Genomic Testing Identifies Monogenic Causes in Patients with Very Early-Onset Inflammatory Bowel Disease: A Multi-center Survey in an Iranian Cohort.

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 multi-center 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 one 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.

Allogenic hematopoietic stem cell transplantation in an Iranian patient with osteopetrosis caused by carbonic anhydrase II deficiency: A case report.

BACKGROUND: Osteopetrosis is a group of geneticall heterogeneous disorders resulting from impaired osteoclast function and bone resorption. The identification of specific genetic mutations can yield important prognostic and therapeutic implications. Herein, we present the diagnosis and successful application of hematopoietic stem cell transplantation (HSCT) in a patient with osteopetrosis caused by carbonic anhydrase II deficiency (Intermediate osteopetrosis). CASE PRESENTATION: Herein, we describe a 2.5-year-old male patient born to consanguineous parents who presented at 8-month-old with hydrocephaly, brain shunt, and developmental delay. Later at 9 months old, he was found to have eye disorder such as nystagmus, fracture of the elbow, abnormal skeletal survey, normal cell blood count (CBC), and severe hypocellularity in the bone marrow. Further evaluation showed renal tubular acidosis type 2. Whole-exome sequencing revealed a pathogenic homozygous variant in intron 2 of the carbonic anhydrase 2 gene (CA2) gene (c.232 + 1 G>T). The diagnosis of intermediate autosomal recessive osteopetrosis was established, and allogenic HSCT from his mother, a full-matched related donor (MRD), was planned. The conditioning regimen included Busulfan, Fludarabine, and Rabbit anti-thymocyte globulin. Cyclosporine and Mycophenolate Mofetil were used for graft-versus-host-disease prophylaxis. He Engrafted on day +13, and 95% chimerism was achieved. He is currently doing well without immunosuppressive therapy, now 12 months post HSCT, with normal calcium level and improving visual quality and FISH analysis revealed complete donor chimerism. DISCUSSION: HSCT could be a promising curative treatment for intermediate osteopetrosis and can provide long-term survival. Ongoing challenges in various aspects of HSCT remain to be addressed.

Immune endotyping and gene expression profile of patients with chronic rhinosinusitis with nasal polyps in the aspirin-exacerbated respiratory disease (AERD) and the non-AERD subgroups.

BACKGROUND: Chronic Rhinosinusitis (CRS) is a paranasal sinus inflammatory disease and is divided into two subgroups defined as CRS with nasal polyps (CRSwNP) and CRS without nasal polyps (CRSsNP). CRSwNP displays a T helper (Th)2 biased phenotype, and based on sensitivity or tolerance to aspirin or non-steroidal anti-inflammatory drugs (NSAID), is further subdivided into Aspirin-exacerbated respiratory disease (AERD) and non-AERD groups. Considering the challenge of diagnosis and treatment in patients with CRSwNP, particularly the AERD subtype, and the significance of endotyping in these patients, we examined the immune profile and endotyping based on gene expression analysis in the AERD and the non-AERD groups of patients with CRSwNP. MATERIAL AND METHOD: In this study, 21 patients were enrolled and were categorized into AERD (N = 10) and non-AERD (N = 11) groups based on their sensitivity to aspirin. After the special washing period, nasal polyps were biopsied in both groups, and the infiltration of eosinophils, neutrophils, plasma cells, and lymphocytes was compared between the AERD and the non-AERD groups. Also, gene expression levels of transcription factors including Tbet, GATA3, RoRγt, and FoxP3 and inflammatory cytokines including interleukin (IL)1ß, IL1RAP (IL1 receptor accessory protein), IL2, IL4, IL5, IL10, IL13, IL17, TNFα, and IFNγ were investigated by quantitative Real-time PCR (qRT-PCR). Statistical analyses were performed using analytical tests including Kolmogorov-Smirnov, Mann-Whitney, and T-test. A P value less than 0.05 was considered statistically significant. RESULTS: The mean ± SD age of the studied groups was 37 ± 8.7 years old (21-50) for the AERD, and 40.4 ± 7.7 years old (31-52) for the non-AERD. LMS/EPOS/SNOT scores and pulmonary function tests showed no difference between the two groups. Serum immunoglobulin E (IgE) levels were found to be higher in patients with AERD (p = 0.04), however, the peripheral blood counts of eosinophils were comparable in the two groups. In the histopathologic analysis, the AERD group showed higher percentages of eosinophils (p = 0.04), neutrophils (p = 0.04), and plasma cells (p = 0.04) than the non-AERD group. Additionally, the gene expression levels of GATA3 (p = 0.001), IL4 (p = 0.04), IL5 (p = 0.007), and IL17 (p = 0.03) were significantly higher in the AERD than the non-AERD groups. CONCLUSION: Higher gene expression levels of GATA3, IL4, IL5, and IL17 were observed in the AERD group compared with the non-AERD group. These findings point to distinct patterns of inflammation in patients with AERD, with a predominance of Th2 inflammation.

Genetic, immunologic, and clinical features of 830 patients with Mendelian susceptibility to mycobacterial diseases (MSMD): A systematic review.

BACKGROUND: Mendelian susceptibility to mycobacterial diseases (MSMD) is a rare clinical syndrome characterized by vulnerability to weakly virulent mycobacterial species, including Bacillus Calmette-Guérin (BCG) vaccines and environmental mycobacteria. OBJECTIVE: We sought to perform a systematic review of the genetic, immunologic, and clinical findings for reported patients with MSMD. METHODS: We searched PubMed, Web of Science, and Scopus databases for publications in English relating to MSMD. All full texts were evaluated for eligibility for inclusion. Two reviewers independently selected the publications, with a third reviewer consulted in cases of disagreement. RESULTS: A primary systematic search and searches of other resources identified 16,155 articles. In total, 158 articles from 63 countries were included in qualitative and quantitative analyses. In total, 830 patients-436 males (52.5%), 369 females (44.5%), and 25 patients of unknown sex (3.0%)-from 581 families were evaluated. A positive family history was reported in 347 patients (45.5%). The patients had a mean age of 10.41 ± 0.42 (SEM) years. The frequency of MSMD was highest in Iran, Turkey, and Saudi Arabia. Lymphadenopathy was the most common clinical manifestation of MSMD, reported in 378 (45.5%) cases and multifocal in 35.1%. Fever, organomegaly, and sepsis were the next most frequent findings, reported in 251 (30.2%), 206 (24.8%), and 171 (20.8%) cases, respectively. In total, 299 unique mutations in 21 genes known to be involved in MSMD were reported: 100 missense (34%), 80 indel-frameshift (insertion or deletion, 27%), 53 nonsense (18%), 35 splice site (12%), 10 indel-in frame (2.7%), 6 indel (2%), and 15 large deletion/duplication mutations. Finally, 61% of the reported patients with MSMD had mutations of IL12RB1 (41%) or IFNGR1 (20%). At the time of the report, 177 of the patients (21.3%) were dead and 597 (71.9%) were still alive. CONCLUSIONS: MSMD is associated with a high mortality rate, mostly due to impaired control of infection. Preexposure strategies, such as changes in vaccination policy in endemic areas, the establishment of a worldwide registry of patients with MSMD, and precise follow-up over generations in affected families, appear to be vital to decrease MSMD-related mortality.

Inborn errors of immunity with kidney and urinary tract disorders: a review.

Human inborn errors of immunity (IEIs), previously referred to as primary immunodeficiency disorders (PIDs), are a heterogeneous spectrum of inherited abnormalities of the immune system with different organ involvement. The number of identified IEIs is rapidly increasing, highlighting the non-negligible role of an interdisciplinary approach in clinical diagnosis. Kidney disorders are one of the important comorbidities in some of the affected patients and play a significant role in the diagnosis and course of disease. According to recent studies, 22 types of human IEI with renal manifestations have been identified so far, including immunodeficiency with congenital thrombocytopenia, thymic defects with additional congenital anomalies, complement deficiencies, type 1 interferonopathies, immunity related to non-hematopoietic tissues, congenital neutropenia's, common variable immunodeficiency disorder (CVID) phenotype and immuno-osseous dysplasia. Based on this classification, we herein review IEIs with renal features and explain the genetic defect, inheritance, and type of renal manifestations.

CARD9 deficiency with allergic bronchopulmonary aspergillosis (ABPA)-like presentation: a case report.

PURPOSE: We present a patient with CARD9 deficiency and allergic bronchopulmonary aspergillosis (ABPA)-like presentation. METHODS: Following medical history taking and routine laboratory investigations, an inborn error of immunity was suspected, and the responsible variant was identified using Whole Exome Sequencing and confirmed by Sanger sequencing. RESULTS: A 14-year-old Iranian female presented with a history of chest pain, productive cough, dyspnea, malaise, and recurrent fever. Imaging by computed tomography (CT scan), chest X-ray (CXR), bronchoscopy, transbronchial lung biopsy (TBLB), and histopathology findings led to a diagnosis of ABPA-like presentation. The genetic study showed an autosomal recessive homozygous mutation in the CARD9 gene. Clinical remission was achieved following the administration of voriconazole, which was continued as prophylaxis. CONCLUSIONS: This is the first-time report of a patient with inherited CARD9 deficiency and ABPA-like presentation due to Aspergillus Terrus. This study paves the way to elucidate immunological mechanisms underlying CARD9 deficiency and aspergillosis.

Immunological Evaluation of Pediatric Patients with Polyautoimmunity.

BACKGROUND: Autoimmunity can be the first or predominant manifestation in patients with primary immunodeficiency disorder, also referred to as inborn errors of immunity (IEI). This study aims to evaluate the immune status of pediatric patients with polyautoimmunity to identify those with underlying immune defects. METHODS: In this cross-sectional study, pediatric patients with polyautoimmunity including at least one confirmed autoimmune endocrine disease were enrolled. Demographic and clinical data were collected using a questionnaire based on medical records and direct family interviews. For each patient, a basic immunologic evaluation was performed. The clinical diagnosis was established according to the criteria of the European Society for Immunodeficiencies (ESID). Based on the presence or absence of a history of severe and/or recurrent infections, patients were divided into two groups for comparison. RESULTS: Thirty-nine patients, 18 males (46.2%) and 21 females (53.8%), were included. Fourteen patients (35.9%) had consanguineous parents. Fifteen patients (38.5%) had a history of severe and/or recurrent infections. The median (interquartile range: IQR) age of our patients at the time of evaluation was 11.1 (9-16) years. The median (IQR) age at the onset of infections and autoimmunities were 3 (1-10.8) and 5 (2.6-8) years, respectively. The most common infectious complications reported were pneumonia and candidiasis, each in 12.8% of the patients. The most prevalent autoimmune disorders were type 1 diabetes (74.3%) and autoimmune thyroiditis (58.9%). IEI was diagnosed in six patients (15.38%), five of which were from the group with severe or recurrent infections: three with selective IgA deficiency, two with common variable immunodeficiency (CVID), and one with immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX), but without a history of infections. CONCLUSION: The occurrence of early onset polyautoimmunity in association with severe and/or recurrent infections or in patients with a positive family history should be a warning sign for physicians to initiate an evaluation for possible immunodeficiency disorders to prevent complications through early treatment.

Clinical Course, Therapeutic Management and Outcome of Coronavirus Disease in Patients With Inborn Errors of Immunity: A Retrospective Multicenter Experience From Iran.

BACKGROUND: Inborn errors of immunity (IEIs) are characterized by defects in the structure and function of the immune system. This study was designed to assess the impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection on this potentially particularly susceptible group of patients. METHODS: This retrospective cross-sectional study analyzed patients from 3 referral immunodeficiency centers in Iran. The demographic, clinical, laboratory and therapeutical data of confirmed IEI patients with SARS-CoV-2 infection were collected and analyzed. RESULTS: A total of 19 IEI patients, 52.6% male and 47.4% female, with coronavirus disease 2019 (COVID-19) were enrolled. The most common diagnosed IEIs were (severe) combined immunodeficiency ((S)CID) (9, 47.4%) and predominantly antibody deficiencies (7, 36.8%). The main presenting symptoms included fever (16, 84.2%), cough (12, 63.2%), dyspnea (9, 47.4%) and myalgia (8, 42.1%). Among additional preexisting comorbidities, atopy ( P = 0.087) and renal disorders ( P = 0.087) were more strongly associated with the development of respiratory failure, although not statistically significant. SARS-CoV-2 infection was determined by polymerase chain reaction (n = 19, 100%) within a median (interquartile range) of 1 (0-6) days following admission. Among all laboratory indices, thrombocytopenia ( P = 0.009) was associated with a need for intensive care unit admission. The overall mortality rate was 36.9% and highest among (S)CID patients (4, 44.4%). CONCLUSIONS: Severe COVID-19 most frequently affected (S)CID and predominantly antibody deficiencies patients among this multicenter Iranian cohort. Further studies are required to evaluate the impact of additional preexisting comorbidities and the development of thrombocytopenia on the severity and prognosis of COVID-19 in IEIs.

Interventional pulmonary procedures and their outcomes in patients with STAT3 hyper IgE syndrome.

BACKGROUND: STAT3 hyperimmunoglobulin E syndrome (STAT3-HIES) also referred to as autosomal dominant HIES (AD-HIES) is an inborn error of immunity characterized by the classic triad of eczema, frequent opportunistic infections, and elevated serum IgE levels. As a consequence of lung sequels due to repeated infections and impaired tissue healing, patients may require interventional pulmonary procedures. METHOD: Four patients with dominant-negative STAT3 mutations who had received interventional pulmonary procedures were enrolled. The demographic, clinical, and molecular characteristics were gathered through a medical record search. All reported STAT3-HIES patients in the literature requiring pulmonary procedures as part of their treatment were reviewed. RESULT: Recurrent episodes of pneumonia and lung abscess were the most prevalent symptoms. The most common non-immunological features were scoliosis, failure to thrive, and dental problems such as primary teeth retention and disseminated decays. Bronchiectasis, lung abscess, pneumatocele, and cavitary lesion were the most prevalent finding on high-resolution computed tomography at the earliest recording. All patients underwent pulmonary surgery and two of them experienced complications. CONCLUSION: Patients with STAT3-HIES have marked pulmonary infection susceptibility which may necessitate thoracic surgeries. Since surgical procedures involve a high risk of complication, surgical options are recommended to be utilized only in cases of drug resistance or emergencies.

Relapse of nephrotic syndrome with unusual thromboembolic event: A case report.

Key Clinical Message: Most children with nephrotic syndrome heal without any sequelae. However, rare life-threatening complications such as thromboembolism may occur in pediatric nephrotic syndrome and should be considered in those with a new-onset neurologic deficit. Abstract: The thromboembolism (TE) as a complication of nephrotic syndrome (NS) is rare and serious, and may involve renal, cerebral, pulmonary, or peripheral venous and/or arterial thrombosis. Here, we describe a 4.5-year-old male with a history of nephrotic syndrome, who developed hemorrhagic stroke in the territory of middle cerebral artery (MCA).

Food allergy masquerading as persistent proteinuria in post-infectious glomerulonephritis: a case report.

BACKGROUND: Post-infectious glomerulonephritis (PIGN) is one of the most common causes of pediatric acute glomerulonephritis. Immune system dysregulation manifesting as food allergy may predispose PIGN patients to nephrotic-range proteinuria. CASE PRESENTATION: The patient was a 3-year-old male that presented with edema, gross hematuria and reduced urine output following a mild fever, rhinorrhea and lethargy. Due to the persistence of proteinuria and hematuria, he underwent a kidney biopsy. The patient was diagnosed with atypical PIGN and was placed on oral prednisolone. During treatment, a relationship between the consumption of dairy products and the degree of proteinuria was noted. The clinical manifestations and urinalysis indices improved upon steroid discontinuation and initiation of a hypoallergic diet. CONCLUSION: The association between the degree of proteinuria and consumption of dairy products in this PIGN patient led to the identification of food allergy as an underlying factor for nephrotic-range proteinuria.

A rare immunological disease, caspase 8 deficiency: case report and literature review.

BACKGROUND: Caspase-8 is a molecule in the FAS pathway that initiates apoptosis. One of the rarest autoimmune lymphoproliferative syndromes is caspase-8 deficiency. Immunodeficiency, splenomegaly, and lymphadenopathy are the common symptoms of this condition. CASE PRESENTATION: A two-year-old boy entered this study with a fever of unknown origin (FUO) and dysentery. Moreover, he suffered from failure to thrive and was allergic to the cow's milk protein. His fever and dysentery did not respond to antibiotic therapy. The colonoscopy revealed diffuse ulcerations regions in the sigmoid along with skipped areas, mimicking Crohn's disease aphthous lesions. He represented very early-onset inflammatory bowel disease (IBD) and was diagnosed with the caspase-8 deficiency. CONCLUSION: There can be diarrhea or dysentery as the first or main symptoms of inborn errors of immunity (IEIs). The cause of diarrhea and dysentery in this case was early-onset IBD. One of the symptoms of IEIs such as caspase-8 deficiency is early-onset of IBD. Patients with early-onset had normal T cell count and low or normal immunoglobulin levels with insufficient immune response.

JAGN1 mutation with distinct clinical features; two case reports and literature review.

Jagunal homolog 1 (JAGN1) has been recognized as an essential protein in neutrophil function. The mutated JAGN1 is responsible for immunodeficiency related to innate and humoral defense mechanisms. This deficiency impairs neutrophil development and function, leading to recurrent infections and facial dysmorphism as phenotypic consequences of severe congenital neutropenia (SCN). We report two siblings having the reported JAGN1 mutation with different clinical manifestations. Recurrent abscess formation unresponsive to antibiotic therapy, a history of delayed umbilical separation, frequent bacterial or fungal infection, dysmorphic face, failure to thrive, and other coexisting organ abnormalities should prompt physicians to syndromic immunodeficiencies involving neutrophils. Genetic investigations to elucidate the responsible mutation is critical as clinical management varies. Once the diagnosis is confirmed, a multi-disciplinary team should perform further workups to investigate other coexisting malformations and neurodevelopmental evaluation.

Successful Hematopoietic Stem Cell Transplant in a Patient with Omenn Syndrome: A Case Report.

Omenn syndrome is a rare subtype of severe combined immunodeficiency. Affected patients present recurrent infections, lymphadenopathy, skin eruptions, eosinophilia, hepatosplenomegaly, failure to thrive, and gastrointestinal complications with variable severity. A 3-month-old female infant, born to consanguineous healthy parents, presented with splenomegaly, erythroderma, failure to thrive, and history of recurrent otitis media, hypothyroidism, and Bacille Calmette-Guérin lymphadenitis following Bacille Calmette-Guérin vaccination.The immunologic workup showed lymphopenia; low levels of CD3+ T cells, CD4+ T cells, and CD8+ T cells; normal levels of CD19+ B cells and CD16+/CD56+ natural killer cells; hypogammaglobulinemia; and a high level of serum immunoglobulin E. She was clinically diagnosed with T-B+NK+ severe combined immunodeficiency. Genetic study revealed a missense homozygous alteration (c.617G>A, p.Arg206Gln) in exon 5 of the IL7R gene in the patient, as well as carrier states for the same variant in both parents. The patient received a peripheral blood stem cell transplant from a matched unrelated donor. A reduced intensity conditioning regimen was applied, including fludarabine, melphalan, rabbit antithymocyte globulin, and graft- versus-host disease prophylaxis by cyclosporine and mycophenolate mofetil. She clinically improved, and after engraftment the donor chimerism was 100% at 1 year after transplant. Hematopoietic stem cell transplantis a curative therapeutic option for patients with Omenn syndrome and, when combined with an early diagnosis, can prevent complications and improve patient survival.

Intestinal hypomagnesemia in an Iranian patient with a novel TRPM6 variant: a case report and review of the literature.

TRPM6 is predominantly expressed in the kidney and colon and encodes a protein containing an ion channel domain and a protein kinase domain. It is crucial for magnesium homeostasis and plays important roles in epithelial magnesium transport and the active magnesium absorption. In this study, we present a 70-day-old Iranian female patient from consanguineous parents with hypomagnesemia and secondary hypocalcemia. She presented with seizures 19 days after birth and refractory watery non-bloody diarrhea. She consequently had failure to thrive. Other features included hypotonia, wide anterior fontanel, ventriculomegaly, and pseudotumor cerebri following administration of nalidixic acid. She had severe hypomagnesemia and hypocalcemia which were treated with magnesium and calcium supplementation. Despite initial unstable response to supplemental magnesium, she eventually improved and the diarrhea discontinued. The patient was discharged by magnesium and calcium therapy. At the last follow-up at age 2.5 years, the patient remained well without any recurrence or complication. Genetic testing by whole-exome sequencing revealed a novel homozygous frameshift insertion-deletion (indel) variant in exon 26 of the TRPM6 gene, c.3693-3699del GCAAGAG ins CTGCTGTTGACATCTGCT, p.L1231Ffs*36. Segregation analysis revealed the TRPM6 heterozygous variant in both parents. Patients with biallelic TRPM6 pathogenic variants typically exhibit hypomagnesemia with secondary hypocalcemia and present with neurologic manifestations including seizures. In some patients, this is also complicated by chronic diarrhea and failure to thrive. Long-term complications are rare and most of the patients show a good prognosis with supplemental magnesium therapy.

Acute Kidney Injury in Pediatric Patients with COVID-19; Clinical Features and Outcome.

INTRODUCTION: Renal disorders have been reported as the underlying cause as well as complications of critical COVID-19 in pediatric patients. The purpose of this study was to investigate the pattern of kidney involvement, particularly acute kidney injury (AKI), among pediatric patients with COVID-19. METHODS: In this prospective study, hospitalized pediatric patients with a clinical diagnosis of COVID-19 were enrolled. Demographic, clinical, and laboratory findings were collected and analyzed using a mixed method of qualitative and quantitative approaches and descriptive statistics. RESULTS: One hundred and eighty-seven patients, including 120 (64.2%) males and 67 (35.8%) females with COVID-19 with a median age (interquartile range) of 60 (24 to 114) months were enrolled in this study. Most patients (n = 108, 58.1%) had one or two underlying comorbidities, mainly malnutrition (77.4%), neurologic/learning disorders (21.4%), and malignancy (10.2%). According to the Kidney Disease Improving Global Outcomes (KDIGO) classification, AKI was detected in 38.5% of patients (stage 1: 55.6%, stage 2: 36.1%, and stage 3: 8.3%) at presentation or during hospitalization. Nine patients (4.8%) required hemodialysis and 16 (8.6%) eventually died. There was no significant association between AKI and admission to the pediatric intensive care unit (PICU) (P > .05), a multisystem inflammatory syndrome in children (MIS-C) (P > .05), comorbidities (P > .05), and mortality rate (P > .05). CONCLUSION: Kidneys are among the major organs affected by COVID-19. Although kidney abnormalities resolve in the majority of pediatric COVID-19 infections, particular attention should be paid to serum creatinine and electrolyte levels in patients affected by COVID-19, particularly children with a history of malnutrition and kidney disorders.  DOI: 10.52547/ijkd.7151.

Allogenic Hematopoietic Stem Cell Transplant in Iranian Patients With Congenital Sideroblastic Anemia: A Single-Center Experience.

Congenital sideroblastic anemia is characterized by anemia and intramitochondrial iron accumulation in erythroid precursors that form ring sideroblasts. The most common recessive forms are caused by sequence variations in the ALAS2 and SLC25A38 genes. In patients with transfusion-dependent and pyridoxine- resistant severe congenital sideroblastic anemia, hematopoietic stem celltransplantis the only curative option. Herein, we described successful implementations of allogeneic hematopoietic stem cell transplant in 4 Iranian children with congenital sideroblastic anemia. The patients had presented with clinical manifestations of anemia early in life, and the diagnoses of congenital sideroblastic anemia were established through blood tests and bone marrow aspiration. Congenital sideroblastic anemia was further confirmed by the identification of pathogenic variants in SLC25A38 in 2 patients. All 4 patients received allogeneic hematopoietic stem cell transplant with myeloablative conditioning regimen that included busulfan, cyclophosphamide, andrabbit antithymocyte globulin. A combination of cyclosporine A and methotrexate or mycophenolate mofetil was used for graft-versus-host disease prophylaxis. Bone marrow and peripheral blood from sibling or related donors with fully matched human leukocyte antigen profiles were applied. The outcomes of hematopoietic stem celltransplantin patients with congenital sideroblastic anemia were favorable. Three patients achieved full donor chimerism (>95%, 98%, and 100%), and the other patient showed mixed chimerism (75%). All patients remained transfusion independent. Hemato- poietic stem celltransplantis a curative treatmentthat can provide long-term survival for patients with congenital sideroblastic anemia, particularly when used in a timely manner. There remain ongoing challenges in various aspects of hematopoietic stem celltransplantin patients with congenital sideroblastic anemia, which remain to be elucidated.

Demographic, clinical, immunological, and molecular features of iranian national cohort of patients with defect in DCLRE1C gene.

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.

The Autoimmune Manifestations in Patients with Genetic Defects in the B Cell Development and Differentiation Stages.

PURPOSE: Primary B cell defects manifesting as predominantly antibody deficiencies result from variable inborn errors of the B cell lineage and their development, including impairments in early bone marrow development, class switch recombination (CSR), or terminal B cell differentiation. In this study, we aimed to investigate autoimmunity in monogenic patients with B cell development and differentiation defects. METHODS: Patients with known genetic defects in the B cell development and differentiation were recruited from the Iranian inborn errors of immunity registry. RESULTS: A total of 393 patients with a known genetic defect in the B cell development and differentiation (257 males; 65.4%) with a median age of 12 (6-20) years were enrolled in this study. After categorizing patients, 109 patients had intrinsic B cell defects. More than half of the patients had defects in one of the ATM (85 patients), BTK (76 patients), LRBA (34 patients), and DOCK8 (33 patients) genes. Fifteen patients (3.8%) showed autoimmune complications as their first manifestation. During the course of the disease, autoimmunity was reported in 81 (20.6%) patients at a median age of 4 (2-7) years, among which 65 patients had mixed intrinsic and extrinsic and 16 had intrinsic B cell defects. The comparison between patients with the mentioned four main gene defects showed that the patient group with LRBA defect had a significantly higher frequency of autoimmunity compared to those with other gene defects. Based on the B cell defect stage, 13% of patients with early B cell defect, 17% of patients with CSR defect, and 40% of patients who had terminal B cell defect presented at least one type of autoimmunity. CONCLUSION: Our results demonstrated that gene mutations involved in human B cell terminal stage development mainly LRBA gene defect have the highest association with autoimmunity.

Assessment of early and post COVID-19 vaccination antibody response in healthcare workers: a multicentre cross-sectional study on inactivated, mRNA and vector-based vaccines.

In this multicentre study, we compared the status of antibody production in healthcare personnel (HCP) before and after vaccination using different brands of COVID-19 vaccines between March 2021 and September 2021. Out of a total of 962 HCP enrolled in our study, the antibody against the S1 domain of SARS-CoV-2 was detected in 48.3%, 95.5% and 96.2% of them before, after the first and the second doses of the vaccines, respectively. Our results showed post-vaccination infection in 3.7% and 5.9% of the individuals after the first and second doses of vaccines, respectively. The infection was significantly lower in HCP who presented higher antibody titres before the vaccination. Although types of vaccines did not show a significant difference in the infection rate, a lower infection rate was recorded for AstraZeneca after the second vaccination course. This rate was equal among individuals receiving a second dose of Sinopharm and Sputnik. Vaccine-related side effects were more frequent among AstraZeneca recipients after the first dose and among Sputnik recipients after the second dose. In conclusion, our results showed diversity among different brands of COVID-19 vaccines; however, it seems that two doses of the vaccines could induce an antibody response in most of HCP. The induced immunity could persist for 3-5 months after the second vaccination course.