bims-conane Biomed News
on Congenital anemias
Issue of 2025–03–30
ten papers selected by
João Conrado Khouri dos Santos, Universidade de São Paulo
  1. Analysis of Common Alpha-Globin Gene Abnormalities and Their Effects as Genetic Modifiers in Thai Children With β-Globin Gene Abnormalities.
  2. iFGF23 Plasma Levels in Transfusion-Dependent β-Thalassemia: Insights into Bone and Iron Metabolism.
  3. Feasibility of Intensive Chemotherapy in Hereditary Spherocytosis.
  4. Diagnosis and treatment of Diamond-Blackfan anemia and Pierre-Robin sequence caused by a novel mutation of RPS28 gene.
  5. Splenic Artery Embolization as a Primary Treatment for Hereditary Spherocytosis: A Case Report.
  6. Characterization Of Beta Thalassaemia Mutations In Patients Having Borderline Haemoglobin A2 Levels.
  7. Tracing a Rare Genetic Disease: Familial Congenital CD59 Deficiency and Carrier Cases Identified Through Village Screening.
  8. What is the importance of monitoring iron levels in different organs over time with magnetic resonance imaging in transfusion-dependent thalassemia patients?
  9. Ancient genomic linkage of α-globin and Nprl3 couples metabolism with erythropoiesis.
  10. Prevalence and Correlates of Dilated and Non-Dilated Left Ventricular Cardiomyopathy in Transfusion-Dependent Thalassemia: Data from a National, Multicenter, Observational Registry.
  1. Anemia. 2025 ;2025 9933808
    Analysis of Common Alpha-Globin Gene Abnormalities and Their Effects as Genetic Modifiers in Thai Children With β-Globin Gene Abnormalities.
    Sethapong Lertsakulbunlue, Boonchai Boonyawat, Chanchai Traivaree, Apichat Photia.
      Beta-thalassemia exhibits a broad phenotypic range influenced by the severity of HBB mutation and various genetic modifiers. One of the most essential modifiers is the coinheritance of α-globin gene mutation. Nevertheless, the understanding of these α-globin variations' impact on beta-thalassemia is lacking among pediatric patients. This study investigated the impact of common α-globin gene mutations on clinical phenotype and hematological parameters in 122 Thai children with either β-thalassemia diseases or carriers recruited from Phramongkutklao Hospital, a major thalassemia center. Clinical characteristics, transfusion history, and hematological parameters were recorded, with molecular testing for common α-globin deletions and Hb CS mutations. The cohort included 8 homozygous β-thalassemia, 55 β-thalassemia/Hb E, 18 homozygous Hb E, 26 heterozygous Hb E, and 15 heterozygous β-thalassemia children. Coinheritance of α-globin mutations was less frequent in β-thalassemia diseases (6 of 63) than in β-thalassemia traits (25 of 59) (p < 0.001), indicating a potential modifier effect that reduces severity. Among β-thalassemia/Hb E patients, single α-globin deletions or Hb CS mutations were linked with lower Hb E, MCV, and MCH. Similarly, in both β-thalassemia and Hb E traits with α-globin gene mutation had significantly lower MCV, MCH and Hb E levels (only in the Hb E trait) and elevated RDW. Moreover, lower hematocrit and hemoglobin in these carriers were noted in cases coinherited with deletional Hb H disease initially undiagnosed by Hb typing. In conclusion, the diagnostic value of hematological parameters and Hb typing in identifying common α-globin mutations in pediatric β-thalassemia patients were highlighted. Hematological parameters are vital indicators that may prompt genetic screening to confirm α-globin abnormalities, supporting improved diagnosis and management of complex αβ-thalassemia syndromes.
    Keywords:  alpha-globin gene mutation; beta-thalassemia; genetic modifiers; pediatrics
    DOI:  https://doi.org/10.1155/anem/9933808
  2. J Clin Med. 2025 Mar 08. pii: 1834. [Epub ahead of print]14(6):
    iFGF23 Plasma Levels in Transfusion-Dependent β-Thalassemia: Insights into Bone and Iron Metabolism.
    Alberto Gobbo, Filomena Longo, Camilla Alice Cattaneo, Martina Verrienti, Gianluca Marzi, Fatima Chamekh, Martina Culcasi, Alberto Cossu, Maria Chiara Zatelli, Maria Rosaria Ambrosio.
      Background: FGF23 is a phosphate homeostasis regulator; the literature suggests a link between FGF23, iron homeostasis and erythropoiesis. Little is known about the FGF23 level variations in β-thalassemia (βT), which is characterized by ineffective erythropoiesis and iron overload. Our cross-sectional study aims to evaluate the iFGF23 level variations in a large cohort of βT patients considering their bone mineral densities (BMDs) and iron loads. Methods: Clinical, biochemical and radiological data were collected from 213 transfusion-dependent βT (TDT) adults referring to the Regional HUB Centre for Thalassaemia and Haemoglobinopathies in Ferrara, Italy. The iFGF23 levels in the TDT patients were compared to the general population's reference range. The BMDs and hearth and liver iron deposits were assessed with DEXA scans and MRI, respectively. Results: The iFGF23 distribution in the TDT subjects is significantly different from that of the general population. The iFGF23 levels are positively correlated with the age at transfusion initiation and calcium and phosphate levels and are negatively correlated with the osteocalcin plasma levels. Patients treated with deferasirox had lower iFGF23 levels than those treated with other chelators. The iFGF23 levels are not correlated with the BMD or iron status. Conclusions: These findings provide insights into the relationship between the iFGF23 and bone and iron metabolism in TDT patients. Further studies are needed to explore its potential clinical relevance.
    Keywords:  FGF23; beta-thalassemia; calcium; ferritin; hemoglobinopathy; iron chelation; iron load; phosphate; transfusion dependent
    DOI:  https://doi.org/10.3390/jcm14061834
  3. Hematol Rep. 2025 Feb 24. pii: 11. [Epub ahead of print]17(2):
    Feasibility of Intensive Chemotherapy in Hereditary Spherocytosis.
    Carrai Valentina, Giubbilei Cristina, Ciceri Manuel, D'Angelo Simona, Nassi Luca, Sordi Benedetta, Vannucchi Alessandro Maria, Puccini Benedetta.
       BACKGROUND: This study presents a young man with hereditary spherocytosis (HS) who underwent intensive chemotherapy for newly diagnosed diffuse large B-cell lymphoma (DLBCL) and achieved complete remission. This case challenges the idea of HS as a barrier to standard DLBCL treatment.
    DISCUSSION: By meticulously monitoring blood counts and providing timely transfusions, the team successfully mitigated potential complications associated with chemotherapy-induced stress on red blood cells.
    CONCLUSIONS: This experience underscores the importance of a multidisciplinary approach and tailored treatment plans for patients with co-existing conditions, suggesting that HS should not automatically disqualify them from potentially curative therapies for aggressive lymphomas.
    Keywords:  chemotherapy; diffuse large B cell lymphoma; hereditary spherocytosis; rare disorders
    DOI:  https://doi.org/10.3390/hematolrep17020011
  4. Hematology. 2025 Dec;30(1): 2481688
    Diagnosis and treatment of Diamond-Blackfan anemia and Pierre-Robin sequence caused by a novel mutation of RPS28 gene.
    Shaofen Lin, Lele Hou, Xinyu Li, Liping Que, Xiaojuan Li, Jianpei Fang, Honggui Xu, Ke Huang.
       BACKGROUND: Diamond-Blackfan anemia (DBA) is a congenital erythroid aplasia associated with physical anomalies and a predisposition to cancer. It is categorized as ribosomopathy related to heterozygous allelic variations in ribosomal protein (RP) genes. Pierre Robin sequence (PRS) is a rare and etiologically heterogeneous condition, defined by the clinical triad of micrognathia, glossoptosis, and cleft palate.
    METHODS AND RESULTS: We present a 5-year-and-2-month-old Chinese boy diagnosed with DBA combined with RPS. He was born with micrognathia, cleft palate, and airway obstruction, resulting in neonatal asphyxia and feeding difficulties, which constitute the classic triad of PRS. Low-set ears, downslanted palpebral fissures, bilateral exotropia, a short neck, hypertelorism, a thenar muscle defect, and bilateral severe sensorineural hearing loss were also observed in the boy. His motor and speech development were significantly delayed. In addition, he was found to be granulocytopenic at birth and severely anemic at 2 years and 10 months of age. Whole exome sequencing of peripheral blood revealed a heterozygous mutation in the RPS28 gene (c.2T > C, p.Met1?), a novel pathogenic mutation in RPS28. RPS28 is one of the ribosomal protein (RP) genes, which may contribute to DBA-related phenotypes. The boy underwent HSCT from 9/10 HLA-matched donor and his neutrophil and hemoglobin levels returned to normal.
    CONCLUSION: It is crucial to perform a genetic evaluation for syndromic bone marrow failure with congenital anomalies. A heterozygous mutation in the RPS28 gene (c.2T > C, p.Met1?) is a novel pathogenic mutation associated with DBA. HSCT is an effective treatment for hematological abnormalities in DBA.
    Keywords:  Diamond-Blackfan anemia; Pierre Robin sequence; RPS28; hematopoietic stem cell transplantation; ribosomopathy
    DOI:  https://doi.org/10.1080/16078454.2025.2481688
  5. Cureus. 2025 Feb;17(2): e79269
    Splenic Artery Embolization as a Primary Treatment for Hereditary Spherocytosis: A Case Report.
    Habiba A Mahamat, Shoroq M Alamin, Amani Alrawi, Omar A Al Mohammad, Ali Alsaadi, Saud Balila.
      The primary management of hereditary spherocytosis (HS) typically involves splenectomy to prevent hemolytic crises. However, splenic artery embolization (SAE) has emerged as a promising minimally invasive alternative. We report a case of a woman in her mid-20s with severe HS who presented with chronic fatigue, anemia resistant to iron supplementation, and splenomegaly. The diagnosis was confirmed through clinical findings, osmotic fragility test, and laboratory results. A partial embolization of the lower two-thirds of the spleen was performed while preserving the function of the upper third. Post-procedure, significant improvements were observed in hemoglobin levels (rising from 7.7 g/dL to 11.3 g/dL), hematocrit, and bilirubin levels, with no major complications reported. This case highlights that partial selective splenic artery embolization (PSE) is a safe and effective non-surgical procedure that can be considered as a potential alternative to splenectomy in the management of hereditary spherocytosis. Further studies are warranted to establish its long-term efficacy.
    Keywords:  chronic anemia; hereditary spherocytosis; minimally invasive procedure; splenic artery embolization; total splenectomy
    DOI:  https://doi.org/10.7759/cureus.79269
  6. J Ayub Med Coll Abbottabad. 2024 Oct-Dec;36(4):36(4): 783-787
    Characterization Of Beta Thalassaemia Mutations In Patients Having Borderline Haemoglobin A2 Levels.
    Afshan Noor, Manzar Bozdar, Hamid Saeed Malik, Rafia Mahmood, Ayesha Khurshid, Aysha Khan, Nighat Seema.
       BACKGROUND: The occurrence of a single beta thalassaemia allele is frequently related with microcytic hypochromic red blood cells and a rise in HbA2 levels. In some beta thalassaemia carriers, the outcome of this allele or its collaboration with other acquired or genetic defects may result in normal or borderline Haemoglobin bA2 levels. Objective was to establish the importance of molecular analysis in borderline HbA2 individuals and its significance in a population screening program.
    METHODS: It was a cross-sectional study conducted over a period of six months, from July-December 2023. All 123 individuals with borderline HbA2 levels between (3‒3.9%) diagnosed by High-performance liquid chromatography (HPLC)/Capillary Zone Electrophoresis underwent molecular testing using multiplex amplification refractory mutation system-Polymerase Chain Reaction (ARMS-PCR) to detect common beta thalassaemia mutations: Fr8-9, IVS1-5, Fr41-42, Cd15, Cd5, IVS1-1, IVS1-1, Cd30, Cd30, Fr16, IVSII-1, Del619, and CAP+1 in the Department of Haematology, Armed Forces Institute of Pathology, Rawalpindi .Statistical tests were applied to compare Red Blood Cell indices and Haemoglobin A2 values among beta thalassaemia carriers and non-carriers.
    RESULTS: Among those tested, 47.1% (n=58) were found to carry Beta thalassaemia mutations. The most prevalent mutations were IVS1-5 (n=19,15.4%) and Fr8-9 (n=19,15.4%) followed by Fr41-42 (n=08,6.5%). Subjects with mutations exhibited significantly lower mean corpuscular volume and mean corpuscular haemoglobin compared to those without mutations (p-value= <0.001). Beta thalassaemia mutations were seen more frequently when HbA2 was in range of 3.5-3.9% (n=37,63.8%), as compared to HbA2 that was 3-3.4% (n=21,36.2%) and this difference was found to be significant (p-value= <0.001). The CAP+1 mutation was associated (n=02,1.6%) with normal mean MCV and MCH compared to other identified mutations.
    CONCLUSIONS: It is concluded that molecular study for the common beta thalassaemia mutations in Pakistani population plays a pivotal role in confirmation of borderline HbA2 thalassaemia carriers, specifically in areas with a high prevalence of the disease. Molecular testing for beta thalassaemia should be offered to all individuals with borderline HbA2 with values especially between 3.4‒3.9% and having microcytic hypochromic indices.
    Keywords:  Borderline HbA2; Silent carriers; Beta Thalassaemia mutation; Red Cell Indices; Molecular analysis
    DOI:  https://doi.org/10.55519/JAMC-04-14046
  7. J Pediatr Hematol Oncol. 2025 Apr 01. 47(3): 109-114
    Tracing a Rare Genetic Disease: Familial Congenital CD59 Deficiency and Carrier Cases Identified Through Village Screening.
    Kökcü Karadag Sefika Ilknur, Karadağ Alpaslan Medine, Karadağ Hüseyin, Uğurtay Eda Turgut, Can Cansu, Yildiran Alisan.
       BACKGROUND: Congenital CD59 deficiency is a rare genetic disorder marked by chronic hemolysis, recurrent cerebrovascular events, and chronic inflammatory demyelinating polyneuropathy (CIDP). In a specific clinic, 3 siblings from a consanguineously married family were diagnosed with this condition, suggesting a genetic predisposition in their village where endogamous marriages are common.
    MATERIALS AND METHODS: Genetic screening was conducted on 71 individuals from the village, including relatives of the diagnosed siblings, to investigate the prevalence and genetic transmission of the disorder.
    RESULTS: The screening identified 18 carriers of the genetic mutation and revealed 2 additional siblings of the index patient with the disease. A past case of a cousin with a similar clinical history was also uncovered.
    CONCLUSION: The findings highlight the increased risk of genetic disorders like CD59 deficiency in populations with frequent consanguineous marriages. The study underscores the importance of genetic counseling and preventive measures in such communities to mitigate the risk of congenital disorders.
    DOI:  https://doi.org/10.1097/MPH.0000000000003008
  8. Expert Rev Hematol. 2025 Mar 28.
    What is the importance of monitoring iron levels in different organs over time with magnetic resonance imaging in transfusion-dependent thalassemia patients?
    Antonella Meloni, Vincenzo Positano, Paolo Ricchi, Alessia Pepe, Riccardo Cau.
       INTRODUCTION: Iron overload is the main pathophysiological driver of organ damage in transfusion-dependent thalassemia (TDT). Magnetic resonance imaging (MRI) provides detailed insights into the distribution and severity of iron accumulation in the different organs.
    AREAS COVERED: This special report describes the impact of MRI on clinical and therapeutic management and short- and long-term outcomes in TDT patients. PubMed, Scopus, and Google Scholar databases were searched to identify the relevant studies published before November 2024.
    EXPERT OPINION: Cardiac and hepatic MRI are now well-established modalities, integrated into the clinical practice. They have become essential for tailoring iron chelation therapies to the specific patient's needs and for monitoring treatment efficacy. The improved control of cardiac iron burden has translated into reduced morbidity and mortality. The MRI accessibility remains limited in resource-limited settings and progress in this field relies on educating and training centers to ensure accurate execution and interpretation. The clinicopathological significance, prognostic value and reproducibility of pancreatic iron levels assessment have been established, charting a path toward its clinical use. There are limited data about renal, adrenal, and pituitary iron deposition, and more research is needed to fully establish the functional significance and to standardize and validate the MRI protocols.
    Keywords:  Iron overload; magnetic resonance imaging; transfusion-dependent thalassemia
    DOI:  https://doi.org/10.1080/17474086.2025.2486379
  9. Nat Commun. 2025 Mar 24. 16(1): 2749
    Ancient genomic linkage of α-globin and Nprl3 couples metabolism with erythropoiesis.
    Alexandra E Preston, Joe N Frost, Megan R Teh, Mohsin Badat, Andrew E Armitage, Ruggiero Norfo, Sarah K Wideman, Muhammad Hanifi, Natasha White, Noémi Ba Roy, Christian Babbs, Bart Ghesquiere, James Davies, Andrew Jm Howden, Linda V Sinclair, Jim R Hughes, Mira Kassouf, Rob Beagrie, Douglas R Higgs, Hal Drakesmith.
      Red blood cell development from erythroid progenitors requires profound reshaping of metabolism and gene expression. How these transcriptional and metabolic alterations are coupled is unclear. Nprl3 (an inhibitor of mTORC1) has remained in synteny with the α-globin genes for >500 million years, and harbours most of the a-globin enhancers. However, whether Nprl3 serves an erythroid role is unknown. We found that while haematopoietic progenitors require basal Nprl3 expression, erythroid Nprl3 expression is further boosted by the α-globin enhancers. This lineage-specific upregulation is required for sufficient erythropoiesis. Loss of Nprl3 affects erythroblast metabolism via elevating mTORC1 signalling, suppressing autophagy and disrupting glycolysis. Broadly consistent with these murine findings, human NPRL3-knockout erythroid progenitors produce fewer enucleated cells and demonstrate dysregulated mTORC1 signalling in response to nutrient availability and erythropoietin. Therefore, we propose that the anciently conserved linkage of NprI3, α-globin and their associated enhancers has coupled metabolic and developmental control of erythropoiesis.
    DOI:  https://doi.org/10.1038/s41467-025-57683-z
  10. J Cardiovasc Dev Dis. 2025 Mar 16. pii: 103. [Epub ahead of print]12(3):
    Prevalence and Correlates of Dilated and Non-Dilated Left Ventricular Cardiomyopathy in Transfusion-Dependent Thalassemia: Data from a National, Multicenter, Observational Registry.
    Antonella Meloni, Laura Pistoia, Anna Spasiano, Francesco Sorrentino, Giuseppe Messina, Michele Santodirocco, Zelia Borsellino, Valerio Cecinati, Vincenzo Positano, Gennaro Restaino, Nicolò Schicchi, Emanuele Grassedonio, Antonino Vallone, Michele Emdin, Alberto Clemente, Andrea Barison.
      We investigated the prevalence, clinical characteristics, and prognostic role of dilated cardiomyopathy (DCM) and non-dilated left ventricular cardiomyopathy (NDLVC) in patients with transfusion-dependent β-thalassemia (β-TDT). We retrospectively included 415 β-TDT patients who underwent cardiovascular magnetic resonance to quantify myocardial iron overload (MIO) and biventricular function parameters and to detect replacement myocardial fibrosis. Demographic and laboratory parameters were comparable among patients with no overt cardiomyopathy (NOCM; n = 294), DCM (n = 12), and NDLVC (n = 109), while cardiac size and systolic function were significantly different. Compared to NOCM patients, DCM and NDLVC patients had a higher prevalence of MIO and replacement myocardial fibrosis. During a mean follow-up of 57.03 ± 18.01 months, cardiac complications occurred in 32 (7.7%) patients: 15 heart failures, 15 supraventricular arrhythmias, and 2 pulmonary hypertensions. Compared to the NOCM group, both the NDLVC and the DCM groups were associated with a significantly increased risk of cardiac complications (hazard ratio = 4.26 and 8.81, respectively). In the multivariate analysis, the independent predictive factors were age, MIO, and the presence of DCM and NDLVC versus the NOCM phenotype. In β-TDT, the detection of NDLVC and DCM phenotypes may hold value in predicting cardiac outcomes.
    Keywords:  cardiovascular magnetic resonance; dilated cardiomyopathy; non-dilated left ventricular cardiomyopathy; prognosis; transfusion-dependent β-thalassemia
    DOI:  https://doi.org/10.3390/jcdd12030103
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