OBJECTIVE: To explore the efficacy of a Thalassemia risk assessment software for the screening of thalassemia mutation carriers and distribution of thalassemia genotypes detected by screening. METHODS: A total of 6 040 individuals were evaluated at Leshan Maternal and Child Health Care Hospital between 2022 and 2024 using the commonly used clinical thalassemia risk assessment method and the thalassemia screening software, respectively, and the performance indicators of the two methods were compared and analyzed against the result of thalassemia gene testing. This study was approved by the Ethics Committee of our hospital (Ethics No.: LfyLL[2022]005). RESULTS: The high-risk rate by the thalassemia screening software was 11.19%, with a sensitivity of 95.12%, specificity of 93.28%, positive predictive value of 43.20%, negative predictive value of 99.72%, and the area under the ROC curve (AUC) was 0.942. The thalassemia gene detection rate of the high-risk samples screened was 4.83%. The high-risk screening rate of the conventional method was 2.50%, with a sensitivity of 51.22%, specificity of 93.28%, positive predictive value of 80.79%, negative predictive value of 97.40%, and the AUC was 0.754. The thalassemia gene detection rate of the high-risk samples was 2.02%. CONCLUSION The software can effectively detect thalassemia carriers and significantly reduce the missed detection compared with conventional method, thereby significantly improve the efficacy of screening.
Humans ; Thalassemia/diagnosis* ; Software ; Female ; Genetic Testing/methods* ; Male ; Mutation ; Adult ; Genotype ; ROC Curve ; Risk Assessment

Introduction: Skeletal disease in transfusion-dependent thalassemia is commonly attributed to reduced bone mineral density and managed with anti-resorptive therapy. However, chronic iron overload can induce progressive endocrine siderosis, disrupting anabolic pathways essential for bone homeostasis. This mechanism remains under-recognized and may underlie treatment failure in severe cases. Case: We describe a 34-year-old female with transfusiondependent HbE β-thalassemia, post-splenectomy, receiving regular transfusions and iron chelation, who sustained multiple pathological fractures following a trivial fall, including bilateral supracondylar femur fractures and a distal radius fracture. She had severe systemic iron overload (ferritin 2,621 ng/mL) complicated by hepatic cirrhosis, insulin-dependent diabetes, and hypogonadotropic hypogonadism. Bone mineral density assessment demonstrated severe osteoporosis (hip T-score −5.4) despite prolonged bisphosphonate therapy, with prior vertebral compression fracture. Endocrine evaluation revealed multiaxis dysfunction, including gonadal failure and probable growth hormone deficiency, consistent with pituitary and peripheral endocrine siderosis. Conclusion This case demonstrates that skeletal fragility in transfusiondependent thalassemia reflects an endocrine-driven failure of bone formation rather than isolated loss of bone mineral density. Iron overload–induced endocrine siderosis impairs osteoblast function and suppresses anabolic signaling, leading to profound skeletal vulnerability. The progression of osteoporosis despite anti-resorptive therapy highlights the limitation of conventional approaches and supports reframing thalassemia-associated bone disease as an endocrine disorder. Severe osteoporosis should prompt systematic endocrine evaluation, with early hormonal replacement and consideration of anabolic therapy to prevent catastrophic fractures and long-term disability.
Siderosis ; Thalassemia

Introduction: Thalassemia is a hemoglobin synthesis disorder associated with chronic anemia and transfusion-related iron overload, which predisposes patients to multiple endocrine complications. Iron deposition in the pituitary and gonads may result in growth hormone deficiency (GHD) and hypogonadism. Empty sella syndrome (ESS), characterized by herniation of the subarachnoid space into the sella turcica, may also contribute to hypopituitarism. The coexistence of thalassemia-related endocrinopathies, ESS, and autoimmune thyroid disease is rare and presents significant diagnostic complexity. Case: A 27-year-old female with transfusion-dependent thalassemia on deferiprone presented with secondary amenorrhea and short stature. Her height was 145 cm (below the target range of 140.5–157.5 cm), body mass index 17.3 kg/m², and Tanner stage M3P1. Laboratory evaluation revealed elevated thyroidstimulating hormone (10.92 mIU/L) with low-normal free thyroxine 4 (11.4 pmol/L), consistent with primary hypothyroidism. Thyroid ultrasound demonstrated features of chronic thyroiditis, and anti-thyroid peroxidase antibodies (8.18 IU/mL) supported a diagnosis of Hashimoto’s thyroiditis. Insulin-like growth factor-1 was markedly reduced (68 ng/mL), indicating GHD. Morning cortisol was within normal range (14.5 µg/dL). Gonadotropins were inappropriately low-normal (folliclestimulating hormone 7.42 mIU/mL, luteinizing hormone 11.41 mIU/mL) with low estradiol (26.49 pg/mL), suggesting hypogonadotropic hypogonadism. Skeletal survey showed thalassemia-related bone changes, including trabecular coarsening and metaphyseal widening, with a predicted adult height of 142.7 cm. Pituitary magnetic resonance imaging revealed an empty sella. Conclusion Thalassemia must be recognized not only as a primary hematologic condition but also as a complex multisystem disorder with profound endocrine implications. Furthermore, the co-occurrence of these conditions with rare manifestations such as ESS and Hashimoto’s thyroiditis underscores the diagnostic complexity faced by clinicians. Therefore, early detection and rigorous, regular endocrine screening are essential to optimize management strategies and improve the long-term quality of life for patients with thalassemia.
Empty Sella Syndrome ; Growth Hormone ; Thalassemia ; Thyroiditis

Introduction: Adolescence is a crucial period for achieving peak bone mass. Risk factors such as chronic inflammation, endocrine issues, corticosteroid use, and extended immobility can lead to severe secondary osteoporosis and fragility fractures. Case: A 15-year-old female with transfusion-dependent thalassemia had been hospitalized for over a year following severe acute gastroenteritis complicated by septic shock, multiorgan failure, and secondary hemophagocytic lymphohistiocytosis (HLH). She received pulse methylprednisolone therapy for HLH, which was tapered over 6 months. Her clinical course was further complicated by critical illness polyneuropathy and post-infectious bronchiectasis, leading to ventilator dependence and a bedbound state. During regular physiotherapy sessions, she developed a sudden onset of severe left shoulder pain. A radiograph of the left shoulder revealed a closed fracture of the humeral neck. Biochemical evaluation showed normal serum calcium and phosphate levels, adequate vitamin D status, and normal alkaline phosphatase levels. However, follicle-stimulating hormone, luteinizing hormone (LH), and estradiol levels were undetectable, consistent with arrested puberty due to chronic illness. A bone mineral density scan showed a lumbar spine Z-score of −6, indicating severe osteoporosis. She was started on intravenous zoledronate for secondary osteoporosis, and physiotherapy was resumed to improve musculoskeletal strength. Conclusion This patient was treated with bisphosphonate therapy for severe secondary osteoporosis caused by multiple risk factors, including chronic illness, prolonged immobility, corticosteroid use, and hypogonadotropic hypogonadism, with limited potential for spontaneous bone recovery. This case highlights the importance of early endocrine monitoring and bone health assessments to identify impaired bone growth and prevent fragility fractures in high-risk adolescents.
Adolescent ; Humans ; Chronic Disease ; Thalassemia

OBJECTIVE: To analyze the correlation between variants in the start codon of the α-globin gene and phenotypes of thalassemia, so as to provide a basis for the diagnosis and prevention of α-thalassemia. METHODS: A retrospective study was conducted on 7 patients diagnosed by Yangjiang People's Hospital and Guangzhou Hybribio Co. Ltd., from June 2019 to October 2022. Routine blood tests and hemoglobin electrophoresis were carried out. Potential variants were identified through polymerase chain reaction (PCR) combined with Reverse dot blotting (RDB), Gap-PCR, and Sanger sequencing. This study has been approved by the Medical Ethics Committee of People's Hospital of Yangjiang (Ethics No: 20240001). RESULTS: For the 7 patients, results of blood routine test of one case was unknown, and that of another was normal. The remaining 5 cases had presented with microcytic hypochromic anemia. The results of hemoglobin electrophoresis showed that one case had normal Hb A and slightly lower Hb A2, whilst another had significantly decreased Hb A and Hb A2, in addition with the appearance of a Hb H band. The content of Hb Bart's in four neonates was ≥ 0.4%. The remaining one case had no result. Genetic testing has identified 4 rare start codon mutations, namely HBA2: c.2delT, HBA2: c.1A>G, HBA2: c.1A>T, and HBA1: c.2T>C. Among these, Patient 1 had harbored compound heterozygous variants of HBA2: c.427T>C (Hb CS) and HBA2: c.2delT. Patient 4 had harbored compound heterozygous variants of HBA2: c.1A>G and Southeast Asian type deletion. CONCLUSION Heterozygotes with HBA start codon variants usually present as silent or mild thalassemia, and the symptoms of anemia may deteriorate when combined with other α-thalassemia variant. The HBA2: c.1A>T start codon variant was unreported previously in China. The detection of start codon variants has helped to clarify the causes of anemia, genetic counseling, and guidance for reproduction.
Humans ; Phenotype ; Codon, Initiator/genetics* ; Female ; Male ; Retrospective Studies ; alpha-Globins/genetics* ; alpha-Thalassemia/genetics* ; Hemoglobin A/genetics* ; Adult ; Mutation

OBJECTIVE: To analyze the hematological characteristics of patients with three common deletional β-thalassemia and concomitant α-thalassemia in Huizhou, Guangdong province. METHODS: A total of 1 335 subjects of childbearing age with hemoglobin F (Hb F) ≥ 5% at the Huizhou First Maternal and Child Health Care Hospital between June 2014 and December 2023 were enrolled as our study cohort. The hematological parameters were determined by blood cell counters and automatic capillary electrophoresis, while liquid phase chip and gap-PCR were employed for the detection of routine thalassemias and the three common deletional β-thalassemia, respectively. The hematological characteristics of patients with the deletional β-thalassemia were analyzed. This study was reviewed and approved by the Ethics Committee of Huizhou First Maternal and Child Health Care Hospital [Ethics No. 20231107(B2)]. RESULTS: A total of 384 cases of the three common deletional β-thalassemia were identified, including 184 cases of Chinese Gγ⁺(Aγδβ)⁰, 191 cases of Southeast Asian hereditary persistence of fetal hemoglobin (SEA-HPFH), and nine cases of Chinese Taiwanese, for a total detection rate of 28.76%. Patients who did not meet the established criteria were excluded from the study, leaving 372 cases. All of which presented with hypochromic microcytic anemia and significantly elevated Hb F. Except for normal or decreasing of Hb A2 levels in patients with Chinese Gγ⁺(Aγδβ)⁰, the levels of Hb A2 in patients with the other two deletional β-thalassemia were increased with different degrees. Differential comparison results showed that significant differences were observed in Hb A2 and Hb F values among the groups of the three common deletional β-thalassemia heterozygotes (P < 0.05). According to the type of gene variation, 180 patients with Chinese Gγ⁺(Aγδβ)⁰ heterozygotes were divided into three groups, including αα/αα, Chinese Gγ⁺(Aγδβ)⁰/β^N (149), -α/αα, Chinese Gγ⁺(Aγδβ)⁰/β^N (14), and --/αα, Chinese Gγ⁺(Aγδβ)⁰/β^N (17). Similarly, 179 patients with SEA-HPFH heterozygotes were divided into three groups, including αα/αα, SEA-HPFH/β^N (150), -α/αα, SEA-HPFH/β^N (12), and --/αα, SEA-HPFH/β^N (17). Differential comparison results showed that the Hb F levels of the Chinese Gγ⁺(Aγδβ)⁰ combined with α⁰-thalassemia group were significantly lower than those of the Chinese Gγ⁺(Aγδβ)⁰ combined with α⁺-thalassemia group and the control group (P < 0.05). The mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), and Hb F values of the SEA-HPFH combined with α⁰-thalassemia group were significantly lower than those of the SEA-HPFH combined with α⁺-thalassemia group and the control group (P < 0.05). CONCLUSION The above research results can not only enhance the ability of clinicians to identify deletional β-thalassemia and concomitant α-thal, improve the level of genetic counseling, but also provide data support for the development of deletional β-thalassemia prevention and control programme and the development of prenatal and postnatal care.
Humans ; beta-Thalassemia/complications* ; alpha-Thalassemia/complications* ; Female ; China ; Male ; Adult ; Fetal Hemoglobin/genetics* ; Adolescent ; Young Adult

OBJECTIVE: To explore the clinical phenotype and genetic etiology of a neonate with X-linked alpha-thalassemia mental retardation syndrome (ATR-X) caused by ATRX gene variant, and review related literature on children with ATR-X caused by ATRX gene variants. METHODS: A case of ATR-X neonate who was transferred to the First Affiliated Hospital of Zhengzhou University on February 11, 2022 for poor effect of treatment in the neonatology department of the hospital where he was born for 4 days due to "postnatal slow response, groaning, and cyanosis of the skin for 30 min" was selected as the study subject. 3 mL of peripheral blood was collected from the child and their parents, and genomic DNA was extracted for whole exome sequencing (WES). Sanger sequencing was used to verify the pathogenic gene variations in the child's family. The pathogenicity of genetic variant sites was assessed based on the Standards and Guidelines for the Interpretation of Sequence Variants by American College of Medical Genetics and Genomics (ACMG). The amino acid sequence conservation analysis of relevant variant proteins was conducted by the Universal Protein Resource Database (UniProt) and visual analysis of these variant proteins was performed by Swiss online protein three-dimensional modeling database (SWISS-MODEL). Using keywords such as "ATRX gene" and " X-linked alpha-thalassemia mental retardation syndrome" both in Chinese and English, relevant literature on ATR-X children caused by ATRX gene variants was retrieved from the CNKI, Wanfang Data Knowledge Service Platform, and PubMed databases, and the clinical phenotypes of ATR-X patients reported in the retrieved literature were analyzed. The literature retrieval time was set from the establishment of each database to December 31st, 2023. This study followed the research procedures approved by the Ethics Committee of the First Affiliated Hospital of Zhengzhou University (Ethics No. 2023-KY-1360-002), and informed consent of clinical study was signed by the guardian of the child. RESULTS: The child in this study presented with symptoms such as delayed response, feeding difficulties accompanied by vomiting, low body temperature, hypotonia in all extremities, apnea, abnormal hearing screening, and a Neonatal Behavioral Neurological Assessment (NBNA) score of 19 (lower than the normal range).Hemoglobin (Hb) electrophoresis suggested the presence of α-thalassemia. The results of WES and Sanger sequencing revealed a hemizygous missense variant c.668G>A (p.C223Y) in exon 9 of the ATRX gene in the child of the study, neither of the parents of the child carried this variant, indicating that it is a de novo variant. Based on the Standards and Guidelines for the Interpretation of Sequence Variants released by ACMG, this gene variant was assessed as pathogenic (PS2+PM2_Supporting+PP3_Strong+PP4_Strong). The results of amino acid sequence analysis revealed that the pathogenic variant site normally encodes cysteine, which is highly conserved among various animal species. This pathogenic variant can lead to alterations in the hydrogen bonding structure of ATRX protein, thereby affecting its structural stability. Based on the clinical manifestations and genetic testing results of the child in this study, a diagnosis of ATR-X syndrome was established Based on the literature retrieval strategy established in this study, 13 relevant articles concerning ATR-X syndrome in children caused by ATRX gene variants were retrieved, including 5 Chinese articles and 8 English articles, involving a total of 311 ATR-X children. Including the child in this study, the total number of ATR-X children reaches 312. All 312 children were male and presented with mental retardation. Among them, 45.8% (143/312) had coexisting α-thalassemia, 45.2% (141/312) had abnormal genital appearance, 44.2% (138/312) had facial malformations, and 30.8% (96/312) had hypotonia. Other phenotypes included microcephaly, skeletal dysplasia, among others. CONCLUSION The ATR-X child in this study exhibit a range of clinical phenotypes, including delayed growth and development, facial malformation, abnormal genital appearance, apnea, vomiting symptoms, among others. The de novo variant of ATRX gene c.668G>A (p.C223Y) was identified as the genetic etiology. This study contributes to the expansion of the clinical phenotype spectrum and genetic variation spectrum of ATR-X children.
Humans ; X-linked Nuclear Protein/genetics* ; alpha-Thalassemia/genetics* ; X-Linked Intellectual Disability/genetics* ; Male ; Infant, Newborn ; Exome Sequencing ; Mutation

The 1985 version of WHO G6PD variation classification is no longer suitable for the development of modern medicine, and it has been revised by the WHO G6PD Technical Advisory Group. According to the genetic variation classification of G6PD by WHO in 2024, G6PD deficiency is divided into four categories: Class A: enzyme activity < 20% with chronic hemolytic anemia; Class B: enzyme activity < 45% in association with acute hemolysis caused by inducement; Class C: enzyme activity > 60%, no hemolysis; Class U: for those with incomplete clinical phenotypic information, and will be classified again with new clinical evidence obtained. The clinical implications of the new classification include: (1) To guide the prevention and treatment of G6PD deficiency; (2) To better understand the pathological and non-pathological status of G6PD deficiency, which lays a foundation for re-determining the birth defect rate in China; (3) To guide the safe use of anti-malarial drugs and related oxidizing drugs in G6PD deficient patients; (4) To promote the hierarchical health management of G6PD deficient individuals throughout their life cycle; (5) To guide the pathogenicity rating of G6PD gene variation; (6) To unify the diagnostic criteria for global G6PD deficiency, promote the homogenization, comparability and data sharing of global relevant data, and lay the foundation for the application of artificial intelligence.
Humans ; Glucosephosphate Dehydrogenase Deficiency/diagnosis* ; Glucosephosphate Dehydrogenase/genetics* ; Genetic Variation ; World Health Organization ; China

OBJECTIVE: To determine the carrier rate for thalassemia mutations in the ethnic Miao population of Qianxinan Prefecture. METHODS: Ethnic Miao people suspected for thalassemia trait at the People's Hospital of Qianxinan Prefecture, Guizhou Province between November 2020 to September 2024 were selected as the study subjects. Gap-PCR technology combined with high-throughput sequencing was used to screen a total of 666 individuals. ArcMap v10.8.2 was used to create a spatial distribution map of thalassemia based on the screening results. This study was approved by the Medical Ethics Committee of the hospital (Ethics No.: 2016-01). RESULTS: In total 254 positive cases were detected, with an overall positive rate of 38.14%. Among these, 173 cases were α-thalassemia (25.98%), 77 cases were β-thalassemia (11.56%), and 4 cases were αβ compound thalassemia (0.60%). The most common genotypes for α-thalassemia were αα/--^SEA (positive rate = 10.06%, accounting for 38.73%), αα/-α^3.7 (positive rate = 8.86%, accounting for 34.10%), and α^CSα/αα (positive rate = 4.95%, accounting for 19.08%). The most common genotypes for β-thalassemia were β^41/42(-TTCT)/β^A (positive rate = 5.11%, accounting for 44.16%) and β^{17 (A>T)}/β^A(positive rate = 4.20%, accounting for 36.36%), with these two genotypes accounting for as much as 80.52%. The spatial distribution map indicated that the highest overall detection rate of thalassemia and α-thalassemia in the Miao population of Qianxinan Prefecture was in Xingyi City. The highest detection rate of β-thalassemia was in Zhenfeng County, and the highest detection rate of αβ compound thalassemia was in Wangmo County. CONCLUSION The detection rate of thalassemia among the ethnic Miaos from Qianxinan Prefecture is relatively high, which primarily consisted of α-thalassemia. Regular monitoring and educational outreach should be conducted.
Humans ; China/ethnology* ; Female ; Male ; Genetic Testing ; Adult ; alpha-Thalassemia/genetics* ; Thalassemia/ethnology* ; Ethnicity/genetics* ; Genotype ; beta-Thalassemia/ethnology* ; Adolescent ; Mutation ; Middle Aged ; Child ; Asian People/genetics* ; Young Adult

INTRODUCTION: Elevated troponin, while essential for diagnosing myocardial infarction, can also be present in non-myocardial infarction conditions. The myocardial-ischaemic-injury-index (MI3) algorithm is a machine learning algorithm that considers age, sex and cardiac troponin I (TnI) results to risk-stratify patients for type 1 myocardial infarction. METHOD: Patients aged ≥25 years who presented to the emergency department (ED) of Singapore General Hospital with symptoms suggestive of acute coronary syndrome with no diagnostic 12-lead electrocardiogram (ECG) changes were included. Participants had serial ECGs and high-sensitivity troponin assays performed at 0, 2 and 7 hours. The primary outcome was the adjudicated diagnosis of type 1 myocardial infarction at 30 days. We compared the performance of MI3 in predicting the primary outcome with the European Society of Cardiology (ESC) 0/2-hour algorithm as well as the 99th percentile upper reference limit (URL) for TnI. RESULTS: There were 1351 patients included (66.7% male, mean age 56 years), 902 (66.8%) of whom had only 0-hour troponin results and 449 (33.2%) with serial (both 0 and 2-hour) troponin results available. MI3 ruled out type 1 myocardial infarction with a higher sensitivity (98.9, 95% confidence interval [CI] 93.4-99.9%) and similar negative predictive value (NPV) 99.8% (95% CI 98.6-100%) as compared to the ESC strategy. The 99th percentile cut-off strategy had the lowest sensitivity, specificity, positive predictive value and NPV. CONCLUSION The MI3 algorithm was accurate in risk stratifying ED patients for myocardial infarction. The 99th percentile URL cut-off was the least accurate in ruling in and out myocardial infarction compared to the other strategies.
Humans ; Male ; Female ; Emergency Service, Hospital ; Middle Aged ; Electrocardiography ; Machine Learning ; Singapore ; Chest Pain/blood* ; Troponin I/blood* ; Myocardial Infarction/blood* ; Risk Assessment/methods* ; Aged ; Algorithms ; Acute Coronary Syndrome/blood* ; Adult ; Sensitivity and Specificity