The relationship between preeclampsia risk and SENCR rs555172 gene polymorphism and expression.

Preeclampsia, the more severe manifestation of gestational hypertensive disorders, is a major cause of maternal and perinatal morbidity and mortality worldwide. Genetic polymorphisms in long non-coding RNAs (lncRNAs) are considered as potential genetic preeclampsia. This study aimed to explore the association between SENCR rs555172 SNP and PE risk in healthy pregnant women compared to women with preeclampsia. A total of 140 healthy pregnant women and 130 preeclampsia cases were included in the study. The rs555172 genotype was determined using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP), and the expression of the SENCR gene was analyzed in 40 placenta tissue samples from both groups. Various statistical approaches were employed to assess the genotypic and allelic frequencies. The results showed no significant difference in the frequency of the rs555172 polymorphism between healthy pregnant women and those with preeclampsia in terms of the dominant (p=0.82), recessive (p=0.39), and over-dominant (p=0.42) models. Additionally, the analysis of SENCR relative expression revealed no significant difference between the two groups (p=0.48). In conclusion, the LncRNA SENCR rs555172(G/A) seems not associated with an increased risk of Preeclampsia in pregnant women.

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.

Non-coding RNAs in Recurrent implantation failure.

Recurrent implantation failure (RIF), defined as the inability to achieve conception following multiple consecutive in-vitro fertilization (IVF) attempts, represents a complex and multifaceted challenge in reproductive medicine. The emerging role of non-coding RNAs in RIF etiopathogenesis has only gained prominence over the last decade, illustrating a new dimension to our understanding of the intricate network underlying RIF. Successful embryo implantation demands a harmonious synchronization between an adequately decidualized endometrium, a competent blastocyst, and effective maternal-embryonic interactions. Emerging evidence has clarified the involvement of a sophisticated network of non-coding RNAs, including microRNAs, circular RNAs, and long non-coding RNAs, in orchestrating these pivotal processes. Disconcerted expression of these molecules can disrupt the delicate equilibrium required for implantation, amplifying the risk of RIF. This comprehensive review presents an in-depth investigation of the complex role played by non-coding RNAs in the pathogenesis of RIF. Furthermore, it underscores the vast potential of non-coding RNAs as diagnostic biomarkers and therapeutic targets, with the ultimate goal of enhancing implantation success rates in IVF cycles. As ongoing research continues to unravel the intercalated web of molecular interactions, exploiting the power of non-coding RNAs may offer promising avenues for mitigating the challenges posed by RIF and improving the outcomes of assisted reproduction.

Impact of Survivin rs9904341 and rs17878467 Polymorphisms On Risk of Preeclampsia in Iran.

Preeclampsia (PE) is a hypertensive disorder that affects pregnancy, mother, and fetus. Early diagnosis of PE remains a challenge. This study aimed to investigate the association between survivin two (rs9904341 and rs17878467) SNPs and PE risk in healthy pregnant women compared to women with preeclampsia. A sample of 166 healthy pregnant women and 160 cases with preeclampsia was included and genotyped for rs9904341 with polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and rs17878467 with amplification-refractory mutation system (ARMS) PCR. The genotypic and allelic assessments were performed using various statistical approaches. The frequency of rs9904341 and rs17878467 polymorphisms was not significantly different between PE and healthy pregnant women. rs9904341: codominant (p = 0.5), dominant (p = 0.24), recessive (p = 0.61), over-dominant model (p = 0.38), and log additive (p = 0.25). rs17878467: codominant (p = 0.41), dominant (p = 0.23), recessive (p = 0.4), over-dominant model (p = 0.42), and log additive (p = 0.24). The frequency of survivin rs9904341 CG and CC genotypes was higher in severe PE women compared to controls and this polymorphism was associated with PE severity only in the dominant model (OR = 1.84, CI 1.04-3.26, P = 0.034). There was a significant association between survivin rs9904341 polymorphism and PE severity. No relationship was found between survivin rs9904341 and rs17878467 polymorphisms and PE onset. The allelic and genotypic frequencies of survivin rs9904341 and rs17878467 polymorphisms are not significantly different between the preeclampsia and control groups in all genetic models. Haplotype analysis showed lower frequency G rs9904341 T rs17878467 haplotype in PE woman and this haplotype was associated with lower risk of PE (OR = 0.54, CI 0.33-0.91, P = 0.02).

Emerging Role of Tumor-Educated Platelets as a New Liquid Biopsy Tool for Colorectal Cancer.

Colorectal cancer (CRC) is a major cause of cancer-associated death universally. Currently, the diagnosis, prognosis, and treatment monitoring of CRC mostly depends on endoscopy integrated with tissue biopsy. Recently, liquid biopsy has gained more and more attention in the area of molecular detection and monitoring of tumors due to ease of sampling, and its safe, non-invasive, and dynamic nature. Platelets, despite their role in hemostasis and thrombosis, are known to have an active, bifacial relationship with cancers. Platelets are the second most common type of cell in the blood and are one of the wealthy liquid biopsy biosources. These cells have the potential to absorb nucleic acids and proteins and modify their transcriptome with regard to external signals, which are termed tumor-educated platelets (TEPs). Liquid biopsies depend on TEPs' biomarkers which can be used to screen and also detect cancer in terms of prognosis, personalized treatment, monitoring, and prediction of recurrence. The value of TEPs as an origin of tumor biomarkers is relatively new, but platelets are commonly isolated using formidable and rapid techniques in clinical practice. Numerous preclinical researches have emphasized the potential of platelets as a new liquid biopsy biosource for detecting several types of tumors. This review discusses the potential use of platelets as a liquid biopsy for CRC.

Maternal and Fetal Factors Affecting Cell-Free Fetal DNA (cffDNA) Fraction: A Systematic Review.

Background: Cell-free fetal DNA (cffDNA) is a novel screening method for fetal aneuploidy that facilitated non-invasive prenatal testing (NIPT) through analysis of cffDNA in maternal plasma. However, despite increased sensitivity, it has a number of limitations that may complicate of its results interpretation. Therefore, elucidating factors affecting fetal fraction, as a critical limitation, guides its clinical application. Methods: In this report, systematic search was carried out through PubMed, Web of Science, and Scopus databases until February 11, 2022 by using keywords consist of "noninvasive prenatal screening", "NIPT", "noninvasive prenatal", "cell free DNA" and "fetal fraction". The articles were screened for eligibility criteria before data extraction. Results: A total of 39 eligible studies, most published between 2010 and 2020, were included. Based on the results of studies, a negative correlation between maternal age and BMI/body weight with fetal fraction was found. Furthermore, LDL, cholesterol, triglyceride level, metformin, heparin and enoxaparin therapy, hemoglobin-related hemoglobinopathies, and physical activity showed to have negative associations. Interestingly, it seems the ethnicity of patients from South and East Asia has a correlation with fetal fraction compared to Caucasians. Positive correlation was observed between gestational age, free ß-hCG, PAPP-A, living in high altitude, and twin pregnancy. Conclusion: Considering each factor, there was significant inconsistency and controversy regarding their impact on outcomes. Indeed, multiple factors can influence the accuracy of NIPS results, and it is worth noting that the impact of these factors may vary depending on the individual's ethnic background. Therefore, it is important to recognize that NIPS remains a screening test, and comprehensive pre- and post-NIPS counseling should be conducted as part of standard clinical practice.

The clinical, molecular, and therapeutic features of patients with IL10/IL10R deficiency: a systematic review.

Interleukin10 (IL10) and IL10 receptor (IL10R) deficiencies are monogenic inborn errors of immunity (IEI) causing early-onset inflammatory bowel diseases (IBD). In this report, we systematically reviewed articles that included related keywords using PubMed, Web of Science, and Scopus databases. The articles were screened for eligibility criteria before data extraction. We assessed 286 patients (44.5% female) with IL10 and/or IL10R deficiencies who were predominantly from China (40.7%), Italy (13.9%), and South Korea (8.5%). The median age of onset was 1.0 (0.3-4.0) months with a median age of genetic diagnosis at 16.0 (7.4-81.0) months. Consanguinity was reported in all evaluable patients with IL10 deficiency and in 38.2% of patients with IL10R deficiency (22.9% of patients with IL10RA, and 79.4% of patients with IL10RB deficiency). The most prevalent mutations in IL10RA were c.301C>T (p.R101W) and c.537G>A (p.T179T), those in IL10RB were c.139A>G (p.K47E) and c.611G>A (p.W204X). Auto-inflammation and enteropathy were present in all cases. The first presentation of both groups was protracted diarrhea (45.7%), bloody diarrhea (17.8%), and colitis (15.5%). Patients with IL10R deficiency had a high frequency of dermatologic manifestations (50.5%) and failure to thrive (60.5%), while IL10-deficient patients lacked those complications. In the majority of patients, the basic immunologic parameters were in normal ranges. Of the entire publications, 30.7% underwent hemopoietic stem cell transplantation, 57.5% surgery, and 86.6% immunosuppressive treatment. The 10-year survival rate was higher in patients with IL10 deficiency than in patients with IL10R deficiency. In conclusion, IL10/IL10R deficiency predominantly presents with treatment-resistant, early-onset IBD within the first months of life. We detected no clear correlation between the phenotype of patients carrying the same variant. The high prevalence of distinct clinical manifestations reported in IL10RA- and IL10RB-deficient patients might be attributable to the interactions between the target tissue and cytokines other than IL10 capable of binding to IL10RB. These results gain translational significance by contributing to earlier diagnosis, adequate therapy, and avoiding delay in the diagnosis and unfavorable outcomes.

Protein Kinase C-Delta Defect in Autoimmune Lymphoproliferative Syndrome-Like Disease: First Case from the National Iranian Registry and Review of the Literature.

BACKGROUND: 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 Delta (PRKCD) gene, present clinical feature of immune dysregulation with susceptibility to Epstein-Barr virus infection. However, a minority of patients present the autoimmune lymphoproliferative syndrome (ALPS). METHODS: The 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. RESULTS: 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, CD8+ T cells, serum IgG level, as well as a reduction in NK cells, was observed in the patient. A homozygous frameshift mutation (c.1293_1294insA) in exon 13 of the PRKCD gene was confirmed. The literature search showed 39 ALPS-like patients with monogenic defects which only six (15.3%) of them were due to PRKCD genes. CONCLUSION: PRKCD should be considered in the context of ALPS clinical manifestations with prominent dermatological involvements.

Maternal and Neonatal Complications, Outcomes and Possibility of Vertical Transmission in Iranian Women with COVID-19.

BACKGROUND: The emergence and fast spread of coronavirus disease 2019 (COVID-19) threatens the world as a new public health crisis. Little is known about its effects during pregnancy. This study aimed to investigate the clinical manifestations of COVID-19 on maternal and neonatal outcomes. METHODS: In this systematic review, PubMed, Scopus, Web of Science, and Google Scholar databases were searched focusing on pregnancy and perinatal outcomes of COVID-19. RESULTS: The initial search yielded 1236 articles, from which finally 21 unique studies, involving 151 pregnant women and 17 neonates, met the criteria. Mean ± SD age of included mothers and mean ± SD gestational age at admission were 30.6 ± 6.2 years and 30.8 ± 8.9 weeks, respectively. The common symptoms were fever, cough, fatigue, dyspnea and myalgia. The mortality rates of pregnant women and neonates were 28 out of 151 (18.5%) and 4 out of 17 (23.5%), respectively. Most of the neonates were preterm at the time of delivery. Three neonates had positive RT-PCR test on the first day after birth and three others on day two. On the average, neonate's PCR became positive on day 4 for the first time. CONCLUSION: Early diagnosis of COVID-19 is crucial due to the possibility of the prenatal complications. Strict prevention strategies may reduce the risk of mother to infant transmission.

Clinical, immunological, and genetic features in 780 patients with autoimmune lymphoproliferative syndrome (ALPS) and ALPS-like diseases: A systematic review.

BACKGROUND: Autoimmune lymphoproliferative syndrome (ALPS) is a group of genetic disorders characterized by early-onset lymphoproliferation, autoimmune cytopenias, and susceptibility to lymphoma. The majority of ALPS patients carry heterozygous germline mutations in the TNFRSF6 gene. In this study, we conducted a systematic review of patients with ALPS and ALPS-like syndrome. METHODS: The literature search was performed in Web of Science, Scopus, and PubMed databases to find eligible studies. Additionally, the reference list of all included papers was hand-searched for additional studies. Demographic, clinical, immunological, and molecular data were extracted and compared between the ALPS and ALPS-like syndrome. RESULTS: Totally, 720 patients with ALPS (532 genetically determined and 189 genetically undetermined ALPS) and 59 cases with ALPS-like phenotype due to mutations in genes other than ALPS genes were assessed. In both ALPS and ALPS-like patients, splenomegaly was the most common clinical presentation followed by autoimmune cytopenias and lymphadenopathy. Among other clinical manifestations, respiratory tract infections were significantly higher in ALPS-like patients than ALPS. The immunological analysis showed a lower serum level of IgA, IgG, and lymphocyte count in ALPS-like patients compared to ALPS. Most (85%) of the ALPS and ALPS-like cases with determined genetic defects carry mutations in the FAS gene. About one-third of patients received immunosuppressive therapy with conventional or targeted immunotherapy agents. A small fraction of patients (3.3%) received hematopoietic stem cell transplantation with successful engraftment, and all except two patients survived after transplantation. CONCLUSION: Our results showed that the FAS gene with 85% frequency is the main etiological cause of genetically diagnosed patients with ALPS phenotype; therefore, the genetic defect of the majority of suspected ALPS patients could be confirmed by mutation analysis of FAS gene.

Clinical, immunological, and genetic features in 938 patients with autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED): a systematic review.

Background: Autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED) is a rare inborn immune error characterized by a triad of chronic mucocutaneous candidiasis (CMC), hypoparathyroidism (HP), and adrenal insufficiency (ADI).Methods: Literature search was conducted in PubMed, Web of Science, and Scopus databases using related keywords, and included studies were systematically evaluated.Results: We reviewed 938 APECED patients and the classic triad of APECED was detected in 57.3% (460 of 803) of patients. CMC (82.5%) was reported as the earliest, HP (84.2%) as the most prevalent, and ADI (72.2%) as the latest presentation within the classic triad. A broad spectrum of non-triad involvements has also been reported; mainly included ectodermal dystrophy (64.5%), infections (58.7%), gastrointestinal disorders (52.0%), gonadal failure (42.0%), neurologic involvements (36.4%), and ocular manifestations (34.3%). A significant positive correlation was detected between certain tissue-specific autoantibodies and particular manifestations including ADI and HP. Neutralizing autoantibodies were detected in at least 60.0% of patients. Nonsense and/or frameshift insertion-deletion mutations were detected in 73.8% of patients with CMC, 70.9% of patients with HP, and 74.6% of patients with primary ADI.Conclusion: Besides penetrance diversity, our review revealed a diverse affected ethnicity (mainly from Italy followed by Finland and Ireland). APECED can initially present in adolescence as 5.2% of the patients were older than 18 years at the disease onset. According to the variety of clinical conditions, which in the majority of patients appear gradually over time, clinical management deserves a separate analysis.

Influence of ß-D-mannuronic Acid, as a New Member of Non-steroidal Anti- Inflammatory Drugs Family, on the Expression Pattern of Chemokines and their Receptors in Rheumatoid Arthritis.

BACKGROUND: Based on the encouraging results of phase III clinical trial of ß-Dmannuronic acid (M2000) (as a new anti-inflammatory drug) in patients with RA, in this study, we aimed to evaluate the effects of this drug on the expression of chemokines and their receptors in PBMCs of RA patients. METHODS: PBMCs of RA patients and healthy controls were separated and the patients' cells were treated with low, moderate and high doses (5, 25 and 50 µg/mL) of M2000 and optimum dose (1 µg/mL) of diclofenac, as a control in RPMI-1640 medium. Real-time PCR was used for evaluating the mRNA expression of CXCR3, CXCR4, CCR2, CCR5 and CCL2/MCP-1. Cell surface expression of CCR2 was investigated using flow cytometry. RESULTS: CCR5 mRNA expression reduced significantly, after treatment of the patients' cells with all three doses of M2000 and optimum dose of diclofenac. CXCR3 mRNA expression was downregulated significantly followed by the treatment of these cells with moderate and high doses of M2000 and optimum dose of diclofenac. CXCR4 mRNA expression declined significantly after the treatment of these cells with moderate and high doses of M2000. CCL2 mRNA expression significantly reduced only followed by the treatment of these cells with a high dose of M2000, whereas, mRNA and cell surface expressions of CCR2 diminished significantly followed by the treatment of these cells with a high dose of M2000 and optimum dose of diclofenac. CONCLUSION: According to our results, M2000 through the down-regulation of chemokines and their receptors may restrict the infiltration of immune cells into the synovium.

Clinical, Immunologic and Molecular Spectrum of Patients with Immunodeficiency, Centromeric Instability, and Facial Anomalies (ICF) Syndrome: A Systematic Review.

BACKGROUND: Immunodeficiency, centromeric instability and facial dysmorphism (ICF) syndrome is a rare autosomal recessive immune disorder presenting with hypogammaglobulinemia, developmental delay, and facial anomalies. The ICF type 1, type 2, type 3 and type 4 are characterized by mutations in DNMT3B, ZBTB24, CDCA7 or HELLS gene, respectively. This study aimed to present a comprehensive description of the clinical, immunologic and genetic features of patients with ICF syndrome. METHODS: PubMed, Web of Science, and Scopus were searched systemically to find eligible studies. RESULTS: Forty-eight studies with 118 ICF patients who met the inclusion criteria were included in our study. Among these patients, 60% reported with ICF-1, 30% with ICF-2, 4% with ICF-3, and 6% with ICF-4. The four most common symptoms reported in patients with ICF syndrome were: delay in motor development, low birth weight, chronic infections, and diarrhea. Intellectual disability and preterm birth among patients with ICF-2 and failure to thrive, sepsis and fungal infections among patients with ICF-1 were also more frequent. Moreover, the median levels of all three immunoglobulins (IgA, IgG, IgM) were markedly reduced within four types of ICF syndrome. CONCLUSION: The frequency of diagnosed patients with ICF syndrome has increased. Early diagnosis of ICF is important since immunoglobulin supplementation or allogeneic stem cell transplantation can improve the disease-free survival rate.

Molecular contribution of BRCA1 and BRCA2 to genome instability in breast cancer patients: review of radiosensitivity assays.

BACKGROUND: DNA repair pathways, cell cycle arrest checkpoints, and cell death induction are present in cells to process DNA damage and prevent genomic instability caused by various extrinsic and intrinsic ionizing factors. Mutations in the genes involved in these pathways enhances the ionizing radiation sensitivity, reduces the individual's capacity to repair DNA damages, and subsequently increases susceptibility to tumorigenesis. BODY: BRCA1 and BRCA2 are two highly penetrant genes involved in the inherited breast cancer and contribute to different DNA damage pathways and cell cycle and apoptosis cascades. Mutations in these genes have been associated with hypersensitivity and genetic instability as well as manifesting severe radiotherapy complications in breast cancer patients. The genomic instability and DNA repair capacity of breast cancer patients with BRCA1/2 mutations have been analyzed in different studies using a variety of assays, including micronucleus assay, comet assay, chromosomal assay, colony-forming assay, γ -H2AX and 53BP1 biomarkers, and fluorescence in situ hybridization. The majority of studies confirmed the enhanced spontaneous & radiation-induced radiosensitivity of breast cancer patients compared to healthy controls. Using G2 micronucleus assay and G2 chromosomal assay, most studies have reported the lymphocyte of healthy carriers with BRCA1 mutation are hypersensitive to invitro ionizing radiation compared to non-carriers without a history of breast cancer. However, it seems this approach is not likely to be useful to distinguish the BRCA carriers from non-carrier with familial history of breast cancer. CONCLUSION: In overall, breast cancer patients are more radiosensitive compared to healthy control; however, inconsistent results exist about the ability of current radiosensitive techniques in screening BRCA1/2 carriers or those susceptible to radiotherapy complications. Therefore, developing further radiosensitivity assay is still warranted to evaluate the DNA repair capacity of individuals with BRCA1/2 mutations and serve as a predictive factor for increased risk of cancer mainly in the relatives of breast cancer patients. Moreover, it can provide more evidence about who is susceptible to manifest severe complication after radiotherapy.

Mendelian Susceptibility to Mycobacterial Disease (MSMD): Clinical and Genetic Features of 32 Iranian Patients.

Mendelian susceptibility to mycobacterial diseases (MSMD) is a rare congenital condition characterized by a selective predisposition to infections caused by weakly virulent mycobacteria and other types of intra-macrophagic pathogens. The 16 genes associated with MSMD display a considerable level of allelic heterogeneity, accounting for 31 distinct disorders with variable clinical presentations and prognosis. Most of MSMD deficiencies are isolated, referred to as selective susceptibility to mycobacterial diseases. However, other deficiencies are syndromic MSMD, defined by the combination of the mycobacterial infection with another, equally common, infectious, specific phenotypes. Herein, we described a series of 32 Iranian MSMD cases identified with seven distinct types of molecular defects, all of which are involved in the interferon gamma (IFNγ) immunity, including interleukin IL-12 receptor-ß1 (IL-12Rß1) deficiency (fifteen cases), IL-12p40 deficiency (ten cases), and IL-23R deficiency (three cases), as well as IFNγ receptor 1 (IFNγR1) deficiency, IFNγ receptor 2 (IFNγR2) deficiency, interferon-stimulated gene 15 (ISG15) deficiency, and tyrosine kinase 2 (TYK2) deficiency each in one case. Since the first report of two MSMD patients in our center, we identified 30 other affected patients with similar clinical manifestations. As the number of reported Iranian cases with MSMD diagnosis has increased in recent years and according to the national vaccination protocol, all Iranian newborns receive BCG vaccination at birth, early diagnosis, and therapeutic intervention which are required for a better outcome and also prevention of similar birth defects. Therefore, we investigated the clinical and molecular features of these 32 patients. The current report also defined novel classes of pathological mutations, further expanding our knowledge of the MSMD molecular basis and associated clinical manifestations.

Clinical, Immunological, and Genetic Features in Patients with Immune Dysregulation, Polyendocrinopathy, Enteropathy, X-linked (IPEX) and IPEX-like Syndrome.

BACKGROUND: Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome is a rare inborn error of immunity caused by mutations in the forkhead box P3 (FOXP3) gene. OBJECTIVE: In this study, we conducted a systematic review of patients with IPEX and IPEX-like syndrome to delineate differences in these 2 major groups. METHODS: The literature search was performed in PubMed, Web of Science, and Scopus databases, and demographic, clinical, immunologic, and molecular data were compared between the IPEX and IPEX-like groups. RESULTS: A total of 459 patients were reported in 148 eligible articles. Major clinical differences between patients with IPEX and IPEX-like syndrome were observed in rates of pneumonia (11% vs 31%, P < .001), bronchiectasis (0.3% vs 14%, P < .001), diarrhea (56% vs 42%, P = .020), and organomegaly (10% vs 23%, P = .001), respectively. Eosinophilia (95% vs 100%), low regulatory T-cell count (68% vs 50%), and elevated IgE (87% vs 61%) were the most prominent laboratory findings in patients with IPEX and IPEX-like syndrome, respectively. In the IPEX group, a lower mortality rate was observed among patients receiving hematopoietic stem cell transplantation (HSCT) (24%) compared with other patients (43%), P = .008; however, in the IPEX-like group, it was not significant (P = .189). CONCLUSIONS: Patients with IPEX syndrome generally suffer from enteropathy, autoimmunity, dermatitis, eosinophilia, and elevated serum IgE. Despite similarities in their clinical presentations, patients with IPEX-like syndrome are more likely to present common variable immunodeficiency-like phenotype such as respiratory tract infections, bronchiectasis, and organomegaly. HSCT is currently the only curative therapy for both IPEX and IPEX-like syndrome and may result in favorable outcome.

Clinical, Immunological, and Genetic Features in 49 Patients With ZAP-70 Deficiency: A Systematic Review.

Background: Zeta-Chain Associated Protein Kinase 70 kDa (ZAP-70) deficiency is a rare combined immunodeficiency (CID) caused by recessive homozygous/compound heterozygous loss-of-function mutations in the ZAP70 gene. Patients with ZAP-70 deficiency present with a variety of clinical manifestations, particularly recurrent respiratory infections and cutaneous involvements. Therefore, a systematic review of ZAP-70 deficiency is helpful to achieve a comprehensive view of this disease. Methods: We searched PubMed, Web of Science, and Scopus databases for all reported ZAP-70 deficient patients and screened against the described eligibility criteria. A total of 49 ZAP-70 deficient patients were identified from 33 articles. For all patients, demographic, clinical, immunologic, and molecular data were collected. Results: ZAP-70 deficient patients have been reported in the literature with a broad spectrum of clinical manifestations including recurrent respiratory infections (81.8%), cutaneous involvement (57.9%), lymphoproliferation (32.4%), autoimmunity (19.4%), enteropathy (18.4%), and increased risk of malignancies (8.1%). The predominant immunologic phenotype was low CD8+ T cell counts (97.9%). Immunologic profiling showed defective antibody production (57%) and decreased lymphocyte responses to mitogenic stimuli such as phytohemagglutinin (PHA) (95%). Mutations of the ZAP70 gene were located throughout the gene, and there was no mutational hotspot. However, most of the mutations were located in the kinase domain. Hematopoietic stem cell transplantation (HSCT) was applied as the major curative treatment in 25 (51%) of the patients, 18 patients survived transplantation, while two patients died and three required a second transplant in order to achieve full remission. Conclusion: Newborns with consanguineous parents, positive family history of CID, and low CD8+ T cell counts should be considered for ZAP-70 deficiency screening, since early diagnosis and treatment with HSCT can lead to a more favorable outcome. Based on the current evidence, there is no genotype-phenotype correlation in ZAP-70 deficient patients.

Dystonia in Ataxia Telangiectasia: A Case Report with Novel Mutations.

Ataxia telangiectasia (A-T) is a common, genetically inherited cause of early childhood-onset ataxia that is classically characterized by progressive cerebellar malfunction, oculocutaneous telangiectasia, genome instability, and immunodeficiency. There is vast phenotype variation in patients with A-T and recently, dystonia, an extrapyramidal movement disorder. Here, we report the case of a 10-year-old girl who had experienced repeated diarrhea and mild gait ataxia since the age of two years. At age seven, ataxia and ocular telangiectasia were evident and immunoglobulin level assessment showed hyper IgM immune phenotype, thus a diagnosis of A-T was made based on clinical and laboratory findings, and she was started on intravenous immunoglobulin therapy. Generalized dystonia appeared when she was 10-years-old. Molecular analysis revealed two heterozygous mutations, c.6259delG and c.6658C>T, in the ATM gene of which one (c.6259delG) is novel. Dystonia can be part of the clinical picture in the A-T disorder and may even mask ataxia. This should be considered as a major feature mainly in variant A-T, which may occur without general ataxia and may be misdiagnosed in adults with primary dystonia.

MiR-4485-3p expression reduced in spermatozoa of men with idiopathic asthenozoospermia.

Asthenozoospermia (AZS), which characterised by reduced forward sperm motility, is a common cause of male infertility. Recently, mitochondrial dysfunction reported in AZS men came to attention for finding the molecular aetiology of AZS. Mitochondria-related microRNAs (miRNAs) are the most important regulators of mitochondrial function through post-transcriptionally modulation of gene expression. Therefore, this study aims to evaluate the expression of four recently reported mitochondrial-related miRNAs (miR-4485-3p/4484/4461 and 4463) in the sperm sample of asthenozoospermic men. RNA was extracted from spermatozoa of 74 volunteers (39 patients with idiopathic AZS and 35 controls with normal fertility), and relative gene expression analysis was performed by quantitative PCR. We used SNORD48 as a normaliser gene, and quantification was calculated by 2-ΔΔCt method. The expression of miR-4484 and miR-4461 was not detected in the spermatozoa of cases and controls. However, miR-4485-3p (p = .006) was significantly downregulated in the AZS men compared with the controls, but the miR-4463 expression was not significantly different between the two groups (p = .5). Bioinformatic analysis identified three target genes for miR-4485-3p (DNAH1, KIT and PARK7) that are related to male infertility. In conclusion, the downregulation of miR-4485-3p was associated with idiopathic AZS, which could be a molecular link between mitochondrial dysfunction and AZS.

Clinical, Immunological, and Genetic Features in Patients with Activated PI3Kδ Syndrome (APDS): a Systematic Review.

Activated phosphoinositide 3-kinase delta syndrome (APDS) is a novel primary immunodeficiency (PID) caused by heterozygous gain of function mutations in PI3Kδ catalytic p110δ (PIK3CD) or regulatory p85α (PIK3R1) subunits leading to APDS1 and APDS2, respectively. Patients with APDS present a spectrum of clinical manifestations, particularly recurrent respiratory infections and lymphoproliferation. We searched PubMed, Web of Science, and Scopus databases for APDS patients and screened for eligibility criteria. A total of 243 APDS patients were identified from 55 articles. For all patients, demographic, clinical, immunologic, and molecular data were collected. Overall, 179 APDS1 and 64 APDS2 patients were identified. The most common clinical manifestations were respiratory tract infections (pneumonia (43.6%), otitis media (28.8%), and sinusitis (25.9%)), lymphoproliferation (70.4%), autoimmunity (28%), enteropathy (26.7%), failure to thrive (20.6%), and malignancy (12.8%). The predominant immunologic phenotype was hyper-IgM syndrome (48.1%). Immunologic profiling showed decreased B cells in 74.8% and CD4+ T cells in 64.8% of APDS patients. The c.3061 G>A (p. E1021K) mutation in APDS1 with 85% frequency and c.1425+1 G> (A, C, T) (p.434-475del) mutation in APDS2 with 79% frequency were hotspot mutations. The majority of APDS patients were placed on long-term immunoglobulin replacement therapy. Immunosuppressive agents such as rituximab, tacrolimus, rapamycin, and leniolisib were also administered for autoimmunity and inflammatory complications. In addition, hematopoietic stem cell transplantation (HSCT) was used in 12.8% of patients. APDS has heterogynous clinical manifestations. It should be suspected in patients with history of recurrent respiratory infections, lymphoproliferation, and raised IgM levels. Moreover, HSCT should be considered in patients with severe and complicated clinical manifestations with no or insufficient response to the conventional therapies.