RESUMO
Outcomes are extremely poor in Down syndrome-associated acute lymphocytic leukemia, particularly in recurrent cases. A 2-year-old boy with Down syndrome-associated acute lymphocytic leukemia achieved complete remission after standard chemotherapy. However, he experienced recurrence twice in the bone marrow and central nervous system. Salvage treatments included whole-brain/whole-spine irradiation. Thereafter, the patient received a second cord blood transplantation after the reduced-intensity conditioning. The graft was characterized by killer cell immunoglobulin-like receptor ligands mismatch. The patient has subsequently survived for 6.5 years without recurrence. We speculate that killer cell immunoglobulin-like receptor ligand-mismatched cord blood transplantation enhanced the graft-versus-leukemia effect through natural killer cells, and conferred long-term remission.
Assuntos
Transplante de Células-Tronco de Sangue do Cordão Umbilical , Síndrome de Down , Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Leucemia-Linfoma Linfoblástico de Células Precursoras , Masculino , Criança , Humanos , Pré-Escolar , Intervalo Livre de Doença , Síndrome de Down/complicações , Síndrome de Down/terapia , Doença Aguda , Doença Crônica , Recidiva , Leucemia-Linfoma Linfoblástico de Células Precursoras/complicações , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Receptores KIR , Condicionamento Pré-TransplanteRESUMO
Children with acute lymphocytic leukemia rarely develop secondary hematological neoplasms. A 5-year-old boy was diagnosed with standard-risk precursor B-cell acute lymphocytic leukemia. The patient exhibited aberrant chromosomal changes in the bone marrow at 6 months postchemotherapy: 46,XY,der(6) t(1;6)(q12;p22) dup(6)(p22p12)[15]. Clinically, the patient has sustained complete remission and has not developed myeloid malignancy over the subsequent period (27 mo). The cytogenetic aberration was observed in 11% of CD34+ cells isolated from the bone marrow. We infer that the abnormal clone acquires self-renewal potency, differentiation, and growth advantage. Further long-term observation is needed to determine the nature of this cytogenetic aberration.
Assuntos
Hematopoiese Clonal , Humanos , Masculino , Criança , Pré-Escolar , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Aberrações Cromossômicas , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/patologia , Segunda Neoplasia Primária/patologia , Segunda Neoplasia Primária/genética , Segunda Neoplasia Primária/tratamento farmacológicoRESUMO
Most chromosomal aberrations revealed by chromosomal microarray testing (CMA) are simple; however, very complex chromosomal structural rearrangements can also be found. Although the mechanism of structural rearrangements has been gradually revealed, not all mechanisms have been elucidated. We analyzed the breakpoint-junctions (BJs) of two or more clustered copy number variations (CNVs) in the same chromosome arms to understand their conformation and the mechanism of complex structural rearrangements. Combining CMA with long-read whole-genome sequencing (WGS) analysis, we successfully determined all BJs for the clustered CNVs identified in four patients. Multiple CNVs were intricately intertwined with each other, and clustered CNVs in four patients were involved in global complex chromosomal rearrangements. The BJs of two clustered deletions identified in two patients showed microhomologies, and their characteristics were explained by chromothripsis. In contrast, the BJs in the other two patients, who showed clustered deletions and duplications, consisted of blunt-end and nontemplated insertions. These findings could be explained only by alternative nonhomologous end-joining, a mechanism related to polymerase theta. All the patients had at least one inverted segment. Three patients showed cryptic aberrations involving a disruption and a deletion/duplication, which were not detected by CMA but were first identified by WGS. This result suggested that complex rearrangements should be considered if clustered CNVs are observed in the same chromosome arms. Because CMA has potential limitations in genotype-phenotype correlation analysis, a more detailed analysis by whole genome examination is recommended in cases of suspected complex structural aberrations.
Assuntos
Variações do Número de Cópias de DNA , Genoma Humano , Humanos , Variações do Número de Cópias de DNA/genética , Rearranjo Gênico/genética , Aberrações Cromossômicas , Análise de SequênciaRESUMO
Interstitial microdeletions in the long arm of chromosome 3 are rare. In this study, we identified two patients with approximately 5-Mb overlapping deletions in the 3q26.2q26.31 region. Both patients showed neurodevelopmental delays, congenital heart defects, and distinctive facial features. One of them showed growth deficiency and brain abnormalities, as shown on a magnetic resonance imaging scan. Haploinsufficiency of NLGN1 and FNDC3B present in the common deletion region was considered to be responsible for neurodevelopmental delay and the distinctive features, respectively. The possibility of unmasked variants in PLD1 was considered and analyzed, but no possible pathogenic variant was found, and the mechanism of the congenital heart defects observed in the patients is unknown. Because 3q26.2q26.31 deletions are rare, more information is required to establish genotype-phenotype correlations associated with microdeletions in this region.
Assuntos
Cardiopatias Congênitas , Malformações do Sistema Nervoso , Humanos , Deleção Cromossômica , Fenótipo , Cardiopatias Congênitas/genética , Malformações do Sistema Nervoso/genéticaRESUMO
Many disease-causing genes have been identified by determining the breakpoints of balanced chromosomal translocations. Recent progress in genomic analysis has accelerated the analysis of chromosomal translocation-breakpoints at the nucleotide level. Using a long-read whole-genome sequence, we analyzed the breakpoints of the cytogenetically balanced chromosomal translocation t(5;15)(q21;26.3), which was confirmed to be of de novo origin, in a patient with a neurodevelopmental disorder. The results showed complex rearrangements with seven fragments consisting of five breakpoint-junctions (BJs). Four of the five BJs showed microhomologies of 1-3-bp, and only one BJ displayed a signature of blunt-end ligation, indicating chromothripsis as the underlying mechanism. Although the BJs did not disrupt any disease-causing gene, the clinical features of the patient were compatible with MEF2C haploinsufficiency syndrome. Complex rearrangements were located approximately 2.5-Mb downstream of MEF2C. Therefore, position effects were considered the mechanism of the occurrence of MEF2C haploinsufficiency syndrome.
Assuntos
Transtornos do Neurodesenvolvimento , Translocação Genética , Humanos , Masculino , Lactente , Encéfalo/patologia , Transtornos do Neurodesenvolvimento/genéticaRESUMO
Recently, germline mutations in SAMD9 and SAMD9L were increasingly found in children with monosomy 7. We report the outcomes in 2 infants with the SAMD9/SAMD9L variant, who presented with anemia and thrombocytopenia (patient 1), and neutropenia and nonsymptomatic white-matter-encephalopathy (patient 2). Both patients received cord blood transplantation and experienced critical post-cord blood transplantation adverse events; patients 1 and 2 developed fulminant engraftment syndrome and life-threatening graft-versus-host disease, respectively. Of note, selective loss of chromosome 7 in bone marrow-derived CD34 + cells was inferred.
Assuntos
Cromossomos Humanos Par 7 , Transplante de Células-Tronco de Sangue do Cordão Umbilical , Criança , Humanos , Lactente , Hematopoiese Clonal , Mutação em Linhagem Germinativa , Hematopoese , Peptídeos e Proteínas de Sinalização Intracelular/genética , Fatores de Transcrição/genética , Proteínas Supressoras de Tumor/genéticaRESUMO
A standard treatment for disseminated intravascular coagulation in neonates has not yet been established. We analyzed the outcomes of 23 neonates who developed disseminated intravascular coagulation due to infection or asphyxia between 2004 and 2017. The overall survival rate was 95.7% on day 28 after anticoagulant therapy. In contrast, the bleeding-free survival rate was 69.6% (95% confidence interval, 53.1%-91.2%). Of the 6 neonates with intracranial bleeding, 2 developed neurological sequelae. The current study showed that intracranial bleeding remained a major problem in the early 2000s, despite the introduction of a new anticoagulant drug, recombinant thrombomodulin, at our institution since 2009.
Assuntos
Coagulação Intravascular Disseminada , Trombomodulina , Anticoagulantes/uso terapêutico , Coagulação Intravascular Disseminada/tratamento farmacológico , Coagulação Intravascular Disseminada/etiologia , Hemorragia/tratamento farmacológico , Humanos , Recém-Nascido , Hemorragias Intracranianas/induzido quimicamente , Hemorragias Intracranianas/tratamento farmacológico , Proteínas Recombinantes/efeitos adversos , Trombomodulina/uso terapêuticoRESUMO
BACKGROUND: Peripheral neuroblastic tumors (pNTs) are the most common childhood extracranial solid tumors. There are several therapeutic strategies targeting disialoganglioside GD2. Disialoganglioside GD3 has become a potential target. However, the mechanism by which pNTs express GD3 and GD2 remains unclear. We investigated the combined expression status of GD3 and GD2 in pNTs and delineated their clinicopathological values. METHODS: GD3 and GD2 expression was examined in pNT tissue samples (n = 35) using immunohistochemistry and multiple immunofluorescence imaging. RESULTS: GD3 and GD2 expression was positive in 32/35 and 25/35 samples, respectively. Combinatorial analysis of GD3 and GD2 expression in neuroblastoma showed that both were heterogeneously expressed from cell to cell. There were higher numbers of GD3-positive and GD2-negative cells in the low-risk group than in the intermediate-risk (P = 0.014) and high-risk (P = 0.009) groups. Cases with high proportions of GD3-positive and GD2-negative cells were associated with the International Neuroblastoma Staging System stage (P = 0.004), Children's Oncology Group risk group (P = 0.001), and outcome (P = 0.019) and tended to have a higher overall survival rate. CONCLUSION: We demonstrated that neuroblastomas from low-risk patients included more GD3-positive and GD2-negative cells than those from high-risk patients. Clarifying the heterogeneity of neuroblastoma aids in better understanding the biological characteristics and clinical behavior.
Assuntos
Gangliosídeos , Neuroblastoma , Criança , Imunofluorescência , Gangliosídeos/metabolismo , Humanos , Imuno-Histoquímica , Neuroblastoma/metabolismoRESUMO
Monosomy 7 (-7) occurs in various types of paediatric myeloid disorders and has a poor prognosis. Recent studies have demonstrated that patients with germline gain-of-function SAMD9/9L variants and loss-of-function GATA2 variants are prone to developing myelodysplastic syndrome (MDS) associated with -7. However, the prevalence of the genetic variants among paediatric haematologic disorders with -7 is unknown. The present study screened germline variants of GATA2 and SAMD9/9L in 25 patients with various types of paediatric haematological disorders associated with -7. The diagnoses of the 25 patients included MDS (n = 10), acute myeloid leukaemia (AML) and myeloid sarcomas (n = 9), juvenile myelomonocytic leukaemia (n = 3) and other disorders (n = 3). Seven patients with a germline pathogenic GATA2 variant were found. For SAMD9/9L screening, next-generation sequencing was used to detect low-abundance variants and found four novel germline variants. Functional analysis revealed that three out of the four variants showed growth-restricting capacity in vitro and thus, were judged to be pathogenic. Cases with GATA2 mutation tended to be older, compared to those with SAMD9/9L mutations. In conclusion, GATA2 and SAMD9/9L were sequenced in 25 patients with paediatric haematologic disorders associated with -7, and 40% of them were found to have some pathogenic germline variants in the three genes.
Assuntos
Fator de Transcrição GATA2/genética , Mutação em Linhagem Germinativa , Neoplasias Hematológicas/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Síndromes Mielodisplásicas/genética , Proteínas Supressoras de Tumor/genética , Adolescente , Criança , Pré-Escolar , Deleção Cromossômica , Cromossomos Humanos Par 7/genética , Feminino , Neoplasias Hematológicas/epidemiologia , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Lactente , Recém-Nascido , Masculino , Síndromes Mielodisplásicas/epidemiologia , PrevalênciaRESUMO
BACKGROUND: Preterm infants sometimes have transient late-onset hemolytic jaundice; however, the etiology has yet to be determined. CASE PRESENTATION: In our case, fetal hemoglobin (HbF) level increased significantly to 100% at 23 days of age. Levels of methemoglobin and carboxyhemoglobin also increased to 2.9% and 3.5%, respectively, following the elevated HbF level. At 26 days, hemolytic jaundice developed. No abnormality of red blood cell membranes and enzyme activities was found. CONCLUSIONS: The etiology of late-onset hemolytic jaundice in preterm infants may associate with an impaired switching from HbF to adult hemoglobin (HbA) or reverse switching from HbA to HbF.
Assuntos
Hemoglobina Fetal/análise , Recém-Nascido de Peso Extremamente Baixo ao Nascer , Icterícia , Eritrócitos/patologia , Humanos , Recém-Nascido , Masculino , Metemoglobina/análiseRESUMO
BACKGROUND: Activated phosphatidylinositol-3-OH kinase δ syndrome type 1 (APDS1) is a recently described primary immunodeficiency syndrome characterized by recurrent respiratory tract infections, lymphoid hyperplasia, and Herpesviridae infections caused by germline gain-of-function mutations of PIK3CD. Hematopoietic stem cell transplantation (HSCT) can be considered to ameliorate progressive immunodeficiency and associated malignancy, but appropriate indications, methods, and outcomes of HSCT for APDS1 remain undefined. OBJECTIVE: Our objective was to analyze the clinical manifestations, laboratory findings, prognosis, and treatment of APDS1 and explore appropriate indications and methods of HSCT. METHODS: We reviewed retrospectively the medical records of cohorts undergoing HSCT at collaborating facilities. RESULTS: Thirty-year overall survival was 86.1%, but event-free survival was 39.6%. Life-threatening events, such as severe infections or lymphoproliferation, were frequent in childhood and adolescence and were common indications for HSCT. Nine patients underwent HSCT with fludarabine-based reduced-intensity conditioning. Seven patients survived after frequent adverse complications and engraftment failure. Most symptoms improved after HSCT. CONCLUSION: Patients with APDS1 showed variable clinical manifestations. Life-threatening progressive combined immunodeficiency and massive lymphoproliferation were common indications for HSCT. Fludarabine-based reduced-intensity conditioning-HSCT ameliorated clinical symptoms, but transplantation-related complications were frequent, including graft failure.
Assuntos
Transplante de Células-Tronco Hematopoéticas , Síndromes de Imunodeficiência , Transtornos Linfoproliferativos , Adolescente , Adulto , Aloenxertos , Criança , Pré-Escolar , Classe I de Fosfatidilinositol 3-Quinases/imunologia , Intervalo Livre de Doença , Feminino , Humanos , Síndromes de Imunodeficiência/imunologia , Síndromes de Imunodeficiência/mortalidade , Síndromes de Imunodeficiência/patologia , Síndromes de Imunodeficiência/terapia , Transtornos Linfoproliferativos/imunologia , Transtornos Linfoproliferativos/mortalidade , Transtornos Linfoproliferativos/patologia , Transtornos Linfoproliferativos/terapia , Masculino , Doenças da Imunodeficiência Primária , Taxa de SobrevidaRESUMO
BACKGROUND: Sarcoidosis is a multi-organ disease of unknown etiology characterised by the presence of epithelioid granulomas, without caseous necrosis. Systemic sarcoidosis is rare among children, while neurosarcoidosis in children is even rarer whether it is systemic or not. CASE PRESENTATION: We described the case of a 12-year-old boy who presented with monocular vision loss accompanied by unusual MRI features of an extensive meningeal infiltrating mass lesion. The patient underwent surgical resection (biopsy) via a frontotemporal craniotomy to establish a definitive diagnosis based on the histopathology, since neurosarcoidosis remains a very difficult diagnosis to establish from neuroradiogenic imagings. Based on the histopathology of the resected mass lesion, neurosarcoidosis was diagnosed. On follow-up after 3 months of steroid therapy, the patient displayed a good response on the imaging studies. MRI revealed that the preexisting mass lesion had regressed extremely. We also conducted a small literature review on imaging studies, manifestations, appropriate treatments, etc., in particular neurosarcoidosis including children. CONCLUSION: Although extremely rare, neurosarcoidosis, even in children, should be considered in the differential diagnosis of skull base mass lesions to avoid unnecessary aggressive surgery and delay in treatment, since surgery may have little role in the treatment of sarcoidosis.
Assuntos
Doenças do Sistema Nervoso Central , Neoplasias Meníngeas , Sarcoidose , Neoplasias da Base do Crânio , Criança , Craniotomia , Humanos , Imageamento por Ressonância Magnética , Masculino , Base do Crânio/diagnóstico por imagem , Base do Crânio/cirurgiaAssuntos
Transplante de Células-Tronco Hematopoéticas , Linfoma de Zona Marginal Tipo Células B , Linfoma Difuso de Grandes Células B , Adolescente , Classe I de Fosfatidilinositol 3-Quinases/genética , Mutação em Linhagem Germinativa , Humanos , Japão , Linfoma de Zona Marginal Tipo Células B/patologia , Linfoma Difuso de Grandes Células B/genética , Linfoma Difuso de Grandes Células B/terapia , Condicionamento Pré-TransplanteRESUMO
BACKGROUND: Currently, the standard management of moderate aplastic anemia (MAA) has not been well described, although the superiority of the combination of antithymocyte globulin (ATG) and cyclosporine (CyA) over CyA alone has been demonstrated in terms of hematological responses and failure-free survival (FFS). PROCEDURE: We adopted this therapeutic strategy and treated 95 children with MAA who were enrolled in two consecutive prospective studies between October 1992 and August 2009. RESULTS: For these patients, the 6-month response rate was 54.7% (complete response, 13.7%; partial response, 41.1%). There were no statistically significant differences in the overall response rates between the transfusion-dependent (48.8%, n = 41) and transfusion-independent groups (59.3%, n = 54; P = 0.4). Treatment failure was defined as the requirement of salvage treatment, and was observed in 52 patients. The 10-year FFS was 44.0% (95% confidence interval [CI], 32.9%-54.6%). Of the 22 patients who underwent a second immunosuppressive therapy (IST), 12 responded. Forty patients underwent hematopoietic stem cell transplantation as second- or third-line therapy and three died of complications. Consequently, the 10-year overall survival rate was 96.0% (95% CI, 88.0%-98.7%) with a median follow-up period of 103 months (range, 29-221 months). CONCLUSIONS: Although current guidelines recommend only observation for patients with transfusion-independent MAA, the results of our study justify early intervention with ATG and CyA in those patients. A prospective randomized trial is warranted to clarify the risks and benefits of early intervention with IST and observation alone until progression to severe AA in patients with MAA.