X-linked agammaglobulinemia (XLA) is a primary immunodeficiency that refers to defects in the humoral link and is characterized by severe recurrent infectious episodes as well as low concentration of serum immunoglobulins up to their complete absence. BTK (Bruton tyrosine kinase), a protein coding gene is responsible for this disease, whose mutations lead to impaired maturation of B-lymphocytes followed by a defect in antibody production. The survival rate of patients with early diagnosis and timely replacement therapy with intravenous (IVIG) and subcutaneous (SCIG) immunoglobulins is quite high. Though patients in this group are predisposed to immune complications such as IBD-like lesions of the gastrointestinal tract (GIT) in addition to recurrent infectious episodes. The differentiation of such complications if often of diagnostic and therapeutic difficulties. This group of patients is being actively studied at the moment aimed to the search for therapeutic options. The Article represents a bibliographical review and clinical case of the development of IBD-like lesions of the GIT in a patient with XLA.

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 paper presents a case of rare primary immunodeficiency belonging to the group of monogenic autoinflammatory diseases with PLCy2-associated antibody deficiency and immune dysregulation (APLAID). Here we describe our experience in the management of a 7-year-old child with this syndrome and discuss key information about the pathogenesis and clinical manifestations of APLAID based on the analysis of the known cases. Due to the rarity and novelty of the disease, there is a lack of established criteria for the identification and diagnosis of APLAID and no established standard of care. We report our experience of treating APLAID with a tumor necrosis factor-a inhibitor and our analysis of the effectiveness of treatment and adverse events. The patient's parents gave consent to the use of their child'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.

The article is devoted to an extremely rare variant of type I interferonopathies associated with a homozygous gain of function (GOF) mutation in the STAT2 gene in a 5-year-old child. This genetic defect was first described in 2019, and so far only 3 cases are known in the world with a similar pathology. Here we present the fourth clinical case and our experience in managing a patient with STAT2 GOF. The article presents the key aspects of the pathogenesis, clinical picture based on the analysis of all known cases of the disease. The absence of established criteria and methods of treatment for this disease is due to the rarity and relative novelty of the described nosology. We present the experience of treatment using a JAK kinase inhibitor, followed by an assessment of the effectiveness of the therapy and side effects. The patient's parents agreed to use the information, including the child's photo, in scientific research and publications.

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

This article is dedicated to one of the auto-respiratory syndromes – adenosine deaminase deficiency 2 (deficiency of adenosine deaminase 2 – DADA2) in the 12-year-old. This rare disease is caused by mutations in the ADA2 gene (CECR1), that encodes the ADA2 protein. Clinical manifestations of DADA2 are very diverse and usually include systemic inflammatory reaction in the form of fever attacts, vasculopathy in the form of livedo reticulum, polyarteritis nodosa, ischemic and/or hemorrhagic strokes, as well as signs of immunodeficiency with hypogammaglobulinemia and bone marrow failure. Complex pathogenetic mechanisms, variety of clinical manifestations complicate both diagnosis of the disease and trial of pathogenetic therapy in patients with DADA2. The article describes DADA2 patient care, as well as provides present state analysis of the DADA2 problem in the world, including terminology, historical references, pathogenesis, diagnosis problems and clinical manifestations.

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.

Chronic nonbacterial osteomyelitis (CNO) is a rare autoinflammatory disease from the group of multifactorial diseases. It is characterized by non-infectious recurrent bone lesions, usually manifesting in childhood. The aim of this study was to analyze the clinical, laboratory, radiological and histological data of 33 patients (12 boys, 21 girls) with a diagnosis of chronic nonbacterial osteomyelitis. 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. 25/33 patients were hospitalized to the Center with suspected neoplastic disease bone. The median age of CNO manifestation was 9.6 years. 24/33 had a multi-focal form of the disease. 5 patients had fever. Nonsteroidal anti-inflammatory drugs were the first therapy for all patients, achieving clinical remission in 4 cases. Zoledronic acid were used in 29 patients with remission in 19, adalimumab in 10 patient with remission in 9. In one patient stabilization was achieved only with the combination  of methotrexate and canakinumab therapy.

The aim of this study was to analyze the clinical, laboratory and molecular genetic data of 26 patients (15 boys, 11 girls) diagnosed with mevalonate kinase deficiency syndrome (MKD).Subjects and methods. The age of MKD manifestation ranged from 0 to 30.0 months (M – 1.5 months). Clinical manifestations and their severity were extremely diverse: from symptoms resembling Marshall’s syndrome to severe systemic manifestations with respiratory failure, hepatosplenomegaly and pancytopenia.Results/Conclusion. All patients had homozygous/compound-heterozygous mutations in the MVK gene, including 10 newly described variants. In all 20 patients, who have been treated with IL-1 inhibitors long enough to assess the effect of the treatment, drastic improvement of the condition was noted, but only in 17/20 patients achieved full remission.

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

Objectives: Mutations in the neuroblastoma-amplified sequence (NBAS) gene were originally described in patients with skeletal dysplasia or isolated liver disease of variable severity. Subsequent publications reported a more complex phenotype. Among multisystemic clinical symptoms, we were particularly interested in the immunological consequences of the NBAS deficiency. Methods: Clinical and laboratory data of 3 patients ages 13, 6, and 5 in whom bi-allelic NBAS mutations had been detected via next-generation sequencing were characterized. Literature review of 23 publications describing 74 patients was performed. Results: We report three Russian patients with compound heterozygous mutations of the NBAS gene who had combined immunodeficiency characterized by hypogammaglobulinemia, low T-cells, and near-absent B-cells, along with liver disease, skeletal dysplasia, optic-nerve atrophy, and dysmorphic features. Analysis of the data of 74 previously reported patients who carried various NBAS mutations demonstrated that although the most severe form of liver disease seems to require disruption of the N-terminal or middle part of NBAS, mutations of variable localizations in the gene have been associated with some form of liver disease, as well as immunological disorders. Conclusions: NBAS deficiency has a broad phenotype, and referral to an immunologist should be made in order to screen for immunodeficiency.

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.

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.

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.