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Inherited hemolytic anemia is one of the most commonly seen anemias encountred in the pediatric age, especially in Türkiye, where consanguineous marriages are common. Inherited hemolytic anemias mainly includes hemoglobinopathies, erythrocyte membrane defects and enzyme defects. Hemolytic anemias have a wide etiology and clinical spectrum with acquired and hereditary causes in childhood. Always a careful self and family history review and synthesis of physical examination and laboratory findings are vital for differential diagnosis. Therefore, physicians should be competent about prevention methods and early diagnosis markers.

Background: In 2014, germline signal transducer and activator of transcription (STAT) 3 gain-of-function (GOF) mutations were first described to cause a novel multisystem disease of early-onset lymphoproliferation and autoimmunity. Objective: This pivotal cohort study defines the scope, natural history, treatment, and overall survival of a large global cohort of patients with pathogenic STAT3 GOF variants. Methods: We identified 191 patients from 33 countries with 72 unique mutations. Inclusion criteria included symptoms of immune dysregulation and a biochemically confirmed germline heterozygous GOF variant in STAT3. Results: Overall survival was 88%, median age at onset of symptoms was 2.3 years, and median age at diagnosis was 12 years. Immune dysregulatory features were present in all patients: lymphoproliferation was the most common manifestation (73%); increased frequencies of double-negative (CD4−CD8−) T cells were found in 83% of patients tested. Autoimmune cytopenias were the second most common clinical manifestation (67%), followed by growth delay, enteropathy, skin disease, pulmonary disease, endocrinopathy, arthritis, autoimmune hepatitis, neurologic disease, vasculopathy, renal disease, and malignancy. Infections were reported in 72% of the cohort. A cellular and humoral immunodeficiency was observed in 37% and 51% of patients, respectively. Clinical symptoms dramatically improved in patients treated with JAK inhibitors, while a variety of other immunomodulatory treatment modalities were less efficacious. Thus far, 23 patients have undergone bone marrow transplantation, with a 62% survival rate. Conclusion:: STAT3 GOF patients present with a wide array of immune-mediated disease including lymphoproliferation, autoimmune cytopenias, and multisystem autoimmunity. Patient care tends to be siloed, without a clear treatment strategy. Thus, early identification and prompt treatment implementation are lifesaving for STAT3 GOF syndrome.

Hemophagocytic lymphohistiocytosis should be considered in patients with persistent fever, hepatosplenomegaly, pancytopenia. Hypercytokinemia originated from genetic disorder effecting the cellular defects of cytotoxic T and natural killer lymphocyte activity is the underlying pathophysiology of the disorder. In this review we summarized the recent advances in the management of hemophagocytic lymphohistiocytosis.

© 2022Background: Sitosterolemia, also known as phytosterolemia, results from increased intestinal absorption of plant sterols and decreased intestinal and biliary excretion of sterols, resulting in increased levels of plant sterols in the plasma. The most common symptoms include xanthomas, premature atherosclerosis, hemolytic anemia and macrothrombocytopenia, however delayed diagnosis or misdiagnosis also occur. Patient and methods: Clinical exome sequencing was performed on a 10-year-old boy whom we followed up with signs of pancytopenia accompanied by macrothrombocytopenia and stomatocytosis. In addition, the blood sterol levels of the patient and his family were studied. Results: A novel homozygous c.904 + 5G > C intronic variant was detected in ABCG5 gene in index case. The mother and father were identified as carriers. The blood plant sterol levels of the patient and his family were studied, and the levels in the patient confirmed Sitosterolemia. Sitosterol levels decreased dramatically with restricted diet and ezetimibe treatment. Conclusion: In children, signs of Sitosterolemia may be subtle and the only symptom may be hematological. Therefore, Sitosterolemia should be kept in mind in children with stomatocytosis and macrothrombocytopenia.

Background Colorectal cancer (CRC) is the second most common cancer in both women and men. Microsatellite instabil (MSI-H) CRC is a molecular subgroup and has distinct clinical and pathologic features from non-MSI-H CRC. Studies have suggested an association between hereditary antigens in the human blood group system and the risk of developing various cancers but the relationship between blood groups and MSI-H colorectal carcinoma has not been investigated. This study aimed to investigate the relationship between microsatellite instability and ABO blood group in patients with MSI-H colorectal carcinoma. Methods A total of 144 patients operated for non-metastatic colorectal cancer including 72 patients with MSI-H and 72 patients with non-MSI-H colorectal cancer as the control group, were included in the study. Demographic and clinicopathological features, blood groups and microsatellite status were examined among two groups. Microsatellit instability was examined by immunhistochemistery(IHC). Results Among all patients, the median age was 59.65 (range 24–89) and 57.6% were male. MSI-H and non-MSI-H groups were similar in terms of age, gender distribution and comorbidities. Patients with MSI-H CRC had significantly common O-blood-group than non-MSI-H group (44.4% vs 18.1%, p:0.001). Also patients with MSI-H colorectal cancer were found to have significantly more right-sided (73.6% vs 36.1%, p

BACKGROUND: Inborn errors of immunity (IEI) are rare diseases, which makes diagnosis a challenge. A better description of the initial presenting manifestations should improve awareness and avoid diagnostic delay. Although increased infection susceptibility is a well-known initial IEI manifestation, less is known about the frequency of other presenting manifestations.OBJECTIVE: We sought to analyze age-related initial presenting manifestations of IEI including different IEI disease cohorts.METHODS: We analyzed data on 16,486 patients of the European Society for Immunodeficiencies Registry. Patients with autoinflammatory diseases were excluded because of the limited number registered.RESULTS: Overall, 68% of patients initially presented with infections only, 9% with immune dysregulation only, and 9% with a combination of both. Syndromic features were the presenting feature in 12%, 4% had laboratory abnormalities only, 1.5% were diagnosed because of family history only, and 0.8% presented with malignancy. Two-third of patients with IEI presented before the age of 6 years, but a quarter of patients developed initial symptoms only as adults. Immune dysregulation was most frequently recognized as an initial IEI manifestation between age 6 and 25 years, with male predominance until age 10 years, shifting to female predominance after age 40 years. Infections were most prevalent as a first manifestation in patients presenting after age 30 years.CONCLUSIONS: An exclusive focus on infection-centered warning signs would have missed around 25% of patients with IEI who initially present with other manifestations.

Background Previous studies have shown that pelvimetry can be valuable in predicting surgical difficulties in rectal cancer operations. However, its usability in predicting circumferential resection margin (CRM) involvement remains debatable. This study investigated the factors affecting CRM status and the importance of computed tomography (CT) pelvimetry in predicting CRM involvement in laparoscopic resection of middle and lower rectal cancer. Methodology In this study, we retrospectively investigated the data of 111 patients who underwent a laparoscopic operation for middle and lower rectum cancer at Ankara University Faculty of Medicine, Department of Surgical Oncology between January 2014 and January 2020. The predictive value of CT pelvimetry and other variables on the CRM status was analyzed. Results The following four pelvic parameters differed significantly between the genders: transverse diameter of the pelvic inlet (p = 0.024), anteroposterior diameter of the pelvic outlet (p = 0.003), transverse diameter of the pelvic outlet (p0.001), and pelvic depth (p0.001). The effect of pelvic anatomic parameters on CRM involvement was not found to be significant. It was found that tumor height from the anal verge (p = 0.004), tumor size (p0.001), and gender (p = 0.033) were significant risk factors for CRM involvement. Survival was poor in patients with male gender (p = 0.032), perineural invasion (p0.001), and grade 3 tumor. Conclusions In this study, no benefit was found in predicting CRM positivity from CT pelvimetry in the laparoscopic resection of middle and lower rectal cancer. Besides, tumor height from the anal verge, tumor size, and gender were important factors for CRM positivity. Although our study sheds light on this issue, prospective randomized studies with larger sample sizes are needed.

The traditional treatment for appendiceal cancer with peritoneal spread is cytoreductive surgery (CRS) but added HİPEC chemotherapy to cytoreductive surgery and has shown that it improves overall survival. The aim of this study was to report the results of CRS and HIPEC treated patients with appendiceal cancers which is based on the experience of at Surgical oncology department.Ankara University School of Medicine, Deparment of Surgical Oncology. The data of patients who underwent CRS + HIPEC for appendiceal cancer between January 2008 - January 2019 was retrospectively analysed. 40 patients who underwent CRS + HIPEC were evaluated retrospectively. Patients with unresectable liver metastasis, large retroperitoneal tumor, tumoral infiltration in the intestinal mesentery and liver hilum were excluded from the study.The mean (±sd) PCI was 17.98 (±8.21). Twenty six patients's completeness of cytoreduction score was 0(65.0%), 10(25.0%) CCS-1, 3(7.5%) CCS-2 and 1(2.5%) CCS-3. There was statistically significant difference with prognosis between ccr score, ASA, lymphovascular invasion, PCI score, albumin categories.In selected patients survival can be increased. However, it is thought that cytoreductive surgery should be performed even if completeness of cytoreduction score is two. In our study we represent that17PCI patients could be managed by CRS/HIPEC if the CC score ≤2 can be reached. Our results suggest that the CRS/HIPEC procedure can improve the benefits of larger patient group and provides longer survival.Appendiceal Neoplasms, Cytoreductive Surgery, Hyperthermic Intraperitoneal Chemotherapy.Il trattamento tradizionale per il cancro dell’appendice con diffusione peritoneale è la chirurgia citoriduttiva (CRS), ma l’aggiunta della chemioterapia HİPEC alla chirurgia citoriduttiva ha dimostrato di migliorare la sopravvivenza globale. Lo scopo di questo studio è stato quello di riportare i risultati dei pazienti trattati con CRS e HIPEC in tumori appendicolari che si basa sull’esperienza del Dipartimento di Oncologia Chirurgica della Facoltà di Medicina dell’Università di Ankara. I dati di 40 pazienti sottoposti a CRS + HIPEC per cancro appendicolare tra gennaio 2008 e gennaio 2019 sono stati analizzati in modo retrospettivo. Sono stati esclusi dallo studio i pazienti con metastasi epatiche non resecabili, grande tumore retroperitoneale, infiltrazione tumorale nel mesentere intestinale e dell’ilo epatico. Risultati: la media (± sd) del PCI era 17,98 (± 8,21). Il punteggio di completamento della citoriduzione di ventisei pazienti era 0 (65,0%), 10 (25,0%) CCS-1, 3 (7,5%) CCS-2 e 1 (2,5%) CCS-3. È risultata una differenza statisticamente significativa nella prognosi tra punteggio ccr, ASA, invasione linfovascolare, punteggio PCI, categorie di albumina. Conclusioni: in pazienti selezionati la sopravvivenza può essere aumentata con questa associazione. Tuttavia, si ritiene che la chirurgia citoriduttiva debba essere eseguita anche se il punteggio di completezza della citoriduzione è due. Nel nostro studio risulta che pazienti con PCI17 potrebbero essere gestiti con CRS / HIPEC se può essere raggiunto il punteggio cc ≤2. I nostri risultati suggeriscono che la procedura CRS / HIPEC può migliorare i benefici di un gruppo di pazienti più ampio e fornisce una sopravvivenza più lunga.

SRPRA and SRP19 are novel genes affected in congenital neutropenia and essential for granule protein processing.Comparative proteomics in neutrophil granulocytesThe mechanisms of coordinated changes in proteome composition and their relevance for the differentiation of neutrophil granulocytes are not well studied. Here, we discover two novel human genetic defects in SRPRA and SRP19, constituents of the mammalian co-translational targeting machinery and characterize their role in neutrophil granulocyte differentiation. We systematically study the proteome of neutrophil granulocytes from patients with variants in the signal recognition particle (SRP) genes, HAX1, and ELANE and identify global as well as specific proteome aberrations. Using in vitro differentiation of human induced pluripotent stem cells and in vivo zebrafish models, we study the effects of SRP-deficiency on neutrophil granulocyte development. In a heterologous cell-based inducible protein expression system, we validate the effects conferred by SRP dysfunction for selected proteins that we identified in our proteome screen. Thus, SRP-dependent protein processing, intracellular trafficking and homeostasis are critically important for the differentiation of neutrophil granulocytes.

Aim: Neuroblastoma is a tumor with a high mortality rate originating from primitive sympathetic ganglion cells. In recent years, the definition of "ultra high-risk" has been used, in which the response to treatment is added in addition to the disease characteristics. In this study, the results of tandem high-dose Iodine 131 (131I) metaiodobenzylguanidine (MIBG) and tandem autologous hematopoietic stem cell transplantation (HSCT) in patients who were diagnosed as refractory after first-line treatments and considered with ultra-high risk nöroblastom (NBL) in Erciyes University Medical Faculty Pediatric Bone Marrow Transplant Center were shared. Material and Method: Eleven patients who underwent tandem MIBG and autologous HSCT with the diagnosis of refractory/ultra high-risk NBL between 2011 and 2021 were included in the study. Patient's data were obtained retrospectively using an electronic or manuscript medical record. Results: Tandem autologous HSCT and MIBG treatment were applied to 11 patients with a median age of 40.5 months who were diagnosed with refractory/ultra high-risk neuroblastoma. In our study, the overall survival rate was 54.5% and event-free survival (EFS) was 39% at a median follow-up of 20.7 (7.8-105.6) months. Of the 6 surviving patients, 4 are followed in complete remission and 2 in partial remission. Conclusion: Our study is the only study that includes a group of patients who received tandem high-dose MIBG and tandem autologous HSCT transplantation in refractory NBL patients without cytokine and immunotherapy. Tandem transplantation and MIBG therapy in ultra-high-risk NBL cases remain promising with acceptable toxicity. Adding immunotherapy to this treatment protocol and combining it with new treatment modalities such as anaplastic lymphoma kinase (ALK), which also takes into account genetic characteristics, may increase survival and event-free survival rates.

Aim: Hodgkin lymphoma (HL) constitutes 40% of childhood lymphomas and approximately 6% of all childhood cancers. It is tried to achieve cure with combined treatment modalities consisting of chemotherapy, radiotherapy, monoclonal antibodies, and new treatment agents such as nivolumab. Radiotherapy-related infertility, secondary cancer, thyroid dysfunction, cardiovascular diseases, pulmonary fibrosis, and local skin reactions can be seen in the pediatric age group with a long life expectancy. In this article, pediatric patients diagnosed with Hodgkin lymphoma without the use of radiotherapy in the treatment were evaluated retrospectively and the survival results were reported as a single-center experience. Material and Method: The patients with Hodgkin Lymphoma in the Pediatrics Hematology-Oncology Center at Erciyes University between January 2010 and December 2019 were included in the study and the data of the patients were evaluated retrospectively. Results: In 68 pediatric patients with a mean age of 10.7 (±4.6) years, the male/female ratio was 1.3. The most detected finding at the time of diagnosis was cervical lymphadenopathy (83.8%). The most common mixed cellular subtype was identified (48.5%). Stage I-II disease was observed in 38.3% of the patients, and stage III-IV disease was observed in 61.7% of the patients. The median follow-up period of the patients was 61 (range, 8.3-161.6) months. Disease-free survival and overall survival were 85.3% and 94.1%, respectively. Treatment modalities to be used in this disease group, which has a high chance of cure after cytotoxic treatment, should be selected considering treatment-related long-term complications. Conclusion: Acceptable good results obtained without radiotherapy are satisfactory and the chance of curative success will increase with the addition of new target agents to the treatment.

Aim: Autoimmune hemolytic anemia (AIHA) is characterized by the production of antibodies directed against red blood cells. We aimed to describe the clinical presentation, hematologic and biochemical profiles, treatment modalities, underlying diseases and outcomes in children suffering from AIHA. Material and Method: In a retrospectively manner, we consecutively recrutied 62 children (aged 1 month-18 years) with AIHA who had been followed in Erciyes University Child Hospital between January, 2000 and November, 2017. Results: The mean age at time of diagnosis was 61.9±51.9 months (range:1-192) in 62 children including 28 girls and 34 boys. The most common complaints included fatigue and fever while the most common findings were jaundice and hepatosplenomegaly. In 22 children (35.4%), there was a comorbid, active, non-specific infection (upper respiratory tract infection, lower respiratory tract infection, diarrhea, urinary tract infection). At time of diagnosis, mean hemoglobin (Hb) level was 6.9±2.5 g/dL (range: 5-9). The glucocorticoid therapy was given in majority of the patients while no medical treatment was given to 4 patients. Of the patients with primary AIHA, 6 patients were unresponsive to the treatment while one patient responded partially. It was found that there were underlying risk factors in 36 patients with secondary AIHA, as immunodeficiency and autoimmune disorders being the most common risk factors. Conclusion: The immunodeficiencies were highly prevalent in children included. By advance of whole exome sequencing technology, we believe that primary immunodeficiencies was the most common underlying disease in our study detected quite high in presented children.

In order to create a nomogram for the gastric cancer no comprehensive study has been performed in Turkey so far and in our study, we tried to forecast the 10-year survival by using risk factors in patients without distant metastasis, who have not previously been diagnosed with another cancer but who underwent curative surgery.The data of 411 patients who underwent gastrectomy for gastric cancer between January 2010 and January 2020 in Surgical Oncology Department were retrospectively examined.It has been shown statistically that the high RDW value point to poor survival (p0.001). There were 173 patients with ≤3.5g/dl and 238 patients with3.5g/dl. It was found out statistically significant that hypoalbuminemia indicated poor survival (p0.001). Moreover, it was determined that high CEA and Ca19-9 with lymphovascular invasion were to be statistically significant with prognosis (p0.001). On the based of all this data, we have created a dekstop application for the mortality estimation.We think that this model will ensure individualization of the treatment for patients and will contribute to the patient's compliance with the treatment by strengthening the communication between the physician.Gastric cancer, Gastrectomy, Survival analysis, Prognosis.Finora non è stato condotto nessuno studio completo in Turchia al fine di creare un nomogramma per il cancro gastrico, e nel nostro studio abbiamo cercato di prevedere la sopravvivenza a 10 anni utilizzando fattori di rischio in pazienti senza metastasi a distanza, che non sono stati precedentemente diagnosticati con un altro cancro ma che hanno subito un intervento chirurgico curativo. Per questo sono stati esaminati retrospettivamente i dati di 411 pazienti sottoposti a gastrectomia per cancro gastrico tra gennaio 2010 e gennaio 2020 presso il Dipartimento di Chirurgia Oncologica. Risultati: è stato dimostrato statisticamente che l’alto valore di RDW indica una scarsa sopravvivenza (p0,001). C’erano 173 pazienti con ≤3,5 g / dl e 238 pazienti con3,5 g / dl. È stato riscontrato statisticamente significativo che l’ipoalbuminemia indicava una scarsa sopravvivenza (p0,001). Inoltre, è stato determinato che un CEA e un Ca19-9 elevati con invasione linfovascolare dovevano essere statisticamente significativi con la prognosi (p0,001). Sulla base di tutti questi dati, abbiamo creato un’applicazione dekstop per la stima della mortalità. Conclusione: riteniamo che questo modello garantirà l’individualizzazione del trattamento per i pazienti e contribuirà alla compliance del paziente al trattamento rafforzando la comunicazione con il medico.

Insufficient dietary folate intake, hereditary malabsorption, or defects in folate metabolism may lead to combined immunodeficiency (CID). Although loss of function mutations in the major intestinal folate transporter PCFT/SLC46A1 was shown to be associated with CID, the evidence for pathogenic variants of RFC/SLC19A1 resulting in immunodeficiency was lacking. In this study, we report two cousins carrying a homozygous pathogenic variant c.1042G>A, resulting in p.G348R substitution who showed clinical symptoms of immunodeficiency associated with defects of folate metabolism. The mutation was identified by whole-exome sequencing. SLC19A1 expression by peripheral blood mononuclear cells (PBMC) was quantified by real-time qPCR and immunostaining. T cell proliferation, methotrexate resistance, NK cell cytotoxicity, Treg cells and cytokine production by T cells were examined by flow cytometric assays. Both patients were treated with and clinically benefited from folinic acid (FA). Functional studies revealed normal NK cell cytotoxicity, Treg cell counts, and naive-memory T cell percentages. Although SLC19A1 mRNA and protein expression were unaltered, remarkably, mitogen induced-T cell proliferation was significantly reduced at sub- and supraoptimal folic acid concentrations. In addition, both patients’ PBMCs were resistant to methotrexate-induced apoptosis supporting a functionally defective SLC19A1 variant. This study, to our knowledge, presents the second pathogenic SLC19A1 variant in the literature, providing the first experimental evidence that loss of function mutations in SLC19A1 may present with symptoms of immunodeficiency, and that those defects could benefit from FA supplementation.

BACKROUND The COVID-19 pandemic has caused delays in diagnosis, and treatment of breast cancer patients. We predicted that the effects of the pandemic on breast cancer patients would decrease during the post-vaccination period. METHODS The data of 131 female patients who were operated on for breast cancer between March 2019, and March 2022, were analyzed into 3 groups: the control group (CG) between March 2019–2020, the pandemic group (PG) between March 2020–2021, and the vaccine group (VG) between March 2021 - March 2022. Patient admission time (PAT), diagnosis time (DT), tumor size, TNM classification and etc data were analyzed. RESULTS Prolonged PAT times in PG compared to CG were observed to be significantly reduced in VG (p = 0.009). In both PG and VG, the DTs were prolonged significantly (p

Recipients of hematopoietic stem cell transplantation (HSCT) with HLA-mismatched donors are more immune suppressed than those with fully matched donors. The immunologic response to vaccines also may differ in HLA-mismatched haploidentical HSCT recipients. In this study, we aimed to evaluate the antibody response to vaccines in pediatric TCRαβ-depleted haploidentical HSCT recipients. This longitudinal study included a study group of 21 children who underwent haploidentical HSCT without CD19 depletion and with TCRαβ depletion and a control group of 38 children who underwent fully matched donor HSCT. Antibody levels were quantified by serologic tests before vaccination and after each dose against tetanus, diphtheria, pneumococcal disease, hepatitis B, hepatitis A, measles, rubella, mumps, and varicella. The median recipient age was significantly lower (P = .037) and the median donor age was significantly higher (P = .000) in the haploidentical group compared with the fully matched group. At 1 year post-transplantation, the median CD4, CD8, and CD19 cell counts and lymphocyte counts were similar in the haploidentical and fully matched groups. The median natural killer cell count was higher in the haploidentical group at the months 1, 3, and 6 post-transplantation (P = .001, .006, and .004, respectively). The median time to first vaccination was similar in the 2 groups (12.5 [range, 11 to 14] months for the haploidentical group and 11 [range, 9 to 13] months for the fully matched group; P = .441). Seroprotection rates were 100% in both groups after the second and third doses of diphtheria vaccine, the third dose of tetanus vaccine, the third dose of hepatitis B vaccine, the second and third doses of pneumococcal conjugate vaccines (PCV13), and pneumococcal polysaccharide vaccine (PSPV23), although lower after the initial doses and before vaccination. Seroprotection for hepatitis A, rubella, and varicella was90% in the fully matched group and 100% for the haploidentical group after the second doses. Measles and mumps seroprotection rates were80% in the haploidentical group and approximately 70% for the fully matched group after the second dose. Antibody response and seroprotection rates against vaccine antigens were similar in the haploidentical group and the fully matched when revaccination was started at 12 months post-transplantation. These findings support the idea that TCRαβ-depleted haploidentical HSCT recipients can be revaccinated according to the same vaccination schedule as fully matched HSCT recipients. Revaccination earlier after transplantation and vaccine responses for recipients of different types of HSCT should be evaluated in future studies.

© 2021 European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd. This article has been contributed to by US Government employees and their work is in the public domain in the USA.Background: Biallelic loss-of-function mutations in CARMIL2 cause combined immunodeficiency associated with dermatitis, inflammatory bowel disease (IBD), and EBV-related smooth muscle tumors. Clinical and immunological characterizations of the disease with long-term follow-up and treatment options have not been previously reported in large cohorts. We sought to determine the clinical and immunological features of CARMIL2 deficiency and long-term efficacy of treatment in controlling different disease manifestations. Methods: The presenting phenotypes, long-term outcomes, and treatment responses were evaluated prospectively in 15 CARMIL2-deficient patients, including 13 novel cases. Lymphocyte subpopulations, protein expression, regulatory T (Treg), and circulating T follicular helper (cTFH) cells were analyzed. Three-dimensional (3D) migration assay was performed to determine T-cell shape. Results: Mean age at disease onset was 38 ± 23 months. Main clinical features were skin manifestations (n = 14, 93%), failure to thrive (n = 10, 67%), recurrent infections (n = 10, 67%), allergic symptoms (n = 8, 53%), chronic diarrhea (n = 4, 27%), and EBV-related leiomyoma (n = 2, 13%). Skin manifestations ranged from atopic and seborrheic dermatitis to psoriasiform rash. Patients had reduced proportions of memory CD4+ T cells, Treg, and cTFH cells. Memory B and NK cells were also decreased. CARMIL2-deficient T cells exhibited reduced T-cell proliferation and cytokine production following CD28 co-stimulation and normal morphology when migrating in a high-density 3D collagen gel matrix. IBD was the most severe clinical manifestation, leading to growth retardation, requiring multiple interventional treatments. All patients were alive with a median follow-up of 10.8 years (range: 3–17 years). Conclusion: This cohort provides clinical and immunological features and long-term follow-up of different manifestations of CARMIL2 deficiency.

The essential characteristics of posterior reversible encephalopathy syndrome (PRES) are the presence of acute onset neurologic symptoms, focal vasogenic edema at neuroimaging, and reversible clinical and/or radiologic findings. This study aimed to evaluate the clinical findings, causes, radiologic findings, and prognoses of patients with PRES.Patients with PRES confirmed with clinical and radiologic findings by a pediatric neurologist were evaluated retrospectively.Seventeen patients with PRES were evaluated (mean age at onset, 10.23 ± 4.65 years; range, 2-17 years; girls, 29.4% [n = 5]). The mean length of follow-up was 6 ± 2.3 years (range, 3.4-10 years). Mortality due to primary disease occurred in 4 patients (23.5%) during follow-up. PRES was derived from renal diseases in 10 patients (58.8%), hematologic diseases in 6 patients (35.3%), and liver disease in one patient (5.9%). Hypertension was present in 16 patients (94.1%) at onset of PRES (99th percentile). Seizure, the most frequent initial symptom, was observed in 82.4% (n = 14). Blurred vision and headache were the initial symptoms in 3 patients (17.6%). Sequelae were observed at magnetic resonance imaging (MRI) in 6 patients. Development of epilepsy was determined as a sequela in 4 patients (23.5%) and mental motor retardation in 2 patients (11.8%).Epilepsy is uncommon in patients who have recovered from PRES. The presence of gliosis on MRI and interictal epileptic discharges on electroencephalograms are major risk factors for the development of epilepsy. Antiepileptic treatment can be stopped in the early period in patients with normal MRI and electroencephalogram by eliminating the factors that trigger the seizures.

© 2022 Taylor & Francis Group, LLC.Aceruloplasminemia inherited autosomal recessively in the ceruloplasmin gene is a progressive disease with iron accumulation in various organs such as the brain, liver, pancreas, and retina. Ceruloplasmin gene encodes ceruloplasmin protein, which has ferroxidase activity and is involved in copper and iron metabolism. Progressive neurotoxicity, retinopathy, and diabetes may develop in about 40-60 decades. In addition, microcytic anemia accompanied by high ferritin and low ceruloplasmin level that develop at earlier ages can be first manifestation. Iron chelation may be utilized in the treatment to reduce the toxicity. Early diagnosis and treatment may delay the onset of symptoms. A 14-year-old male patient was followed up with microcytic anemia since an eight-years old. Anemia was accompanied by microcytosis, high ferritin, and low copper and ceruloplasmin levels. A novel homozygous c.690delG variant was detected in ceruloplasmin by whole exome sequencing. Clinical, laboratory and imaging findings of the patient demonstrated aceruloplasminemia. We present a boy with persistent microcytic anemia of the first manifestation at the age of eight, as the youngest case of aceruloplasminemia in the literature. Thereby, aceruloplasminemia should be kept in mind in the etiology of microcytic anemia whose cause couldn’t found in childhood.

Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.Severe congenital neutropenia (SCN) is a rare disease. Autosomal recessive forms of SCN are more frequent in countries where consanguineous marriages are common. In this report, we describe a 54-day-old female with neutropenia who presented with ecthyma gangrenosum. Clinical exome sequencing was used to identify the mutation. HAX1 messenger RNA and isoforms were examined by real-time quantitative and conventional polymerase chain reaction. Bone marrow aspiration was stained by hematoxylin and eosin. Granulocytes were tested for apoptosis upon H2O2 exposure. T-cell proliferation was tested by flow cytometry. Clinical exome sequencing revealed a novel homozygous acceptor splice site mutation in intron 3 of HAX1 (c.505-1G > C), which reduced both isoforms A and B of HAX1 messenger RNA. The Western blot studies showed a complete absence of HAX1 protein. The purified neutrophils from the patient showed increased apoptosis upon H2O2 exposure, whereas T-cell proliferative responses to various stimuli were intact. The patient was treated with combined antibiotics, filgrastim, and placed on antibiotics prophylaxis. To the best of our knowledge, our data provide the first experimental evidence for HAX1 deficiency because of a splice site mutation. Although 3 other splice site variants have been deposited in databases, functional studies were missing. This novel variant of HAX1 may explain the SCN and secondary infections in our patients.

Objective Hemophilia A (HA) is the most severe X-linked inherited bleeding disorder caused by hemizygous mutations in the factor 8 (F8) gene. The aim of this study is to determine the mutation spectrum of the F8 gene in a large HA cohort from Turkey, and then to establish a phenotype-genotype correlation. Materials and methods All HA cases (270 patients) analyzed molecularly in the Ege University Pediatric Genetics Molecular Laboratory between March 2017 and March 2018 were included in this study. To identify intron 22 inversion (Inv22), intron 1 inversion (Inv1), small deletion/insertions, and point mutations, molecular analyses of F8 were performed using a sequential application of molecular techniques. Results The mutation detection success rate was 95.2%. Positive Inv22 was found in 106 patients (39.3%), Inv1 was found in 4 patients (1.5%), and 106 different disease-causing sequence variants were identified in 137 patients (50.6%). In 10 patients (3.7%), amplification failures involving one or more exonic regions, considered to be large intragenic deletions, were identified. Of 106 different F8 mutations, 36 were novel. The relationship between F8 genotype and inhibitor development was considered significant. Conclusion A high mutation detection rate was achieved via the broad molecular techniques applied in this study, including 36 novel mutations. With regard to mutation types, mutation distribution and their impact on clinical severity and inhibitor development were found to be similar to those previously reported in other hemophilia population studies.

Children with constitutional mismatch repair deficiency syndrome (CMMRDS) are prone to different types of cancers. A 16-year-old girl who was misdiagnosed with neurofibromatosis Type-I (NF-I) for 1 years had experienced glioblastoma and colonic adenocarcinoma. After operation, chemotherapy and radiotherapy were started for adenocarcinoma. Genetic analysis from the patient, effected brother, and mother showed heterozygote (c.479 + 36A> G) mutation in the intron 4 region of NF-1 gene. Initially, it was thought that this genetic variant was causative. Furthermore, next generation sequencing showed that the index patient and his brother have homozygote (c.1444 C>T) mutations in the MSH6 gene which are associated with CMMRDS both died because of colonic adenocarcinoma, and T cell non-Hodgkin lymphoma, respectively. Patients with CMMRDS may resemble NF-I. The physicians must not be confused with the previous diagnosis. Increased awareness of CMMRDS, and prompt evaluation for an underlying genetic background is advised if there are unexpected cancer in patients with NF-I.

OBJECTIVE: Vena cava superior syndrome comprises various symptoms of compression of vena cava superior. The results of increased venous pressure in the upper body may cause edema of the head and neck associated with cyanosis, plethora and distended subcutaneous vessels. Vena cava superior syndrome is rare in childhood. Therefore, we planned this retrospective study. METHODS: The retrospective study was carried out on the children with mediastinal tumors in the Department of Pediatric Hematology-oncology, Erciyes University Faculty of Medicine, Kayseri, Turkey , from January 2010 to December 2017. Diagnostic procedures included hematological investigations, chestradiography, thoracic computed tomography, echocardiography and lymph node or mediastinal biopsy. RESULTS: In this study, 19 (five were female) of 41 patients with mediastinal tumors had Vena cava superior syndrome. Diagnosis included Hodgkin’s lymphoma in seven (37%), non-Hodgkin’s lymphoma in six (32%), acute T- lymphoblastic leukemia in four (21%), neuroblastoma and anaplastic round cell sarcoma in one each respectively. All of the 19 patients’ facial swelling, venous distention and mediastinal widening. All patients received intravenous corticosteroids (0.6 mg/kg dexamethasone). Furthermore, the patient with anaplastic round cell sarcoma received emergency radiotherapy. No patients died because of Vena cava superior syndrome. CONCLUSION: Vena cava superior syndrome is a medical emergency that requiresurgent treatment. Vena cava superior syndrome studies in children are rare. In this retrospective study, we found that the most common cause of Vena cava superior syndrome was Hodgkin’s lymphoma different from literature.

Clathrin-mediated endocytosis (CME) is critical for internalisation of molecules across cell membranes. The FCH domain only 1 (FCHO1) protein is key molecule involved in the early stages of CME formation. The consequences of mutations in FCHO1 in humans were unknown. We identify ten unrelated patients with variable T and B cell lymphopenia, who are homozygous for six distinct mutations in FCHO1. We demonstrate that these mutations either lead to mislocalisation of the protein or prevent its interaction with binding partners. Live-cell imaging of cells expressing mutant variants of FCHO1 provide evidence of impaired formation of clathrin coated pits (CCP). Patient T cells are unresponsive to T cell receptor (TCR) triggering. Internalisation of the TCR receptor is severely perturbed in FCHO1-deficient Jurkat T cells but can be rescued by expression of wild-type FCHO1. Thus, we discovered a previously unrecognised critical role of FCHO1 and CME during T-cell development and function in humans. FCH domain only 1 (FCHO1) is a key molecule involved in clathrin-mediated endocytosis (CME). Here, the authors report homozygous FCHO1 mutations in individuals with variable T and B cell lymphopenia, which are associated with loss-of-function of FCHO1 and impaired formation of clathrin-coated pits in T cells.

Allogeneic hematopoietic stem cell transplantation is the treatment of choice for autosomal recessive osteopetrosis caused by defects in the TCIRG1 gene. Despite recent progress in conditioning, an important number of patients are not eligible for allogeneic stem cell transplantation because of the severity of the disease and significant transplant-related morbidity. We exploited peripheral CD34(+) cells, known to circulate at high frequency in the peripheral blood of TCIRG1-deficient patients, as a novel cell source for autologous transplantation of gene corrected cells. Detailed phenotypical analysis showed that circulating CD34(+). cells have a cellular composition that resembles bone marrow (BM), supporting their use in gene therapy protocols. Transcriptomic profile revealed enrichment in genes expressed by hematopoietic stem and progenitor cells (HSPC). To overcome the limit of BM harvest/HSPC mobilization and serial blood drawings in TCIRG1 patients, we applied UM171-based ex vivo expansion of HSPC coupled with lentiviral gene transfer. Circulating CD34(+). cells from TCIRG1-defective patients were transduced with a clinically-optimized lentiviral vector expressing TCIRG1 under the control of phosphoglycerate promoter and expanded ex vivo. Expanded cells maintained long-term engraftment capacity and multi-lineage repopulating potential when transplanted in vivo both in primary and secondary NOD scid gamma common chain (NSG) recipients. Moreover, when CD34(+) cells were differentiated in vitro, genetically corrected osteoclasts resorbed the bone efficiently. Overall, we provide evidence that expansion of circulating HSPC coupled to gene therapy can overcome the limit of stem cell harvest in osteopetrotic patients, thus opening the way to future gene-based treatment of skeletal diseases caused by BM fibrosis.

X-linked immunodeficiency with magnesium defect, EBV infection, and neoplasia (XMEN) disease are caused by deficiency of the magnesium transporter 1 (MAGT1) gene. We studied 23 patients with XMEN, 8 of whom were EBV naive. We observed lymphadenopathy (LAD), cytopenias, liver disease, cavum septum pellucidum (CSP), and increased CD4-CD8-B220-TCRαβ+ T cells (αβDNTs), in addition to the previously described features of an inverted CD4/CD8 ratio, CD4+ T lymphocytopenia, increased B cells, dysgammaglobulinemia, and decreased expression of the natural killer group 2, member D (NKG2D) receptor. EBV-associated B cell malignancies occurred frequently in EBV-infected patients. We studied patients with XMEN and patients with autoimmune lymphoproliferative syndrome (ALPS) by deep immunophenotyping (32 immune markers) using time-of-flight mass cytometry (CyTOF). Our analysis revealed that the abundance of 2 populations of naive B cells (CD20+CD27-CD22+IgM+HLA-DR+CXCR5+CXCR4++CD10+CD38+ and CD20+CD27-CD22+IgM+HLA-DR+CXCR5+CXCR4+CD10-CD38-) could differentially classify XMEN, ALPS, and healthy individuals. We also performed glycoproteomics analysis on T lymphocytes and show that XMEN disease is a congenital disorder of glycosylation that affects a restricted subset of glycoproteins. Transfection of MAGT1 mRNA enabled us to rescue proteins with defective glycosylation. Together, these data provide new clinical and pathophysiological foundations with important ramifications for the diagnosis and treatment of XMEN disease.

The scale of the COVID-19 pandemic forced urgent measures for the development of new therapeutics. One of these strategies is the use ofconvalescentplasma(CP) as a conventional source for passiveimmunity. Recently, there has been interest in CP-derivedexosomes. In this report, we present a structural, biochemical, and biological characterization of our proprietary product,convalescenthumanimmuneplasma-derivedexosome(ChipEXO), following the guidelines set forth by the Turkish Ministry of Health and the Turkish Red Crescent, the Good Manufacturing Practice, the International Society for Extracellular Vesicles, and the Gene Ontology Consortium. The data support the safety and efficacy of this product againstSARS-CoV-2 infections inpreclinicalmodels.

Dermatofibrosarcoma protuberans (DFSP) is a rare, slowly growing, painless mesenchimal tumor particularly originating from cutaneous and subcutaneous tissues. This neoplasy mostly presents as protrude indurated plaque with brownreddish color or same color of the skin. DFSP has a high rate of recurrence but a low rate of metastasis.We present a retrospective study of 23 patients who were diagnosed with DFSP and operated at our institution. We examined the clinicopathological parameters with clinical outcome and the follow-up.We retrospectively analysed the data of 23 patients operated for DFSP in Ankara University Medical School Department of Surgical Oncology between 2006 and 2017. Out of these 23 patients, 14 of them were male and 9 of them were female. Dermatofibrosarcoma protuberans has been detected within body in 13 patients, extremities in 7 patients, chest in 2 patients, neck in one patient as well. 6 patients were opereted one times and 17 patients were operated twice due to getting tumor free margins. One patient devaloped local recurrence and reexcision was performed. All patients are still alive and follow up period varied from 12 up to 144 months with a median of 54.2.In conclusion, DFSP is an uncommon, low-grade sarcoma of dermal fibroblast origin with a high local recurrence rate. Diagnosis is established by histology and immunohistochemistry. The greatest clinical challenge in the management of DFSP is achieving local control. Surgical excision is the treatment of choice.Dermatofibrosarcoma protuberans, Local Recurrence, Mesenchymal tumor.Il dermatofibrosarcoma protuberans (DFSP) è un tumore mesenchimale raro, a crescita lenta e indolore, originato in particolare dai tessuti cutanei e sottocutanei. Questa neoplasia si presenta principalmente come una placca indurita sporgente di colore bruno-rossastro o dello stesso colore della pelle, ha un alto tasso di recidiva ma un basso tasso di metastatizzazione. Presentiamo qui uno studio retrospettivo su 23 pazienti a cui è stata diagnosticata la DFSP e sono stati operati presso il Dipartimento di Oncologia Chirurgica dell’Università di Ankara Medical School tra il 2006 e il 2017. Abbiamo esaminato i parametri clinicopatologici l’esito clinico e il follow-up. Di questi 23 pazienti, 14 erano maschi e 9 erano femmine. Il dermatofibrosarcoma protuberans è stato rilevato al livello del corpo in 13 pazienti, alle estremità in 7 pazienti, nel torace in 2 pazienti, sul collo in un paziente. 6 pazienti sono stati operati una volta e 17 pazienti sono stati operati due volte per poter ottenere margini liberi dal tumore. Un paziente ha sviluppato una recidiva locale ed è stata eseguita una nuova escissione. Tutti i pazienti sono ancora vivi e il periodo di followup varia da 12 a 144 mesi con una mediana di 54,2. CONCLUSIONE: In conclusione, DFSP è un sarcoma raro di basso grado di origine fibroblastica dermica con un alto tasso di recidiva locale. La diagnosi è stabilita dall’istologia e dall’immunoistochimica. La più grande sfida clinica nella gestione della DFSP è ottenere il controllo locale. L’escissione chirurgica è il trattamento di scelta.

Hyper-IgE syndromes and chronic mucocutaneous candidiasis constitute rare primary immunodeficiency syndromes with an overlapping clinical phenotype. In recent years, a growing number of underlying genetic defects have been identified. To characterize the underlying genetic defects in a large international cohort of 275 patients, of whom 211 had been clinically diagnosed with hyper-IgE syndrome and 64 with chronic mucocutaneous candidiasis, targeted panel sequencing was performed, relying on Agilent HaloPlex and Illumina MiSeq technologies. The targeted panel sequencing approach allowed us to identify 87 (32 novel and 55 previously described) mutations in 78 patients, which generated a diagnostic success rate of 28.4%. Specifically, mutations in DOCK8 (26 patients), STAT3 (21), STAT1 (15), CARD9 (6), AIRE (3), IL17RA (2), SPINK5 (3), ZNF341 (2), CARMIL2/RLTPR (1), IL12RB1 (1), and WAS (1) have been detected. The most common clinical findings in this cohort were elevated IgE (81.5%), eczema (71.7%), and eosinophilia (62.9%). Regarding infections, 54.7% of patients had a history of radiologically proven pneumonia, and 28.3% have had other serious infections. History of fungal infection was noted in 53% of cases and skin abscesses in 52.9%. Skeletal or dental abnormalities were observed in 46.2% of patients with a characteristic face being the most commonly reported feature (23.1%), followed by retained primary teeth in 18.9% of patients. Targeted panel sequencing provides a cost-effective first-line genetic screening method which allows for the identification of mutations also in patients with atypical clinical presentations and should be routinely implemented in referral centers., Projekt DEAL; German Ministry of Education and Research (BMBF) [01E01303, 01ZX1306F, 01ZX1306A]; E-rare program of the European Commission EURO-CMC [01GM1502]; German Center for Infection Research DZIF [8000805-3, TTU-IICH_07.801]; German Research Foundation (DFG) [390939984, 39087428], Open Access funding enabled and organized by Projekt DEAL. Financial support for this research came from the German Ministry of Education and Research (BMBF, grant no. 01E01303; sys-INFLAME grant nos. 01ZX1306F and 01ZX1306A), from the E-rare program of the European Commission EURO-CMC (01GM1502), and from the German Center for Infection Research DZIF (8000805-3 and TTU-IICH_07.801). This study was supported by the German Research Foundation (DFG) under Germany's Excellence Strategy CIBSS (EXC-2189) (Project ID 390939984) and RESIST (EXC 2155) (Project ID 39087428).

© 2022 Elsevier LtdAim: Extracorporeal photochemotherapy (ECP) is emphasized chiefly as it has a high safety profile. However, the genotoxic effects of ECP are not known. This experimental study aimed to assess the potential genotoxic impact of ECP treatment by the AKLIDES system, a new generation standardized and automated evaluation method. Materials and Methods: Buffy coats were obtained from the blood of 26 healthy volunteers, and ECP was applied to 2 j/cm2 UV-A for two hours. After the DNA isolation procedure, all slides were stained with DAPI to visualize lymphocytes, FITC for visualization of damage foci marker (γH2AX), and APC for visualization of repair foci marker (53BP1). With the AKLIDES imaging system, all parameters were evaluated. Results: Median damage marker Foci γ-H2AX before and after ECP were 11.42 and 18.65 arbitrary units, respectively (p = 0.153). Median repair marker foci 53BP1 (repair biomarker) before and after ECP were measured as 4.17 and 6.7 arbitrary units. The difference was also not statistically significant (p = 0.088). Although 58 % of cells were affected by ECP irradiation, as shown by FITC fluorescent staining, no statistical difference was found in any genotoxicity parameters. Conclusion: We found an increase in the foci γ-H2AX parameter, one of the objective indicators of DNA breaks, and an increase in the foci 53BP1 parameter, which indicates the post-damage repair mechanisms after ECP. However, further in vitro, and in vivo studies are needed with large sample volumes to demonstrate the significance.

There is no standardization in videos uploaded to Youtube. Were the videos capable of contributing to adequate technical quality and surgical training? We are aiming to answer these questions in this paper. It is a cross-sectional study. In January 2022, we searched the Youtube platform using the keyword "distal pancreatectomy." The substantiality, transparency, reliability, quality, popularity and educational values of the video content were evaluated after exclusion criteria. These parameters were evaluated using we the modified Journal of American Medical Association benchmark criteria, Global Quality Score (GQS), Video Power Index, modified laparoscopic pancreatectomy scoring system. The videos uploaded after the pandemic had a statistically significant higher GQS score (P.001). Video Power Index, like GQS, had a statistically significant difference before and after the pandemic. (P = .046). There was no significant difference in the evaluation of the reliability and substantiality. Until the development of Youtube videos is completed, peer-reviewed, more reliable and content-rich online education platforms should be preferred in the first place. Care should be taken to watch selected videos on Youtube videos.

Durable and environment friendly superhydrophobic surfaces are needed for a set of important applications. Biomedical applications, in particular, impose stringent requirements on the biocompatibility of the materials used in the fabrication of superhydrophobic surfaces. In this study, we demonstrate the fabrication of mechanically durable superhydrophobic surfaces via an in-situ structuring strategy starting from natural carnauba wax and biocompatible polydimethylsiloxane (PDMS) materials. The transfer of the structure of the paper to a free-standing PDMS film provided the microscale structure. On top of this structured surface, the wax was spraycoated, initially resulting in a relatively homogeneous film with limited liquid repellence. The key in achieving superhydrophobicity was rubbing the surface for in-situ generation of a finely textured wax coating with a water contact angle of 169 degrees and a sliding angle of 3 degrees. The hierarchically structured surface exhibits mechanical robustness as demonstrated with water impact and linear abrasion tests. We finally demonstrate repellence of the surfaces against a range of blood products including platelet suspension, erythrocyte suspension, fresh plasma, and whole blood.

Background: Signet ring cell gastric cancer differs from gastric adenocarcinoma in terms of demographic and clinical features, age, gender, tumour grade and stage. In this study, we aimed to evaluate the clinical features and overall survival of gastric signet ring cell carcinoma and the prognostic factors affecting survival.Methods: We analysed 138 patients who were operated on with the diagnosis of signet ring cell gastric cancer. The univariant and multivariate hazard ratios of these parameters were analysed and the factors affecting the long-term average survival outcomes were investigated.Results: We performed Cox regression univariate analysis to investigate the effects of clinicopathological factors on mean survival follow-up in signet ring cell gastric cancer. As age increases, the mean survival follow-up period decreases. This relationship is also statistically significant. Mean survival follow-up for the open technique was lower than for laparoscopic procedures. The mean survival follow-up time of patients with positive perineural invasion (PNI) and lymphovascular invasion (LVI) is lower than patients with negative LVI and PNI. We did not find a significant relationship between the hazard ratios (HRs) of tumour markers and systemic inflammatory response parameters. However, we found a significant relationship between the increase in fibrinogen value and HR.Conclusions: We investigated the clinicopathological features of nonmetastatic signet ring cell gastric carcinomas and identified predictors of long survival. Age, lymphovascular and perineural invasion, open surgery, higher tumor infiltration, and lymph node involvement were independent predictors of shorter survival times in nonmetastatic signet ring cell gastric cancers.

Background Acute rheumatic fever (ARF) is an autoimmune disease caused by group A β-hemolytic streptococci (GAS) and may develop into rheumatic heart disease (RHD). The pathogenesis of ARF and RHD involves molecular mimicry and antibody-mediated mechanisms. T cell involvement is described in various stages of the disease. Mucosal associated invariant T (MAIT) cells are enriched at the mucosa and are present in the blood and may be activated by GAS. Methods In this study, we investigated the quantity and activity of CD3+TCRVα7.2+CD161+ cells in the active and recovered ARF patients and healthy controls. Twenty newly diagnosed, 20 recovered-ARF children, and 20 healthy controls were enrolled in the study. Peripheral blood (PB) mononuclear cells were isolated by Ficoll-Paque density gradient. CD4+, CD4− subsets of CD3+CD161+TCRVα7.2+ cells and IFN-γ and TNF-α production were quantified by Flow cytometry. Results Acute and recovered ARF patients had significantly elevated the number of CD3+TCRVα7.2+CD161+ cells in their PB. Both CD4+ and CD4− subsets were increased. Moreover, total CD3+TCRVα7.2+CD161+ cell numbers were significantly higher in the recovered patients' PB compared with active ARF patients. In addition, CD3+TCRVα7.2+CD161+ cells in both acute and recovered patients produced significantly more IFN-γ and TNF-α. Non-MAIT total CD3+ T cell, CD4+ and CD4− T cell subsets were also increased in active and recovered ARF patients and they also produced more IFN-γ and TNF-α. Conclusion Our data reveal that CD3+TCRVα7.2+CD161+ cells are elevated and actively producing IFN-γ and TNF-α in acute and recovered ARF patients and may contribute to ARF pathology.

OBJECTIVE: Mutations in IKZF1, which encodes Ikaros family zinc finger 1 (IKAROS) transcription factor, are associated with recurrent infections, cytopenia, autoimmune diseases, and hematological malignancies. Diverse clinical phenotypes resulting from IKZF1 mutations include pulmonary fungal infections, cytopenia, autoimmune hemolytic anemia (AIHA), and malignancies. In this study, we aimed to assess the DNA-binding ability and pericentromeric localization of a variant of IKZF discovered in a patient. METHODS: DNA-binding ability of a pathogenic IKZF variant was tested via electrophoretic mobility shift assay, and pericentromeric localization of the variant was assessed by immunofluorescent microscopy in NIH3T3 cells. RESULTS: Clinical features of a three-month-old male infant who underwent hematopoietic stem cell transplantation due to an IKZF1 mutation-associated common variable immunodeficiency, AIHA, and pancytopenia are described. DNA studies revealed a heterozygous missense variant (IKZF1 NM_006060 c.427C>T, p.R143W). Co-transfection studies revealed that mutant R143W has a partial dominant-negative effect over pericentromeric targeting as well as DNA binding. CONCLUSIONS: IKZF1 mutation must be kept in mind if neonatal AIHA, common variable immune deficiency and pancytopenia are observed.

Dysregulated immune responses are essential underlying causes of a plethora of pathologies including cancer, autoimmunity, and immunodeficiency. We here investigated 4 patients from unrelated families presenting with immunodeficiency, autoimmunity, and malignancy. We identified 4 distinct homozygous mutations in TNFRSF9 encoding the tumor necrosis factor receptor superfamily member CD137/4-1BB, leading to reduced, or loss of, protein expression. Lymphocytic responses crucial for immune surveillance, including activation, proliferation, and differentiation, were impaired. Genetic reconstitution of CD137 reversed these defects. CD137 deficiency is a novel inborn error of human immunity characterized by lymphocytic defects with early-onset Epstein-Barr virus (EBV)-associated lymphoma. Our findings elucidate a functional role and relevance of CD137 in human immune homeostasis and antitumor responses.