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1.
J Pediatr Hematol Oncol ; 46(5): e338-e347, 2024 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-38857202

RESUMO

Primary mitochondrial disorders (PMDs) are known for their pleiotropic manifestations in humans, affecting almost any organ or system at any time. Hematologic manifestations, such as cytopenias and sideroblastic anemia, occur in 10% to 30% of patients with confirmed PMDs. These can be the initial presenting features or complications that develop over time. Surveillance for these manifestations allows for prompt identification and treatment. This article provides an overview of the pathophysiology underpinning the hematologic effects of mitochondrial dysfunction, discussing the 3 key roles of the mitochondria in hematopoiesis: providing energy for cell differentiation and function, synthesizing heme, and generating iron-sulfur clusters. Subsequently, the diagnosis and management of mitochondrial disorders are discussed, focusing on hematologic manifestations and the specific conditions commonly associated with them. Through this, we aimed to provide a concise point of reference for those considering a mitochondrial cause for a patient's hematologic abnormality, or for those considering a hematologic manifestation in a patient with known or suspected mitochondrial disease.


Assuntos
Doenças Hematológicas , Doenças Mitocondriais , Humanos , Doenças Mitocondriais/complicações , Doenças Hematológicas/sangue , Doenças Hematológicas/complicações , Doenças Hematológicas/patologia , Mitocôndrias/patologia , Hematopoese , Anemia Sideroblástica/diagnóstico , Anemia Sideroblástica/terapia
2.
J Mol Diagn ; 26(5): 430-444, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38360212

RESUMO

Inherited iron metabolism defects are possibly missed or underdiagnosed in iron-deficient endemic settings because of a lack of awareness or a methodical screening approach. Hence, we systematically evaluated anemia cases (2019 to 2021) based on clinical phenotype, normal screening tests (high-performance liquid chromatography, α gene sequencing, erythrocyte sedimentation rate, C-reactive protein, and tissue transglutaminase), and abnormal iron profile by targeted next-generation sequencing (26-gene panel) supplemented with whole-exome sequencing, multiplex ligation probe amplification/mitochondrial DNA sequencing, and chromosomal microarray. Novel variants in ALAS2, STEAP3, and HSPA9 genes were functionally validated. A total of 290 anemia cases were screened, and 41 (14%) enrolled for genomic testing as per inclusion criteria. Comprehensive genomic testing revealed pathogenic variants in 23 of 41 cases (56%). Congenital sideroblastic anemia was the most common diagnosis (14/23; 61%), with pathogenic variations in ALAS2 (n = 6), SLC25A38 (n = 3), HSPA9 (n = 2) and HSCB, SLC19A2, and mitochondrial DNA deletion (n = 1 each). Nonsideroblastic iron defects included STEAP3-related microcytic anemia (2/23; 8.7%) and hypotransferrenemia (1/23; 4.3%). A total of 6 of 22 cases (27%) revealed a non-iron metabolism gene defect on whole-exome sequencing. Eleven novel variants (including variants of uncertain significance) were noted in 13 cases. Genotype-phenotype correlation revealed a significant association of frameshift/nonsense/splice variants with lower presentation age (0.8 months versus 9 years; P < 0.01) compared with missense variants. The systematic evaluation helped uncover an inherited iron defect in 41% (17/41) of cases, suggesting the need for active screening and awareness for these rare diseases in an iron-deficient endemic population.


Assuntos
Anemia Sideroblástica , Ferro , Humanos , Lactente , Ferro/metabolismo , Mutação , Anemia Sideroblástica/epidemiologia , Anemia Sideroblástica/genética , Anemia Sideroblástica/diagnóstico , Genômica , DNA Mitocondrial , Proteínas de Membrana Transportadoras/genética , 5-Aminolevulinato Sintetase/genética , 5-Aminolevulinato Sintetase/metabolismo
3.
BMJ Case Rep ; 16(5)2023 May 02.
Artigo em Inglês | MEDLINE | ID: mdl-37130647

RESUMO

Sideroblastic anaemia with B-cell immunodeficiency, periodic fever and developmental delay is a recently described, rare syndrome characterised by numerous manifestations underpinned by mutations in transfer RNA nucleotidyltransferase. The pathogenesis arises from mitochondrial dysfunction, with impaired intracellular stress response, deficient metabolism and cellular and systemic inflammation. This yields multiorgan dysfunction and early death in many patients with survivors suffering significant disability and morbidity. New cases, often youths, are still being described, expanding the horizon of recognisable phenotypes. We present a mature patient with spontaneous bilateral hip osteonecrosis that likely arises from the impaired RNA quality control and inflammation caused by this syndrome.


Assuntos
Amiloidose , Anemia Sideroblástica , Síndromes de Imunodeficiência , Osteonecrose , Humanos , Anemia Sideroblástica/complicações , Anemia Sideroblástica/diagnóstico , Anemia Sideroblástica/genética , Cabeça do Fêmur , Síndromes de Imunodeficiência/complicações , Febre , Inflamação
4.
Ann Hum Genet ; 87(4): 166-173, 2023 07.
Artigo em Inglês | MEDLINE | ID: mdl-36916508

RESUMO

INTRODUCTION: Congenital sideroblastic anemias (CSAs) are a group of inherited bone-marrow disorders manifesting with erythroid hyperplasia and ineffective erythropoiesis. METHODS: We describe a detailed clinical and genetic characterization of three siblings with CSA. RESULTS: Two of them had limb-girdle myopathy and global developmental delay. The two elder siblings performed allogenic hematopoietic stem-cell transplantation 5 and 3 years prior with stabilization of the hematological features. Exome sequencing in the non-transplanted sibling revealed a novel homozygous nonsense variant in SLC25A38 gene NM_017875.2:c.559C > T; p.(Arg187*) causing autosomal-recessive sideroblastic anemia type-2, and a second homozygous pathogenic previously reported variant in GMPPB gene NM_013334.3:c.458C > T; p.(Thr153Ile) causing autosomal-recessive muscular dystrophy-dystroglycanopathy type B14. With the established diagnosis, hematopoietic stem cell transplantation is now being scheduled for the youngest sibling, and a trial therapy with acetylcholine esterase inhibitors was started for the two neurologically affected patients with partial clinical improvement. CONCLUSION: This family emphasizes the importance of whole-exome sequencing for familial cases with complex phenotypes and vague neurological manifestations.


Assuntos
Anemia Sideroblástica , Humanos , Anemia Sideroblástica/genética , Anemia Sideroblástica/diagnóstico , Anemia Sideroblástica/patologia , Irmãos , Genótipo , Fenótipo , Mutação
5.
Exp Clin Transplant ; 21(1): 70-75, 2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-36757170

RESUMO

Congenital sideroblastic anemia is characterized by anemia and intramitochondrial iron accumulation in erythroid precursors that form ring sideroblasts. The most common recessive forms are caused by sequence variations in the ALAS2 and SLC25A38 genes. In patients with transfusion-dependent and pyridoxine- resistant severe congenital sideroblastic anemia, hematopoietic stem celltransplantis the only curative option. Herein, we described successful implementations of allogeneic hematopoietic stem cell transplant in 4 Iranian children with congenital sideroblastic anemia. The patients had presented with clinical manifestations of anemia early in life, and the diagnoses of congenital sideroblastic anemia were established through blood tests and bone marrow aspiration. Congenital sideroblastic anemia was further confirmed by the identification of pathogenic variants in SLC25A38 in 2 patients. All 4 patients received allogeneic hematopoietic stem cell transplant with myeloablative conditioning regimen that included busulfan, cyclophosphamide, andrabbit antithymocyte globulin. A combination of cyclosporine A and methotrexate or mycophenolate mofetil was used for graft-versus-host disease prophylaxis. Bone marrow and peripheral blood from sibling or related donors with fully matched human leukocyte antigen profiles were applied. The outcomes of hematopoietic stem celltransplantin patients with congenital sideroblastic anemia were favorable. Three patients achieved full donor chimerism (>95%, 98%, and 100%), and the other patient showed mixed chimerism (75%). All patients remained transfusion independent. Hemato- poietic stem celltransplantis a curative treatmentthat can provide long-term survival for patients with congenital sideroblastic anemia, particularly when used in a timely manner. There remain ongoing challenges in various aspects of hematopoietic stem celltransplantin patients with congenital sideroblastic anemia, which remain to be elucidated.


Assuntos
Anemia Sideroblástica , Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Criança , Humanos , 5-Aminolevulinato Sintetase/genética , Anemia Sideroblástica/diagnóstico , Anemia Sideroblástica/genética , Anemia Sideroblástica/congênito , Ciclosporina , Irã (Geográfico) , Condicionamento Pré-Transplante
6.
J Clin Immunol ; 43(1): 1-30, 2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-35984545

RESUMO

BACKGROUND AND PURPOSE: Sideroblastic anaemia with B-cell immunodeficiency, periodic fever and developmental delay (SIFD) syndrome is a novel rare autoinflammatory multisystem disorder. We performed a systematic review of the available clinical and therapeutics aspects of the SIFD syndrome. METHODS: A systematic review according to PRISMA approach, including all articles published before the 30th of July 2021 in Pubmed and EMBASE database, was performed. RESULTS: The search identified 29 publications describing 58 unique patients. To date, 41 unique mutations have been reported. Onset of disease is very early with a median age of 4 months (range 0-252 months). The most frequent manifestations are haematologic such as microcytic anaemia or sideroblastic anaemia (55/58), recurrent fever (52/58), neurologic abnormalities (48/58), immunologic abnormalities in particular a humoral immunodeficiency (48/58), gastrointestinal signs and symptoms (38/58), eye diseases as cataract and retinitis pigmentosa (27/58), failure to thrive (26/58), mucocutaneous involvement (29/58), sensorineural deafness (19/58) and others. To date, 19 patients (35.85%) died because of disease course (16) and complications of hematopoietic cell stems transplantation (3). The use of anti-TNFα and hematopoietic cell stems transplantation (HCST) is dramatically changing the natural history of this disease. CONCLUSIONS: SIFD syndrome is a novel entity to consider in a child presenting with recurrent fever, anaemia, B-cell immunodeficiency and neurodevelopmental delay. To date, therapeutic guidelines are lacking but anti-TNFα treatment and/or HCST are attractive and might modify the clinical course of this syndrome.


Assuntos
Anemia Sideroblástica , Síndromes de Imunodeficiência , Criança , Humanos , Anemia Sideroblástica/diagnóstico , Anemia Sideroblástica/terapia , Anemia Sideroblástica/complicações , Síndromes de Imunodeficiência/genética , Febre , Mutação , Deficiências do Desenvolvimento/diagnóstico , Deficiências do Desenvolvimento/terapia
7.
Clin Lab ; 68(4)2022 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-35443589

RESUMO

BACKGROUND: Myelodysplastic/myeloproliferative neoplasm with ring sideroblasts and thrombocytosis (MDS/ MPN-RS-T) was newly introduced as a full entity in the 2016 revision of the WHO classification. In this study, we investigated the morphologic, laboratory, and clinical features of MDS/MPN-RS-T. METHODS: We reviewed the bone marrow and genetic studies of patients whose diagnoses were coded as "refractory anemia with ring sideroblasts (RARS)" or "MDS/MPN, unclassifiable" between January 2008 and April 2018. RESULTS: A total of 8 cases fulfilled the criteria for a diagnosis of MDS/MPN-RS-T. All of them had no specific symptoms. Half of the cases had less than 450 × 109/L platelet counts by an automated hematology analyzer; however, all platelet counts exceeded 450 × 109/L when performed manually. JAK2 mutation tests were performed in 7 cases, and a heterozygous mutation was detected in 1 case. SF3B1 mutations were present in 3 of the 4 cases tested. CONCLUSIONS: When RARS is suspected in patients without thrombocytopenia, manual platelet counts should be performed. For patients with suspected essential thrombocythemia, RS evaluation through careful observation of an iron-stained slide is crucial. Since the independent evaluation of RS was reflected in the revised classification, the ambiguous disease classification becomes clearer and more consistent.


Assuntos
Anemia Refratária , Anemia Sideroblástica , Doenças Mieloproliferativas-Mielodisplásicas , Neoplasias , Trombocitose , Anemia Refratária/diagnóstico , Anemia Refratária/genética , Anemia Sideroblástica/diagnóstico , Anemia Sideroblástica/genética , Humanos , Mutação , Doenças Mieloproliferativas-Mielodisplásicas/diagnóstico , Doenças Mieloproliferativas-Mielodisplásicas/genética , Trombocitose/diagnóstico , Trombocitose/genética
8.
Int J Hematol ; 115(4): 508-514, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35064465

RESUMO

The incidence of MDS-RS in Japan has been recognized as about 5% which is lower than that in European countries. Insufficient use of iron staining tests in Japan has been noted as one conceivable factor contributing to this apparently lower prevalence. To investigate this issue, we analyzed the proportion of ring sideroblasts (RS) in 1300 bone marrow samples from patients with hematological diseases at Kitasato University Hospital, including iron staining of all samples. Sixteen of 96 patients with MDS (16.7%) were diagnosed with MDS-RS, and this accounted for 26.2% of MDS without excess blasts. Some MDS-EB (22.9%) and AML-MRC (13.8%) patients also had ≥ 15% RS. In contrast, RS were rarely found in myeloid neoplasms without dysplasia and non-myeloid diseases: only 1 in 46 (2.2%) patients with AML without dysplasia, 2 in 93 (2.2%) with MPN, and 8 in 984 (0.8%) with non-myeloid diseases had ≥ 5% RS. These results indicate that prevalence of MDS-RS in Japan may be higher than conventionally recognized and that RS are principally restricted to myelodysplastic disorders. Further multicenter studies using consecutive bone marrow samples with iron staining tests will be required to confirm our findings.


Assuntos
Anemia Sideroblástica , Transtornos Mieloproliferativos , Trombocitose , Anemia Sideroblástica/diagnóstico , Medula Óssea , Humanos , Mutação , Transtornos Mieloproliferativos/complicações
9.
Leuk Lymphoma ; 63(1): 199-204, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34448437

RESUMO

Myelodysplastic syndrome/myeloproliferative neoplasm with ring sideroblasts and thrombocytosis (MDS/MPN-RS-T) is characterized by anemia, ring sideroblast erythroid precursors, and persistent thrombocytosis. Case reports suggest lenalidomide may be effective in treating MDS/MPN-RS-T. We evaluated a large series of patients with MDS/MPN-RS-T to compare hematological improvement (HI) response rates among different drug therapies including lenalidomide. We identified 167 patients with MDS/MPN-RS-T. Among the patients tested, 84% had SF3B1 mutations and 43% had JAK2 V617F mutations. The median OS for the cohort was 81 months. Overall, 76 patients (46%) received erythropoiesis-stimulating agents (ESAs), 47 patients (28%) received lenalidomide, and 45 patients (27%) received hypomethylating agents (HMAs). The HI rates were 58%, 53%, and 24%, respectively. The median duration of treatment was 11 months for lenalidomide compared to 6 months for HMAs. Rates of HI improvement were higher in patients with MDS/MPN-RS-T treated with ESAs or lenalidomide, in comparison to those treated with HMAs.


Assuntos
Anemia Sideroblástica , Doenças Mieloproliferativas-Mielodisplásicas , Neoplasias , Trombocitose , Anemia Sideroblástica/diagnóstico , Anemia Sideroblástica/tratamento farmacológico , Anemia Sideroblástica/etiologia , Humanos , Mutação , Doenças Mieloproliferativas-Mielodisplásicas/complicações , Doenças Mieloproliferativas-Mielodisplásicas/diagnóstico , Doenças Mieloproliferativas-Mielodisplásicas/tratamento farmacológico , Trombocitose/tratamento farmacológico , Trombocitose/genética , Resultado do Tratamento
11.
PLoS One ; 16(7): e0254851, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34283879

RESUMO

Erythroferrone (ERFE), the erythroid regulator of iron metabolism, inhibits hepcidin to increase iron availability for erythropoiesis. ERFE plays a pathological role during ineffective erythropoiesis as occurs in X-linked sideroblastic anemia (XLSA) and ß-thalassemia. Its measurement might serve as an indicator of severity for these diseases. However, for reliable quantification of ERFE analytical characterization is indispensable to determine the assay's limitations and define proper methodology. We developed a sandwich ELISA for human serum ERFE using polyclonal antibodies and report its extensive analytical validation. This new assay showed, for the first time, the differentiation of XLSA and ß-thalassemia major patients from healthy controls (p = 0.03) and from each other (p<0.01), showing the assay provides biological plausible results. Despite poor dilution linearity, parallelism and recovery in patient serum matrix, which indicated presence of a matrix effect and/or different immunoreactivity of the antibodies to the recombinant standard and the endogenous analyte, our assay correlated well with two other existing ERFE ELISAs (both R2 = 0.83). Nevertheless, employment of one optimal dilution of all serum samples is warranted to obtain reliable results. When adequately performed, the assay can be used to further unravel the human erythropoiesis-hepcidin-iron axis in various disorders and assess the added diagnostic value of ERFE.


Assuntos
Anemia Sideroblástica/diagnóstico , Hormônios Peptídicos/análise , Talassemia beta/diagnóstico , Adulto , Idoso , Anemia/sangue , Anemia/diagnóstico , Anemia Sideroblástica/sangue , Citocinas/metabolismo , Ensaio de Imunoadsorção Enzimática , Eritropoese , Feminino , Hepcidinas/sangue , Humanos , Ferro/metabolismo , Sobrecarga de Ferro/diagnóstico , Sobrecarga de Ferro/metabolismo , Masculino , Pessoa de Meia-Idade , Hormônios Peptídicos/sangue , Talassemia beta/sangue
12.
Front Immunol ; 12: 586320, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33936027

RESUMO

Since the first description of the syndrome of sideroblastic anemia with immunodeficiency, fevers and development delay (SIFD), clinical pictures lacking both neurological and hematological manifestations have been reported. Moreover, prominent skin involvement, such as with relapsing erythema nodosum, is not a common finding. Up to this moment, no genotype and phenotype correlation could be done, but mild phenotypes seem to be located in the N or C part. B-cell deficiency is a hallmark of SIFD syndrome, and multiple others immunological defects have been reported, but not high levels of double negative T cells. Here we report a Brazilian patient with a novel phenotype of SFID syndrome, carrying multiple immune defects and harboring a novel mutation on TRNT1 gene.


Assuntos
Anemia Sideroblástica/diagnóstico , Anemia Sideroblástica/etiologia , Deficiências do Desenvolvimento/diagnóstico , Suscetibilidade a Doenças , Febre , Síndromes de Imunodeficiência/diagnóstico , Fenótipo , Alelos , Biópsia , Análise Mutacional de DNA , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Genótipo , Humanos , Linfócitos/imunologia , Linfócitos/metabolismo , Mutação
14.
Ann Biol Clin (Paris) ; 79(1): 69-74, 2021 Feb 01.
Artigo em Francês | MEDLINE | ID: mdl-33527906

RESUMO

Sideroblastic anemias in adults are often quickly labeled as myelodysplasias. We report two unfrequent observations of secondary acquired forms. The first one is a 15-year-old girl presented with severe cytopenias. The myelogram revealed the presence of vacuolated myeloid and erythroblastic precursors, with ring sideroblasts. Copper deficiency has been demonstrated in front of the association with collapsed cupremia and ceruleoplasminemia, with normal cupruria. The second case is a 70-year-old man, treated for 1 month with several lines of antibiotics for a skin infection, referred for cytopenias. The myelogram found vacuolated erythroblastic precursors and ring sideroblasts. Linezolid's responsibility has been proposed, with a favorable development after treatment has been stopped. These two observations, which describe unfrequent sideroblastic anemias, point out that this discovery should not lead to the diagnosis of myelodysplasia before having considered the many other etiologies.


Assuntos
Anemia Sideroblástica , Síndromes Mielodisplásicas , Adolescente , Idoso , Anemia Sideroblástica/diagnóstico , Feminino , Humanos , Masculino , Síndromes Mielodisplásicas/complicações , Síndromes Mielodisplásicas/diagnóstico
15.
Am J Hematol ; 96(3): 379-394, 2021 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-33428785

RESUMO

DISEASE OVERVIEW: Ring sideroblasts (RS) are erythroid precursors with abnormal perinuclear mitochondrial iron accumulation. Two myeloid neoplasms defined by the presence of RS, include myelodysplastic syndromes with RS (MDS-RS) and MDS/myeloproliferative neoplasm with RS and thrombocytosis (MDS/MPN-RS-T). DIAGNOSIS: MDS-RS is a lower risk MDS, with single or multilineage dysplasia (MDS-RS-SLD/MLD), <5% bone marrow (BM) blasts, <1% peripheral blood blasts and ≥15% BM RS (≥5% in the presence of SF3B1 mutations). MDS/MPN-RS-T, now a formal entity in the MDS/MPN overlap syndromes, has diagnostic features of MDS-RS-SLD, along with a platelet count ≥450 × 109 /L and large atypical megakaryocytes. MUTATIONS AND KARYOTYPE: Mutations in SF3B1 are seen in ≥80% of patients with MDS-RS-SLD and MDS/MPN-RS-T, and strongly correlate with the presence of BM RS; MDS/MPN-RS-T patients also demonstrate JAK2V617F (50%), DNMT3A, TET2 and ASXL1 mutations. Cytogenetic abnormalities are uncommon in both. RISK STRATIFICATION: Most patients with MDS-RS-SLD are stratified into lower risk groups by the revised-IPSS. Disease outcome in MDS/MPN-RS-T is better than that of MDS-RS-SLD, but worse than that of essential thrombocythemia (MPN). Both diseases are associated with a low risk of leukemic transformation. TREATMENT: Anemia and iron overload are complications seen in both and are managed similar to lower risk MDS and MPN. Luspatercept, a first-in-class erythroid maturation agent is now approved for the management of anemia in patients with MDS-RS and MDS/MPN-RS-T. Aspirin therapy is reasonable in MDS/MPN-RS-T, especially in the presence of JAK2V617F, but the value of platelet-lowering drugs remains to be defined.


Assuntos
Anemia Sideroblástica , Doenças Mieloproliferativas-Mielodisplásicas , Aloenxertos , Anemia Sideroblástica/diagnóstico , Anemia Sideroblástica/etiologia , Anemia Sideroblástica/patologia , Anemia Sideroblástica/terapia , Medula Óssea/patologia , Linhagem da Célula , Células Clonais/patologia , Terapia Combinada , Metilação de DNA/efeitos dos fármacos , Gerenciamento Clínico , Eritroblastos/ultraestrutura , Ferritinas/análise , Hematínicos/uso terapêutico , Transplante de Células-Tronco Hematopoéticas , Humanos , Quelantes de Ferro/uso terapêutico , Mitocôndrias/química , Mutação , Doenças Mieloproliferativas-Mielodisplásicas/diagnóstico , Doenças Mieloproliferativas-Mielodisplásicas/genética , Doenças Mieloproliferativas-Mielodisplásicas/terapia , Fosfoproteínas/genética , Prognóstico , Fatores de Processamento de RNA/genética , Medição de Risco , Trombocitose/diagnóstico , Trombocitose/terapia
16.
Australas J Dermatol ; 62(2): e276-e279, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33332575

RESUMO

Sideroblastic anaemia, B-cell immunodeficiency, periodic fever and developmental delay (SIFD) is caused by mutations of TRNT1, an enzyme essential for mitochondrial protein synthesis, and has been reported in 23 cases. A 6-month-old girl was evaluated with recurrent fever, failure to thrive, skin lesions and anaemia. She received blood transfusions and empirical antibiotics. Skin lesions, previously interpreted as insect bites, consisted of numerous firm asymptomatic erythematous papules and nodules, distributed over trunk and limbs. Skin histopathology revealed an intense dermal neutrophilic infiltrate extending to the subcutaneous, with numerous atypical myeloid cells, requiring the diagnosis of leukaemia cutis, to be ruled out. Over the follow-up, she developed herpetic stomatitis, tonsillitis, lobar pneumonia and Metapneumovirus tracheitis, and also deeper skin lesions, resembling panniculitis. Hypogammaglobulinaemia was diagnosed. An autoinflammatory disease was confirmed by whole exome sequencing: heterozygous mutations for TRNT1 NM_182916 c.495_498del, p.F167Tfs * 9 and TRNT1 NM_182916 c.1246A>G, p.K416E. The patient has been treated with subcutaneous immunoglobulin and etanercept. She presented with developmental delay and short stature for age. The fever, anaemia, skin neutrophilic infiltration and the inflammatory parameters improved. We describe a novel mutation in SIFD and the first to present skin manifestations, namely neutrophilic dermal and hypodermal infiltration.


Assuntos
Anemia Sideroblástica/diagnóstico , Deficiências do Desenvolvimento/complicações , Síndromes de Imunodeficiência/diagnóstico , Neutrófilos/metabolismo , Dermatopatias/etiologia , Anemia Sideroblástica/genética , Derme/metabolismo , Deficiências do Desenvolvimento/genética , Feminino , Febre/etiologia , Humanos , Síndromes de Imunodeficiência/congênito , Síndromes de Imunodeficiência/genética , Lactente , Mutação , Nucleotidiltransferases/genética , Sequenciamento do Exoma
17.
Hematol Oncol Clin North Am ; 34(2): 401-420, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32089219

RESUMO

Sideroblastic anemias are a heterogeneous group of disorders unified by the presence of abnormal erythroid precursors with perinuclear mitochondrial iron deposition in the bone marrow. Based on etiology, they are classified into clonal and nonclonal. Clonal sideroblastic anemias refer to myeloid neoplasms with ring sideroblasts (RS) and frequently have somatic perturbations in the SF3B1 gene. Anemia is a major cause of morbidity in patients, and restoration of effective erythropoiesis is a major treatment goal. Morbidity includes transfusion and disease-related complications. This article focuses on treatment of acquired sideroblastic anemias and highlights areas of future investigation.


Assuntos
Anemia Sideroblástica/terapia , Anemia Sideroblástica/diagnóstico , Anemia Sideroblástica/etiologia , Biomarcadores , Evolução Clonal , Terapia Combinada , Gerenciamento Clínico , Progressão da Doença , Suscetibilidade a Doenças , Células Eritroides/efeitos dos fármacos , Células Eritroides/metabolismo , Células Eritroides/patologia , Eritropoese/efeitos dos fármacos , Hematínicos/farmacologia , Hematínicos/uso terapêutico , Humanos , Hiperplasia , Fatores Imunológicos/imunologia , Fatores Imunológicos/uso terapêutico , Mutação , Síndromes Mielodisplásicas/diagnóstico , Síndromes Mielodisplásicas/etiologia , Síndromes Mielodisplásicas/terapia , Resultado do Tratamento
18.
Am J Hematol ; 94(4): 475-488, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30618061

RESUMO

DISEASE OVERVIEW: Ring sideroblasts (RS) are erythroid precursors with abnormal perinuclear mitochondrial iron accumulation. Two myeloid neoplasms defined by the presence of RS, include refractory anemia with ring sideroblasts (RARS), now classified under myelodysplastic syndromes with RS (MDS-RS) and RARS with thrombocytosis (RARS-T); now called myelodysplastic/myeloproliferative neoplasm with RS and thrombocytosis (MDS/MPN-RS-T). DIAGNOSIS: MDS-RS is a lower-risk MDS, with single or multilineage dysplasia (SLD/MLD), <5% bone marrow (BM) blasts and ≥ 15% BM RS (≥5% in the presence of SF3B1 mutations). MDS/MPN-RS-T, now a formal entity in the MDS/MPN overlap syndromes, has diagnostic features of MDS-RS-SLD, along with a platelet count ≥450 × 10(9)/L and large atypical megakaryocytes. MUTATIONS AND KARYOTYPE: Mutations in SF3B1 are seen in ≥80% of patients with MDS-RS-SLD and MDS/MPN-RS-T, and strongly correlate with the presence of BM RS; MDS/MPN-RS-T patients also demonstrate JAK2V617F, ASXL1, DNMT3A, SETBP1, and TET2 mutations. Cytogenetic abnormalities are uncommon in both. RISK STRATIFICATION: Most patients with MDS-RS-SLD are stratified into lower-risk groups by the revised-IPSS. Disease outcome in MDS/MPN-RS-T is better than that of MDS-RS-SLD, but worse than that of essential thrombocythemia. Both diseases have a low risk of leukemic transformation. TREATMENT: Anemia and iron overload are complications seen in both and are managed similar to lower-risk MDS and MPN. The advent of luspatercept, a first-in-class erythroid maturation agent will tremendously boost the ability to manage anemia. Aspirin therapy is reasonable in MDS/MPN-RS-T, especially in the presence of JAK2V617F, but the value of platelet-lowering drugs remains uncertain.


Assuntos
Anemia Refratária , Mutação , Anemia Refratária/sangue , Anemia Refratária/diagnóstico , Anemia Refratária/genética , Anemia Refratária/terapia , Anemia Sideroblástica/sangue , Anemia Sideroblástica/diagnóstico , Anemia Sideroblástica/genética , Anemia Sideroblástica/terapia , Eritroblastos/metabolismo , Feminino , Humanos , Sobrecarga de Ferro/sangue , Sobrecarga de Ferro/diagnóstico , Sobrecarga de Ferro/genética , Sobrecarga de Ferro/terapia , Masculino , Doenças Mieloproliferativas-Mielodisplásicas , Trombocitose/sangue , Trombocitose/diagnóstico , Trombocitose/genética , Trombocitose/terapia
20.
Eur J Haematol ; 101(3): 297-304, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29786897

RESUMO

BACKGROUND: Most patients with anemia are diagnosed through clinical phenotype and basic laboratory testing. Nonetheless, in cases of rare congenital anemias, some patients remain undiagnosed despite undergoing an exhaustive workup. Genetic testing is complicated by the large number of genes involved in rare anemias and the similarities in the clinical presentation of the different syndromes. OBJECTIVE: We aimed to enhance the diagnosis of patients with congenital anemias by using targeted next-generation sequencing. METHODS: Genetic diagnosis was performed by gene capture followed by next-generation sequencing of 76 genes known to cause anemia syndromes. RESULTS: Genetic diagnosis was achieved in 13 out of 21 patients (62%). Six patients were diagnosed with pyruvate kinase deficiency, 4 with dehydrated hereditary stomatocytosis, 2 with sideroblastic anemia, and 1 with CDA type IV. Eight novel mutations were found. In 7 patients, the genetic diagnosis differed from the pretest presumed diagnosis. The mean lag time from presentation to diagnosis was over 13 years. CONCLUSIONS: Targeted next-generation sequencing led to an accurate diagnosis in over 60% of patients with rare anemias. These patients do not need further diagnostic workup. Earlier incorporation of this method into the workup of patients with congenital anemia may improve patients' care and enable genetic counseling.


Assuntos
Anemia/congênito , Anemia/diagnóstico , Estudos de Associação Genética , Adolescente , Adulto , Anemia/sangue , Anemia/terapia , Anemia Diseritropoética Congênita/diagnóstico , Anemia Diseritropoética Congênita/genética , Anemia Diseritropoética Congênita/terapia , Anemia Hemolítica Congênita/diagnóstico , Anemia Hemolítica Congênita/genética , Anemia Hemolítica Congênita não Esferocítica/diagnóstico , Anemia Hemolítica Congênita não Esferocítica/genética , Anemia Sideroblástica/diagnóstico , Anemia Sideroblástica/genética , Medula Óssea/patologia , Criança , Pré-Escolar , Biologia Computacional , Índices de Eritrócitos , Feminino , Predisposição Genética para Doença , Testes Genéticos , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Hidropisia Fetal/diagnóstico , Hidropisia Fetal/genética , Masculino , Mutação , Piruvato Quinase/deficiência , Piruvato Quinase/genética , Erros Inatos do Metabolismo dos Piruvatos/diagnóstico , Erros Inatos do Metabolismo dos Piruvatos/genética , Doenças Raras , Adulto Jovem
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