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Diamond-Blackfan anaemia (DBA), first described over 80 years ago, is a congenital disorder of erythropoiesis with a predilection for birth defects and cancer. Despite scientific advances, this chronic, debilitating, and life-limiting disorder continues to cause a substantial physical, psychological, and financial toll on patients and their families. The highly complex medical needs of affected patients require specialised expertise and multidisciplinary care. However, gaps remain in effectively bridging scientific discoveries to clinical practice and disseminating the latest knowledge and best practices to providers. Following the publication of the first international consensus in 2008, advances in our understanding of the genetics, natural history, and clinical management of DBA have strongly supported the need for new consensus recommendations. In 2014 in Freiburg, Germany, a panel of 53 experts including clinicians, diagnosticians, and researchers from 27 countries convened. With support from patient advocates, the panel met repeatedly over subsequent years, engaging in ongoing discussions. These meetings led to the development of new consensus recommendations in 2024, replacing the previous guidelines. To account for the diverse phenotypes including presentation without anaemia, the panel agreed to adopt the term DBA syndrome. We propose new simplified diagnostic criteria, describe the genetics of DBA syndrome and its phenocopies, and introduce major changes in therapeutic standards. These changes include lowering the prednisone maintenance dose to maximum 0·3 mg/kg per day, raising the pre-transfusion haemoglobin to 9–10 g/dL independent of age, recommending early aggressive chelation, broadening indications for haematopoietic stem-cell transplantation, and recommending systematic clinical surveillance including early colorectal cancer screening. In summary, the current practice guidelines standardise the diagnostics, treatment, and long-term surveillance of patients with DBA syndrome of all ages worldwide.

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.

In patients with non-transfusion-dependent β-thalassaemia, haemoglobin concentrations lower than 10 g/dL are associated with a higher risk of morbidity, mortality, and impaired quality of life. No drugs are specifically approved for anaemia management in patients with non-transfusion-dependent β-thalassaemia, other than transfusion therapy administered infrequently in accordance with patients’ needs. We assessed the efficacy and safety of luspatercept versus placebo in patients with non-transfusion-dependent β-thalassaemia.

Exagamglogene autotemcel (exa-cel) is a cell therapy designed to reactivate fetal hemoglobin (HbF) via non-viral, ex vivo CRISPR/Cas9 gene-editing at the erythroid enhancer region of BCL11Ain autologous CD34+ hematopoietic stem and progenitor cells (HSPCs). We report results from the first 44 patients (pts) dosed with exa-cel in the CLIMB THAL-111 trial.

•Deletion of the α-globin genes induces a lethal phenotype associated with high levels of red blood cells in circulation.•Transduction with a lentiviral vector expressing the human α-globin gene prevents mice from developing the lethal phenotype.

Dabigatran etexilate is a direct oral anticoagulant with potential to overcome the limitations of standard of care in children with venous thromboembolism. The aims of this clinical trial were to study the appropriateness of a paediatric dabigatran dosing algorithm, and the efficacy and safety of dabigatran dosed according to that algorithm versus standard of care in treating children with venous thromboembolism.

Background: Thalassemia Major (TM) is a hereditary disease caused by defective globin synthesis. Because of the significant increase in life expectancy, these patients suffer from various health conditions, including endocrinopathies and low bone mineral density. Aim: The aim of the present study was to evaluate the fracture incidence regarding the markers of bone metabolism, bone mineral density and treatment of osteoporosis as well as the treatment of comorbidities. Methods: Sixty-four patients with TM (32 men and 32 women) participated in a cross-sectional study design. The patients were recruited from “Aghia Sofia” Children’s Hospital and evaluated using Dual-energy X-ray Absorptiometry (DXA) of the lumbar spine and femoral neck and with markers of bone remodeling including Receptor Activator of Nuclear factor Kappa-β Ligand (RANKL), Osteoprotegerin (OPG), C-Terminal Telopeptide (CTX), and sclerostin. Results: The statistical analysis of markers of bone metabolism in relation to fractures revealed no statistical significance. However, statistical analysis of bone mineral density and markers of bone metabolism in relation to fractures was also not significant. Conclusions: In TM patients, fractures are not related to bone mineral density. Maybe some other conditions are the cause, haemosidirosis, drugs, comorbid conditions.

Transfusion-dependent haemoglobinopathies require lifelong iron chelation therapy with one of the three iron chelators (deferiprone, deferasirox, or deferoxamine). Deferasirox and deferiprone are the only two oral chelators used in adult patients with transfusion-dependent haemoglobinopathies. To our knowledge, there are no randomised clinical trials comparing deferiprone, a less expensive iron chelator, with deferasirox in paediatric patients. We aimed to show the non-inferiority of deferiprone versus deferasirox.

ABSTRACTGiven the complexity of neurocutaneous syndromes, a multidisciplinary approach has been advocated in order to provide optimum care.Subjects and Methods:Retrospective analysis of a cohort of 157 patients during a 3-year period, seen at a newly developed neurocutaneous clinic in a pediatric tertiary care hospital in Athens (Greece); and systematic chart review of the patients diagnosed with neurofibromatosis type 1 during this time period.Results:The most frequent neurocutaneous syndromes were neurofibromatosis type 1 (NF1) in 89 patients and tuberous sclerosis complex in 17. In 20.38% of patients a neurocutaneous syndrome was not confirmed. Approximately 2/3 of the NF1 patients underwent genetic analysis, and for 76.67% of them, a pathogenic mutation on the NF1gene was revealed. Eighty-one patients manifested with generalized NF1 and eight with mosaic NF1. Dermatological manifestations included café-au-lait macules in all patients, followed by axillary and/or inguinal freckling (n = 57), external plexiform neurofibromas (n = 17), and cutaneous and subcutaneous neurofibromas (n = 11). Approximately half of patients had learning disabilities and attention deficit hyperactivity disorder, followed by mental retardation (n = 9), autistic spectrum disorders (n = 4), headaches (n = 3) and seizures (n = 2). Neuroimaging showed characteristic areas of hyperintensity on T2-weighted images in 74.07% of patients and optic pathway glioma in 19.75%. Two patients developed malignant peripheral sheath nerve tumor.Conclusions:Neurocutaneous syndromes are clinically heterogeneous and the surveillance of potential clinical complications is challenging. The availability of genetic diagnosis and novel imaging methods in this group of disorders is likely to further expand their clinical spectrum. Guidelines for assessment and management will need to be modified based on new available data.

Introduction

Introduction:In humans, the CYCSgene encodes Cytochrome c, a protein important for the respiratory electron transport chain in mitochondria and for apoptosis. The clinical features of known CYCSpathogenic variants have been reported to be linked with thrombocytopenia. Herein, we present a novel variant of CYCSgene found in a Greek family with thrombocytopenia and its effects in apoptosis.

Background:Suboptimal anemia management in patients (pts) with non-transfusion-dependent (NTD) β-thalassemia may lead to serious clinical complications. Improvements in hemoglobin (Hb) levels were shown to significantly decrease the risk of developing morbidities (Musallam KM, et al. Ann Hematol2022;101:203-204; Musallam KM, et al. Ann Hematol2021;100:1903-1905). There is a need for therapies that increase Hb levels besides red blood cell transfusions (RBCT), which lead to secondary iron overload. Primary and longer-term data from the BEYOND study showed that luspatercept led to significant increases in Hb levels and had a manageable safety profile in pts with NTD β-thalassemia (Taher AT, et al. Lancet Haematol2022;9:e733-e744; Taher AT, et al. Blood2022;140[suppl 1];8210-8212). Here we report the final data (up to last patient last visit [LPLV] date Nov 28, 2022), of the phase 2, randomized, double-blind, placebo-controlled BEYOND trial (NCT03342404).

Background:Exagamglogene autotemcel (exa-cel) is a non-viral cell therapy designed to reactivate fetal hemoglobin (HbF) via ex vivo CRISPR-Cas9 gene-editing of autologous CD34+ hematopoietic stem and progenitor cells (HSPCs) at the erythroid-specific enhancer region of BCL11A in patients (pts) with transfusion-dependent β-thalassemia (TDT). Here we report that in a pre-specified interim analysis, the pivotal CLIMB THAL-111 trial of exa-cel met primary and key secondary endpoints.

Background: Patients with non-transfusion dependent beta-thalassemia (NTDT) suffer from chronic anemia due to ineffective erythropoiesis. The phase 2, randomized, placebo-controlled BEYOND study demonstrated that luspatercept increased hemoglobin (Hb), reduced transfusion burden, and improved NTDT-related symptoms based on the data with 48 weeks of follow-up (Taher A, et al. Lancet Haematol.2022;9(10):E733).

Introduction: During the last decades, improvements in the treatment of transfusion-dependent thalassemia (TDT) with safer transfusion schemas, improved management of iron overload and of comorbidities, have resulted in significantly increased life expectancy. With increased survival, the pattern of characteristics of death is changing.

Background: Thalassemia major (TM) patients eventually face many new health conditions, including endocrinopathies and low bone mineral density, usually observed in the aging general population. Objective: The aim of the current study was to evaluate the biomarkers of bone remodeling in TM patients and to compare them with both osteoporotic and healthy population, in order to investigate the new therapeutic paths. Methods: Sixty-four patients with TM (32 men and 32 women) participated in the study. The patients were evaluated with dual-energy X-ray absorptiometry (DXA) of the lumbar spine and femoral neck and with markers of bone remodeling including receptor activator of nuclear factor kappa- ligand (RANKL), osteoprotegerin (OPG), C-terminal telopeptide (CTX), and sclerostin. Results were compared with those from 12 postmenopausal women with osteoporosis and 12 women with normal bone mineral density. Results: The statistical analysis of the biochemical markers of bone metabolism revealed overall significant differences between the three groups only for RANKL and OPG/RANKL (p=0.049 and p=0.009). RANKL was higher and OPG/RANKL was lower in TM patients compared to osteoporosis group. Conclusion: Patients with TM do not have a higher probability of suffering from osteoporosis from the general population. However, some markers of osteoclast activity differ between patients with TM and osteoporosis, indicating the possible differences in terms of anti-osteoporotic treatment. The lack of significant differences among the three groups in regards to the levels of CTX and sclerostin may indicate the potential efficacy of the current osteoporotic treatment also for TM patients.

Chuvash polycythemia is an autosomal recessive form of erythrocytosis associated with a homozygous p.Arg200Trp mutation in the von Hippel-Lindau (VHL) gene. Since this discovery, additional VHL mutations have been identified in patients with congenital erythrocytosis, in a homozygous or compound-heterozygous state. VHL is a major tumor suppressor gene, mutations in which were first described in patients presenting with VHL disease, which is characterized by the development of highly vascularized tumors. Here, we identify a new VHL cryptic exon (termed E1′) deep in intron 1 that is naturally expressed in many tissues. More importantly, we identify mutations in E1′ in 7 families with erythrocytosis (1 homozygous case and 6 compound-heterozygous cases with a mutation in E1′ in addition to a mutation in VHL coding sequences) and in 1 large family with typical VHL disease but without any alteration in the other VHL exons. In this study, we show that the mutations induced a dysregulation of VHL splicing with excessive retention of E1′ and were associated with a downregulation of VHL protein expression. In addition, we demonstrate a pathogenic role for synonymous mutations in VHL exon 2 that altered splicing through E2-skipping in 5 families with erythrocytosis or VHL disease. In all the studied cases, the mutations differentially affected splicing, correlating with phenotype severity. This study demonstrates that cryptic exon retention and exon skipping are new VHL alterations and reveals a novel complex splicing regulation of the VHL gene. These findings open new avenues for diagnosis and research regarding the VHL-related hypoxia-signaling pathway.

Chuvash polycythemia is an autosomal recessive form of erythrocytosis associated with a homozygous p.Arg200Trp mutation in the von Hippel-Lindau (VHL) gene. Since this discovery, additional VHLmutations have been identified in patients with congenital erythrocytosis, in a homozygous or compound-heterozygous state. VHLis a major tumor suppressor gene, mutations in which were first described in patients presenting with VHL disease, which is characterized by the development of highly vascularized tumors. Here, we identify a new VHLcryptic exon (termed E1′) deep in intron 1 that is naturally expressed in many tissues. More importantly, we identify mutations in E1′ in 7 families with erythrocytosis (1 homozygous case and 6 compound-heterozygous cases with a mutation in E1′ in addition to a mutation in VHLcoding sequences) and in 1 large family with typical VHL disease but without any alteration in the other VHLexons. In this study, we show that the mutations induced a dysregulation of VHLsplicing with excessive retention of E1′ and were associated with a downregulation of VHL protein expression. In addition, we demonstrate a pathogenic role for synonymous mutations in VHLexon 2 that altered splicing through E2-skipping in 5 families with erythrocytosis or VHL disease. In all the studied cases, the mutations differentially affected splicing, correlating with phenotype severity. This study demonstrates that cryptic exon retention and exon skipping are new VHLalterations and reveals a novel complex splicing regulation of the VHLgene. These findings open new avenues for diagnosis and research regarding the VHL-related hypoxia-signaling pathway.

Despite attempts to improve the definitions of ambiguous lineage leukemia (ALAL) during the last 2 decades, general therapy recommendations are missing. Herein, we report a large cohort of children with ALAL and propose a treatment strategy. A retrospective multinational study (International Berlin-Frankfurt-Münster Study of Leukemias of Ambiguous Lineage [iBFM-AMBI2012]) of 233 cases of pediatric ALAL patients is presented. Survival statistics were used to compare the prognosis of subsets and types of treatment. Five-year event-free survival (EFS) of patients with acute lymphoblastic leukemia (ALL)–type primary therapy (80% ± 4%) was superior to that of children who received acute myeloid leukemia (AML)–type or combined-type treatment (36% ± 7.2% and 50% ± 12%, respectively). When ALL- or AML-specific gene fusions were excluded, 5-year EFS of CD19+ leukemia was 83% ± 5.3% on ALL-type primary treatment compared with 0% ± 0% and 28% ± 14% on AML-type and combined-type primary treatment, respectively. Superiority of ALL-type treatment was documented in single-population mixed phenotype ALAL (using World Health Organization and/or European Group for Immunophenotyping of Leukemia definitions) and bilineal ALAL. Treatment with ALL-type protocols is recommended for the majority of pediatric patients with ALAL, including cases with CD19+ ALAL. AML-type treatment is preferred in a minority of ALAL cases with CD19− and no other lymphoid features. No overall benefit of transplantation was documented, and it could be introduced in some patients with a poor response to treatment. As no clear indicator was found for a change in treatment type, this is to be considered only in cases with ≥5% blasts after remission induction. The results provide a basis for a prospective trial.

Despite attempts to improve the definitions of ambiguous lineage leukemia (ALAL) during the last 2 decades, general therapy recommendations are missing. Herein, we report a large cohort of children with ALAL and propose a treatment strategy. A retrospective multinational study (International Berlin-Frankfurt-Münster Study of Leukemias of Ambiguous Lineage [iBFM-AMBI2012]) of 233 cases of pediatric ALAL patients is presented. Survival statistics were used to compare the prognosis of subsets and types of treatment. Five-year event-free survival (EFS) of patients with acute lymphoblastic leukemia (ALL)–type primary therapy (80% ± 4%) was superior to that of children who received acute myeloid leukemia (AML)–type or combined-type treatment (36% ± 7.2% and 50% ± 12%, respectively). When ALL- or AML-specific gene fusions were excluded, 5-year EFS of CD19+leukemia was 83% ± 5.3% on ALL-type primary treatment compared with 0% ± 0% and 28% ± 14% on AML-type and combined-type primary treatment, respectively. Superiority of ALL-type treatment was documented in single-population mixed phenotype ALAL (using World Health Organization and/or European Group for Immunophenotyping of Leukemia definitions) and bilineal ALAL. Treatment with ALL-type protocols is recommended for the majority of pediatric patients with ALAL, including cases with CD19+ALAL. AML-type treatment is preferred in a minority of ALAL cases with CD19−and no other lymphoid features. No overall benefit of transplantation was documented, and it could be introduced in some patients with a poor response to treatment. As no clear indicator was found for a change in treatment type, this is to be considered only in cases with ≥5% blasts after remission induction. The results provide a basis for a prospective trial.

Thalassemia Major (TM) is a clinical entity with a high prevalence of low bone mass. The aim of the present study was to perform a meta-analysis of all available data on the role of bisphosphonates (BPs) in the therapy of thalassemia major-induced osteoporosis. The PRISMA recommendations for reporting systematic reviews and meta-analyses were used to guide the present study. We searched PubMed and the Cochrane Central Register of Controlled Trials (CENTRAL) through March 31, 2017 for articles related to thalassemia and BPs. To meta-analytically synthesize the primary endpoint, we used the standardized mean difference (SMD) after Hedges’s gtransformation under the scenario of a random effects model. Heterogeneity across studies was examined using the I2statistic. Nine randomized controlled trials (RCTs) containing original data were included in this review. Three studies were performed in Italy, one in Australia, three in Greece, one in Cyprus, and one in China. The BPs investigated included zoledronate, alendronate, pamidronate, clodronate, and neridronate. Zoledronate and alendronate showed a tendency to perform best as compared to neridronate and the placebo effect with respect to femoral neck, lumbar spine, total hip, and total body in terms of bone mass density (g/cm2). BPs and in particular, zolendronate, were quite effective in the treatment of osteoporosis. These findings suggested that bisphosphonates are still a front-line treatment of osteoporosis in TM. However, to draw more meaningful and significant conclusions for the use and efficacy of BP in TM, larger and more complete RCTs should be conducted.