One of the well-known groups of primary immunodeficiency conditions includes primary immunodeficiencies with impaired DNA repair. Primary immunodeficiencies with impaired DNA repair include immunodeficiency with Cernunnos protein deficiency. Pathogenic biallelic genetic variants in the NHEJ1 gene lead to the development of this immunodeficiency. The Cernunnos protein is involved in the processes of non-homologous DNA repair and V(D)J recombination of T- and B-lymphocyte receptors. In the clinical picture of patients with Cernunnos protein deficiency, the leading manifestations are the following: infectious complications within the framework of combined immunodeficiency, cytopenia, autoimmune complications. Like most primary immunodeficiencies with impaired DNA repair, immunodeficiencies with a defect in the NHEJ1 gene are characterized by a predisposition to the development of malignant neoplasms. The only curative treatment for patients with primary immunodeficiency conditions associated with Cernunnos protein deficiency is allogeneic hematopoietic stem cell transplantation.

Purpose. The purpose of the study is to show the importance of a multidisciplinary approach in the early verification of the primary immunodeficiency — Nijmegen breakage syndrome. A girl was admitted with complaints of daily productive cough, persistent obstruction of nasal breathing, mucopurulent discharge, recurrent respiratory tract infections for three years. From the age of 2, she suffered from protracted recurrent respiratory infections, repeatedly received inpatient treatment with systemic antibiotic therapy with insufficient effect in the form of maintaining complaints. When examining according to CT scan of the chest — single atelectasis, ground glass areas. Immunodeficiency states were excluded at the place of residence. On examination: phenotypic features of the type of «bird-like» face — sloping forehead, middle part of the face protruding forward, beak-shaped nose, large ears. Physical development is low: weight and height indicators are less than the 3rd percentile. From the nasal passages mucopurulent discharge, productive cough. Auscultatory — moist rales in all lung fields. For other organs and systems — without features. On examination: deep T-cell lymphopenia, according to CT scan signs of pansinusitis, bilateral otitis media; post-inflammatory pneumofibrotic changes. According to the results ofspirometry — mixed lesions. According to the results of immunological and genetic additional examination, the immunodeficiency state — Nijmegen breakage syndrome was verified, constant anti-inflammatory, antibacterial and antifungal, immunoglobulin replacement therapy was initiated.Conclusion. The presented clinical observation reflects the features of the course of the Nijmegen breakage syndrome. This example demonstrates the diagnostic complexity in verifying the diagnosis and shows the great importance of a multidisciplinary approach for the timely initiation of appropriate therapy, which, in turn, affects the severity of the disease and quality of life.

Nijmegen breakage syndrome (NBS) and ataxia-telangiectasia (AT; Louis–Bar syndrome) are primary immunodeficiencies (PID) associated with chromosome instability and DNA repair defects that predispose individuals to an increased risk of various malignancies. In our study, we retrospectively analyzed clinical characteristics and outcomes of 28 cancer cases in 14 patients with AT and 10 patients with NBS who had been treated at the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology between January 2007 and December 2022. The study was approved by the Independent Ethics Committee and the Scientific Council of the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology. The most common type of malignancy was mature B-cell non-Hodgkin lymphoma (B-NHL) (42%), with diffuse large B-cell lymphoma (DLBCL) accounting for 91% of all B-NHL cases. Other cases included T-cell acute lymphoblastic leukemia (ALL) ( n = 3), B-cell ALL ( n = 2), Hodgkin lymphoma ( n = 3), NK/T-cell lymphoma ( n = 1), T-cell lymphoblastic lymphoma ( n = 1), peripheral T- cell lymphoma ( n = 2), medulloblastoma ( n = 1) epithelioid rhabdomyosarcoma ( n = 1), T-cell prolymphocytic leukemia ( n = 2). A total of 4 patients were diagnosed with second malignancies (2 children with AT and 2 children with NBS. The diagnosis of PID was suspected or confirmed before the initiation of cancer therapy in 62% of AT patients and in 100% of NBS patients. Treatment was given in accordance with standard protocols with chemotherapy dose modifications. A total of 93% of patients with AT and 80% of patients with NBS required dose reduction. The level of response was quite high: 81% of patients with AT and 58% of patients with NBS achieved complete remission. According to our data, the use of reduced-dose chemotherapy regimens helps to achieve an acceptable toxicity profile without reducing the overall effectiveness of treatment.

Immunoglobulin replacement therapy is the gold standard of treatment for patients with antibody deficiencies. We aimed to investigate the efficacy and safety of replacement therapy with subcutaneous immunoglobulin (SCIG) Hizentra in patients with primary immunodeficiencies. This study was approved by the Independent Ethics Committee and the Academic Council of the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology. All patients and / or their legal representatives gave informed consent for this treatment. In our study, 12 patients under 18 years of age with various forms of primary immunodeficiencies who had previously received intravenous immunoglobulin were switched to SCIG treatment to receive weekly infusions of Hizentra. Therapy SCIG was administered weekly at a dose of 0.1–0.15 g/kg by rapid push infusion. All patients received Hizentra for at least 3 months. None of the patients included in the study developed severe infections. Immunoglobulin G levels in blood after 3 months of SCIG therapy were significantly higher compared to those achieved on previous intravenous immunoglobulin therapy. There were no severe adverse events associated with Hizentra administration. Our study demonstrated Hizentra to be effective and safe for the treatment of children with various forms of primary immunodeficiencies.

This study presents the clinical and laboratory data of 50 patients with ataxia-telangioectasia syndrome (AT) (Louis-Bar syndrome) treated at the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology (Moscow, Russia) between 2012 and 2021. The study was approved by the Independent Ethics Committee and the Scientific Council of the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology of Ministry of Healthcare of the Russian Federation. We found that the patients experienced a significant diagnostic delay (the median delay in diagnosis was 4.5 years), although the first typical symptoms of AT were present at an earlier age (the median age was 1.5 years). The majority of patients showed laboratory signs of immunodeficiency, yet only 24% of the children developed severe infections. However, lung infections resulted in bronchiectasis in 16% of the patients and were the cause of death in 4/10 cases. Fifty-two percent of the patients had autoimmune complications, including interstitial lung disease and skin granulomas, and 24% of the patients developed malignant neoplasms. Of patients who underwent testing, 85% had KREC and/or TREC levels below the cutoff values used for neonatal screening of primary immunodeficiency disorders in Russia, which suggests that the majority of AT cases could be diagnosed by neonatal screening. Early diagnosis, multidisciplinary approach and high clinical suspicion for neoplastic manifestations are crucial for the successful management of AT.

Ataxia-telangiectasia (АТ) represents a typical syndromic form of primary immunodeficiencies. Besides progressive neurological features, patients with AT have a high risk of malignancies, as well as autoimmune complications, with interstitial lung disease being one of the most frequent. AT is also characterized by a significant diagnostic delay, which was demonstrated in our case report. The patients’ parents gave their consent to the use of their children’s data, including photographs, for research purposes and in publications.

The aim of this study was to analyze the clinical, laboratory and molecular genetic data of 20 patients (9 boys, 11 girls) diagnosed with cryopyrin-associated periodic syndrome (CAPS) with an assessment of the efficacy and safety of therapy in 6 patients with an inhibitor of the interleukin-1 receptor – anakinra. The study was approved by the Independent Ethics Committee and the Scientific Council of the D. Rogachev NMRCPHOI. The patients' parents gave their consent to the use of their child's data, including photographs, for research purposes and in publications. The age of CAPS manifestation ranged from 0 to 27.0 months (median – 2 months). The clinical manifestations were dominated by fever, rash, lesions of the central nervous system, musculoskeletal system. During the attack, all 20 patients had an increase acute phase proteins of blood. All patients had heterozygous mutation in the NLRP3 gene, with the highest frequency of localization in exon 3 (17/20). 6/20 patients were initiated on anakinra therapy. All 6 patients who have been treated of anakinra enough to assess the effect of the treatment, drastic improvement of the condition was noted, but only in 5/6 patients achieved full remission.

Chronic granulomatous disease (CGD) is a primary immunodeficiency (PID), characterized by a defective production of reactive oxygen species by phagocytes. Infectious diseases are a classic manifestation of this form of PID; however, many patients present with a variety of inflammatory and immune non-infectious complications. We analyzed non-infectious complications in a group of 60 patients with CGD, who were treated in Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology (Moscow, Russia) since 2012 to February 2020. 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. Non-infectious manifestations were recorded in 53/60 patients, the most frequent of which were granulomatous complications (81.7% (49/60) of cases) in the following organs - the gastrointestinal tract, lungs, liver and lymph nodes. The median age of granulomas presentation was 3 years, and 45.8% of patients had a combined granulomatous lesion of several organs. Hepatomegaly (40%), splenomegaly (31.7%), dermatitis (21.7%) and chorioretinal lesions (11.3%) were other non-infectious complications. Hematological features outside acute infectious episodes included monocytosis (26.7%), eosinophilia (20%), neutrophilia (13.3%). 96.7% of patients had anemia with a decrease level of serum iron (65%), 31.7% - with signs of hemolysis. Autoimmune manifestations included arthritis, thyroiditis, immune thrombocytopenia or immune neutropenia. Non-infectious complications comprise a significant part of the CGD manifestations and often are the first symptoms of the disease. Awareness of this fact is very important for multidisciplinary approach in treatment of CGD. Delayed diagnosis and immunosuppressive therapy of non-infectious complications without prophylactic antimicrobial therapy can be life-threatening for patients with CGD.

Correspondence: Natalia B. Kuzmenko, MD, PhD, Head of the Department of Epidemiology and Monitoring of Immunodeficiencies, Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology, Ministry of Healthcare of the Russian Federation Address: 1 Samory Mashela St., Moscow 117997, Russia E-mail: plunge@list.ru DOI: 10.24287/1726-1708-2020-19-4suppl-62-67 Хромосомные аберрации как причина комплексного фенотипа у детей с первичными иммунодефицитами

Chronic granulomatous disease (CGD) is a primary immunodeficiency (PID), characterized by a defective production of reactive oxygen species by phagocytes. Infectious diseases are a classic manifestation of this form of PID; however, many patients present with a variety of inflammatory and immune non-infectious complications. We analyzed non-infectious complications in a group of 60 patients with CGD, who were treated in Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology (Moscow, Russia) since 2012 to February 2020. 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. Non-infectious manifestations were recorded in 53/60 patients, the most frequent of which were granulomatous complications (81.7% (49/60) of cases) in the following organs - the gastrointestinal tract, lungs, liver and lymph nodes. The median age of granulomas presentation was 3 years, and 45.8% of patients had a combined granulomatous lesion of several organs. Hepatomegaly (40%), splenomegaly (31.7%), dermatitis (21.7%) and chorioretinal lesions (11.3%) were other non-infectious complications. Hematological features outside acute infectious episodes included monocytosis (26.7%), eosinophilia (20%), neutrophilia (13.3%). 96.7% of patients had anemia with a decrease level of serum iron (65%), 31.7% - with signs of hemolysis. Autoimmune manifestations included arthritis, thyroiditis, immune thrombocytopenia or immune neutropenia. Non-infectious complications comprise a significant part of the CGD manifestations and often are the first symptoms of the disease. Awareness of this fact is very important for multidisciplinary approach in treatment of CGD. Delayed diagnosis and immunosuppressive therapy of non-infectious complications without prophylactic antimicrobial therapy can be life-threatening for patients with CGD.

Most of known primary immunodeficiencies (PID) are monogenic diseases, mainly due to the point defects in the immune system genes. However, in some rare cases the immunodeficiency is caused by various chromosomal aberrations. 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. A retrospective analysis was performed on a group of 15 patients with clinical and laboratory signs of immunodeficiency, whose chromosomal aberrations were detected by various methods. In six patients from four different families, microdeletions with inclusion of a gene ( CTLA4 , NFKB1 ) or a part of a known PID gene ( NBAS , DCLRE1C ) were detected. Four patients had a complex phenotype, where a mutation in the known PID genes ( BTK , CYBB , STAT1 GOF , ATM ) was combined with a chromosomal defect. In one case, a homozygous damage in the  USB1 gene was confirmed by detection of dysomy chromosome 16 from the father`s side. Two patients were diagnosed with known chromosomal defects – DiGeorge2 and Jacobsen syndrome. Two other patients had various chromosome abnormalities not previously described in PID`s patients. 12/15 (80%) patients had syndromic features – various skeletal dysmorphisms, malformations, and developmental delay. Immunodeficiency genes can be damaged within the chromosomal aberrations. The combination of the various methods of genetic testing is important for patients with PID. Even in PID patients without syndromic features the chromosomal analysis methods or PID diagnosis are necessary.

Primary immunodeficiencies (PID) are caused by defects in genes of immune system. The mutations may occur de novo or can be inherited. The frequency of familial PID cases varies in different populations and depends on multiple factors. The aim of this study was to analyze familial PID cases among pediatric patients from NMRCPHOI D. Rogachev. The study was approved by the Independent Ethics Committee and the Scientific Council of the D. Rogachev NMRCPHOI. 1075 children from 1020 families with molecular PID diagnosis were analyzed retrospectively. One hundred and forty-six children had at least one relative with the same disorder; mutations were identified in 31 PID’s genes. The frequency of familial cases was 13.6%. The proportion of families with two or more affected children was 5.4%. Patients born in a consanguineous marriage made up 3% of the observed children. Autosomal dominant PID were typical for families with affected adult relatives. Because of the high amount of familial cases, all parents of children with PID as well as adult PID patients of childbearing age should seek a familial genetic counselling immediately after the corresponding diagnosis. Patients whose PID diagnosis has not been genetically verified, should be urgently tested to find an underlying molecular genetic cause of the disease. Prenatal/preimplantation diagnostic and screening of their close relatives are very important in these families.

CTLA4 deficiency is a primary immunodeficiency state (PIDS) caused by monoallelic mutations in the gene of the same name, and belongs to the group of immunodeficiencies with immune dysregulation. This work analyzes the results of 11 patients with CTLA4 mutations observed at the Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology from October 2012 to January 2021. In 10 of 11 patients had some manifestations of immune dysregulation, the most frequent were cytopenias (10/11), lymphoproliferation (9/11) and lung damage caused by the type of interstitial lymphocytic lungs disease (9/11). Almost all patients had such abnormal immune parameters as hypogammaglobulinemia or dysgammaglobulinemia, lymphopenia. Currently, there is no standardized treatment for these patients, however, targeted therapy with biologically modified CTLA4 is a promising approach to the treatment of autoimmune complications in patients with CTLA4 deficiency. The only curative treatment option for patients with PIDS is hematopoietic stem cell transplantation, but in order to make conclusions about the effectiveness and safety of this treatment, a long period of observation and large groups of patients are required.

Снижение риска развития жизнеугрожающих кровотечений и улучшение качества жизни пациентов с синдромом Вискотта–Олдрича (СВО) до проведения трансплантации гемопоэтических стволовых клеток является одной из главных задач ведения этих больных. Основной целью данной работы явилась оценка эффективности и безопасности терапии пациентов с СВО с использованием агониста рецептора тромбопоэтина ромиплостима, направленной на достижение нормального уровня тромбоцитов и снижение риска развития тяжелых кровотечений. Данное исследование одобрено независимым этическим комитетом и утверждено решением ученого совета ФГБУ «НМИЦ ДГОИ им. Дмитрия Рогачева» Минздрава России. В исследование были включены 67 пациентов с генетически верифицированным диагнозом СВО, получавших терапию ромиплостимом в дозе 9 мкг/кг еженедельно в НМИЦ ДГОИ им. Дмитрия Рогачева в период с 2012 по 2019 г. Медиана длительности лечения составила 8 (1–12) мес. Полный ответ достигнут у 22 (33%) пациентов и частичный ответ – у 18 (27%). Тяжелых нежелательных явлений на фоне терапии ромиплостимом не отмечено. Единственным нежелательным явлением, возникшим на фоне проводимого лечения и, возможно, не связанным с ним, было развитие артериального тромбоза у пациента с системным васкулитом и аневризмой аорты в анамнезе. Применение ромиплостима у детей с СВО показало безопасность и высокую эффективность в коррекции тромбоцитопении и кровотечений у большинства пациентов. Ключевые слова: синдром Вискотта–Олдрича, ромиплостим, тромбоцитопения, геморрагический синдром

Severe combined immunodeficiency (SCID) is a primary immunodeficiency that presents with life-threating symptoms in early infancy and has poor prognosis if not promptly treated. Here we present an analysis of infectious presentation and its course depending on clinical and immunophenotypic form of SCID. 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. 54 patients were diagnosed with SCID in our center from 2012 to June 2020 and included to this study. The median age at diagnosis was 5.8 months. All patients were divided into 3 groups: classic SCID ( n = 31); Omenn syndrome ( n = 11); SCID with maternal fetal engraftment ( n = 12). To determine opportunistic infections severity, based on a number of infected organs at disease presentation, 3 groups were formed: with no infections or 1 infected organ, n=15; with 2 infected organs ( n = 15); with 3 and more infected organs ( n = 22). 22 of 46 BCG vaccinated patients (48%) developed BCG-infection: 16 local and 6 disseminated. There was no difference in severity of infections between 3 groups of SCID ( p = 0.22), with more severe infections found in patients older than 6 months of age at diagnosis. T- and NK-cell numbers lower than median level predisposed to severer infections in Omenn syndrome patients ( p = 0.041). There was a higher risk of BCG infections in classic SCID with low levels of NK-cells ( p = 0.009). 45 patients received allogeneic hematopoietic stem cell transplantation (HSCT). 9 patients died before HSCT and 21 after HSCT of infections and infections-related inflammatory syndromes. Though Т- and NKcells might have a role in protecting from severe infections, the early diagnosis is the most important factor of better prognosis of SCID patients.

The article presents data on the features of COVID-19 infection in patients with primary immunodeficiencies (PIDs) in the Russian Federation, obtained through the National association of experts in PID (NAEPID) registry. Materials and methods: from March 1, 2020 to October 15, 2020, 15 cases of close intrafamilial contact between PIDs patients and COVID-19 patients without reliable infection of the first and 23 cases of COVID-19 infection in PIDs patients were reported. Results: 6/23 infected people had asymptomatic course of infection, 9/23 patients – mild form, 8/23 – moderate form of disease, one patient had a severe course with a fatal outcome. 19/23 patients were under 18 years of age, which corresponds with the age data of the national Russia PID registry. Conclusion: perhaps this age composition partially explains the milder course of COVID-19 in PIDs patients compared to the European data. Other possible reasons for a milder course may be the lower pathogenicity of the coronavirus strain circulating in the Russian Federation.

Epstein–Barr virus-associated smooth muscle tumors (EBV-SMTs) are rare soft tissue neoplasms that typically occur in conditions of secondary immunodeficiency due to human immunodeficiency virus or immunosuppression after organ transplantation. Beyond that, EBV-SMTs occur in patients with primary immunodeficiencies (PIDs). EBV-SMTs pathogenesis is still unclear but it was shown that the key mechanism of the tumor development is T- and NK-cell defect. Treatment strategy depends not only on tumor localization and resectability, but also on immunodeficiency etiology and its correction possibility. Here we report literature review and two patients with combined PIDs (CARMIL2- and ATM-genes deficiency) who developed EBV-SMT. In each case, the parents gave consent to the use of their child's data, including photographs, for research purposes and in publications.

The hyper-IgE syndrome with dominant-negative mutations in signal transducer and activator of transcription 3 (STAT3) gene is a combined primary immunodeficiency characterized by severe bacterial infections (skin and lungs with bullae formation), characteristic phenotype, serum IgE elevation, eosinophilia, as well as connective tissue, and bone anomalies. Patients also have high risk of cancer. STAT3 is a transcription factor important for the JAK/STAT signaling pathway, which plays the key role in the synthesis of cytokines, hormones, and bioactive agents. Hyper-IgE syndrome therapy includes antimicrobial prophylaxis, immunoglobulin replacement, and use of bisphosphonates. Hematopoietic stem cell transplantation is an alternative way for the disease treatment. Here we describe a patient with severe autosomal dominant hyper-IgE-syndrome with thte loss-of-function mutation in the STAT3 gene. Patient's parents agreed to use personal dats and photos in research and publications.

Primary immunodeficiencies (PIDS) are genetically caused heterogeneous diseases of the immune system. One of the genetic phenomenon affecting the phenotypic diversity of PIDS is a reverse somatic mosaicism (RM) observed in different groups of PIDS. The majority of RM cases are described in patients with Wiskott–Aldrich syndrome (WAS). Despite the fact that PM does not always lead to a mild form of the disease, the presence of this phenomenon can cause the delay of diagnosis and start of the appropriate treatment. This article presents the case of a patient with Wiskott–Aldrich syndrome with a reverse mutation in the WAS gene. Parents gave their consent to use information about the child in the article.