Search

Alpha-thalassemia is an inherited blood disorder caused by impaired α-globin chain production, leading to anemia and other complications. Hemoglobin H (HbH) disease is caused by a combination of mutations generally affecting the expression of three of four α-globin alleles; disease severity is highly heterogeneous, largely driven by genotype. Notably, non-deletional mutations cause a greater degree of ineffective erythropoiesis and hemolysis, higher transfusion burden, and increased complication risks versus deletional mutations. There are limited treatment options for HbH disease, and effective therapies are needed. This review discusses the pathophysiology of HbH disease, current management strategies, unmet needs, and emerging treatment options., (© 2024 The Author(s). American Journal of Hematology published by Wiley Periodicals LLC.)

Abnormality of three α-globin genes, either deletion or point mutation results in symptomatic Hemoglobin H (HbH) phenotype. Most of such cases of α-globin defects are inherited from the parents, de-novo cases are exceedingly rare. Herein, a case of HbH is reported where the proband inherited one α-globin gene with a point mutation (α Evanston ) from the mother. This was associated with large de-novo deletion of chromosome 16p13.3 resulting in α-thalassemia and mental retardation (ATR-16) syndrome. This deletion also encompassed two α-globin genes from chromosome 16, eventually leading to --/αα Evanston genotype, explaining the clinical presentation of the proband. The challenges in screening of such cases and confirming the molecular diagnosis along with the mode of inheritance has been discussed., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Rationale: This study reports the first case of congenital hypothyroidism (CH) and alpha thalassemia in a child in China, with anemia and muscle damage as the main manifestations. Analyzing and studying this case is of great significance in reducing missed and misdiagnosed CH and will provide a clinical strategy for treating these patients., Patient Concerns: Child, female, 2 years and 7 months old, the child appeared dispirited, had poor appetite, shallow complexion, reduced activities with anemia, elevated muscle enzymes, height, and growth retardation., Diagnoses: The child was diagnosed with CH with alpha thalassemia., Interventions: The patient was treated with levothyroxine sodium and anemia correction., Outcomes: The children's current spirit, appetite, red face, normal limb activity, physical development, and intelligence were significantly better than those of normal children of the same age., Conclusions: CH with alpha thalassemia, especially anemia and muscle damage as the main manifestations, has not been reported. Administration of levothyroxine sodium is effective in correcting anemia in patients with CH and alpha thalassemia., Lesson: Due to CH and alpha thalassemia, there are no specific symptoms and they are prone to missed diagnosis and misdiagnosis. Therefore, patients with anemia and elevated muscle enzyme levels should be routinely tested for thyroid function to diagnose them early and provide proper treatment to avoid negative consequences., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

A term baby presented with cholestatic jaundice since birth. She was diagnosed as gestational alloimmune liver disease-neonatal haemochromatosis (GALD-NH) on evaluation. The baby received intravenous immunoglobulin (IVIG) and recovered gradually from the illness. She was also diagnosed with alpha thalassaemia during the course of evaluation, confirmed by genetic testing. NH is a very rare disorder that results in fetal loss or neonatal death due to liver failure. NH is now known to be a phenotypic expression of GALD. Worldwide, NH is seen in less than one in a million pregnancies. The mortality rate of GALD has traditionally been around 80% with almost all babies needing liver transplantation, with advent of maternal and neonatal IVIG treatment, this has reduced significantly. There is no reported case of GALD-NH treated successfully with IVIG from India. Here, we report an interesting case of GALD-NH with alpha thalassaemia., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

ATRX mutations are commonly associated with alpha-thalassaemia mental retardation syndrome (ATR-X syndrome) with a notable variable expressivity. This X-linked disorder is characterized by intellectual disability (ID) in a higher or lesser degree, in which the alpha-thalassaemia feature is not always present. Other phenotypic manifestations like facial dimorphism, hypotonia, microcephaly, skeletal abnormalities or urogenital malformations have been frequently observed in ATR-X syndrome. Herein, we report a missense ATRX mutation (Thr1621Met) in a patient with an autism spectrum disorder (ASD) diagnosis. Except for ID, no typical signs of ATR-X syndrome were found in the patient. These results confirm the extensive phenotypic variability associated to ATRX mutations and show the involvement of this gene in the ASD., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

We report three cases of fetalis hydrops associated with nondeletional α-thalassemia. Two cases were caused by hemoglobin (Hb) H-Quong Sz disease, and one caused by homozygous Hb Constant Spring. Fetal hydrops occurred in the late second trimester in all three cases. Our study indicates that for pregnancies at risk for fetal nondeletional Hb H disease, strict ultrasound follow-up is particularly important. Even without techniques of intrauterine transfusion treatment, early prenatal diagnosis can enable parents to make timely decisions.

Importance: Sickle cell disease (SCD) is a monogenic disorder, yet clinical outcomes are influenced by additional genetic factors. Despite decades of research, the genetics of SCD remain poorly understood., Objective: To assess all reported genetic modifiers of SCD, evaluate the design of associated studies, and provide guidelines for future analyses according to modern genetic study recommendations., Data Sources: PubMed, Web of Science, and Scopus were searched through May 16, 2023, identifying 5290 publications., Study Selection: At least 2 reviewers identified 571 original, peer-reviewed English-language publications reporting genetic modifiers of human SCD phenotypes, wherein the outcome was not treatment response, and the comparison was not between SCD subtypes or including healthy controls., Data Extraction and Synthesis: Data relevant to all genetic modifiers of SCD were extracted, evaluated, and presented following STREGA and PRISMA guidelines. Weighted z score meta-analyses and pathway analyses were conducted., Main Outcomes and Measures: Outcomes were aggregated into 25 categories, grouped as acute complications, chronic conditions, hematologic parameters or biomarkers, and general or mixed measures of SCD severity., Results: The 571 included studies reported on 29 670 unique individuals (50% ≤ 18 years of age) from 43 countries. Of the 17 757 extracted results (4890 significant) in 1552 genes, 3675 results met the study criteria for meta-analysis: reported phenotype and genotype, association size and direction, variability measure, sample size, and statistical test. Only 173 results for 62 associations could be cross-study combined. The remaining associations could not be aggregated because they were only reported once or methods (eg, study design, reporting practice) and genotype or phenotype definitions were insufficiently harmonized. Gene variants regulating fetal hemoglobin and α-thalassemia (important markers for SCD severity) were frequently identified: 19 single-nucleotide variants in BCL11A, HBS1L-MYB, and HBG2 were significantly associated with fetal hemoglobin (absolute value of Z = 4.00 to 20.66; P = 8.63 × 10-95 to 6.19 × 10-5), and α-thalassemia deletions were significantly associated with increased hemoglobin level and reduced risk of albuminuria, abnormal transcranial Doppler velocity, and stroke (absolute value of Z = 3.43 to 5.16; P = 2.42 × 10-7 to 6.00 × 10-4). However, other associations remain unconfirmed. Pathway analyses of significant genes highlighted the importance of cellular adhesion, inflammation, oxidative and toxic stress, and blood vessel regulation in SCD (23 of the top 25 Gene Ontology pathways involve these processes) and suggested future research areas., Conclusions and Relevance: The findings of this comprehensive systematic review and meta-analysis of all published genetic modifiers of SCD indicated that implementation of standardized phenotypes, statistical methods, and reporting practices should accelerate discovery and validation of genetic modifiers and development of clinically actionable genetic profiles.

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 β-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, β-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, β-thalassemia and the elderly. Public awareness of the health burden of severe thalassemia syndromes should also be campaigned., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Pyae et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

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.

A man in his 30s with alpha thalassaemia (four-alpha globin gene deletion) presented with 1 week of shortness of breath and 1 month of general malaise. Pulse oximetry monitoring revealed low peripheral oxygen saturation of approximately 80% despite maximal high-flow nasal cannula oxygen (fractional inspired oxygen 1.0-60 L/min flow). Arterial blood gas samples were chocolate brown in colour, with a low arterial partial pressure of oxygen of 197 mm Hg. This large oxygen saturation gap raised suspicion for methaemoglobinaemia. However, the patient's co-oximetry results were suppressed by the blood gas analyser and delayed a definitive diagnosis. A methaemalbumin screen was sent instead, which was positive at 65 mg/L (reference interval: <3 mg/L). Treatment with methylene blue was initiated but did not result in complete resolution of cyanosis. This patient had been red cell exchange dependent since childhood for thalassaemia. Therefore, an urgent red cell exchange was initiated overnight, leading to an improvement in symptoms and interpretability of co-oximetry results. This resulted in rapid improvement without residual sequelae or complications. We conclude that a methaemalbumin screen can be used as a surrogate test for prompt confirmation of diagnosis in lieu of co-oximetry in cases of severe methaemoglobinaemia or in cases with underlying haemoglobinopathy. Red cell exchange can allow prompt methaemoglobinaemia reversal, especially if methylene blue is only partially effective., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

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., (Copyright © 2022 Société Nationale Française de Médecine Interne (SNFMI). Published by Elsevier Masson SAS. All rights reserved.)

Alpha thalassemia major (ATM) is a hemoglobinopathy that usually results in perinatal demise if in utero transfusions (IUTs) are not performed. We established an international registry (NCT04872179) to evaluate the impact of IUTs on survival to discharge (primary outcome) as well as perinatal and neurodevelopmental secondary outcomes. Forty-nine patients were diagnosed prenatally, 11 were diagnosed postnatally, and all 11 spontaneous survivor genotypes had preserved embryonic zeta-globin levels. We compared 3 groups of patients; group 1, prenatally diagnosed and alive at hospital discharge (n = 14), group 2, prenatally diagnosed and deceased perinatally (n = 5), and group 3, postnatally diagnosed and alive at hospital discharge (n = 11). Group 1 had better outcomes than groups 2 and 3 in terms of the resolution of hydrops, delivery closer to term, shorter hospitalizations, and more frequent average or greater neurodevelopmental outcomes. Earlier IUT initiation was correlated with higher neurodevelopmental (Vineland-3) scores (r = -0.72, P = .02). Preterm delivery after IUT was seen in 3/16 (19%) patients who continued their pregnancy. When we combined our data with those from 2 published series, patients who received ≥2 IUTs had better outcomes than those with 0 to 1 IUT, including resolution of hydrops, delivery at ≥34 weeks gestation, and 5-minute appearance, pulse, grimace, activity, and respiration scores ≥7. Neurodevelopmental assessments were normal in 17/18 of the ≥2 IUT vs 5/13 of the 0 to 1 IUT group (OR 2.74; P = .01). Thus, fetal transfusions enable the survival of patients with ATM and normal neurodevelopment, even in those patients presenting with hydrops. Nondirective prenatal counseling for expectant parents should include the option of IUTs., (Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Background: Sickle cell anemia (SCA) is a hereditary disease whose cardiovascular complications are the main cause of death, the same being observed in other hemoglobinopathies. Early identification of these changes can favorably modify the course of the disease., Objective: To compare the prevalence of cardiovascular complications between individuals with SCA and individuals with other hemoglobinopathies., Method: Following the recommendations of the PRISMA protocol, a systematic literature review was carried out with searches in PubMed/Medline databases, associated with a manual search. Studies that analyzed the prevalence of cardiovascular alterations in hemoglobinopathies (SCA, sickle cell trait, SC hemoglobinopathy, alpha-thalassemia and beta-thalassemia) were included. The methodological quality of the articles was assessed using the Newcastle-Ottawa scale., Results: Four studies were selected for analysis, resulting in a sample size of 582 participants: 289 with SCA, 133 with SC hemoglobinopathy, 40 with beta-thalassemia, 100 healthy individuals and none with alpha-thalassemia or sickle cell trait. Dilatation of the cardiac chambers, left and right ventricular hypertrophy, pulmonary hypertension, diastolic dysfunction, mitral regurgitation and tricuspid regurgitation are more prevalent in SCA than in the other hemoglobinopathies considered. Myocardial iron overload is more frequent in thalassemia major than in sickle cell anemia. Systolic function is similar between different hemoglobinopathies., Conclusion: There is greater cardiovascular impairment in individuals with SCA than in those with other hemoglobinopathies, reinforcing the necessity for regular cardiovascular follow-up in sickle cell patients.

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% α 0 -thalassemia, 0.8% β-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., (© 2022. The Author(s).)

α-Thalassemia is one of the most important genetic modulators of sickle cell disease (SCD). Both beneficial and detrimental effects have been described previously. We use a 12-year data set on a large cohort of patients with HbSS (n = 411) and HbSC (n = 146) to examine a wide range of these clinical and laboratory associations. Our novel findings are that α-thalassemia strongly reduces erythrocyte potassium chloride co-transporter (KCC) activity in both HbSS and HbSC (p = .035 and p = .00045 respectively), suggesting a novel mechanism through which α-thalassemia induces a milder phenotype by reducing red cell cation loss. This may be particularly important in HbSC where reduction in mean cell hemoglobin concentration is not seen and where KCC activity has previously been found to correlate with disease severity. Additionally, we show that α-thalassemia not only increases hemoglobin in patients with HbSS (p = .0009) but also reduces erythropoietin values (p = .0005), demonstrating a measurable response to improved tissue oxygenation. We confirm the reno-protective effect of α-thalassemia in patients with HbSS, with reduced proteinuria (p = .003) and demonstrate a novel association with increased serum sodium (p = .0004) and reduced serum potassium values (p = 5.74 × 10 -10 ). We found patients with α-thalassemia had a reduced annualized transfusion burden in both HbSS and HbSC, but α-thalassemia had no impact on annualized admission rates in either group. Finally, in a larger cohort, we report a median survival of 62 years in patients with HbSS (n = 899) and 80 years in those with HbSC (n = 240). α-thalassemia did not influence survival in HbSS, but a nonsignificant trend was seen in those with HbSC., (© 2022 The Authors. American Journal of Hematology published by Wiley Periodicals LLC.)

Alpha-thalassemia X-linked intellectual disability syndrome (ATRX) is a rare genetic condition caused by mutations in the ATRX gene characterized by distinctive dysmorphic features, alpha thalassemia, mild-to-profound intellectual disability, and epilepsy, reported in nearly 30% of the patients. To date, different types of seizures are reported in patients with ATRX syndrome including either clonic, tonic, myoclonic seizures or myoclonic absences. However, an accurate analysis of electroencephalographic features is lacking in literature. We report on the epileptic and electroencephalographic phenotype of seven unpublished patients with ATRX syndrome, highlighting the presence of a peculiar EEG pattern characterized by diffuse background slowing with superimposed low voltage fast activity. Likewise, we also review the available literature on this topic., Competing Interests: Declaration of competing interest All authors declare no conflict of interest., (© 2022 Published by Elsevier Ltd on behalf of European Paediatric Neurology Society.)

Competing Interests: Declaration of competing interest The authors declare no conflict of interest.

Background: Sickle cell anemia is a disease that develops episodes of acute pain and multiple organ dysfunction that can affect the growth hormone/insulin-like growth factor 1 (GH/IGF-1) axis. The severity of sickle cell anemia is influenced by modifying factors, such as levels of fetal hemoglobin (HbF), the co-inheritance of alphathalassemia, or treatment with hydroxyurea., Methods: This cross-sectional study in children with sickle cell anemia evaluated bone age (BA), adult height prediction (AHP) using BA, a target height (TH) calculated as the mean SDS of the parents, and laboratory parameters. Children were grouped according to serum levels of HbF, co-inheritance of alpha-thalassemia, and hydroxyurea therapy.., Results: The mean age of the 39 children was 8.2 ± 2.2 years old. The average height was -0.75 ± 0.30 SDS, and 10.3% (4/39) had short stature. Adjusted levels of IGF-1 or IGFBP- 3 were significantly higher in children with sickle cell anemia on hydroxyurea treatment, in children with HbF levels >10%, and in those without alpha-thalassemia. Using SDS, the growth potential of children with sickle cell anemia in relation to their parents calculated by the difference between AHP and TH as well as the difference between children's height and their TH, were lower in children with co-inheritance of alphathalassemia., Conclusion: The study showed an association between modifying factors and the GH/IGF-1 axis in children with sickle cell anemia. Additionally, the co-inheritance of alpha-thalassemia was associated with decreased height in these children when adjusted for their parents' height., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

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&#95;000489.5:c.6848A>C, (p.Lys2283Thr) in exon 31 of the ATRX gene., (Copyright © 2021 Elsevier Inc. All rights reserved.)

The present study tested the impact of α-thalassaemia on oxygen gradient ektacytometry in sickle cell anaemia (SCA). Three SCA groups were compared: (i) no α-thalassaemia (four α-genes, n = 62), (ii) silent α-thalassaemia (three α-genes, n = 35) and (iii) homozygous α-thalassaemia (two α-genes, n = 12). Red blood cell (RBC) deformability measured in normoxia was not different between the three groups. The lowest RBC deformability reached at low oxygen partial pressure (pO 2 ) was greater and the pO 2 at which RBC started to sickle was lower in the two α-genes group compared to the other groups. Our present study showed an effect of α-thalassaemia on oxygen gradient ektacytometry in SCA., (© 2021 British Society for Haematology and John Wiley & Sons Ltd.)

Background: Mirror syndrome (MS) is a rare obstetric disorder complicated with high maternal morbidity and fetal mortality. MS is often misdiagnosed or underdiagnosed due to the low incidence and lack of awareness of its diverse features. This study aimed to summarise the etiology, clinical characteristics, and risk factors of MS among mothers with fetal hydrops., Methods: This retrospective case-control study included 37 pregnant women with fetal hydrops in the second and third trimesters from 58,428 deliveries performed at the Third Affiliated Hospital of Sun Yat-Sen University between January 2012 and December 2020. Cases were categorized as MS and non-MS according to the presence or absence of maternal mirroring symptoms. Binary logistic regression was performed for analysis., Results: Fourteen women developed MS with an overall incidence of 0.024% (14/58,428) and 37.8% (14/37) in the fetal hydrops cases. Among the 11 MS cases with known associated etiologies, seven had alpha thalassemia major. Onset of fetal hydrops was later (27.8 vs. 23.0 weeks) and the rate of placental thickening was higher (85.7% vs. 34.8%) in the MS group than in the non-MS group (P < 0.05). Regarding maternal characteristics, the MS group had higher maternal morbidity (85.7% vs. 8.7%), more weight gain (9.0 vs. 5.5 kg), higher rates of hypertension (35.7 vs. 0%) and proteinuria (64.3% vs. 4.3%), and lower levels of hemoglobin (88 vs. 105 g/L) and serum albumin (25.8 vs. 35.0 g/L) than the non-MS group (P < 0.05). Logistic regression analysis showed that onset of fetal hydrops at ≥24 weeks and placental thickening were associated with the risk of MS among fetal hydrops cases (OR 15.83, 95% CI 1.56-160.10 and OR 8.63, 95% CI 1.29-57.72, respectively)., Conclusions: MS is relatively common among fetal hydrops cases in the late second and third trimesters, and alpha thalassemia major is the main etiology for fetal hydrops and also MS in this population. Complicated with high maternal morbidity, the key maternal features of MS include more weight gain, hemodilution, and hypertension. Among those with fetal hydrops, the onset time of ≥24 weeks and placental thickening are risk factors for MS., (© 2021. The Author(s).)

Alpha-thalassemia X-linked intellectual disability (ATR-X) syndrome affects males and is associated with profound developmental delay, facial dysmorphism, genital abnormalities, and alpha thalassemia. Appropriate oral health management for affected patients is important. The purposes of this report are to describe a case involving six years of oral health management, including training in eating, drinking and swallowing, for a patient with ATR-X syndrome, and to discuss the morphological and functional oral characteristics of this disorder. The patient's oral dysfunctions were incompetent lip-closing, inappropriate tongue protrusion, deviation of chewing acquisition, and incompetent oral and pharyngeal bolus propulsion. Other problems included inappropriate ingestion posture, low interest in meals, and poor oral hygiene. A stable oral intake and an improved eating posture were achieved through an intervention; however, the patient's inappropriate tongue protrusion, deviation of chewing acquisition, and incompetent bolus propulsion remained unchanged.

Background: Stroke is a devastating complication of sickle cell anemia (SCA) and can be predicted through abnormally high cerebral blood flow velocity using transcranial Doppler Ultrasonography (TCD). The evidence on the role of alpha-thalassemia and glucose-6-phosphate dehydrogenase (G6PD) deficiency in the development of stroke in children with SCA is conflicting. Thus, this study investigated the association of alpha-thalassemia and G6PD(A - ) variant with abnormal TCD velocities among Nigerian children with SCA., Methods: One hundred and forty-one children with SCA were recruited: 72 children presented with normal TCD (defined as the time-averaged mean of the maximum velocity: < 170 cm/s) and 69 children with abnormal TCD (TAMMV ≥ 200 cm/s). Alpha-thalassemia (the α-3.7 globin gene deletion) was determined by multiplex gap-PCR, while G6PD polymorphisms (202G > A and 376A > G) were genotyped using restriction fragment length polymorphism-polymerase chain reaction., Results: The frequency of α-thalassemia trait in the children with normal TCD was higher than those with abnormal TCD: 38/72 (52.8%) [α-/ α α: 41.7%, α -/ α -: 11.1%] versus 21/69 (30.4%) [α-/ α α: 27.5%, α -/ α -: 2.9%], and the odds of abnormal TCD were reduced in the presence of the α-thalassemia trait [Odds Ratio: 0.39, 95% confidence interval: 0.20-0.78, p = 0.007]. However, the frequencies of G6PDA - variant in children with abnormal and normal TCD were similar (11.6% vs. 15.3%, p = 0.522)., Conclusion: Our study reveals the protective role of α-thalassemia against the risk of abnormal TCD in Nigerian children with SCA., (© 2021 The Authors. Journal of Clinical Laboratory Analysis published by Wiley Periodicals LLC.)

Fetal anemia is common in malaria-endemic areas and a risk factor for anemia as well as mortality during infancy. Placental malaria (PM) and red cell abnormalities have been proposed as possible etiologies, but the relationship between PM and fetal anemia has varied in earlier studies, and the role of red cell abnormalities has not been studied in malaria-endemic areas. In a Tanzanian birth cohort study designed to elucidate the pathogenesis of severe malaria in young infants, we performed a cross-sectional analysis of risk factors for fetal anemia. We determined PM status, newborn red cell abnormalities, and maternal and cord blood levels of iron regulatory proteins, erythropoietin (EPO), cytokines and cytokine receptors. We examined the relationship between these factors and fetal anemia. Fetal anemia was present in 46.2% of the neonates but was not related to PM. Maternal iron deficiency was common (81.6%), most frequent in multigravidae, and interacted with parity to modify risk of fetal anemia, but it was not directly related to risk. Among offspring of iron-deficient women, the odds of fetal anemia increased with fetal α + -thalassemia, as well as these patterns of cord blood cytokines: increased cord IL-6, decreased TNF-RI, and decreased sTfR. The EPO response to fetal anemia was low or absent and EPO levels were significantly decreased in newborns with the most severe anemia. This study from an area of high malaria transmission provides evidence that 1) fetal α + -thalassemia and cytokine balance, but not PM at delivery, are related to fetal anemia; 2) maternal iron deficiency increases the risk that other factors may cause fetal anemia; and 3) fetal anemia has a multifactorial etiology that may require a variety of interventions, although measures that reduce maternal iron deficiency may be generally beneficial., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Kabyemela, Fried, Kurtis, Moses, Gorres, Muehlenbachs and Duffy.)

Alpha thalassemia and beta-globin haplotype are considered classical genetic disease modifiers in sickle cell anemia (SCA) causing clinical heterogeneity. Nevertheless, their functional impact on SCA disease emergence and progression remains elusive. To better understand the role of alpha thalassemia and beta-globin haplotype in SCA, we performed a retrospective study evaluating the clinical manifestations of 614 patients. The univariate analysis showed that the presence of alpha-thalassemia -3.7-kb mutation (αα/-α and -α/-α) decreased the risk of stroke development (p = 0.046), priapism (p = 0.033), and cholelithiasis (p = 0.021). Furthermore, the cumulative incidence of stroke (p = 0.023) and cholelithiasis (p = 0.006) was also significantly lower for patients carrying the alpha thalassemia -3.7-kb mutation. No clinical effects were associated with the beta-globin haplotype analysis, which could be explained by the relatively homogeneous haplotype composition in our cohort. Our results reinforce that alpha thalassemia can provide protective functions against hemolysis-related symptoms in SCA. Although, several genetic modifiers can impact the inflammatory state of SCA patients, the alpha thalassemia mutation remains one of the most recurrent genetic aberration and should therefore always be considered first.

Hyperbilirubinemia in patients with sickle cell anemia (SCA) as a result of enhanced erythrocyte destruction, lead to cholelithiasis development in a subset of patients. Evidence suggests that hyperbilirubinemia may be related to genetic variations, such as the UGT1A1 gene promoter polymorphism, which causes Gilbert syndrome (GS). Here, we aimed to determine the frequencies of UGT1A1 promoter alleles, alpha thalassemia, and β S haplotypes and analyze their association with cholelithiasis and bilirubin levels. The UGT1A1 alleles, -3.7 kb alpha thalassemia deletion and β S haplotypes were determined using DNA sequencing and PCR-based assays in 913 patients with SCA. The mean of total and unconjugated bilirubin and the frequency of cholelithiasis in GS patients were higher when compared to those without this condition, regardless of age (P < 0.05). Cumulative analysis demonstrated an early age-at-onset for cholelithiasis in GS genotypes (P < 0.05). Low fetal hemoglobin (HbF) levels and normal alpha thalassemia genotype were related to cholelithiasis development (P > 0.05). However, not cholelithiasis but total and unconjugated bilirubin levels were associated with β S haplotype. These findings confirm in a large cohort that the UGT1A1 polymorphism influences cholelithiasis and hyperbilirubinemia in SCA. HbF and alpha thalassemia also appear as modulators for cholelithiasis risk.

Haemoglobin H (HbH) disease is a type of non-transfusion-dependent thalassaemia. This cross-sectional study aimed at determining the prevalence and severity of liver iron overload and liver fibrosis in patients with HbH disease. Risk factors for advanced liver fibrosis were also identified. A total of 80 patients were evaluated [median (range) age 53 (24-79) years, male 34%, non-deletional HbH disease 24%]. Patients underwent 'observed' T2-weighted magnetic resonance imaging examination for liver iron concentration (LIC) quantification, and transient elastography for liver stiffness measurement (LSM) and fibrosis staging. In all, 25 patients (31%) had moderate-to-severe liver iron overload (LIC ≥7 mg/g dry weight). The median LIC was higher in non-deletional than in deletional HbH disease (7·8 vs. 2.9 mg/g dry weight, P = 0·002). In all, 16 patients (20%) had advanced liver fibrosis (LSM >7.9 kPa) and seven (9%) out of them had probable cirrhosis (LSM >11.9 kPa). LSM positively correlated with age (R = 0·24, P = 0·03), serum ferritin (R = 0·36, P = 0·001) and LIC (R = 0·28, P = 0·01). In multivariable regression, age ≥65 years [odds ratio (OR) 4·97, 95% confidence interval (CI) 1·52-17·50; P = 0·047] and moderate-to-severe liver iron overload (OR 3·47, 95% CI 1·01-12·14; P = 0·01) were independently associated with advanced liver fibrosis. The findings suggest that regular screening for liver complications should be considered in the management of HbH disease., (© 2020 British Society for Haematology and John Wiley & Sons Ltd.)

Background: ATR-X syndrome is an X-linked clinical condition usually associated with profound intellectual disability, facial dysmorphism and alpha-thalassemia. The syndrome is clinically heterogeneous with a broad phenotypic spectrum. Although, alpha-thalassaemia is commonly present, it may not manifest in some patients. Case report: A novel missence mutation (NM&#95;000489: ATRX; c.6130C > T; p.Leu2044Phe) was detected in the ATR-X gene in two male siblings with severe intellectual disability, dysmorphic facial appearance and skeletal anomalies. Severe kyphoscoliosis was the main finding. Hematologic findings, one of the well-known clinical entities, were not present. Conclusion: The missense mutation we have described in our patients has not been previously reported. This finding enriches mutation spectrum of ATRX (OMIM #300032) gene. This missense mutation, which is associated with ID and kyphoscoliosis and without alpha-thalassemia, contributes to genotype-phenotype correlation of the ATR-X spectrum. This case report provides further evidence that reverse genetics is a useful approach in diagnostic process of syndromic patients in adulthood.

Objectives: We analyzed hemoglobin (Hb) levels and degree of anemia in relation to genotype in patients with hemoglobin H (Hb H) disease, thereby providing a scientific basis for the prevention and treatment of Hb H disease in the Guangxi region of China., Methods: Hb analysis was conducted in 615 patients using high performance liquid chromatography. Seven α-thalassemia and 17 β-thalassemia genotypes commonly found in the Chinese population were detected by Gap-polymerase chain reaction and reverse dot hybridization. Multiple ligation-dependent probe amplification and sequencing were used to detect α-globin gene., Results: On analyzing the degree of anemia, we found that the proportion of severe and moderate anemia was the highest among cases with - SEA /α CS α genotype, followed by - SEA /α QS α. When Hb H disease was present in combination with β-thalassemia, the clinical symptoms of most patients were milder than those with simple Hb H disease., Conclusion: The clinical manifestations of various types of Hb H disease are heterogeneous; the Hb levels of patients with deletional Hb H are generally higher than those with non-deletional Hb H ( P < 0.05). In-depth knowledge of the gene mutation spectrum of thalassemia in Guangxi can provide a basis for genetic counseling of couples and enable prenatal diagnosis.

Elevated Hb A 2 level (≥4.0%) is considered to be reliable parameter to identify β-thalassemia (β-thal) carriers. However, some β-thal carriers have been misdiagnosed as their Hb A 2 levels are below 4.0%. In addition, coinheritance of α-thalassemia (α-thal) and β-thal might affect Hb A 2 levels. Therefore, the aim of this study was to investigate the mutations of β- and α-globin genes in individuals with borderline Hb A 2 levels in Thailand. Three hundred samples from individuals with Hb A 2 levels of 3.5-3.9% were collected for molecular diagnosis of β-globin gene mutations. In addition, the α 0 -thal, α + -thal, Hb Constant Spring (Hb CS, HBA2 : c.427T>C), and Hb Paksé ( HBA2 : c.429A>T) diagnostics were also performed. Sixteen samples (5.33%) had β-globin gene mutations, and codon 41/42 (-TTCT) ( HBB : c.126&#95;129delCTTT) was the most prevalent mutation. Ninety-eight samples (32.67%) had α-globin gene mutations including four Hb H (β4)-Hb CS disease, two Hb H disease, 13 heterozygous α 0 -thal, 11 homozygous α + -thal, two α + -thal/Hb CS, one α + -thal/Hb Paksé, 61 heterozygous α + -thal, and four Hb CS. Furthermore, seven cases of β-thal carriers coinheriting α-thal were observed, and five of them carried Hb H disease. High prevalence of both α- and β-thal in subjects with borderline Hb A 2 levels suggested that molecular diagnosis of α- and β-thal should be performed, especially in a high prevalence area of thalasssemia carriers, for accurate diagnosis and genetic counseling to prevent and control new severe thalassemia cases. Moreover, β-thal carriers who coinherited Hb H disease might have reduced Hb A 2 levels, leading to a misdiagnosis of β-thal in analysis programs.

Background: Cardiorenal syndrome (CRS), a serious condition with high morbidity and mortality, is characterized by the coexistence of cardiac abnormality and renal dysfunction. There is limited information about CRS in association thalassemia. This study aimed to investigate the prevalence of CRS in thalassemia patients and also associated risk factors., Methods: Thalassemia patients who attended the out-patient clinic of a tertiary care university hospital from October 2016 to September 2017 were enrolled onto this cross-sectional study. Clinical and laboratory findings from 2 consecutive visits, 3 months apart, were assessed. The criteria for diagnosis of CRS was based on a system proposed by Ronco and McCullough. Cardiac abnormalities are assessed by clinical presentation, establishment of acute or chronic heart failure using definitions from 2016 ESC guidelines or from structural abnormalities shown in an echocardiogram. Renal dysfunction was defined as chronic kidney disease according to the 2012 KDIGO guidelines., Results: Out of 90 thalassemia patients, 25 (27.8%) had CRS. The multivariable analysis showed a significant association between CRS and extramedullary hematopoiesis (EMH) (odds ratio (OR) 20.55, p = 0.016); thalassemia type [β 0 /β E vs β 0 /β 0 thalassemia (OR 0.005, p = 0.002)]; pulmonary hypertension (OR 178.1, p = 0.001); elevated serum NT-proBNP (OR 1.028, p = 0.022), and elevated 24-h urine magnesium (OR 1.913, p = 0.016). There was no association found between CRS and frequency of blood transfusion, serum ferritin, liver iron concentration, cardiac T2*, type of iron chelating agents, or urine neutrophil gelatinase-associated lipocalin level., Conclusions: CRS is relatively common in thalassemia patients. Its occurrence is associated with laboratory parameters which are easily measured in clinical practice.

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.

Objective:  To assess fetal cardiac remodeling in response to anemia, by comparing the fetal cardiac dimensions and global sphericity index (GSI) of normal fetuses and fetuses with anemia using fetal Hb Bart's disease as a study model., Methods:  Fetuses at risk for Hb Bart's disease undergoing cordocentesis at 18 to 22 weeks of gestation were recruited. Fetal cardiac dimensions including GSI (cardiac length to cardiac width ratio), interventricular septum thickness (IVST), left ventricular wall thickness (LVWT) and right ventricular wall thickness (RVWT) were measured., Results:  215 pregnancies at risk met the inclusion criteria, including 54 affected fetuses and 161 normal fetuses. The mean GSI was significantly lower in the affected group (1.11 ± 0.06 vs. 1.26 ± 0.09, p-value 0.017). The GSI of the normal group was relatively constant regardless of gestational age. The IVST and LVWT tended to increase, but not significantly, in the affected group, whereas the RVWT was minimally but significantly increased. The ROC curve for GSI had an area under curve of 0.844. The best cut-off of GSI was 1.17, giving a sensitivity of 74.1 % and a specificity of 88.2 %., Conclusion:  Fetal cardiac remodeling in response to anemia causes a marked decrease in global GSI with minimal hypertrophy as an adaption to volume overload. Importantly, GSI is a new maker for anemia and may play a role in clinical application for early detection of fetal anemia, possibly due to any cause. Additionally, GSI measurement is simple and gestational age-independent., Competing Interests: The authors declare that they have no conflict of interest., (© Georg Thieme Verlag KG Stuttgart · New York.)

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 β-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 β-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 β-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., (© 2019 Wiley Periodicals, Inc.)

Hb S ( HBB : c.20A>T) and α- and/or β-thalassemia (α- and/or β-thal) coinheritance is a common genetic disorder in regions with a high prevalence of thalassemia and sickle cell disease. The clinical manifestations of this coinheritance vary from mild to severe complications. Iran is a country with a high incidence of thalassemia and sickle cell disease. This study aimed to evaluate the coinheritance of sickle cell disease with α- and/or β-thal in Iranian patients. In this cross-sectional study from 2018-2019, a total of 47 participants with the Hb S abnormality, who were referred to the Zafar Thalassemia Clinic (Tehran, Iran), were selected as a study group. Molecular analysis for the evaluation of α and β gene mutations was performed in all participants. Hb SS, Hb S/β-thal and Hb S/Hb D-Punjab (also known as Hb D-Los Angeles, Hb D-Chicago, Hb D-North Carolina, Hb D-Portugal and Hb Oak Ridge) ( HBB : c.364G>C) were detected in 21 (44.7%), 23 (48.9%) and three (6.4%) patients, respectively. α Gene mutations were also detected in five patients with Hb S/β-thal, four patients with sickle cell disease and one patient with Hb S/Hb D-Punjab. In the current study, -α 3.7 /αα with β gene abnormalities was the most common genotype. Our study showed that the coinheritance of sickle cell disease with α- and β-thal is common and evaluation of these disorders, especially in pre marriage screening is important for diagnosis and management strategies.

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.

The X-linked alpha thalassemia mental retardation (ATR-X) syndrome is a genetic disorder caused by X-linked recessive mutations in ATRX gene, related to a wide spectrum of clinical manifestations, such as alpha thalassemia, developmental delay, genital abnormalities, and gastrointestinal disorders. Patients with ATR-X syndrome can suffer from different types of epileptic seizures, but a severe epileptic encephalopathy pattern has not been described to date. We describe, for the first time, two brothers with genetically confirmed ATR-X syndrome who presented with drug-resistant epileptic encephalopathy, with tonic and polimorphic seizures reported in the elder brother and epileptic spasms in the younger brother. Moreover, both brothers showed a peculiar movement disorder with myoclonus-dystonia, worsened during periods of distress or pain. These cases expand the clinical spectrum of ATR-X syndrome and open new opportunities for the molecular diagnosis of ATRX mutations in male patients with severe epileptic encephalopathies and movement disorders., Competing Interests: None of the authors have any conflicts of interest to disclose.., (Georg Thieme Verlag KG Stuttgart · New York.)

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., (© 2019 Wiley Periodicals, Inc.)

Background: The genetic background of patients with hemoglobin (Hb) H disease in Taiwan has been investigated; however, the clinical features and treatment outcomes were not reported., Objective: To analyze the clinical features and genotypes of patients with HbH who reside in Taiwan., Methods: We conducted a retrospective analysis of the clinical and molecular characteristics of 38 patients with HbH disease who were undergoing treatment at Kaohsiung Medical University Hospital, Taiwan., Results: Initial Hb levels were lower and the numbers of patients requiring iron-chelation therapy were higher in the nondeletional HbH group than in the deletional HbH group (P <.05). Compared with the healthy population, the patients with HbH disease exhibited short body length, low body weight, and low body mass index (BMI)., Conclusions: Patients with nondeletional HbH disease had lower Hb levels and a higher requirement for splenectomy and iron-chelation therapy than did those with deletional HbH disease. Also, growth status was compromised in patients with HbH disease., (© American Society for Clinical Pathology 2018. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objective: Determine the effect of fetal hemoglobin (HbF) and α-thalassemia on red blood cell (RBC) deformability of patients with sickle-cell anemia (SCA) with and without hydroxyurea (HU)., Methods: Adult patients were enrolled in the Sickle Cell Program of the Cardeza Foundation (Thomas Jefferson University) and were followed up prospectively during the period in which the Multicenter Study of Hydroxyurea (MSH) in patients with SCA was conducted. Ninety-one patients did not receive HU, 20 patients were enrolled in MSH, and 10 patients were enrolled in an open-label study of HU in SCA. Of the 20 patients enrolled in MSH, 11 took HU and nine took placebo. Control group included 113 normal individuals. Red blood cell deformability index (DI) was measured by ektacytometry., Results: Patients with SCA taking HU (n = 21) had higher DI than those taking placebo (n = 9) or who were not taking this therapy (n = 91). In patients without therapy, those with α-thalassemia (n = 31) had higher DI than those without. We showed a significant positive correlation between the level of HbF and DI. SCA patients without α-thalassemia and HbF <10% (n = 48) had lower DI than patients with α-thalassemia and HbF <10% (n = 23) and patients with (n = 8) or without α-thalassemia but with HbF >10% (n = 12). DI measured in patients without α-thalassemia and HbF >10% was higher than in the three other subgroups., Conclusion: Elevated levels of HbF with or without HU and α-thalassemia improve sickle RBC rheology, which, in turn, improve the clinical picture of SCA., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

In sub-Saharan Africa, inherited causes of anemia are common, but data are limited regarding the geographical prevalence and coinheritance of these conditions and their overall contributions to childhood anemia. To address these questions in Malawi, we performed a secondary analysis of the 2015-2016 Malawi Micronutrient Survey, a nationally and regionally representative survey that estimated the prevalence of micronutrient deficiencies and evaluated both inherited and noninherited determinants of anemia. Children age 6 to 59 months were sampled from 105 clusters within the 2015-2016 Malawi Demographic Health Survey. Hemoglobin, ferritin, retinol binding protein, malaria, and inflammatory biomarkers were measured from venous blood. Molecular studies were performed using dried blood spots to determine the presence of sickle cell disease or trait, α-thalassemia trait, and glucose-6-phosphate dehydrogenase (G6PD) deficiency. Of 1279 eligible children, 1071 were included in the final analysis. Anemia, iron deficiency, and malaria were common, affecting 30.9%, 21.5%, and 27.8% of the participating children, respectively. α-Thalassemia trait was common (>40% of children demonstrating deletion of 1 [33.1%] or 2 [10.0%] α-globin genes) and associated with higher prevalence of anemia ( P < .001). Approximately 20% of males had G6PD deficiency, which was associated with a 1.0 g/dL protection in hemoglobin decline during malaria infection ( P = .02). These data document that inherited blood disorders are common and likely play an important role in the prevalence of anemia and malaria in Malawian children.

Introduction: Anaemia in women during pregnancy and child bearing age is one of the most common global health problems. Reasons are numerous, but in many cases only minimal attempts are made to elucidate the underlying causes. In this study we aim to identify aetiology of anaemia in women of child bearing age and to determine the relative contributions, effects and interactions of α- and β-thalassaemia in a region of the world where thalassaemia is endemic., Methods: A cross sectional study was conducted at the Colombo North Teaching Hospital of Sri Lanka. The patient database of deliveries between January 2015 and September 2016 at University Obstetrics Unit was screened to identify women with anaemia during pregnancy and 253 anaemic females were randomly re-called for the study. Data were collected using an interviewer-administered questionnaire and haematological investigations were done to identify aetiologies., Results: Out of the 253 females who were anaemic during pregnancy and were re-called, 8 were excluded due to being currently pregnant. Of the remaining 245 females, 117(47.8%) remained anaemic and another 22(9.0%) had non-anaemic microcytosis. Of anaemic females, 28(24.8%) were iron deficient, 40(35.4%) had low-normal serum ferritin without fulfilling the criteria for iron deficiency,18(15.3%) had β-haemoglobinopathy trait and 20(17.0%) had α-thalassaemia trait. Of females who had non-anaemic microcytosis, 14(66.0%) had α-thalassaemia trait. In 4 females, both α- and β-thalassaemia trait coexist. These females had higher levels of haemoglobin (p = 0.06), MCV (p<0.05) and MCH (p<0.01) compared to individuals with only β-thalassaemia trait. A significantly higher proportion of premature births (p<0.01) and lower mean birth weights (p<0.05) were observed in patients with α-thalassaemia trait., Conclusions: Nearly one third of anaemic females in child bearing age had thalassaemia trait of which α-thalassemia contributes to a majority. Both α- and β-thalassaemia trait can co-exist and have ameliorating effects on red cell indices in heterozygous states. α-Thalassaemia trait was significantly associated with premature births and low birth weight. It is of paramount importance to investigate the causes of anaemia in women of child bearing age and during pregnancy in addition to providing universal iron supplementation., Competing Interests: The authors have declared that no competing interests exist.

α-thalassemia X-linked intellectual disability (ATR-X) syndrome is caused by mutations in ATRX . An ATR-X model mouse lacking Atrx exon 2 displays phenotypes that resemble symptoms in the human intellectual disability: cognitive defects and abnormal dendritic spine formation. We herein target activation of sigma-1 receptor (Sig-1R) that can induce potent neuroprotective and neuroregenerative effects by promoting the activity of neurotrophic factors, such as brain-derived neurotrophic factor (BDNF). We demonstrated that treatment with SA4503, a potent activator of Sig-1R, reverses axonal development and dendritic spine abnormalities in cultured cortical neurons from ATR-X model mice. Moreover, the SA4503 treatment rescued cognitive deficits exhibited by the ATR-X model mice. We further found that significant decreases in the BDNF-protein level in the medial prefrontal cortex of ATR-X model mice were recovered with treatment of SA4503. These results indicate that the rescue of dendritic spine abnormalities through the activation of Sig-1R has a potential for post-diagnostic therapy in ATR-X syndrome.

Background: Evidence for association between sickle cell and alpha thalassemia trait and severe malaria is compelling. However, for these polymorphisms associations with uncomplicated malaria, and for G6PD deficiency associations with uncomplicated and severe malaria, findings have been inconsistent. We studied samples from a three-arm case-control study with the objective of determining associations between common host erythrocyte polymorphisms and both uncomplicated and severe malaria, including different severe malaria phenotypes., Method: We assessed hemoglobin abnormalities, α-thalassemia, and G6PD deficiency by molecular methods in 325 children with severe malaria age-matched to 325 children with uncomplicated malaria and 325 healthy community controls. Conditional logistic regression was used to measure associations between specified genotypes and malaria outcomes., Results: No tested polymorphisms offered significant protection against uncomplicated malaria. α-thalassemia homozygotes (&#95;α/&#95;α) had increased risk of uncomplicated malaria (OR 2.40; 95%CI 1.15, 5.03, p = 0.020). HbAS and α-thalassemia heterozygous (&#95;α/αα) genotypes protected against severe malaria compared to uncomplicated malaria (HbAS OR 0.46; 0.23, 0.95, p = 0.036; &#95;α/αα OR 0.51; 0.24, 0.77; p = 0.001) or community (HbAS OR 0.23; 0.11, 0.50; p<0.001; &#95;α/αα; OR 0.49; 0.32, 0.76; p = 0.002) controls. The α-thalassemia homozygous (&#95;α/&#95;α) genotype protected against severe malaria when compared to uncomplicated malaria controls (OR 0.34; 95%CI 0.156, 0.73, p = 0.005), but not community controls (OR 1.03; 0.46, 2.27, p = 0.935). Stratifying by the severe malaria phenotype, compared to community controls, the protective effect of HbAS was limited to children with severe anemia (OR 0.17; 95%CI 0.04, 0.65; p = 0.009) and that of &#95;α/αα to those with altered consciousness (OR 0.24; 0.09, 0.59; p = 0.002). A negative epistatic effect was seen between HbAS and &#95;α/αα; protection compared to uncomplicated malaria controls was not seen in individuals with both polymorphisms (OR 0.45; 0.11, 1.84; p = 0.269). G6PD deficiency was not protective against severe malaria., Conclusion: Associations were complex, with HbAS principally protective against severe anemia, &#95;α/αα against altered consciousness, and negative epistasis between the two polymorphisms., Competing Interests: The authors have declared that no competing interests exist.

Hb D-Los Angeles (or Hb D-Punjab) (HBB: c.364G > C) is found worldwide and is derived from a point mutation in the β-globin gene prevalent in the Punjab region of Northwestern India. Heterozygous or homozygous inheritance does not cause significant medical problems, whereas association with other hemoglobinopathies, especially β-thalassemia (β-thal) and sickle cell disease, changes the phenotype. Coinheritance of Hb D-Los Angeles with Hb H disease (α-/- -) has never been reported before. The presence of this rare combination in a family of Greek origin is herein described, and the challenges involving clinical management are discussed.