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Concept: Microcytic anemia

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Abstract Anemia is a global health issue with disproportionately high prevalence in women. In addition to being an independent risk factor for decreased quality of life and increased morbidity and mortality, anemia in women has been linked to unfavorable outcomes of pregnancy and other issues for children born to anemic women. Iron deficiency is the leading cause of anemia in many populations. Guidelines recommend proactive screening for anemia, particularly in the preoperative setting. Once anemia is diagnosed, treatment should be based on etiology (most commonly, iron deficiency followed, in order of prevalence, by inflammation or chronic disease). Iron supplementation (oral and intravenous) offers safe and effective treatment for anemia associated with iron deficiency. Anemia of chronic disease may be more challenging to treat, and attention must be given to the underlying disease, along with use of hematinic agents. Given its enormous impact on the health and well-being of women and the availability of simple and effective treatment options, anemia should never be left unmanaged.

Concepts: Hemoglobin, Medicine, Epidemiology, Anemia, Iron deficiency anemia, Transferrin, Human iron metabolism, Microcytic anemia

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Iron-refractory iron-deficiency anemia (IRIDA) is an autosomal recessive disorder caused by mutations in TMPRSS6. Patients have hypochromic microcytic anemia refractory to oral iron and are only partially responsive to parenteral iron administration. We report a French-Canadian kindred in which 2 siblings presented in early childhood with severe microcytic anemia, hypoferremia, and hyperferritinemia. Both children have been successfully treated solely with low-dose oral iron since diagnosis. Clinical and biological presentation did not fit any previously described genetic iron-deficiency anemia. Whole exome sequencing identified in both patients compound heterozygous mutations of TMPRSS6 leading to p.G442R and p.E522K, 2 mutations previously reported to cause classic IRIDA, and no additional mutations in known iron-regulatory genes. Thus, the phenotype associated with the unique combination of mutations uncovered in both patients expands the spectrum of disease associated with TMPRSS6 mutations to include iron deficiency anemia that is accompanied by hyperferritinemia at initial presentation and is responsive to continued oral iron therapy. Our results have implications for genetic testing in early childhood iron deficiency anemia. Importantly, they emphasize that whole exome sequencing can be used as a diagnostic tool and greatly facilitate the elucidation of the genetic basis of unusual clinical presentations, including hypomorphic mutations or compound heterozygosity leading to different phenotypes in known Mendelian diseases.

Concepts: Hemoglobin, Gene, Genetics, Anemia, Iron deficiency anemia, Gregor Mendel, Microcytic anemia, Iron supplements

26

An 8.5-year-old girl presented with breast development, irregular uterine bleeding, and a spurt in height during the previous 9 months. She also complained of rapid increase of abdominal girth and body weight (4 kg). No remarkable past history or family history was noted. Her height (143 cm), breast development (Tanner stage 3), and pubic hair (Tanner stage 2) were compatible with precocious puberty. Laboratory examinations showed microcytic hypochromic anemia (Hb 9.2 g/dL), and serum estradiol was 138 pg/mL. LH and FSH were in the undetectable level even after a LH-RH (100 μg) injection. Ovarian tumor markers including CEA, CA19-9, CA125, α-fetoprotein, and hCG were within the normal range. Magnetic resonance imaging revealed a giant multilocular cystic tumor (25 × 14 × 10 cm) in the lower abdomen.Tumor resection was performed. The tumor originated from the right ovary and contained 3500 × mL of yellowish serous fluid. The left ovary was grossly normal. The resected right ovarian tumor was multilocular cystic, measuring 16.0 × cm in the greatest dimension, with occasional foci of whitish yellow elevated components in the cystic wall.

Concepts: Oncology, Menopause, Ovarian cancer, Pelvis, Puberty, Teratoma, Microcytic anemia, Pubic hair

25

α-Thalassemia (α-thal) is a common genetic disorder in Iran and many parts of the world. Genetic defects in the α-globin gene cluster can result in α-thal that may develop into a clinical phenotype varying from almost asymptomatic to a lethal hemolytic anemia. Loss of one functional α gene, indicated as heterozygous α(+)-thal, shows minor hematological abnormalities. Homozygosity for α(+)- or heterozygosity for α(0)-thal have more severe hematological abnormalities due to a markedly reduced α chain output. At the molecular level, the absence of three α-globin genes resulting from the compound heterozygous state for α(0)- and α(+)-thal, lead to Hb H disease. Here we present a 21 nucleotide (nt) duplication consisting of six amino acids and 3 bp of intronic sequence at the exon-intron boundary, in both the α-globin genes, detected by direct DNA sequencing. This duplication was identified in three patients originating from two different Iranian ethnic groups and one Arab during more than 12 years. The clinical presentation of these individuals varies widely from a mild asymptomatic anemia (heterozygote in α1-globin gene) to a severely anemic state, diagnosed as an Hb H individual requiring blood transfusion (duplication on the α2-globin gene in combination with the - -(MED) double α-globin gene deletion). The third individual, who was homozygous for this nt duplication on the α1-globin gene, showed severe hypochromic microcytic anemia and splenomegaly. In the last decade, numerous α-globin mutations have demonstrated the necessity of prenatal diagnosis (PND) for α-thal, and this study has contributed another mutation as important enough that needs to be considered.

Concepts: DNA, Gene, Genetics, Mutation, Red blood cell, Anemia, Hematology, Microcytic anemia

2

SIFD (Sideroblastic anemia with B-cell immunodeficiency, periodic fevers, and developmental delay) is a novel form of congenital sideroblastic anemia associated with B-cell immunodeficiency, periodic fevers, and developmental delay caused by mutations in the CCA-adding enzyme TRNT1, but the precise molecular pathophysiology is not known.

Concepts: Oxygen, Metabolism, Adenosine triphosphate, Cellular respiration, Nicotinamide adenine dinucleotide, Disability, Microcytic anemia, Sideroblastic anemia

1

The cargo receptor NCOA4 mediates autophagic ferritin degradation. Here we show that NCOA4 deficiency in a knockout mouse model causes iron accumulation in the liver and spleen, increased levels of transferrin saturation, serum ferritin, and liver hepcidin, and decreased levels of duodenal ferroportin. Despite signs of iron overload, NCOA4-null mice had mild microcytic hypochromic anemia. Under an iron-deprived diet (2-3 mg/kg), mice failed to release iron from ferritin storage and developed severe microcytic hypochromic anemia and ineffective erythropoiesis associated with increased erythropoietin levels. When fed an iron-enriched diet (2 g/kg), mice died prematurely and showed signs of liver damage. Ferritin accumulated in primary embryonic fibroblasts from NCOA4-null mice consequent to impaired autophagic targeting. Adoptive expression of the NCOA4 COOH terminus (aa 239-614) restored this function. In conclusion, NCOA4 prevents iron accumulation and ensures efficient erythropoiesis, playing a central role in balancing iron levels in vivo.

Concepts: Liver, Anemia, Hematology, Iron deficiency anemia, Human iron metabolism, Microcytic anemia, Iron metabolism, Anemia of chronic disease

1

Microcytic anemia is characterized by smaller-than-normal red cells due to decreased production of hemoglobin. This review discusses diagnosis and treatment of thalassemia, anemia of inflammation, and iron-deficiency anemia, highlighting recent findings.

Concepts: Hemoglobin, Red blood cell, Anemia, Hematology, Iron deficiency anemia, Microcytic anemia, Mean corpuscular volume, Anemia of chronic disease

1

Key points A novel clinical syndrome of congenital sideroblastic anemia, B cell immunodeficiency, periodic fevers and developmental delay is describedBone marrow transplant resulted in complete and durable resolution of the hematologic and immunologic manifestations.

Concepts: Medicine, Bone marrow, Anemia, Hematology, Microcytic anemia, Sideroblastic anemia

0

Blood tests (e.g., red blood cell (RBC) count) are crucial for detecting, diagnosing, and monitoring the progression of blood disorders. Here, we report the development of a new and rapid method for electrochemically detecting RBCs using single-particle collision events. The principle of this method relies on the electrochemical oxidation of an electroactive redox species (potassium ferrocyanide) hindered by an RBC attached to an electrode surface. A decrease in staircase current, caused by the collision of RBCs on the electrode, was observed. The magnitude of this current decrease could provide quantitative information on the size and concentration of RBCs, which could be converted into the mean corpuscular volume (MCV) and used for diagnosis. Anemia-related diseases caused by abnormal count of RBCs (e.g., erythrocytosis, pernicious anemia) or abnormal RBC size (e.g. megaloblastic anemia, microcytic anemia) could be detected easily and quickly using this electrochemical collision method, potentially leading to extensive applications in hematology and point-of-care blood testing devices.

Concepts: Blood, Red blood cell, Anemia, Hematology, Hematocrit, Microcytic anemia, Mean corpuscular volume, Pernicious anemia

0

The utilization of placental blood for neonatal admission laboratory tests, specifically the complete blood cell (CBC) count and blood culture, has the potential to delay the onset of anemia of prematurity and intraventricular hemorrhage, frequency of blood transfusions and associated complications, and painful procedures related to laboratory sampling.

Concepts: Blood, Red blood cell, Anemia, Hematology, Hematocrit, Complete blood count, Microcytic anemia, Mean corpuscular volume