Alterations of Hematologic Function in Children

No matter the cause, a deficiency of iron produces a hypochromic-microcytic anemia. In the early stages, however, the body may respond by increasing RBC activity in the bone marrow, which may temporarily prevent the development of anemia. As the body's iron stores are depleted, anemia develops (also see Chapter 29). Alterations in hepcidin have an essential role in diseases involving disturbances of iron metabolism (see Chapters 28 and 29). Low serum levels of ferritin and transferrin saturation lead to lowered hemoglobin and hematocrit levels (see Mechanisms of iron depletion are described in Chapter 29).

The evaluation and treatment of IDA are similar in children and adults (see Chapter 29). The diagnosis of IDA is confirmed by laboratory tests. These tests include hemoglobin, hematocrit, serum iron, ferritin levels and the total iron binding capacity. Obtaining a thorough history of the child's present illness and dietary history and performing a complete physical examination also are essential to the evaluation and subsequent clinical management of IDA. Oral administration of a simple ferrous salt is usually sufficient. Taking iron supplements with a vitamin C source helps promote absorption.¹⁹ If liquid iron supplements are used, they should be given with a straw or a dropper placed back on the tongue to prevent staining the teeth. Iron therapy is continued for at least 2 months after erythrocyte indexes have returned to normal to replenish iron stores.²⁰

Dietary modification is required to prevent recurrences of IDA.

Intake of iron-rich foods is increased, and the intake of cow's milk may be restricted, with the exact amount restricted to 16 to 32 ounces per day depending on the child's age. Limiting milk intake makes the child hungrier for other iron-rich foods and prevents gastrointestinal blood loss in children whose anemia is aggravated or caused by inflammatory reactions to proteins in cow's milk.

Three conditions must be present for HDFN to occur:

In most cases of HDFN, the mother has blood type O, and the fetus has blood type A or B. Maternal antibodies may be formed against type B fetal erythrocytes if the mother has blood type A or against type A fetal erythrocytes if the mother has blood type B.

ABO incompatibility can cause HDFN even if fetal erythrocytes do not escape into the maternal circulation during pregnancy because the blood of most adults already contains anti-A or anti-B antibodies. These antibodies are produced on exposure to certain foods or infection by gram-negative bacteria. As a result, IgG against type A or B erythrocytes is usually already present in maternal blood and can enter the fetal circulation during the first incompatible pregnancy. Anti-O antibodies do not exist because type O erythrocytes are not antigenic.

Anti-Rh antibodies, on the other hand, form only in response to the presence of Rh-positive erythrocytes from the fetus in the blood of an Rh-negative mother. This exposure typically occurs when fetal blood is mixed with the mother's blood at the time of delivery. Exposure may also occur through transfused blood, and, rarely, previous sensitization of the mother by her own mother's incompatible blood.

The first Rh-incompatible pregnancy generally presents no difficulties for the fetus because few fetal erythrocytes cross the placental barrier during the pregnancy. When the placenta detaches at birth, many fetal erythrocytes often enter the mother's bloodstream. If the mother is Rh-negative and the fetus is Rh-positive, the mother produces anti-Rh antibodies. The capacity of the mother's immune system to produce anti-Rh antibodies depends on many factors, including her genetic capacity to make antibodies against the Rh antigen D, the amount of fetal-to-maternal bleeding, and the occurrence of any bleeding earlier in the pregnancy. These anti-Rh antibodies persist in the mother's bloodstream for a long time. If the next offspring is Rh-positive, the mother's anti-Rh antibodies can enter the bloodstream of the fetus and destroy the erythrocytes. Antibodies against Rh antigen D are of the IgG class and easily cross the placenta.

Antibody-coated fetal erythrocytes are usually destroyed through extravascular hemolysis, primarily by phagocytic cells in the spleen. As hemolysis proceeds, the fetus becomes anemic. Erythropoiesis accelerates, particularly in the liver and spleen. Immature nucleated cells (erythroblasts) are released into the bloodstream, hence the name erythroblastosis fetalis. The degree of anemia depends on several factors: (1) the length of time the antibody has been in the fetal circulation, (2) the concentration of the antibody, and (3) the ability of the fetus to compensate for increased hemolysis. During the pregnancy, unconjugated (indirect) bilirubin, which forms during the breakdown of hemoglobin, is transported across the placental barrier into the maternal circulation and is excreted by the mother. Hyperbilirubinemia, an increase in bilirubin concentration in the blood occurs in the neonate shortly after birth because lipid-soluble unconjugated bilirubin is no longer excreted through the placenta.

HDFN is typically more severe in Rh incompatibility than in ABO incompatibility. ABO incompatibility may resolve after birth without life-threatening complications. Maternal-fetal incompatibility in which a mother with type O blood has a child with type A or B blood usually is so mild that it does not require treatment.

Rh incompatibility is more likely to result in severe or even life-threatening anemia, death in utero, or damage to the central nervous system (CNS). Severe anemia alone can cause death because of cardiovascular complications. Extensive hemolysis can result in increased levels of unconjugated bilirubin in the neonate's circulation. If bilirubin levels exceed the liver's ability to conjugate and excrete bilirubin, it can be deposited in the brain, a condition known as kernicterus, causing cellular damage and, eventually, death if the neonate does not receive exchange transfusions.

Fetuses that do not survive anemia in utero are usually stillborn with gross edema in the entire body, a condition called hydrops fetalis. Death can occur as early as 17 weeks’ gestation and results in spontaneous abortion.

Because the maternal antibodies remain in the neonate's circulatory system after birth, erythrocyte destruction can continue causing hyperbilirubinemia and icterus neonatorum (neonatal jaundice) that occurs shortly after birth. Without replacement transfusions, in which the child receives Rh-negative erythrocytes, the bilirubin can be deposited in the brain, causing a condition termed kernicterus. If kernicterus develops, it can cause cerebral damage, including intellectual disabilities, cerebral palsy, high-frequency deafness, and even death (icterus gravis neonatorum).21

Fetuses and neonates with ABO incompatibility typically do not require additional monitoring or treatment. Fetuses and infants at risk for HDFN because of Rh incompatibility may require additional monitoring and treatment. Routine evaluation of fetuses at risk for HDFN includes the Coombs test. The indirect Coombs test measures antibody in the mother's circulation and indicates whether the fetus is at risk for HDFN. The direct Coombs test measures antibody already bound to the surfaces of fetal erythrocytes. It is used primarily to confirm the diagnosis of antibody-mediated HDFN. If a prior history of fetal hemolytic disease is present, additional diagnostic tests are done to determine risk with the current pregnancy. These include maternal antibody titers, fetal blood sampling, amniotic fluid spectrophotometry, and ultrasound fetal assessment.22

Prevention is the key to managing HDFN that results from Rh incompatibility. Immunoprophylaxis through the use of Rh immune globulin (RhoGAM), a preparation of antibody against Rh antigen D (anti-D Ig), prevents an Rh-negative woman from producing antibodies. If an Rh-negative woman is given Rh immune globulin within 72 hours of exposure to Rh-positive erythrocytes, she will not produce antibody against the D antigen. As a result, the next Rh-positive baby she conceives will be protected. Updated United States and United Kingdom guidelines also state that if anti-D Ig is not given within 72 hours, every effort should be made to administer it within 10 days.^23,24

The injected (anti-D Ig) antibodies remain in the mother's bloodstream long enough to prevent her immune system from producing its own anti-Rh antibodies but not long enough to affect subsequent offspring. The mother must be given Rh immune globulin injections after the birth of each Rh-positive baby and after a miscarriage. The mother also must be especially careful not to receive a transfusion containing Rh-positive blood because this would stimulate production of anti-Rh antibodies.

If antigenic incompatibility of the mother's erythrocytes is not discovered in time to administer Rh immune globulin and a child is born with HDFN, treatment consists of exchange transfusions in which the neonate's blood is replaced with new Rh-positive blood that is not contaminated with anti-Rh antibodies. This treatment is instituted during the first 24 hours of extrauterine life to prevent kernicterus. Phototherapy also is used to reduce the toxic effects of unconjugated bilirubin.

Jaundice and indirect hyperbilirubinemia are reduced when the infant is exposed to high-intensity light in the visible spectrum from 460 to 490 nm.²⁵ Bilirubin in the skin absorbs light energy, which converts the toxic unconjugated bilirubin into its conjugated water-soluble form that is excreted in the bile. Phototherapy also causes autosensitization that results in oxidation reactions. Breakdown products from the oxidation reactions are excreted by the liver and kidney without need for conjugation. The therapeutic effect of phototherapy depends on the light energy emitted in the effective wavelengths, the distance between the infant and the light source, and the amount of skin exposed. The rate of hemolysis and the infant's ability to excrete bilirubin also are factors in determining the effectiveness of phototherapy in lowering serum bilirubin levels.

Prevention of hemolysis is the most important therapeutic measure. Prevention includes avoiding medications and dietary substances associated with hemolysis. Because of the high frequency of G6PD deficiency in areas of the world that are endemic for malaria, the World Health Organization (WHO) currently recommends testing for G6PD deficiency before administration of antimalarial medications in these regions.28 When hemolysis occurs, supportive treatment may include blood transfusions and oral iron therapy. Spontaneous recovery generally follows treatment.

The presenting signs of HS are anemia, jaundice, and splenomegaly, which can be mild to severe depending on the individual's physiologic compensation. In these cases, the reticulocyte count will be elevated. In infancy, hemolytic anemia and hyperbilirubinemia may be severe.29 Infants and children may have life-threatening anemia with clinical symptoms ranging from difficulty feeding, circumoral pallor, tachycardia, nasal flaring, and diaphoresis to lethargy. They also are at increased risk for gallstones because of the presence of extra bile pigment from hemolysis. Infection (specifically parvovirus),³⁰ fever, and stress stimulate the spleen to destroy more RBCs than usual, leading to a worsening anemia in a child with baseline anemia. The parvovirus also infects erythroid progenitor cells in the bone marrow resulting in an aplastic crisis.³¹

Ascertaining a family history of spherocytosis is important. Laboratory findings include spherocytes in the peripheral blood smear (spherocytosis), elevated reticulocyte count (with or without anemia), indirect hyperbilirubinemia, and a positive osmotic fragility test. An osmotic fragility test is performed by placing RBCs in a saline solution for 24 hours. Spherocytes do not tolerate saline solutions; as a result, they burst more readily than normal RBCs. In addition, flow cytometry can detect reductions in RBC transmembrane proteins. Band 3 Protein Reduction testing can confirm the diagnosis of HS. Treatment of HS is based on disease severity and some children or adolescents may require RBC transfusions; however, this is somewhat rare. Management includes regular monitoring for anemia and splenomegaly. Daily folic acid supplementation supports the increased production of healthy RBCs. In the past, splenectomy was the first line of treatment. Currently, however, splenectomy is only recommended for those children more than 5 years of age with severe anemia or splenomegaly. Some children who develop gallstones may undergo splenectomy and cholecystectomy. Partial splenectomy, in which only a portion of the spleen is removed, is being performed on children with HS to decrease the risk of postsplenectomy complications.31

The sickling process is an occasional, intermittent phenomenon that can be triggered or sustained by one or more of the following stressors: decreased oxygen tension (PO₂) of the blood (e.g., hypoxemia), acidosis (decreased pH), increased plasma osmolality, decreased plasma volume, and low temperature (Fig. 30.4). Low temperatures can precipitate sickle crisis, presumably because of vasoconstriction.³⁷

A flowchart shows the sequence of sickling of erythrocytes. 1. Abnormal H b S present in erythrocytes. Leads to 2. 2. Hypoxemia, decreased p H, low temperature, and or decreased plasma volume occurs. Leads to 3. 3. Persistent hypoxemia causes further reduction in partial pressure of oxygen in the microcirculation; erythrocytes sickle. Leads to 4 and 6. 4. Reversal of hypoxemia (reoxygenation, rehydration). Leads to 5. 5. Sickled erythrocytes regain normal shape, resume normal function. 6. Sickled cells clog vessels. Leads to 7. 7. Sickled cells slow blood flow, promote hypoxemia, and increase sickling. Leads to 8. 8. Decreased blood p H decreases hemoglobin’s affinity for oxygen; partial pressure of oxygen drops, increases sickling.

The pathophysiology of the sickling process includes erythrocyte derangement, chronic hemolysis (hemolytic anemia), microvascular occlusions, and tissue damage. HbS is soluble and usually causes no problem when it is properly oxygenated; therefore, deoxygenation is probably the most important variable in determining the occurrence of sickling. Other significant variables that affect sickling include interaction of HbS with other types of hemoglobin in the cell, mean cell hemoglobin concentration (MCHC), intracellular pH, and transit times of erythrocytes through the microcirculation. Among individuals who are heterozygous for sickle cell trait, the presence of other types of Hb prevents sickling except under conditions of severe hypoxia.

As the sickling process begins, intracellular dehydration increases the MCHC, which increases sickling. A decrease in pH reduces the oxygen affinity of hemoglobin, resulting in a further increase in the quantity of deoxygenated HbS regardless of the oxygen tension. These changes, in turn, increase the sickling process. Inflammation in the microcirculation will slow erythrocyte transit times because blood flow is sluggish with adhesion of leukocytes to activated endothelial cells. Increased osmolality of the plasma draws water out of the erythrocytes. The result is sickling by raising the relative HbS content in erythrocytes. Investigators are studying the optimal intravenous fluid to increase erythrocyte deformability and biomechanical properties.38

Sickling causes damage to erythrocytes through several mechanisms, including (1) membrane derangements occur because as HbS units (polymers) grow they protrude through the membrane skeleton by only the lipid layer, causing changes in membrane structure: (2) membrane derangement leads to changes in ionic flow with an influx in Ca⁺⁺ ions, which induces cross-linking of membrane proteins and activation of an ion channel that induces the efflux of K⁺ and H₂O; and (3) with time the damaged cells are converted to end-stage, nondeformable or stiff and irreversibly sickled cells (Fig. 30.5). Recent studies have shown that elevated red cell levels of the enzyme sphingosine kinase 1 (SPH1) underlie sickling and disease progression by increasing sphingosine 1-phosphate (S1P) production in the blood.^39,40S1P level, a bioactive lipid enriched in red cells, is elevated in red cells and plasma of mice and humans with SCD.⁴⁰ S1P also is a signaling molecule that regulates diverse biologic functions including inflammation.⁴¹ Additionally, investigators demonstrated that the compound 5 C can inhibit SPHK1 and, thus, has antisickling properties.⁴² These data are important for identifying the structure of the sickling process to assess potential new therapeutics.

Left panel, A. The illustration shows a normal hemoglobin beta-chain and sickle cell anemia hemoglobin beta-chain. The normal hemoglobin beta-chain shows the following sequence: valine, histidine, leucine, threonine, proline, glutamic acid, and glutamic acid. The sickle cell anemia hemoglobin beta-chain shows the following sequence: valine, histidine, leucine, threonine, proline, valine, and glutamic acid. Right panel, B. The illustration shows the point mutation of H b A to H b S in a D N A helical structure with G C, T A, and G C. The sequence of pathogenesis is as follows. • R B C undergoes deoxygenation. • Cell absorbs calcium ions and releases potassium ions and water. • Hemolysis: Deoxygenated cell undergoes extensive membrane damage and becomes an irreversibly sickled cell. • Microvascular occlusion: Deoxygenated cell undergoes oxygenation and becomes cell with dehydration and membrane damage. Deoxygenation and prolonged transit times of dehydrated cell results in microvascular occlusion. • Cyclic mechanism: Deoxygenated cell undergoes oxygenation resulting in a dehydrated cell. Dehydrated cell undergoes additional cycles of deoxygenation.

Some cells remain sickled even with full oxygenation and are vulnerable to hemolysis. Polymerization of sickled hemoglobin is central to the disorder. Polymerization stiffens the sickled erythrocyte, changing it from a flexible, beneficial cell to an inflexible one where HbS molecules stack into polymers that starve and damage tissues. The pathogenesis of SCD derives from the tendency of HbS molecules to stack into polymers even when deoxygenated and assemble into needle-like fibers within cells, producing the distorted crescent-like sickle or holly-leaf shape (see Figs. 30.2 and 30.3). Sickled cells undergo hemolysis in the spleen or become sequestered there, causing blood pooling and infarction of splenic vessels. The anemia that follows triggers erythropoiesis in the marrow and, in extreme cases, in the liver.^43,44

The pathogenesis of microvascular occlusions, a main feature of SCD is not fully understood. This process is responsible for the most serious and urgent manifestations of SCD. Microvascular occlusions are not related to the quantity of irreversibly sickled cells in the blood. Rather, they are dependent on understated RBC membrane damages and other local factors, such as inflammation or vasoconstriction, that tend to decrease blood flow or arrest red cells through the microcirculation.⁴⁵ Sickled RBCs express higher than normal amounts of adhesion molecules and are sticky. During inflammatory reactions, leukocyte release of meditators increases the expression of adhesion molecules on endothelial cells. These reactions further promote sickled erythrocytes to become arrested during movement through the microvasculature.⁴⁵ The sluggish and stagnant red cells within the inflamed vascular vessels result in extended exposure to low oxygen tension, sickling, and vascular obstruction. Lysed sickle erythrocytes release hemoglobin. This free hemoglobin can bind and inactivate nitric oxide (NO), which is a powerful vasodilator and inhibitor of platelet aggregation. A decrease in blood pH reduces hemoglobin's affinity for oxygen leading to an increasing fraction of deoxygenated HbS at any oxygen tension and predisposition to sickling. As less oxygen is taken up by hemoglobin in the lungs, the PO₂ drops, promoting additional sickling.

Sickling usually is not permanent. Most sickled erythrocytes regain a normal shape after reoxygenation, a return of the PO₂ to normal, and rehydration. Irreversible sickling is caused by permanent plasma membrane damage, which in turn is caused by sickling. In persons with sickle cell anemia, in which the erythrocytes contain a high percentage of HbS (75% to 95%), up to 30% of the erythrocytes can become irreversibly sickled.

The extent, severity, and clinical manifestations of sickling depend to a great extent on the percentage of hemoglobin that is HbS. That is why homozygous inheritance of HbS produces the severest form of SCD—sickle cell anemia. The presence of sickle cell trait rarely results in sickling because these individuals also produce normal HbF and HbA which do not contribute to sickling at all. Anemia persists because HbF does not live 120 days.

The clinical manifestations of sickle cell disease can vary. Some individuals have mild symptoms; others suffer from repeated vasoocclusive crises. The clinical manifestations of sickle cell disease usually do not appear until the infant is at least 6 months old. At this time, postnatal concentrations of HbF decrease, causing concentrations of HbS to rise (Fig. 30.6). Two key attributes of SCD contribute to its presentation: the first is its nature to be a chronic disease with acute exacerbations; the second is that it is a condition affecting RBCs that supply oxygen to all cells of the body. As a consequence, SCD can affect any part of the body. Sites of specific dysfunction are shown in Fig. 30.7.

Top-left panel, A. The illustration shows normal red blood cells. Top-right panel, B. The illustration shows sickle and normal red blood cells. Right panel, C. An illustration of the anterior view of the human body identifies the following tissue effects from the top to the bottom. • C V A (stroke), paralysis, and death. • Retinopathy, blindness, and hemorrhage. • Avascular necrosis (shoulder). • Hepatomegaly and gallstones. • Splenomegaly, splenic sequestration, and autosplenectomy. • Hematuria and hyposthenuria (dilute urine). • Avascular necrosis (hip). • Abdominal pain. • Dactylitis (hand-foot syndrome). • Priapism. • Pain and osteomyelitis. • Chronic ulcers (rare in children).

An illustration of the anterior view of the human body shows acute and chronic manifestations by organ. Acute manifestations are as follows. • Brain: thrombosis or hemorrhage causing paralysis; sensory deficits or death. • Lung: atelectasis (incomplete expansion); infarction; and pneumonia. • Abdominal organs: acute hepatomegaly; gallstones; splenic sequestration; splenomegaly; and infarction. • Bones and joints: hand-foot- syndrome (painful swelling of hands and feet). • Kidney: hematuria (blood in urine). Chronic manifestations are as follows. • Eye: hemorrhage; exudation; blindness; and retinopathy. • Pulmonary: hypertension and tachypnea. • Heart: high-output failure (congestive heart failure). • Spleen: splenic atrophy (autosplenectomy). • Kidney: hyposthenuria (dilute urine) and diuresis. • Penis: priapism. • Skin: stasis ulcers of hands, ankles, and feet.

The general manifestations of hemolytic anemia from the sickling process include pallor, fatigue, jaundice, and irritability. Extensive sickling can precipitate four types of acute manifestations, often referred to as crises: (1) vaso-occlusive crisis, (2) aplastic crisis, (3) sequestration crisis, or rarely (4) hyperhemolytic crisis.

Vasoocclusive crisis (pain crisis). This type of crisis involves hypoxic injury and infarction that can cause severe pain in the microcirculation. The frequency of this type of crisis is variable and unpredictable because it may develop spontaneously or be precipitated by infection, exposure to cold, dehydration, low PO₂, acidosis (low pH), or localized hypoxemia. Vaso-occlusive crises are extremely painful, and the specific cause of this sensory pain is not well characterized.46,47

As blood flow is obstructed by sickled cells, vasospasm occurs, and a logjam effect blocks all blood flow through the vessel. Unless the process is reversed, thrombosis and infarction of local tissue occur. Vasoocclusive crisis may last for days or even weeks, with an average duration of 4 to 6 days. The most common sites include bones, lungs, spleen, liver, brain, and penis. Painful bone crises are common in young children and are difficult to distinguish from acute osteomyelitis. These bone alterations can manifest as painful swelling of the hands and feet (hand-foot syndrome or dactylitis).

A high-risk type of vaso-occlusive crisis involving the lungs is known as acute chest syndrome. It typically presents with fever, cough, chest pain, and accumulations of lung infiltrates. The complications in the lungs create a worsening cycle of hypoxemia, sickling, and vaso-occlusion. Acute chest syndrome remains a leading cause of death among people with SCD.^48,49Priapism, or prolonged erection of the penis, can lead to hypoxic damage and erectile dysfunction. Vaso-occlusion in vessels to the brain can result in stroke. Chronic vaso-occlusion in vessels to the kidneys results in end-stage renal disease.

Aplastic crisis. This type of crisis involves profound anemia caused by a transient cessation in RBC production despite a need for new RBCs. In sickle cell anemia, erythrocyte survival is only 10 to 20 days; however, the bone marrow is typically able to compensate to replace RBCs that are lost through hemolysis. Aplastic crisis is often precipitated by a viral infection, such as parvovirus B1. The virus causes temporary shutdown of RBC production with an accompanying sudden drop in hemoglobin level with an extremely low reticulocyte count. This type of crisis typically lasts 7 to 10 days.

Sequestration crisis. This type of crisis is typically seen only in children less than 5 years of age. It occurs when large amounts of sickled RBCs become acutely pooled in the liver and spleen. Because the spleen can hold as much as one-fifth of the body's blood supply, hypovolemia and, sometimes shock, can occur (see Chapter 49). The risk of mortality is high if the condition is not recognized and managed appropriately. Clinical management may include exchange transfusions.³² Approximately half of children who experience sequestration crises will have recurrent episodes.

Hyperhemolytic crisis. This type of crisis, associated with an accelerated rate of RBC destruction, is unusual, but it may occur in association with certain drugs or infections. It is characterized by anemia, jaundice, and reticulocytosis. The concomitant presence of G6PD deficiency (see Glucose-6-Phosphate Dehydrogenase Deficiency) contributes to hyperhemolytic episodes, especially when combined with infections. It has also been reported as an acute or chronic reaction following a blood transfusion.

Infection is the most common cause of death related to sickle cell disease. Infection is also an important cause of disease-related morbidity, particularly for children with impaired splenic function. Sepsis and meningitis develop in as many as 10% of children with sickle cell anemia during the first 5 years of life. Splenic congestion and poor blood flow compromise splenic function and lead to splenic infarction. As a consequence, the risk of infection from Pneumococcus pneumoniae and Haemophilus influenzae is increased.

Glomerular disease, characterized by damage to the glomeruli allowing protein and often RBCs to leak into the urine, is caused by sickling of RBCs in the kidneys. Extensive damage to the glomeruli results in nephropathy that may progress to renal failure. The earliest manifestation of SCD in the kidney is hyposthenuria, or the inability of the tubules of the kidneys to concentrate urine. As a result, the specific gravity of the urine tends to be very low. In young children, hyposthenuria can result in bed-wetting. Proteinuria also is an early manifestation of nephropathy associated with sickle cell disease.

Cholecystitis, inflammation of the gallbladder, occurs when a gallstone blocks the cystic duct. It can also be caused by hemolysis resulting in an increase of bilirubin concentration, which in turn causes the formation of gallstones in the gallbladder. The presence of gallstones can cause right upper quadrant pain, nausea, vomiting, and an elevated white blood cell count and alkaline phosphatase level. Cholecystectomy may be required.

Sickle cell–hemoglobin C (HbC) disease is usually milder than sickle cell anemia. HbC results when lysine is substituted for glutamic acid in the amino acid chain. HbC is less soluble than HbA; however, it does not polymerize under conditions of decreased oxygen tension as does HbS. The main clinical problems are related to vasoocclusive crises, which are thought to result from higher hematocrit values and viscosity. In older children, sickle cell retinopathy, renal necrosis, and aseptic necrosis of the femoral heads can occur along with obstructive crises.

Sickle cell–thalassemia has the mildest clinical manifestations of all the sickle cell diseases. Individuals with sickle cell–thalassemia have mutations in each allele coding for hemoglobin. One mutation results in HbS formation, and the other is associated with β-thalassemia, which results in decreased production of hemoglobin. Even though most of the child's hemoglobin is HbS (60% to 90%), normal hemoglobins (HbA and HbF) also are present. The normal hemoglobins, particularly HbF, inhibit sickling. The erythrocytes tend to be small (microcytic) and to contain relatively little hemoglobin (hypochromic). As a result, these cells are less likely to occlude the microcirculation, even when in a sickled state.

The parents’ hematologic history and clinical manifestations may suggest that a child has sickle cell disease, but hematologic tests are necessary to confirm the diagnosis. If the sickle solubility test confirms the presence of HbS in peripheral blood, hemoglobin electrophoresis will be performed to provide information about the amount of HbS in erythrocytes. Prenatal diagnosis can be made by chorionic villus sampling (CVS) as early as 8 to 10 weeks’ gestation or by amniotic fluid analysis at 15 weeks’ gestation (Fig. 30.8). Hemoglobinopathies, including sickle cell disease, are now included as part of routine newborn screening in all 50 states and the District of Columbia.

An illustrated flowchart shows the prepregnancy sickle cell test. The illustration shows sperm and eggs. Fertilization of sperm and eggs leads to embryos (1). The illustration shows embryonic cells in a culture dish (2). The embryos are implanted in the endometrium (3). The embryo develops into a fetus (4). A syringe collects sample from the amniotic cavity. Birth of a newborn (5). The placenta and the uterine wall are identified. The illustration shows a newborn.

Advances in identification of SCD and supportive care have led to decreased morbidity and improved survival of children with SCD. Supportive care emphasizes preventing consequences of anemia and avoiding crises, including adequate hydration, infection prevention, and pain management. Genetic counseling and psychologic support are important for the child and family.

Health maintenance activities are key to reduce the risk of crises and other aspects of disease-related morbidity. In addition to regular childhood vaccines, children with SCD should receive vaccination against pneumococcus and other encapsulated microorganisms. Children under 5 years of age may also be prescribed prophylactic penicillin to further reduce the risk of infection.32 Because of the high infection-related mortality, individuals with SCD and their families should be instructed to seek immediate medical attention in the event of fever. Evidence-based guidance for screening for nephropathy, hypertension, retinopathy, pulmonary disease, and the risk of stroke have been published by the National Heart, Lung, and Blood Institute.³²

Sickle cell trait typically does not affect life expectancy or interfere with daily activities. On rare occasions, however, severe hypoxia caused by shock, vigorous exercising at high altitudes, flying at high altitudes in unpressurized aircraft, or undergoing anesthesia may precipitate vasoocclusive episodes in persons with sickle cell trait. Persons with sickle cell trait are at risk for hyphema with traumatic injury to the eye. Untreated hyphema may result in glaucoma and potential vision loss. In 2010, the National Collegiate Athletic Association implemented testing for sickle cell trait for all incoming student athletes. While having sickle cell trait does not disqualify the individual from participation in athletics, the goal of this testing is to ensure the safety of student athletes.⁵⁰

Treatment advances since the late 1980s have significantly decreased morbidity and mortality in children with SCD. Aggressive management of fever, early diagnosis of acute chest syndrome (hypoxia, anemia, progressive multilobar pneumonia, fat emboli), and proper pain management can improve quality of life and prognosis for these children. Treatment of SCD consists of supportive care aimed at preventing consequences of anemia and avoiding crises. Crises can be prevented by avoiding fever, infection, acidosis, dehydration, constricting clothes, and exposure to cold. Immediate correction of acidosis and dehydration with appropriate intravenous fluids is imperative. Infections require aggressive antibiotic therapy, and infections can be reduced by vaccination. Oxygen is not needed unless the child becomes hypoxic. Pain associated with SCD is very complex, requiring accurate assessment and multimodal management.^51,52

A common treatment for sickle cell disease is hydroxyurea. Hydroxyurea inhibits deoxyribonucleic acid (DNA) synthesis, which causes an increase in HbF concentration. HbF will not sickle. It also provides an anti-inflammatory effect by decreasing leukocyte production. These outcomes are thought to decrease mechanisms that lead to crises.

Two new medications were approved by the US Food and Drug Administration for use in individuals with sickle cell disease in 2019.³² Voxelotor is an oral medication approved for individuals 12 years of age and older. It is proposed to inhibit HbS polymerization and the sickling process by modifying the affinity between hemoglobin and oxygen.⁵³ Crizanlizumab is a monoclonal antibody against the adhesion molecule P-selectin. P-selectin is involved in the underlying process by which blood cells adhere to blood vessel walls, thereby contributing to vaso-occlusion.⁵⁴ Crizanlizumab is administered as an IV infusion.

Transfusion therapy can decrease morbidity and mortality associated with sickle cell disease, particularly in those at increased risk for stroke.³² Despite these benefits, it can result in iron overload in the liver, heart, and endocrine glands causing disruption of normal function, including delayed physical and sexual development and heart disease. Chelation therapy to remove excess iron is often required for individuals with SCD who require chronic transfusion of RBCs

HSCT offers the only cure for sickle cell disease; however, it is not without important risks. Observational studies to date have demonstrated improved survival and prevention of long-term complications. Additional studies are needed to evaluate benefits and risks by comparing individuals based on disease severity.⁵⁵ Current research is seeking to reduce the toxicities associated with transplantation while optimizing long-term outcomes. Clinical trials evaluating the feasibility of GT using an RNA viral vector are presently underway. One type of trial seeks to inhibit the BCL11a gene with the goal of increasing hemoglobin F production, thereby creating a sickle cell trait phenotype.⁵⁶

The β-thalassemias are caused by mutations in the HBB gene that decrease the synthesis of β-globin chains and lead to anemia, tissue hypoxia, and RBC hemolysis. The β-thalassemias are classified into three types depending on the severity of symptoms: thalassemia major, intermedia, or minor. Both beta-thalassemia major (Cooley anemia) and beta-thalassemia intermedia are inherited in an autosomal recessive pattern in which both copies of the HBB gene in each cell have mutations; however, beta thalassemia major is more severe. β-globin chain production is moderately depressed in the heterozygous form, beta-thalassemia minor, and is known as beta-thalassemia trait. In a small percentage of families, the HBB gene mutation, associated with beta-thalassemia major, is inherited in an autosomal dominant manner.57

The mutations associated with beta-thalassemia are classified as (1) β⁰ mutations or absent β-globin synthesis and (2) β⁺ mutations with reduced amounts of β-globin synthesis. More than 200 different causative mutations have been identified, and most are point (missense) mutations. The clinical classification of β-thalassemias is based on the severity of the anemia, which is dependent on the type of mutation (β⁰ or β⁺ allele) and whether the individual is homozygous or heterozygous for mutations.⁵⁷ Individuals who have β-thalassemia major, a β⁰/β⁰ genotype, will lack HbA and have severe anemia. Those with β⁺/β⁺ or β⁰/β⁺ genotypes, β-thalassemia intermedia, may produce small amounts of HbA. β-Chain production is depressed in the heterozygous form, thalassemia minor (β⁰ or β⁺ allele); and anemia, if present, is mild. The predominant type of hemoglobin is HbF and typically comprises more than 90% of the total hemoglobin among individuals who are homozygous for mutations. HbA₂ levels are variable among individuals who are homozygous but may be increased among individuals with beta thalassemia minor.⁵⁸

The depression of β-chain synthesis that occurs in beta-thalassemia results in erythrocytes having a reduced amount of hemoglobin and accumulations of free α chains (Fig. 30.9). Free α-chains are unstable and easily precipitate in the cell. Most erythroblasts that contain precipitates are destroyed by mononuclear phagocytes in the marrow. Destruction results in ineffective erythropoiesis and anemia. Some of the precipitate-carrying cells mature and enter the bloodstream. These cells are destroyed prematurely in the spleen, resulting in mild hemolytic anemia.

An illustrated flowchart shows the pathogenesis of beta-thalassemia major. • The illustration shows a normal cell with H b A (alpha sub 2 beta sub 2). • Normal erythroblast results in normal red blood cells. • Normal cell undergoes reduced beta-globin synthesis, with relative excess of alpha-globin, leading to beta-thalassemia. • The illustration of the abnormal erythroblast shows a cell with insoluble alpha-globin aggregate and H b A. • The illustration shows a bone. Few abnormal red cell leave the bone, forming a hypochromic red cell with alpha-globin aggregate and normal H b A. • Hypochromic red cell leads to extravascular hemolysis (destruction of aggregate-containing red cells in spleen), leading to anemia. • Ineffective erythropoiesis in bone marrow leads to most erythroblasts dying in bone marrow, resulting in anemia. • Ineffective erythropoiesis leads to increased iron absorption (from dietary iron), which leads to systemic iron overload (secondary hemochromatosis) in heart and liver. • Anemia leads to tissue hypoxia, which leads to erythropoietin increase, which leads to marrow expansion and skeletal deformities. • Blood transfusions reduce tissue hypoxia and erythropoietin. • Blood transfusions leads to systemic iron overload.

The alpha (α)thalassemias result from deletions involving the HBA1 and HBA2 genes. These genes provide instructions for making a protein called α-globin, a subunit of hemoglobin. The different types of α-thalassemia result from mutations in one or more of the four alleles involved in producing α-globin. These alleles include the two copies of the HBA1 gene and the two copies of the HBA2 gene that are present in each cell. The characteristic features of α-thalassemia are anemia, weakness, fatigue, and other more severe complications. The four types of α-thalassemia include

Prenatal diagnosis may be performed, and families with an affected fetus will be referred for genetic counseling. Identification of thalassemia is now included as part of routine newborn screening for hemoglobinopathies in all 50 states and the District of Columbia. Molecular genetic testing of at-risk siblings should be offered to allow for early diagnosis and appropriate treatment. Women with thalassemia intermedia who have never received a blood transfusion or who received a minimal quantity of blood are at risk for severe alloimmune anemia if blood transfusions are required during pregnancy.61 Treatment for thalassemia is largely supportive. Typical treatment involves a regular transfusion program and chelation therapy to reduce transfusion iron overload. Individuals with milder forms of thalassemia rarely require transfusion. These individuals are at risk for iron overload secondary to increased intestinal absorption of iron from ineffective erythropoiesis.⁶¹ Optimal clinical management may decrease the need for splenectomy. Treatment of thalassemia intermedia is based on the individual’s symptoms, and splenectomy may be performed for those who are more symptomatic. These individuals may also require sporadic red cell transfusions, folic acid supplementation, and iron chelation.⁶¹ The only available definitive cure for thalassemia major is allogeneic HSCT from a matched family or unrelated donor or cord blood transplantation from a related donor.⁶¹ In addition, on-going clinical trials are investigating the use of GT strategies for thalassemia.^62,63

Hemophilias A and B occur with varying degrees of clinical severity, depending on concentrations of clotting factor VIII or IX in the blood. Severe hemophilia (concentration of clotting factors less than 1% of normal) is associated with spontaneous bleeding. This manifestation of hemophilia is associated with mutations that eliminate the activity of factors VIII or XI. In moderate hemophilia (1% to 5% of normal), bleeding may occur with injury, trauma, or surgery; in the mild form (6% to 50% of normal), bleeding typically occurs only after severe trauma or surgery. Moderate and mild hemophilia are associated with mutations that reduce but do not eliminate the activity of these coagulation factors.63

Hemophilia is equally prevalent across racial groups. The incidence of hemophilia A is approximately 1 in 5000 male births. Hemophilia B is five times less common, with an incidence of approximately 1 in 20,000 male births.⁶⁴ Hemophilia C, which results from a deficiency of Factor XI is inherited as an autosomal recessive condition and is extremely rare. It affects approximately 1 in 1,000,000 individuals.⁶⁵ The worldwide prevalence of severe hemophilia is estimated to be around 400,000 people. A recent meta-analysis of worldwide registry data, however, suggests that approximately 1,125,000 males are living with hemophilia, with manifestations ranging from mild to severe disease.⁶⁶

As X-linked recessive conditions, hemophilias A and B are most frequently inherited from a mother who is heterozygous, that is, a carrier, for a mutation in either the F8 or F9 gene. Approximately 30% of cases, however, result from a new mutation. This new mutation can occur in either a carrier female or in an affected male. Multiple types of genetic mutations are associated with hemophilias A and B. More than 2000 unique mutations have been identified for hemophilia A,67 and more than 1000 mutations have been described for hemophilia B.⁶⁸ The type of mutation also affects the phenotype, or severity, of the disease. Mutations tend to be identical among affected members of a given family; however, mutations often differ across families.⁶⁹

The F8 and F9 genes are located on the long arm of the X chromosome. A mutation in either of these genes typically results in either deficient or abnormal function of the corresponding clotting factor. Because males have only one copy of the X chromosome, the mutation results in the clinical manifestations of hemophilia. Females who are heterozygous carriers typically do not experience excessive bleeding. However, 50% of female carriers have lower than normal clotting factor levels. Those females without a sufficient quantity of normal functioning clotting factor may have bleeding similar to a male with mild hemophilia. Because X-inactivation, or lyonization (see Chapter 4), is a random process, phenotypes of females who are heterozygous carriers can vary. Although very uncommon, it is plausible for a female to be homozygous for mutations in the F8 or F9 gene and therefore have hemophilia.

Inversions in introns 1 and 22 of the factor VIII gene are the most frequently observed mutations and account for the most severe cases of hemophilia A.⁶⁸ Point mutations, in which a single base in the DNA is inserted in the place of another base, are another type of mutation that causes hemophilia. This type of mutation comprises the majority of unique mutations associated with hemophilia.⁶⁷ When a point mutation gives rise to a de novo stop codon (nonsense mutation), translation of the protein ceases, and a shortened version of the protein is synthesized. Usually, the protein is destroyed intracellularly and never reaches the plasma. A point mutation defect also is associated with severe hemophilia, that is, with coagulant activity levels below 1%. Point mutations resulting in the substitution of one amino acid for another can cause phenotypes of varying severity. The altered amino acid chain can destroy protein function, activation, or folding; inhibit intracellular processing; or cause protein clearance.⁶⁹

Joint bleeding, or hemarthrosis, is the most characteristic type of bleeding in hemophilia. The joints most often affected are the knees, ankles, and elbows.70 Hemarthrosis causes pain, limits joint mobility, and predisposes the child to degenerative joint changes. Bleeding into muscles, usually from trauma, also can occur. Oral bleeding is common in the setting of traumatic injury to the mouth or dental surgery. Spontaneous painless hematuria is relatively common in hemophilia; it does not result in significant blood loss but requires evaluation. Hematuria accompanied by pain requires prompt evaluation and treatment. Spontaneous epistaxis may also occur. Although troublesome, it tends to be a minor complication.

Recurrent bleeding—spontaneous and after minor trauma—is a lifelong problem. Intracranial bleeding, bleeding of internal organs, and bleeding into the tissues of the neck, chest, or abdomen are all life-threatening. Delayed or suboptimal treatment of these bleeding episodes may lead to permanent brain injury, loss of organ function, or death.

Primary prophylaxis consists of regular infusions of factor VIII or IX with the goal of preventing joint bleeding. It is usually given to children with severe hemophilia. A 5-year, multicenter trial, which has now become the standard of care,71,72 found prophylaxis initiated in children between 6 and 30 months of age to be effective in the prevention of joint bleeding, structural joint damage, and frequency of bleeding in boys with factor VIII deficiency. Recent multisite trials have demonstrated the safety and efficacy of pegylated, recombinant factors VIII and IX. These pegylated products have extended half-lives and require less frequent dosing.^73,74 Newer generation products are fully produced in human cell lines and help reduce the risk of the development of inhibitors that limit the efficacy of the infused product.⁷⁵ Recently approved substitution therapies using monoclonal antibodies have shown great promise in the management of bleeding in hemophilia. Ongoing investigation of rebalancing therapies and GT may transform disease severity and management.

Laboratory examination reveals an isolated low platelet count. The few platelets observed on a peripheral smear are large, reflecting increased bone marrow production. The Ivy bleeding time is prolonged. Bone marrow aspiration is not recommended for children with typical features of ITP. The primary management for children newly diagnosed with ITP, with no or mild bleeding (skin manifestations), is only observation regardless of the platelet count. When non-life-threatening mucosal bleeding or diminished quality of life is present, a short burst of corticosteroids is recommended.84

Even without treatment, the prognosis for children with ITP is excellent: 75% recover completely within 3 months. After the initial acute phase, spontaneous clinical manifestations subside. By 6 months after onset, 80% to 90% of affected children have regained normal platelet counts. ITP that persists longer than 12 months in children is considered chronic. Thrombopoietin receptor agonists (TPO-RA) are recommended for the management of children with ITP who are unresponsive to first-line therapies.⁸⁴

The exact cause of most childhood cancer, including leukemia, is unknown. The occurrence of leukemia in monozygotic twins is estimated as being as high as 25%. About 5% of all childhood cancers are caused by inherited mutations. Genetic mutations that predispose the child to cancer development can occur during fetal development. Genetic conditions associated with leukemia include Down syndrome, neurofibromatosis, Li-Fraumeni syndrome, Shwachman-Diamond syndrome, Bloom syndrome, Fanconi anemia, and ataxia-telangiectasia.93 AML in children is sometimes associated with loss or deletion of chromosome 7 in the leukemia cells. AML can develop from preexisting myeloproliferative disorders that also are preleukemia syndromes, such as myelodysplastic syndrome. Epigenetic modifications, including DNA methylation, have been proposed as mediating events between environmental exposures and subsequent disease development.^94,95

Multiple types of exposures have been investigated in relation to the development of leukemia. Many studies have shown that exposure to ionizing radiation (prenatal exposure to x-rays and postnatal exposure to high doses) can lead to the development of childhood leukemia and possibly other cancers.⁹⁶ There is recent concern for performing computed tomography (CT) scans in children. The increased use of these scans combined with wide variability in radiation doses has resulted in many children receiving a high dose of radiation.⁹⁷ Studies of other possible environmental risk factors, including parental exposure to cancer-causing chemicals, prenatal exposure to pesticides, childhood exposure to common infectious agents, and living near a nuclear power plant, have so far produced inconsistent results. Higher risks of cancer have not been seen in children of individuals treated for sporadic cancer (cancer not caused by an inherited mutation).^98,99

Exposure to prenatal and postnatal smoking has also been investigated in relation to the development of leukemia and other childhood cancers. A recent meta-analysis identified an association between the development of ALL and paternal smoking in both the preconception and prenatal periods.¹⁰⁰ Paternal smoking before, during, and after a pregnancy was identified as contributing to an increased risk of both ALL and AML in another recent meta-analysis; however, maternal smoking was not.¹⁰¹

Prenatal exposure to pesticides is hypothesized to increase the risk of childhood leukemia by resulting in oxidative stress leading to the generation of free radicals that induce breaks in the DNA of early hematopoietic stem cells. Results of recent meta-analyses support associations between parental exposure to pesticides and other potential environmental toxins before or during pregnancy and subsequent development of childhood leukemia.^102,103

Chemicals such as benzene have been associated with the development of AML in adults. Recent meta-analyses provide evidence of a possible association between benzene exposure, occurring in the context of traffic-related air pollution and childhood leukemia.^104,105 Previous treatment with chemotherapy for other cancer types is also a risk factor for developing ALL and AML.⁹¹

Studies investigating other types of exposures have had inconclusive results. Leukemic “clusters” that represent a greater number of leukemia cases occurring in a particular geographic location have raised speculation about environmental factors or infectious patterns of transmission. Follow-up studies, however, have not provided evidence of increased risk in the context of these exposures.^106,107

ALL involves immature B (pre-B) or T (pre-T) cells called lymphoblasts. As leukemia develops, the bone marrow becomes dense with lymphoblasts that replace the normal marrow and disrupt normal function. Many of the chromosomal abnormalities documented in ALL cause dysregulation of the expression and function of transcription factors required for normal B-cell and T-cell development.108,109 The mutations can include both gain of function and loss of function that are required for normal development.

AML is caused by acquired oncogenic mutations that impair differentiation, resulting in the accumulation of immature myeloid blasts in the marrow and other organs. Epigenetic alterations are frequent in AML and have a central role. The bone marrow crowding by blast cells produces marrow failure and complications, including anemia, thrombocytopenia, and neutropenia. AML is very heterogeneous because myeloid cell differentiation is very complex. Leukemia, whether ALL or AML, is typically distinguished from lymphoma by the presence of greater than 20% leukemic blasts in the bone marrow.

Renal failure as a result of hyperuricemia (high uric acid levels) can be associated with ALL, particularly at diagnosis or during the initial phase of treatment. Uric acid levels rise as an end product of purine metabolism from cellular destruction. Because the major excretory pathway is through the kidney, urates can precipitate in renal tubules or ureters and can lead to oliguria and acute renal failure. Renal failure is typically preventable if uric acid levels are monitored, and initial management is aimed at optimal hydration and blockage of further uric acid formation by administration of the drug allopurinol. Rasburicase, a medication that directly inhibits existing uric acid, may be administered to children with elevated uric acid levels and deemed at increased risk for renal failure.110

Extramedullary invasion with leukemic cells can occur in nearly all body tissue. Most children with ALL have some extramedullary involvement at diagnosis. Leukemic invasion of tissue other than bone marrow is believed to represent metastatic infiltration. Hepatosplenomegaly and lymphadenopathy, resulting from extramedullary hematopoiesis, occur in nearly half of children with ALL, but they are less common in children with AML.

The CNS is a common site of infiltration of extramedullary leukemia. Less than 10% of children with ALL, however, will have CNS involvement at diagnosis. The most common symptoms of CNS involvement relate to increased intracranial pressure, causing early morning headaches, nausea, vomiting, irritability, and lethargy. Gonadal involvement with testicular infiltration also may occur.

Leukemic infiltration into bones and joints is common. Reports of bone or joint pain actually lead to the diagnosis of leukemia in some children. In most children, bone pain is characterized as migratory, vague, and without areas of swelling or inflammation. In some cases, however, joint pain is the primary symptom, and some swelling is associated with the pain. Occasionally, these children are initially misdiagnosed as having rheumatoid arthritis. Other organs reported to be sites of leukemic invasion include the kidneys, heart, lungs, thymus, eyes, skin, and gastrointestinal tract. Skin involvement is more common in AML than in ALL.

Leukemia is diagnosed through blood tests and examination of peripheral blood smears. A bone marrow aspiration is usually performed to further characterize the leukemia. The blast cell is the hallmark of acute leukemia (Fig. 30.10A). The blast cell is a relatively undifferentiated cell characterized by diffusely distributed nuclear chromatin, with one or more nucleoli and basophilic cytoplasm (Fig. 30.10B).

Two photomicrographs of bone marrow smears A and B show the morphology of acute myeloid leukemia. Photomicrograph A shows large blast cells with a low nucleus. Photomicrograph B shows numerous blasts cell with round nuclei.

Healthy children have less than 5% blast cells in the bone marrow and none in the peripheral blood. In ALL, the bone marrow often is replaced by 80% to 100% blast cells. The bone marrow, at the time of diagnosis, is typically considered hypercellular and is composed of a homogeneous population of cells. Counts of normally developing RBCs, granulocytes, and platelets are typically reduced. Occasionally, the marrow appears hypocellular, making the diagnosis difficult to differentiate from aplastic anemia. When this occurs, bone marrow biopsy or biopsy of extramedullary sites is necessary to confirm the diagnosis.

Approximately 85% of children with ALL will become 5-year survivors of their illness. Chemotherapy, using a combination of medications, is the treatment of choice for acute leukemia. Radiation of the CNS is used only in selected cases. Identification of various risk groups among children with ALL has led to the development of different intensities of drug protocols. As a result, treatment can be targeted specifically for a particular risk group. For example, enhanced technologies to detect minimal residual disease have improved the ability to identify children who are at increased risk of relapse. These children are then able to receive intensified treatment with emerging therapeutic approaches, including bi-specific antibodies earlier in their course of treatment.¹¹¹ Children who experience relapses of ALL may receive hematopoietic stem cell transplants. Treatment with chimeric antigen receptor T cells (CAR-T cells) is also showing promise.⁹³

AML is more difficult to treat than ALL. Combination chemotherapy is the most common approach to treatment. Those children with unfavorable cytogenetic markers and those who experience a relapse of their disease will often undergo HSCT.¹¹²

CML accounts for less than 5% of childhood leukemias. Biologically targeted therapies, specifically tyrosine kinase inhibitors (TKIs), are becoming the mainstay of treatment, specifically for individuals whose disease has the BCR/ABL translocation.¹¹² TKIs are administered orally, and several are now approved for use in children. Treatment requires continued adherence to the medication regimen, and the health impact of long-term TKI therapy is not yet known.

Burkitt lymphoma will be discussed as an example of the pathogenesis of NHL in children. Burkitt lymphoma includes three clinical variants: sporadic, endemic, and immunodeficiency associated. Each of these variants is associated with translocations of the MYC gene on chromosome 8 that lead to increased MYC protein levels.115 MYC is a transcription factor, meaning that it influences the rate of transcription of DNA into messenger RNA. Overexpression of MYC further increases the expression of genes required for aerobic glycolysis, called the Warburg effect (see Chapter 12). Many Burkitt lymphomas are associated with latent infection of the EBV.¹¹⁶ EBV is present in nearly all cases of endemic Burkitt lymphoma, which occur mostly among individuals living in areas of the world where malaria is highly prevalent. Malaria is believed to reduce resistance to EBV, thereby increasing susceptibility to lymphoma. EBV is also present in 15% to 20% of sporadic cases of Burkitt lymphoma and about 25% of tumors associated with human immunodeficiency virus (HIV) infection.^116,117 Other immunodeficiency conditions that increase the risk for Burkitt and other NHLs include receipt of a solid organ transplant, Wiskott-Aldrich syndrome, ataxia-telangiectasia, and Bloom syndrome.

The abnormal pattern of gene expression in HRS cells suggests that the activity of many transcription factors is also altered.119 NGS studies have identified mutations in signaling pathways, including transcription factor nuclear factor-kappa B (NF-κB) and other epigenetic regulators. Abnormalities in the activation of NF-κB may be influenced by EBV infection. NF-κB is involved in many biologic processes, including inflammation, immunity, cell growth, differentiation, and apoptosis. EBV-infected B cells, resembling Reed-Sternberg cells, are found in lymph nodes in individuals with infectious mononucleosis, suggesting that the EBV proteins may have a role in changes of the B cells into HRS cells.¹²⁰ Altered expression of major histocompatibility class antigens may allow HRS cells to avoid the normal host immune response.¹²¹

Painless lymphadenopathy in the lower cervical chain, with or without fever, is the most common symptom in children. These nodes are firm and rubbery and may be sensitive to palpation if they have grown rapidly. Other lymph nodes and organs also may be involved (Fig. 30.12). At least two-thirds of individuals have mediastinal involvement that may cause symptoms ranging from a nonproductive cough to tracheal or bronchial compression leading to airway obstruction. Extranodal primary sites in Hodgkin lymphoma are rare. Systemic symptoms at the time of diagnosis may include fatigue, anorexia, weight loss, malaise, drenching night sweats, and pruritus. Intermittent fever is present in 30% of children, and weight loss may be present.

An illustration of the anterior view of the human body shows the main areas of lymphadenopathy and organ involvement in Hodgkin lymphoma: Waldeyer ring, cervical supraclavicular, mediastinal, axillary, liver, spleen, para-aortic and mesenteric, and iliac.

The Ann Arbor staging system considers extent and location of disease, as well as substage classifications that consider systemic symptoms (presence of fever of 38°C [100.4°F] for 3 consecutive days, drenching night sweats, or unexplained loss of 10% or more of body weight in the 6 months preceding diagnosis), extranodal manifestations, or bulky disease. Combination chemotherapy used with or without low-dose radiation has been an effective treatment, with long-term cure rates reported from 90% to 95%.118

Historically, survivors had a much greater risk of developing a secondary cancer, such as lung cancer, melanoma, and breast cancer. Treatment protocols have been modified to minimize the use of radiotherapy and use less toxic chemotherapy. Targeted therapies, including monoclonal antibodies such as brentuximab vedotin and immune checkpoint inhibitors, may have a greater role in treating Hodgkin lymphoma.