bims-conane 2026-05-03 papers

bims-conane

Biomed News

on Congenital anemias

Issue of 2026–05–03
nine papers selected by
João Conrado Khouri dos Santos, Universidade de São Paulo

Clinicohematological and Genetic Profile of Hereditary Spherocytosis in Children: An Experience From a North Indian Center.
Evaluation of the Eosin-5'-Maleimide Flow Cytometry Test for the Diagnosis of Hereditary Spherocytosis.
From Splenectomy to Partial Splenic Embolization, Which is Better for Hereditary Spherocytosis?
Genetic dissection of clinical heterogeneity in Hemoglobin H patients by targeted long-read sequencing.
Two Novel PKLR Variants in Pyruvate Kinase Deficiency: Insights From Clinical, Molecular and Functional Analysis.
Best Practices for Thalassaemia Management: Recommendations by Indian Society of Haematology and Blood Transfusion.
Sitosterolemia: Unveiling an Underdiagnosed Case Series of Haemolytic Anaemia.
Recurrent Hemolytic Anemia in an Infant with Hereditary Elliptocytosis at a Nigerian Hospital.
Erythroferrone derived from osteoblasts regulates stress erythropoiesis.

J Pediatr Hematol Oncol. 2026 Apr 23.

Clinicohematological and Genetic Profile of Hereditary Spherocytosis in Children: An Experience From a North Indian Center.

Ankita Chakraborty, Manas Kalra, Anupam Sachdeva, Jyoti Kotwal, Sabina Langer, Amrita Saraf, Pallavi Rana, Surbhi Dahiya, Vandana Arya, Satish Aggarwal, Alpana Prasad.

   BACKGROUND: Hereditary spherocytosis (HS) is a genetically and clinically diverse red cell membrane disorder, with limited clinical and molecular data on pediatric patients from India.
METHODS: This ambispective study, conducted at a North Indian tertiary center over a period of 6 years, evaluated HS patients for clinical, laboratory, genetic, and treatment outcomes.
RESULTS: Forty-seven patients (33 males, 14 females; mean age 12.1±8.7 yrs) were analyzed. Family history was contributory in 40.4%. Around 72.3% patients required at least one PRBC transfusion by the time of analysis, while 9 were transfusion dependent. Hemolytic facies and growth retardation were seen in 25.6% and 30.7%, while gallstones were found in 42.5%. MCHC was 32.2±1.92% and was not found to be a useful screening test. Incubated osmotic fragility testing (iOFT) was positive in 36 cases (sensitivity 76.6%), while eosin-5-maleimide (EMA) binding by flow cytometry was positive in 41 cases (sensitivity 87.2%), detecting all cases missed or equivocal on iOFT and demonstrating superior diagnostic yield. The remaining 6 cases were confirmed by genetic testing, which served as the definitive diagnostic modality. Among 34 patients tested genetically, mutations were found in ANK1 (n=14), SPTB (n=12), SLC4A1 (n=3), EPB42 (n=4), and SPTA1 (n=1). Beyond classic HS mutations, additional findings included PKLR mutations (n=2), hereditary elliptocytosis (n=2), dehydrated stomatocytosis (n=2), and Gilbert syndrome (n=4) with cholelithiasis. Genetic testing refined diagnoses, reclassifying one Congenital Dyserythropoietic Anemia (CDA) case as HS and 4 HS cases as alternative etiologies.
CONCLUSION: This study underscores the clinical and genetic heterogeneity of Indian HS, demonstrating the value of combining the EMA dye test with genetic sequencing. The disease impacted facial features and growth, while splenectomy showed good outcomes in severe cases.

Keywords:  Genetic testing; eosin-5- maleimide; gallstones; hereditary spherocytosis; osmotic fragility test; splenectomy

DOI:  https://doi.org/10.1097/MPH.0000000000003205
Eur J Haematol. 2026 Apr 27.

Evaluation of the Eosin-5'-Maleimide Flow Cytometry Test for the Diagnosis of Hereditary Spherocytosis.

Pablo Adrian Biaggioni, Alejandro Ceferino López Romero.

   INTRODUCTION: Hereditary spherocytosis (HS) is a congenital hemolytic anemia caused by erythrocyte membrane protein defects. While the eosin-5'-maleimide (EMA) binding test by flow cytometry is the established first-line assay, this study evaluates its optimal cut-offs and performance within a large, real-world cohort.
METHODS: We retrospectively analyzed 181 consecutive samples (2017-2024) with suspected HS. EMA binding was performed by flow cytometry using conventional and standardized protocols; the latter (implemented in 2023) utilized fixed erythrocyte counts and FL1 bead calibration. Accuracy was assessed against a composite clinical-laboratory reference standard. ROC analysis determined sensitivity, specificity, likelihood ratios, and AUC.
RESULTS: HS was confirmed in 50/181 cases (27.6%). EMA fluorescence reduction was significantly greater in HS (median 23.0%) than in non-HS samples (9.0%). The optimal cut-off (16.5%) yielded 96.0% sensitivity, 96.9% specificity, and AUC = 0.990 (95% CI 0.979-0.998). Both conventional and standardized protocols showed equivalent accuracy (AUC 0.988 vs. 0.992). False positives were mainly associated with severe microcytosis or autoimmune hemolytic anemia.
CONCLUSIONS: In a consecutive, real-world cohort of patients with suspected hereditary spherocytosis referred to a single reference laboratory receiving samples from across the country, the EMA test demonstrated high diagnostic accuracy consistent with previous reports. Importantly, implementation of a standardized protocol resolved reproducibility issues in fluorescence intensity measurement without compromising diagnostic performance, supporting its robustness and applicability in routine clinical laboratories.

Keywords:  diagnostic accuracy; eosin‐5′‐maleimide; flow cytometry; hereditary spherocytosis; red blood cell membrane disorders; standardization

DOI:  https://doi.org/10.1111/ejh.70204
J Blood Med. 2026 ;17 595335

From Splenectomy to Partial Splenic Embolization, Which is Better for Hereditary Spherocytosis?

Mengyuan Si, Shanghong Yang, Zijian Chen, Aixia Dou.

  Hereditary Spherocytosis (HS), with characteristic red blood cells (RBCs), is a group of genetic hemolytic disorders that occur in an autosomal-dominant manner. It is clinically characterized by anemia, splenomegaly, jaundice, and mutations in key genes. Splenectomy is the standard treatment for HS. Alternatively, partial splenic embolization (PSE) balances efficacy and safety, making it a promising solution. To determine how to choose surgery and ensure correct management, we reviewed the indications, techniques, efficacies, complications, and progress of alternative solutions to reach a comprehensive conclusion. Core clinical dimensions between Splenectomy and PSE in the treatment of HS, including surgical indications, operative techniques, hemoglobin improvement, infection risk, immune function preservation, long-term complications and recurrence rate. PSE is better than Splenectomy. Furthermore, forefront-targeted drugs, precise embolization ranges, and multidisciplinary team (MDT) discussions were reviewed. Collaboration requires multiple departments and family members. Through this narrative review, we hope to provide practical advice for long-term follow-up and emergency management.

Keywords:  hereditary spherocytosis; partial splenic embolization; splenectomy

DOI:  https://doi.org/10.2147/JBM.S595335
J Genet Genomics. 2026 Apr 24. pii: S1673-8527(26)00141-4. [Epub ahead of print]

Genetic dissection of clinical heterogeneity in Hemoglobin H patients by targeted long-read sequencing.

Yuhua Ye, Chao Niu, Aiping Mao, Li Chen, Lang Qin, Weijie Chen, Zhentian Liu, Tiantian Xie, Yong Long, Xuan Shang, Yushan Huang, Qianqian Zhang, Libao Chen, Hualei Luo, Yihong Li, Yulin Lu, Yumeng Liu, Liuhua Liao, Junqin Cai, Riyang Liu, Xinhua Zhang, Lihong Zeng, Yaoyun Li, Jianhong Chen, Zeyan Zhong, Jianpei Fang, Xinyu Li, Xingkun Yang, Bin Lin, Kui Li, Xiaoyun Hua, Binbin Huang, Honggui Qin, Yueyan Huang, Zhijing Huang, Jinquan Lao, Xiang Qu, Juanjuan Chen, Xiaoqin Feng, Qiujun Liu, Wanying Lin, Xiaoman Zhou, Yidan Liang, Xingjiang Long, Jiaofeng Qin, Lixiang Yan, Weijian Zhu, Lian Yu, Chengwu Fan, Deguo Tang, Tianyu Zhong, Jufang Tan, Zhilin Ren, Yang Gao, Xiangmin Xu.

  Hemoglobin H (HbH) disease is a subtype of α-thalassemia typically caused by genetic defects in three out of four α-globin genes. To date, the genetic factors contributing to the highly heterogeneous clinical severity of HbH disease remain largely unknown. In this study, we perform targeted long-read sequencing (T-LRS) on a cohort of 591 HbH patients, aiming to profile the genomic variants and their haplotypes within the α/β-globin gene clusters and key erythroid genes. Phenotypic analysis confirms that non-deletional HbH patients generally exhibit more severe clinical manifestations compared to deletional ones. Moreover, we identify the co-inheritance of β-thalassemia mutations to be a mitigating factor for HbH patients, as reflected by higher hemoglobin levels and lower serum ferritin, suggesting the less imbalanced synthesis of α/β-globin among these patients. Furthermore, through haplotype phasing using long-sequencing reads, we find a haplotype of HS40 associated with milder clinical symptoms of HbH patients, validated by reporter gene assay, and that functional mutations in erythroid transcription factors BCL11A and MYB-HBS1L exert significant effects on β-thalassemia but not on HbH patients. This study presents the largest T-LRS study for α-thalassemia patients, which may provide insight into precise clinical diagnosis and phenotyping of HbH diseases.

Keywords:  Clinical heterogeneity; Hemoglobin H; Population study; Targeted long read sequencing; Thalassemia

DOI:  https://doi.org/10.1016/j.jgg.2026.04.011
Int J Lab Hematol. 2026 Apr 28.

Two Novel PKLR Variants in Pyruvate Kinase Deficiency: Insights From Clinical, Molecular and Functional Analysis.

Huaxia Xiang, Yuxiu Wen, Mengxin Yang, Jiali Jiang, Yuping Li, Changjin He, Zhihao Lin, Hongying Wei.

   INTRODUCTION: Pyruvate kinase deficiency (PKD) is a rare cause of hereditary non-spherocytic hemolytic anemia. This study reports the clinical and molecular characterization of three pediatric PKD cases, focusing on two novel PKLR variants.
METHODS: Clinical and laboratory data were reviewed. PKLR gene was analyzed by next-generation sequencing and validated by Sanger sequencing. Pathogenicity was predicted using in silico tools and ACMG criteria. Structural consequences were modeled with AlphaFold3 and Chimera-X. Functional impact was assessed by Western blot and immunofluorescence in transfected 293T cells.
RESULTS: All patients presented with neonatal hemolytic anemia. Genetic analysis revealed compound heterozygosity for PKLR mutations. Two novel variants were identified: c.1708G>A (p.Val570Met) and c.1430C>T (p.Thr477Ile). In silico analysis predicted both as damaging. Structural modeling suggested p.Val570Met disrupts inter-subunit hydrogen bonds, while p.Thr477Ile lies within the fructose-1,6-bisphosphate (FBP) binding loop. In vitro, both mutants showed reduced protein expression compared to wild-type but normal cytoplasmic localization.
CONCLUSION: We identified two novel PKLR variants expanding the mutational spectrum of PKD. Integrated analysis suggests p.Val570Met may impair tetramer stability, whereas p.Thr477Ile likely affects allosteric regulation. These findings underscore the value of combining clinical phenotyping with functional studies for accurate variant interpretation in PKD.

Keywords:  R‐pyruvate kinase; novel mutation; pathogenicity; pyruvate kinase; pyruvate kinase deficiency

DOI:  https://doi.org/10.1111/ijlh.70125
Indian J Hematol Blood Transfus. 2026 May;42(3): 679-696

Best Practices for Thalassaemia Management: Recommendations by Indian Society of Haematology and Blood Transfusion.

Tuphan Kanti Dolai, Rabindra Kumar Jena, Shipla Roy, Maitreyee Bhattacharyya, Amiya Ranjan Nayak, Manoranjan Mahapatra, Kaustav Ghosh, Mukul Aggarwal, Ashish Dixit, Bontha V Babu, Jina Bhattacharyya, J S Arora, Sudha Sethy, V P Choudhry, Prashant Sharma, Rajib De, Reena Das, Sailendra Prasad Verma, Jyoti Kotwal, Vikram Mathews.

  Thalassemia comprises a heterogeneous group of most common monogenetic disorder and inherited autosomal recessive hemoglobin disorders characterized by defective globin chain synthesis, resulting in hemolysis, ineffective erythropoiesis, chronic anemia, and multisystem complications. India bears a substantial thalassemia burden, with millions of carriers and over 12,000 affected births annually, necessitating standardized, context-appropriate management strategies. These recommendations by the Indian Society of Haematology and Blood Transfusion (ISHBT) provide comprehensive, evidence-informed guidance for the diagnosis, treatment, monitoring, and prevention of thalassemia across diverse healthcare settings in India. The recommendation developed through a structured, multidisciplinary consensus process and expert review, these guidelines aim to harmonize best practices nationwide while allowing flexibility for regional adaptation. Their implementation is expected to improve survival, quality of life, and long-term outcomes for individuals living with thalassemia in India. The guidelines address the clinical spectrum, including transfusion-dependent thalassemia (TDT) and non-transfusion-dependent thalassemia (NTDT), emphasizing early diagnosis through hematological indices, hemoglobin fraction analysis, and molecular testing when indicated. Clear recommendations are provided for rational blood transfusion practices, iron overload monitoring, and timely initiation of iron chelation therapy to prevent cardiac, hepatic, endocrine, and skeletal complications. Disease-specific management of iron-related organ damage, infections, endocrine dysfunction, fertility issues, pregnancy, and emergency scenarios is outlined. Curative and disease-modifying options including hematopoietic stem cell transplantation, gene therapy, and newer agents such as luspatercept, hydroxyurea, and thalidomide are outlined. Preventive strategies, highlighting carrier screening, antenatal and prenatal diagnosis, genetic counseling, and public awareness initiatives.

Keywords:  HSCT; Hydroxyurea; Iron Chelation; NTDT; TDT; Thalassemia; Thalidomide

DOI:  https://doi.org/10.1007/s12288-026-02390-y
Indian J Hematol Blood Transfus. 2026 May;42(3): 1061-1064

Sitosterolemia: Unveiling an Underdiagnosed Case Series of Haemolytic Anaemia.

Mehak Trehan, Rachit Agrawal, Amiya Ranjan Nayak, Rishi Dhawan, Jasmita Dass, Ganesh Kumar, Pradeep Kumar, Richa Chauhan, Tulika Seth, Manoranjan Mahapatra, Mukul Aggarwal.

  Sitosterolemia is a rare autosomal recessive lipid metabolic condition characterized by excessive absorption of plant sterols through the intestinal mucosa, resulting in excessive sterols in the blood. Four patients of age ranging from 10 to 29 years presented to the outpatient department with clinical features of hemolytic anemia without any features of hypercholesterolemia. Peripheral smear examination of all patients showed stomatocytes and macro-thrombocytopenia. Next-generation sequencing revealed mutations in the ABCG5 gene: a homozygous c.727 C > T mutation, compound heterozygous c.1336 C > T and c.1292 C > G mutations in two cases, and homozygous mutation and deletion in the ABCG8 c.1720 G > A and c.408 del in two cases, respectively. Three of them were put on ezetimibe along with a low plant sterol diet and have shown significant hemoglobin improvement; the fourth patient has just started on the same. Our case series highlights a rare but manageable cause of hemolytic anemia suspected from peripheral blood examination, needing molecular genetic diagnosis with good results on proper management.

Keywords:  Genetic diagnosis; Hemolytic anemia; Rare anemia syndromes; Sitosterolemia; Sterol metabolism disorders; Stomatocytosis

DOI:  https://doi.org/10.1007/s12288-025-02153-1
Ann Afr Med. 2026 Apr 28.

Recurrent Hemolytic Anemia in an Infant with Hereditary Elliptocytosis at a Nigerian Hospital.

Efeturi Agelebe, Oshiname Frederick Pamehase, Temitope Eunice Agelebe, Oyetoke Christina Oderanti.

   ABSTRACT: Hereditary elliptocytosis (HE) is a genetic disorder of the red blood cell membrane leading to chronic hemolytic anemia. It is under-recognized as a cause of anemia in Nigerian infants. We report the case of a 6 month old male Nigerian infant presenting with recurrent pallor over 3 months, necessitating five prior blood transfusions at the Pediatric Emergency Unit of Efeturi's Lifeline Hospital, Osogbo, Nigeria. Physical examination revealed severe pallor and a tachycardia of 160 beats/min. Investigations conducted revealed a packed cell volume of 22% and a peripheral blood film showing numerous elliptocytes and poikilocytes. Anemia was managed with packed cell transfusion, and the patient was discharged and followed up monthly. This case underscores the role of peripheral blood morphology in diagnosing HE even in private practice in resource-limited settings. It illustrates the substantial burden of recurrent, transfusion-dependent anemia caused by HE in infancy and highlights the need for improved access to diagnostic and long-term care for chronic hematological disorders in this region.

Keywords:  Elliptocytose; Elliptocytosis; anémie récurrente; hereditary; héréditaire; recurrent anemia

DOI:  https://doi.org/10.4103/aam.aam_767_25
Proc Natl Acad Sci U S A. 2026 May 05. 123(18): e2537627123

Erythroferrone derived from osteoblasts regulates stress erythropoiesis.

Pinanong Na-Phatthalung, Gabrielle van Caloen, Marina Planoutene, Emily Tai, Anisa Gumerova, Ronit Witztum, Eva Ingber, Leon Kautz, Farhath Sultana, Funda Korkmaz, Maayan Levy, Tony Yuen, Mone Zaidi, Yelena Z Ginzburg.

  Erythroferrone (ERFE), secreted by erythroblasts, is regarded as a classical regulator of iron metabolism through its suppression of hepcidin. Thus, as a consequence of insufficient hepcidin suppression and reduced iron availability, global Erfe-/- mice exhibit delayed recovery after phlebotomy. We have shown previously that, apart from erythroblasts, ERFE is notably expressed in osteoblasts. To explore the effect specifically of osteoblast-derived ERFE during stress erythropoiesis, we first created Erfefl/fl mice, which were then crossed with Col2.3-Cre mice to generate osteoblast-selective Erfe mutants (or Col2.3-Cre;Erfefl/fl mice). The induction of stress erythropoiesis in these latter mice by phlebotomy resulted in reduced serum ERFE levels and increased liver Hamp (hepcidin) expression. Importantly, Col2.3-Cre;Erfefl/fl mice showed a more robust red blood cell (RBC) recovery 6 d postphlebotomy, with no differences in bone marrow Erfe relative to Erfefl/fl mice. Furthermore, despite no differences in the baseline RBC count, reticulocyte count, spleen size, or bone marrow cellularity, osteoblast-selective ERFE loss resulted in enhanced erythropoietin receptor (Epor) and bone morphogenetic protein 4 (Bmp4) expression in whole bone in vivo and in osteoblasts ex vivo. Finally, the osteoblast-selective Erfe mutants showed erythroid lineage proliferation and enhanced EPO responsiveness in a BMP4-dependent manner. Taken together, we posit that ERFE loss specifically from osteoblasts enhances RBC recovery during stress erythropoiesis-defining mechanisms of regulation in the crosstalk between osteoblasts and erythroblasts.

Keywords:  ERFE; bone; erythropoiesis; transgenic mice

DOI:  https://doi.org/10.1073/pnas.2537627123