Schwachman-Diamond syndrome (SDS) is a rare autosomal recessive disease from the group of ribosomopathies characterized by exocrine pancreatic insufficiency, bone marrow dysfunction, malnutrition, protein-energy malnutrition, growth retardation, skeletal abnormalities and a predisposition to the development of myelodysplastic syndrome and acute myeloid leukemia. Severe hematological disorders, a high risk of developing MDS/AML, with a high percentage of unfavorable outcomes, prompted the consideration of alternative routes for the therapy in these circumstances. The possibility for the use of L-leucine, an essential amino acid, as a pathogenetic therapy in patients with severe dyshematopoiesis in SDS by analogy with its use in another ribosomopathy disease, Diamond-Blackfan anemia (DBA), is discussed in the Article.

Evans syndrome, a combination of autoimmune hemolytic anemia and immune thrombocytopenia, is a rare disease in children. In childhood, it may turn out to be one of the first manifestations of a primary immunodeficiency or an immune dysregulation syndrome. Here we present a clinical case of a patient who was initially diagnosed with Evans syndrome and did not respond well to therapy. Based on the results of genetic testing, the child was then diagnosed with primary immunodeficiency, namely, activated PI(3)kd syndrome. During follow-up, the patient developed lymphoma and had to undergo radical treatment (allogeneic hematopoietic stem cell transplantation). The patient's parents gave consent to the use of their child's data, including photographs, for research purposes and in publications.

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.

The aim of this study was to analyze the clinical and laboratory data of 101 patients (61 boys, 40 girls) diagnosed with PFAPA syndrome. The age of onset of PFAPA syndrome ranged from 8 to 36 months (the median age of onset was 18 months). 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. In most cases, clinical manifestations included recurrent fevers, acute tonsillitis (in 84% of cases, the tonsils were covered with a whitish coating), and cervical lymphadenitis. More rarely, the patients had diarrhea, vomiting, myalgia, arthralgia, and rash. All of the patients met the criteria proposed by G.S. Marshall. Our management strategies for patients with PFAPA syndrome include symptomatic treatment with antipyretics, short-term glucocorticosteroid therapy, and tonsillectomy. The majority of patients have complete resolution of PFAPA symptoms by the age of 7 regardless of the type of therapy.

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.

WHIM syndrome (warts, hypogammaglobulinemia, infections, myelokathexis) is a rare combined primary immunodeficiency. Here we describe 10 Russian patients with WHIM syndrome that were followed in the Dmitry Rogachev National Medical Research Center оf Pediatric Hematology, Oncology and Immunology. 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. Neutropenia and lymphopenia were observed in all 10 patients, hypogammaglobulinemia – in 7/10 patients. In all cases bone marrow analysis demonstrated myelokathexis features (cytoplasmic vacuolization in neutrophils and eosinophils, hyperlobulated pyknotic nuclear lobes connected by long thin strands, hypogranular and hypersegmented neutrophils). All patients were treated with granulocyte colony-stimulating factor and intravenous immunoglobulin. In 3/10 poor disease control was an indication to perform HSCT. In 2 of 3 patients HSTC was successful and all symptoms of the disease resolved. In conclusion, the diagnosis of WHIM syndrome must be considered in patients with early onset of neutro- and lymphopenia in conjunction with morphological features of myelokathexis. Treatment of this disease is still a challenging problem.

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

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.

Evans syndrome (ES) is a rare disorder accompanied by autoimmune hemolytic anemia and immune thrombocytopenia. ES in children is often associated with the defect of immune system regulation. This article presents an analysis of the results of investigation of 54 children with ES admitted to the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology during the period 2012–2019. The male-to-female ratio was 1.07:1 and the median age of the disease onset was 4 years (0 months – 16 years). Based on the results of molecular genetic testing, the diagnosis was changed in three patients to congenital TTP. Thus, for further analysis 51 patients were available. Thirty-nine out of 51 children (76.5%) had secondary ES, the median age of the disease onset was 4 years (2 months – 12 years), the male-to-female ratio was 1.05:1. PID was genetically confimed in 25 out of 39 patients, in the remaining 14 cases the diagnosis of PID was based on clinical and laboratory fidings only. Twelve patients (22.2%) had idiopathic (primary) ES, the median age of the disease onset was 8 years (7 months – 16 years) and the male-to-female ratio was 1:1. The disease onset in ES was more often accompanied by isolated cytopenia: ITP – 22 (43.1%) patients, AIHA – 15 (29.4%) patients, immune neutropenia – 1 (2%) patient, simultaneously with AIHA and ITP – 8 (15.7%) patients, pancytopenia – 5 (9.8%) patients. The second cytopenia developed on average after 2 years (1 month – 9 years). Neutropenia was observed only in secondary ES. The mortality rate for ES was 9.8%. First-line therapy (IVIG, glucocorticoids) for ES showed low effctiveness and sustained remission was observed only in 5.9% of patients. Thirty-four (87%) patients with secondary ES and 9 (75%) patients with idiopathic ES required other lines of therapy. The next-line drugs that showed good effctiveness were rituximab (76.5%), MMF (94%), and sirolimus (83%). Combinations of rituximab and MMF, rituximab and sirolimus were also effctive and induced sustained remission without other therapy in 83.3% and 75% of patients respectively. Children with ES need thorough examination, including genetic testing, for the early diagnosis of PID and the exclusion of congenital TTP. The combination of rituximab and MMF proved to be the most effctive treatment for ES.

Evans syndrome (ES) is a rare disorder accompanied by autoimmune hemolytic anemia and immune thrombocytopenia. ES in children is often associated with the defect of immune system regulation. This article presents an analysis of the results of investigation of 54 children with ES admitted to the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology during the period 2012–2019. The male-to-female ratio was 1.07:1 and the median age of the disease onset was 4 years (0 months – 16 years). Based on the results of molecular genetic testing, the diagnosis was changed in three patients to congenital TTP. Thus, for further analysis 51 patients were available. Thirty-nine out of 51 children (76.5%) had secondary ES, the median age of the disease onset was 4 years (2 months – 12 years), the male-to-female ratio was 1.05:1. PID was genetically confimed in 25 out of 39 patients, in the remaining 14 cases the diagnosis of PID was based on clinical and laboratory fidings only. Twelve patients (22.2%) had idiopathic (primary) ES, the median age of the disease onset was 8 years (7 months – 16 years) and the male-to-female ratio was 1:1. The disease onset in ES was more often accompanied by isolated cytopenia: ITP – 22 (43.1%) patients, AIHA – 15 (29.4%) patients, immune neutropenia – 1 (2%) patient, simultaneously with AIHA and ITP – 8 (15.7%) patients, pancytopenia – 5 (9.8%) patients. The second cytopenia developed on average after 2 years (1 month – 9 years). Neutropenia was observed only in secondary ES. The mortality rate for ES was 9.8%. First-line therapy (IVIG, glucocorticoids) for ES showed low effctiveness and sustained remission was observed only in 5.9% of patients. Thirty-four (87%) patients with secondary ES and 9 (75%) patients with idiopathic ES required other lines of therapy. The next-line drugs that showed good effctiveness were rituximab (76.5%), MMF (94%), and sirolimus (83%). Combinations of rituximab and MMF, rituximab and sirolimus were also effctive and induced sustained remission without other therapy in 83.3% and 75% of patients respectively. Children with ES need thorough examination, including genetic testing, for the early diagnosis of PID and the exclusion of congenital TTP. The combination of rituximab and MMF proved to be the most effctive treatment for ES.

Autoimmune lymphoproliferative syndrome is a primary immunodeficiency caused by defective FAS-mediated apoptosis and usually accompanied by hypergammaglobulinemia. Yet some exceptions take place in the cohort of patients that complicated timely diagnosis, in particular, some symptoms may resemble common variable immune deficiency. In this article, we describe the patient with rare case of agammaglobulinemia and genetically confirmed autoimmune lymphoproliferative syndrome. The patient's parents agreed to use the information, including the child's photo, in scientific research and publications.

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.

Wiskott–Aldrich Syndrome (WAS) is a primary immunodeficiency (PID), characterized by varying severity of typical symptoms: thrombocytopenia, infections, immune dysregulation and cancer predisposition. Therefore any lymphoproliferative complications in WAS patients require lymph node biopsy. However, the interpretation of the histological picture is often complicated and requires the knowledge of the lymph node pathomorphology in patients with immunodeficiency. This article describes a rare combination of late diagnosis of WAS complicated by lymphadenopathy, which clinically and morphologically resembles Rosai–Dorfman disease (RDD). Parents gave their consent to use information about the child, including the fotos, in the article.

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.

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.

Background. Shwachman-Diamond syndrome (SDS) is the rare genetic autosomal recessive disorder with pathogenic variants in SBDS gene. The spectrum of SBDS gene variants in patients with SDS and features of disease course have not been studied before in Russian population. Objective. The aim of the study was to describe all the variants of SBDS gene and clinical and laboratory abnormalities in children with SDS. Methods. In this prospective study exocrine pancreatic function was estimated by amylase and lipase activity in blood, steatorrhea presence and stool elastase levels during the initial hospitalization. Haematological disorders were analysed by complete blood count. Bone abnormalities were diagnosed via X-ray imaging. Growth delay was established due to anthropometry indicators and percentile curves. Molecular genetic testing was performed with using next generation sequencing and Senger sequencing. Results. Pathogenic variants in SBDS gene (8 in general) were revealed in 25 (89%) out of 28 children with SDS. The most common variant (in 23 patients, 82%) was с.258+2T>C, and in 18 cases it was in compound heterozygous state with c.183_184delTAinsCT. Two patients had с.653G>A (p.Arg218Gln) variant and for one patient for every of the following variants: c.258+1G>A, c.107delT, с.356G>A, c.297_300delAAGA, c.338C>T. All children with SDS had growth delay, in 11 (39%) cases we revealed bone abnormalities. In blood samples of 24 (86%) children we revealed neutropenia and less frequently anemia and thrombocytopenia. The stool elastase I decreased activity ( C and c.183_184delTAinsCT variants. Clinical signs of Shwachman-Diamond syndrome manifest since birth with growth delay, steatorrhea and haematological disorders.