Anemia in an ethnic minority group in lower northern Thailand: A community-based study investigating the prevalence in relation to inherited hemoglobin disorders and iron deficiency.

BACKGROUND: Anemia is a globally well-known major public health problem. In Southeast Asia where there is ethnic diversity, both iron deficiency (ID) and inherited hemoglobin disorders (IHDs) are prevalent and are considered to be the major factors contributing to anemia. However, little is known about the anemia burden among the ethnic minorities. In this study, we determine the burden of anemia, in relation to ID and IHDs, among the Karen ethnic minorities living in the rural area of lower northern Thailand. METHODS: A cross-sectional community-based study was conducted at Ban Rai district, Uthai Thani province. Study participants included 337 Karen people aged over 18 years. Socio-economic and health-related information were obtained through interviews and recorded by local health staff. Anemia, IHDs and ID were diagnosed according to standard laboratory methods. Multivariate logistic regression analysis was applied to identify risk factors of moderate-to-severe anemia. RESULTS: The prevalence of overall anemia was 27.9% (95% CI = 23.2-33.0). Mild and moderate anemia were detected in 18.7% (95% CI = 14.7-23.3) and 8.9% (95% CI = 6.1-12.5) respectively. Severe anemia was found in one case (0.3%). Various forms of IHDs were identified in 166 participants, constituting 49.3% (95% CI = 43.8-54.7). The most common form of IHDs was α+-thalassemia (32.9%), followed by ß-thalassemia (12.2%), α0-thalassemia (4.2%), hemoglobin E (3.9%), and hemoglobin Constant Spring (0.9%). Among 308 participants who were investigated for ID, the prevalence was discovered to be 6.8% (95% CI = 4.3-10.2). Analysis of risk factors of moderate-to-severe anemia revealed that individuals with ID, ß-thalassemia and age > 65 years were at high risk with adjusted odds ratio of 17 (95% CI = 3.8-75.2), 6.2 (95% CI = 1.4-27.8) and 8.1 (95% CI = 1.6-40.4) respectively. CONCLUSIONS: Anemia among the Karen is of public health significance; and IHDs are the major contributing factors. Because of the high risk of developing moderate-to-severe anemia, special attention should be paid to individuals affected with ID, ß-thalassemia and the elderly. Public awareness of the health burden of severe thalassemia syndromes should also be campaigned.

Placenta-Derived Extracellular Vesicles in Pregnancy Complications and Prospects on a Liquid Biopsy for Hemoglobin Bart's Disease.

Extracellular vesicles (EVs) are nano-scaled vesicles released from all cell types into extracellular fluids and specifically contain signature molecules of the original cells and tissues, including the placenta. Placenta-derived EVs can be detected in maternal circulation at as early as six weeks of gestation, and their release can be triggered by the oxygen level and glucose concentration. Placental-associated complications such as preeclampsia, fetal growth restriction, and gestational diabetes have alterations in placenta-derived EVs in maternal plasma, and this can be used as a liquid biopsy for the diagnosis, prediction, and monitoring of such pregnancy complications. Alpha-thalassemia major ("homozygous alpha-thalassemia-1") or hemoglobin Bart's disease is the most severe form of thalassemia disease, and this condition is lethal for the fetus. Women with Bart's hydrops fetalis demonstrate signs of placental hypoxia and placentomegaly, thereby placenta-derived EVs provide an opportunity for a non-invasive liquid biopsy of this lethal condition. In this article, we introduced clinical features and current diagnostic markers of Bart's hydrops fetalis, extensively summarize the characteristics and biology of placenta-derived EVs, and discuss the challenges and opportunities of placenta-derived EVs as part of diagnostic tests for placental complications focusing on Bart's hydrop fetalis.

[Acquired alpha-thalassemia in an 86-year-old patient with myelodysplastic syndrome]. / Une alpha thalassémie acquise chez un patient de 86 ans avec un syndrome myélodysplasique.

BACKGROUND: Alpha thalassemia-myelodysplastic syndrome (ATMDS) is one of the possible complications related to the genetic instability typical of clonal hemopoietic disorders such as myelodysplastic syndromes (MDS). Hemoglobin H acquisition, which is hemoglobin without alpha chains and with 4 beta chains is the hallmark of this disease. OBSERVATION: An 86-year-old male with chronic, microcytic anemia was referred due to a fall in his hemoglobin level. The blood smear was remarkable for intense anisocytoses and poikilocytosis. Bone marrow analysis was followed by a diagnosis of MDS with a good prognostic score. Peripheral blood coloration with brilliant cresyl blue showed "golf ball-like" erythrocytes. Hemoglobin electrophoresis is notable for the presence of H hemoglobin. The new generation sequencing confirmed the diagnosis of ATMDS showing a non-sense mutation in the gene ATRX. CONCLUSION: The diagnosis of ATMDS should be considered in the presence of the association of MDS, microcytic anemia and marked blood smear abnormalities such as anisocytosis and poikilocytosis. A little less than 10% of all MDS are complicated by ATMDS.

Anemia, iron deficiency, and thalassemia among the Thai population inhabiting at the Thailand-Lao PDR-Cambodia triangle.

Anemia is a major public health problem in many areas of Southeast Asia. Ascertaining anemia and defining its underlying causes is essential for providing appropriate care, management, and establishment of a control program. Limited studies on these have been carried out on people living at the borders of Thailand, Lao PDR, and Cambodia. This cross-sectional study was done in four areas along the borders of Thailand, Lao PDR, and Cambodia. Blood specimens were collected from subjects aged 15-18 years in four districts including Kantharalak, Si Sa Ket province (n = 36), Nam Khun (n = 109), Nam Yuen (n = 98), and Na Chaluai (n = 128), Ubon Ratchathani province, Thailand. RBC parameters were recorded, and serum ferritin (SF) level was measured. Diagnosis of thalassemia and hemoglobinopathies was based on hemoglobin (Hb) and DNA analyses. Measurement of C-reactive protein was performed to exclude false-negative result of iron deficiency. The prevalence of anemia was found to be 25.1%. ID accounted for only 10.5%. Various types of thalassemia were identified in 67.7% of the subjects. The overall prevalence of thalassemia included 3.5% α0-thalassemia, 0.8% ß-thalassemia, 47.7% Hb E, and 53.6% α+-thalassemia. The proportions of ID, thalassemia and combined ID and thalassemia among anemic subjects were 6.5%, 66.6%, and 20.4%, respectively. The results indicate that thalassemia and hemoglobinopathies rather than ID are major causes of anemia in Thailand-Lao PDR-Cambodia triangle. This information should prove useful for implementing an anemia control program in the regions.

A novel ATRX splice variant causing acquired HbH disease in myelodysplastic syndrome with excess blasts-1.

A 60-year-old male with myelodysplastic syndrome with excess blasts-1 had unexplained microcytic hypochromic anemia. The cause of his anemia was revealed on supravital staining, hemoglobin studies and next-generation sequencing to be a novel hemizygous potentially pathogenic missense/splice site variant NM_000489.5:c.6848A>C, (p.Lys2283Thr) in exon 31 of the ATRX gene.

IgA nephropathy associated with thalassemia: a case report.

BACKGROUND: Thalassemia is a group of hereditary diseases characterized by a common recessive monogenic hematological disorder, presenting a significant public health concern in the developing countries. Recent studies have identified the renal effects of thalassemia syndrome. Chronic hypoxia, long-term anemia, iron overload, and iron chelators are the major causes of renal tubular dysfunction and glomerular filtration abnormalities, while glomerulonephritis is not considered a major cause of abnormal urinalysis. CASE PRESENTATION: We report a case of a 38-year-old female patient with immunoglobulin A (IgA) nephropathy accompanied by anemia who was misdiagnosed initially, but was diagnosed with alpha-thalassemia after gene tests. We administered a combination of oral prednisolone, leflunomide, and angiotensin receptor blockers as well as folic acid and mecobalamin. During the follow-up, her proteinuria was significantly reduced, and her anemia was improved. CONCLUSIONS: The possibility of occurrence of thalassemia should be considered in IgA nephropathy complicated with refractory anemia, especially in high-incidence areas of the disease.

Early development of decreased ß-cell insulin secretion in children and adolescents with hemoglobin H disease and its relationship with levels of anemia.

BACKGROUND: Diabetes mellitus (DM) associated with iron overload has been reported among adults with transfusion-dependent thalassemia and those with non-transfusion-dependent thalassemia (NTDT), especially in ß-thalassemia disease. However, little is known about glucose metabolism and how early its dysregulation can develop in α-thalassemia hemoglobin H (Hb H) disease, which is one of the most common types of NTDT worldwide. PROCEDURE: We prospectively calculated glucose metabolism index in 40 patients (aged 10-25 years) with Hb H disease. Glucose metabolism data were compared between patients with deletional versus nondeletional Hb H, and between patients with normal versus abnormal insulin secretion/sensitivity. RESULTS: Despite normal glucose tolerance in all patients, 52.5% had abnormal insulinogenic index indicating decreased ß-cell insulin secretion. Patients with functional hemoglobin < 8 g/dL had significantly higher percentages of abnormal insulinogenic index. There was no significant difference in abnormal insulinogenic index between deletional and nondeletional Hb H. CONCLUSION: Decreased ß-cell insulin secretion is highly prevalent among children and adolescents with Hb H disease, and it is associated with levels of functional anemia at baseline, but not with the type of Hb H disease. This result warrants heightened awareness among hematologists due to potentially increased risk of DM later in life.

A large intrathoracic extramedullary hematopoiesis in alpha-thalassemia: A case report.

RATIONALE: Extramedullary hematopoiesis (EMH) is a rare disease characterized by the formation of hematopoietic elements outside the bone marrow driven by several hematological disease. To the best of our knowledge, EMH is relatively common in patient with beta-thalassemia or hereditary spherocytosis but rarely reported in patients with alpha-thalassemia. Here, we discuss a large intrathoracic EMH (measuring 95 mm × 66 mm) without presenting severe complications in alpha-thalassemia along with literature review. PATIENT CONCERNS: A 55-year-old Chinese female patient with alpha-thalassemia presented with ipsilateral pleural effusion and low hemoglobin level. DIAGNOSIS: Lung cancer was suspected at first and the mass was subjected to CT-guided percutaneous mediastinum biopsy and the pathology confirmed the final diagnosis of extramedullary hematopoiesis. INTERVENTIONS: Blood transfusion, thoracentesis and regular follow up were scheduled rather than surgical interventions or radiotherapy since our patient did not exhibit significant symptoms. OUTCOMES: After 6 months' regular follow up, the patient exhibited no evidence of disease progress. LESSONS: EMH is frequently misdiagnosed and should be differentiated from other masses in thoracic cavity, especially when the underlying hematological disease is discovered. Treatment methods of EMH include surgical resection, hyper-transfusion, hydroxyurea, low-dose radiation or a combination of them.

Sickle cell screening in Uganda: High burden, human immunodeficiency virus comorbidity, and genetic modifiers.

BACKGROUND: The Uganda Sickle Surveillance Study provided evidence for a large sickle burden among HIV-exposed infants in Uganda. To date, however, no large scale screening program has been developed for Central or East Africa. METHODS: A 3-year targeted sickle cell screening project in Uganda was designed by the Ministry of Health to (1) determine sickle cell trait and disease prevalence within high-burden districts, (2) document the prevalence among HIV-exposed and nonexposed children, (3) confirm previously suggested HIV comorbidity, and (4) estimate the co-inheritance of known genetic modifiers of sickle cell disease. RESULTS: A total of 163 334 dried blood spot samples collected between April 2015 and March 2018 were analyzed, including 112 352 samples within the HIV Early Infant Diagnosis program. A high burden with >1% sickle cell disease was found within targeted East Central and Mid-Northern districts, in both HIV-exposed and nonexposed children. Based on crude birth-rate data, 236 905 sickle cell trait births and 16 695 sickle cell disease births will occur annually in Uganda. Compared to sickle cell disease without HIV, the odds ratio of having sickle cell disease plus HIV was 0.50 (95% confidence interval = 0.40-0.64, P < .0001). Alpha-thalassemia trait and G6PD deficiency were common with sickle cell disease, but with different geospatial distribution. CONCLUSIONS: High sickle cell burden and potential HIV comorbidity are confirmed in Uganda. Genetic modifiers are common and likely influence laboratory and clinical phenotypes. These prospective data document that targeted sickle cell screening is feasible and effective in Uganda, and support development of district-level comprehensive care programs.

Does ATRX germline variation predispose to osteosarcoma? Three additional cases of osteosarcoma in two ATR-X syndrome patients.

Osteosarcoma is the most common malignant bone tumor in adolescents and young adults. Most osteosarcomas are sporadic but the risk of osteosarcoma is also increased by germline variants in TP53, RB1 and RECQL4 genes. ATRX germline variations are responsible for the rare genetic disorder X-linked alpha-thalassemia mental retardation (ATR-X) syndrome characterized by severe developmental delay and alpha-thalassemia but no obvious increased risk of cancer. Here we report two children with ATR-X syndrome who developed osteosarcoma. Notably, one of the children developed two osteosarcomas separated by 10 years. Those two cases raise the possibility that ATRX germline variant could be associated with an increased risk of osteosarcoma.

Inherited haemochromatosis with C282Y mutation in a patient with alpha-thalassaemia: a treatment dilemma.

A Caucasian 24-year-old female patient suffers from two hereditary disorders: alpha-thalassaemia, which is prevalent in Asia and rare in Europe, and haemochromatosis, which is prevalent among northern Europe and rare in Asia. The clinical presentation and management of one of these diseases is controversial for the other. She presented 5 years ago with a clinical picture of refractory iron-deficiency anaemia secondary to menorrhagia. On treating her with the standard iron therapy, her anaemia persists although with adquate iron stores. This prompted further investigations that revealed in addition to hereditary haemochromatosis, alpha-thalassaemia because of abnormal blood indices. The treatment of thalassaemia with either iron or blood transfusion is not advisable in haemochromatosis, while standard treatment of haemochromatosis with venesection will worsen the anaemia. As iron chelating agents were not approved in Australia for haemochromatosis, haematinics support was commenced with a satisfactory improvement of anaemia thus allowing for further venesection.

Results of Coexistence of ß-Thalassemia Minor in Hb H Disease Patients.

The aim of this study was to determine the hematological characteristics in a large group of Hb H (ß4) patients with or without a coexisting ß-thalassemia (ß-thal), identified by a thalassemia screening program in mainland China. A total of 361 patients with Hb H disease were found, including 343 with deletional types and 18 with nondeletional types. ß-Thalassemia was found in 28 (7.8%) out of the 361 Hb H cases, and all of the 28 cases had the deletional type of Hb H disease. Lower hemoglobin (Hb) levels were detected in cases with the nondeletional type compared to those in cases with the deletional type. ß-Thalassemia significantly increases the Hb levels in Hb H cases. The Hb H and Hb Bart's (γ4) fractions were visible in 270 (85.7%) and 122 (38.7%) out of 315 deletional type cases, respectively, while no Hb H or Hb Bart's fractions were detectable in 28 deletional type cases with ß-thal. Therefore, the diagnosis of Hb H disease in a ß-thal carrier is challenging. Molecular analysis of α- and ß-globin genes is imperative in all cases with a ß-thal trait.

Dual-Genotype Diffuse Low-Grade Glioma: Is It Really Time to Abandon Oligoastrocytoma As a Distinct Entity?

We report a unique case of dual-genotype oligoastrocytoma characterized by IDH2 gene mutation. The tumor was resected from the temporal lobe of a 25-year-old man. At histological examination with hematoxylin and eosin stain, it showed distinct oligodendroglial and astrocytic areas. The former retained alpha-thalassaemia/mental retardation X-linked (ATRX) immuno-expression and had absent staining for p53, while the latter had ATRX loss and p53 over-expression. Molecular analyses were separately assessed in the 2 tumor components. Gene sequencing disclosed IDH2 mutation in both, whereas oligodendroglial, but not astrocytic areas, had 1p/19q codeletion and telomerase reverse transcriptase promoter mutation. Distinction of dual-genotype oligoastrocytoma from oligodendroglioma and astrocytoma might be clinically relevant for prognosis and therapy. Because most studies that investigated the molecular phenotype of oligoastrocytomas have focused on IDH1 R132H mutated cases, we suggest further analyses on diffuse gliomas with heterogeneous (astrocytic and oligodendroglial) morphology before oligoastrocytoma is dismissed as a distinct nosological entity.

Inherited germline ATRX mutation in two brothers with ATR-X syndrome and osteosarcoma.

We report a family in which two brothers had an undiagnosed genetic disorder comprised of dysmorphic features, microcephaly, severe intellectual disability (non-verbal), mild anemia, and cryptorchidism. Both developed osteosarcoma. Trio exome sequencing (using blood samples from the younger brother and both parents) was performed and a nonsense NM_000489.4:c.7156C>T (p.Arg2386*) mutation in the ATRX gene was identified in the proband (hemizygous) and in the mother's peripheral blood DNA (heterozygous). The mother is healthy, does not exhibit any clinical manifestations of ATR-X syndrome and there was no family history of cancer. The same hemizygous pathogenic variant was confirmed in the affected older brother's skin tissue by subsequent Sanger sequencing. Chromosomal microarray studies of both brothers' osteosarcomas revealed complex copy number alterations consistent with the clinical diagnosis of osteosarcoma. Recently, somatic mutations in the ATRX gene have been observed as recurrent alterations in both osteosarcoma and brain tumors. However, it is unclear if there is any association between osteosarcoma and germline ATRX mutations, specifically in patients with constitutional ATR-X syndrome. This is the first report of osteosarcoma diagnosed in two males with ATR-X syndrome, suggesting a potential increased risk for cancer in patients with this disorder.

Clinical management of the homozygous α-thalassemia with unusual mandibular manifestation of hematopoiesis.

Alpha (α)-thalassemias are the most common genetic disorder of hemoglobin (Hb) synthesis, affecting up to 5% of the world's population. These congenital hemolytic anemias induce extramedullary hematopoiesis, including the liver, spleen, sinuses, and the diploic spaces of the skull. Oral health problems in patients with thalassemias are mostly related to a varied degree of facial deformities, malocclusions, and/or dental arch dimensions. We present a case with a 49-year-old man, diagnosed with homozygous α thalassemia that came to the Faculty of Dentistry at the University of Murcia for a dental treatment. It was observed that the patient had an unusual mandibular manifestation of hematopoiesis.

Coinheritance of Hereditary Elliptocytosis and Deletional Hemoglobin H Disease.

Hereditary elliptocytosis is an inherited red blood cell membrane disorder characterized by typical peripheral blood smear findings of elliptocytes or rod-like red blood cells. Hemoglobin H disease is a form of α-thalassemia disease resulting in mild to moderate hemolytic anemia. The authors report 1 case of a girl who was diagnosed with oculo-auriculo-vertebral spectrum and a coinheritance of hereditary elliptocytosis and deletional hemoglobin H disease. She had moderate, non-transfusion-dependent anemia. The red blood cells showed marked poikilocytosis and fragmentation. The parents were α-thalassemia carriers and the father had the typical red blood cell morphology of common hereditary elliptocytosis.

Alpha-thalassaemia promotes frequent vaso-occlusive crises in children with sickle cell anaemia through haemorheological changes.

BACKGROUND: Sickle cell anaemia (SCA) is a severe hereditary haemoglobinopathy characterised by haemorheological abnormalities, which play a role in the occurrence of several acute and chronic clinical complications. While ßS -haplotypes and alpha-thalassaemia modulate SCA clinical severity, their effects on blood rheology have been incompletely described. The aim of this study was to test the effects of these genetic modifiers on the haemorheological properties and clinical complication of children with SCA. PROCEDURE: Steady-state haemorheological profile, biological parameters, ßS -haplotypes, alpha-globin status, vaso-occlusive crisis (VOC) and acute chest syndrome frequencies were analysed in 128 children (aged 5 to 18 years) with SCA. RESULTS: Patients with alpha-thalassaemia showed increased red blood cell (RBC) deformability and aggregation compared to those without. Median VOC rate was higher in patients with homozygous alpha-thalassaemia compared to those with a normal alpha genotype. Conversely, the haemorheological profile and clinical complications were not influenced by the ßS -haplotypes in our study. CONCLUSION: Our results demonstrate that alpha-thalassaemia is associated with higher risk for VOC events in children with SCA, which may be due in part to its effects on RBC deformability and aggregation.