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Acquired haemophilia (AH) is a rare disorder characterized by bleeding in patients with no personal or family history of coagulation/clotting-related diseases. This disease occurs when the immune system, by mistake, generates autoantibodies that target FVIII, causing bleeding. Small RNAs from plasma collected from AH patients (n = 2), mild classical haemophilia (n = 3), severe classical haemophilia (n = 3) and healthy donors (n = 2), for sequencing by Illumina, NextSeq500. Based on bioinformatic analysis, AH patients were compared to all experimental groups and a significant number of altered transcripts were identified with one transcript being modified compared to all groups at fold change level. The Venn diagram shows that haemoglobin subunit alpha 1 was highlighted to be the common upregulated transcript in AH compared to classical haemophilia and healthy patients. Non-coding RNAs might play a role in AH pathogenesis; however, due to the rarity of HA, the current study needs to be translated on a larger number of AH samples and classical haemophilia samples to generate more solid data that can confirm our findings.
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Hemofilia A , Humanos , Hemofilia A/genética , Fator VIII/genética , Hemorragia , Análise de Sequência de RNA , RNA não TraduzidoRESUMO
Background and Objectives: Despite the vast heterogeneity in the genetic defects causing hemophilia A (HA), large intron inversions represent a major cause of disease, accounting for almost half of the cases of severe HA worldwide. We investigated the intron 22 and intron 1 inversion status in a cohort of Romanian unrelated patients with severe HA. Moreover, we evaluated the role of these inversions as relative risk factors in inhibitor occurrence. Materials and Methods: Inverse shifting-a polymerase chain reaction method was used to detect the presence of intron 22 and intron 1 inversions in 156 Romanian patients with HA. Results: Intron inversion 22 was found in 41.7% of the patients, while intron 1 inversion was detected in 3.2% of the patients. Overall, large intron inversions represented the molecular defect in 44.9% of the studied patients. Our findings are in accord with previously published reports from Eastern Europe countries and with other international studies. The risk of inhibitor development was higher in patients with inversion 1 compared to the patients with HA without any inversion detected. Conclusions: The current study demonstrates the major causative role of large intron inversions in severe HA in Romanian patients. Moreover, our study confirms the contribution of intron 1 inversion in inhibitor development.
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Hemofilia A , Humanos , Hemofilia A/genética , Fator VIII/genética , Íntrons/genética , Romênia , Inversão Cromossômica/genéticaRESUMO
BACKGROUND/AIMS: Down syndrome associated disorders are caused by a complex genetic context where trisomy 21 is a central component in relation to other changes involving epigenetic regulators and signaling molecules. This unique genetic context is responsible for the predisposition of people with Down syndrome to acute leukemia. Although, the research in this field has discovered some important pathogenic keys, the exact mechanism of this predisposition is not known. METHODS: In this study we applied functional enrichment analysis to evaluate the interactions between genes localized on chromosome 21, genes already identify as having a key role in acute leukemia of Down syndrome, miRNAs and signaling pathways implicated in cancer and cell development and found that miR-155 has a high impact in genes present on chromosome 21. Forward, we performed next generation sequencing on DNA samples from a cohort of patients diagnosed with acute leukemia of Down syndrome and in vitro functional assay using a CMK-86 cell line, transfected with either mimic or inhibitor of the microRNA-155-5p. RESULTS: Our results show that the epigenetic alteration of the TNF superfamily receptors in Down syndrome, which can be correlated to microRNA-155-5p aberrant activity, may play an important role in cell signaling and thus be linked to acute myeloid leukemia. CONCLUSION: Some genes, already shown to be mutated in AML-DS, are potential targets for miR-155. Our results show that the epigenetic alteration of the TNF superfamily receptors in Down syndrome may play an important role in cell signaling and thus be linked to acute myeloid leukemia.
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Síndrome de Down/complicações , Epigênese Genética , Regulação Leucêmica da Expressão Gênica , Leucemia Mieloide Aguda/patologia , Reação Leucemoide/patologia , MicroRNAs/genética , Receptores do Fator de Necrose Tumoral/genética , Diferenciação Celular , Estudos de Coortes , Síndrome de Down/etiologia , Síndrome de Down/genética , Síndrome de Down/metabolismo , Síndrome de Down/patologia , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Leucemia Mieloide Aguda/etiologia , Leucemia Mieloide Aguda/metabolismo , Reação Leucemoide/etiologia , Reação Leucemoide/metabolismo , Masculino , Receptores do Fator de Necrose Tumoral/metabolismoRESUMO
Deletion mutations of WAS are relatively rare and the precise localization of large deletions in the genome has rarely been described in previous studies. We report here a 5-month-old boy with a large deletion mutation in WAS that completely abolished protein expression. To localize the deletion, a 2816-bp-length sequence that spans between exons 9 and 12 was amplified. PCR amplification of the patient's sample revealed a single band of about 1 kb in contrast to the 2816-bp-amplicon in the control. Genomic DNA sequencing of the patient revealed a 1595-bp-deletion and an adenine insertion (g.5247_6841del1595insA). This large deletion of WAS resulted in partial loss of exon 10 and intron 11, and a complete loss of intron 10 and exon 11.
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Éxons , Mutação INDEL , Proteína da Síndrome de Wiskott-Aldrich/genética , Síndrome de Wiskott-Aldrich/diagnóstico , Síndrome de Wiskott-Aldrich/genética , Sequência de Bases , Humanos , Lactente , Íntrons , Leucócitos Mononucleares/metabolismo , Leucócitos Mononucleares/patologia , Masculino , Dados de Sequência Molecular , Reação em Cadeia da Polimerase , Análise de Sequência de DNA , Síndrome de Wiskott-Aldrich/metabolismo , Síndrome de Wiskott-Aldrich/patologia , Proteína da Síndrome de Wiskott-Aldrich/deficiênciaRESUMO
BACKGROUND: Patients with severe hemophilia A and factor VIII inhibitors are at increased risk for serious bleeding complications and progression to end-stage joint disease. Effective strategies to prevent bleeding in such patients have not yet been established. METHODS: We enrolled patients with hemophilia A who were older than 2 years of age, had high-titer inhibitors, and used concentrates known as bypassing agents for bleeding in a prospective, randomized, crossover study comparing 6 months of anti-inhibitor coagulant complex (AICC), infused prophylactically at a target dose of 85 U per kilogram of body weight (±15%) on 3 nonconsecutive days per week, with 6 months of on-demand therapy (AICC at a target dose of 85 U per kilogram [±15%] used for bleeding episodes). The two treatment periods were separated by a 3-month washout period, during which patients received on-demand therapy for bleeding. The primary outcome was the number of bleeding episodes during each 6-month treatment period. RESULTS: Thirty-four patients underwent randomization; 26 patients completed both treatment periods and could be evaluated per protocol for the efficacy analysis. As compared with on-demand therapy, prophylaxis was associated with a 62% reduction in all bleeding episodes (P<0.001), a 61% reduction in hemarthroses (P<0.001), and a 72% reduction in target-joint bleeding (≥3 hemarthroses in a single joint during a 6-month treatment period) (P<0.001). Thirty-three randomly assigned patients received at least one infusion of the study drug and were evaluated for safety. One patient had an allergic reaction to the study drug. CONCLUSIONS: AICC prophylaxis at the dosage evaluated significantly and safely decreased the frequency of joint and other bleeding events in patients with severe hemophilia A and factor VIII inhibitors. (Funded by Baxter BioScience; Pro-FEIBA ClinicalTrials.gov number, NCT00221195.).
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Fatores de Coagulação Sanguínea/administração & dosagem , Hemofilia A/tratamento farmacológico , Hemorragia/prevenção & controle , Adolescente , Adulto , Idoso , Fatores de Coagulação Sanguínea/efeitos adversos , Criança , Pré-Escolar , Estudos Cross-Over , Esquema de Medicação , Fator VIII/administração & dosagem , Fator VIII/antagonistas & inibidores , Feminino , Hemofilia A/complicações , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Estatísticas não Paramétricas , Adulto JovemRESUMO
A coincidental occurrence of severe haemophilia A and Turner syndrome in a female person is extremely rare (less than 10 cases published). In such challenging cases, a multidisciplinary approach based on medicine of precision with full access to genetic and bio-molecular exploration is indispensable. The article presents an eight-year-old girl, with a family history of haemophilia, without significant disease signs (only post-dental extraction bleeding and a shorter stature). Discordantly, however, the investigations revealed a challenging condition: a genotype of 46,X,i(Xq), with an Isochromosome Xq responsible for the Turner syndrome and simultaneously, for the detrimental transformation, interfering with X chromosome inactivation, of an obligate hemophilia carrier into a severe hemophilia case-two distinct and provocative diseases.
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(1) Background: Mild and moderate hemophilia, synonymous with non-severe hemophilia (NSH), are of constant interest for the clinicians. Bleeding occurs usually after trauma, injury, surgery, or inhibitor development, sometimes leading to a shift of the clinical phenotype from mild to severe, even with life-threatening and unexpected outcomes. (2) Methods: We performed a retrospective observational study conducted on 112 persons with congenital coagulopathies, 26 of them with NSH, admitted to our clinic in the period 2000 to 2022. For the diagnosis, we used laboratory studies (complete blood cell count, coagulation assays, biochemistry, thromboelastography, genetic tests) and imaging investigations (X-ray, ultrasound, CT, MRI). We selected four cases confronted with pitfalls of diagnosis and evolution in order to illustrate the sometimes provocative field of NSH. (3) Results: Confronted with challenging cases with under-, missed or delayed diagnosis and severe consequences, we aimed at presenting four such selected cases with mild or moderate hemophilia, real pitfalls in our clinical activity. (4) Conclusions: In the field of NSH, if not timely recognized, tending sometimes to remain ignored by caregivers and patients themselves, we can be confronted with challenging diagnostic situations and life-threatening bleeds.
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Subcutaneous IgG treatment for primary immunodeficiencies (PI) is particularly well suited for children because it does not require venous access and is mostly free of systemic adverse events (AEs). In a prospective, open-label, multicenter, single-arm, Phase III study, 18 children and five adolescents with PI were switched from previous intravenous (IVIG) or subcutaneous (SCIG) IgG treatment to receive dose-equivalent, weekly subcutaneous infusions of Hizentra(®) for 40 weeks. Mean IgG trough levels were maintained in patients previously on SCIG, or increased in those previously on IVIG, regardless of age. No serious bacterial infections were reported during the efficacy period of the study. The rates of non-serious infections were 4.77 (children) and 5.18 (adolescents) infections per patient per year. Related AEs were observed in seven children (38.9%) and two adolescents (40%). Three serious AEs and two AEs leading to discontinuation (all unrelated) were reported in children. Hizentra(®) is an effective and well-tolerated treatment for pediatric patients.
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Imunoglobulina G/administração & dosagem , Imunoglobulinas Intravenosas/administração & dosagem , Síndromes de Imunodeficiência/terapia , Adolescente , Criança , Pré-Escolar , Substituição de Medicamentos , Feminino , Humanos , Imunoglobulina G/efeitos adversos , Imunoglobulinas Intravenosas/efeitos adversos , Síndromes de Imunodeficiência/imunologia , Síndromes de Imunodeficiência/patologia , Síndromes de Imunodeficiência/fisiopatologia , Injeções Subcutâneas , Masculino , Estudos Prospectivos , Resultado do Tratamento , Suspensão de TratamentoRESUMO
Neutropenia is commonly diagnosed in pediatric clinics. Due to the special vulnerability of neutropenic patients, the assessment of the etiopathogenic background of neutropenia is mandatory. In this retrospective cross-sectional cohort study, we aimed to establish the status of primary autoimmune neutropenia (AIN) from the point of view of its clinical and biological features and its outcome in a cohort of pediatric patients. We recorded all of the 3,488 cases consecutively admitted to our hospital for different diagnoses but presenting neutropenia, during a period of 3 years (January 2016 to December 2018). We had to exclude 224 patients from the analysis due to incomplete data. Our study focused on patients with AIN or chronic benign neutropenia of infancy and childhood. In these patients, a granulocyte antibody screening by granulocyte immunofluorescence test (GIFT) and the granulocyte agglutination test (GAT) were performed. Regarding their pathogenic background, 0.1% of the patients presenting neutropenia were congenital forms, the rest being acquired forms. Primary AIN was encountered in 18 cases, representing approximately 0.5%. The median age at onset for primary AIN was 7.5 months. Male/female ratio in AIN was 1.94. In 72% of the patients with AIN, neutropenia was severe during the course of disease. In 3 patients, both GIFT and GAT were positive and in 8 patients, only GIFT was positive. For the remaining 7 patients (39%), both GIFT and GAT revealed negative results. 50% of the patients needed hospitalization, but only 3 patients presented severe infections. On-demand G-CSF was administered in 22% of the patients. Our study provides insight with regard to neutropenia, showing the high frequency and etiological diversity in childhood. Primary AIN is usually diagnosed by exclusion of the other causes of neutropenia. GIFT and GAT are useful, but rarely available diagnostic tools for the confirmation of primary AIN.
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Hemophilia type A (HA) is the most common type of blood coagulation disorder. While the vast majority of cases are inherited and caused by mutations in the F8 gene, recent data raises new questions regarding the non-heritability of this disease, as well as how other molecular mechanisms might lead to the development of HA or increase the severity of the disease. Some data suggest that miRNAs may affect the severity of HA, but for some patients, miRNA-based interference might cause HA, in the absence of an F8 mutation. A mechanism in HA installation that is also worth investigating and which could be identified in the future is the epigenetic silencing of the F8 gene that might be only temporarily. Acquired HA is increasingly reported and as more cases are identified, the description of the disease might become challenging, as cases without FVIII autoantibodies might be identified.
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The management of patients with hemophilia has evolved significantly since the first treatment attempts were made in the late 1930s. Since then, each new step in the treatment of patients with hemophilia has brought important advancements, as well as its unique set of challenges. Today, a patient-centered, individualized comprehensive approach is the new paradigm, moving away from the traditional "one size-fits-all" approach, to provide the best possible care for each patient with a bleeding disorder. As part of this complex task, mobile health applications might have the capacity to play an important role in reaching that goal. However, the use of new electronic technologies as part of a comprehensive treatment approach for patients with hemophilia simultaneously presents a new set of challenges that needs consideration. In the first section, currently available treatment of hemophilia patients will be revised, while in the second part the role of IT software in the treatment monitoring of hemophilia patients will be discussed.
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Hemophilia A (HA) and hemophilia B (HB) are rare disorders, being caused by the total lack or under-expression of two factors from the coagulation cascade coded by genes of the X chromosome. Thus, in hemophilic patients, the blood does not clot properly. This results in spontaneous bleeding episodes after an injury or surgical intervention. A patient-centered regimen is considered optimal. Age, pharmacokinetics, bleeding phenotype, joint status, adherence, physical activity, personal goals are all factors that should be considered when individualizing therapy. In the past 10 years, many innovations in the diagnostic and treatment options were presented as being either approved or in development, thus helping clinicians to improve the standard-of-care for patients with hemophilia. Recombinant factors still remain the standard of care in hemophilia, however they pose a challenge to treatment adherence because they have short half-life, which where the extended half-life (EHL) factors come with the solution, increasing the half-life to 96 hours. Gene therapies have a promising future with proven beneficial effects in clinical trials. We present and critically analyze in the current manuscript the pros and cons of all the major discoveries in the diagnosis and treatment of HA and HB, as well as identify key areas of hemophilia research where improvements are needed.
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The benefit of reporting unsolicited findings in Next Generation Sequencing (NGS) related to cancer genes in children may have implications for family members, nevertheless, could also cause distress. We aimed to retrospectively investigate germline variants in 94 genes implicated in oncogenesis, in patients referred to NGS testing for various rare genetic diseases and reevaluate the utility of reporting different classes of pathogenicity. We used in silico prediction software to classify variants and conducted manual review to examine unsolicited findings frequencies in 145 children with rare diseases, that underwent sequencing - using a 4813 gene panel. The anonymized reanalysis revealed 18250 variants, of which 126 were considered after filtering. Six pathogenic variants (in BRCA1,BMPR1A,FANCA,FANCC,NBN genes) with cancer related phenotype and three unsolicited variants (in BRCA2,PALB2,RAD50 genes) were reported to patients. Additionally, three unsolicited variants in ATR, BLM (in two individuals), and FANCB genes presented potential cancer susceptibility, were not reported to patients. In retrospect, 4.8% (7/145) of individuals in our cohort had unsolicited NGS findings related to cancer. More efforts are needed to create an updatable consensus in reporting variants in cancer predisposing genes, especially for children. Consent process is crucial to inform of both value and risk of additional genetic information.
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Sequenciamento de Nucleotídeos em Larga Escala/métodos , Mutação , Proteínas de Neoplasias/genética , Neoplasias/genética , Neoplasias/patologia , Criança , Feminino , Humanos , Masculino , Prognóstico , Estudos RetrospectivosRESUMO
This phase 3, prospective, open-label, multicenter, continuation study (NCT01286779) investigated the use of a recombinant factor IX (FIX), nonacog gamma (BAX 326, RIXUBIS®) in patients with severe or moderately severe hemophilia B. The study population included 85 patients transitioning from a phase 1/3 pivotal study (NCT01174446), a pediatric study (NCT01488994), and 30 newly recruited patients, naïve to nonacog gamma. Patients received nonacog gamma as prophylaxis treatment (standard, modified or PK-tailored) or on-demand, as determined by the investigator. Treatment was assessed for safety, immunogenicity, hemostatic efficacy and consumption. In this study, after ≥100 exposure days, nonacog gamma resulted in no treatment-related serious adverse events, and no patients developed inhibitory antibodies to FIX. Nonacog gamma was efficacious at controlling bleeding episodes, with an 89.1% overall hemostatic efficacy rating of excellent or good, and 56% of bleeds resolved with one infusion. The annualized bleeding rate was considerably lower during prophylactic treatment (median ABR of 1.3 in 108 patients) than during on-demand treatment (median ABR of 16.5 in 13 patients). These results show that in previously treated patients and nonacog gamma-naïve patients, long-term use of nonacog gamma had acceptable safety and tolerability, and was efficacious as a prophylactic treatment for the management of bleeding episodes.NCT01286779, EudraCT: 2010-022726-33.
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Fator IX/uso terapêutico , Hemofilia B/tratamento farmacológico , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Fator IX/farmacologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Adulto JovemRESUMO
PURPOSE: Down syndrome (DS) or trisomy 21, brings together some unique aspects from clinical pediatrics. Among the hematological disorders present in DS, by far the most important is the predisposition for developing acute leukemia. Acute myeloid leukemia (AML) of DS has a preleukemic state with the onset in the neonatal period, rarely symptomatic but with the presence of blasts in peripheral blood smear and apparently a spontaneous remission. The unique tumor profile of DS underlines the importance of chromosome 21 in hematopoiesis and it can help understanding leukemogenesis in general. The purpose of this study was to present the very rare cases with DS and transient leukemia and/or acute leukemia that were found in a nationwide survey of Romania, in three centers of pediatric hematology and oncology. METHODS: A nationwide analysis of the very rare cases of transient leukemia of DS are described, involving the three major pediatric hematology centers of Romania: Cluj Napoca, Bucharest and Timisoara. Data analysis was performed using R 3.5.3. Categorical variables were presented as absolute value (percent). Contingency tables were analyzed using the Fisher test. Normality of the distribution was assessed using the Shapiro test and histogram visualization, but also took into consideration the sample size. Non-normally distributed variables were presented as median (quartile 1, quartile 3). Wilcoxon test was used to determine the differences between two non-normally distributed groups. A p value under 0.05 was considered statistically significant. RESULTS: It appears that the more aggressive entity at presentation is represented by CD45 positive leukemia, which is the more frequent of the myeloid lineage and has lower counts at diagnosis. CONCLUSION: We address this manuscript to pediatricians and neonatologists in order to emphasize the importance of diagnosing hematological disorders in children with DS, especially neonates, even if they are asymptomatic.
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Síndrome de Down/complicações , Leucemia Mieloide Aguda/etiologia , Pré-Escolar , Estudos de Coortes , Feminino , Humanos , Leucemia Mieloide Aguda/fisiopatologia , MasculinoRESUMO
OBJECTIVE: In countries with low factor concentrate consumption, disabling joint disease remains the major morbidity in patients with haemophilia. The objective of the present analysis is to express the trend and profile of invasive orthopaedic interventions in our country with low usage of factor replacement, lacking the prophylaxis program until recent years. PATIENTS AND METHODS: This retrospective descriptive study was conducted in our university centre in Timisoara with long-lasting experience in haemophilia care, which succeeded in developing an exceptionally valuable genuine comprehensive inter-institutional cooperation. This study refers to 115 invasive interventions performed on 97 patients: 83 with haemophilia A, 10 with haemophilia B and 4 with von Willebrand disease in the period of 2001 to 2017; 17 of them had inhibitors, 5 developing inhibitors after the intervention. RESULTS AND DISCUSSION: The cohort of patients consisted mostly of young adults, aged between 7 and 49 years. The vast majority of them, 91.3% of the patients, had the burden of severe chronic arthropathy. This was the reason for 95 interventions, with programmed solution. In 20 cases the cause of invasive interventions was emergency. Knee and hip replacement represented 28% of the major interventions. The complications we encountered were excessive bleeding (12.2%), infection (13%) and inhibitor development (4.3%). CONCLUSION: Surgery is a demanding intervention in patients with haemophilia, which unfortunately cannot be ignored in our country. Hopefully, the improved availability and accessibility to replacement therapy will eliminate the necessity of these interventions, optimizing the outcomes for the next generations.
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Hemofilia A/terapia , Ortopedia/tendências , Humanos , Masculino , Ortopedia/métodos , Estudos Retrospectivos , RomêniaRESUMO
BACKGROUND: Haemophilia is a congenital disorder of coagulation with high economic burden due to its requirement for an expensive, lifelong replacement therapy, with additional costs for the frequent complications and for the severe handicapping consequences. The objective of this cross-sectional study aimed at giving an insight into the health condition of young haemophiliacs in the absence of a regular prophylactic therapy. METHODS: It was conducted on a heterogeneous group of 37 children and adolescents (4-24 years of age), with similar on demand therapeutic regimen, coming from the whole country, focusing on the joint status by using the Haemophila Joint Health Score (HJHS) system and on quality of life (QoL) by using the EQ-5D-3L-Y questionnaire. RESULTS: The results revealed an impressive situation: 70.3 % with chronic arthropathy, 19 % with target joints, 69 % with multiple joint involvement, mainly elbow (41 %) and knee (34 %), joint damage starting in the age group 6-12 years (18.18 % arthropathy vs. 96 % in the age group above 12 years). Joint score (6.67 ± 7.92), gait score (0.75 ± 1.14) and HJHS (7.43 ± 8.78) were highly correlated (r = 0.7, p = 0.001) with the annualised bleeding rate ABR (16.2 ± 12.1). They impacted the QoL in all domains, also expressed by a VAS of 68.39 ± 21.6. CONCLUSION: We concluded that in the situation of an international consensus that prophylactic replacement can prevent cost-effectively and cost-efficiently the deleterious joint damages, our study is supporting the introduction even of secondary and tertiary prophylaxis in young patients in our country.
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Países em Desenvolvimento , Hemartrose/epidemiologia , Hemofilia A/epidemiologia , Qualidade de Vida , Adolescente , Criança , Pré-Escolar , Doença Crônica , Correlação de Dados , Efeitos Psicossociais da Doença , Estudos Transversais , Feminino , Marcha , Hemartrose/diagnóstico , Hemartrose/psicologia , Hemartrose/terapia , Hemofilia A/diagnóstico , Hemofilia A/psicologia , Hemofilia A/terapia , Humanos , Masculino , Qualidade de Vida/psicologia , Romênia , Inquéritos e Questionários , Adulto JovemRESUMO
Primary immunodeficiency disorders are a recognized public health problem worldwide. The prototype of these conditions is X-linked agammaglobulinemia (XLA) or Bruton's disease. XLA is caused by mutations in Bruton's tyrosine kinase gene (BTK), preventing B cell development and resulting in the almost total absence of serum immunoglobulins. The genetic profile and prevalence of XLA have not previously been studied in Eastern and Central European (ECE) countries. We studied the genetic and demographic features of XLA in Belarus, Croatia Hungary, Poland, Republic of Macedonia, Romania, Russia, Serbia, Slovenia, and Ukraine. We collected clinical, immunological, and genetic information for 122 patients from 109 families. The BTK gene was sequenced from the genomic DNA of patients with a high susceptibility to infection, almost no CD19(+) peripheral blood B cells, and low or undetectable levels of serum immunoglobulins M, G, and A, compatible with a clinical and immunological diagnosis of XLA. BTK sequence analysis revealed 98 different mutations, 46 of which are reported for the first time here. The mutations included single nucleotide changes in the coding exons (35 missense and 17 nonsense), 23 splicing defects, 13 small deletions, 7 large deletions, and 3 insertions. The mutations were scattered throughout the BTK gene and most frequently concerned the SH1 domain; no missense mutation was detected in the SH3 domain. The prevalence of XLA in ECE countries (total population 145,530,870) was found to be 1 per 1,399,000 individuals. This report provides the first comprehensive overview of the molecular genetic and demographic features of XLA in Eastern and Central Europe.
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Agamaglobulinemia/genética , Doenças Genéticas Ligadas ao Cromossomo X/genética , População Branca/genética , Tirosina Quinase da Agamaglobulinemia , Agamaglobulinemia/epidemiologia , Estudos de Coortes , Demografia , Europa (Continente)/epidemiologia , Doenças Genéticas Ligadas ao Cromossomo X/epidemiologia , Humanos , Mutação/genética , Prevalência , Estrutura Terciária de Proteína , Proteínas Tirosina Quinases/química , Proteínas Tirosina Quinases/genéticaRESUMO
INTRODUCTION: Patients having severe hemophilia (levels of deficient factor below 1%) frequently suffer from disabling chronic arthropathy. An adequate substitution treatment using the coagulation factor VIII or IX concentrates renders an elective surgery feasible. OBJECTIVE: The objective of the study was to check the results of different surgical procedures in the treatment of hemophilic arthropathies, and to propose the best protocol of their treatment. METHODS: This is a retrospective study on 26 hemophilic patients operated in the Orthopedics and Trauma Clinic II, Timisoara, from 2002 to 2005. Elective surgical procedures were mainly performed in the knee (21 arthroscopic procedures, 1 open arthrodesis), elbow (2 open synovectomies, 2 radial head excisions), ankle (1 arthroscopic synovectomy and debridement) and thigh (1 giant pseudo tumor excision, other minor procedures). The results after operations on moderate and severe chronic knee, elbow and ankle arthropathy were evaluated, with approximately 24-month follow-up period. RESULTS: Arthroscopic procedures (22) yielded good and satisfactory results with significant improvement according to the evaluation criteria recommended by the World Hemophilia Federation (Gilbert clinical score, Pettersson radiological score, Nuss MRI score). CONCLUSION: Mini-invasive elective surgery in moderate to severe chronic arthropathy produces good results when performed in a specialized centre and with multi-disciplinary approach.