RESUMO
In May 2003, Madrid established the universal newborn screening (NBS) for sickle cell disease (SCD). However, there are no studies resembling the evolution of a SCD neonate cohort followed according to national guidelines in Spain. The aim of this study is to describe the morbimortality and the stroke prevention programme in patients diagnosed by SCD NBS in Madrid. This is a multicentre, observational, prospective cohort study between 2003 and 2018; 187 patients diagnosed with SCD were included (151 HbSS, 6 HbSß0, 27 HbSC, 3 HbSß +), and median follow-up was 5.2 years (0.03-14.9). There were 5 deaths: 2 related to SCD in patients with severe genotype (HbSS/HbSß0). Overall survival reached 95% and SCD-related survival 96.8%. The most frequent events were fever without focus, vaso-occlusive crises and acute chest syndromes. Eight strokes occurred in 5 patients which led to a 90.7% stroke-free survival in severe genotype patients (first stroke rate, 0.54 per 100 patient-years). Transcranial Doppler (TCD) was performed in 95% of eligible patients; 75% of children with pathological TCD remained stroke-free. Regarding HbSS/HbSß0 patients, 50.1% received hydroxyurea and 9.5% haematopoietic stem cell transplantation. This study reflects the evolution of Madrid SCD cohort and provides morbimortality data similar to other developed countries.
Assuntos
Síndrome Torácica Aguda , Anemia Falciforme , Acidente Vascular Cerebral , Criança , Humanos , Recém-Nascido , Anemia Falciforme/terapia , Anemia Falciforme/tratamento farmacológico , Hemoglobina Falciforme , Hidroxiureia/uso terapêutico , Estudos Prospectivos , Acidente Vascular Cerebral/epidemiologia , Acidente Vascular Cerebral/etiologia , Acidente Vascular Cerebral/prevenção & controle , Lactente , Pré-Escolar , AdolescenteRESUMO
INTRODUCTION: The increase in the number of patients with hemoglobinopathies in Europe in recent decades highlights the need for more detailed epidemiological information in Spain. To fulfil this need, the Spanish Society of Pediatric Hematology and Oncology (SEHOP) sponsored the creation of a national registry of hemoglobinopathies known as REHem-AR (Spanish Registry of Hemoglobinopathies and Rare Anemias). Data from the transfusion-dependent (TDT) and non-transfusion-dependent (NTDT) ß-thalassemia cohorts are described and analyzed. METHODS: We performed an observational, multicenter, and ambispective study, which included patients of any age with TDT and NTDT, registered up to December 31, 2021. RESULTS: Among the 1741 patients included, 168 cases of thalassemia were identified (103 TDT and 65 NTDT-patients). Survival at 18 years was 93% for TDT and 100% for NTDT. Regarding management, 80 patients with TDT (77.7%) and 23 patients with NTDT (35.4%) started chelation treatment during follow-up, with deferasirox being the most widely used. A total of 76 patients within the TDT cohort presented at least 1 complication (73.8%), the most frequent being hemosiderosis and osteopenia-osteoporosis. Comparison of both cohorts revealed significant differences in the diagnosis of hepatic hemosiderosis (p = 0.00024), although these were not observed in the case of cardiac iron overload (p = 0.27). DISCUSSION: Our registry enabled us to describe the management of ß thalassemia in Spain and to analyze the morbidity and mortality of the cohorts of patients with TDT and NTDT. Complications related to iron overload in TDT and NTDT account for most of the morbidity and mortality of the disease, which is associated with a considerable social, psychological, and economic impact, although cardiac, osteopathy and endocrinological complications requiring more attention. The convenience and simplicity of online registries make it possible to homogenize variables and periodically update data, thus providing valuable information on these diseases.
Assuntos
Hemossiderose , Sobrecarga de Ferro , Talassemia beta , Humanos , Talassemia beta/complicações , Talassemia beta/epidemiologia , Talassemia beta/terapia , Transfusão de Sangue , Demografia , Sobrecarga de Ferro/etiologiaRESUMO
REHem-AR was created in 2013. The progressive implementation of neonatal screening for haemoglobinopathies in Spanish autonomous communities where the registry had not been implemented, as well as the addition of new centres during this period, has considerably increased the sample of patients covered. In this study, we update our previous publication in this area, after a follow-up of more than 5 years. An observational, descriptive, multicentre and ambispective study of adult and paediatric patients with haemoglobinopathies and rare anaemias registered in REHem was performed. The data are from a cross-sectional analysis performed on 1 June, 2023. The study population comprised 1,756 patients, of whom 1,317 had SCD, 214 had thalassaemia and 224 were diagnosed with another condition. Slightly more than one third of SCD patients (37%) were diagnosed based on neonatal bloodspot screening, and the mean age at diagnosis was 2.5 years; 71% of thalassaemia patients were diagnosed based on the presence of anaemia. Vaso-occlusive crisis and acute chest syndrome continue to be the most frequent complications in SCD. HSCT was performed in 83 patients with SCD and in 50 patients with thalassaemia. Since the previous publication, REHem-AR has grown in size by more than 500 cases. SCD and TM are less frequent in Spain than in other European countries, although the data show that rare anaemias are frequent within rare diseases. REHem-AR constitutes an important structure for following the natural history of rare anaemias and enables us to calculate investment needs for current and future treatments.
Assuntos
Hemoglobinopatias , Sistema de Registros , Humanos , Espanha/epidemiologia , Masculino , Feminino , Criança , Hemoglobinopatias/epidemiologia , Hemoglobinopatias/diagnóstico , Pré-Escolar , Adulto , Recém-Nascido , Estudos Transversais , Adolescente , Lactente , Doenças Raras/epidemiologia , Triagem Neonatal , Pessoa de Meia-Idade , Adulto Jovem , Seguimentos , Talassemia/epidemiologia , Talassemia/terapiaRESUMO
OBJECTIVES: The prevalence of sickle cell disease (SCD) in Spain is markedly inferior compared with other European and Mediterranean countries. However, the diagnosis of new patients with SCD is expected to increase. In this multicenter retrospective study, we analyze the hematopoietic stem cell transplantation (HSCT) results obtained in Spain. METHODS: Forty-five patients who underwent a matched sibling donor (MSD) HSCT between 1999 and 2018 were included. Primary endpoint was event-free survival (EFS), and secondary endpoints included acute and chronic graft-versus-host disease (GvHD) and overall survival (OS). RESULTS: Bone marrow was the most frequent stem cell source (93.3%). Most patients received a conditioning regimen based on busulfan and cyclophosphamide (69%). Cumulative incidence of grade III-IV acute GvHD and chronic GvHD was 6.8% (95% CI: 2.3%-20.1%) and 5.4% (95% CI: 1.38%-19.9%), respectively. EFS and overall survival (OS) at 3 years post-HSCT were 89.4% (95% CI: 73.9%-95.9%) and 92.1% (95% CI: 77.2%-97.4%), respectively. All patients aged ≤ 5 presented 100% EFS and OS. CONCLUSIONS: An early referral to HSCT centers should be proposed early in life, before severe complications occur. MSD HSCT should be considered a curative option for all patients aged ≤ 5 years and for older pediatric patients who present complications derived from the disease.
Assuntos
Anemia Falciforme/terapia , Transplante de Células-Tronco Hematopoéticas , Irmãos , Anemia Falciforme/epidemiologia , Criança , Feminino , Doença Enxerto-Hospedeiro/diagnóstico , Doença Enxerto-Hospedeiro/epidemiologia , Doença Enxerto-Hospedeiro/etiologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos , Incidência , Masculino , Estudos Retrospectivos , Índice de Gravidade de Doença , Espanha , Condicionamento Pré-Transplante , Transplante HomólogoRESUMO
Inhibition of platelet activation may reduce vaso-occlusion rates in patients with sickle cell disease (SCD). In the HESTIA4 (NCT03492931) study, 21 children with SCD received a single oral dose of the antiplatelet agent ticagrelor (0.1 mg/kg <6 months; 0.2 mg/kg ≥6 to <24 months). All patients had measurable ticagrelor plasma concentrations. Ticagrelor and active metabolite (AR-C124910XX) exposure were comparable across all groups (<6 months, ≥6 to <12 months and ≥12 to <24 months). Ticagrelor was well tolerated. Palatability was generally acceptable. These data will be used to enable dose selection for further investigations of ticagrelor efficacy and safety in children with SCD.
Assuntos
Anemia Falciforme/tratamento farmacológico , Inibidores da Agregação Plaquetária/efeitos adversos , Inibidores da Agregação Plaquetária/farmacocinética , Ticagrelor/efeitos adversos , Ticagrelor/farmacocinética , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Agregação Plaquetária/efeitos dos fármacosRESUMO
Pediatric patients with sickle cell disease and thalassemia major present clinical characteristics that could lead to a higher incidence of central venous access devices-associated complications (CVAD-C). With the objective of analyzing the safety of the use of CVAD in these patients, a retrospective review including all pediatric patients with these pathologies who required the implantation of a CVAD between 2004 and 2019 was performed. In all, 54 patients with 100 CVAD (65 totally implantable venous access port with subcutaneous reservoir, 35 single-lumen or double-lumen partially tunneled catheter) were included. During 60,410 days at risk of suffering a CVAD-C, 55 complications (complication rate [CR]/1000 catheter-days at risk=0.91) were reported in 46 CVAD: 19 mechanicals (CR=0.32), 32 infectious (CR=0.53), and 4 thrombotic complications (CR=0.066). Incidence of mechanical and infectious complications was significantly higher in double-lumen partially tunneled catheter than in totally implantable venous access port with subcutaneous reservoir (P<0.001). Lower age at insertion was related with a higher incidence of any complication (odds ratio=0.88/y, P=0.02). Patients who required a stem cell transplantation (31 patients and 65 CVAD) had no significant higher incidences of CVAD-C. In conclusion, our study supports the safety of using CVAD in these patients, with a low incidence of infectious, thrombotic, and mechanical complications.
Assuntos
Anemia Falciforme/complicações , Infecções Relacionadas a Cateter/etiologia , Cateteres Venosos Centrais/efeitos adversos , Trombose/etiologia , Talassemia beta/complicações , Adolescente , Cateterismo Venoso Central/efeitos adversos , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Estudos RetrospectivosRESUMO
PURPOSE: Patients with Fanconi anaemia (FA), a rare DNA repair genetic disease, exhibit chromosome fragility, bone marrow failure, malformations and cancer susceptibility. FA molecular diagnosis is challenging since FA is caused by point mutations and large deletions in 22 genes following three heritability patterns. To optimise FA patients' characterisation, we developed a simplified but effective methodology based on whole exome sequencing (WES) and functional studies. METHODS: 68 patients with FA were analysed by commercial WES services. Copy number variations were evaluated by sequencing data analysis with RStudio. To test FANCA missense variants, wt FANCA cDNA was cloned and variants were introduced by site-directed mutagenesis. Vectors were then tested for their ability to complement DNA repair defects of a FANCA-KO human cell line generated by TALEN technologies. RESULTS: We identified 93.3% of mutated alleles including large deletions. We determined the pathogenicity of three FANCA missense variants and demonstrated that two FANCA variants reported in mutations databases as 'affecting functions' are SNPs. Deep analysis of sequencing data revealed patients' true mutations, highlighting the importance of functional analysis. In one patient, no pathogenic variant could be identified in any of the 22 known FA genes, and in seven patients, only one deleterious variant could be identified (three patients each with FANCA and FANCD2 and one patient with FANCE mutations) CONCLUSION: WES and proper bioinformatics analysis are sufficient to effectively characterise patients with FA regardless of the rarity of their complementation group, type of mutations, mosaic condition and DNA source.
Assuntos
Sequenciamento do Exoma , Proteína do Grupo de Complementação A da Anemia de Fanconi/genética , Anemia de Fanconi/genética , Predisposição Genética para Doença , Linhagem Celular , Variações do Número de Cópias de DNA/genética , Reparo do DNA/genética , Proteínas de Ligação a DNA/genética , Anemia de Fanconi/patologia , Feminino , Técnicas de Inativação de Genes , Humanos , Masculino , Mutação de Sentido Incorreto/genética , Polimorfismo de Nucleotídeo Único/genéticaRESUMO
Sickle cell disease (SCD) describes a set of chronic inherited anemias characterized by hemolysis, episodes of vaso-occlusion, and high infectious risk, with high morbidity and mortality. Newborn screening (NBS) for SCD allows family health education and early start of infectious prophylaxis. In the Community of Madrid, a pilot universal NBS study found that the SCA birth prevalence was 1/5851 in newborns, higher than expected, confirming the need to include early detection in the NBS program. The aim of the present prospective single-center study is to analyze the results of newborn SCD screening in Madrid in terms of epidemiological data and its inclusion in a comprehensive care program during the last 15 years, between 1st of May 2003 and 1st of May 2018. During the study period, 1,048,222 dried bloodspots were analyzed. One hundred ninety-seven patients were diagnosed with possible SCD (HPLC phenotype of FS, FSA, FSC, FSE, FSDPunjab, FSOArab), with 187 patients finally confirmed (birth prevalence 1/5552 newborns, 0.18 per 1000 live births), and 1 out of 213 infants carried Hb S. All of them were seen by a specialist clinician; median age at the first visit consultation was 35 days and median age at the beginning of penicillin treatment was 66 days. The Madrid SCD NBS program achieved high rates of sensitivity and specificity and good quality of care assistance. Establishing a good relationship with the family, a strong education program, and a multidisciplinary team that includes social workers and a psychologist are needed to ensure the success of early intervention.
Assuntos
Anemia Falciforme/diagnóstico , Anemia Falciforme/epidemiologia , Triagem Neonatal , Europa (Continente)/epidemiologia , Feminino , História do Século XXI , Humanos , Recém-Nascido , Masculino , Triagem Neonatal/história , Triagem Neonatal/tendências , Prevalência , Estudos Prospectivos , Espanha/epidemiologiaRESUMO
Sickle Cell Disease (SCD) is an increasing global health problem and presents significant challenges to European health care systems. Newborn screening (NBS) for SCD enables early initiation of preventive measures and has contributed to a reduction in childhood mortality from SCD. Policies and methodologies for NBS vary in different countries, and this might have consequences for the quality of care and clinical outcomes for SCD across Europe. A two-day Pan-European consensus conference was held in Berlin in April 2017 in order to appraise the current status of NBS for SCD and to develop consensus-based statements on indications and methodology for NBS for SCD in Europe. More than 50 SCD experts from 13 European countries participated in the conference. This paper aims to summarise the discussions and present consensus recommendations which can be used to support the development of NBS programmes in European countries where they do not yet exist, and to review existing programmes.
Assuntos
Anemia Falciforme/diagnóstico por imagem , Anemia Falciforme/genética , Anemia Falciforme/epidemiologia , Conferências de Consenso como Assunto , Europa (Continente)/epidemiologia , Feminino , Humanos , Recém-Nascido , Masculino , Triagem Neonatal , Guias de Prática Clínica como AssuntoRESUMO
BACKGROUND: Although highly prevalent throughout the world, the accurate prevalence of hemoglobinopathies in Spain is unknown. PROCEDURE: This study presents data on the national registry of hemoglobinopathies of patients with thalassemia major (TM), thalassemia intermedia (TI), and sickle cell disease (SCD) in Spain created in 2014. Fifty centers reported cases retrospectively. Data were registered from neonatal screening or from the first contact at diagnosis until last follow-up or death. RESULTS: Data of the 715 eligible patients were collected: 615 SCD (497 SS, 64 SC, 54 SBeta phenotypes), 73 thalassemia, 9 CC phenotype, and 18 other variants. Most of the SCD patients were born in Spain (65%), and 51% of these were diagnosed at newborn screening. Median age at the first diagnosis was 0.4 years for thalassemia and 1.0 years for SCD. The estimated incidence was 0.002 thalassemia cases and 0.03 SCD cases/1,000 live births. Median age was 8.9 years (0.2-33.7) for thalassemia and 8.1 years (0.2-32.8) for SCD patients. Stroke was registered in 16 SCD cases. Transplantation was performed in 43 TM and 23 SCD patients at a median age of 5.2 and 7.8 years, respectively. Twenty-one patients died (3 TM, 17 SCD, 1 CC) and 200 were lost to follow-up. Causes of death were related to transplantation in three patients with TM and three patients with SCD. Death did not seem to be associated with SCD in six patients, but nine patients died secondary to disease complications. Overall survival was 95% at 15 years of age. CONCLUSIONS: The registry provides data about the prevalence of hemoglobinopathies in Spain and will permit future cohort studies and the possibility of comparison with other registries.
Assuntos
Hemoglobinopatias/epidemiologia , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Prevalência , Sistema de Registros , Espanha/epidemiologiaRESUMO
BACKGROUND: Structural hemoglobinopathies do not usually have a clinical impact, but they can interfere with the analytical determination of some parameters, such as the glycated hemoglobin in diabetic patients. Thalassemias represent a serious health problem in areas where their incidence is high. The defects in the post-translational modifications produce hyper-unstable hemoglobin that is not detected by most of electrophoretic or chromatographic methods that are available so far. METHODS: We studied seven patients who belong to six unrelated families. The first two families were studied because they had peak abnormal hemoglobin (Hb) during routine analytical assays. The other four families were studied because they had microcytosis and hypochromia with normal HbA2 and HbF without iron deficiency. HbA2 and F quantification and abnormal Hb separation were performed by chromatographic and electrophoretic methods. The molecular characterization was performed using specific sequencing. RESULTS: The Hb Puerta del Sol presents electrophoretic mobility and elution in HPLC that is different from HbA and similar to HbS. The electrophoretic and chromatographic profiles of the four other variants are normal and do not show any anomalies, and their identification was only possible with sequencing. CONCLUSIONS: Some variants, such as Hb Valdecilla, Hb Gran Vía, Hb Macarena and Hb El Retiro, have significant clinical impact when they are associated with other forms of α-thalassemia, which could lead to more serious forms of this group of pathologies as for HbH disease. Therefore, it is important to maintain an adequate program for screening these diseases in countries where the prevalence is high to prevent the occurrence of severe forms.
Assuntos
Hemoglobinopatias/genética , Hemoglobinas/análise , Hemoglobinas/genética , Adulto , Idoso de 80 Anos ou mais , Pré-Escolar , Cromatografia Líquida de Alta Pressão , Testes Hematológicos , Hemoglobinopatias/sangue , Hemoglobinas/química , Humanos , Lactente , Masculino , Pessoa de Meia-IdadeRESUMO
The aim of this study was to describe the characteristics of vaso-occlusive crises (VOC) in children with sickle cell disease and to identify factors associated with greater severity. We performed a prospective observational study from August 2012 to January 2014. The study population comprised patients with sickle cell disease who consulted at the emergency department (ED) for VOC. We recorded demographic variables, history of complications related to the disease, and data on usual treatment. We also assessed pain, analgesia at home, need for admission, length of stay, and analgesia during admission. Analytical parameters were collected. A total of 29 patients with VOC were included. The patient's usual treatment was hydroxyurea (HU) in 69.0%, and 7.0% required chronic transfusions. In the ED, 90.0% had moderate or severe pain, even though 86.0% had received analgesia at home (41.4% minor opioids). Overall, 27 of the 29 patients were admitted, and 56.0% needed major opioids. Higher lactate dehydrogenase (LDH) levels were related to the use of major opioids during admission (p = 0.038). A significant difference was recorded between the median number of days of admission for patients receiving non-steroidal anti-inflammatory drugs and for those requiring intravenous opioids (p = 0.005). Most patients with VOC were admitted to hospital. Lactate dehydrogenase level in the ED was a predictor of severity and was associated with the need for major opioids during admission and more days of admission.
Assuntos
Anemia Falciforme/complicações , Arteriopatias Oclusivas/diagnóstico , L-Lactato Desidrogenase/sangue , Índice de Gravidade de Doença , Adolescente , Analgésicos Opioides/uso terapêutico , Criança , Pré-Escolar , Serviço Hospitalar de Emergência , Feminino , Hospitalização , Humanos , Hidroxiureia/uso terapêutico , Masculino , Dor/tratamento farmacológico , Manejo da Dor/métodos , Estudos ProspectivosAssuntos
Infecções por Coronavirus/complicações , Infecções por Coronavirus/tratamento farmacológico , Neoplasias/complicações , Pneumonia Viral/complicações , Pneumonia Viral/tratamento farmacológico , Adolescente , Antivirais/uso terapêutico , Betacoronavirus , COVID-19 , Criança , Pré-Escolar , Feminino , Hospitalização/estatística & dados numéricos , Humanos , Hidroxicloroquina/uso terapêutico , Lactente , Tempo de Internação , Masculino , Neoplasias/virologia , Pandemias , Prevalência , Fatores de Risco , SARS-CoV-2 , EspanhaRESUMO
Fanconi anemia is characterized by congenital abnormalities, bone marrow failure, and cancer predisposition. To investigate the origin, functional role, and clinical impact of FANCA mutations, we determined a FANCA mutational spectrum with 130 pathogenic alleles. Some of these mutations were further characterized for their distribution in populations, mode of emergence, or functional consequences at cellular and clinical level. The world most frequent FANCA mutation is not the result of a mutational "hot-spot" but results from worldwide dissemination of an ancestral Indo-European mutation. We provide molecular evidence that total absence of FANCA in humans does not reduce embryonic viability, as the observed frequency of mutation carriers in the Gypsy population equals the expected by Hardy-Weinberg equilibrium. We also prove that long distance Alu-Alu recombination can cause Fanconi anemia by originating large interstitial deletions involving FANCA and 2 adjacent genes. Finally, we show that all missense mutations studied lead to an altered FANCA protein that is unable to relocate to the nucleus and activate the FA/BRCA pathway. This may explain the observed lack of correlation between type of FANCA mutation and cellular phenotype or clinical severity in terms of age of onset of hematologic disease or number of malformations.
Assuntos
Proteína do Grupo de Complementação A da Anemia de Fanconi/genética , Proteína do Grupo de Complementação A da Anemia de Fanconi/fisiologia , Anemia de Fanconi/genética , Anemia de Fanconi/patologia , Mutação , Adolescente , Idade de Início , Sequência de Bases , Técnicas de Cultura de Células , Células Cultivadas , Criança , Pré-Escolar , Aberrações Cromossômicas , Hibridização Genômica Comparativa , Análise Mutacional de DNA , Anemia de Fanconi/diagnóstico , Anemia de Fanconi/epidemiologia , Proteína do Grupo de Complementação A da Anemia de Fanconi/metabolismo , Frequência do Gene , Humanos , Lactente , Modelos Biológicos , Dados de Sequência Molecular , Mutação/fisiologia , Fenótipo , Espanha/epidemiologiaRESUMO
We report a rare association of δß-thalassemia (δß-thal) and a hemoglobin (Hb) variant with high oxygen affinity in a Spanish newborn. The proband had no Hb A and showed microcytosis and hypochromia; the peripheral blood smear was compatible with a thalassemia trait. Molecular studies revealed that the proband had a Spanish (δß)(0)-thal (inherited from his father) and also carried a de novo variant (Hb Andrew-Minneapolis) because from the point of hematology, his mother was quite normal. The hemoglobinopathies with high affinity for oxygen constitute an infrequent cause of secondary congenital erythrocytosis. The degree of erythrocytosis and the resulting clinical manifestations are highly variable, depending on the degree of altered oxygen affinity and the presence of thalassemic genes. Thus, when these variants are associated with ß(0)- or δß-thal, as in our case, the proportion of abnormal Hb is â¼100.0%, which may cause polycythemia, hyperviscosity, and iron deficiency. This type of association is very rare and few have been described, especially in children, as they would normally be detected in adults as the increased packed cell volume (PCV) also increases blood viscosity and causes the typical symptoms (cephalalgia, drowsiness, dizziness). The association of a high oxygen affinity Hb and a δß-thal presents a greater degree of erythrocytosis than when this same variant is associated with a ß(0)-thal, mainly because the Hb F percentage is usually greater in the δß-thal, and Hb F normally shows a greater affinity for oxygen and a reduced P(50), although one must always take into account the degree of oxygen affinity of the Hb variant. Familial erythrocytosis and an abnormal electrophoresis finding are indicative of a high affinity Hb. However, the absence of these findings does not reject the possibility of hemoglobinopathies, and in these cases, functional and molecular studies would be justified and should be mandatory for the differential diagnosis of erythrocytosis.
Assuntos
Hemoglobinas Anormais/metabolismo , Policitemia/complicações , Talassemia beta/complicações , Talassemia delta/complicações , Hemoglobinas Anormais/genética , Humanos , Recém-Nascido , Oxigênio/metabolismo , Policitemia/sangue , Policitemia/genética , Talassemia beta/sangue , Talassemia beta/genética , Talassemia delta/sangue , Talassemia delta/genéticaRESUMO
In the 5' untranslated region (5'UTR), which is transcribed but not translated and is involved in posttranscriptional regulation of the gene promoting and stabilizing the mRNA translation, several mutations associated with mild ß-thalassemia (ß-thal) have been described. One of these, the +20 (C>T) mutation, is described in the HbVar database as a mutation responsible for ß(+)-thal. In heterozygote cases, it gives rise to a phenotype of ß-thal minor and ß-thal intermediate (ß-TI) when the mutation is associated with ß(+) IVS-II-745 (C>G). To clarify if this mutation is responsible for ß(+)-thal, we studied nine cases where we found an association of the +20 and IVS-II-745 mutations. All patients were carriers of four α genes. Three patients carried ß-thal major (ß-TM), two were compound heterozygotes for IVS-II-745 and codon 8 (-AA) or codon 39 (C>T), and the third was homozygous for IVS-II-745; all had the +20 mutation in the 5'UTR. The remaining patients showed the mutation IVS-II-745 associated with a replacement of C>T at nucleotide (nt) +20 of the 5'UTR. Contrary to reports in the HbVar database, the +20 mutation should be considered as an innocuous single nt polymorphism associated with the IVS-II-745 mutation in cis.
Assuntos
Regiões 5' não Traduzidas/genética , Íntrons/genética , Mutação Puntual , Globinas beta/genética , Talassemia beta/genética , Adulto , Pré-Escolar , Análise Mutacional de DNA , Saúde da Família , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Linhagem , Polimorfismo de Nucleotídeo Único , Adulto Jovem , Talassemia beta/diagnósticoRESUMO
BACKGROUND: Children with sickle cell disease (SCD) are at a high risk of invasive bacterial infections (IBI). Universal penicillin prophylaxis and vaccination, especially against Streptococcus pneumoniae, have deeply changed its epidemiology. Analysis of IBI in children with SCD in a post-13-valent pneumococcal vaccine era is limited. METHODS: Twenty-eight pediatric hospitals from 5 European countries retrospectively collected IBI episodes in SCD children aged 1 month to 18 years between 2014 and 2019. IBI was defined as a positive bacterial culture or polymerase chain reaction from a normally sterile fluid: blood, cerebrospinal, joint, or pleural fluid and deep surgical specimen. RESULTS: We recorded 169 IBI episodes. Salmonella spp. was the main isolated bacteria (n = 44, 26%), followed by Streptococcus pneumonia (Sp; n = 31, 18%) and Staphylococcus aureus (n = 20, 12%). Salmonella prevailed in osteoarticular infections and in primary bacteremia (45% and 23% of episodes, respectively) and Sp in meningitis and acute chest syndrome (88% and 50%, respectively). All Sp IBI occurred in children ≤10 years old, including 35% in children 5 to 10 years old. Twenty-seven (17%) children had complications of infection and 3 died: 2 because of Sp, and 1 because of Salmonella. The main risk factors for a severe IBI were a previous IBI and pneumococcal infection (17 Sp/51 cases). CONCLUSIONS: In a post-13-valent pneumococcal vaccine era, Salmonella was the leading cause of bacteremia in IBI in children with SCD in Europe. Sp came second, was isolated in children ≤10 years old, and was more likely to cause severe and fatal cases.
RESUMO
Sickle cell disease is a hereditary multiorgan disease that is considered rare in the EU. In 2017, the Rare Diseases Plan was implemented within the EU and 24 European Reference Networks (ERNs) were created, including the ERN on Rare Haematological Diseases (ERN-EuroBloodNet), dedicated to rare haematological diseases. This EU initiative has made it possible to accentuate existing collaborations and create new ones. The project also made it possible to list all the needs of people with rare haematological diseases not yet covered health-care providers in the EU to allow optimised care of individuals with rare pathologies, including sickle cell disease. This Viewpoint is the result of joint work within 12 EU member states (ie, Belgium, Cyprus, Denmark, France, Germany, Greece, Ireland, Italy, Portugal, Spain, Sweden, and The Netherlands), all members of the ERN-EuroBloodNet. We describe the role of the ERN-EuroBloodNet to improve the overall approach to and the management of individuals with sickle cell disease in the EU through specific on the pooling of expertise, knowledge, and best practices; the development of training and education programmes; the strategy for systematic gathering and standardisation of clinical data; and its reuse in clinical research. Epidemiology and research strategies from ongoing implementation of the Rare Anaemia Disorders European Epidemiological Platform is depicted.
Assuntos
Anemia Falciforme , Doenças Raras , Humanos , Países Baixos , Alemanha , Grécia , Itália , Doenças Raras/epidemiologia , Doenças Raras/terapia , Anemia Falciforme/epidemiologia , Anemia Falciforme/terapia , Europa (Continente)/epidemiologiaRESUMO
UNLABELLED: Patients with sickle cell disease have vitamin D deficiency and poor bone health which makes them prone to have an increased risk of fractures and osteoporosis in adulthood. We performed a prospective, cross-sectional study in children diagnosed with sickle cell disease living in Madrid, Spain. The purpose of this study was to evaluate the status of vitamin D of these children. Patients 0-16 years old were enrolled between 2008 and 2011. We studied demographics, calcium metabolism, and bone health, especially by measuring levels of 25-hydroxyvitamin D (25(OH)D), during different seasons of the year, and bone densitometry (beyond 4 years of age). Seventy-eight children were included in the study. Mean age was 4.8 ± 4.3 years, and mean serum 25(OH)D level was 21.50 ± 13.14 ng/ml, with no differences in 25(OH)D levels within different seasons. Fifty-six percent of children had levels of 25(OH) vitamin D of <20 ng/ml, whereas 79 and 18 % of them had levels of <30 and <11 ng/ml, respectively. Secondary hyperparathyroidism was observed in 25 % of children. Densitometry was performed in 33 children, and an abnormal z-score was seen in 15.2 % of them with no correlation with levels of 25(OH)D. CONCLUSIONS: Vitamin D deficiency is highly prevalent in children with sickle cell disease, who are residing in Madrid, Spain, and it is detected at a young age. We propose that early intervention may increase the possibility of an adequate bone density later in life.