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Assistant Professor Dr. Akrem Atrushi Two B -globin genes are present in diploid cells, one on each chromosome 11. Some B-thalassemia genes produce no βglobin chains and are termed β0thalassemia. Other β-globin genes produce some βglobin, but in diminished quantities, and are termed β+thalassemia There is an excess of α-globin chains relative to β- and γ-globin chains; α-globin tetramers (α4) are formed, and these inclusions interact with the red cell membrane and shorten red cell survival, leading to anemia and increased erythroid production. The γ-globin chains are produced in normal amounts, leading to an elevated Hb F (α2γ2). The δ-globin chains are also produced in normal amounts, leading to an elevated Hb A2 (α2δ2) in β-thalassemia. These children usually become symptomatic from progressive hemolytic anemia with profound weakness and cardiac decompensation during the second 6 mo of life with fatigue, poor appetite, and lethargy severe thalassemic facies, pathologic fractures, marked hepatosplenomegaly, cachexia , splenomegaly causing mechanical discomfort and secondary hypersplenism, greenish brown complexion Complications of iron overload: in the liver, fibrosis and cirrhosis; in the beta cells of the pancreas, diabetes mellitus; in the pituitary, testis, and ovaries, growth retardation and hypogonadotropic hypogonadism; in the parathyroid, hypocalcemia and osteoporosis; in the heart, arrhythmias, myocarditis, and intractable cardiac failure. CBC: *a decreased MCV with or without mild anemia. *moderately raised reticulocyte count but the reticulocyte index is normal to decreased *The peripheral blood smear typically shows hypochromia, target cells, and sometimes basophilic stippling *nucleated red blood cells often exceed the number of circulating white blood cells Hemoglobin electrophoresis performed after 6–12 months of age is usually diagnostic when levels of hemoglobin A2, hemoglobin F, or both are elevated. The unconjugated serum bilirubin level is usually elevated Serum ferritin and saturation of the transferrin are elevated Skull X-ray has typical ‘hair-on-end’ appearance due to medullary expansion Chronic transfusion with iron chelation is generally targeted to maintain a nadir hemoglobin level of 9–10 g/dL. This approach gives increased vigor and wellbeing, improved growth, and fewer overall complications. Iron chelation with desferrioxamine usually given by subcutaneous infusion over several hours daily 5-6 days a week . Small doses of supplemental ascorbic acid may enhance the efficacy of iron chelation. Splenectomy to reduce transfusion requirements, and hence iron loading preceded by pneumococcal vaccine and prophylactic penicillin Bone marrow or umbilical cord blood transplantation with cure rate greater than 90% when transplantation is performed prior to the development of hepatomegaly or portal fibrosis. Thalassemia intermedia can be any combination of β-thalassemia mutations (β0/β+, β0/βvariant, E/β0) Phenotype of microcytic anemia with hemoglobin of about 7 g/dL. There is controversy about whether to transfuse these children. They will certainly develop a degree of medullary hyperplasia and nutritional hemosiderosis. Extramedullary hematopoiesis can occur in the vertebral canal, compressing the spinal cord and causing neurologic symptoms requiring immediate local radiation therapy to halt erythropoiesis. Transfusion will alleviate the thalassemic manifestations and hasten the need for chelation. A splenectomy puts the child at risk for infection and pulmonary hypertension. Thalassemia trait is frequently misdiagnosed as iron deficiency in children because the two are similar hematologically and iron deficiency is much more prevalent. A short course of iron and re-evaluation is all that is required to separate those children who will need further evaluation. Children who have β-thalassemia trait will have a persistent red cell distribution width, and on hemoglobin electrophoresis they will have an elevated Hb F and diagnostically elevated Hb A2. There are "silent" forms of thalassemia trait, and if the family history is suggestive, further studies may be indicated. A 5 years old girl presents recurrently with attacks of severe pain in the back, abdomen, upper limbs and lower limbs that last for several days every time and mandate hospital admission. She is not well thriving, pale and jaundiced. What lab test is needed for making the diagnosis? What is the daignosis? How can you explain the presence of such attacks? Hb S is the result of a single base-pair change, thymine for adenine, at the sixth codon of the β gene. This change encodes valine instead of glutamine in the sixth position on the βglobin molecule. The charge at this site is altered and allows for polymerization of hemoglobin under conditions of hypoxia Polymerization of sickle hemoglobin distorts erythrocyte morphology, decreases red cell deformability, causes a marked reduction in red cell life span Because of the disruption of the red cell membrane, the increased adhesiveness of sickle reticulocytes, and the increased leukocyte count there is a thrombotic coagulopathy associated with sickle cell anemia that contributes to the severity of the disease Moderate-to-severe anemia is poorly manifested, since they readily adjust by increasing heart rate and stroke volume; however, there is decreased stamina, which may be noted on the playground or when participating in physical education class. Splenic sequestration is an anemic crisis. Although hypofunctional at an early age, the spleen has an anatomic structure that responds to certain stimuli, usually febrile illnesses. It suddenly becomes enlargedand traps blood cells. Hemoglobin levels dramatically drop from baseline values and the reticulocyte count is elevated. The platelet count often is slightly decreased, and hypovolemic shock occurs if a large volume of blood is trapped or sequestered. Aplastic crisis is also an anemic crisis. Most commonly, it is caused by infections with parvovirus, which results in the rapid onset of severe anemia. Reticulocyte count is very low, Functional asplenia results in extreme susceptibility to infection especially encapsulated respiratory bacteria, particularly Streptococcus pneumoniae, osteomyelitis due to Staphylococcus or Salmonella , meningitis and urinary tract infection leading to bacteremia Chest syndrome caused by infection in young children or infarction in the older. It is the combination of respiratory symptoms, new lung infiltrates, and fever. Bone marrow embolism with severe pain Bone pain often is due to bone marrow infarction. During the first 18 months of life, the metatarsals and metacarpals can be involved, presenting as dactylitis or hand-foot syndrome. long bones of the extremities in the older. Proximity to the joints and occasional sympathetic effusions lead to the belief that the pain the joints. As marrow activity recedes further during adolescence, pain involves the vertebral bodies, especially in the lumbar region. Abdominal pain can result from referred pain from other sites or intra-abdominal solid organ or soft tissue infarction. Reactive ileus leads to intestinal distention and pain Stroke occurs in approximately 11% of patients with hemiparesis or other deficits may be found, depending on the location of the infarct. Convulsions frequently are associated with stroke. Cholecystitis due to chronic hemolysis leading to cholelithiasis Avascular necrosis of the femoral or humeral head Priapism with severe pain if erection persists longer than 3 hours. Renal function is progressively impaired by diffuse glomerular and tubular fibrosis leading to hyposthenuria with polyuria and enuresis in patients older than 5 yr. Renal papillary necrosis and nephrotic syndrome also develop occasionally Poor growth and delayed maturation associated with Zinc deficiency Skin ulcers may also develop in adolescence Retinopathy may develop and hyphema is a medical emergency CBC : Baseline hemoglobin level of 7–10 g/dL. The baseline reticulocyte count is elevated markedly. The anemia is usually normocytic or macrocytic, and the peripheral blood smear typically shows the characteristic sickle cells, target cells, poikilocytes, hypochromasia, nucleated RBCs, and Howell-Jolly bodies. Hemoglobin electrophoresis. Children with sickle cell anemia and with sickle β 0-thalassemia have only hemoglobins S and F. Persons with sickle β +-thalassemia have a preponderance of hemoglobin S with a lesser amount of hemoglobin A. Persons with sickle hemoglobin C disease have equal amounts of hemoglobins S and C Radiologic studies may reveal characteristic bony findings of sickle cell disease in the vertebral bodies, mild expansion of the marrow cavities, osteoporosis, and possibly sclerosis of the long bones and femoral heads Babies should receive penicillin daily initiated by age 2 months and continued at least until age 5 years and be immunised against Streptococcus pneumoniae, Haemophilus influenzae type b, and Neisseria meningitidis. Because of the thrombotic nature of the sickle hemoglobins and the high red cell turnover, folate supplementation is recommended. Parents should be warned to seek medical advice on any suspicion of infection. Painful crises should be managed with adequate analgesics, hydration, oxygen and correction of acidosis if present, . The patient should be observed carefully for a source of infection and a drop in haemoglobin concentration. Strokes should be treated with a transfusion; there is good evidence now that they can be prevented by regular surveillance of cerebral blood flow by Doppler examination and prophylactic transfusion. Blood transfusion is indicated for acute chest syndrome, stroke, stroke prevention, severe anemia, and splenic sequestration and before general surgery Simple or partial exchange transfusion to reduce the percentage of circulating sickle cells is indicated for some severe acute vaso-occlusive events and may be lifesaving Bone marrow transplantation is the only cure for sickle cell disease, but it is only an option for children younger than 16 yr of age who have an HLA-matched sibling Daily administration of oral hydroxyurea increases levels of fetal hemoglobin, decreases hemolysis, and reduces by 50% episodes of pain in severely affected patients The most commonly occurring sickle syndromes besides Hb SS are Hb SC and Sβ0-thalassemia and Sβ+-thalassemia. Sβ0-thalassemia is a severe sickle cell anemia. Hb SC does not polymerize like Hb SS, but the presence of crystals of Hb C interact with the membrane ion transport dehydrating the cell, inducing sickling. Children who have Hb SC disease can experience the same symptoms and complications as those with severe Hb SS disease, but the frequency is less. These children have an increased hemoglobin concentration and better growth. However, they have more fat in their bone marrow, and this can lead to more severe acute chest syndrome and organ failure caused by fat emboli from bone necrosis. There is also an increased incidence of retinopathy and chronic hypersplenism. Despite a well-developed appearance, these children may develop all the chronic complications of sickle cell disease. Sβ+-thalassemia is a less severe form of sickle cell disease with a much lower frequency of the severe manifestations.