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Hereditary dyserythropoietic anemias, or congenital dyserythropoietic anemias (CDAs), are rare disorders disrupting normal erythroid lineage development, resulting in ineffective erythropoiesis and monolinear cytopenia. CDAs include three main types (I, II, III), transcription‐factor‐related forms, and syndromic forms. The widespread use of next‐generation sequencing in the last decade has unveiled novel causative genes and unexpected genotype–phenotype correlations. The discovery of the genetic defects underlying the CDAs not only facilitates accurate diagnosis but also enhances understanding of CDA pathophysiology. Notable advancements include identifying a hepatic‐specific role of the SEC23B loss‐of‐function in iron metabolism dysregulation in CDA II, deepening CDIN1 dysfunction during erythroid differentiation, and uncovering a recessive CDA III form associated with RACGAP1 variants. Current treatments primarily rely on supportive measures tailored to disease severity and clinical features. Comparative studies with pyruvate kinase deficiency have illuminated new therapeutic avenues by elucidating iron dyshomeostasis and dyserythropoiesis mechanisms. We herein discuss recent progress in diagnostic methodologies, novel gene discoveries, and enhanced comprehension of CDA pathogenesis and molecular genetics. [ABSTRACT FROM AUTHOR]

Background: Transient erythroblastopenia of childhood (TEC) is an acquired, self-limited pure red cell aplasia that usually occurs in children 4 years old and younger. This clinical condition has been priorly described to be linked to numerous viral and immunologic mechanisms. COVID-19, caused by the coronavirus SARS-CoV-2, was initially discovered in China in December 2019. The disease quickly spread worldwide, resulting in pandemic. Case Presentation: This manuscript reports a new clinically relevant condition associated to COVID-19, describing a child with clinical and biochemical signs of Pure Red Blood cells aplasia and complete absence of erythroblasts at the bone marrow needle aspiration with signs of erythrophagocytosis, resembling morphological signs such as in hemophagocytic lymphohistiocytosis (HLH), temporally associated to SARS-CoV-2 infection. Conclusion: This report highlights a newly described continuum laboratory and clinical spectrum of immune/hematological dysregulations secondary to SARS-CoV-2. SARS-CoV‐2 infection-linked TEC has never been described in literature, but, according to our findings, should be considered in all the patients with transient erythroblastopenia without congenital red blood cell abnormalities and serology negative for major infections associated with TEC. This condition must be considered in the same spectrum of MIS-C and the inter-links among the two clinical manifestations, as well as a potential interdependence among them, should be considered in the future. [ABSTRACT FROM AUTHOR]

Congenital hemolytic anemia (CHA) is defined as the premature destruction of red blood cells (RBC) due to congenital or acquired defects. The hereditary form of hemolytic anemia can be divided into hemoglobinopathies, membranopathies, and enzymopathies. Hereditary spherocytosis (HS) is the most common inherited RBC membranopathy leading to congenital hemolytic anemia. To date; five genes have been associated with HS coding for cytoskeleton and transmembrane proteins, those genes are SPTB, SLC4A1, EPB42, ANK1, and SPTA1. Due to genetic heterogeneity, clinical exome sequencing (CES) was performed on four unrelated Moroccan patients referred for CHA investigation. Sanger sequencing and qPCR were performed to confirm CES results and to study the de novo character of identified variants. The molecular analysis revealed 3 novel mutations and one previously reported pathogenic variant of the SPTB gene confirming the diagnosis of HS in the four patients. Hereditary spherocytosis anemia is a genetically heterogenous disease which could be misdiagnosed clinically. The introduction of novel sequencing technologies can facilitate accurate genetic diagnosis, allowing an adapted care of the patient and his family. [ABSTRACT FROM AUTHOR]

Hereditary spherocytosis (HS) is a membranopathy that impacts the vertical junctions between the cytoskeleton and the plasma membrane of erythrocytes. The gold standard method for diagnosing it is osmotic gradient ektacytometry (OGE). However, access to this technique is scarce. We have devised a straightforward approach utilizing flow cytometry to quantify variations in an osmotic gradient, relying on FSC-H/SSC-H patterns. We studied 14 patients (9 pediatric, 5 adults) and 54 healthy controls (16 pediatric, 38 adults). After assessing the behavior of the samples in several osmolar gradients we selected for the study the 176, 308, and 458 mOsm/kg levels as hypo-osmolar, iso-osmolar, and hyper-osmolar references. We then selected the iso-osmolar point for assessment to determine its efficacy in discriminating between patient and control groups using a receiver operating characteristic curve. In the pediatric group, the area under the curve (AUC) was 1.0, indicating 100% sensitivity and 93.3% specificity. Conversely, in the adult group, the AUC was 0.98, with 80% sensitivity and 90.9% specificity. We introduce a method that is easily replicable and demonstrates high sensitivity and specificity. This technique could prove valuable in the diagnosis of spherocytosis. [ABSTRACT FROM AUTHOR]

Hereditary spherocytosis (HS) is a membranopathy that impacts the vertical junctions between the cytoskeleton and the plasma membrane of erythrocytes. The gold standard method for diagnosing it is osmotic gradient ektacytometry (OGE). However, access to this technique is scarce. We have devised a straightforward approach utilizing flow cytometry to quantify variations in an osmotic gradient, relying on FSC-H/SSC-H patterns. We studied 14 patients (9 pediatric, 5 adults) and 54 healthy controls (16 pediatric, 38 adults). After assessing the behavior of the samples in several osmolar gradients we selected for the study the 176, 308, and 458 mOsm/kg levels as hypo-osmolar, iso-osmolar, and hyper-osmolar references. We then selected the iso-osmolar point for assessment to determine its efficacy in discriminating between patient and control groups using a receiver operating characteristic curve. In the pediatric group, the area under the curve (AUC) was 1.0, indicating 100% sensitivity and 93.3% specificity. Conversely, in the adult group, the AUC was 0.98, with 80% sensitivity and 90.9% specificity. We introduce a method that is easily replicable and demonstrates high sensitivity and specificity. This technique could prove valuable in the diagnosis of spherocytosis.

Background: Pyruvate kinase (PK) deficiency is a rare hereditary disorder characterized by chronic hemolytic anemia and serious sequalae which negatively affect patient quality of life. This study aimed to psychometrically validate the first disease-specific patient-reported outcome (PRO) instruments: the 7-item PK Deficiency Diary (PKDD) and 12-item PK Deficiency Impact Assessment (PKDIA), designed to assess signs, symptoms, and impacts of PK deficiency in patients enrolled in the ACTIVATE global phase 3 study of mitapivat versus placebo (NCT03548220). Methods: All validation analyses for the PKDD and PKDIA were performed on blinded data, with analyses on item integrity, scoring, reliability, and validity conducted on data from screening and baseline. Completion rates and baseline response distributions were characterized using descriptive statistics. Item response modelling was used to inform a weighted scoring system. Reliability was assessed by internal consistency and test–retest reliability; and validity by convergent and known-groups analyses. Results: Of the 80 adults enrolled, baseline data were available for 77 (96.3%) and 78 (97.5%) patients for the PKDD and PKDIA, respectively. Item responses skewed right, indicating that mean values exceeded median values, especially for items utilizing a 0–10 numeric scale, which were subsequently recoded to a 0–4 scale; 4 items were removed from the PKDIA due to redundancy or low relevance to the trial population. Both the PKDD and PKDIA demonstrated high internal consistency (McDonald's coefficient ω = 0.86 and 0.90, respectively), test–retest reliability (intra-class coefficients of 0.94 and 0.87, respectively), and convergent validity with other PROs (linear correlation coefficients [|r|] between 0.30–0.73 and 0.50–0.82, respectively). Conclusions: The findings provide evidence of validity and reliability for the PKDD and PKDIA, the first disease-specific PRO measures for PK deficiency, and can therefore increase understanding of, and more accurately capture, the wider impact of PK deficiency on health-related quality of life. Trial registration ClinicalTrials.gov, NCT03548220. Registered June 07, 2018; https://www.clinicaltrials.gov/ct2/show/NCT03548220. Plain language summary: Pyruvate kinase (PK) deficiency is a rare genetic blood disorder with a wide range of signs and symptoms that may have a negative impact on patients' quality of life. Patient-reported outcome (PRO) instruments are tools that assess how a disease affects a patient from the patient's perspective. These instruments must go through a validation process to make sure they truly capture the patient's experience with their condition or its treatment. This study aimed to validate two new PRO instruments in adult patients enrolled in the ACTIVATE clinical trial (NCT03548220), where patients with PK deficiency received the drug mitapivat or a placebo. These two new PRO instruments are the first to be developed specifically for PK deficiency: the PK Deficiency Diary (PKDD), a daily diary that asks 7 questions to measure the core signs and symptoms of PK deficiency, and the PK Deficiency Impact Assessment (PKDIA), a weekly questionnaire with 12 questions to assess the impact of PK deficiency on a patient's life. The results of this study showed that the PKDD and PKDIA properly and reliably measured the signs, symptoms, and impacts of PK deficiency that they aimed to capture. These findings indicate that the PKDD and PKDIA are the first validated PROs specifically for PK deficiency and can help improve the understanding of the impact of PK deficiency on patients' quality of life. [ABSTRACT FROM AUTHOR]

A male infant of Han descent, with a G1P1 mother and gestational age of 40+4 weeks, was born via cesarean section owing to his mother having pregnancy complications, including premature rupture of membranes, chorioamnionitis, and gestational diabetes. On the first day after birth, routine blood examination showed that his total red blood cells count was 2.32 × 1012/L, hemoglobin count was 77 g/L, and C-reactive protein count was 48.99 mg/L. After receiving an anti-infection treatment for 10 days and two blood transfusions (100 mL in total), he was discharged from a neonatal intensive care unit (NICU). Accessory examinations showed that reticulocytes in the peripheral blood were significantly increased, the morphology of red blood cells was normal, and all hemolysis-related examinations were normal; bone marrow examinations showed that the proliferation of the red blood cell system was low and serum ferritin and vitamin B12 levels were elevated. Because of the unexplained hemolysis, a whole-exome sequencing examination was performed. The results showed a hemizygous variant of the ATP11C gene (c.3136a>t/p ile 1046phe) and a frame-shift variant of the ANK1 gene (c.937del/pala313 leufs*19). After a six-month follow-up, the serum ferritin and vitamin B12 levels had gradually decreased to normal levels, and hemoglobin and reticulocyte values were 97 g/L and 7.17%, respectively, in the peripheral blood. No splenomegaly was found in physical examination. [ABSTRACT FROM AUTHOR]

Background: Congenital dyserythropoietic anemias (CDAs) are a very rare and heterogeneous group of disorders characterized by ineffective erythropoiesis. CDA II is caused by mutations in the SEC23B gene. The most common mutation reported in India is c.1385 A > G, p.Y462C. There is no simple and cost-effective confirmatory diagnostic test available for CDA, and therefore, many patients remain undiagnosed. High-resolution melting curve (HRM) analysis is a polymerase chain reaction (PCR) based technique applied to identify genetic differences and scan nucleic acid sequences. HRM can be used to rapidly screen the common mutation causing CDA II in the Indian population. Thus, we studied the use of High-Resolution Melting Curve Analysis to detect common mutation causing CDA II in the Indian population. Method: 11 patients having SEC23B (Y462C) mutation causing CDA II are considered for this study. HRM was used to check the presence of Y462C mutation. To verify the accuracy of the HRM analysis, we compared HRM results with the results of Sanger sequencing. This helped us to confirm the diagnosis. Results: We have described the clinical, hematological, and genetic data of eleven patients suffering from CDAII. According to HRM and Sanger sequencing, a homozygous SEC23B (Y462C) mutation was present in all patients, whereas a heterozygous Y462C mutation was present in their parents. Conclusion: Our data showed that High-Resolution Melting (HRM) analysis could be used to rapidly screen common SEC23B mutation that causes CDA II in the Indian population. [ABSTRACT FROM AUTHOR]

Summary: Posterior reversible encephalopathy syndrome is a rare and serious condition that presents with acute neurological symptoms with characteristic changes on imaging. It can lead to substantial morbidity and mortality, but can be reversible if recognised and treated. Here, we report a case of posterior reversible encephalopathy syndrome in a child post‐splenectomy under general anaesthesia with spinal anaesthesia. As far as we are aware, this condition has not previously been described in relation to spinal anaesthesia in the paediatric population. This case demonstrates the importance of recognising blood pressure changes in children, which can be challenging due to age‐, sex‐ and height‐related centiles for blood pressure measurements. Posterior reversible encephalopathy syndrome should be considered as a differential diagnosis for headache in a patient that has had a spinal anaesthesia. [ABSTRACT FROM AUTHOR]

Congenital hemolytic anemia (CHA) especially hemoglobinopathies is quite prevalent in certain ethnic groups in India and commonly seen in pediatric age group. Adult presentations are being seen due to better treatment options and increased life span. This study was conducted to determine the clinical profile, laboratory parameters, transfusion requirements, and transfusion-related infectious complications of adult patients with CHA. A total of 84 patients of CHA aged more than 12 years were enrolled and studied over 18 months period. 63% patients were males with mean age of 19.98±4.99 SD years and maximum (57%) in the age group of 13-20 years. Family history of CHA was present in 19 (22.61%) patients and consanguinity in 16 (19.04%) cases which were statistically significant (P

Hereditary pyropoikilocytosis (HPP) is characterised by severe hemolytic anemia due to membrane instability. We report the case of a 13-day-old boy with neonatal jaundice and severe hemolytic anemia. A peripheral smear examination showed severe anisopoikylocytosis. DNA sequencing revealed compound double heterozygous for mutant α-spectrin SPTA1 (Arg28His) and homozygous αLELY polymorphism (low expression α-spectrin allele), compatible with diagnosis of HPP.The patient required a blood transfusion initially, but spontaneously improved after two years. Our case illustrates that, despite the presence of the allele αLELY in homozygous, the clinical phenotype is similar to cases with a mutation in SPTA1 associated with αLELY in trans.

OBJECTIVE: The current meta-analysis was carried out to identify the efficacy and safety of thalidomide in transfusion-dependent β-thalassemia (TDT) patients. METHODS: Six databases: PubMed, EMBASE, Scopus, Cochrane Library, EBSCOhost, and MEDLINE were searched until November 18, 2021, for studies that assessed the efficacy of thalidomide in TDT patients by using the following search terms: “Thalidomide”, “thalidomid”, “thalomid”, “N-phthaloylglutamimide”, and Thalassemia” using Boolean or wildcard operators. Original research publications in English with observational and/or experimental designs having a sample size ≥10, regardless of age and gender, used thalidomide for ≥3 months exploring the impact of thalidomide in ameliorating transfusion needs among TDT patients were included in this meta-analysis. Data were independently extracted by two reviewers using a data extraction form. The National Institutes of Health tool was used for quality assessment. RESULTS: Nine studies collectively involving 407 TDT patients fulfilled eligibility criteria. Thalidomide was associated with complete cessation of blood transfusion requirements with an overall response of 54% (95% CI, 34–75%) to a transfusion-independent state; heterogeneity was considered high with an I2 of 94.7%, p-value

In this case study, we report an adult patient presenting with generalized weakness, marked anemia, spherocytosis, and no features of thalassemia. The patient was treated for suspicion of autoimmune hemolytic anemia but was recalcitrant to treatment. Genetic analysis revealed the patient to be homozygous for SLC4A1 c.2573C>A (p.Ala858Asp). Distal renal tubular acidosis (dRTA) can be caused by mutations in SLC4A1, which encodes the Cl-/HCO3- exchanger of the renal type A intercalated cell, kidney AE1. SLC4A1 variants have been reported in dRTA patients from North America, Europe, and Southeast Asia. In some rare instances, SLC4A1 dRTA can present with hemolytic anemia resulting in marked anemia that is not responsive to standard interventions. This report identifies an autosomal recessive inheritance pattern for SLC4A1 variants in a patient presenting with dRTA and hemolytic anemia. [ABSTRACT FROM AUTHOR]

Pyruvate kinase (PK) deficiency is a genetically and clinically heterogeneous congenital hemolytic anemia which manifests with a wide range of symptoms and complications. Given the clinical heterogeneity, clinicians should have a high suspicion of PK deficiency in patients with congenital hemolytic anemias, and both red cell enzyme and genetic testing should be pursued. Complications in PK deficiency can be associated with significant morbidity and mortality in transfused and non-transfused patients, including iron overload, osteopenia, and impact on quality of life and mental health, which require regular monitoring and management. A definitive diagnosis of PK deficiency has become critical with the availability of disease-modifying therapy with mitapivat, an oral PK activator which increases hemoglobin and decreases hemolysis in many patients, as well as the potential future curative option of gene therapy. Mutations in the PKLR gene lead to pyruvate kinase (PK) deficiency, causing chronic hemolytic anemia secondary to reduced red cell energy, which is crucial for maintenance of the red cell membrane and function. Heterogeneous clinical manifestations can result in significant morbidity and reduced health-related quality of life. Treatment options have historically been limited to supportive care, including red cell transfusions and splenectomy. Current disease-modifying treatment considerations include an oral allosteric PK activator, mitapivat, which was recently approved for adults with PK deficiency, and gene therapy, which is currently undergoing clinical trials. Studies evaluating the role of PK activators in other congenital hemolytic anemias are ongoing. The long-term effect of treatment with disease-modifying therapy in PK deficiency will require continued evaluation. [ABSTRACT FROM AUTHOR]

Objectives: It is uncommon for autoimmune hepatitis (AIH) to occur in combination with hereditary spherocytosis (HS). The present study examined the genetic and clinical features of a seven-year-old girl with yellow sclerae and abnormalities in liver function test results. Methods: Blood samples were taken from this girl, her parents, and a parental grandmother to be analyzed using laboratory tests and Sanger and next-generation sequencing (NGS). Results: Spectrin alpha, erythrocytic 1 (SPTA1) gene compound heterozygous mutations, were detected from this proband. Moreover, the proband inherited mutations c.6544G>C (p.D2182H) and Thec.134G>A (p.R45K) from her father and mother respectively. Moreover, both her father and grandmother shared an identical mutation. The mutations were not depicted in the Human Gene Mutation Database. Conclusions: HS shares some clinical features close to AIH hence, in the co-existence of AIH, its diagnosis can be challenging. The concurrent disorder may exist if a single autoimmune hepatopathy cannot explain laboratory findings. Pedigree investigations and genetic analyses might be required for the final diagnosis. [ABSTRACT FROM AUTHOR]

Background: Pyruvate Kinase (PK) deficiency is the most common enzyme defect of glycolysis, leading to congenital hemolytic anemia, which can occur during the neonatal period. Study Design and Methods: We report the prenatal management of fetal anemia related to PK deficiency in a family with a severe proband. Results: The couple had a first child born with hydrops, whose PK deficiency was diagnosed at 18 months of life. He was treated with allogeneic bone marrow transplantation. The second child was free from disease. For the third pregnancy, the amniocentesis revealed a PK deficiency. Weekly ultrasound monitoring of the middle cerebral artery velocity allowed the detection of severe fetal anemia. Two intrauterine red blood cell transfusions (IUTs) were performed, raising the fetal hemoglobin from 6.6 to 14.5 g/dl at 28 weeks' gestation and from 8.9 to 15.3 g/dl at 31 weeks. A hematopoietic stem cell allograft was discussed prenatally but not chosen, as it would not have significantly changed the perinatal prognosis. The patient delivered a 2730 g girl at 37 weeks, with hemoglobin of 13.6 g/dl. The child presented with neonatal jaundice treated with phototherapy and received postnatal transfusions. Discussion: When a proband is identified in a family, fetal investigation is warranted, to set up third‐trimester ultrasound surveillance and perinatal management. In case of fetal severe anemia of unknown etiology, the workup on fetal blood sampling before IUT should comprise the search for erythrocytes enzymopathies, such as PK deficiency. IUTs allow safer full‐term delivery in cases with PK deficiency. [ABSTRACT FROM AUTHOR]

Congenital hemolytic anemia (CHA) especially hemoglobinopathies is quite prevalent in certain ethnic groups in India and commonly seen in pediatric age group. Adult presentations are being seen due to better treatment options and increased life span. This study was conducted to determine the clinical profile, laboratory parameters, transfusion requirements, and transfusion-related infectious complications of adult patients with CHA. A total of 84 patients of CHA aged more than 12 years were enrolled and studied over 18 months period. 63% patients were males with mean age of 19.98±4.99 SD years and maximum (57%) in the age group of 13-20 years. Family history of CHA was present in 19 (22.61%) patients and consanguinity in 16 (19.04%) cases which were statistically significant (P<0.05). Easy fatigability (76.19%) was the most common symptom followed by dyspnea on exertion (36.19%), whereas pallor (98.80%) was the commonest finding on examination followed by spleenomegaly (40.47%). The mean average (mean±SD) values for hemoglobin was 7.37±1.23gm/dl, Red blood cell count was 4.71±0.44 million/µL, Mean Corpuscular Volume was 77±5.05 fL, Mean Corpuscular Hemoglobin concentration was 33±1.38 g/dl, Mean Corpuscular Hemoglobin was 23±1.22 pg and mean Mentzer's index was 16.59±2.24. The most common type of CHA in our study was ß thalassemia major (58%), followed by ß thalassemia intermedia (17%) and Sickle cell homozygous (13%). 45% of CHA patients required monthly transfusion (p <0.05) especially sickle cell homozygous (90%) and thalassemia major (65%) patients. 24 (28.57%) patients were Hepatitis C virus-positive and 1 was HIV virus-positive. Among adult patients with CHA, ß thalassemia major, intermedia and sickle cell anemia were predominant diagnoses. Consanguinity played a role in one-fifth of patients. A majority of the patients had monthly blood transfusion requirements. The high prevalence of hepatitis C virus infection is a major concern. [ABSTRACT FROM AUTHOR]

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Hereditary pyropoikilocytosis (HPP) is characterised by severe hemolytic anemia due to membrane instability. We report the case of a 13-day-old boy with neonatal jaundice and severe hemolytic anemia. A peripheral smear examination showed severe anisopoikylocytosis. DNA sequencing revealed compound double heterozygous for mutant _-spectrin SPTA1 (Arg28His) and homozygous αLELY polymorphism (low expression α-spectrin allele), compatible with diagnosis of HPP. The patient required a blood transfusion initially, but spontaneously improved after two years. Our case illustrates that, despite the presence of the allele αLELY in homozygous, the clinical phenotype is similar to cases with a mutation in SPTA1 associated with αLELY in trans. [ABSTRACT FROM AUTHOR]

Background: After ruling out the most common causes of severe hemolytic anemia by routine diagnostic tests, certain patients remain without a diagnosis. The aim of this study was to elucidate the genetic cause of the disease in these patients using next generation sequencing (NGS). Methods: Four unrelated Iranian families including six blood transfusion dependent cases and their parents were referred to us from a specialist center in Tehran. There was no previous history of anemia in the families and the parents had no abnormal hematological presentations. All probands presented severe congenital hemolytic anemia, neonatal jaundice and splenomegaly. Common causes of hemolytic anemia were ruled out prior to this investigation in these patients and they had no diagnosis. Whole exome sequencing (WES) was performed in the probands and the results were confirmed by Sanger sequencing and subsequent family studies. Results: We identified five variants in the PKLR gene, including a novel unpublished frameshift in these families. These variants were predicted as pathogenic according to the ACMG guidelines by Intervar and/or Varsome prediction tools. Subsequent family studies by Sanger sequencing supported the diagnosis of pyruvate kinase deficiency (PKD) in six affected individuals and the carrier status of disease in their parents. Conclusion: These findings show that PKD is among the rare blood disorders that could remain undiagnosed or even ruled out in Iranian population without performing NGS. This could be due to pitfalls in clinical, hematological or biochemical approaches in diagnosing PKD. Furthermore, genotyping PKD patients in Iran could reveal novel mutations in the PKLR gene. [ABSTRACT FROM AUTHOR]

Inborn hemolytic anemia requiring frequent blood transfusions can be a life-threatening disease. Treatment, besides blood transfusion, includes iron chelation for prevention of iron accumulation due to frequent blood transfusions. We present the results of a clinical investigation where the proband was diagnosed with severe hemolytic anemia of unknown origin soon after birth. Transfusion was required every 4–6 weeks. After whole exome sequencing of the proband and his parents as well as a healthy sibling, we established that the proband had a compound heterozygous state carrying two rare variants in the erythrocytic spectrin gene, SPTA1. The maternal allele was a stop mutation (rs755630903) and the paternal allele was a missense mutation (rs375506528). The healthy sibling had the paternal variant but not the maternal variant. These rare variants of SPTA1 most likely account for the hemolytic anemia. A severely reduced osmotic resistance in the erythrocytes from the proband was demonstrated. Splenectomy considerably improved the hemolytic anemia and obviated the need for blood transfusion despite the severe clinical presentation. [ABSTRACT FROM AUTHOR]

Simple Summary: ALK translocation is present in 4–5% of patients with non-small-cell lung cancer. Patients treated with alectinib invariably develop subclinical hemolysis, which is presumably caused by acanthocytic deformation and splenic trapping of blood erythrocytes. Morphologic red blood cell changes, decreased EMA testing, and reactive reticulocytosis develop in literally all patients early after the initiation of alectinib, but not other ALK inhibitors. These alterations are not associated with the efficacy of alectinib or the molecular features of ALK+ disease and resolve within a few months after a switch to other ALK–TKI but complicate any hematologic workup. Furthermore, the risk of long-term complications, such as cholelithiasis due to increased serum bilirubin in the majority of cases, remains unclear at present. Alectinib is a standard initial treatment for patients with advanced anaplastic lymphoma kinase (ALK) rearranged non-small-cell lung cancer (NSCLC). The current study analyzed a prospective cohort of 24 consecutive alectinib-treated patients and controls in order to comprehensively characterize longitudinal erythrocyte changes under treatment with ALK inhibitors. Upon starting alectinib, all examined patients developed reticulocytosis and abnormal erythrocyte morphology with anisocytosis and a predominance of acanthocytes (64% of red blood cells on average, range 36–100%) in the peripheral blood smear within approximately 2 weeks. Changes were accompanied by a gradual reduction in Eosin-5-maleimide (EMA) binding, which became pathologic (<80% of cells) within 1–2 months in all cases, mimicking an abortive form of hereditary spherocytosis. The latter could be ruled out in 3/3 of analyzed cases by normal sequencing results for the ANK1, EPB42, SLC4A1, SPTA1, or SBTB genes. The direct Coombs test was also negative in 11/11 tested cases. Besides, anemia, increased LDH, and increased bilirubin were noted in a fraction of patients only, ranging between 42 and 68%. Furthermore, haptoglobin decreases were infrequent, occurring in approximately 1/3 of cases only, and mild, with an average value of 0.93 g/L within the normal range of 0.3–2 g/dL, suggesting that hemolysis occurred predominantly in the extravascular compartment, likely due to splenic trapping of the deformed erythrocytes. These changes showed no association with progression-free survival under alectinib or molecular features, i.e., ALK fusion variant or TP53 status of the disease, and resolved upon a switch to an alternative ALK inhibitor. Thus, alectinib induces mild, reversible erythrocyte changes in practically all treated patients, whose most sensitive signs are aberrant red cell morphology in the peripheral smear, a pathologic EMA test, and reactive reticulocytosis. Frank hemolytic anemia is rare, but mild subclinical hemolysis is very frequent and poses differential-diagnostic problems. Alectinib can be continued under the regular control of hemolysis parameters, but the risk of long-term complications, such as cholelithiasis due to increased serum bilirubin in most patients, remains unclear at present. [ABSTRACT FROM AUTHOR]

Abstract Background Adenylate kinase (AK) deficiency is a rare red cell enzymopathy associated with moderate to severe congenital nonspherocytic hemolytic anemia, along with mental and psychomotor retardation (in exceptional cases). Only ten mutations have been detected in the AK1 gene to date. In this study, we aimed to diagnose the unexplained issue of haemolytic anaemia and offer antenatal screening to the family. Methods Genomic DNA was isolated from whole blood by a standard protocol. Targeted next-generation sequencing (t-NGS) was performed to identify pathogenic variants in the patient and control samples. A chronic villus sample was collected at 11 weeks of gestation from the mother, and molecular testing was performed. Genetic confirmation was concluded by Sanger DNA sequencing. Bioinformatics tools predicted the pathogenicity of the variant. Results t-NGS revealed a homozygous variant (c.301C > A, p. Gln101Lys) in the AK1 gene in the patient and heterozygosity in the fetus and parental samples. The prediction tools SIFT, Polyphen2, Provean, PMUT, Mutation taster, and Mutation Assessor, confirmed the damaging effect of the variant on the AK1 protein structure Conclusion We have presented a novel mutation in the AK1 gene (p. Gln101Lys) associated with adenylate kinase deficiency. It is the first prenatal diagnosis of AK deficiency in India, where heterogeneity is exceptionally high.

The aim of this paper is to assess the effectiveness and perioperative complications of splenic surgeries in children. In 41 splenectomies, an anterior abdominal laparoscopic approach was used, with 35 including a partial laparoscopic splenectomy. Of these, three needed a conversion to open. Six patients had a total splenectomy, three of which were open. Patients ranged in age from 5 to 18 years. Splenectomy was performed for a variety of causes, including hereditary spherocytosis (n = 20), splenic cysts (n = 13), sickle cell disease (n = 3), primary malignancy (n = 1), sepsis (n = 1), embolism (n = 1), anemia (n = 1), and hypersplenism (n = 1). The average length of stay was 7.6 days, and the average operation time was 169.3 min. Pleural effusion in the left hemithorax was found in 31.6% of the patients, with 5.3% requiring a thorax drain. The majority of patients had the highest platelet count two weeks after surgery. There was no evidence of wound infection, pancreatic leak, colon perforation, or postoperative sepsis. The most encountered perioperative complication was bleeding with the need of transfusion (n = 6), and one patient needed a diaphragm repair. A partial splenectomy (PS) can be a difficult procedure with a steep learning curve. For most children who require a splenic operation, this should be the primary procedure of choice. [ABSTRACT FROM AUTHOR]

Background: Hereditary spherocytosis (HS) complicated by splenic infarction is very rare, and it is even rarer to develop splenic infarction after infectious mononucleosis (IM) as a result of Epstein-Barr virus (EBV) infection. Therefore, misdiagnosis or missed diagnosis is prone to occur.Case Presentation: A 19-year-old Chinese female previously diagnosed with HS was admitted to our institution with persistent high fever and icterus. On admission, the physical examination showed anemia, jaundice, marked splenomegaly, obvious tenderness in the left upper abdomen (LUA). Peripheral blood film shows that spherical red blood cells accounted for about 6%, and Immunoglobulin M (IgM) antibodies specific to Epstein-Barr virus (EBV) viral capsid antigen were detected. An abdominal CT scan revealed a splenic infarction. The patient was diagnosed with HS with splenic infarction following EBV infection and underwent an emergency laparoscopic splenectomy (LS). Pathological analysis showed a splenic infarction with red pulp expansion, white pulp atrophy and a splenic sinus filled with red blood cells. After two months of follow-up visits, the patient showed no signs of relapse.Conclusions: HS complicated by splenic infarction is very rare and mostly occurs in men under 20 years of age and is often accompanied by other diseases, such as sickle cell traits (SCT) or IM. Although symptomatic management may be sufficient, emergency laparoscopic splenectomy may be safe and effective when conservative treatment is ineffective. [ABSTRACT FROM AUTHOR]

Background: Neonatal myocardial infarction (MI) in a structurally normal heart is frequently an obscure event that remains undiagnosed until autopsy. Causal attributions usually cite underlying maternal or fetal conditions. Refinement in understanding of pathogenic mechanisms underlying neonatal MI is key to advancements in diagnosis, prevention, treatments and prognosis. Objective: This study presents a 36-week gestational age female with perinatal asphyxia, congenital hemolytic anemia and umbilical vein thrombosis who sustained catastrophic MI with reperfusion injury; and it reviews pertinent literature. Results: We propose a pathogenic sequence that links maternal vascular malperfusion, fetal vascular malperfusion, hemolytic anemia, umbilical venous thrombosis, and paradoxical thromboemboli. Conclusion: This case highlights the importance of placental examination in connecting complex neonatal events with adverse maternal/placental conditions. A high index of suspicion is essential for early diagnosis of neonatal MI. [ABSTRACT FROM AUTHOR]

A case study of a boy with a normal birth weight is presented who was admitted to the neonatal ward because of the increased risk on hypoglycemia due to maternal diabetes mellitus. Topics include examines on the second day, jaundice was noted and the total plasma bilirubin raised for which he received phototherapy for four days.

Background: Pyruvate kinase deficiency is an exceptionally rare autosomal recessive Mendelian disorder caused by bi-allelic pathogenic variants in the PKLR gene. It is mainly characterized by chronic nonspherocytic hemolytic anemia though other symptoms such as splenomegaly, hepatomegaly, pallor, fatigue, iron overload, shortness of breath, hyperbilirubinemia, and gallstones might also prevail.Case Presentation: We present here a novel genetic defect in the PKLR gene that correlates with pyruvate kinase deficiency phenotype in a consanguineous family from North-Western Pakistan. The family included three affected individuals who were all born to consanguineous parents. The proband, a 13-year-old female of Pashtun ethnicity, showed chronic nonautoimmune hemolytic anemia since birth, extremely low hemoglobin (7.6 g/dL) and pyruvate kinase (12.4 U/g Hb) levels, splenomegaly, and hepatomegaly. Bone marrow aspirate showed a markedly decreased myeloid to erythroid ratio and hypercellular marrow particles due to hyperplasia of the erythroid elements. Molecular characterization of the proband's genomic DNA uncovered a likely pathogenic homozygous missense variant p.[D339N] in exon 7 of the PKLR gene. In-depth in silico analysis and familial cosegregation implies p.[D339N] as the likely cause of pyruvate kinase deficiency in this family. Further in vitro or in vivo studies are required to validate the impact of p.[D339N] on protein structure and/or stability, and to determine its role in the disease pathophysiology.Conclusions: In summary, these findings suggest a novel genetic defect in the PKLR gene as a likely cause of pyruvate kinase deficiency, thus further expanding the mutational landscape of this rare Mendelian disorder. [ABSTRACT FROM AUTHOR]

The article presents a case study of 18-year-old woman, who was referred to hospital for further investigation of her severe anemia which developed since childhood. It mentions detection of disease-causing allele confirmed the diagnosis of Hereditary spherocytosis (HS); and also mentions frame‑shift mutation in SPTB gene.

Objective: Majeed syndrome (MJS) is an autosomal recessive, systemic autoinflammatory disease (SAID) caused by biallelic loss-of-function variants in the LPIN2 gene. It is characterized by early-onset chronic recurrent multifocal osteomyelitis (CRMO), dyserythropoietic anemia, and neutrophilic dermatosis. We analyzed a cohort of uncharacterized Indian patients for pathogenic variants in LPIN2 and other genes associated with SAIDs.Methods: We performed whole-exome sequencing (WES) for 1 patient and next-generation sequencing (NGS) targeted gene panel for SAIDs in 3 patients. One patient was a referral from neurology after clinical exome sequencing identified a novel variant in LPIN2. We reviewed the literature for all published studies of mutation-positive MJS patients and have summarized their clinical features and disease-causing variants.Results: We describe the largest series of patients with MJS outside of the Middle East. All 5 patients are homozygous for novel, possibly pathogenic variants in the LPIN2 gene. Two of these variants are missense substitutions, and 3 are predicted to alter transcript splicing and create a truncated protein. In addition to the classical features of CRMO and anemia, patients exhibited previously unreported features, including abdominal pain, recurrent diarrhea/ear discharge, and erythema nodosum.Conclusion: Patients with MJS may present initially to different specialists, and thus it is important to create awareness in the medical community. In India, consanguinity is a common sociocultural factor in many ethnic communities and an abbreviated NGS gene panel for autoinflammatory diseases should include MJS. The unavailability of interleukin 1 inhibitors in some countries poses a treatment challenge. [ABSTRACT FROM AUTHOR]

Congenital hemolytic anemias (CHAs) comprise defects of the erythrocyte membrane proteins and of red blood cell enzymes metabolism, along with alterations of erythropoiesis. These rare and heterogeneous conditions may generate several difficulties from the diagnostic point of view. Membrane defects include hereditary spherocytosis and elliptocytosis, and the group of hereditary stomatocytosis; glucose-6-phosphate dehydrogenase and pyruvate kinase, are the most common enzyme deficiencies. Among ultra-rare forms, it is worth reminding other enzyme defects (glucosephosphate isomerase, phosphofructokinase, adenylate kinase, triosephosphate isomerase, phosphoglycerate kinase, hexokinase, and pyrimidine 5'-nucleotidase), and congenital dyserythropoietic anemias. Family history, clinical findings (anemia, hemolysis, splenomegaly, gallstones, and iron overload), red cells morphology, and biochemical tests are well recognized diagnostic tools. Molecular findings are increasingly used, particularly in recessive and de novo cases, and may be fundamental in unraveling the diagnosis. Notably, several confounders may further challenge the diagnostic workup, including concomitant blood loss, nutrients deficiency, alterations of hemolytic markers due to other causes (alloimmunization, infectious agents, rare metabolic disorders), coexistence of other hemolytic disorders (autoimmune hemolytic anemia, paroxysmal nocturnal hemoglobinuria, etc.). Additional factors to be considered are the possible association with bone marrow, renal or hepatic diseases, other causes of iron overload (hereditary hemochromatosis, hemoglobinopathies, metabolic diseases), and the presence of extra-hematological signs/symptoms. In this review we provide some instructive clinical vignettes that highlight the difficulties and confounders encountered in the diagnosis and clinical management of CHAs. [ABSTRACT FROM AUTHOR]

Background: Laparoscopic partial splenectomy (LPS) may allow avoiding total splenectomy (TS) complications and maximizing the advantages of mini-invasive approach. The objective of this review is to assess feasibility and safety of LPS, to compare this approach with alternative options. Materials and Methods: A literature review of articles reporting LPS is performed. Several parameters, including age, indication, surgical technique, devices used for splenic section/hemostasis, adverse outcomes, including morbidity/mortality, conversions to open surgery, conversions to TS, operative time (OT), and hospital stay (HS), are analyzed. Articles comparing LPS' results with those of open partial splenectomy and laparoscopic TS are also analyzed. Results: Fifty-nine articles reporting 457 LPS were included. Patients' characteristics varied widely, concerning age and indications, including hematological disease (hereditary spherocytosis, drepanocytosis), splenic focal masses, and trauma. Several technical options are reported. Mean OT and HS are 128 ± 43.7 minutes and 4.9 ± 3.8 days, respectively. No mortality and 5.7% morbidity are reported. Conversion rates to open surgery and to TS are 3.9% and 3.7%, respectively. Conclusions: In conclusion LPS is feasible and safe, with no mortality, low morbidity, and low conversion rates to laparotomy and to TS. LPS may be accomplished by various techniques and tools. Major complications are sporadically reported, thus potential risks should not be underestimated. [ABSTRACT FROM AUTHOR]

BACKGROUND AND OBJECTIVES: The neonatal hereditary spherocytosis (HS) index, defined as the mean corpuscular hemoglobin concentration divided by the mean corpuscular volume, has been proposed as a screening tool for HS in neonates. In a population of mostly white infants, an HS Index >0.36 was 97% sensitive and >99% specific. We evaluated the utility of the HS Index among a more racially and ethnically diverse population and determined if its discrimination varies with total serum bilirubin (TSB) levels. METHODS: Infants born at $35 weeks' gestation at 15 Kaiser Permanente Northern California hospitals from 1995 to 2015 were eligible (N 5 670 272). Erythrocyte indices from the first complete blood count drawn at #7 days and TSB levels drawn at #30 days were obtained. Diagnoses of HS were confirmed via chart review. RESULTS: HS was confirmed in 79 infants, 1.2 per 10 000. HS was more common among infants of white and "other" race or ethnicity and among those with higher peak TSB levels. The area under the receiver operating characteristic curve for the HS Index was 0.84 (95% confidence interval 0.78-0.90). Likelihood ratios ranged from 10.1 for an HS Index $0.380 to 0.1 for an HS Index <0.310. Dichotomized at 0.36, the HS Index was 56% sensitive and 93% specific. Discrimination of the HS Index appeared best among infants with TSB levels <10 mg/dL. CONCLUSIONS: The HS Index, when obtained from a CBC drawn within the first week after birth, had only modest ability to alter the probability of HS. [ABSTRACT FROM AUTHOR]

Background: Adenylate kinase (AK) deficiency is a rare red cell enzymopathy associated with moderate to severe congenital nonspherocytic hemolytic anemia, along with mental and psychomotor retardation (in exceptional cases). Only ten mutations have been detected in the AK1 gene to date. In this study, we aimed to diagnose the unexplained issue of haemolytic anaemia and offer antenatal screening to the family. Methods: Genomic DNA was isolated from whole blood by a standard protocol. Targeted next-generation sequencing (t-NGS) was performed to identify pathogenic variants in the patient and control samples. A chronic villus sample was collected at 11 weeks of gestation from the mother, and molecular testing was performed. Genetic confirmation was concluded by Sanger DNA sequencing. Bioinformatics tools predicted the pathogenicity of the variant. Results: t-NGS revealed a homozygous variant (c.301C > A, p. Gln101Lys) in the AK1 gene in the patient and heterozygosity in the fetus and parental samples. The prediction tools SIFT, Polyphen2, Provean, PMUT, Mutation taster, and Mutation Assessor, confirmed the damaging effect of the variant on the AK1 protein structure Conclusion: We have presented a novel mutation in the AK1 gene (p. Gln101Lys) associated with adenylate kinase deficiency. It is the first prenatal diagnosis of AK deficiency in India, where heterogeneity is exceptionally high. [ABSTRACT FROM AUTHOR]

Background: Erythrocyte pyruvate kinase is expressed under the control of the PKLR gene located on chromosome 1q21. Pyruvate kinase catalyzes the final steps of the glycolytic pathway and creates 50% of the red cell total adenosine triphosphate. Pyruvate kinase deficiency is the commonest glycolytic defect causing congenital non-spherocytic hemolytic anemia inherited in an autosomal recessive trait in which homozygotes and compound heterozygotes are common. Over 200 mutations have been described in patients with pyruvate kinase deficiency. This case report identifies a new pathogenic variant in PKLR gene detected in a patient with severe pyruvate kinase deficiency.Case Presentation: A Sri Lankan Sinhalese girl who developed neonatal anemia and jaundice within 24 hours of birth with mild hepatomegaly. She was from a nonconsanguineous marriage and had two siblings who had no hematological disorders. She had repeated admissions due to similar illnesses and at the age of 8 years was found to have pyruvate kinase deficiency associated with a novel homozygous pathogenic variant c.507+1delG in the PKLR gene.Conclusions: A novel genetic variant in PKLR gene, consistent with pyruvate kinase deficiency, was detected in a Sri Lankan girl. This genetic variant may be specific to the Asian population and requires further studies. [ABSTRACT FROM AUTHOR]

Objective: This study aims to evaluate the demographic information, clinical and laboratory findings of patients with glucose 6 phosphate dehydrogenase deficiency. Material and Methods: We collected data by reviewing files and electronic records of 65 patients with glucose 6 phosphate dehydrogenase deficiency under the age of 18 years who were followed up in our clinic between 2007 and 2019. Demographic, clinical, and laboratory features, family history, complications of the disease, and history of splenectomy and cholecystectomy were evaluated. Mean, standard deviation, and median values were used when descriptive analyses were presented. Results: The age of diagnosis ranged between 1-192 months and the median age of diagnosis was two months. Fifty-nine patients (90.7%) were boys and six (9.2%) were girls. The mean value of glucose 6 phosphate dehydrogenase enzyme on admission was 1,9±1,4 U/g of hemoglobin (Hb). Family history was present in 40% of patients in whom information was available. The most common presentation was prolonged jaundice and the most common physical finding was jaundice. Splenomegaly was detected in none of the patients. Cholelithiasis was present in one of 21 patients who were evaluated with ultrasonography. None of the patients required splenectomy, cholecystectomy, and regular erythrocyte transfusion during follow-up. Conclusion: As G6PD variants with chronic hemolysis are not usually seen in Turkey, patients who required splenectomy, cholecystectomy, and regular erythrocyte transfusion were not detected. Although glucose 6 phosphate dehydrogenase deficiency is more common in males, it can also be seen in girls. In Turkey, glucose 6 phosphate dehydrogenase deficiency should be considered in patients presenting with prolonged jaundice. [ABSTRACT FROM AUTHOR]

Congenital hemolytic anemias (CHAs) are heterogeneous and rare disorders caused by alterations in structure, membrane transport, metabolism, or red blood cell production. The pathophysiology of these diseases, in particular the rarest, is often poorly understood, and easy-to-apply tools for diagnosis, clinical management, and patient stratification are still lacking. We report the 3-years monocentric experience with a 43 genes targeted Next Generation Sequencing (t-NGS) panel in diagnosis of CHAs; 122 patients from 105 unrelated families were investigated and the results compared with conventional laboratory pathway. Patients were divided in two groups: 1) cases diagnosed with hematologic investigations to be confirmed at molecular level, and 2) patients with unexplained anemia after extensive hematologic investigation. The overall sensitivity of t-NGS was 74 and 35% for families of groups 1 and 2, respectively. Inside this cohort of patients we identified 26 new pathogenic variants confirmed by functional evidence. The implementation of laboratory work-up with t-NGS increased the number of diagnoses in cases with unexplained anemia; cytoskeleton defects are well detected by conventional tools, deserving t-NGS to atypical cases; the diagnosis of Gardos channelopathy, some enzyme deficiencies, familial siterosterolemia, X-linked defects in females and other rare and ultra-rare diseases definitely benefits of t-NGS approaches.

Background and objectives: Regular blood transfusion has improved the overall survival and quality of life for patients with hereditary hemolytic anemias. Nevertheless, it carries a real risk of acquisition of blood-borne virus infections, especially viral hepatitis. The purpose of the current study is to present an Egyptian update on blood-borne hepatitis C & B viruses (HCV & HBV) and cytomegalovirus (CMV) among multi-transfused Egyptian children with hereditary hemolytic anemias, especially after implementation of national preventive programs in Egypt. Patients and methods: All pediatric patients with hereditary hemolytic anemias who have regular follow-up and received frequent blood transfusion at the Pediatric Hematology Units, Menuofia and Zagazig Universities Hospitals, Egypt, during the study period, were recruited. They were tested for hepatitis B surface antigen (HBVsAg), hepatitis C antibody (HCVab), and CMV immunoglobulin M (IgM) serology. Those with positive results were confirmed by real-time polymerase chain reaction (PCR). Results: Four hundred and seventy-seven hereditary hemolytic anemia patients fulfilled the study inclusion criteria. Their ages ranged from 2 to 18 years, 54.9% of them were males. Seroprevalence of HCVab and CMV-IgM were (14.7% & 6.7% respectively) and they were confirmed by PCR. None of the studied cases were HBVsAg positive. Seropositivity for HCV was significantly associated with older age of the patients, higher transfusion frequency, longer disease duration, and higher mean serum ferritin. Conclusion: HCV followed by CMV infections still represent a significant problem for patients with hereditary hemolytic anemias. Nationwide plans should be taken to ensure meticulous and highly sensitive methods of blood screening before transfusion. On the other hand, it seems that HBV compulsory vaccination had succeeded to eliminate HBV infection. [ABSTRACT FROM AUTHOR]

Congenital hemolytic anemias (CHAs) are heterogeneous and rare disorders caused by alterations in structure, membrane transport, metabolism, or red blood cell production. The pathophysiology of these diseases, in particular the rarest, is often poorly understood, and easy-to-apply tools for diagnosis, clinical management, and patient stratification are still lacking. We report the 3-years monocentric experience with a 43 genes targeted Next Generation Sequencing (t-NGS) panel in diagnosis of CHAs; 122 patients from 105 unrelated families were investigated and the results compared with conventional laboratory pathway. Patients were divided in two groups: 1) cases diagnosed with hematologic investigations to be confirmed at molecular level, and 2) patients with unexplained anemia after extensive hematologic investigation. The overall sensitivity of t-NGS was 74 and 35% for families of groups 1 and 2, respectively. Inside this cohort of patients we identified 26 new pathogenic variants confirmed by functional evidence. The implementation of laboratory work-up with t-NGS increased the number of diagnoses in cases with unexplained anemia; cytoskeleton defects are well detected by conventional tools, deserving t-NGS to atypical cases; the diagnosis of Gardos channelopathy, some enzyme deficiencies, familial siterosterolemia, X-linked defects in females and other rare and ultra-rare diseases definitely benefits of t-NGS approaches. [ABSTRACT FROM AUTHOR]

Hereditary spherocytosis (HS) is a familial hemolytic disorder with intracorpuscular mechanism that characterized by the production of red blood cells with sphere-like shape prone to hemolysis and can lead to hemolytic anemia, splenomegaly, jaundice and gallstones. One of the main reasons for referring these patients to the operating room is splenectomy and cholecystectomy to treat the complications of HS. Perioperative concerns in these patients include severe anemia with a need for blood transfusion, aplastic attacks, hypoxemia and acidosis. On the other hand, management of anesthesia during splenectomy and cholecystectomy in pregnant woman with HS is very challenging due to physiological changes associated with pregnancy, choosing the appropriate time to perform the surgeries, and complications of anesthesia drugs on mother and fetus. This case study report the management of anesthesia in a pregnant woman with HS, candidate for simultaneous cholecystectomy and splenectomy [ABSTRACT FROM AUTHOR]

Hemoglobin M (HbM) is a group of abnormal hemoglobin variants that form methemoglobin, which leads to cyanosis and hemolytic anemia. HbM-Milwaukee-2 is a rare variant caused by the point mutation CAC>TAC on codon 93 of the hemoglobin subunit beta (HBB) gene, resulting in the replacement of histidine by tyrosine. We here report the first Korean family with HbM-Milwaukee- 2, whose diagnosis was confirmed by gene sequencing. A high index of suspicion for this rare Hb variant is necessary in a patient presenting with cyanosis since childhood, along with methemoglobinemia and a family history of cyanosis. [ABSTRACT FROM AUTHOR]

Context: Glycated hemoglobin A1c (HbA1c) level is used to screen and diagnose diabetes. Genetic determinants of HbA1c can vary across populations and many of the genetic variants influencing HbA1c level were specific to populations.Objective: To discover genetic variants associated with HbA1c level in nondiabetic Malay individuals.Design and Participants: We conducted a genome-wide association study (GWAS) analysis for HbA1c using 2 Malay studies, the Singapore Malay Eye Study (SiMES, N = 1721 on GWAS array) and the Living Biobank study (N = 983 on GWAS array and whole-exome sequenced). We built a Malay-specific reference panel to impute ethnic-specific variants and validate the associations with HbA1c at ethnic-specific variants.Results: Meta-analysis of the 1000 Genomes imputed array data identified 4 loci at genome-wide significance (P < 5 × 10-8). Of the 4 loci, 3 (ADAM15, LINC02226, JUP) were novel for HbA1c associations. At the previously reported HbA1c locus ATXN7L3-G6PC3, association analysis using the exome data fine-mapped the HbA1c associations to a 27-bp deletion (rs769664228) at SLC4A1 that reduced HbA1c by 0.38 ± 0.06% (P = 3.5 × 10-10). Further imputation of this variant in SiMES confirmed the association with HbA1c at SLC4A1. We also showed that these genetic variants influence HbA1c level independent of glucose level.Conclusion: We identified a deletion at SLC4A1 associated with HbA1c in Malay. The nonglycemic lowering of HbA1c at rs769664228 might cause individuals carrying this variant to be underdiagnosed for diabetes or prediabetes when HbA1c is used as the only diagnostic test for diabetes. [ABSTRACT FROM AUTHOR]

Background: Dehydrated hereditary stomatocytosis (DHS) or hereditary xerocytosis is a rare, autosomal dominant hemolytic anemia characterized by macrocytosis, presence of stomatocytes and dehydration of red blood cells (RBCs). The dehydration is caused by a defect in cellular cation content. The most frequent expression of the pathology is hemolytic well-compensated anemia with high reticulocyte count, a tendency to macrocytosis, increased mean corpuscular hemoglobin concentration (MCHC) and mild jaundice. We here describe a new mutation of PIEZO1 gene, the most frequent mutated gene in DHS, in a family affected by hereditary hemolytic anemia. Case presentation: We describe the case of a 12-years-old girl with well-compensated chronic hemolysis, increased MCHC and a father who had the same hematological characteristics. After excluding secondary causes of chronic hemolysis and enzymatic defects of the RBCs, microscopic observation of the peripheral blood smear, tests of RBC lysis, ektacytometry, SDS-PAGE and in last instance genetic analysis has been performed. This complex diagnostic workup identified a new variant in the PIEZO1 gene, never described in literature, causative of DHS. This pathogenetic variant was also detected in the father. Conclusions: This case report highlights the importance of a correct and exhaustive diagnostic-workup in patients with clinical suspicious for hemolytic anemia in order to make a differential diagnosis. This is relevant for the management of these patients because splenectomy is contraindicated in DHS due to high thrombotic risk. [ABSTRACT FROM AUTHOR]

Hereditary anemias are a group of heterogeneous disorders including hemolytic anemias and hyporegenerative anemias, as congenital dyserythropoietic anemia (CDA). Causative mutations occur in a wide range of genes leading to deficiencies in red cell production, structure, or function. The genetic screening of the main genes is important for timely diagnosis, since routine laboratory tests fail in a percentage of the cases, appropriate treatment decisions, and genetic counseling purposes. A conventional gene-by-gene sequencing approach is expensive and highly time-consuming, due to the genetic complexity of these diseases. To overcome this problem, we customized a targeted sequencing panel covering 35 genes previously associated to red cell disorders. We analyzed 36 patients, and potentially pathogenic variants were identified in 26 cases (72%). Twenty variants were novel. Remarkably, mutations in the SPTB gene (β-spectrin) were found in 34.6% of the patients with hereditary spherocytosis (HS), suggesting that SPTB is a major HS gene in the Southeast of Brazil. We also identified two cases with dominant HS presenting null mutations in trans with α-LELY in SPTA1 gene. This is the first comprehensive genetic analysis for hereditary anemias in the Brazilian population, contributing to a better understanding of the genetic basis and phenotypic consequences of these rare conditions in our population. [ABSTRACT FROM AUTHOR]