Autosomal recessive hyper IgM syndrome associated with activation-induced cytidine deaminase gene in three Turkish siblings presented with tuberculosis lymphadenitis — Case report

The hyper-immunoglobulin M (HIGM) syndrome is a heterogeneous group of genetic disorders characterized by recurrent infections, decreased serum levels of immunoglobulin G (IgG) and IgA, and normal/increased serum levels of IgM. Herein, we describe three Turkish siblings with HIGM syndrome who had a homozygous missense mutation (c.70C>T, p.Arg24Trp) in the activation-induced cytidine deaminase gene which results in autosomal recessive HIGM syndrome. Two of the siblings, sibling 1 and sibling 3, presented with cervical deep abscess and cervical tuberculosis lymphadenitis, respectively

Splenic infarction as a complication of celiac artery thromboembolism: an unusual cause of abdominal pain

Splenic infarction is a relatively uncommon diagnosis and this clinical presentation can mimic other causes of acute abdominal pain. Cardiologic and hematologic disorders are common reasons for this entity. There have been a few series and single case reports of splenic infarction published in peer-reviewed medical journals. We report a 53-year-old patient who had splenic infarction caused by celiac artery thromboembolism. The importance of this case, without any etiological predisposing factors, is that this kind of clinical situation should be considered in the differential diagnosis of abdominal pain

Targeted high-throughput sequencing for genetic diagnostics of hemophagocytic lymphohistiocytosis

Background: Hemophagocytic lymphohistiocytosis (HLH) is a rapid-onset, potentially fatal hyperinflammatory syndrome. A prompt molecular diagnosis is crucial for appropriate clinical management. Here, we validated and prospectively evaluated a targeted high-throughput sequencing approach for HLH diagnostics. Methods: A high-throughput sequencing strategy of 12 genes linked to HLH was validated in 13 patients with previously identified HLH-associated mutations and prospectively evaluated in 58 HLH patients. Moreover, 2504 healthy individuals from the 1000 Genomes project were analyzed in silico for variants in the same genes. Results: Analyses revealed a mutation detection sensitivity of 97.3 %, an average coverage per gene of 98.0 %, and adequate coverage over 98.6 % of sites previously reported as mutated in these genes. In the prospective cohort, we achieved a diagnosis in 22 out of 58 patients (38 %). Genetically undiagnosed HLH patients had a later age at onset and manifested higher frequencies of known secondary HLH triggers. Rare, putatively pathogenic monoallelic variants were identified in nine patients. However, such monoallelic variants were not enriched compared with healthy individuals. Conclusions: We have established a comprehensive high-throughput platform for genetic screening of patients with HLH. Almost all cases with reduced natural killer cell function received a diagnosis, but the majority of the prospective cases remain genetically unexplained, highlighting genetic heterogeneity and environmental impact within HLH. Moreover, in silico analyses of the genetic variation affecting HLH-related genes in the general population suggest caution with respect to interpreting causality between monoallelic mutations and HLH. A complete understanding of the genetic susceptibility to HLH thus requires further in-depth investigations, including genome sequencing and detailed immunological characterization.Peer reviewe

Expanded circulating hematopoietic stem/progenitor cells as novel cell source for the treatment of TCIRG1 osteopetrosis

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, a relevant 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, supporting their use in gene therapy protocols. Transcriptomic profile revealed enrichment in genes expressed by hematopoietic stem and progenitor cells (HSPCs). To overcome the limit of bone marrow harvest/ HSPC mobilization and serial blood drawings in TCIRG1 patients, we applied UM171-based ex-vivo expansion of HSPCs coupled with lentiviral gene transfer. Circulating CD34+ cells from TCIRG1-defective patients were transduced with a clinically-optimized lentiviral vector (LV) 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 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 HSPCs 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 bone marrow fibrosis

Physiological parameters for Prognosis in Abdominal Sepsis (PIPAS) Study : a WSES observational study

BackgroundTiming and adequacy of peritoneal source control are the most important pillars in the management of patients with acute peritonitis. Therefore, early prognostic evaluation of acute peritonitis is paramount to assess the severity and establish a prompt and appropriate treatment. The objectives of this study were to identify clinical and laboratory predictors for in-hospital mortality in patients with acute peritonitis and to develop a warning score system, based on easily recognizable and assessable variables, globally accepted.MethodsThis worldwide multicentre observational study included 153 surgical departments across 56 countries over a 4-month study period between February 1, 2018, and May 31, 2018.ResultsA total of 3137 patients were included, with 1815 (57.9%) men and 1322 (42.1%) women, with a median age of 47years (interquartile range [IQR] 28-66). The overall in-hospital mortality rate was 8.9%, with a median length of stay of 6days (IQR 4-10). Using multivariable logistic regression, independent variables associated with in-hospital mortality were identified: age > 80years, malignancy, severe cardiovascular disease, severe chronic kidney disease, respiratory rate >= 22 breaths/min, systolic blood pressure 4mmol/l. These variables were used to create the PIPAS Severity Score, a bedside early warning score for patients with acute peritonitis. The overall mortality was 2.9% for patients who had scores of 0-1, 22.7% for those who had scores of 2-3, 46.8% for those who had scores of 4-5, and 86.7% for those who have scores of 7-8.ConclusionsThe simple PIPAS Severity Score can be used on a global level and can help clinicians to identify patients at high risk for treatment failure and mortality.Peer reviewe

The Importance of Cystatin-C for Predicting Nephrotoxicity in Children with Acute Leukemia and Non-Hodgkin Lymphoma

Determination of renal function in patients with childhood cancer by a simple and accurate test is crucial. The aim of this study is to determine the incidence of nephrotoxicity in patients with acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML) and non-Hodgkin lymphoma (NHL) and evaluate the importance of serum cystatin-C for an early predictor of impairment of renal function. 27 patients (ages varied from 1.5 to 16 years, median age 10 year-old) were enrolled to this study. Serum urea, creatinine, cystatin-C concentrations and calculated creatinine clearances of the patients were determined during the treatment. Twenty (74%) of patients were male and seven (26%) were female. The frequencies of the diagnosis for ALL, AML and NHL were 13 (48.1%), 8 (29.6%) and 6 (22.3%), respectively. The mean values of cystatin C during the treatment were 0.77 +/- 0.3 mg/l, 0.86 +/- 0.5 mg/l and 0.81 +/- 0.3 mg/l, respectively. The values of urea, cystatin-C, and creatinine clearance did not differ statistically by duration of the treatment. We did not observe any renal impairment in our study group by the treatment. Cystatin-C has high values of sensitivity and specificity to predict the glomeruler filtration rate. Therefore cystatin C might be useful for determination glomeruler filtration rate in children with cancer; especially who have difficulties in collecting 24-hours urine sample