diseases and the spectrum of clinical manifestations of primary immunodeficiency disorders (PIDs) are ever-expanding. Molecular diagnosis using genomic approaches should be performed for all PID patients since it provides a resource to improve the management and to estimate the prognosis of patients with these rare immune disorders. The current update of Iranian PID registry (IPIDR) contains the clinical phenotype of newly registered patients during last 5 years (2013–2018) and the result of molecular diagnosis in patients enrolled for targeted and next-generation sequencing. Considering the newly diagnosed patients (n = 1395), the total number of registered PID patients reached 3056 (1852 male and 1204 female) from 31 medical centers. The predominantly antibody deficiency was the most common subcategory of PID (29.5%). The putative causative genetic defect was identified in 1014 patients (33.1%) and an autosomal recessive pattern was found in 79.3% of these patients. Among the genetically different categories of PID patients, the diagnostic rate was highest in defects in immune dysregulation and lowest in predominantly antibody deficiencies and mutations in the MEFV gene were the most frequent genetic disorder in our cohort. During a 20-year registration of Iranian PID patients, significant changes have been observed by increasing the awareness of the medical community, national PID network establishment, improving therapeutic facilities, and recently by inclusion of the molecular diagnosis. The current collective study of PID phenotypes and genotypes provides a major source for ethnic surveillance, newborn screening, and genetic consultation for prenatal and preimplantation genetic diagnosis.

Background Combined immunodeficiencies (CIDs) are diseases of defective adaptive immunity with diverse clinical phenotypes. Although CIDs are more prevalent in the Middle East than Western countries, the resources for genetic diagnosis are limited. Objectives This study aims to characterize the categories of patients with CIDs in Iran clinically and genetically. Methods Clinical and laboratory data were obtained from 696 patients with CIDs. Patients were subdivided into those with syndromic (344 patients) and nonsyndromic (352 patients) CIDs. Targeted DNA sequencing was performed on 243 (34.9%) patients. Results The overall diagnostic yield of the 243 sequenced patients was 77.8% (189 patients). The clinical diagnosis of hyper-IgE syndrome ( P P = .02), and absence of multiple affected family members ( P = .04) were significantly more frequent in the patients without a genetic diagnosis. An autosomal recessive disease was found in 62.9% of patients, reflecting the high rate of consanguinity in this cohort. Mutations impairing VDJ recombination and DNA repair were the most common underlying causes of CIDs. However, in patients with syndromic CIDs, autosomal recessive mutations in ataxia-telangiectasia mutated (ATM) , autosomal dominant mutations in signal transducer and activator of transcription 3 (STAT3) , and microdeletions in 22q11.21 were the most commonly affected genomic loci. Patients with syndromic CIDs had a significantly lower 5-year survival rate rather than those with nonsyndromic CIDs. Conclusions This study provides proof of principle for the application of targeted next-generation sequencing panels in countries with limited diagnostic resources. The effect of genetic diagnosis on clinical care requires continued improvements in therapeutic resources for these patients.

Background. Primary immunodeficiency diseases (PIDs) are life-threatening disorders, which manifest commonly with gastrointestinal (GI) signs, mainly as chronic diarrhea. Objective. To investigate and compare infectious etiology of chronic diarrhea in different PIDs. Patients and methods. Assessing clinical features, obtaining immunological profiles, as well as characterizing infectious etiology of diarrhea were performed in 38 PID patients with chronic diarrhea. Stool samples and/or biopsy specimens were checked using culture, microscopic examination, RT-PCR, and PCR, as appropriate. The patients were diagnosed to have common variable immunodeficiency (CVID), severe combined immunodeficiency (SCID), X-linked agammaglobulinemia (XLA), and hyper-IgM (HIgM) syndrome. Results. In 32 patients we identified 41 infectious agents including 16 parasitic (39.0, the most common Giardia lamblia), 11 bacterial (26.8, the most common salmonella spp), 8 viral (19.5, the most frequent group A rotavirus), and 6 fungal organisms (14.7, the most common Candida albicans). From 6 of the patients, no infectious agent was isolated. In CVID bacteria and parasites, in SCID bacteria and viruses, in XLA parasites, and in individuals with HIgM syndrome parasites were the leading causes of chronic diarrhea. Infection with giardia and cryptosporidium were more frequent in XLA and HIgM, respectively. Conclusion. The current study suggests considering both usual and unusual pathogens in laboratory investigation and in the empiric treatment of chronic diarrhea. Opportunistic pathogens should be taken into account when no other pathogen is identified, especially in patients on long-term treatment or prophylaxis with antifungals/antibiotics and in those from geographical locations that favor pathogenicity of these organisms. © 2019, EDRA S.p.A. All rights reserved.

BACKGROUND: Predominantly antibody deficiencies (PADs) are the most common primary immunodeficiencies, characterized by hypogammaglobulinemia and inability to generate effective antibody responses. OBJECTIVE: We intended to report most common monogenic PADs and to investigate how patients with PAD who were primarily diagnosed as suffering from agammaglobulinemia, hyper-IgM (HIgM) syndrome, and common variable immunodeficiency (CVID) have different clinical and immunological findings. METHODS: Stepwise next-generation sequencing and Sanger sequencing were performed for confirmation of the mutations in the patients clinically diagnosed as suffering from agammaglobulinemia, HIgM syndrome, and CVID. RESULTS: Among 550 registered patients, the predominant genetic defects associated with agammaglobulinemia (48 Bruton's tyrosine kinase BTK and 6 mu heavy chain deficiencies), HIgM syndrome (21 CD40 ligand and 7 activation-induced cytidine deaminase deficiencies), and CVID (17 lipopolysaccharides-responsive beige-like anchor deficiency and 12 atypical Immunodeficiency, Centromeric instability, and Facial dysmorphism syndromes) were identified. Clinical disease severity was significantly higher in patients with mu heavy chain and CD40 ligand mutations compared with patients with BTK (P = .003) and activation-induced cytidine deaminase (P = .009) mutations. Paralysis following live polio vaccination was considerably higher in patients with mu heavy chain deficiency compared with BTK deficiency (P < .001). We found a genotype-phenotype correlation among patients with BTK mutations regarding clinical manifestation of meningitis and chronic diarrhea. Surprisingly, we noticed that first presentations in most patients with Immunodeficiency, Centromeric instability, and Facial dysmorphism were respiratory complications (P = .008), whereas first presentations in patients with lipopolysaccharides-responsive beige-like anchor deficiency were nonrespiratory complications (P = .008). CONCLUSIONS: This study highlights similarities and differences in the clinical and genetic spectrum of the most common PAD-associated gene defects. This comprehensive comparison will facilitate clinical decision making, and improve prognosis and targeted treatment.

Central venous pressure (CVP) measurement is a reliable method for evaluating intravascular volume status and cardiac function, but it is an invasive method that results in some complications such as arterial puncture, pneumothorax, and development of infection. The current study was performed to compare CVP measurements between central and peripheral catheters in infants and children with congenital heart disease referred for right-sided heart catheterization. The CVP and peripheral venous pressure (PVP) in 45 patients were measured simultaneously. The mean difference between CVPs measured from the central and peripheral catheters was 8 +/- 4 cm H(2)O. The linear regression equation showed that CVP = 0.32 PVP + 3.8 (r = 0.67; p0.005). There was no difference in CVP measurements depending on the intravenous cannula and chest diameters, arm diameter, arm length, body surface area, patient's age (or =10 years and10 years), and type of congenital heart disease (cyanotic or noncyanotic). In conclusion, although CVP measured from a peripheral intravenous catheter in infants and children with congenital heart disease is not as accurate as the measurement in adults, the aforementioned linear regression equation based on measurement of PVP gives a reliable estimate of CVP.

Common variable immune deficiency (CVID) is the most frequent form of symptomatic primary immunodeficiency disease, characterized by hypogammaglobulinemia, recurrent infections and increased predisposition to autoimmunity and malignancies. The aim of this study was to reconsider important points of previously performed studies on Iranian CVID patients diagnosed and followed from 1984 to 2013.Diagnosis was made using approved criteria including reductions of serum levels of immunoglobulins and exclusion of well-known single gene defects in individuals with an age4 years and evidence of specific antibody deficiency.Detailed information on demographic data, survival rates, clinical phenotypes, immunologic and genetic data and treatment of 173 patients are provided. The early onset presentation (74.5%) and rate of consanguineous marriage (61.2%) were considerably higher in our cohort. Our study revealed clinically related correlations regarding consanguinity, the population of naïve CD4(+) T cells and switched-memory B cells, cytokine levels and special genetic factors (including HLA and AID genes).Despite current efforts, more comprehensive studies are needed, especially for classification and investigation of the genetic background and prognostic factors for patients with CVID in order to better managment and followup of patinets.

Although autoimmunity phenotype is surprisingly common in patients with different types of primary antibody deficiency, it is much less frequent in X-linked agammaglobulinemia (XLA). Herein, we report on a 15-month-old boy with XLA who also suffered from Kawasaki disease. The current case presentation is the first report of an association between Kawasaki disease and XLA. XLA could be considered as a special opportunity to understand autoimmunity in the near absence of immunoglobulins.

Atopic dermatitis (AD) is a chronic skin disorder of unknown origin that usually manifests for the first time in early infancy. Different types of genetic predisposition and environmental factors seem to be associated with the disease.This study was performed to evaluate the frequency of alleles, genotypes, and haplotypes of interleukin (IL) 6 single-nucleotide polymorphisms (SNPs) at positions -174 and nt565 in 89 Iranian children with AD and 139 healthy controls.The G allele was significantly more frequent at position -174 in IL6 in atopic patients than in the healthy controls (P.001; OR, 2.82). Genotype GG was found at the same position in 71% of the patients; this frequency was significantly higher than the frequency of 30% recorded in the controls (P.001; OR, 5.60). The GG haplotype of IL6 (-174, nt565) was significantly more frequent in the atopic patients than in the healthy controls (P.001; OR, 2.99).A significant increase in the frequency of the G allele and GG genotype at position -174 of IL6 was found in patients with AD, thus suggesting that production of this cytokine is greater in atopic patients.