Ataxia-telangiectasia (AT) is a rare neurodegenerative disease characterized by an early onset ataxia, oculocutaneous telangiectasia, immunodeficiency, recurrent infections, radio-sensitivity, and a ...predisposition to malignancy. We present the case of a child with coexistent AT and trisomy X (47,XXX). We used fluorescent in situ hybridization (FISH) to confirm that this person had 47,XXX karyotype in blood cells, bone marrow, fibroblasts, and buccal smear. Standard cytogenetic studies (not banded) were conducted on blood cells. G-banding analysis was performed on bone marrow cells at the time of the leukemia diagnosis. Flow cytometric investigation of lymphocytes and Sanger sequencing of the
ATM
gene were used for diagnosis confirmation and description. We report the case of an 11-year-old girl at remission after having T cell acute leukemia for 7 years with progressive signs of ataxia-telangiectasia and with additional X chromosome since birth. At the age of 2 years and 7 months, she was diagnosed with pre-T acute leukemia. From the age of four, she had gait abnormalities. AT was established at the age of seven based on clinical signs and laboratory findings (increased alpha fetoprotein—AFP 227) and confirmed by detecting compound heterozygous truncating mutations in the
ATM
gene (p.Y705X and p.L2312I). These genetic findings have not been previously reported in AT and our “double hit” case demonstrates the value of careful clinical evaluation of children with an established genetic diagnosis. Measurement of AFP levels should be considered in patients with neurologic abnormalities after leukemia treatment.
Abstract Introduction Here we present an unusual case of DNA ligase IV deficiency syndrome without dysmorphic facial findings and microcephaly complicated with Epstein–Barr virus-associated large ...B-cell lymphoma with the right lung involvement and a massive brain tumor lesion in a two-year-old female. Methods PID panel was used for sequencing 55 genes. Most genes have > 98% exon coverage including splicing sites. LIG4 gene has 100% exon and splicing site coverage. This was used in Ion Torrent PGM system, the library kit was made by Agilent with Haloplex technology. The sequence analysis software was Alamut, direct sequencing of LIG4 gene was performed after NGS results. Result We identified three heterozygous mutations in LIG4 gene c.2736 + 3delC and c.8 C > T (p.A3V) inherited from mother and c.26C > T (p.T9I) – from father after PID panel sequencing and some additional polymorphisms in ATM , NOD2 and NLRP3 genes. Conclusion This case broadens the clinical spectrum of DNA ligase IV deficiency.
Children with acute myeloid leukemia and relapses of leukemia are at high risk of developing fungal infections and need antifungal prophylaxis. This study aimed to compare the efficacy and toxicity ...of two different dosage regimens of voriconazole (VRC) during prophylactic administration in children with malignancy and neutropenia.
This prospective study was conducted at the Belarusian Research Center for Pediatric Oncology, Hematology, and Immunology from May 2017 to December 2019. The present study included 21 Caucasian patients with malignant hematological diseases (20 patients with acute myeloid leukemia and relapses of leukemia and 1 patient with Non-Hodgkin's lymphoma) aged 2-18 years. All patients were randomly divided into two groups that received different dosage regimens of VRCZ prophylaxis. Patients in the "high-dose" group received VRCZ at a dose of 9 mg/kg twice a day PO, or 8 mg/kg twice a day IV without a loading dose (children of 2-11 and adolescents and of 12-14 years old with <50 kg weight body), or a dose of 4 mg/kg twice a day PO or IV (adolescents of 12-14 years old with ≥50 kg body weight and all adolescents over 14 years old). Patients in the "low-dose" group received VRCZ at a dose of 4 mg/kg twice a day, PO or IV, without a loading dose (children of 2-11 and adolescents of 12-14 years old with <50 kg body weight), or at a dose of 3 mg/kg twice a day, PO or IV (adolescents of 12-14 years old with ≥ 50 kg body weight and all adolescents over 14 years old). When neutropenia recurred (after the next chemotherapy block), the patients were re-randomized and prophylaxis was resumed in the absence of fungal infection. Therefore, some patients (n=12, 57%) entered the study several times (maximum four times, after each chemotherapy block). In total, 21 patients experienced 40 episodes of VRCZ prophylaxis.
In the high-dose group (n=20 episodes of prophylaxis), invasive fungal infections (IFI) signs were recorded in one (5%) case. In the low-dose group (n=20 episodes), IFI signs were observed in six (30%) cases (
=0.0375). The residual serum concentration was significantly higher in patients who received high doses of VRCZ (
<0.0001). Most patients with IFI (n=6, 86%) had a mean value (i.e., <0.74 μg/ml) of the residual serum concentration of the medication. Median of the first signs of fungal infection was 22 days from the start of prophylaxis. The dosage was the only highly significant factor that affected the metabolism of VRCZ.
The likelihood of IFI was significantly lower in children who prophylactically received VRCZ in high doses (
=0.0375) and had ≥ 0.74 μg/ml residual serum concentration of the medication (
=0.0258). Residual serum concentration of VRCZ reached a plateau by day sixth of the treatment. In children, the dosage was the only highly significant factor affecting the metabolism of VRCZ.
Abstract Background Venous thrombosis is a complication of treatment of children with cancer but studies devoted to the epidemiology of thrombosis in children with cancer are rare and data are ...scanty. Objective To determine the prevalence and clinical characteristics of VT as a secondary complication in children with malignant disease and to estimate the ten-year experience of our hospital. Method Retrospective analysis of data of Children's Cancer Subregistry of Belarus, which included information about age, gender, details of diagnosis, classification of malignant neoplasm according to ICD-10, treatment protocol and outcome. Clinical information was obtained from case histories. Results For the specified period, 2061 children with newly diagnosed cancer and 44 cases of VT have been registered. Among VT cases, hematological malignancies prevailed (32 of total 44). Higher incidence of VT in AML and APL groups was shown (p‹0.05). In patients with VT, boys (M/F = 1,6/1) and teenagers prevailed (65,9%). Of 44 patients, 33 had catheter-associated thrombosis (CAT). Almost all CAT (91,7%) were in the upper venous system. Children with non-CAT (11 out of 44) had more prolonged duration of immobilization, than children with CAT (p‹0.05) and in this group, thrombosis affected predominantly the lower limb (9 out of 11). Conclusion The present study has shown that venous thrombosis occurs significantly more often in children with AML and APL. Prevalence of boys in patients with venous thrombosis has been noted. Increased frequency of VT events in teenagers has been observed and the provoking role of CVC and immobilization for thrombosis has been confirmed.
•A new model for the organization of the RUNX1/RUNX1T1 fusion oncogene was developed.•Expression of splicing and NMD genes is deregulated in t(8;21)-positive AML.•Alternative splicing of the ...RUNX1/RUNX1T1 mRNAs follows a power-law behavior.•Alternative splicing is extremely sensitive to targeted skipping of “exons-hubs”.
The t(8;21) translocation is the most widespread genetic defect found in human acute myeloid leukemia. This translocation results in the RUNX1–RUNX1T1 fusion gene that produces a wide variety of alternative transcripts and influences the course of the disease. The rules of combinatorics and splicing of exons in the RUNX1–RUNX1T1 transcripts are not known. To address this issue, we developed an exon graph model of the fusion gene organization and evaluated its local exon combinatorics by the exon combinatorial index (ECI). Here we show that the local exon combinatorics of the RUNX1–RUNX1T1 gene follows a power-law behavior and (i) the vast majority of exons has a low ECI, (ii) only a small part is represented by “exons-hubs” of splicing with very high ECI values, and (iii) it is scale-free and very sensitive to targeted skipping of “exons-hubs”. Stochasticity of the splicing machinery and preferred usage of exons in alternative splicing can explain such behavior of the system. Stochasticity may explain up to 12% of the ECI variance and results in a number of non-coding and unproductive transcripts that can be considered as a noise. Half-life of these transcripts is increased due to the deregulation of some key genes of the nonsense-mediated decay system in leukemia cells. On the other hand, preferred usage of exons may explain up to 75% of the ECI variability. Our analysis revealed a set of splicing-related cis-regulatory motifs that can explain “attractiveness” of exons in alternative splicing but only when they are considered together. Cis-regulatory motifs are guides for splicing trans-factors and we observed a leukemia-specific profile of expression of the splicing genes in t(8;21)-positive blasts. Altogether, our results show that alternative splicing of the RUNX1–RUNX1T1 transcripts follows strict rules and that the power-law component of the fusion gene organization confers a high flexibility to this process.
Background
Omenn syndrome Mendelian Inheritance (OMIM 603554) is a genetic disease of the immune system, characterized by the presence of fatal generalized severe erythroderma, lymphoadenopathy, ...eosinophilia and profound immunodeficiency.
Objective
We studied clinical and immunologic presentation of the disease manifestation among East Slavs population with genetically confirmed Omenn syndrome.
Results
We collected clinical and immunologic data of 11 patients (1 from Belarus, 5 – Ukraine, 5 – Russia): 6 females, 5 males. The age of Omenn syndrome manifestation varied from the 1st day of life to 1 year and 1 month, the age of diagnosis – 20 days to 1 year and 10 months. Nine out of 11 patients had classic immunologic phenotype T(+/−)B-NK+, 1 pt had TlowB + NK+ with CD3 + TCRgd + expansion and 1 had TlowB+/−NK+ phenotype. Eight out of 11 pts had mutation in
RAG1
gene, 4 out of 8 had c.368-369delAA (p.K86fsX118) in homozygous state or heterozygous compound. In our cohort of patients, we also described two new mutations in
RAG
genes (p.E722Q in
RAG1
and p.M459R in
RAG2
). At present, 7/11 were transplanted and 5 out of the transplanted are alive.
Conclusion
This study demonstrates that the most popular genetic abnormality in East Slavs children with Omenn syndrome is c.368-369delAA (p.K86fs118) in
RAG1
gene, which may be connected with more favorable prognosis because 4/4 patients survived after hematopoietic stem cells transplantation.
X-linked lymphoproliferative disease type I (XLP I) is caused by mutations in the SH2D1A gene and characterized mainly by hypogammaglobulinemia and abnormal response to Epstein-Barr virus with a high ...predisposition to B-cell non-Hodgkin lymphoma development.
In this article, we describe the experience of 2 centers in Belarus and in Russia that follow 3 male patients who were diagnosed with XLP I after lymphoma development and treatment. Three novel mutations c.51G>C (p.E17D), c.192G>T (p.W64C), and c.53insA (p.K18KfsX67) were found in 3 males patients with XLP I. Two of them did not have any signs of immunodeficiency before B-cell non-Hodgkin lymphoma development.
We propose SH2D1A mutational screening be considered in male patients with or without hypogammaglobulinemia who received rituximab treatment for lymphoma and did not recover immunoglobulin G in a year after B-depleting therapy.
Abstract The RUNX1 - RUNX1T1 fusion gene, a product of the nonhomologous balanced translocation t(8;21)(q22;q22), is a complex genetic locus. We performed extensive bioinformatic analysis of ...transcription initiation as well as transcription termination sites in this locus and predicted a number of different RUNX1T1 transcripts. To confirm and quantify the RUNX1T1 gene expression, we analyzed samples from seven acute myeloid leukemia (AML) patients and from the Kasumi-1 cell line. We found variable activity of the four predicted RUNX1T1 promoters located downstream of the chromosome breakpoint. Nineteen alternative RUNX1T1 transcripts were identified by sequencing at least seventeen of which predictably can be translated into functional proteins. While the RUNX1T1 gene is not expressed in normal hematopoietic cells, it may participate in t(8;21)(q22;q22)-dependent leukemic transformation due to its multiple interactions in cell regulatory network particularly through synergistic or antagonistic effects in relation to activity of RUNX1 - RUNX1T1 fusion gene.
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