Assuntos
Anemia Hipocrômica/genética , Sequência de Bases , Hemoglobinas Anormais/genética , Deleção de Sequência , Talassemia alfa/genética , Anemia Hipocrômica/patologia , Pré-Escolar , Feminino , Hemoglobinas Glicadas/genética , Grécia , Hemoglobina A2/genética , Humanos , Talassemia alfa/patologia , Globinas beta/genéticaRESUMO
CD55 has been revealed to have an important role in tumor genesis, and presence of small populations of cells with strong CD55 expression would be sufficient to predict poor prognosis of several tumors. In our study we revealed that CD55 is a novel target of hypoxia-inducible factor HIF-2α in neuroblastoma (NB) cells. We show that HIF-2α expression is sufficient to sustain stem-like features of NB cells, whereas CD55 protein upon HIF-2α expression contributes to growth of colonies and to invasion of cells, but not to stemness features. Interestingly, in NB tissues, CD55 expression is limited to quite a small population of cells that are HIF-2α positive, and the gene expression of CD55 in the NB data set reveals that the presence of CD55(high) affects prognosis of NB patients. The functional characterization of CD55-positive populations within heterogeneous NB monoclonal cell lines shows that CD55 has pro-invading and anti-adhesive properties that might provide the basis for the ability of solid tumors to survive as microscopic residual disease. The easy accessibility to CD55 membrane antigen will offer the possibility of a novel antibody approach in the treatment of recurrent tumors and will provide a ready target for antibody-based visualization in NB diagnosis and prognosis.
RESUMO
INTRODUCTION: Hereditary spherocytosis (HS), hereditary elliptocytosis (HE), and hereditary stomatocytosis (HSt) are inherited red cell disorders caused by defects in various membrane proteins. The heterogeneous clinical presentation, biochemical and genetic abnormalities in HS and HE have been well documented. The need to raise the awareness of HSt, albeit its much lower prevalence than HS, is due to the undesirable outcome of splenectomy in these patients. METHODS: The scope of this guideline is to identify the characteristic clinical features, the red cell parameters (including red cell morphology) for these red cell disorders associated, respectively, with defective cytoskeleton (HS and HE) and abnormal cation permeability in the lipid bilayer (HSt) of the red cell. The current screening tests for HS are described, and their limitations are highlighted. RESULTS: An appropriate diagnosis can often be made when the screening test result(s) is reviewed together with the patient's clinical/family history, blood count results, reticulocyte count, red cell morphology, and chemistry results. SDS-polyacrylamide gel electrophoresis of erythrocyte membrane proteins, monovalent cation flux measurement, and molecular analysis of membrane protein genes are specialist tests for further investigation. CONCLUSION: Specialist tests provide additional evidence in supporting the diagnosis and that will facilitate the management of the patient. In the case of a patient's clinical phenotype being more severe than the affected members within the immediate family, molecular testing of all family members is useful for confirming the diagnosis and allows an insight into the molecular basis of the abnormality such as a recessive mode of inheritance or a de novo mutation.
Assuntos
Anemia Hemolítica Congênita/diagnóstico , Anemia Hemolítica Congênita/etiologia , Membrana Eritrocítica/metabolismo , Anemia Hemolítica Congênita/complicações , Eliptocitose Hereditária/diagnóstico , Membrana Eritrocítica/química , Humanos , Esferocitose Hereditária/diagnósticoRESUMO
We report on a truncated α-spectrin chain, spectrin(Exeter), associated with ellipto-poikilocytosis. Analysis of erythrocyte membranes of affected individuals revealed a truncated α-spectrin chain with normal amounts of spectrin dimer. In the proband and her father, one haploid set of α-spectrin cDNA lacked exons 11 and 12, leading to partial deletion of repeats α4 and α5 (83 amino acids) of the α-spectrin chain. In one allele of genomic DNA, a 3567bp deletion starting in intron 10 and ending in intron 12 of the SPTA1 gene was found. The common polymorphic SPTA1 α(LELY) allele was found in trans to the SPTA1αExeter allele in the proband. The proband had inherited the SPTA1Exeter allele from her father and the αLELY allele from her healthy, asymptomatic mother. This is the first report of an interstitial deletion in the SPTA1 gene associated with ellipto-poikilocytosis.
Assuntos
Eliptocitose Hereditária/genética , Deleção de Sequência , Espectrina/genética , Espectrina/metabolismo , Alelos , Sequência de Aminoácidos , Sequência de Bases , Criança , Eliptocitose Hereditária/metabolismo , Éxons , Feminino , Humanos , Lactente , Íntrons , Masculino , Dados de Sequência Molecular , Espectrina/químicaRESUMO
Hereditary spherocytosis is a common hemolytic disorder characterized by a defect or deficiency in one or more of the proteins composing red blood cell membrane. As a result, red blood cells have an abnormal shape, higher metabolic requirements, and are prematurely trapped and destroyed in the spleen. Hereditary spherocytosis, including the very mild or subclinical forms, is the most common cause of non-immune hemolytic anemia among people of Northern European ancestry, with a prevalence of approximately 1 in 2000. However very mild forms of the disease may be much more common. Hereditary spherocytosis is inherited in a dominant fashion in 75% of cases, whereas the remaining are truly recessive cases and de novo mutations. This review reports current concepts on red cell membrane structure and it will attempt to clarify molecular defects leading to spherocyte and their consequences.
Assuntos
Esferocitose Hereditária/sangue , Anemia Hemolítica/epidemiologia , Anemia Hemolítica/genética , Proteína 1 de Troca de Ânion do Eritrócito/genética , Diagnóstico Diferencial , Deformação Eritrocítica/genética , Membrana Eritrocítica/metabolismo , Europa (Continente)/epidemiologia , Genes Dominantes , Genes Recessivos , Humanos , Proteínas de Membrana/sangue , Proteínas de Membrana/genética , Mutação , Esferocitose Hereditária/diagnóstico , Esferocitose Hereditária/genética , Esferocitose Hereditária/metabolismo , População Branca/genéticaRESUMO
Expression of Trk receptors is an important prognostic factor in neuroblastoma (NB) and other cancers. TrkB and its ligand brain-derived neurotrophic factor (BDNF) are preferentially expressed in NB with poor prognosis, conferring invasive and metastatic potential to the tumor cells as well as enhancing therapy resistance. Galectin-1 (Gal-1) has emerged as an interesting cancer target, as it is involved in modulating cell proliferation, cell death and cell migration, all of which are linked to cancer initiation and progression. We previously identified Gal-1 mRNA to be upregulated in patients with aggressive, relapsing NB and found that Gal-1 protein was upregulated in human SY5Y NB cells on activation of ectopically expressed TrkB (SY5Y-TrkB), but not TrkA (SY5Y-TrkA). Here, we report that Gal-1 mRNA levels positively correlated with TrkB expression and anticorrelated with TrkA expression in a cohort of 102 primary NB. Immunohistochemical analyses of 92 primary NB specimens revealed high Gal-1 expression in stromal septae and in neuroblasts. BDNF-mediated activation of TrkB enhanced invasiveness and migration in vitro, which could be impaired by transient transfection using Gal-1-specific siRNA or a neutralizing antibody directed against Gal-1. The addition of recombinant Gal-1 (rGal-1) in the absence of BDNF partially restored migration and invasive capacity. Using the Trk inhibitor K252a, we could show that the upregulation of Gal-1 protein strictly depended on activated TrkB. Our data suggest that targeting Gal-1 might be a promising strategy for the treatment of aggressive NB.
Assuntos
Galectina 1/metabolismo , Neuroblastoma/fisiopatologia , Receptor trkB/metabolismo , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Linhagem Celular Tumoral , Movimento Celular , Regulação para Baixo , Galectina 1/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Receptor trkA/metabolismoRESUMO
BACKGROUND: The response to antiviral therapy of chronic hepatitis C virus (HCV) infection is determined by virological, environmental and genetic factors. OBJECTIVE: The hypothesis was tested that the expression of specific genes and their haplotype frequencies can differentiate between non-responders (NRs) and sustained virological responders (SVRs) to antiviral treatment. METHODS: A methodological approach based on molecular marker discovery and validation was used to study the genes influencing the antiviral treatment in lymphoblastoid cell lines from 74 genotype 1b HCV patients (44 from Southern Italy and 30 from Northern Italy) treated with pegylated interferon (IFN) alpha and ribavirin. Furthermore, an association study was performed, testing three single nucleotide polymorphisms (SNPs) of suppressor of cytokine signalling 3 (SOCS3) in 162 NR and 184 SVR subjects (SOCS3 -8464 A/C (rs12952093), -4874 A/G (rs4969170) and 1383 A/G, (rs4969168)). RESULTS: SOCS3 basal expression levels were significantly increased in two independent sets of NR groups (p<0.05). A highly significant association was found between NRs and both the positively associated haplotype (OR = 2.01, 95% CI 1.45 to 2.79, p = 0.0002) and the negatively associated haplotype (OR = 0.56, 95% CI 0.42 to 0.76, p = 0.0014). In particular, the SOCS3 -4874 AA genotype was strongly associated with failure of antiviral therapy (OR = 4.00, 95% CI 2.09 to 7.66, p = 0.0003) and the AA genotype carriers had significantly higher SOCS3 mRNA and protein levels (p<0.05). CONCLUSIONS: Basal levels of SOCS3, an inhibitor of the IFN alpha-induced Janus kinase-signal transducer and activator of transcription pathways, and its genetic polymorphisms influence the outcome of antiviral treatment. SOCS3 thus represents a novel blood biomarker for the a priori prediction of treatment response.
Assuntos
Antivirais/uso terapêutico , Hepatite C Crônica/tratamento farmacológico , Hepatite C Crônica/genética , Proteínas Supressoras da Sinalização de Citocina/genética , Adulto , Idoso , Biomarcadores/sangue , Linhagem Celular Transformada , Quimioterapia Combinada , Feminino , Perfilação da Expressão Gênica/métodos , Marcadores Genéticos , Haplótipos , Humanos , Interferon-alfa/uso terapêutico , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Prognóstico , RNA Mensageiro/genética , Ribavirina/uso terapêutico , Proteína 3 Supressora da Sinalização de Citocinas , Proteínas Supressoras da Sinalização de Citocina/sangue , Falha de Tratamento , Resultado do TratamentoRESUMO
DMT1 deficiency causes microcytic hypochromic anemia due to decreased erythroid iron utilization. Anemia is present from birth. Transferrin saturation is high and serum ferritin is mildly elevated, despite liver iron overload. DMT1 deficiency must be considered in the differential diagnosis of microcytic hypochromic anemia observed in the newborn period.
Assuntos
Anemia Hipocrômica/genética , Proteínas de Transporte de Cátions/genética , Genes Recessivos , Mutação , Anemia Hipocrômica/diagnóstico , Anemia Hipocrômica/tratamento farmacológico , Proteínas de Transporte de Cátions/deficiência , Diagnóstico Diferencial , Eritrócitos/metabolismo , Eritropoetina/uso terapêutico , Ferritinas/sangue , Genótipo , Humanos , Recém-Nascido , Quelantes de Ferro/uso terapêutico , Fenótipo , Transferrina/metabolismoRESUMO
The combination of an increase in the cAMP-phosphodiesterase activity of h-prune and its interaction with nm23-H1 have been shown to be key steps in the induction of cellular motility in breast cancer cells. Here we present the molecular mechanisms of this interaction. The region of the nm23-h-prune interaction lies between S120 and S125 of nm23, where missense mutants show impaired binding; this region has been highly conserved throughout evolution, and can undergo serine phosphorylation by casein kinase I. Thus, the casein kinase I delta-epsilon specific inhibitor IC261 impairs the formation of the nm23-h-prune complex, which translates 'in vitro' into inhibition of cellular motility in a breast cancer cellular model. A competitive permeable peptide containing the region for phosphorylation by casein kinase I impairs cellular motility to the same extent as IC261. The identification of these two modes of inhibition of formation of the nm23-H1-h-prune protein complex pave the way toward new challenges, including translational studies using IC261 or this competitive peptide 'in vivo' to inhibit cellular motility induced by nm23-H1-h-prune complex formation during progression of breast cancer.
Assuntos
Neoplasias da Mama/metabolismo , Proteínas de Transporte/metabolismo , Movimento Celular , Proteínas Inibidoras de Quinase Dependente de Ciclina/metabolismo , Nucleosídeo NM23 Difosfato Quinases/metabolismo , Animais , Ligação Competitiva , Neoplasias da Mama/genética , Células COS , Caenorhabditis elegans/embriologia , Caenorhabditis elegans/metabolismo , Proteínas de Transporte/genética , Comunicação Celular , Chlorocebus aethiops , Proteínas Inibidoras de Quinase Dependente de Ciclina/genética , Drosophila melanogaster/embriologia , Drosophila melanogaster/metabolismo , Humanos , Indóis/farmacologia , Nucleosídeo NM23 Difosfato Quinases/genética , Fragmentos de Peptídeos/farmacologia , Floroglucinol/análogos & derivados , Floroglucinol/farmacologia , Diester Fosfórico Hidrolases/metabolismo , Monoéster Fosfórico Hidrolases , Fosforilação , Xenopus laevis/embriologia , Xenopus laevis/metabolismoRESUMO
We evaluated the neurological and neurophysiological features in ten patients with genetically characterized Crigler-Najjar (CN) syndrome: four with typical type I CN had undergone orthotopic liver transplantation (OLT); six had type II CN, and three of them developed severe hyperbilirubinemia with a limited response to phenobarbital leading to an intermediate phenotype I/II. Clinical neurological and multimodal electrophysiological evaluations [electroencephalogram (EEG), visual (VEPs), motor (MEPs) and brainstem auditory (BAEPs) evoked potentials] were performed. Neurological examinations showed mild hand tremor in four patients (one pre-OLT and one post-OLT type I, two type I/II). EEG revealed high voltage paroxysmal discharges in four patients (three type I/II, and one type I with a marked improvement after OLT). VEPs showed P100 wave increased latency in five patients (three type I, and two type I/II considered for OLT evaluation). MEPs showed prolonged central motor conduction time in five patients (two type I; one type I/II; two type II). Only EEG and VEPs findings showed a correlation with high bilirubin levels. BAEPs were normal. In conclusion, VEPs and EEG contribute to identify and monitor bilirubin neurotoxic effects, and may play a decisional role in some cases of severe hyperbilirubinemia without overt neurologic damage.
Assuntos
Síndrome de Crigler-Najjar/fisiopatologia , Eletrofisiologia , Potenciais Evocados/fisiologia , Adolescente , Adulto , Fatores Etários , Síndrome de Crigler-Najjar/diagnóstico , Síndrome de Crigler-Najjar/cirurgia , Eletroencefalografia , Feminino , Seguimentos , Humanos , Transplante de Fígado/métodos , Masculino , Exame Neurológico , Estimulação Física/métodos , Tempo de ReaçãoRESUMO
The purpose of this study was to establish if estrogen-induced hepatocyte proliferation in vitro involves the cell cycle regulators cyclin D1, p21(Cip1), and p27(Kip1). Male rat hepatocytes were cultured in presence of 17-beta-estradiol (E2) +/- ICI-182780, a pure estrogen antagonist, and [3H]-thymidine, as required. DNA synthesis as well as p21(Cip1), p27(Kip1), and cyclin D1mRNA and protein levels were evaluated at different times (12, 24, 36, and 48 hours) of incubation. E2-increased DNA synthesis was correlated with cyclin D1 and p21(Cip1) (mRNA and protein) variations that were reversed by the addition of ICI-182780. p27(Kip1) protein levels progressively increased regardless of the presence of E2 or ICI-182780. Our data confirm that estrogens' stimulatory effect is related to their ability to increase cyclin D1 levels. The increase of p21(Cip1) is probably related to the reentry of hepatocytes in the quiescent state. p27(Kip1) protein is not able to arrest hepatocyte proliferation.
Assuntos
Proliferação de Células/efeitos dos fármacos , Ciclina D1/metabolismo , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Inibidor de Quinase Dependente de Ciclina p27/farmacologia , Estrogênios/farmacologia , Hepatócitos/efeitos dos fármacos , Animais , Células Cultivadas , Ciclina D1/efeitos dos fármacos , Inibidor de Quinase Dependente de Ciclina p21/análise , Hepatócitos/metabolismo , Immunoblotting , Masculino , Modelos Animais , RNA Mensageiro/metabolismo , Ratos , Ratos Endogâmicos F344 , Sensibilidade e EspecificidadeRESUMO
Aplastic anemia (AA) is a rare disease with a major autoimmune pathogenetic component. CTLA4 is a T-lymphocyte surface molecule involved in the maintenance of immune tolerance. Some polymorphisms associated with a reduced expression of CTLA4, and thus presumably with increased tendency to autoimmunity, have been associated with various autoimmune diseases. In this study, we evaluated the distribution of the low expression polymorphisms -318C > T and 49A > G of CTLA4 in a population of 67 patients with acquired AA and in 100 normal controls. There was no difference in the distribution of the tested polymorphism between patients and controls and, within the patient group, between those who responded to immunosuppression vs those who did not respond. This study indicates that the polymorphisms -318C > T and 49A > G of CTLA4 do not affect the risk of developing AA and do not influence the response to immunosuppression.
Assuntos
Anemia Aplástica/genética , Antígenos de Diferenciação/genética , Éxons/genética , Polimorfismo de Nucleotídeo Único , Regiões Promotoras Genéticas , Adolescente , Adulto , Antígenos CD , Antígeno CTLA-4 , Estudos de Casos e Controles , Criança , Pré-Escolar , Feminino , Regulação da Expressão Gênica , Predisposição Genética para Doença , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Fatores de Risco , População BrancaRESUMO
In this study, we investigated the mRNA level of several genes involved in cell cycle regulation in alveolar (ARMS) and embryonal rhabdomyosarcomas (ERMS). p21(Cip1), Cyclin D1, Cyclin D2, Cyclin D3, CDK2, and CDK4 were evaluated by RT-PCR. All (13 out of 13) ERMS expressed the p21(Cip1) gene compared with only 40% (4 out of 10) of the ARMS. Moreover, the amount of p21(Cip1) mRNA was noticeably higher in the ERMS samples than in the positive ARMS specimens. p27(Kip1) protein were analysed by immunohistochemical and immunoblotting. A noticeable difference was observed, in that ERMS had higher amounts of the cell cycle inhibitor compared with the ARMS. Finally, treatment of two rhabdomyosarcoma cell lines, RH-30 and RD, with butyrate, resulted in complete growth inhibition and in the upregulation of the p21(Cip1) and p27(Kip1) levels. Our results demonstrate that ERMS have a much higher level of p27(Kip1) and p21(Cip1) than the alveolar types, explaining, at least in part, the distinct features and outcomes (i.e. a poor prognosis of the alveolar type) of the two forms of this childhood solid cancer. Moreover, the data on butyrate-treated cell lines suggest that the two genes are potential novel therapeutic targets for the treatment of rhabdomyosarcomas.
Assuntos
Quinases relacionadas a CDC2 e CDC28 , Proteínas de Ciclo Celular/metabolismo , Ciclo Celular/fisiologia , Rabdomiossarcoma Alveolar/patologia , Rabdomiossarcoma Embrionário/patologia , Ciclina D1/metabolismo , Ciclina D2 , Ciclina D3 , Quinase 2 Dependente de Ciclina , Inibidor de Quinase Dependente de Ciclina p21 , Quinases Ciclina-Dependentes/metabolismo , Ciclinas/metabolismo , Humanos , Imuno-Histoquímica/métodos , Proteína Oncogênica p21(ras)/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Células Tumorais CultivadasAssuntos
Talassemia/complicações , Trombofilia/etiologia , Adolescente , Adulto , Criança , Análise Mutacional de DNA , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Risco , Talassemia/sangue , Talassemia/genética , Trombofilia/sangue , Trombofilia/genéticaRESUMO
Congenital dyserythropoietic anemia type II (CDA-II) is an autosomal recessive disease characterized by anemia, jaundice, splenomegaly, and erythroblast multinuclearity. The natural history of the disease is unknown. The frequency, the relevance of complications, and the use of splenectomy are poorly defined. This study examined 98 patients from unrelated families enrolled in the International Registry of CDA-II. Retrospective data were obtained using an appropriate questionnaire. The mean age at presentation was 5.2 +/- 6.1 years. Anemia was present in 66% and jaundice in 53.4% of cases. The mean age at correct diagnosis was 15.9 +/- 11.8 years. Twenty-three percent of patients for whom data were available developed anemia during the neonatal period, and 10 of these individuals required transfusions. Splenectomy produced an increased hemoglobin (P <.001) and a reduced bilirubin level (P =.007) in comparison with values before splenectomy. Preliminary data indicate that iron overload occurs irrespective of the hemochromatosis genotype. (Blood. 2001;98:1258-1260)
Assuntos
Anemia Diseritropoética Congênita/complicações , Adolescente , Adulto , Idade de Início , Idoso , Anemia Diseritropoética Congênita/sangue , Anemia Diseritropoética Congênita/terapia , Transfusão de Sangue , Criança , Pré-Escolar , Progressão da Doença , Saúde da Família , Feminino , Humanos , Lactente , Sobrecarga de Ferro/etiologia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Esplenectomia , Esplenomegalia/etiologia , Inquéritos e QuestionáriosRESUMO
Congenital dyserythropoietic anaemia type II (CDA II) is the most common congenital dyserythropoietic anaemia. CDA II is frequently misdiagnosed as Hereditary Spherocytosis (HS) due to the presence of mild chronic haemolytic anaemia with splenomegaly, increased osmotic fragility, and presence of microspherocytes. Accurate diagnosis of CDA II is important to prevent severe iron overload. Erythrocyte and reticulocyte indices were assessed in 10 patients from six families with CDA II, 18 patients from eight families with HS, and 50 normal controls. Characteristic increases in distribution width were present in CDA II for cell volume (RDW, anisocytosis) and in HS for cell haemoglobin concentration (HDW, anisochromia), resulting in an RDW/HDW ratio which was significantly greater in CDA than HS (P < 0.0002). A cut-off value for RDW/HDW of 5.34 resulted in 89% sensitivity and 70% specificity in distinguishing CDA II from HS. Distribution width for cell haemoglobin content of reticulocytes (CHDWr) was characteristically increased in CDA II, resulting in a CHDW/CHDWr ratio significantly lower in CDA II than HS (P < 0.0002). A cut-off value of 0.98 provided 89% sensitivity and 80% specificity in distinguishing CDA II from HS. These differences in distribution widths of flow-cytometric parameters of reticulocytes and mature erythrocytes reflect the different pathogeneses of the two diseases and are helpful for the differential diagnosis of these two conditions.
Assuntos
Anemia Diseritropoética Congênita/diagnóstico , Eritrócitos/patologia , Citometria de Fluxo/normas , Reticulócitos/patologia , Adolescente , Adulto , Anemia Diseritropoética Congênita/sangue , Criança , Pré-Escolar , Diagnóstico Diferencial , Índices de Eritrócitos , Saúde da Família , Humanos , Testes de Função Hepática , Pessoa de Meia-Idade , Esferocitose Hereditária/sangue , Esferocitose Hereditária/diagnósticoRESUMO
Environmental and genetic risk factors interact to cause venous thromboembolism. Renal vein thrombosis in the newborn has been frequently associated with "risk factors" as catheters, surgery or trauma, but it has also been demonstrated a pathogenetic role of genetic prothrombotic risk factors, i.e. activated protein C resistance and FV Leiden. The treatment of neonatal venous thrombosis varies worldwide and different approaches have been proposed. We present a case of renal vein thrombosis in a female newborn with normal plasma levels of protein C, protein S and antithrombin III, but with her genotype characterized by the presence of three prothrombotic risk factors: factor V Leiden, methylentetrahydrofolate reductase and platelet glycoprotein IIIa polymorphisms. The treatment with recombinant tissue plasminogen determined complete thrombus dissolution.
Assuntos
Veias Renais , Trombose Venosa/genética , Fator V/genética , Feminino , Predisposição Genética para Doença , Genótipo , Humanos , Recém-Nascido , Metilenotetra-Hidrofolato Redutase (NADPH2) , Oxirredutases atuantes sobre Doadores de Grupo CH-NH/genética , Complexo Glicoproteico GPIIb-IIIa de Plaquetas/genética , Polimorfismo Genético , Proteínas Recombinantes/uso terapêutico , Ativador de Plasminogênio Tecidual/uso terapêutico , Trombose Venosa/tratamento farmacológicoRESUMO
Type II congenital dyserythropoietic anaemia (CDA-II or HEMPAS) is an autosomal recessive disorder, representing the most frequent form of congenital dyserythropoiesis. It is characterised by normocytic anaemia, variable jaundice and hepato-splenomegaly. Gallbladder disease and secondary haemochromatosis are frequent complications. We report a case characterised by severe transfusion-dependent anaemia. The proband inherited CDA-II in association with beta-thalassaemia trait. Splenectomy did not abolish the transfusion dependence and this, in association with poor compliance to iron-chelation therapy, prompted us to consider bone marrow transplantation (BMT) from his HLA-identical sibling. The preparative regimen included busulfan, thiotepa and fludarabine, and graft-versus-host disease prophylaxis consisted of cyclosporin A and short-term methotrexate. Engraftment of donor cells was prompt and the post-transplant course uncomplicated. The patient is alive and transfusion-independent 36 months after allograft. This is the first case of severe CDA-II to undergo BMT. Analysis of this pedigree suggests that interaction with beta-thalassaemia enhanced the clinical severity of CDA-II, making BMT an attractive therapy for patients with transfusion dependence.