Linfoma de Burkitt como complicación de la agammaglobulinemia de Bruton / Burkitt's lymphoma as a complication of Bruton's Agammaglobulinemia

Introducción: La agammaglobulinemia de Bruton es una inmunodeficiencia primaria (IDP) originada por una mutación del gen que codifica la tirosina kinasa de Bruton (BTK). Se sospecha principalmente en varones con infecciones frecuentes de las vías respiratorias y tiene entre otras complicaciones, los tumores, fundamentalmente linfoproliferativos. Se reportan agammaglobulinemias autosómicas recesivas con similares características clínicas en ambos sexos. Objetivo: Presentar el primer caso pediátrico reportado en Cuba, con diagnóstico de linfoma de Burkitt asociado a esta inmunodeficiencia primaria y que además utilizó tratamiento combinado sustitutivo de inmunoglobulinas y antitumoral. Presentación del caso: Paciente masculino, que a los 2 años se le realizó diagnóstico de enfermedad de Bruton. Con el tratamiento de reemplazo con inmunoglobulina endovenosa (Intacglobín) se mantuvo tres años sin infecciones graves. A los 5 años de edad presentó linfoma de Burkitt, tratado con poliquimioterapia, según el esquema AEIOP al que se asoció rituximab. Aunque no se dispone de la detección por biología molecular de la mutación del gen BTK, la disminución por debajo del 2 por ciento de las células B CD19+ y los valores ausentes de IgG, IgA e IgM permitieron el diagnóstico. Conclusión: Coexistieron con resultados clínicos satisfactorios el tratamiento antitumoral y la terapia de reemplazo con inmunoglobulina endovenosa. El paciente se mantiene con buen estado general(AU)

Introduction: Bruton's Agammaglobulinemia is a primary immunodeficiency (PID) caused by a mutation in the gene that encodes Bruton's tyrosine kinase (BTK). It is suspected mainly in men with frequent respiratory tract infections and has, among other complications, tumors, mainly lymphoproliferative. Autosomal recessive agammaglobulinemias with similar clinical characteristics have been reported in both sexes. Objective: To present the first pediatric case reported in Cuba, with a diagnosis of Burkitt's lymphoma associated with PID and that also used combined immunoglobulin replacement and antitumor therapy. Case report: 2-year-old male diagnosed with Bruton's disease. With the replacement treatment with intravenous immunoglobulin (Intacglobin), he maintained three years without serious infections. At 5 years of age, he presented Burkitt's lymphoma, treated with polychemotherapy according to the AEIOP scheme, associating Rituximab. Although do not have molecular biology detection of the BTK gene mutation, the decrease of CD19 + B cells to below 2 percent and the absent values of IgG, IgA and IgM allowed the diagnosis. Conclusion: Antitumor treatment and intravenous immunoglobulin replacement therapy coexisted with satisfactory clinical results. The patient remains in good general condition(AU)

Genetic study of an X-linked agammaglobulinemia pedigree caused by an BTK mutation / 中华医学遗传学杂志

OBJECTIVE@#To explore the genetic pathogenesis of X-linked agammaglobulinemia in two patients for clinical diagnosis and family counseling.@*METHODS@#Data was collected from the patients' family including clinical information, blood immunoglobulin level, as well as classification and subgrouping of B lymphocytes. Gene mutations were screened by whole exome sequencing (WES) through next-generation sequencing (NGS), the result was verified with Sanger sequencing.@*RESULTS@#A BTK c.1627T>C (p.Ser543Pro) variant was found in the pedigree. The phenotype and variant have co-segregated in the pedigree. The variant was not found in population database. The variant has affected in the kinase domain which contained no benign variants and is harmful as predicted through bioinformatic analysis.@*CONCLUSION@#BTK c.1627T>C (p.Ser543Pro) is a pathogenic variant contributing to X-linked agammaglobulinemia in this pedigree. Above finding has provided reproduction guidance for this family.

Diagnóstico genético de pacientes con agammaglobulinemia primaria atendidos en centros peruanos de tercer nivel / Genetic diagnosis of patients with primary agammaglobulinemia treated at third level peruvian centers

Las agammaglobulinemias primarias (AP) resultan de alteraciones específicas en las células B, lo cual, conduce a baja producción de anticuerpos. La sospecha diagnóstica se establece con el antecedente de infecciones a repetición, inmunoglobulinas bajas y la ausencia linfocitos B CD19+. El diagnóstico se confirma mediante el análisis genético y la detección de una mutación ligada en el cromosoma X o autosómico recesiva o dominante. En Perú, no hay literatura sobre AP ni reportes sobre el genotipo de los pacientes con sospecha de AP. Bajo este escenario, se realizó un estudio que describió el genotipo de pacientes con sospecha de AP. Se encontraron 20 pacientes con mutaciones en el gen BTK y una mutación autosómica recesiva IGHM. Se hallaron 13 mutaciones hereditarias y siete mutaciones de novo. Se concluye que las AP son, en su mayoría, mutaciones en el gen BTK que corresponden con AP ligadas al cromosoma X.

Primary agammaglobulinemia result from specific alterations in B cells, which lead to low antibody production. Diagnostic suspicion is established with a history of repeated infections, low immunoglobulins, and absence of CD19+ B lymphocytes. The diagnosis is confirmed by genetic analysis and the detection of a mutation linked to the X or autosomal recessive or dominant chromosome. In Peru, there is no literature on primary agammaglobulinemia and no reports on the genotype of patients with suspected primary agammaglobulinemia. Under this scenario, a study was performed to describe the genotype of patients with suspected primary agammaglobulinemia. Twenty (20) patients were found with mutations in the BTK gene and an autosomal recessive IGHM mutation. Thirteen (13) hereditary mutations and seven de novo mutations were found. It is concluded that the group of primary agammaglobulinemia are mostly mutations in the BTK gene, corresponding to X-linked agammaglobulinemia.

Effects of Bruton's tyrosine kinase on the proliferation and differentiation of osteoclasts / 华西口腔医学杂志

OBJECTIVE@#To observe the effect of Bruton's tyrosine kinase (BTK) on the proliferation and differentiation of osteoclasts and to explore the mechanism of BTK on bone destruction in periapical periodontitis.@*METHODS@#After RAW264.7 cells induced with 100 ng·L⁻¹ receptor activator for nuclear factor-κB ligand (RANKL) for 5 days, osteoclast induction was confirmed by light microscopy, tartrate-resistant acid phosphatase (TRAP) staining, and quantitative real-time PCR (RT-qPCR). Then, BTK-small interfering RNA (BTK-siRNA) was transfected into cells induced for 5 days. After 24 h, the expression of TRAP mRNA was measured using RT-qPCR, and the proliferation and differentiation of osteoclasts were detected using CCK-8 and TRAP activity assay. Statistical analysis was performed.@*RESULTS@#After RAW264.7 was induced with RANKL for 5 days, a large number of round, ellipse, irregularly protuberant, and TRAP-positive macrophages were observed under light microscopy. The expression of TRAP mRNA significantly reduced after 24 h of BTK-siRNA transfection (P<0.05). The detection of CCK-8 and TRAP activities showed that the proliferation and differentiation of osteoclasts significantly decreased (P<0.05).@*CONCLUSIONS@#Silencing of BTK can inhibit the proliferation and differentiation of osteoclasts. BTK can be used as a new target for the inhibition of osteoclasts.

Clinical features and gene mutations of primary immunodeficiency disease: an analysis of 7 cases / 中国当代儿科杂志

This research investigated the clinical features of immunodeficiency disease and the features of the mutation of its pathogenic genes. All 7 patients were boys aged 5 months to 4 years and 6 months and had a history of recurrent respiratory infection and pneumonia, low levels of IgM and IgG, and abnormal absolute values or percentages of lymphocyte subsets. High-throughput sequencing showed c.1684C>T mutations in the BTK gene in patient 1 and IVS8+2T>C splice site mutations in the BTK gene in patient 2. Both of these mutations came from their mothers. Patients 3, 4, and 5 had mutations in the IL2RG gene, i.e., c.298C>T, IVS3-2A>G, and c.164T>A, among which c.164T>A mutations had not been reported. Patient 6 had c.204C>G mutations in the RAG2 gene. Patient 7 had complex heterozygous mutations of c.913C>T and c.824G>A in the RAG2 gene, which came from his father and mother, respectively. Patients with immunodeficiency disease have abnormal immunological indices, and high-throughput sequencing helps to make a definite diagnosis.

The emerging roles of the DDX41 protein in immunity and diseases

RNA helicases are involved in almost every aspect of RNA, from transcription to RNA decay. DExD/H-box helicases comprise the largest SF2 helicase superfamily, which are characterized by two conserved RecA-like domains. In recent years, an increasing number of unexpected functions of these proteins have been discovered. They play important roles not only in innate immune response but also in diseases like cancers and chronic hepatitis C. In this review, we summarize the recent literatures on one member of the SF2 superfamily, the DEAD-box protein DDX41. After bacterial or viral infection, DNA or cyclic-di-GMP is released to cells. After phosphorylation of Tyr414 by BTK kinase, DDX41 will act as a sensor to recognize the invaders, followed by induction of type I interferons (IFN). After the immune response, DDX41 is degraded by the E3 ligase TRIM21, using Lys9 and Lys115 of DDX41 as the ubiquitination sites. Besides the roles in innate immunity, DDX41 is also related to diseases. An increasing number of both inherited and acquired mutations in DDX41 gene are identified from myelodysplastic syndrome and/or acute myeloid leukemia (MDS/AML) patients. The review focuses on DDX41, as well as its homolog Abstrakt in Drosophila, which is important for survival at all stages throughout the life cycle of the fly.

Primary hypogammaglobulinemia: The impact of early diagnosis in lung complications / Hipogamaglobulinemia primária: o impacto do diagnóstico precoce nas complicações pulmonares

Summary Objective: To describe clinical features, tomographic findings and pulmonary function in pediatric patients with primary hypogammaglobulinemia (PH). Method: A retrospective cohort study of children with PH who received intravenous immunoglobulin (IVIG) and prophylactic antibiotics between 2005 and 2010. Epidemiological and clinical features, computed tomography (CT) findings, and spirometric data were compared, assuming a 5% significance level. Results: We evaluated 30 patients with PH. After the start of IVIG replacement, there was a decline in the frequency of pneumonia (p<0.001). The 11 patients with bronchiectasis in their first CT scan were older at diagnosis (p=0.001) and had greater diagnostic delay (p=0.001) compared to patients without bronchiectasis. At the end of the study, 18 patients had bronchiectasis and 27 also had other lung disorders, alone or in combination. The Bhalla score was applied to the last CT scan of 16 patients, with a median score of 11 (range 7-21), with a positive correlation between the score and the number of pneumonias after the start of treatment (r=0.561; p=0.024). The score was also correlated with forced expiratory volume in one second (FEV1) and forced vital capacity (FVC) values in 13/16 patients, with negative correlation to FEV1 previously to bronchodilator (r=-0.778; p=0.002) and after bronchodilator (r =-0.837; p<0.001) and FVC (r=-0.773; p=0.002). Conclusion: Pulmonary complications were common in this cohort, despite the decrease in the frequency of pneumonia with treatment. Early investigation of patients with recurrent infections for primary immunodeficiencies can reduce the frequency of these complications. The monitoring of changes in spirometry may indicate the need to carry out radiological investigation.

Resumo Objetivo: descrever características clínicas, tomográficas e de função pulmonar em pacientes pediátricos com hipogamaglobulinemia primária (HP). Método: estudo de coorte retrospectivo de crianças com HP que recebiam gamaglobulina endovenosa (GEV) e antibiótico profilático entre 2005 e 2010. As características epidemiológicas, clínicas, os achados de tomografia e espirometria foram comparadas adotando níveis de significância de 5%. Resultados: foram avaliados 30 pacientes com HP. Após o início da reposição de GEV, houve redução da frequência de pneumonias (p<0,001). Os 11 pacientes que apresentavam bronquiectasias na primeira tomografia computadorizada (TC) eram mais velhos ao diagnóstico (p=0,001) e tiveram maior atraso no diagnóstico (p=0,001) quando comparados aos pacientes sem bronquiectasias. Ao final do estudo, 18 pacientes apresentavam bronquiectasias e 27/30 também apresentaram outras alterações pulmonares, isoladas ou concomitantes. O escore de Bhalla foi aplicado à última TC de 16/30 pacientes, com mediana do escore de 11 (variação 7-21), com correlação positiva entre o escore e o número de pneumonias após o início do tratamento (r=0,561; p=0,024). O escore foi ainda correlacionado com valores de volume expiratório forçado no primeiro segundo (VEF1) e capacidade vital forçada (CVF) obtidos por espirometria de 13/16 pacientes, com correlação negativa com VEF1 pré- (r=-0,778; p=0,002) e pós-broncodilatador (r=-0,837; p<0,001) e CVF (r=-0,773; p=0,002). Conclusão: complicações pulmonares foram frequentes nesta coorte, apesar da diminuição na frequência de pneumonias com o tratamento. A investigação precoce de pacientes com infecções de repetição para imunodeficiências primárias pode reduzir a frequência dessas complicações. A monitorização de alterações na espirometria pode indicar a necessidade de investigação radiológica.