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1.
Mol Immunol ; 121: 28-37, 2020 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-32151906

RESUMO

INTRODUCTION: H Syndrome is an autosomal recessive (AR) disease caused by defects in SLCA29A3 gene. This gene encodes the equilibrative nucleoside transporter, the protein which is highly expressed in spleen, lymph node and bone marrow. Autoinflammation and autoimmunity accompanies H Syndrome (HS). AIM: The aim was to further elucidate the mechanisms of disease by molecular studies in a patient with SLC29A3 gene defect. PATIENT AND METHODS: Mitochondrial dysfunction, lysosomal integrity, cytokine response in response to stimulation with different pattern recognition receptor ligands, and circulating cell-free mitochondrial-DNA(ccf-mtDNA) level in plasma were analyzed compared to controls to understand the cellular triggers of autoinflammation. RNA sequencing (RS) analyses were also performed in monocytes before/after culture with lipopolysaccharide. RESULTS: Patient had progressive destructive arthropathy in addition to clinical findings due to combined immunodeficiency. Pure red cell aplasia (PRCA), vitiligo, diabetes, multiple autoantibody positivity, lymphopenia, increased acute phase reactants were present. Recent thymic emigrants (RTE), naïve T cells were decreased, effector memory CD4 + T cells, nonclassical inflammatory monocytes were increased. Patient's peripheral blood mononuclear cells secreted more IL-1ß and IL-6, showed lysosomal disruption and significant mitochondrial dysfunction compared to healthy controls. Plasma ccf-mtDNA level was significantly elevated compared to age-matched controls (p < 0.05). RNA sequencing studies revealed decreased expression of NLR Family Caspase Recrument-Domain Containing 4(NLRC4), 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 4(PFKFB4), serine dehydratase(SDS), heparan sulfate(Glucosamine) 3-O-sulfotransferase 1(HS3ST1), neutral cholesterol ester hydrolase 1 (NCEH1), and interleukin-8 (IL-8) in patient's monocytes compared to controls. Longstanding PRCA, which is possibly autoimmune, resolved after initiating monthly intravenous immunoglobulins (IVIG) and low dose steroids to the patient. CONCLUSION: Although autoinflammation and autoimmunity are reported in HS, by functional analyses we here show in the present patient that over-active inflammasome pathway in HS might be related with mitochondrial and lysosomal dysfunction. Increased plasma ccf-mtDNA may be used as a biomarker of inflammasomopathy in HS. HS should be included in the classification of primary immunodeficiency diseases.

4.
J Rheumatol ; 47(1): 117-125, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31043544

RESUMO

OBJECTIVE: Deficiency of adenosine deaminase 2 (DADA2) is an autosomal recessive autoinflammatory disorder associated with ADA2 mutations. We aimed to investigate the characteristics and ADA2 enzyme activities of patients with DADA2 compared to non-DADA2 patients. METHODS: This is a descriptive study of 24 patients with DADA2 who were admitted to the Adult and Pediatric Rheumatology, Pediatric Haematology, and Pediatric Immunology Departments of Hacettepe University. All ADA2 exons were screened by Sanger sequencing. Serum ADA2 enzyme activity was measured by modified spectrophotometric method. RESULTS: Twenty-four patients with DADA2 were included: 14 with polyarteritis nodosa (PAN)-like phenotype (Group 1); 9 with Diamond-Blackfan anemia (DBA)-like features, and 1 with immunodeficiency (Group 2). Fourteen PAN-like DADA2 patients did not have the typical thrombocytosis seen in classic PAN. Inflammatory attacks were evident only in Group 1 patients. Serum ADA2 activity was low in all patients with DADA2 except one, who was tested after hematopoietic stem cell transplantation. There was no significant difference in ADA2 activities between PAN-like and DBA-like patients. In DADA2 patients with one ADA2 mutation, serum ADA2 activities were as low as those of patients with homozygote DADA2. ADA2 activities were normal in non-DADA2 patients. ADA2 mutations were affecting the dimerization domain in Group 1 patients and the catalytic domain in Group 2 patients. CONCLUSION: We suggest assessing ADA2 activity along with genetic analysis because there are patients with one ADA2 mutation and absent enzyme activity. Our data suggest a possible genotype-phenotype correlation in which dimerization domain mutations are associated with PAN-like phenotype, and catalytic domain mutations are associated with hematological manifestations.

5.
J Clin Immunol ; 39(7): 726-738, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31432443

RESUMO

INTRODUCTION: Autosomal recessively inherited lipopolysaccharide-responsive beige-like anchor (LRBA) protein deficiency was shown to be responsible for different types of inborn errors of immunity, such as common variable immunodeficiency (CVID) and autoimmune lymphoproliferative syndrome (ALPS). The aim of this study was to compare patients with LRBA-related ALPS and LRBA-related CVID, to describe their clinical and laboratory phenotypes, and to prepare an algorithm for their diagnosis and management. METHODS: Fifteen LRBA-deficient patients were identified among 31 CVID and 14 possible ALPS patients with Western blotting (WB), primary immunodeficiency disease (PIDD) gene, next-generation panel screening (NGS), and whole exome sequencing (WES). RESULTS: The median age on admission and age of diagnosis were 7 years (0.3-16.5) and 11 years (5-44), respectively. Splenomegaly was seen in 93.3% (14/15) of the patients on admission. Splenectomy was performed to 1/5. Recurrent upper respiratory tract infections (93.3% (14/15)), autoimmune cytopenia (80% (12/15)), chronic diarrhea (53.3% (8/15)), lower respiratory tract infections (53.3% (8/15)), lymphoma (26.6% (4/15)), Evans syndrome (26.6% (4/15)), and autoimmune thyroiditis (20% (3/15)) were common clinical findings and diseases. Lymphopenia (5/15), intermittant neutropenia (4/15), eosinophilia (4/15), and progressive hypogammaglobulinemia are recorded in given number of patients. Double negative T cells (TCRαß+CD4-CD8-) were increased in 80% (8/10) of the patients. B cell percentage/numbers were low in 60% (9/15) of the patients on admission. Decreased switched memory B cells, decreased naive and recent thymic emigrant (RTE) Thelper (Th) cells, markedly increased effector memory/effector memory RA+ (TEMRA) Th were documented. Large PD1+ population, increased memory, and enlarged follicular helper T cell population in the CD4+ T cell compartment was seen in one of the patients. Most of the deleterious missense mutations were located in the DUF1088 and BEACH domains. Interestingly, one of the two siblings with the same homozygous LRBA defect did not have any clinical symptom. Hematopoietic stem cell transplantation (HSCT) was performed to 7/15 (46.6%) of the patients. Transplanted patients are alive and well after a median of 2 years (1-3). In total, one patient died from sepsis during adulthood before HSCT. CONCLUSION: Patients with LRBA deficiency may initially be diagnosed as CVID or ALPS in the clinical practice. Progressive decrease in B cells as well as IgG in ALPS-like patients and addition of IBD symptoms in the follow-up should raise the suspicion for LRBA deficiency. Decreased switched memory B cells, decreased naive and recent thymic emigrant (RTE) Th cells, and markedly increased effector memory/effector memory RA+ Th cells (TEMRA Th) cells are important for the diagnosis of the patients in addition to clinical features. Analysis of protein by either WB or flow cytometry is required when the clinicians come across especially with missense LRBA variants of uncertain significance. High rate of malignancy shows the regulatory T cell's important role of immune surveillance. HSCT is curative and succesful in patients with HLA-matched family donor.

7.
J Pediatr Hematol Oncol ; 41(3): 243-246, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30339652

RESUMO

A unique consanguineous family with 2 genomic instability disorders, Fanconi anemia and ataxia telangiectasia, revealed exceptional combinations of null mutations in the FANCA and ATM genes. Two siblings with Fanconi anemia had novel homozygous consecutive microdeletions (c.1361-1370delCCTCCTTTGG, c.1374delC) adjoined to upstream 65 nucleotide direct tandem repeats and deletion hotspot motifs in the FANCA gene. The sibling with ataxia telangiectasia revealed a homozygous p.Arg2993Stop (c.8977C>T) null mutation in the ATM gene. All patients were also heterozygous for the opposite mutations without any additional clinical or laboratory manifestations. Double heterozygote parents did not present any clinical symptoms suggestive of the 2 disorders.


Assuntos
Proteínas Mutadas de Ataxia Telangiectasia/genética , Ataxia Telangiectasia/genética , Proteína do Grupo de Complementação A da Anemia de Fanconi/genética , Anemia de Fanconi/genética , Feminino , Heterozigoto , Homozigoto , Humanos , Masculino , Deleção de Sequência , Irmãos
8.
Eur J Haematol ; 102(2): 123-130, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30300449

RESUMO

OBJECTIVES: To evaluate the long-term efficacy and safety of deferasirox therapy in a large observational cohort of children with transfusion-dependent thalassemia (TDT) and sickle cell anemia (SCA) in Turkey. METHODS: This was a multicenter, prospective cohort study including TDT and SCA patients aged 2-18 years with iron overload (≥100 mL/kg of pRBC or a serum ferritin [SF] level >1000 µg/L) receiving deferasirox. Patients were followed for up to 3 years according to standard practice. RESULTS: A total of 439 patients were evaluated (415 [94.5%] TDT, 143 [32.6%] between 2 and 6 years). Serum ferritin levels consistently and significantly decreased across 3 years of deferasirox therapy from a median of 1775.5 to 1250.5 µg/L (P < 0.001). Serum ferritin decreases were noted in TDT (1804.9 to 1241 µg/L), SCA (1655.5 to 1260 µg/L), and across age groups of 2-6 years (1971.5 to 1499 µg/L), 7-12 years (1688.5 to 1159.8 µg/L), and 13-18 years (1496.5 to 1107 µg/L). Serum ferritin decreases were also noted for all deferasirox dose groups but only significant in patients with doses ≥30 mg/kg/d (n = 120, -579.6 median reduction, P < 0.001). Only 9 (2%) patients had adverse events suspected to be related to deferasirox. Serum creatinine slightly increased but remained within the normal range. CONCLUSIONS: Deferasirox has long-term efficacy and safety in children with TDT and SCA, although higher doses (≥30 mg/kg/d) may be required to achieve iron balance.


Assuntos
Anemia Falciforme/complicações , Deferasirox/uso terapêutico , Quelantes de Ferro/uso terapêutico , Sobrecarga de Ferro/tratamento farmacológico , Sobrecarga de Ferro/etiologia , Talassemia/complicações , Adolescente , Anemia Falciforme/terapia , Biomarcadores , Transfusão de Sangue , Criança , Pré-Escolar , Estudos de Coortes , Deferasirox/administração & dosagem , Deferasirox/efeitos adversos , Feminino , Ferritinas/sangue , Ferritinas/metabolismo , Humanos , Ferro/sangue , Ferro/metabolismo , Quelantes de Ferro/administração & dosagem , Quelantes de Ferro/efeitos adversos , Sobrecarga de Ferro/metabolismo , Masculino , Talassemia/terapia , Resultado do Tratamento , Turquia
9.
Minerva Pediatr ; 71(5): 449-454, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26200522

RESUMO

BACKGROUND: The purpose of this study was to compare the effectiveness of different oral iron preparations in children with iron deficiency anemia (IDA). METHODS: Sixty children with IDA, aged between 6 months and 180 months, were randomly assigned into three treatment groups. Group I included children with IDA who received ferrous sulfate (Fe-S); Group II included children receiving iron polymaltose complexes (Fe-OH-PM), and Group III included children receiving a single preparation of combined iron and zinc (Fe-Zn). The effect of different iron preparations were evaluated and compared. The duration of treatment was 8 weeks. Hemoglobin (Hgb) levels, as well as other hematological parameters were determined at admission and the first, fourth, and eighth weeks of the treatment. RESULTS: The Hgb levels of patients in all three groups were statistically higher in the fourth (P=0.001) and eighth (P<0.001) weeks compared to baseline; although there was no difference between the groups at the end of the treatment period (P>0.05). CONCLUSIONS: Our results indicate that, Fe-OH-PM and Fe-Zn preparations may also be preferred as a choice like Fe-S for treatment of children with IDA.

10.
Turk J Pediatr ; 61(4): 477-484, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31990462

RESUMO

Kesici S, Ünal S, Kuskonmaz B, Aytaç S, Çetin M, Gümrük F. Fanconi anemia: a single center experience of a large cohort. Turk J Pediatr 2019; 61: 477-484. Fanconi anemia (FA) is an inherited disease, characterized by congenital malformations, short stature, progressive bone marrow failure and predisposition to leukemia and solid tumors. The aim of this study was to evaluate the clinical and prognostic features of FA patients followed in a single center. The charts of FA patients were reviewed 35 years retrospectively and a total of 175 patients were included in the study in which 51.4% of patients were male. The mean age at diagnosis was 6.3±4.1 years. The incidence of microcephaly was 92.6%, skin findings were 88.0%, eye abnormality was 74.3%, thumb and radius abnormality was 53.1%, urinary system abnormality was 30.9%, skeletal system abnormality other than thumb and radius was 18.9%, genital system abnormality was 11.4%, cardiovascular system abnormality was 11.4%, ear and hearing abnormalities were 9.7% and gastrointestinal system abnormality was 5.7%. Short stature was present in 75.4% of the patients. Of the 175 patients 167 (95.4%) developed bone marrow failure during follow-up and the mean age of bone marrow failure was 7.1 ±3.7 years (1 month-old-19.8 years). The first clinical symptom was thrombocytopenia in 83.4% of patients. Malignancy developed in a total of 23 (13.1 %) patients (20 leukemia, 3 solid tumors) during follow-up. Of 175 patients, 35 (20%) underwent hematopoietic stem cell transplantation. Fatality rate among patients who underwent hematopoietic stem cell transplantation was 31.4% (11/35) and fatality rate among other patients was 63.4% (83/131; p < 0.05). Of 94 patients who deceased, death was due to bleeding in 44.7%, infection in 34%, leukemia progression in 16.0% and graft versus host disease in 5.3%. In terms of the number of patients included, this study is one of the largest cohorts with a remarkable duration of follow-up time. Hematopoietic stem cell transplantation was found to have a good impact on sur vival of patients.

11.
Turk J Pediatr ; 61(3): 325-329, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31916708

RESUMO

Yaman-Bajin I, Aytaç S, Kuskonmaz B, Uçkan-Çetinkaya D, Ünal S, Gümrük F, Çetin M. Infant lymphoblastic leukemia: a single centers 10 year experience. Turk J Pediatr 2019; 61: 325-329. Infant acute lymphoblastic leukemia (ALL) is a rare disease and consists of 4-5% of all childhood ALL. Despite improved survival rates in childhood ALL, infants with ALL have a worse prognosis. We aimed to evaluate the clinical features and treatment outcomes of our patients diagnosed with infant ALL at Hacettepe University, Pediatric Hematology Department between 1 January 2008 and 1 January 2018 retrospectively. There were 13 patients with a median age of 7 months. Three of the patients were triplets born from a spontaneous monozygotic triplet pregnancy. Relapse were observed in 4 patients. Hematopoietic stem cell transplantation (HSCT) was performed for five patients. Relapse after HSCT was observed in 3 patients. After a median follow-up period of 18 months, 6 patients (45%) (3 after HSCT and 3 who only received chemotherapy) were alive and in remission. Prognosis of infant ALL is poor in that only half of the patients survive. Our results suggest that bone marrow transplantation seems to be a good and efficient choice of treatment for selected patients. However, there is still a big issue to decide which patient should undergo transplantation and more studies are needed to reevaluate the eligibility criteria for HSCT in this group of patients.

12.
J Assist Reprod Genet ; 35(12): 2149-2154, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30362058

RESUMO

PURPOSE: Vanished twin (VT) has been associated with poor perinatal outcomes. Our research aimed to investigate the outcomes of pregnancies with vanished twin and its possible association with methylenetetrahydrofolate reductase (MTHFR) polymorphisms. METHODS: This study consisted of 30 of 38 VT pregnancies (group 1, VT group), 109 singletons (group 2), 70 spontaneous twins (group 3), and 101 in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) twins (group 4). RESULTS: Most patients in group 1 (28/30) were tested for MTHFR genes (C677T or A1298C polymorphisms). Eight of the 38 pregnancies with VT (21.1%) resulted in miscarriage. The prevalence of "2 or more pregnancy losses" in the "obstetric history" in group 1 was higher (23.3%) than those in the other groups (p = 0.007, χ2 = 17.8). The allelic frequencies of MTHFR 677 and MTHFR 1298 in group 1 were 0.268 and 0.429, respectively (higher than those in healthy population). The median birthweights in groups 1, 2, 3, and 4 were 2940, 3200, 2300, and 2095 g, respectively. The prevalence of respiratory distress syndrome was significantly higher in the IVF/ICSI twin pregnancy group (p < 0.001, χ2 = 21.2). Early pregnancy loss and the presence of "2 or more miscarriages" in the obstetric history of pregnancies with VT were more frequent. CONCLUSION: The coincidence of VT and MTHFR polymorphisms might play an incidental or factual role in this connection.


Assuntos
Estudos de Associação Genética , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Resultado da Gravidez/genética , Gravidez de Gêmeos/genética , Aborto Espontâneo/genética , Aborto Espontâneo/fisiopatologia , Adulto , Feminino , Fertilização In Vitro , Frequência do Gene/genética , Humanos , Polimorfismo de Nucleotídeo Único/genética , Gravidez , Complicações na Gravidez/genética , Complicações na Gravidez/fisiopatologia , Resultado da Gravidez/epidemiologia , Gravidez de Gêmeos/fisiologia , Injeções de Esperma Intracitoplásmicas , Gêmeos/genética
13.
Geburtshilfe Frauenheilkd ; 78(9): 871-878, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30258247

RESUMO

Introduction Aim of the study was to evaluate the effect of methylenetetrahydrofolate reductase (MTHFR) polymorphisms on pregnancy outcome. Materials and Methods A total of 617 pregnancies of women who were investigated for MTHFR C677T and A1298C polymorphisms prior to pregnancy were included in the study. Cases were classified into "homozygous polymorphisms" (Group I), "heterozygous polymorphisms" (Group II), and patients without polymorphisms who functioned as controls (Group III). Patients with polymorphisms were assigned to a specific protocol at least 3 months before becoming pregnant. Administration of low molecular weight heparin (LMWH) was started very early during pregnancy. The Beksac Obstetrics Index (BOI) was used to estimate the obstetric risk levels for the different groups. Results We found that the early pregnancy loss (EPL) rate increased as MTHFR polymorphism complexity increased and that the early EPL rate was significantly higher in patients with MTHFR C677T polymorphism compared to patients with MTHFR A1298C polymorphism (p = 0.039). There were significant differences between the previous pregnancies of the patients in the 3 study groups in terms of perinatal complications and EPLs (p = 0.003 and p = 0.019). The BOI decreased as the severity of polymorphisms increased. An association between MTHFR polymorphisms and congenital malformations and chromosomal abnormalities was observed. We could not demonstrate any statistically significant difference between study groups when the 3 groups were compared with regard to the pregnancy outcomes under specific management protocols. Conclusion MTHFR polymorphisms are potential risk factors for adverse pregnancy outcomes.

14.
Hemoglobin ; 42(2): 113-116, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30200834

RESUMO

Peripheral neuropathy is one of the complications of ß-thalassemia (ß-thal) that has been investigated in limited reports. We aimed to detect the rate of peripheral neuropathy and risk factors for neuropathy development in patients with ß-thal. The study was performed in patients with ß-thal intermedia (ß-TI) or ß-thal major (ß-TM). Prospective electrophysiological studies were achieved via standard procedures. A total of 27 patients were enrolled in the study. Electrophysiological studies for both motor and sensory nerves were within normal range. In motor nerve studies, delayed peroneal nerve latency was found in patients with high ferritin levels, increased ulnar nerve amplitude was detected in patients ≥20 years old, and increased tibial nerve amplitude was seen in patients with low copper levels. We could not show peripheral neuropathy in our patients. Increased ferritin level, older age, and copper deficiency may cause mild changes in electrophysiological studies of motor nerves.


Assuntos
Eletrofisiologia/métodos , Quelantes de Ferro/farmacologia , Doenças do Sistema Nervoso Periférico/diagnóstico , Talassemia beta/complicações , Adulto , Fatores Etários , Cobre/metabolismo , Ferritinas/metabolismo , Humanos , Pessoa de Meia-Idade , Nervo Fibular , Estudos Prospectivos , Nervo Tibial , Nervo Ulnar , Adulto Jovem
15.
Proc Natl Acad Sci U S A ; 115(20): 5241-5246, 2018 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-29712865

RESUMO

BRCA1 is essential for repair of DNA double-strand breaks by homologous recombination, and hence for survival. Complete loss of its function is lethal during early embryonic development. Patients who are compound heterozygous for BRCA1 truncating mutations and missense alleles that retain some DNA repair capacity may survive, albeit with very high risk of early onset breast or ovarian cancer and features of Fanconi anemia. However, a mechanism enabling survival of patients homozygous for BRCA1 truncating mutations has not been described. We studied two unrelated families in which four children presented with multiple congenital anomalies and severe chromosomal fragility. One child developed T cell acute lymphocytic leukemia (ALL), and a second child developed neuroblastoma. Each of the four children was homozygous for a nonsense mutation in BRCA1 exon 11. Homozygosity for the nonsense mutations was viable thanks to the presence of a naturally occurring alternative splice donor in BRCA1 exon 11 that lies 5' of the mutations. The mutations did not affect the alternative splice site, but transcription from it produced an in-frame BRCA1 message with deletion of 3,309 bp. The translated BRCA1 protein was only 40% of normal length, but with intact N- and C-terminal sequences. These patients extend the range of BRCA1-related phenotypes and illustrate how naturally occurring alternative splicing can enable survival, albeit with severe consequences, of otherwise lethal genotypes of an essential gene.


Assuntos
Processamento Alternativo , Proteína BRCA1/genética , Neoplasias da Mama/genética , Códon sem Sentido , Homozigoto , Neoplasias Ovarianas/genética , Adolescente , Adulto , Neoplasias da Mama/patologia , Criança , Pré-Escolar , Feminino , Humanos , Neoplasias Ovarianas/patologia , Linhagem
16.
Blood Transfus ; 16(1): 105-113, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-27723456

RESUMO

BACKGROUND: Factor XI (FXI) deficiency is an autosomal bleeding disease associated with genetic defects in the F11 gene which cause decreased FXI levels or impaired FXI function. An increasing number of mutations has been reported in the FXI mutation database, most of which affect the serine protease domain of the protein. FXI is a heterogeneous disorder associated with a variable bleeding tendency and a variety of causative F11 gene mutations. The molecular basis of FXI deficiency in 14 patients from ten unrelated families in Turkey was analysed to establish genotype-phenotype correlations and inheritance of the mutations in the patients' families. MATERIAL AND METHODS: Fourteen index cases with a diagnosis of FXI deficiency and family members of these patients were enrolled into the study. The patients' F11 genes were amplified by polymerase chain reaction and subjected to direct DNA sequencing analysis. The findings were analysed statistically using bivariate correlations, Pearson's correlation coefficient and the nonparametric Mann-Whitney test. RESULTS: Direct DNA sequencing analysis of the F11 genes revealed that all of the 14 patients had a F11 gene mutation. Eight different mutations were identified in the apple 1, apple 2 or serine protease domains, except one which was a splice site mutation. Six of the mutations were recurrent. Two of the mutations were novel missense mutations, p.Val522Gly and p.Cys581Arg, within the catalytic domain. The p.Trp519Stop mutation was observed in two families whereas all the other mutations were specific to a single family. DISCUSSION: Identification of mutations confirmed the genetic heterogeneity of FXI deficiency. Most of the patients with mutations did not have any bleeding complications, whereas some had severe bleeding symptoms. Genetic screening for F11 gene mutations is important to decrease the mortality and morbidity rate associated with FXI deficiency, which can be life-threatening if bleeding occurs in tissues with high fibrinolytic activity.


Assuntos
Deficiência do Fator XI/genética , Fator XI/genética , Mutação , Adulto , Criança , Pré-Escolar , Família , Feminino , Humanos , Masculino , Domínios Proteicos , Turquia
17.
Haematologica ; 103(2): 231-236, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29146706

RESUMO

Familial hemophagocytic lymphohistiocytosis is an autosomal recessive, life-threatening condition characterized by defective immune response. A retrospective analysis was performed on 57 patients diagnosed with familial hemophagocytic lymphohistiocytosis at Hacettepe University Pediatric Hematology Department, Ankara, Turkey. Mutation analysis was performed on 37 patients, and of these: 11 had UNC13D, 10 had PRF1 and 3 had STX11 gene mutation. Of these patients, 44% were found to have central nervous system involvement on admission and spinal cord involvement was also seen in 5 patients. Remission was achieved in 24 patients with the treatment, in a median time of 76 days (min-max: 15-705 days). Time to remission was prolonged 3.1 times in patients with a ferritin level 1500 mg/dL or more. When patients were grouped according to age [Group 1 (≤ 2 years), Group 2 (>2 years)]; patients in Group 1 had higher ferritin and aspartate aminotransferase levels but lower fibrinogen levels. The 5-year survival rate was also lower in Group 1. When patients in Group 1 were divided into two sub-groups according to hepatic involvement, the 5-year survival rate of patients who had hepatic involvement was significantly lower than those patients without hepatic involvement (0.7%, 27%, respectively) (P=0.002). The 5-year survival rate of patients who underwent hematopoietic stem cell transplantation was significantly higher than the patients who didn't (44%, 16%, respectively) (P=0.02). In conclusion, age two years and under, ferritin level above 1500 mg/dL, spinal cord or hepatic involvement should be considered as poor prognostic factors in familial hemophagocytic lymphohistiocytosis.


Assuntos
Linfo-Histiocitose Hemofagocítica/patologia , Adolescente , Doenças do Sistema Nervoso Central/diagnóstico , Doenças do Sistema Nervoso Central/terapia , Criança , Pré-Escolar , Feminino , Ferritinas/sangue , Transplante de Células-Tronco Hematopoéticas , Humanos , Lactente , Hepatopatias/diagnóstico , Hepatopatias/terapia , Linfo-Histiocitose Hemofagocítica/diagnóstico , Linfo-Histiocitose Hemofagocítica/mortalidade , Linfo-Histiocitose Hemofagocítica/terapia , Masculino , Prognóstico , Estudos Retrospectivos , Fatores de Risco , Doenças da Medula Espinal/diagnóstico , Doenças da Medula Espinal/terapia , Taxa de Sobrevida
18.
Stem Cell Rev Rep ; 14(3): 425-437, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29247345

RESUMO

Transforming growth factor beta (TGF-ß) secretion from cells in the bone marrow (BM) niche affects hematopoietic stem cell (HSC) fate and has a cardinal role in HSC quiescence. BM mesenchymal stem cells (BM-MSCs), a component of the BM niche, may produce abnormal levels of TGF-ß in Fanconi anemia (FA) and may play a role in bone marrow failure. Here, we molecularly and cellularly characterized FA BM-MSCs by addressing their immunophenotype, proliferation- and differentiation- capacity, reactive oxygen species (ROS) production, senescence activity as well as expression and secretion levels of TGF-ß isoforms. In ten FA patients, mutations were detected in FANCA (n = 7), FANCG (n = 1) and FANCD2 (n = 2) genes. The immunophenotype, with the exception of CD29, and differentiation capacity of FA BM-MSCs were similar to healthy donors. FA BM-MSCs showed decreased proliferation, increased ROS level and an arrest in G2 following DEB treatment. ß-galactosidase staining indicated elevated senescence of FANCD2-deficient cells. FA BM-MSCs displayed TGF-ß1 mRNA levels similar to donor BM-MSCs, and was not affected by DEB treatment. However, secretion of TGF-ß was absent in FA-D2 BM-MSCs. Absence of TGF-ß secretion may be related to early onset of senescence of the FANCD2-deficient BM-MSCs. The proliferative response of FA-D2 BM-MSCs to rTGF-ß1 was not different from FANCA-deficient and donor cells and raises the possibility that rTGF-ß1 may reverse the senescence of the FANCD2-deficient BM-MSCs which needs to be investigated further.


Assuntos
Proteína do Grupo de Complementação D2 da Anemia de Fanconi/genética , Anemia de Fanconi/metabolismo , Células-Tronco Mesenquimais/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Células da Medula Óssea/metabolismo , Diferenciação Celular/genética , Diferenciação Celular/fisiologia , Células Cultivadas , Análise Mutacional de DNA , Anemia de Fanconi/genética , Proteína do Grupo de Complementação D2 da Anemia de Fanconi/metabolismo , Proteína do Grupo de Complementação G da Anemia de Fanconi/genética , Proteína do Grupo de Complementação G da Anemia de Fanconi/metabolismo , Humanos , Mutação/genética , Transdução de Sinais/genética , Transdução de Sinais/fisiologia
19.
Transfus Apher Sci ; 56(4): 539-543, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28818403

RESUMO

OBJECTIVES: Iron is taken into enterocytes at the duodenum via apical divalent metal-ion transporter 1 protein. Besides iron, divalent metal-ion transporter 1 also transports other divalent metals. We aimed to investigate blood heavy metal levels in patients with ineffective erythropoiesis. METHODS: Blood levels of heavy metals including Pb, Al, Cd, Cr, Co, Cu, and Zn were measured in patients with thalassemia major (TM), thalassemia intermedia (TI), congenital dyserythropoietic anemia (CDA), and age- and sex-matched healthy controls. RESULTS: Blood samples were obtained from 68 patients (51 patients with TM, 8 with TI, 9 with CDA), and a control group that included 65 volunteers. Patients with TM were found to have lower Al, Pb, and Zn, and higher Cd levels compared with the control group. The patients treated with deferasirox were further analyzed and Pb and Zn levels were found lower compared with the control group. DISCUSSION: Patients with TM had tendency to have elevated levels of plasma cadmium; however, the median level was not at a toxic level. Increased metal-ion transporter 1 activity may cause heavy metal accumulation, but deferasirox chelation may be protective against heavy metals besides iron.


Assuntos
Anemia Diseritropoética Congênita/sangue , Eritropoese , Metais Pesados/sangue , Talassemia beta/sangue , Adolescente , Adulto , Anemia Diseritropoética Congênita/tratamento farmacológico , Benzoatos/administração & dosagem , Criança , Pré-Escolar , Deferasirox , Feminino , Humanos , Masculino , Triazóis/administração & dosagem , Talassemia beta/tratamento farmacológico
20.
J Pediatr Hematol Oncol ; 39(8): e504-e507, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-28731923

RESUMO

With improvements in molecular diagnostic methods, report of Human bocavirus (HBoV) as an etiologic agent in many studies on viral respiratory and gastrointestinal infections has been increasing. Two pediatric patients who presented with secondary hemophagocytic lymphohistiocytosis were examined for etiologic causes, including viruses. Whole bacterial and fungal cultures and viral serological studies were negative. Viral polymerase chain reaction of nasopharyngeal secretions showed HBoV. One was successfully treated with intravenous immunoglobulins, whereas the other died with multiorgan failure. Here we report 2 pediatric patients with secondary hemophagocytic lymphohistiocytosis and detection of HBoV as the sole agent, predicting an association.


Assuntos
Bocavirus Humano , Linfo-Histiocitose Hemofagocítica/diagnóstico , Linfo-Histiocitose Hemofagocítica/etiologia , Infecções por Parvoviridae/complicações , Biomarcadores , Medula Óssea/patologia , Pré-Escolar , Exantema/patologia , Evolução Fatal , Feminino , Bocavirus Humano/genética , Humanos , Imunoglobulinas Intravenosas/uso terapêutico , Lactente , Linfo-Histiocitose Hemofagocítica/tratamento farmacológico , Masculino , Infecções por Parvoviridae/diagnóstico , Infecções por Parvoviridae/virologia , Reação em Cadeia da Polimerase , Resultado do Tratamento
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