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Patients with very early-onset inflammatory bowel disease (VEO-IBD) may present because of underlying monogenic inborn errors of immunity (IEI). Strong differences have been observed in the causes of monogenic IBD among ethnic populations. This multicenter study was carried out on 16 Iranian patients with VEO-IBD. We reviewed clinical and basic immunologic evaluation including flow cytometry and immunoglobulin levels. All patients underwent clinical whole exome sequencing (WES). Sixteen patients (8 females and 8 males) with a median age of 43.5 months were enrolled. The median age at the onset of symptoms was 4 months. Most patients (12, 75%) had consanguineous parents. Chronic non-bloody diarrhea (13, 81.3%) and perianal diseases including perianal abscess (6, 37.5%), anal fissure (6, 37.5%), or anal fistula (2, 12.5%) were the most common manifestations. WES identified a spectrum of genetic variants in 13 patients (81.3%): IL10RB (6, 37.5%), MVK (3, 18.8%), and CASP8, SLC35C1, G6PC3, and IKBKB in 1 patient, respectively. In 3 patients (18.7%), no variant was identified. Flow cytometry identified a spectrum of abnormalities that helped to assess the evidence of genetic diagnosis. At the end of the survey, 3 (18.8%) patients were deceased. This high rate of monogenic defects with a broad spectrum of genes reiterates the importance of investigating IEI in patients with infantile-onset IBD.
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Secuenciación del Exoma , Enfermedades Inflamatorias del Intestino , Humanos , Masculino , Femenino , Irán , Enfermedades Inflamatorias del Intestino/genética , Preescolar , Lactante , Edad de Inicio , Niño , Pruebas Genéticas/métodos , Estudios de Cohortes , Mutación , Quinasa I-kappa B/genética , Consanguinidad , Receptores de Interleucina-10/genéticaRESUMEN
We describe humans with rare biallelic loss-of-function PTCRA variants impairing pre-α T cell receptor (pre-TCRα) expression. Low circulating naive αß T cell counts at birth persisted over time, with normal memory αß and high γδ T cell counts. Their TCRα repertoire was biased, which suggests that noncanonical thymic differentiation pathways can rescue αß T cell development. Only a minority of these individuals were sick, with infection, lymphoproliferation, and/or autoimmunity. We also report that 1 in 4000 individuals from the Middle East and South Asia are homozygous for a common hypomorphic PTCRA variant. They had normal circulating naive αß T cell counts but high γδ T cell counts. Although residual pre-TCRα expression drove the differentiation of more αß T cells, autoimmune conditions were more frequent in these patients compared with the general population.
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Autoinmunidad , Linfocitos Intraepiteliales , Glicoproteínas de Membrana , Receptores de Antígenos de Linfocitos T alfa-beta , Humanos , Autoinmunidad/genética , Diferenciación Celular , Homocigoto , Linfocitos Intraepiteliales/inmunología , Receptores de Antígenos de Linfocitos T alfa-beta/genética , Glicoproteínas de Membrana/genética , Mutación con Pérdida de Función , Recuento de Linfocitos , Alelos , Infecciones/inmunología , Trastornos Linfoproliferativos/inmunología , Linaje , Masculino , Femenino , Persona de Mediana Edad , Anciano , Anciano de 80 o más AñosRESUMEN
BACKGROUND: Inborn errors of immunity (IEI) are a diverse range of genetic immune system illnesses affecting the innate and/or adaptive immune systems. Variable expressivity and incomplete penetrance have been reported in IEI patients with similar clinical diagnoses or even the same genetic mutation. METHODS: Among all recorded patients in the national IEI registry, 193 families with multiple cases have been recognized. Clinical, laboratory and genetic variability were compared between 451 patients with different IEI entities. RESULTS: The diagnosis of the first children led to the earlier diagnosis, lower diagnostic delay, timely treatment and improved survival in the second children in the majority of IEI. The highest discordance in familial lymphoproliferation, autoimmunity and malignancy were respectively observed in STK4 deficiency, DNMT3B deficiency and ATM deficiency. Regarding immunological heterogeneity within a unique family with multiple cases of IEI, the highest discordance in CD3+, CD4+, CD19+, IgM and IgA levels was observed in syndromic combined immunodeficiencies (CID), while non-syndromic CID particularly severe combined immunodeficiency (SCID) manifested the highest discordance in IgG levels. Identification of the first ATM-deficient patient can lead to improved care and better survival in the next IEI children from the same family. CONCLUSION: Intrafamilial heterogeneity in immunological and/or clinical features could be observed in families with multiple cases of IEI indicating the indisputable role of appropriate treatment and preventive environmental factors besides specific gene mutations in the variable observed penetrance or expressivity of the disease. This also emphasizes the importance of implementing genetic evaluation in all members of a family with a history of IEI even if there is no suspicion of an underlying IEI as other factors besides the underlying genetic defects might cause a milder phenotype or delay in presentation of clinical features. Thus, affected patients could be timely diagnosed and treated, and their quality of life and survival would improve.
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Diagnóstico Tardío , Calidad de Vida , Niño , Humanos , Proteínas Adaptadoras Transductoras de Señales , Antígenos CD19 , Autoinmunidad , Proteínas Serina-Treonina Quinasas , Péptidos y Proteínas de Señalización IntracelularRESUMEN
BACKGROUND: In order to support the comprehensive classification of Leukocyte Adhesion Deficiency-I (LAD-I) severity by simultaneous screening of CD11a/CD18, this study assessed clinical, laboratory, and genetic findings along with outcomes of 69 LAD-I patients during the last 15 years. METHODS: Sixty-nine patients (40 females and 29 males) with a clinical phenotype suspected of LAD-I were referred to Immunology, Asthma, and Allergy research institute, Tehran, Iran between 2007 and 2022 for further advanced immunological screening and genetic evaluations as well as treatment, were enrolled in this study. RESULTS: The diagnosis median age of the patients was 6 months. Delayed umbilical cord separation was found in 25 patients (36.2%). The median diagnostic delay time was 4 months (min-max: 0-82 months). Forty-six patients (66.7%) were categorized as severe (CD18 and/or CD11a: below 2%); while 23 children (33.3%) were in moderate category (CD18 and/or CD11a: 2%-30%). During the follow-ups, 55.1% of children were alive with a mortality rate of 44.9%. Skin ulcers (75.4%), omphalitis (65.2%), and gingivitis (37.7%) were the most frequent complaints. Genetic analysis of the patients revealed 14 previously reported and three novel pathogenic mutations in the ITGB2 gene. The overall survival of patients with and without hematopoietic stem cell transplantation was 79.3% and 55.6%, respectively. CONCLUSION: Physicians' awareness of LAD-I considering delayed separation of umbilical cord marked neutrophilic leukocytosis, and variability in CD11 and CD18 expression levels, and genetic analysis leads to early diagnosis and defining disease severity. Moreover, the prenatal diagnosis would benefit families with a history of LAD-I.
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Antígenos CD18 , Síndrome de Deficiencia de Adhesión del Leucocito , Masculino , Embarazo , Femenino , Humanos , Antígenos CD18/genética , Síndrome de Deficiencia de Adhesión del Leucocito/diagnóstico , Síndrome de Deficiencia de Adhesión del Leucocito/genética , Diagnóstico Tardío , Irán , Leucocitos/metabolismoRESUMEN
BACKGROUND: DCLRE1C gene mutation leads to Artemis deficiency, a severe form of combined immunodeficiency (SCID). Impaired DNA repair and block in early adaptive immunity maturation results in T-B-NK+ immunodeficiency associated with radiosensitivity. Recurrent infections early in life are the main characteristic of Artemis patients. METHOD: Among 5373 registered patients, 9 Iranian patients (33.3% female) with confirmed DCLRE1C mutation were identified since 1999-2022. The demographic, clinical, immunological and genetic features were collected through retrospective investigation of medical records and using next generation sequencing. RESULTS: Seven patients were born in a consanguineous family (77.8%). The median age of onset was 6.0 (5.0-17.0) months. Severe combined immunodeficiency (SCID) was clinically detected at a median (IQR) age of 7.0 (6.0-20.5) months, following a median diagnostic delay of 2.0 (1.0-3.5) months The most typical first presentation was pneumonia (44.4%) and otitis media (3.33%), followed by BCG lymphadenitis (22.2%) and gastroenteritis (11.1%). The most prevalent manifestations were respiratory tract infections (including otitis media) (66.6%) and chronic diarrhea (66.6%). In addition, juvenile idiopathic arthritis (P5) and celiac disease and idiopathic thrombocytopenic purpura (P9) as autoimmune disorders were reported in 2 patients. All patients had reduced B CD19+ and CD4+ cell counts. IgA deficiency occurred in 77.8% of individuals. CONCLUSION: Recurrent infections particulary respiratory tract infection and chronic diarrhea during the first months of life in patients born to consanguineous parents should raise the suspicion for inborn errors of immunity, even in the presence of normal growth and development.
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BACKGROUND: Mendelian susceptibility to mycobacterial disease (MSMD) is an uncommon disorder with increased susceptibility to less virulent mycobacteria including bacillus Calmette-Guérin (BCG). Fibrosing mediastinitis (FM) is also a rare condition defined by excessive fibrotic reactions in the mediastinum. So far, some infectious organisms and autoimmune diseases have been introduced as possible etiologies of FM. However, no study has ever discussed the possible association of BCG infection and FM. CASE PRESENTATION: In this study, we report a 3-year-old female presenting with persistent fever, weakness, and bloody diarrhea in addition to mediastinal lymphadenopathy, hepatosplenomegaly, and pleural and pericardial effusion. Further examinations established a diagnosis of MSMD based on her clinical condition, immunologic data, positive tests for mycobacterial species, positive family history, and genetic study (IL12RB1 gene, c.G1193C, p.W398S). A year and a half later, she was referred with submandibular lymphadenitis and underwent immunologic work-up which revealed high inflammatory indices, a slight reduction in numbers of CD3 + and CD4 + cells as well as elevated CD16/56 + cell count and hyperimmunoglobulinemia. Purified protein derivative (PPD), QuantiFERON, and gastric washing test were all negative. Her chest computed tomography (CT) scan revealed suspicious para-aortic soft tissue and her echocardiography was indicative of strictures in superior vena cava and pulmonary veins. She further underwent chest CT angiography which confirmed FM development. Meanwhile, she has been treated with anti-mycobacterial agents and subcutaneous IFN-γ. CONCLUSION: In summary, we described a novel case of MSMD in a child presenting with granulomatous FM possibly following BCG infection. This is the first report introducing aberrant BCG infection as the underlying cause of FM. This result could assist physicians in identifying early-onset FM in suspicious cases with MSMD. However, more studies are required to support this matter.
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Background. The etiology of obstructive sleep apnea (OSA) syndrome in children significantly differs from adults. In previous studies, only some of the indices have been investigated using CBCT. This study compares all the measurable indices of airway dimensions and anatomical cephalometric landmarks between children with OSA and healthy ones using cone-beam computed tomography (CBCT). Methods. Dimensions of the airway and cephalometric values were measured on CBCT scans of 50 children aged 8-12 (25 patients with OSA and 25 healthy subjects) and then compared between the two groups. The results of this study were analyzed with independent t test using SPSS 17 at a significance level of P<0.05. Results. Area, length, volume, anteroposterior length, and size of the upper airway in subjects with OSA were lower than those in healthy children, while the average values of SNA, SNB, and ANB in the OSA group were higher than those in the healthy group (P=0.366, P=0.012, and P=0.114, respectively). Also, BaSN, PNS/AD1, and PNS/AD2 measurements in subjects with OSA were lower than healthy subjects (P=0.041, P=0.913, and P=0.015, respectively). In addition, the width and anteroposterior length of the upper airway, SNB, BaSN, PNS/AD1, and PNS/AD2 indices were significantly different between the healthy group and those with OSA (P<0.05). Conclusion. Reduced upper airway dimensions, adenoid tissue enlargement, and cranial base flexion might play an important role in OSA development in children. However, most skeletal variables, such as the anteroposterior relationship of jaws and jaw rotation, were not significantly different between the two groups.
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BACKGROUND: Adenotonsillar hypertrophy (AH) is the most common cause of respiratory obstruction of the upper airway, and tonsillectomy is one of the most frequently performed surgical interventions in children. It has been proposed that medical treatment in an allergic state could decrease the size of AH. Therefore, this study aimed to compare the outcomes of surgery and medical therapies among allergic children with AH. MATERIALS AND METHODS: This case-control study was carried out on 68 children with AH in an allergic state who were referred to the Pediatrics Hospital of Tabriz Medical University. They were divided into two groups and matched according to sex, age, and primary clinical signs and symptoms. Patients received surgery (case group) and medication (control groups) for treated AH. Finally, they were compared according to the results of treatment and recurrence rate. RESULTS: The mean age of children in the case and control groups was 6.3±2.3 and 6.8±2.1 years, respectively. There was no significant difference in improving clinical signs and symptoms between the two groups. In the case group, no improvement of clinical signs and symptoms was observed in one patient compared with two patients in the control group. In the control group, no decrease in the size of the tonsils was observed in three patients. Recurrence of clinical signs of AH was observed in six (17.6%) patients of the control group, and there was a significant difference between the two groups (P0.001). CONCLUSION: Our findings showed no significant differences in the outcomes of the two therapeutic methods for AH in an allergic state. However, medical treatment needs a long time to affect, but surgery can act quickly. Recurrence of AH after medical therapy could occur.
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BACKGROUND: Activated phosphoinositide 3-kinase δ syndrome (APDS) is a recently defined combined primary immunodeficiency disease (PID) characterized by recurrent respiratory tract infections, lymphoproliferation, autoimmunity and lymphoma. Gain-of-function mutations in PIK3CD and loss-of-function of PIK3R1 genes lead to APDS1 and APDS2, respectively. METHODS: Demographic, clinical, immunological and genetic data were collected from medical records of 15 pediatric patients, who were genetically identified using the whole-exome sequencing method. RESULTS: Fifteen patients (6 APDS1 and 9 APDS2) were enrolled in this study. Recurrent respiratory tract infections followed by lymphoproliferation and autoimmunity were the most common manifestations (86.7%, 53.3% and 26.7%, respectively). Five patients (33.3%) had a Hyper-IgM-syndrome-like immunoglobulin profile. In the APDS1 group, splice site and missense mutations were found in half of the patients and the C-lobe domain of PIK3CD was the most affected region (50%). In the APDS2 group, splice site mutation was the most frequent mutation (77.8%) and the inter-SH2 domain was the most affected region of PIK3R1 (66.7%). Mortality rate was significantly higher in APDS2 group (P = .02) mainly due to chronic lung infections. CONCLUSION: Respiratory tract infections and humoral immunodeficiency are commonly the most important complication in pediatric APDS patients, and they can be fatal by ultimately causing catastrophic damage to the structure of lungs. Hence, physicians should be aware of its significance and further work-up of patients with recurrent respiratory tract infections especially in patients with lymphoproliferation. Moreover, delineation of genotype-phenotype associations with disease severity could be helpful in the timely application of appropriate management and patients' survival.
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Síndromes de Inmunodeficiencia , Enfermedades de Inmunodeficiencia Primaria , Niño , Fosfatidilinositol 3-Quinasa Clase I/genética , Humanos , Síndromes de Inmunodeficiencia/genética , Irán , Mutación , Fosfatidilinositol 3-Quinasa/genética , Fosfatidilinositol 3-Quinasas/genética , Enfermedades de Inmunodeficiencia Primaria/genéticaRESUMEN
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, immunologic, 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%), and 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 to discover responsible genes for the immune dysregulation at an early stage of the disease.
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Enfermedades Autoinmunes , Inmunodeficiencia Variable Común , Proteínas Adaptadoras Transductoras de Señales/genética , Adolescente , Adulto , Enfermedades Autoinmunes/epidemiología , Enfermedades Autoinmunes/genética , Autoinmunidad/genética , Niño , Femenino , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Irán/epidemiología , Masculino , Estudios Retrospectivos , Adulto JovenRESUMEN
Ataxia-telangiectasia (AT) is a rare autosomal recessive neurodegenerative multisystem disorder. A minority of AT patients can present late-onset atypical presentations due to unknown mechanisms. The demographic, clinical, immunological and genetic data were collected by direct interview and examining the Iranian AT patients with late-onset manifestations. We also conducted a systematic literature review for reported atypical AT patients. We identified three Iranian AT patients (3/249, 1.2% of total registry) with later age at ataxia onset and slower neurologic progression despite elevated alpha-fetoprotein levels, history of respiratory infections, and immunological features of the syndrome. Of note, all patients developed autoimmunity in which a decrease of naïve T cells and regulatory T cells were observed. The literature searches also summarized data from 73 variant AT patients with atypical presentation indicating biallelic mild mutations mainly lead to an atypical phenotype with an increased risk of cancer. Variant AT patients present with milder phenotype or atypical form of classical symptoms causing under- or mis- diagnosis. Although missense mutations are more frequent, an atypical presentation can be associated with deleterious mutations due to unknown modifying factors.
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Ataxia Telangiectasia/genética , Ataxia/genética , Mutación Missense/genética , Adolescente , Adulto , Ataxia/inmunología , Ataxia Telangiectasia/inmunología , Niño , Preescolar , Femenino , Humanos , Irán , Masculino , Mutación Missense/inmunología , Fenotipo , Linfocitos T Reguladores/inmunología , Adulto Joven , alfa-Fetoproteínas/genética , alfa-Fetoproteínas/inmunologíaRESUMEN
BACKGROUND: X-linked chronic granulomatous disease (X-CGD) is an immunodeficiency disorder caused by defects in the gp91phox subunit that leads to life-threatening infections. We aimed to identify CYBB gene mutations and study clinical phenotypes in Iranian patients with probable X-CGD. METHODS: We studied four unrelated Iranian patients with probable X-CGD and their families recruited in several years. We isolated genomic DNA from whole blood and performed Sanger sequencing in the CYBB gene's coding and flanking regions. We also performed pathogenicity predictions using in silico tools. RESULTS: We detected four different mutations, including a novel insertion mutation in exon 5 (p.Ile117AsnfsX6), in the patient. Bioinformatics analysis confirmed the pathogenic effect of this mutation. We predicted protein modeling and demonstrated lost functional domains. The patient with the insertion mutation presented pneumonia and acute sinusitis during his life. We also detected three other known nonsense mutations (p.Arg157Ter, p.Arg226Ter, and p.Trp424Ter) in the CYBB gene. The patient with p.Arg157Ter developed lymphadenitis and pneumonia. Moreover, the patient with inflammatory bowel disease showed p.Arg226Ter and the patient with tuberculosis presented p.Trp424Ter. We detected different clinical features in the patients compared to other Iranian patients with the same mutations. CONCLUSION: Our results expand the genetic database of patients with X-CGD from Iran and make it much easier and faster to identify patients with X-CGD. Our results also help to detect carriers and enable prenatal diagnosis in high-risk families as a cost-effective strategy.
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Enfermedad Granulomatosa Crónica/etiología , Mutación , NADPH Oxidasa 2/genética , Preescolar , Exones , Femenino , Enfermedad Granulomatosa Crónica/genética , Humanos , Enfermedades Inflamatorias del Intestino/etiología , Enfermedades Inflamatorias del Intestino/genética , Irán , Masculino , Linaje , Neumonía/etiología , Neumonía/genéticaRESUMEN
Although it is estimated that COVID-19 life-threatening conditions may be diagnosed in less than 1:1000 infected individuals below the age of 50, but the real impact of this pandemic on pediatric patients with different types of primary immunodeficiency (PID) is not elucidated. The current prospective study on a national registry of PID patients showed that with only 1.23 folds higher incidence of infections, these patients present a 10-folds higher mortality rate compared to population mainly in patients with combined immunodeficiency and immune dysregulation. Therefore, further management modalities against COVID-19 should be considered to improve the survival rate in these two PID entities using hematopoietic stem cell transplantation and immunomodulatory agents.
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COVID-19/complicaciones , COVID-19/epidemiología , Evaluación del Impacto en la Salud , Enfermedades de Inmunodeficiencia Primaria/complicaciones , Enfermedades de Inmunodeficiencia Primaria/epidemiología , SARS-CoV-2 , COVID-19/diagnóstico , COVID-19/virología , Preescolar , Toma de Decisiones Clínicas , Comorbilidad , Manejo de la Enfermedad , Femenino , Humanos , Lactante , Masculino , Mortalidad , Enfermedades de Inmunodeficiencia Primaria/diagnóstico , Vigilancia en Salud Pública , Índice de Severidad de la EnfermedadRESUMEN
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.
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Proteínas Adaptadoras Transductoras de Señales/genética , Enfermedades Autoinmunes/genética , Inmunodeficiencia Variable Común/genética , Síndromes de Inmunodeficiencia/genética , Mutación/genética , Adolescente , Adulto , Enfermedades Autoinmunes/diagnóstico , Enfermedades Autoinmunes/epidemiología , Autoinmunidad/genética , Niño , Estudios de Cohortes , Inmunodeficiencia Variable Común/diagnóstico , Inmunodeficiencia Variable Común/epidemiología , Diagnóstico Tardío , Femenino , Humanos , Síndromes de Inmunodeficiencia/diagnóstico , Síndromes de Inmunodeficiencia/epidemiología , Irán/epidemiología , Masculino , Secuenciación del Exoma , Adulto JovenRESUMEN
INTRODUCTION: During the last 4 decades, registration of patients with primary immunodeficiencies (PID) has played an essential role in different aspects of these diseases worldwide including epidemiological indexes, policymaking, quality controls of care/life, facilitation of genetic studies and clinical trials as well as improving our understanding about the natural history of the disease and the immune system function. However, due to the limitation of sustainable resources supporting these registries, inconsistency in diagnostic criteria and lack of molecular diagnosis as well as difficulties in the documentation and designing any universal platform, the global perspective of these diseases remains unclear. AREAS COVERED: Published and unpublished studies from January 1981 to June 2020 were systematically reviewed on PubMed, Web of Science and Scopus. Additionally, the reference list of all studies was hand-searched for additional studies. This effort identified a total of 104614 registered patients and suggests identification of at least 10590 additional PID patients, mainly from countries located in Asia and Africa. Molecular defects in genes known to cause PID were identified and reported in 13852 (13.2% of all registered) patients. EXPERT OPINION: Although these data suggest some progress in the identification and documentation of PID patients worldwide, achieving the basic requirement for the global PID burden estimation and registration of undiagnosed patients will require more reinforcement of the progress, involving both improved diagnostic facilities and neonatal screening.
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Enfermedades de Inmunodeficiencia Primaria/inmunología , Sistema de Registros , África/epidemiología , Animales , Asia/epidemiología , Humanos , Recién Nacido , Mutación/genética , Tamizaje Neonatal , Patología Molecular , Prevalencia , Enfermedades de Inmunodeficiencia Primaria/epidemiología , Enfermedades de Inmunodeficiencia Primaria/genéticaRESUMEN
BACKGROUND: Allergic rhinitis (AR) is one of the most common diseases in the world and affects about 10-50% of the general population. Probiotics are live microorganisms that help the normal state of the intestine, and if prescribed correctly, they can stimulate the mucosal immune system to prevent inflammatory symptoms of allergy and atopy. The present study aims to investigate the role of probiotics in the treatment of AR when added to standard therapy as adjuvant agents. MATERIALS AND METHODS: In this clinical trial study, 28 patients older than 15 years with AR randomly divided into probiotics and control groups. The probiotics group received standard therapy for AR accompanied by probiotic capsules every 12 hours for eight weeks, whereas the control group received standard therapy for AR with placebo capsules as the same protocol. Data were analyzed using SPSS Version 23 (IBM Corporation, Armonk, NY, USA) and, the P-value less than 0.05 was considered statistically significant. RESULTS: In the probiotics group, 14.3% of patients had sneezing at the baseline, which significantly decreased to 4.6% (P<0.01). Also, the necessity for nasal and oral corticosteroids after treatment with probiotics in the probiotics group was less than the control group (P<0.01). Although cough, nasal discharge, conchae hypertrophy, and night sleep disorders reduced after treatment with probiotics, this reduction was not statistically significant between the two groups. CONCLUSION: Based on the results of this clinical trial, the use of probiotics had no significant effect on the outcome of patients with AR.
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Background: Up to 40% of the world populations are affected by allergic rhinitis (AR). Interplay between genetics, epigenetics, and environmental factors leads to allergic disease. Objective: In this study, we evaluated the accompaniment between polymorphic variants of IL-13 and IL-4 and aeroallergens among Iranian-Azeri children and adolescent in AR's risk. Methods: Five-hundred AR patients and 300 healthy individuals were enrolled in this study after diagnosis via blood testing for IgE and skin prick test by subspecialty of Allergy and Immunology from Azerbaijan, northwest of Iran, from 2017 to 2019. Genomic DNA was prepared from all samples for genotyping of IL-4 and IL-13. Results: We identified genetic variation of IL-13 and IL-4 and important aeroallergens that could increase the AR risk during childhood and adolescent. The risk of AR increased in the subjects with +2044GA genotype of IL13 [adjusted odds ratio (OR), 1.80; 95% confidence interval (CI), 0.97-3.33] and -590CT genotype of IL4 (adjusted OR, 1.94; 95% CI, 1.00-3.87) in childhoods, compared with the control subjects. However, none of genotypes and allele frequencies of IL4 -590C/T and IL13 +2044G/A polymorphisms revealed significant variation between the AR patients and controls in adulthood. The frequency of sensitization to pollens was high in all genotypes of IL4 -590C/T and IL13 +2044G/A polymorphisms in both age groups of AR patients. Conclusion: AR is considered to be the most common form of atopic disease. Susceptible individuals had family history of allergic disease and indicated sensitivity to various environmental factors. In this study, pollen and feather played an important role in occurrence of AR. Childhood with GA at IL13 +2044 and CT at IL4 -590 are at increased risk for AR. Moreover, further studies with more samples are required to confirm our findings and also to help us develop new procedure for genetically detecting more efficient proceedings of prevention and intervention.
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Predisposición Genética a la Enfermedad , Exposición por Inhalación/efectos adversos , Interleucina-13/genética , Interleucina-4/genética , Rinitis Alérgica/genética , Adolescente , Adulto , Alérgenos/efectos adversos , Estudios de Casos y Controles , Niño , Preescolar , Femenino , Técnicas de Genotipaje , Voluntarios Sanos , Humanos , Irán/epidemiología , Masculino , Polimorfismo de Nucleótido Simple , Rinitis Alérgica/diagnóstico , Rinitis Alérgica/epidemiología , Rinitis Alérgica/inmunología , Pruebas Cutáneas , Adulto JovenRESUMEN
BACKGROUND: Severe combined immunodeficiency (SCID) is the most severe form of primary immunodeficiency disorders that is characterized by impaired early T lymphocyte differentiation and is variably associated with abnormal development of other lymphocyte lineages. SCID can be caused by mutations in more than 20 different genes. Molecular diagnosis in SCID patients contributes to genetic counseling, prenatal diagnosis, treatment modalities, and overall prognosis. In this cohort, the clinical, laboratory and genetic data related to Iranian SCID patients were comprehensively evaluated and efficiency of stepwise sequencing methods approach based on immunophenotype grouping was investigated METHODS: Clinical and laboratory data from 242 patients with SCID phenotype were evaluated. Molecular genetic analysis methods including Sanger sequencing, targeted gene panel and whole exome sequencing were performed on 62 patients. RESULTS: Mortality rate was 78.9% in the cohort with a median follow-up of four months. The majority of the patients had a phenotype of T-NK-B+ (34.3%) and the most severe clinical manifestation and highest mortality rate were observed in T-NK-B- SCID cases. Genetic mutations were confirmed in 50 patients (80.6%), of which defects in recombination-activating genes (RAG1 and RAG2) were found in 16 patients (32.0%). The lowest level of CD4+ and CD8+ cells were observed in patients with ADA deficiency (pâ¯=â¯0.026) and IL2RG deficiency (pâ¯=â¯0.019), respectively. CONCLUSION: Current findings suggest that candidate gene approach based on patient's immunophenotype might accelerate molecular diagnosis of SCID patients. Candidate gene selection should be done according to the frequency of disease-causing genes in different populations. Targeted gene panel, WES and WGS methods can be used for the cases which are not diagnosed using this method.
Asunto(s)
Pruebas Genéticas/métodos , Inmunofenotipificación/métodos , Mutación/inmunología , Inmunodeficiencia Combinada Grave/diagnóstico , Linfocitos B/inmunología , Análisis Mutacional de ADN , Estudios de Factibilidad , Femenino , Estudios de Seguimiento , Asesoramiento Genético , Humanos , Irán/epidemiología , Células Asesinas Naturales/inmunología , Masculino , Técnicas de Diagnóstico Molecular/métodos , Inmunodeficiencia Combinada Grave/genética , Inmunodeficiencia Combinada Grave/inmunología , Inmunodeficiencia Combinada Grave/mortalidad , Linfocitos T/inmunología , Secuenciación del Exoma , Adulto JovenRESUMEN
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 µ 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 µ 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 µ 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.
Asunto(s)
Agammaglobulinemia , Inmunodeficiencia Variable Común , Síndrome de Inmunodeficiencia con Hiper-IgM , Adolescente , Adulto , Agammaglobulinemia Tirosina Quinasa/genética , Agammaglobulinemia/genética , Agammaglobulinemia/mortalidad , Ligando de CD40/genética , Niño , Preescolar , Inmunodeficiencia Variable Común/genética , Inmunodeficiencia Variable Común/mortalidad , Diarrea/genética , Diarrea/mortalidad , Femenino , Estudios de Asociación Genética , Humanos , Síndrome de Inmunodeficiencia con Hiper-IgM/genética , Síndrome de Inmunodeficiencia con Hiper-IgM/mortalidad , Cadenas mu de Inmunoglobulina/genética , Masculino , Meningitis/genética , Meningitis/mortalidad , Mutación , Poliomielitis/genética , Poliomielitis/mortalidad , Índice de Severidad de la Enfermedad , Adulto JovenRESUMEN
BACKGROUND: 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. METHOD: 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. RESULTS: 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. CONCLUSIONS: 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.