Spanish registry of hemoglobinopathies and rare anemias (REHem-AR): demographics, complications, and management of patients with ß-thalassemia.

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.

A Newborn Screening Program for Sickle Cell Disease in Murcia (Spain).

Sickle cell disease (SCD) is an inherited autosomal recessive hemoglobin disorder caused by the presence of hemoglobin S, a mutant abnormal hemoglobin caused by a nucleotide change in codon 6 of the ß-globin chain gene. SCD involves a chronic inflammatory state, exacerbated during vaso-occlusive crises, which leads to end-organ damage that occurs throughout the lifespan. SCD is associated with premature mortality in the first years of life. The process of sickling provokes asplenia in the first years of life with an increased risk of infection by encapsulated germs. These complications can be life-threatening and require early diagnosis and management. The most important interventions recommend an early diagnosis of SCD to ensure that affected newborns receive immediate care to reduce mortality and morbidity. The newborn screening program in the region of Murcia for SCD began in March 2016. We aimed to determine the incidence of sickle cell anemia and other structural hemoglobinopathies in the neonatal population of the region of Murcia, an area of high migratory stress, and to systematically assess the benefit of newborn screening for SCD, leading to earlier treatment, as well as to offer genetic counseling to all carriers. The prevalence of SCD in our region is similar to others in Spain, except for Catalonia and Madrid. The newborns with confirmed diagnoses of SCD received early attention, and all the carriers received genetic counseling.

Evaluation of the outcomes of newly diagnosed patients with high-risk myelodysplastic syndrome according to the initial therapeutical strategies chosen in usual clinical practice.

Myelodysplastic syndromes (MDS) are a heterogeneous group of diseases without a care standard and show variability in treatment outcomes. This Spanish, observational, prospective study ERASME (CEL-SMD-2012-01) assessed the evolution of newly diagnosed and treatment-naïve high-risk MDS patients (according to IPPS-R). 204 patients were included: median age 73.0 years, 54.4% males, 69.6% 0-1 ECOG, and 94.6% with comorbidities. Active treatment was the most common strategy (52.0%) vs. stem cell transplantation (25.5%) and supportive care/watchful-waiting (22.5%). Overall (median) event-free survival was 7.9 months (9.1, 8.3, and 5.3); progression-free survival: 10.1 months (12.9, 12.8, and 4.3); and overall survival: 13.8 months (15.4, 14.9; 8.4), respectively, with significant differences among groups. Adverse events (AEs) of ≥3 grade were reported in 72.6% of patients; serious AEs reported in 60.6%. 33.1% of patients died due to AEs. Three patients developed second primary malignant neoplasms (median: 8.2 months). Our study showed better outcomes in patients receiving active therapy early after diagnosis.

Case Report: α-Spectrin Mutation Associated with αLELY Polymorphism Responsible for Hereditary Pyropoikilocytosis.

Hereditary pyropoikilocytosis (HPP) is characterised by severe hemolytic anemia due to membrane instability. We report the case of a 13-day-old boy with neonatal jaundice and severe hemolytic anemia. A peripheral smear examination showed severe anisopoikylocytosis. DNA sequencing revealed compound double heterozygous for mutant α-spectrin SPTA1 (Arg28His) and homozygous αLELY polymorphism (low expression α-spectrin allele), compatible with diagnosis of HPP.The patient required a blood transfusion initially, but spontaneously improved after two years. Our case illustrates that, despite the presence of the allele αLELY in homozygous, the clinical phenotype is similar to cases with a mutation in SPTA1 associated with αLELY in trans.

Next generation sequencing for diagnosis of hereditary anemia: Experience in a Spanish reference center.

BACKGROUND AND AIMS: Hereditary anemia (HA) encloses a wide group of rare inherited disorders with clinical and hematologic overlaps that complicate diagnosis. MATERIALS AND METHODS: A 48-gene panel was developed to diagnose HA by Next Generation Sequencing (NGS) in a large cohort of 165 patients from 160 unrelated families. RESULTS: Patients were divided in: A) patients who had a suspicion of a specific type of HA (n = 109), and B) patients who had a suspicion of HA but with no clear type (n = 56). Diagnostic performance was 83.5% in group A and a change of the initial diagnosis occurred in 11% of these patients. In group B, 35.7% of patients achieved a genetic diagnosis. NGS identified 6 cases of xerocytosis, 6 of pyruvate kinase (PK) deficiency, 4 of G6PD, and 1 case of phytosterolemia with no initial suspicion of these pathologies, which is clinically relevant since they have specific treatment. Five patients were found to carry variants associated to two different pathologies (4 of them combining a metabolic deficiency and a membrane defect), and 44 new variants were identified in 41 patients. CONCLUSION: The use of NGS is a sensitive technique to diagnose HA and it shows better performance when patients are better characterized.

Are there differences in basal thrombophilias and C-reactive protein between women with or without PCOS?

RESEARCH QUESTION: Polycystic ovary syndrome (PCOS) women have increased cardiovascular risks, although it is unclear whether the haemostatic system and coagulation contribute to that increased risk. DESIGN: Women attending the Gynecology Unit of the 'Virgen de la Arrixaca' University Hospital (Murcia, Spain) for routine gynaecological examinations between September 2014 and May 2016 were assessed for PCOS using the Rotterdam criteria (hyperandrogenism [H], oligo/amenorrhoea [O] and polycystic ovarian morphology [POM]) and were classified into four phenotypic. In total, 126 cases were identified and 159 control women were selected. All women underwent physical and gynaecological examinations, and blood tests between the second and fifth day of the menstrual cycle. Differences in hormonal, basal thrombophilia and metabolic parameters, and C-reactive protein (CRP) between PCOS and controls were analysed. RESULTS: After adjusting by BMI and age, PCOS women had higher LH (P < 0.001), testosterone (P < 0.001), free testosterone (P = 0.01) and anti-Müllerian hormone (P < 0.001) and lower FSH (P = 0.03) compared with controls, whereas sex hormone-binding globulin was no different. Cases showed significantly higher protein S, glucose, insulin and insulin resistance (HOMA-IR) compared with controls (P < 0.05). There were no differences in protein C levels, antithrombin III, prothrombin time, homocysteine, D-dimer, factor V Leyden, prothrombin G20210A polymorphism or CRP. The H+O phenotype showed the poorest results for insulin and HOMA-IR (P = 0.04 and 0.05). CONCLUSIONS: The results suggest that there are no differences in the basal thrombophilias between women with and without PCOS. However, PCOS with H+O shows the poorest metabolic profile.

Transcriptomic rationale for synthetic lethality-targeting ERCC1 and CDKN1A in chronic myelomonocytic leukaemia.

Despite the absence of mutations in the DNA repair machinery in myeloid malignancies, the advent of high-throughput sequencing and discovery of splicing and epigenetics defects in chronic myelomonocytic leukaemia (CMML) prompted us to revisit a pathogenic role for genes involved in DNA damage response. We screened for misregulated DNA repair genes by enhanced RNA-sequencing on bone marrow from a discovery cohort of 27 CMML patients and 9 controls. We validated 4 differentially expressed candidates in CMML CD34+ bone marrow selected cells and in an independent cohort of 74 CMML patients, mutationally contextualized by targeted sequencing, and assessed their transcriptional behavior in 70 myelodysplastic syndrome, 66 acute myeloid leukaemia and 25 chronic myeloid leukaemia cases. We found BAP1 and PARP1 down-regulation to be specific to CMML compared with other related disorders. Chromatin-regulator mutated cases showed decreased BAP1 dosage. We validated a significant over-expression of the double strand break-fidelity genes CDKN1A and ERCC1, independent of promoter methylation and associated with chemorefractoriness. In addition, patients bearing mutations in the splicing component SRSF2 displayed numerous aberrant splicing events in DNA repair genes, with a quantitative predominance in the single strand break pathway. Our results highlight potential targets in this disease, which currently has few therapeutic options.

Pure red cell aplasia in a simultaneous pancreas-kidney transplantation patient: inside the erythroblast.

A case of pure red cell aplasia in a simultaneous kidney-pancreas transplant recipient on immunosuppressive therapy is reported here. The patient presented with anemia unresponsive to erythropoietin treatment. Bone marrow cytomorphology was highly suggestive of parvovirus pure red cell aplasia, which was confirmed with serology and polymerase chain reaction positive for parvovirus B19 DNA in peripheral blood. After the administration of intravenous immunoglobulin the anemia improved with a rising number of the reticulocytes.