Vol 19, No 3 (2020)

Hemophilia is a genetic disease that impairs quality of life due to its chronicity of nature where the individual will experience spontaneous bleeding or bleeding after an injury which requires frequent visits to the hospital for treatment. The objective of this study was to find the Health-related quality of life (HRQoL) of children and adolescents with moderate and severe hemophilia between 6 years and 16 years using the Haemo-QoL questionnaire. A prospective survey was carried out among 107 children and adolescents from two hemophilia treatment centers in Karnataka state. Approval was taken from the ethical committee. The data was analyzed using SPSS version 16.0. The mean age was 11.00 ± 2.98 years. Among the 107 participants, 89.70% had hemophilia A and 10.30% had hemophilia B. Moderate hemophilia was found among 54.20% participants and 45.80% had severe hemophilia. Overall, the HRQoL scores (55.41) were higher in the age group of 6–7 years compared to 8–12 years and 13–16 years. The mean HRQoL in the domain of family were: 77.84 ± 23.12 among 6–7 years, 66.00 ± 17.34 among the 8–12 years and 60.38 ± 16.72 among 13–16 years. Children demonstrated poor HRQoL in the domains of family and friends. The results indicate a need for continuous monitoring of QoL to identify better treatment methods.

Immune thrombocytopenia (ITP) is the most common cause of thrombocytopenia in children. Approximately 20–25% of children develop a chronic course of the disease. Many treatment options are available, including chronic use of first-line therapies, e.g., corticosteroids, intravenous immunoglobulin or anti-Rh-D, and second-line therapies, including dexamethasone, high-dose methylprednisolone, intensive immunosuppressants, rituximab, thrombopoietin receptor agonists (TPO-RAs), splenectomy, and many others; however, none of these treatments have been determined to be the best. In this study, we retrospectively reviewed the course, response to different treatment lines and outcome of children with chronic ITP over a period of ten years to compare the efficacy of different treatment options, aiming to determine a scale of priority for selecting the most costeffective treatment. A retrospective study was conducted and included children diagnosed with chronic ITP from January 2008 until December 2018 who were followed at the Pediatric Hematology Unit of Mansoura University Children Hospital, Mansoura, Egypt. The study proposal was approved on February 14, 2017 (approval No 17.02.59) by the Institutional Review Board (IRB) of the Faculty of Medicine, Mansoura University, Egypt. All research steps were conducted according to the Declaration of Helsinki. The diagnosis of chronic ITP was based upon the persistence of thrombocytopenia lasting for more than 1 year with or without therapy. Bone marrow aspiration was performed for all patients to confirm the diagnosis of chronic ITP and exclude other causes of thrombocytopenia. Data relevant to chronic ITP patients diagnosed from 2008 to 2018 were retrieved from the Electronic Data System of Hospital Management of Mansoura University Children Hospital, including age, sex, diagnosis date, duration of chronicity, treatment given during the chronic phase and response. Treatment regimen was immune modulatory therapies (high-dose dexamethasone, IV rituximab or low-dose dexamethasone + azathioprine), thrombopoietin receptor agonists (TPO-RAs) (eltrombopag or romiplostim). Out of 405 newly diagnosed ITP patients in a period of 10 years in our center, 103 progressed to chronic disease, of whom 29 were lost to follow-up, while 74 patients were followed at the hematology outpatient clinic and enrolled in the current study (32 males and 42 females, median age – 10 years, median initial platelet count – 16 × 109 /l). Approximately one-third of patients (25~33.8%) were managed conservatively; of them, 19 patients achieved sustained remission, and 6 patients needed another treatment line. Forty-six (62%) patients received immunomodulatory therapies. Twentyeight patients (37.8%) were treated with TPO-RAs. No differences were observed between the 3 types of immunomodulatory therapies regarding relapse-free survival and duration of remission (р value: 0.7). Additionally, no differences were noted according to relapse-free survival among those treated with eltrombopag and romiplostim (р value: 0.7). The number of male children who had a sustained response was significantly higher than that of female children among patients receiving immunomodulatory therapies (71.4% vs 28.6%, respectively) (р value 0.01). There were significantly more patients on TPO-RA with a sustained response than patients on immune modulators, and consequently, the number of patients who relapsed on immunomodulators was higher than that of those on TPO-RA (67.9% vs 30.4% compared to 69.9% vs 32.1%, р value 0.01). Many of our patients who received immunomodulators and failed to achieve or lost a response before 2015 were switched to TPO-RAs with comparable efficacy apart from sustainability, which was in favor of the latter. Additionally, among the types of immunomodulators, rituximab did not show superior efficacy compared to other types, with lower costs for the latter, leading to the abandonment of its use, particularly in limited resource countries such as ours.

Acceleration of the differential diagnosis of microcytic hypochromic anemia is still an urgent problem. With the development of laboratory technology, new possibilities appear for differentiating iron deficiency and hemoglobinopathies as the main causes of hypochromic microcytic anemia. This study was conducted to assess the information content of the calculated indices of red blood cells M, Si, M-H and M-H-RDW in the primary diagnosis of thalassemia. This study is supported by the Independent Ethics Committee and approved by the Academic Council of the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology, and Immunology. 110 patients with microcytic hypochromic anemia were examined. The material for research was whole venous blood with the anticoagulant K3 EDTA. Blood samples were studied by flow cytometry using an Sysmex XT 4000i (Sysmex Corporation, Япония) automated hematology analyzer in CBC + DIFF + RET mode. It was found that with a probability of 96.3%, it is possible to assume the presence of thalassemia in the primary diagnosis of microcytic hypochromic anemia using the parameters of an automatic hematological analyzer and calculated indices M, Si, M-H and M-H-RDW. Assessment of the information content of the calculated indices M, Si and M-H, M-H-RDW in the primary diagnosis of thalassemia showed their high predictive value in case of simultaneous changes in all 4 indices. For the correct assessment and exclusion of false negative results, a strict observance of the preanalytical stage and the availability of information on transfusions of erythrocyte-containing media carried out by the patient are necessary.

Hemoglobinopathies are a group of hereditary hemolytic anemias common in the countries of the Mediterranean, Southeast Asia and Africa, where malaria was previously common. Due to population migration and an increase in the number of mixed marriages, hemoglobinopathies are also relevant to Russia. Among the Russian Federation's subjects, the Republic of Dagestan is the most endemic region for the incidence of hemoglobinopathies. This study aimed to identify the spectrum of mutations in patients with hemoglobinopathies living in the Republic of Dagestan. The research was approved by Independent ethic committee and the academic board of Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology (Moscow, Russia). Material from 100 patients was sent for molecular genetic research to the Laboratory of Molecular Biology, Federal State Budget Scientific Institution Scientific Research Center for Surgery named after Dmitry Rogachev. Genetic variants of the genes of the a- and b-globin clusters were determined using multiplex ligase-dependent amplification of samples and Sequencing by the Sanger method. Eighteen genetic variants with different frequencies were detected. The mutation frequency of the b-globin cluster was 62.5%, the a-globin cluster was 23.2%, and the variants leading to the appearance of abnormal hemoglobin were 14.3%. The five most common genetic variants among this cohort were also identified: CD8(-AA) and IVSI-110 (G>A), -(a) 3.7 and -(a) 20.5 and the CD6 variant GAG>GTG [Glu>Val] leading to abnormal hemoglobin S.

X-linked lymphoproliferative syndrome type 1 (XLP1) and 2 (XLP2) are primary immunodeficiencies (PID), combined in one group because of shared abnormal response to Epstein–Barr virus (EBV) and caused by mutations in SH2D1A and XIAP genes, respectively. Hemophagocytic lymphohistiocytosis (HLH) is a frequent life-threatening complication of both diseases. We analyzed haematological complications, such as HLH and cytopenia, in 12 patients with XLP1 and 11 – with XLP2. The research was approved by Independent ethic committee and the academic board of Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology (Moscow, Russia). Analyzed were patients who were treated or consulted in Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology (Moscow, Russia) since 2012 and in Russian Clinical Children's Hospital (Moscow, Russia) since 2003 to February 2020. 19 XLP1 patients from 13 families and 16 XLP2 patients from 14 families were included. For patients with haematological complications XLP diagnosis was based on the ESID criteria and genetically confirmed in 19 cases by detecting mutations in SH2D1A or XIAP gene (8 XLP1 and 11 XLP2 patients). Intracellular expression of corresponding SAP and XIAP proteins was performed by intracellular staining of SAP/XIAP in lymphocytes. Genetic analysis to detect mutations in SH2D1A and XIAP genes was performed by the Sanger sequencing method on Genetic Analyzer 3130х1 (Applied Biosystems, USA) according to the manufacturer protocol, or by the Multiplex Ligation-Dependent Probe Amplification method using SALSA MLPA Probemix P205 SH2D1A-XIAP-ITK (MRC-Holland, the Netherlands), or by the next-generation sequencing (NGS) method on NextSeq (Illumina) platform using a paired end tag (PET) sequencing method. Varying degree of cytopenia was present in 4 patients with XLP1 and 2 – with XLP2. None of XLP1 patients with cytopenia, and all XLP2 patients with cytopenia subsequently developed full HLH. Overall 8 XLP1 and 11 XLP2 patients developed HLH. HLH-associated mortality before hematopoietic stem cell transplantation (HSCT) was 75% in a group of XLP1 patients and 0% – in XLP2. HSCT was performed in 3 XLP1 patients, which was not sufficient for survival analysis and in 9 XLP2 patients, in whom overall survival was 74%. HLH is the most often haematological complication of XLP1 and XLP2. Fulminant HLH in XLP1 requires early and aggressive treatment. In XLP2 patients HLH remission can be reached on mono- or bicomponent immunosuppressive therapy which allows to reduce therapy-associated toxicity. In XLP2 patients cytopenia can precede HLH, while in XLP1 patients cytopenia is probably caused by other mechanisms. HSCT is a curative treatment for XLP1 and 2 which should be considered as soon as the diagnosis is made.

Thalassemia is a group of hereditary hemolytic anemias, caused by a quantitative violation of the globin chains synthesis. In adults, the main hemoglobin (HbA) consists of two a- and two b-chains. Normally, regulatory mechanisms maintain a balance between a- and non-a-globin chains in a 1:1 ratio. Mutations in the b-globin gene, leading to a quantitative disruption of the synthesis of b-globin chains, lead to the development of b-thalassemia. In such patients, the presence of concomitant breakdowns of a-globin genes can determine the variability of the clinical symptoms, both mitigating or increasing the severity of the manifestations of beta-thalassemia. The article describes two clinical cases of transfusion-dependent thalassemia with a rare genotype: aaa^anti-3.7/aa and b-thalassemia. Parents gave their consent to use information about the child, including fotos, in the article. 

Lymphoblastic lymphoma (LBL) is a rapidly progressive, malignant disease from T and B progenitor cells. Lymphomas from T cell precursors (T-LBL) account for up to 80% of all LBLs. Despite the rather rare occurrence of T-LBL, the relapsing and refractory course of this disease is an actual problem. Programs for the treatment of relapses and refractory forms of T-LBL are currently being actively developing. The role and place of targeted drugs in the multimodal T-LBL relapse strategy is determined. Further fundamental research is aimed at overcoming drug resistance, studying the molecular genetic mechanisms, tumor cell signaling pathways, which will improve treatment outcomes and survival. Based on clinical case the authors will be considered clinical features of relapses and refractory form of T-LBL and possible methods of treatment. Parents gave their consent to use information about the child, including fotos, in the article.

Infantile hemangioma may be accompanied by malformations of internal organs and blood vessels. In 1996 PHACE syndrome was defined as a disease which is characterized by the association of segmental infantile hemangioma with localization in the head/neck region and the presence of malformations in the posterior cranial fossa, abnormalities of arterial blood vessels including coarctation of the aorta, heart defects, as well as malformations of the eyes and central nervous system. This article presents a clinical case of a child who was diagnosed this syndrome at the age of 1.5 months based on the presence of segmental hemangioma, as well as large and small criteria specific for this disease. In addition to the main symptoms, the child had an accompanying pathology: Wolff–Parkinson–White syndrome. Therapy with non-selective b-blockers and polychemotherapy allowed stopping already developed and prevent possible complications associated with this syndrome. Parents gave their consent to use information about the child, including fotos, in the article.

Jacobsen syndrome (JS) is a rare combined immunodeficiency caused by partial deletion of the long arm of chromosome 11. Clinical features include physical growth retardation, psychomotor retardation, characteristic facial dysmorphism (skull deformities, hypertelorism, ptosis, coloboma, epicanthal folds, broad nasal bridge, short nose, v-shaped mouth, small low set ears). Patients commonly have malformations of the heart, kidney, gastrointestinal tract, genitalia, central nervous system and skeleton. Abnormal platelet function and immunological problems are usually present. Here we describe a patient with deletion of 11(q) chromosome resulting in clinical phenotype of the facial dysmorphisms, congenital malformations, neurological symptoms, as well as clinical and laboratory features of immunodeficiency. Features of immune dysregulation in a patient with JS are clearly characterized. Patient's parents agreed to use personal dats and photos in research and publications.

The review is devoted to one of the main regulatory enzymes of glycolysis in erythrocytes – pyruvate kinase, a deficiency of which is often the cause of hereditary nonspherocytic hemolytic anemia. The article presents data on the structure and function of pyruvate kinase and the currently known mutations of coding this enzyme gene. Authors analyzed associations between various genetic types and impaired enzyme function and the severity of the hemoly sis.

Post-thrombotic syndrome (PTS) is one of the most significant complications that develops in patients after deep vein thrombosis. Patients with PTS have persistent and often worsening chronic venous insufficiency which can lead to permanent impairment of the affected organ, tissue or limb. Despite their importance, the issues of diagnosis and prevention of PTS in children are understudied in Russia. This paper is based on the analysis of recently published data and presents the current state of affairs regarding PTS in pediatrics.

An oncological disease affects all aspects of the life of a sick child and leaves its mark on its further development, including causing serious changes in the emotional, cognitive, personal and behavioral areas. This leads to a decrease in the quality of life, difficulties of social adaptation. Therefore, such children need psychological help. The article provides an overview of modern research on psychological rehabilitation methods. The following methods are described: sports, artistic activities, the study of foreign languages, laughter therapy, etc. Attention is paid to what methods are most effective for violations in a particular psychological field.

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare acquired clonal blood disorder caused by somatic mutations in phosphatidylinositol glycan, class A gene (PIG-A) in hematopoietic stem cells which manifests as haemolytic anemia, bone marrow failure, thromboses, impaired renal function, and other severe clinical symptoms. The management of PNH is a clinical challenge requiring a comprehensive approach. Over the past decade, target therapy with eculizumab, an antibody inhibitor of terminal complement activation, has played a key role in the treatment of PNH. Eculizumab is the first humanized anti-C5 monoclonal antibody that was proven effective in inhibiting the complement system and was approved as a standard treatment for PNH in many countries. Elizaria, the first biosimilar version of eculizumab, whose similarity to the original drug in terms of efficacy and safety was demonstrated in clinical trials, has been widely used in Russia since 2019. New complement inhibitors classified by their mechanism of action into inhibitors targeting complement component C5 (the terminal pathway) and those targeting early phases of complement activation cascade (the proximal pathway) are currently in development. These new drugs include monoclonal antibodies, small molecules, small peptide inhibitors, small interfering RNA, and recombinant proteins based on endogenous regulators of complement activation.

Telemedicine is an integral health service in conditions when distance is a critical factor for both the delivery of medical care and the physicians’ trainings. Nowadays due to significant location remoteness, a pronounced personnel shortage as well as the necessity to make complex diagnostic and therapeutic decisions that often require a multidisciplinary communication, telemedicine allows to promote the quick delivery of quality medical services. Telemedicine today is a tool that may be considered to optimize the logistics of medical care and to reduce the financial costs of clinics. The article presents a brief report on the Center’s activities in the field of “telemedicine” and identifies the main difficulties and prospects for this work.