Fanconi anemia gene-associated germline predisposition in aplastic anemia and hematologic malignancies / 医学前沿

Whether Fanconi anemia (FA) heterozygotes are predisposed to bone marrow failure and hematologic neoplasm is a crucial but unsettled issue in cancer prevention and family consulting. We retrospectively analyzed rare possibly significant variations (PSVs) in the five most obligated FA genes, BRCA2, FANCA, FANCC, FANCD2, and FANCG, in 788 patients with aplastic anemia (AA) and hematologic malignancy. Sixty-eight variants were identified in 66 patients (8.38%). FANCA was the most frequently mutated gene (n = 29), followed by BRCA2 (n = 20). Compared with that of the ExAC East Asian dataset, the overall frequency of rare PSVs was higher in our cohort (P = 0.016). BRCA2 PSVs showed higher frequency in acute lymphocytic leukemia (P = 0.038), and FANCA PSVs were significantly enriched in AA and AML subgroups (P = 0.020; P = 0.008). FA-PSV-positive MDS/AML patients had a higher tumor mutation burden, higher rate of cytogenetic abnormalities, less epigenetic regulation, and fewer spliceosome gene mutations than those of FA-PSV-negative MDS/AML patients (P = 0.024, P = 0.029, P = 0.024, and P = 0.013). The overall PSV enrichment in our cohort suggests that heterozygous mutations of FA genes contribute to hematopoietic failure and leukemogenesis.

Evaluation of concentration and storage effects of mitomycin C in the diagnosis of Fanconi anemia among idiopatic aplastic anemia patients.

BACKGROUND: Fanconi anemia (FA) is a rare autosomal recessive genetic disorder that shows an increased sensitivity to the intercalating agents such as mytomycin C (MMC), measured as chromosomal aberrations. This study was conducted to differentiate between FA and “idiopathic” aplastic anemia on the basis of induced chromosomal breakage study with MMC. MATERIALS AND METHODS: MMC stress tests in different final concentrations of 20 and 50 ng/ml of MMC were conducted on peripheral blood lymphocytes from 32 patients with aplastic anemia and 13 healthy controls. Fifty nanograms per milliliter of MMC from old, fresh and frozen stocks was used to check the sensitivity of diagnosis on FA-diagnosed patients. Statistical analysis was used for the assessment of aberrations, including chromatid and chromosome breaks and exchanges. RESULTS: Eight patients (25%) with a very high percentage of chromosomal breakage were diagnosed as FA on the basis of the chromosomal breakage study. Six of these patients exhibited congenital anomalies at presentation, while another two lacked such anomalies or had minor physical problems. Freshly made MMC has shown more sensitivity to detect FA patients compared with frozen or 1-week-old MMC stock. CONCLUSIONS: The study indicates that freshly made MMC stress test provides an unequivocal means of differentiation between FA and “idiopathic” aplastic anemia. Further, the study, the first of its kind from Iran, stresses on the need for conducting this test in all aplastic anemia cases, even those without congenital anomalies, for accurate and timely diagnosis of FA to implement appropriate therapy.

[Singular etiology of inherited aplastlc anemia: a case report of congenital dyskeratosis]

Congenital Dyskeratosis [CD] is a severe inherited disease characterised by a triad of clinical manifestations including abnormal skin pigmentation, nail dystrophy and mucosal leucoplakia. Other clinical manifestations including lung fibrosis and liver cirrhosis worsen the prognosis. Bone marrow hypoplasia is frequently reported, 50 per cent of patients develop pancytopenia before the age of 10 years. We report here the first Tunisian case of DC diagnosed in paediatric age and revealed by a severe bone marrow failure by the age of ten years. The classic triad appeared in the first decade, epiphora, blepharitis, teeth abnormalities and a single kidney were also noted. Androgen therapy stabilised peripheral cytopenia and, decreased the need of red blood cell transfusion

Differentiation of Fanconi and aplastic anemia using chromosomal breakage test in Southern Iran

Fanconi anemia [FA] is a chromosomal breakage disorder characterized by familial aplastic anemia [AA], various congenital anomalies, and a characteristic chromosomal response to clastogenic stress. In this study, chromosome breakage test was performed for 38 patients suspected of having FA and age-matched controls. According to the results, ten patients were considered as FA cases and 15 patients with no chromosomal breaks were considered as AA. Differentiation of FA from AA is very important because the primary treatment is different. This test should be done in every primary presentation of AA

Mitochondrial DNA Aberrations of Bone Marrow Cells from Patients with Aplastic Anemia

This study was undertaken primarily to test the hypothesis that mitochondrial DNA (mtDNA) mutations may be associated with aplastic anemia. Complete mtDNA nucleotide sequence was analyzed in nine and eight bone marrow specimens from Korean patients with aplastic anemia and healthy individuals, respectively. We found a large number of polymorphisms as well as apparent new mutations in both patients and controls throughout the entire mtDNA genome; 12 mutations harbored amino acid changes in patients and none of the mutations in controls produced amino acid changes. There were heteroplasmic mutations and more nonsynonymous mtDNA changes observed in patients, so the mean number of mtDNA aberrations of bone marrow cells showed statistically significant difference overall between patients (mean=25.6) and controls (mean=12.8) (p=0.019). Our data may support an association of mtDNA aberrations with aplastic anemia.

XmnI polymorphism is associated with fetal hemoglobin levels in hypoplastic syndromes

CONTEXTO E OBJETIVO: O aumento adquirido da hemoglobina fetal (HbF) já foi implicado como fator prognóstico em distúrbios diseritropoiéticos. Nossos objetivos foram de examinar elevações adquiridas na HbF em pacientes com anemia aplástica (AA) e hemoglobinúria paroxística noturna (PNH), e de avaliar se há associação entre a presença de polimorfismos XmnI e de região de controle de locus gênico 5' (LCR-HS2) e os níveis de HbF. TIPO DE ESTUDO E LOCAL: Estudo longitudinal no Serviço de Hematologia e Transfusão de Sangue da Universidade Federal de São Paulo – Escola Paulista de Medicina.MÉTODOS: Estudamos um grupo de 37 pacientes com AA e/ou PNH. Reação de polimerase em cadeia (PCR) e digestão enzimática foram usadas para analisar polimorfismos XmnI; e PCR para clonagem e sequenciamento automático dos polimorfismos HS2. RESULTADOS: O nível médio de HbF foi de 2,32%, mas não houve diferença significativa entre o nível de HbF dos pacientes AA e PNH (p = 0.46). Os níveis de HbF menores que 1,0% mostraram correlação estatisticamente significativa com ausência do polimorfismo XmnI (+) (p = 0.007). CONCLUSÕES: Ausência de polimorfismo XmnI está associado com diminuição de HbF. Mais estudos são necessários para confirmar estas observações e fazer comparações sobre tratamento, prognóstico e sobrevida.

Aplastic manifestations of myelodysplastic syndrome as evidenced by cytogenetic studies

To detect chromosomal aberrations characteristic of myelodysplastic syndrome [MDS] in cases presenting as aplastic anaemia. A prospective study of all newly diagnosed cases of aplastic anaemia for the detection of chromosomal abnormalities over a period of two years. Twenty cases of aplastic anaemia and 8 cases of Myelodysplastic Syndrome [control] were analyzed cytogenetically. The suspected cases of congenital aplastic anaemia and those already on some treatment [other than supportive] were not included in the study. Cytogenetic analysis was done by Giemsa-Trypsin banding technique. Both direct and stimulated cultures were set up. Out of 20 patients studied, in 4 there was culture failure. Number of available patients was thus 1 6. Only 2 out of 16 patients diagnosed as aplastic anaemia showed chromosomal abnormalities. One had Robertsonian translocation t [13:15] of no clinical significance. However, 1 out of 16 patients [6.25%] had clonal change characteristic of MDS i.e. 46, XY/45.XY, del [5q],-6. In the control group of 8 patients of MDS, 5 showed chromosomal aberrations. In 2 out of 5 monosomy 7 was detected, in 1 del [5q] and in other del [7q] was detected. One patient showed Robertsonian translocation t [13:15]. Clonal changes in cases of aplastic anaemia although low in frequency at the time of presentation may be seen in upto 6.25% of cases. These cases may very well be of Hypoplastic MDS. If serial cytogenetic analysis and monitoring of blood counts are carried out more patients may be found to develop cytogenetic abnormalities and finally MDS

Chromosome fragility in hematologic disease presumably induced by environmental pollutants

Chromosome instability consists of chromosome abnoprmalities as multiple breaks in in metaphase chromosomes in syndromes of chromosaome instability such as fanconi's anemia (FA) which is mainly characaterized by bone marrow aplasia; some cases progress to acute leukemia. FA is a hereditary disease with recessive and monogenic transmission. This pair of mutated genes is related to chromosome fragility and therefore is responsible for the inefficiency of DNA repair. In normal individuals, these genes are assumed to be expressed normally, but their products ara insufficient to perform DNA repair when the intensity of the polluting agent lelads to exposure above basal levels. In the present study, the bone marrow of four patients with different hematologic diseases was submitted to cytogenetic analysis. Two had aplastic anemia, and one bad lymphoblastic leukemia. These patients were from towns unb the Amazon Region where the mercuri used for gold prospecting and the substances used and/or released in aluminium mining have been introduced into the environment. The last patient had fanconi's anemia and was used as a model in the discussion of the results. The cytogenetic findings were similar for all patients, the major ones being chromosome fragmentation and pulverization. In view of these findings, we believe that chromosome fragility, observed in the first three patients, presumably was induced by environmental pllutants

Estudio inmunogenético en niños con anemia aplástica / Immunogenetic study in children with aplastic anemia

La anemia aplástica es un padecimiento en el que posiblemente haya cierta participación del sistema inmune. Con el fin de explorar esta posibilidad, en el presente trabajo, se estudiaron las frecuencias fenotípicas de los antígenos clase I y clase II del complejo principal de histocompatibilidad, en la sangre de 14 pacientes con anemia aplástica y en 100 sujetos tomados como grupo de comparación. Los pacientes mostraron tener una mayor frecuencia de los antígenos HLA-B21 (P=0.03, RM=4.04) y HLA-DR2 y HLA DR5 (P=0.002, RM=5.33). Los resultados parecen apoyar el fondo autoinmune del padecimiento y sugieren que estos antígenos puedieran servir como marcadores de la susceptibilidad para desarrollar anemia aplástica.

Estudio de heterogeneidad genética en anemia de Fanconi por medio de la adición del plasma / Genetic heterogenicity study in Fanconis anemia by the addition of plasma

Con el objetivo de investigar heterogeneidad genética en la variedad infantil de anemia de Fanconi (AF) se realizaron cultivos de linfocitos de pacientes con Af con plasma autólogo, con plasma de otros pacientes con AF y con plasma normal. Se sembraron además linfocitos de un sujeto normal con plasma autólogo y con plasma de cada uno de los pacientes con AF. Para cada tipo de cultivo se cuantificó la freuencia de aberraciones cromossómicas inducidas por MMC. Los linfocitos de pacientes con AF cultivados con plasma autólogo mostraron hipersensibilidad a la MMC y una disminución significativa de la frecuencia de aberraciones inducidas en los cultivos con plasma normal. Sin embargo, en presencia del plasma de los otros pacientes la gran variabilidad en la respuesta de los linfocitos de los pacientes con AF a la MMC no permitió demostrar heterogeneidad genética. Esto pudiera deberse a que a pesar de existir heterogeneidad genética la metodología empleada no pudiera evidenciarla o bien, a que nuestros pacientes correspondiean ala mismo tipo de AF

Anemia aplástica adquirida familiar / Familial acquired aplastic anemia

Una variedad poco frecuente de la anemia aplástica adquirida (AAA) es la forma familiar. Lo anterior se ejemplifica al considerar que de 200 casos con AAA atendidos en el servicio, sólo dos presentaron la característica de ser integrantes de una misma familia; éstos correspondieron a dos hermanos no gemelos, uno con AAA leve secundaria a derivados del benceno y que curó espontáneamente, y el otro con AAA grave relacionado con cloranfenicol y que falleció por hemorragia del sistema nervioso central. El estudio del sistema HLA mostró los mismos antígenos en ambos pacientes (A2, A28, B16, B40)