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.

This paper considers the use of machine learning for diagnosis of diseases that is based on the analysis of a complete gene expression profile. This distinguishes our study from other approaches that require a preliminary step of finding a limited number of relevant genes (tens or hundreds of genes). We conducted experiments with complete genetic expression profiles (20 531 genes) that we obtained after processing transcriptomes of 801 patients with known oncologic diagnoses (oncology of the lung, kidneys, breast, prostate, and colon). Using the indextron (instant learning index system) for a new purpose, i.e., for complete expression profile processing, provided diagnostic accuracy that is 99.75% in agreement with the results of histological verification.

This paper considers the use of machine learning for diagnosis of diseases that is based on the analysis of a complete gene expression profile. This distinguishes our study from other approaches that require a preliminary step of finding a limited number of relevant genes (tens or hundreds of genes). We conducted experiments with complete genetic expression profiles (20 531 genes) that we obtained after processing transcriptomes of 801 patients with known oncologic diagnoses (oncology of the lung, kidneys, breast, prostate, and colon). Using the indextron (instant learning index system) for a new purpose, i.e., for complete expression profile processing, provided diagnostic accuracy that is 99.75% in agreement with the results of histological verification.

Introduction: Nephroblastoma (Wilms tumor (WT)) is an embryonal tumor accounting for >90% of pediatric renal cancers. About 10% of WTs harbor pathogenic germline mutations. The REST gene, classified as a putative tumor suppressor, is affected in 2% of WTs. High-throughput molecular methods facilitate advanced diagnostics of cancer. In addition to this, germline mutations in REST are also associated with familial gingival fibromatosis (GFM). Reciprocally, none of the articles on RESTmut WT mentions GFM as a comorbid condition. This report provides unique evidence on the WT-GFM comorbidity in RESTmut carriers. Case presentation: Patient 1 (a 5-year-old boy with unilateral WT) is a proband, who has two healthy siblings. Patient 2 (a 4-year-old girl with bilateral WT) is a proband from in vitro fertilization (IVF) triplets, with a sister and brother without WT. We analyzed probands' DNA extracted from peripheral blood leucocytes with a custom-targeted next-generation sequencing (NGS)-198 gene panel. The detected variants were checked in family members by Sanger sequencing. Patient 1 had a pathogenic germline mutation in REST: c.1035_1036insTA, p.(E346*), as did his mother and both brothers. There were two other WT cases in this family (proband's maternal uncles). Patient 2 had a pathogenic germline variant in REST: c.2668_2671del, p.(E891Pfs*6), as well as her sister. The mutation was probably inherited from their deceased father, as he had gingival fibromatosis. Family members with REST mutations from both families had gingival fibromatosis. A somatic REST c.663C>A p.C221* mutation was identified in one patient with WT. At the moment both patients with WT are under dynamic observation without signs of the disease. Conclusion: Here, we describe two clinical cases of WT in nonrelated young children with germline-inactivating REST variants identified by next-generation sequencing. Both patients present with familial gingival fibromatosis, regarded as clinically useful comorbidity indicative of the tumor predisposition syndrome. The two cases illustrate Wilms tumor-gingival fibromatosis comorbidity in carriers of germline-inactivated REST alleles previously identified as a predisposition factor for both conditions.

Primary hyperparathyroidism (or PHPT) is a rare pediatric disease occurring in 1 case per 200 to 300 thousand children. The most common cause of PHPT in the adult population is a solitary parathyroid (PT) adenoma with up to 16% of PT adenomas having an ectopic location. There are no epidemiological data on pancreatic adenomas in pediatric population including atypically located ones, and clinical data are extremely scarce. This article describes a clinical observation of an adolescent patient with PHPT whose disease has been manifested with increased fragility and deformation of the bones of the skeleton. Only one year after the onset of primary symptoms a complex set of diagnostic measures was initiated, as a result of which a diagnosis was established: PHPT against the background of adenoma of the pancreas, ectopic in the left lobe of the thymus. The surgical treatment was carried out in the amount of thoracoscopic hemithymectomy which led to the relief of hyperparathyroidism. Despite the surgical intervention the systemic osteoporosis and persistent pathological changes in the bone skeleton that have been formed by the time of diagnosis require long-term observation and treatment of the patient by a pediatric endocrinologist, pediatric orthopedist and rehabilitologist. Thus, based on the presented clinical observation, the conclusion is as follows: in order to minimize the risk of disability in children and adolescents with PHPT it is extremely important to establish the correct diagnosis as early as possible coupled with the timely etiotropic and pathogenetic treatment.

Malignant rhabdoid tumor (MRT) is a rare malignant neoplasm of childhood, characterized by an aggressive course and an extremely unfavorable prognosis. The frequency of MRT outside the central nervous system (extracranial MRT) is 0.02–0.03 per 100,000 children. In most cases, MRT is based on an inactivating mutations of the tumor suppressor gene SMARCB1, which leads to the absence of expression of the SMARCB1 ((INI1/hSNF5/BAF47) protein in tumor cells. Aberrations of the SMARCA4 gene, which is an extremely rare molecular event, have been described among the MRTs expressing SMARCB1 (INI1). Few case reports have been described in the international literature.This article contains a description of a clinical case of a patient diagnosed with soft tissue MRT with SMARCA4 gene alteration. The distinctive features of the presented case are the congenital nature of the tumor, atypical localization, and extremely aggressive clinical course of the disease. On the example of the described clinical case, diagnostics of SMARCA4-associated MRT are presented, as well as the place of molecular methods in diagnosis verification. In addition, it is highlighted that the detection of somatic changes in the SMARCB1 and SMARCA4 genes requires additional investigation of their germinal status to exclude or confirm the rhabdoid tumor predisposition syndrome.

Pleuropulmonary blastoma (PPB) is a very rare tumor of childhood that arises from the mesenchyme of the lung and is associated with mutations in the DICER1 gene. The present article describes a familial case of DICER1 syndrome in a patient aged 3 years and 11 months who underwent investigations and treatment for type II/III PPB of the lower lobe of the left lung at the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology of Ministry of Healthcare of the Russian Federation. The patient's parents gave their consent to the use of their child's data, including photographs, for research purposes and in publications. The diagnosis was made based on the results of the pathology investigation of the tissue obtained by open biopsy. Furthermore, the diagnosis was confirmed by the review of histological specimens in the International PPB Registry (Minneapolis, USA). According to the data from the chest CT with intravenous contrast enhancement, the tumor was described as a mass consisting of cystic cavities of various calibers accumulating a contrast agent along the periphery, and a solid component. Specific combination treatment was based on the recommendations of the International PPB Registry and included chemotherapy according to the IVADo/IVA regimen and surgical treatment as a local control. Currently, specific treatment has been completed, the patient is alive with no signs of the disease, the follow-up period was 20 months. As regards the patient's family history, he has a sibling (older brother) who was diagnosed with a cystic nephroma at the age of 1 year and 4 months. Molecular genetic testing of the tumor tissues obtained from the patient (PPB) and his sibling (cystic nephroma) revealed pathogenic somatic variants in the DICER1 gene. Along with the somatic genetic variants, another pathogenic variant was found in both children, the germline status of which was confirmed. The germline variant in the DICER1 gene was inherited from the mother. Thus, the investigations confirmed a familial case of DICER1 syndrome. The case described in this article indicates that families in which DICER1 syndrome was found require special management aimed at early detection of tumors and non-tumor conditions associated with this syndrome in the carriers of pathogenic alleles.

Mutations in the MECOM gene (MDS1 and EVI1 complex locus) may be one of the causes of a rare combination of congenital radioulnar synostosis resulting in extremely limited forearm pronation and supination, and amegakaryocytic thrombocytopenia. The clinical spectrum of the disease can range from isolated radioulnar synostosis with or without hematologic manifestations to severe bone marrow failure without skeletal abnormalities. Other phenotypic manifestations include clinodactyly, brachydactyly, cardiac and renal malformations, presenile hearing loss, and B-cell deficiency. In view of the heterogeneity of phenotypic manifestations of the disease, the term “MECOM-associated syndrome” was proposed for all patients with mutations in the MECOM gene. Here we report 3 pediatric cases of MECOM-associated syndrome with different clinical manifestations, diagnostic approaches, therapeutic options, and outcomes. The patient’s parents agreed to use the information, including the child’s photo, in scientific research and 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.

Introduction . Neuroblastoma (NB) is the most common embryonic extracranial malignant neoplasm in children. The contribution of the NF1 gene to the development of NB is discussed in the literature, but there is no evidence of the pathogenetic role of NF1 gene aberrations in NB. According to various literature sources, the occurrence of pathogenic variants in the NF1 gene in the general cohort of patients with NB does not exceed 1–6 %. Materials and methods. The molecular genetic examination by next generation sequencing (NGS) was performed in 77 patients with NB during the period from April 2019 to July 2021 in the Laboratory of Molecular Oncology Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology, Immunology. The staging of patients was carried out within the framework of the international staging system, stratification into risk groups and therapy according to the protocol of the German Group for the study of NB GPOH NB-2004. International criteria of the response assessment system for patients with NB were used to assess the response to treatment. Calculations of event-free and overall survival by the Kaplan–Mayer method for the follow-up period up to 12.01.2022 were performed. Results and discussion . The cohort of patients included in the study was represented by patients with an initially unfavorable prognosis. Patients were divided into 3 groups: without pathogenic variants in genes belonging to the RAS-RAF-MEK pathway and TP53 – “RAS-/ TP53-” (n = 43), with clinically significant variants in the NF1 gene – “NF1+” (n = 12), clinically significant variants in the genes of RAS-RAF-MEK and TP53 pathway – “RAS+/TP53+” except NF1 (n = 22). The median age for the entire group of patients at the time of diagnosis was 41 months (0.1–173 months). Boys prevailed over girls with a ratio of 1.5:1. Patients with stage 4 of the disease according to the INSS classification prevailed – 81.8 % (63/77), high-risk groups according to the NB-2004 protocol – 77.9 % (60/77).In our study 13 clinically significant variants in NF1 were identified in 12 patients (15.6 %), of which 4 were germinal, 9 were somatic. The frequency of detection of pathogenic aberrations in the NF1 gene was much higher than the literature data, which can be associated with a selective cohort of studied patients with an unfavorable prognosis and patients with suspected hereditary genetic syndrome. The presentation of adverse events was observed in 83.3 % of patients, more often against the background of specific therapy (in 60 % of cases), which may be due to the rapid acquisition of NB chemoresistance, among other things. When comparing the three groups, it was shown that the frequency of objective responses to induction therapy was statistically significantly lower in the group of patients “NF1+”, when compared with other groups (p = 0.015; p = 0.024), which may also indicate the chemoresistance of NF1-aberrated NB. When analyzing survival there was no statistical difference between the compared groups. Conclusions . The data obtained by us do not allow us to consider the presence of genetic variants in NF1 separately as a prognostic factor, however, it can be assumed that a group of patients with an unfavorable prognosis may be enriched with cases with mutations in the NF1 gene. Refractory course of the disease/development of adverse events in the presence of genetic variants of NF1, causing the activation of the RASRAF- MEK signaling pathway, leads to the induction of tumor chemoresistance. The presence of clinical significance of aberrations in the NF1 gene does not lead to a statistically significant difference in prognosis when compared with patients with aberrations in other components of the RAS-RAF-MEK pathway, however, longer catamnestic follow-up of patients is necessary.Currently, there are no effective drugs for the treatment of NF1-associated NB in clinical practice that requires further study of the mechanisms of chemoresistance development in such patients. Understanding the molecular and genetic features of the course of NF1-associated NB can become the basis for the development of personalized therapy in the future.

ПАПИЛЛЯРНЫЙ РАК ЩИТОВИДНОЙ ЖЕЛЕЗЫ У ПАЦИЕНТА С СЕМЕЙНЫМ АДЕНОМАТОЗНЫМ ПОЛИПОЗОМАвторы: А.В

1ФГБУ «Национальный медицинский исследовательский центр детской гематологии, онкологии и иммунологии им. Дмитрия Рогачева» Минздрава России, Москва 2ФГАОУ ВО «Российский национальный исследовательский медицинский университет им. Н.И. Пирогова» Минздрава России, Москва 3ГУ «Республиканская детская клиническая больница» Министерства здравоохранения Республики Коми, Сыктывкар 4ГБУЗ «Самарская областная детская клиническая больница им. Н.Н. Ивановой», Самара

Succinate dehydrogenase-deficient renal cell carcinoma (SDH-deficient RCC) is histological variant of RCC recently recognized and included in the classification of renal tumors. SDH-deficient RCC constitutes only 0,02–0,5% of all RCC. The main role in the development of this malignant neoplasm (MN) belongs to mutations in the genes of succinate dehydrogenase (SDHx). The article presents a clinical case report of SDH-deficient RCC in the 15-year-old child. RCC developed as a consequence of the syndrome of hereditary pheochromocytoma and paraganglioma type 4. A literature review describes the histological and molecular genetic characteristics of SDH-deficient RCC, the clinical picture, approaches to therapy and monitoring of patients, as well as indications for genetic testing of patients and their relatives to identify cancer predisposition syndromes.

Hemorrhagic thrombocytopathy with defective signal transduction CalDAG-GEFI is a rare disease associated with a mutation in the RASGRP2 gene. At the moment, this disease is described in 10 person in the world. We present clinical case report of this pathology of a 9-year-old child. We also offer a review of the available literature about pathogenetic features, clinical manifestations and prevalence of this rare disease. The patient’s parents gave their consent to the use of their child’s data, including photographs, for research purposes and in publications.

The article presents retrospective data analysis of a cohort of patients with PKD (n = 41 patients, aged 4 months – 26,5 years, median of age – 5 years 1 month) who were examined at the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology for unspecifid hereditary hemolytic anemia during the period 2013–2020. The study was approved by the Independent Ethics Committee of the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology. In all patients, the diagnosis was confimed by Next Generation sequencing (NGS). The homozygous mutations in the PKLR gene were found in 10 patients (24.39%), compound heterozygous mutations in 31 patients (75.61%), 77.78% of them were missense mutations. Gender distribution (male:female) was 1:1.73. At least once transfusion of erythrocyte suspension was required to 40 (97.56%) patients. The minimum age at the time of the debut of transfusion dependence was the fist day of life, the maximum was 4 years. Exchange blood transfusion was performed in 13 children, severe normocytic hyperregenerative anemia with transfusion of red blood cells in the fist days of life was noted in 12 children, at the 1st month of life – in 9 children, at the 2nd month of life – in 8 children, at the 3rd month – in 6 children, at the 5th month – in 2 children, at the 1st year – in 1 child, and 2 children underwent single transfusions on the background of infectious episodes at 3 and 4 years respectively. Splenectomy due to high transfusion dependence was performed in 10 patients: transfusion independence was achieved in 5 patients, in 5 – an increase in the interval between blood transfusions. Median of surgical intervention (9 patients): 7 years 4 months, minimum age – 1 year 4 months, maximum – 14 years 4 months. In total, 36 genotypes were described in 41 patients, among them were: c.1529G>A in 3 patients, c.1137_1139del / c.1456C>T – in 2 patients, c.1079G>A/c.1529G>A in 2 patients, c.1130T>C/c.1456C>T in 2 patients, other genotypes occurred once. Two mutations were the most frequent: c.1456C>T (16.67%) and c.1529G>A (16.67%). 19 (46,34%) of patients had previously not described mutations.

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.

Neurofibromatosis is a genetic disorder that affects the bones, soft tissues, skin, and the nervous system. Neurofibromatosis has been described in 1882, however, there is still no specific treatment for this disease and no treatment protocols for the most frequent and life-threatening complications such as non-malignant tumors deriving from the cells of the peripheral nerve sheaths. Progress in molecular genetic study discovered the underlying genetic alteration in this tumor. This knowledge provides the base for clinical trials with new drugs. MEK-inhibitors are acting on the RAS-MAPK signaling pathway and have shown their efficacy in decreasing the size of inoperable tumors in children with type 1 neurofibromatosis (NF1). Although, this therapy does not completely reduce the tumor volume, it can significantly improve the quality of life. This article presents a clinical case of the trametinib efficacy in a child suffering from NF1-associated plexiform neurofibromas.

Cystic nephroma (CN) is a rare renal tumor occurring in children which belongs to a group of neoplasms linked with the inherited DICER1 syndrome. Given the rarity of CNs, it is important to describe clinical, radiological, and molecular genetic characteristics of these tumors in children and adolescents as well as to analyze treatment outcomes. We present our experience in managing 8 patients with histologically verified CN who received treatment and consultations at the D. Rogachev NMRCPHOI over a period of 9 years (2012–2020). 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. We performed a retrospective analysis of clinical presentation, radiological findings, the extent of treatment given to patients, treatment outcomes, and the results of molecular genetic testing. The study included patients aged between 8.6 and 197 months at diagnosis (the median age was 14.2 months). The analysis of initial complaints revealed that six patients (75%) had an increased abdominal girth and a palpable mass in the abdomen, one patient (12.5%) presented with arterial hypertension, and another patient (12.5%) had a mass detected by a routine abdominal ultrasound examination. On contrast-enhanced computed tomography scans, CNs appeared as multicystic masses with thin, contrast-enhancing septa; the CN volume ranged from 59.7 to 1293.1 cm3 (the median volume was 626.3 cm3 ). In all cases, the diagnosis of CN was verified histologically. Surgical treatment included nephrectomy (n = 6) or partial resection of the affected kidney (n = 2) with the removal of the tumor. Some patients (n = 5) included in our analysis received pre-operative chemotherapy at the discretion of their treating physicians. Molecular genetic testing was carried out for 7 children: 4 out of 7 patients (57.1%) were found to have somatic and germline mutations in the DICER1 gene. Carriers of pathogenic DICER1 variant were identified in the family of 1 patient. The median duration of follow-up was 17.6 months (range: 1.7 to 58.9 months). Currently, all patients are alive, no relapses have occurred. Cystic renal neoplasms detected by radiological investigations should be reviewed at the reference centers for pediatric oncological diseases and included CN in the differential diagnosis. Initial surgery is the first line of treatment for cystic nephroma. The final diagnosis is made on the basis of a histological examination of tumor tissue. All patients with confirmed CN should be referred for genetic counseling and molecular genetic testing for germline mutations in the DICER1 gene and should receive surveillance recommendations for the early detection of other metachronous DICER1-associated tumors.

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.