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Clin Immunol ; 205: 1-5, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31071452


Here we describe a 10-year-old girl with combined immunodeficiency presenting as recurring chest infections, lung disease and herpetic skin infections. The patient experienced two hematopoietic stem cell transplantations and despite full chimerism, she developed bone marrow aplasia due to adenovirus infection and died at post-transplant day 86. Immunologic investigation revealed low numbers of TRECs/KRECs, a severe reduction of memory B cells, absence of isohemagglutinins, and low IgG levels. Whole exome sequencing (WES) identified a novel heterozygous mutation in RAC2(c.275A > C, p.N92 T). Flow cytometric investigation of neutrophil migration demonstrated an absence of chemotaxis to fMLP. Cell lines transfected with RAC2 [N92 T] displayed characteristics of active GTP-bound RAC2 including enhanced NADPH oxidase-derived superoxide production both at rest and in response to PMA. Our findings broaden the clinical picture of RAC2 dysfunction, showing that some individuals can present with a combined immunodeficiency later in childhood rather than a congenital neutrophil disease.

Immunogenetics ; 70(9): 613-617, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29492593


Ataxia-telangiectasia (AT) is a rare neurodegenerative disease characterized by an early onset ataxia, oculocutaneous telangiectasia, immunodeficiency, recurrent infections, radio-sensitivity, and a predisposition to malignancy. We present the case of a child with coexistent AT and trisomy X (47,XXX). We used fluorescent in situ hybridization (FISH) to confirm that this person had 47,XXX karyotype in blood cells, bone marrow, fibroblasts, and buccal smear. Standard cytogenetic studies (not banded) were conducted on blood cells. G-banding analysis was performed on bone marrow cells at the time of the leukemia diagnosis. Flow cytometric investigation of lymphocytes and Sanger sequencing of the ATM gene were used for diagnosis confirmation and description. We report the case of an 11-year-old girl at remission after having T cell acute leukemia for 7 years with progressive signs of ataxia-telangiectasia and with additional X chromosome since birth. At the age of 2 years and 7 months, she was diagnosed with pre-T acute leukemia. From the age of four, she had gait abnormalities. AT was established at the age of seven based on clinical signs and laboratory findings (increased alpha fetoprotein-AFP [227]) and confirmed by detecting compound heterozygous truncating mutations in the ATM gene (p.Y705X and p.L2312I). These genetic findings have not been previously reported in AT and our "double hit" case demonstrates the value of careful clinical evaluation of children with an established genetic diagnosis. Measurement of AFP levels should be considered in patients with neurologic abnormalities after leukemia treatment.

Proteínas Mutadas de Ataxia Telangiectasia/genética , Mutação , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Transtornos do Cromossomo Sexual no Desenvolvimento Sexual/genética , Trissomia/genética , Criança , Cromossomos Humanos X/genética , Feminino , Humanos , Mosaicismo , Leucemia-Linfoma Linfoblástico de Células T Precursoras/etiologia , Aberrações dos Cromossomos Sexuais , Transtornos do Cromossomo Sexual no Desenvolvimento Sexual/etiologia
J Pediatr Hematol Oncol ; 39(4): e203-e206, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-28267077


BACKGROUND: X-linked lymphoproliferative disease type I (XLP I) is caused by mutations in the SH2D1A gene and characterized mainly by hypogammaglobulinemia and abnormal response to Epstein-Barr virus with a high predisposition to B-cell non-Hodgkin lymphoma development. OBSERVATIONS: In this article, we describe the experience of 2 centers in Belarus and in Russia that follow 3 male patients who were diagnosed with XLP I after lymphoma development and treatment. Three novel mutations c.51G>C (p.E17D), c.192G>T (p.W64C), and c.53insA (p.K18KfsX67) were found in 3 males patients with XLP I. Two of them did not have any signs of immunodeficiency before B-cell non-Hodgkin lymphoma development. CONCLUSIONS: We propose SH2D1A mutational screening be considered in male patients with or without hypogammaglobulinemia who received rituximab treatment for lymphoma and did not recover immunoglobulin G in a year after B-depleting therapy.

Linfoma não Hodgkin/complicações , Transtornos Linfoproliferativos/complicações , Transtornos Linfoproliferativos/genética , Proteína Associada à Molécula de Sinalização da Ativação Linfocitária/genética , Agamaglobulinemia , Criança , Humanos , Imunoglobulina G/sangue , Linfoma não Hodgkin/tratamento farmacológico , Transtornos Linfoproliferativos/diagnóstico , Masculino , Mutação , Rituximab/uso terapêutico
Clin Immunol ; 163: 108-10, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26774591


INTRODUCTION: Here we present an unusual case of DNA ligase IV deficiency syndrome without dysmorphic facial findings and microcephaly complicated with Epstein-Barr virus-associated large B-cell lymphoma with the right lung involvement and a massive brain tumor lesion in a two-year-old female. METHODS: PID panel was used for sequencing 55 genes. Most genes have >98% exon coverage including splicing sites. LIG4 gene has 100% exon and splicing site coverage. This was used in Ion Torrent PGM system, the library kit was made by Agilent with Haloplex technology. The sequence analysis software was Alamut, direct sequencing of LIG4 gene was performed after NGS results. RESULT: We identified three heterozygous mutations in LIG4 gene c.2736+3delC and c.8 C>T (p.A3V) inherited from mother and c.26C>T (p.T9I) - from father after PID panel sequencing and some additional polymorphisms in ATM, NOD2 and NLRP3 genes. CONCLUSION: This case broadens the clinical spectrum of DNA ligase IV deficiency.

Neoplasias Encefálicas/imunologia , DNA Ligases/deficiência , Infecções por Vírus Epstein-Barr/imunologia , Síndromes de Imunodeficiência/imunologia , Neoplasias Pulmonares/imunologia , Linfoma Difuso de Grandes Células B/imunologia , Neoplasias Primárias Múltiplas/imunologia , Neoplasias Encefálicas/virologia , Pré-Escolar , DNA Ligase Dependente de ATP , DNA Ligases/genética , Feminino , Herpesvirus Humano 4 , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Síndromes de Imunodeficiência/genética , Neoplasias Pulmonares/virologia , Linfoma Difuso de Grandes Células B/virologia , Mutação , Neoplasias Primárias Múltiplas/virologia , Análise de Sequência de DNA
J Clin Immunol ; 36(1): 46-55, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26596586


BACKGROUND: Omenn syndrome [Mendelian Inheritance (OMIM 603554)] is a genetic disease of the immune system, characterized by the presence of fatal generalized severe erythroderma, lymphoadenopathy, eosinophilia and profound immunodeficiency. OBJECTIVE: We studied clinical and immunologic presentation of the disease manifestation among East Slavs population with genetically confirmed Omenn syndrome. RESULTS: We collected clinical and immunologic data of 11 patients (1 from Belarus, 5--Ukraine, 5--Russia): 6 females, 5 males. The age of Omenn syndrome manifestation varied from the 1st day of life to 1 year and 1 month, the age of diagnosis--20 days to 1 year and 10 months. Nine out of 11 patients had classic immunologic phenotype T(+/-)B-NK+, 1 pt had TlowB + NK+ with CD3 + TCRgd + expansion and 1 had TlowB+/-NK+ phenotype. Eight out of 11 pts had mutation in RAG1 gene, 4 out of 8 had c.368-369delAA (p.K86fsX118) in homozygous state or heterozygous compound. In our cohort of patients, we also described two new mutations in RAG genes (p.E722Q in RAG1 and p.M459R in RAG2). At present, 7/11 were transplanted and 5 out of the transplanted are alive. CONCLUSION: This study demonstrates that the most popular genetic abnormality in East Slavs children with Omenn syndrome is c.368-369delAA (p.K86fs118) in RAG1 gene, which may be connected with more favorable prognosis because 4/4 patients survived after hematopoietic stem cells transplantation.

Grupo com Ancestrais do Continente Europeu , Transplante de Células-Tronco Hematopoéticas , Proteínas de Homeodomínio/genética , Linfócitos/imunologia , Imunodeficiência Combinada Severa/diagnóstico , Feminino , Humanos , Imunofenotipagem , Lactente , Recém-Nascido , Masculino , Mutação/genética , Polimorfismo Genético , Prognóstico , República de Belarus , Federação Russa , Imunodeficiência Combinada Severa/mortalidade , Imunodeficiência Combinada Severa/terapia , Análise de Sobrevida , Ucrânia
Hum Immunol ; 74(1): 18-22, 2013 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-23085344


We report a male with atypical severe combined immunodeficiency caused by heterozygous compound mutations c.256-257del and c.C1331T in RAG1 gene. The patient presents with recurrent bronchopneumonias with obstruction, chronic fibrosing alveolitis, complicated by respiratory failure, pulmonary hypertension and hepatosplenomegaly. He was diagnosed with agammaglobulinemia at the age of 9. His condition was complicated by granulomatous skin disease at the age of 12 despite regular IVIg substitution. Immunological presentation included profound hypogammaglobulinemia and absence of B cells. Under immunoglobulin substitution for 5 years patient has permanent lymphopenia, skewed phenotype of T cells and diminished number of recent thymic emigrants.

Agamaglobulinemia/patologia , Granuloma/patologia , Proteínas de Homeodomínio/genética , Mutação , Imunodeficiência Combinada Severa/genética , Imunodeficiência Combinada Severa/patologia , Pele/patologia , Adolescente , Agamaglobulinemia/tratamento farmacológico , Agamaglobulinemia/genética , Agamaglobulinemia/imunologia , Linfócitos B/imunologia , Linfócitos B/patologia , Granuloma/tratamento farmacológico , Granuloma/genética , Granuloma/imunologia , Heterozigoto , Proteínas de Homeodomínio/imunologia , Humanos , Imunoglobulinas Intravenosas/administração & dosagem , Masculino , Fenótipo , Imunodeficiência Combinada Severa/tratamento farmacológico , Imunodeficiência Combinada Severa/imunologia , Pele/imunologia , Linfócitos T/imunologia , Linfócitos T/patologia , Fatores de Tempo