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Sickle Cell Disease
Published in Vincenzo Berghella, Maternal-Fetal Evidence Based Guidelines, 2022
Sickle cell disease describes a group of inherited disorders characterized by the presence of HbS. Sickle cell disease is associated with a mild to moderate chronic anemia. The term sickle cell disease includes sickle cell anemia (HbSS) (70% of cases), hemoglobin S combined with hemoglobin C (HbSC) (most of the remaining cases), hemoglobin S combined with β-thalassemia (HbSβ+ or HbSβ0), and other double heterozygous conditions causing sickling and thus, clinical disease (e.g., hereditary persistence of fetal hemoglobin (HgS/HPHP), and hemoglobin E (HbS/HbE) [7]. The clinical manifestations vary among these genotypes, with HbSβ0 usually with a similar severe phenotype as HbSS, HbSC associated with intermediate disease, and HbSβ+, HbSHPHP, and HbSE with mild or symptom-free disease [1, 5]. The term sickle cell anemia includes HbSS, and also HbSβ0 (due to its similar phenotype). The sickle cell trait is the heterozygous inheritance of HgbS and is characterized by benign clinical course without anemia, with protection against malaria [8].
Prenatal diagnosis of fetal abnormality using fetal cells in maternal circulation
Published in Hung N. Winn, Frank A. Chervenak, Roberto Romero, Clinical Maternal-Fetal Medicine Online, 2021
Gian Carlo Di Renzo, Elena Picchiassi, Michela Centra, Giuliana Coata
Since the enrichment methods supply fetal cell samples still contaminated by maternal cells, scientific community has focused on the research of a specific fetal cell marker for their identification. Until now, fetal cell markers widely used are fetal hemoglobin, as a protein marker and Y chromosome, as a genetic marker. It has been shown that fetal hemoglobin is not a particularly relevant marker because it is partially present in maternal cells. Fetal cell identification based on Y chromo-some by using cytogenetic (FISH) and biomolecular (PCR) techniques is an effective approach but it is limited to women carrying male fetuses.
Hematopoiesis and Storage Iron in Infants
Published in Bo Lönnerdal, Iron Metabolism in Infants, 2020
Several developmental changes occur in the erythropoiesis of the fetus. The site of red blood cell production is primarily in liver tissues by 3 months of gestation age. The bone marrow takes over gradually, starting around 5 months of gestation age (Figure 1). Usually by term of pregnancy, the bone marrow is almost exclusively responsible for erythropoiesis. In preterm newborns, the liver plays a role in red blood cell production even at birth. There are also other developmental changes that occur simultaneously. The size of the red cell gradually becomes smaller during fetal life so that the red cell mean corpuscular volume (MCV) tends to be larger in premature than in full-term newborns. The concentration of hemoglobin seems to rise in the fetus during pregnancy although the details of this development are not well known. Finally, the specific fetal hemoglobin-F is partially replaced by adult hemoglobin-A by term of pregnancy. Thus, premature infants have proportionally more hemoglobin-F than full-term newborns.
Distinctive phenotypes in two children with novel germline RUNX1 mutations - one with myeloid malignancy and increased fetal hemoglobin
Published in Pediatric Hematology and Oncology, 2020
Shruti Bagla, Katherine A. Regling, Erin N. Wakeling, Manisha Gadgeel, Steven Buck, Ahmar U. Zaidi, Leigh A. Flore, Michael Chicka, Charles A. Schiffer, Meera B. Chitlur, Yaddanapudi Ravindranath
Based on the emerging use of hypomethylating agents in CMML and more recently in JMML,31,32 treatment was started with two five-day courses of intravenous decitabine (20 mg/m2/dose) four weeks apart. Normoblastemia resolved but there was no objective platelet response and there was a modest increase in CD16+ monocytes (Figure 1C, 1D*). Fetal hemoglobin remained elevated. A trial of valproic acid (50 mg/kg/day) for 7 days was given based on in vitro studies showing increased megakaryocyte ploidy in experimental systems.33,34 Despite this, the patient continued to be transfusion dependent for platelets and red blood cells (RBCs); repeat bone marrow aspirate and biopsy showed clearance of sea blue histiocytes but persistent blast cells and decreased megakaryocytes. Our patient had no full siblings, and her half-sister was not a haplo-match. Therefore, she underwent a 4/6 match umbilical cord blood stem cell transplant. Post HSCT she developed grade IV acute graft-versus-host disease (aGVHD) of her skin, gastrointestinal tract, and liver. She subsequently died after developing disseminated aspergillosis.
Germline Gene Editing for Sickle Cell Disease
Published in The American Journal of Bioethics, 2020
Akshay Sharma, Nickhill Bhakta, Liza-Marie Johnson
Correction of the sickle cell mutation through direct correction of the mutated allele or by recreating naturally occurring mutations that increase the fetal hemoglobin production, thus reducing morbidity from sickle hemoglobin (Hemoglobin S) in erythroid cells without affecting the function or survival or any other cells in the body are widely described (Metais et al. 2019). Such genetic interventions can theoretically be introduced in the germline cells without many off target effects. Such germline correction of the mutation would not only eliminate SCD in index patients but also in their future children eventually making the therapy much more accessible, affordable and cost effective not only for individual patients but also global health systems. Thus, germline gene editing in conditions such as SCD will make the treatment of SCD much more available and hopefully eradicate this disease in the future.
Hb F-Wentzville [Gγ24(B6)Gly→Glu; HBG2: c.74G>A, p.Gly25Glu]: An Unstable Gγ-Globin Variant Associated with Neonatal Hemolytic Anemia
Published in Hemoglobin, 2020
Katarina M. Semkiu, Jennifer L. Oliveira, Phuong L. Nguyen, Tavanna R. Porter, David B. Wilson
Fetal hemoglobin (Hb F), the principal hemoglobin (Hb) produced by the fetus, is a tetramer composed of two α- and two γ-globin chains [1]. γ-Globins are encoded by the paralogous HBG1 and HBG2 genes. The resultant proteins, Aγ- and Gγ-globin, are nearly identical, differing only in the amino acid at position 136 (alanine vs. glycine) [1]. Gγ is the predominant γ-globin in neonatal erythrocytes (Gγ:Aγ = 7:3) [2]. γ Chain variants may be evident at birth but rapidly disappear over the first months of life owing to globin switching, wherein γ-globin expression is extinguished and adult globin (β, δ) expression is activated [3]. Most γ-globin variants are clinically insignificant, but some cause transient hemolytic anemia, cyanosis or methemoglobinemia [1,3,4]. In this report, we describe a novel Gγ-globin variant associated with neonatal hemolysis.