HEMATOLOGY AND ONCOLOGY - McGraw-Hill Specialty Board Review Pediatrics, 2nd Edition

McGraw-Hill Specialty Board Review Pediatrics, 2nd Edition

Chapter 11. HEMATOLOGY AND ONCOLOGY

CASE 87: A NEONATE WITH HYPERBILIRUBINEMIA

You are called to evaluate a 4-day-old infant in the nursery for worsening jaundice. The patient is the first child of a 32-year-old mother, who had an uncomplicated full-term pregnancy and normal spontaneous vaginal delivery. The mother is otherwise healthy but has a sister who had her gallbladder removed as a child. The infant has been formula fed and has been eating and stooling normally. The total bilirubin level is 19.2 mg/dL, with a direct fraction of 0.3 mg/dL.

On physical examination, the infant is jaundiced but otherwise well, with no other significant physical findings.

SELECT THE ONE BEST ANSWER

1. The differential diagnosis of the unconjugated hyperbilirubinemia in this child includes which of the following?

(A) biliary atresia

(B) alpha₁-antitrypsin deficiency

(D) Caroli syndrome

(E) Sickle cell anemia

2. The laboratory evaluation of this infant’s hyperbilirubinemia should include all of the following except

(A) complete blood count with smear

(B) indirect and direct Coombs test

(D) maternal blood type

(E) reticulocyte count

3. Which of the following combinations of parents’ blood types place an infant at highest risk for hemolytic anemia?

(A) maternal Rh negative, paternal Rh negative, first child

(B) maternal Rh negative, paternal Rh positive, second child

(D) maternal type AB, paternal type B, second child

(E) maternal type AB, paternal type A, first child

4. The differential diagnosis of a neonate with hemolytic anemia includes all of the following except

(A) pyruvate kinase deficiency

(B) ABO incompatibility

(D) hereditary spherocytosis

(E) Rh disease

5. Erythroblastosis fetalis is characterized by all of the following except

(A) elevated amniotic fluid bilirubin levels

(B) fetal anasarca

(D) fetal hepatosplenomegaly

(E) elevated reticulocyte count

6. Treatment of the infant with Rh-hemolytic disease could include which of the following?

(A) red blood cell exchange transfusion with neonatal cross-matched blood

(B) red blood cell transfusion with maternal crossmatched blood

(D) intravenous immunoglobulin for the mother before delivery

(E) cryoprecipitate transfusion

7. The direct Coombs test is an evaluation for which of the following?

(A) anti-white blood cell antibodies in the serum

(B) anti-platelet antibodies bound to the patient’s platelets

(D) serum antibodies against all blood cells

(E) Rh antibodies

8. Physiologic anemia of infancy occurs at what age for healthy full-term infants?

(A) 1-2 days old

(B) 2-3 weeks old

(D) 10-12 months old

(E) 3-6 months old

9. Which of the following is the best treatment for physiologic anemia of infancy?

(A) oral ferrous sulfate

(B) careful observation

(D) monthly red blood cell transfusions

(E) vitamin B₁₂supplementation

10. G6PD (glucose-6-phosphate dehydrogenase) deficiency is least common in which of the following ethnic groups?

(A) northern African

(B) northern European

(D) southern European

(E) South America

11. G6PD deficiency is inherited in what fashion?

(A) X-linked

(B) autosomal recessive

(D) mitochondrial

(E) autosomal recessive with variable penetrance

12. The presence of Heinz bodies on the peripheral blood smear is a feature of which of the following disorders?

(A) G6PD deficiency

(B) autoimmune hemolytic anemia

(D) sickle cell disease

(E) spherocytosis

13. Which of the following, when ingested, is not associated with hemolytic crisis in patients with G6PD deficiency?

(A) primaquine

(B) trimethoprim-sulfamethoxazole

(D) acetaminophen

(E) moth balls

14. Which of the following is not a feature of hemolytic crises in patients with G6PD deficiency?

(A) hemoglobinuria

(B) splenomegaly

(D) jaundice

(E) elevated reticulocyte count

15. Hereditary spherocytosis is most commonly caused by a defect in which red blood cell protein?

(A) hemoglobin

(B) spectrin

(D) ankyrin

(E) G6PD

16. Which of the following laboratory tests would be most useful in diagnosing hereditary spherocytosis?

(A) Coombs test

(B) osmotic fragility test

(D) hemoglobin electrophoresis

(E) serum iron

17. Which of the following is the most effective long-term treatment for patients with hereditary spherocytosis?

(A) monthly exchange transfusions

(B) splenectomy

(D) intravenous spectrin replacement therapy

(E) monthly intravenous gammaglobulin infusions

18. Postsplenectomy patients are not at increased risk for infections from which of the following bacteria?

(A) Streptococcus pneumoniae type 19A

(B) Haemophilus influenzae

(D) Escherichia coli

(E) Streptococcus pneumoniae type 3

ANSWERS

1. (C) Neonatal jaundice occurs in approximately twothirds of infants and is defined by bilirubin levels higher than 5 mg/dL. Bilirubin is generated as one of the products of the breakdown of hemoglobin, and the conjugation of bilirubin to bilirubin glucuronide occurs in the liver. Neonatal unconjugated hyperbilirubinemia is therefore the result of either increased bilirubin production or decreased conjugation. Neonatal hemolytic anemias, with increased bilirubin production, can result in severely abnormal unconjugated hyperbilirubinemia levels in neonates. Blood group mismatches because of ABO or Rh mismatches are common causes of neonatal hemolytic anemia and unconjugated hyperbilirubinemia. Other causes of unconjugated hyperbilirubinemia include hemolytic anemias because of red blood cell membrane or enzyme defects and increased red blood cell turnover associated with polycythemia, internal hemorrhages such as cephalohematomas or intraventricular hemorrhages. Decreased bilirubin conjugation as a result of Crigler-Najjar or Gilbert syndromes also result in unconjugated hyperbilirubinemia. Biliary atresia, α₁-antitrypsin deficiency, and Caroli syndrome are all causes of neonatal conjugated hyperbilirubinemia.

2. (C) Evaluation for suspected neonatal hemolytic anemias should include evaluation of the complete blood count along with indirect and direct Coombs tests and maternal and neonatal blood types. In the absence of excessive bleeding or bruising, there is no indication for coagulation studies. The complete blood count will reveal the degree of anemia, if any, and the peripheral smear will demonstrate the morphologic features of the red blood cells that could suggest underlying etiologies. The Coombs tests will evaluate whether or not there are antibodies that could be contributing to autoimmune or alloimmune hemolysis. Neonatal and maternal blood types are needed to evaluate the possible presence of ABO and Rh incompatibility.

3. (B) Mothers with Rh negative blood type develop antibodies against the Rh antigen after exposure during pregnancy to an Rh-positive fetus or after transfusion with Rh-positive blood. In the presence of an Rh-positive fetus, the mother’s antibodies can cross the placenta and destroy fetal red blood cells, resulting in neonatal hemolytic anemia. Rh hemolytic disease can be prevented with high titer Rho(D) immune globulin treatment for Rh-negative mothers who have been exposed to Rh-positive infants. Similarly, mothers with type O blood have antibodies against antigens for blood types A and B that can react to and destroy fetal red blood cells with these blood type antigens. However, a fetus that also possesses type O blood will not be susceptible to hemolysis from these antibodies. A mother with type AB blood has no antibodies to blood group antigens, and therefore the fetus is not exposed to any anti-red blood cell antigen antibodies. Despite the presence of these antibodies, only 33% of infants with ABO “mismatch” will have a positive direct Coombs test, and of those, only 20% will develop jaundice from excessive hemolysis.

4. (C) Crigler-Najjar syndrome is caused by the absence of glucuronyl transferase and results in severe indirect hyperbilirubinemia. Pyruvate kinase and G6PD are both red blood cell enzymes that, when deficient, can result in neonatal hemolytic anemia. Hereditary spherocytosis, as well as other syndromes with red blood cell structural abnormalities, such as hereditary elliptocytosis and paroxysmal nocturnal hemoglobinuria, can also result in neonatal hemolytic anemia. A maternal-fetal blood type mismatch such as ABO incompatibility results in alloimmune hemolytic anemia, with the mother’s antibodies reacting to and destroying the neonatal red blood cells.

5. (C) Erythroblastosis fetalis, or hydrops fetalis secondary to Rh hemolytic disease, is characterized by severe fetal hemolytic anemia as a result of anti-Rh antibody from an Rh-negative mother crossing the placenta and attacking fetal Rh-positive red blood cells. The hemolysis results in intrauterine hyperbilirubinemia, which can be detected in amniotic fluid samples. Furthermore, the severe anemia results in high output cardiac failure with anasarca and peripheral edema. Hepatosplenomegaly as a result of extramedullary hematopoiesis also occurs. Nucleated red blood cells, or “erythroblasts,” are elevated as a result of fetal marrow hyperproduction to compensate for the anemia (see Figure 87-1).

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FIGURE 87-1. Hemolytic disease of the newborn (erythroblastosis fetalis). Polychromatophilic cells, spherocytes, and circulating erythroblasts. (Reproduced, with permission, from Lichtman MA, Beutler E, Kipps TJ, et al. Williams Hematology, 7th ed. New York: McGraw-Hill; 2006: Plate II-2.)

6. (B) Red blood cell transfusions or exchange transfusions are often required for infants suffering from Rh-hemolytic disease but must be cross-matched against the mother and not the infant because the mother’s antibodies are the source of the hemolytic anemia. Fresh-frozen plasma (FFP) has no role in the management of the hemolytic anemia in the infant. Treatment of the mother with Rho(D) immune globulin before delivery can reduce the autoimmune hemolysis, but intravenous immunoglobulin does not have the same beneficial effect.

7. (C) The direct Coombs test takes the patient’s red blood cells and places them in the presence of complement proteins in vitro. The occurrence of hemolysis confirms the presence of antibodies directly bound to the patient’s red blood cells. The indirect Coombs test evaluates the patient for antibodies to red blood cells that are circulating freely in the serum. The Coombs tests do not evaluate antibodies against any other types of blood cells.

8. (C) Infants in their first few days of life cease producing new red blood cells as a result of the oxygen-rich environment (relative to in utero) and decreased responsiveness of their bone marrow to erythropoietin. The hemoglobin levels fall to a nadir of 9-10 g/dL at 10-12 weeks of age, at which time erythropoiesis resumes. Premature infants or infants with other causes of neonatal anemia have an earlier onset of physiologic anemia with a lower nadir level of hemoglobin, often down to 6-8 g/dL at 4-8 weeks of age.

9. (B) Careful observation is generally all that is required for physiologic anemia because the infant’s erythropoietic system matures and the anemia resolves. Iron and folic acid supplementation are not indicated for isolated physiologic anemia, and transfusions are only indicated for severe symptomatic anemia, which does not occur with isolated physiologic anemia. Blood transfusions can suppress the endogenous erythropoietin production and delay recovery from physiologic anemia.

10. (B) The presence of G6PD deficiency is most common in African populations and populations that dwell or dwelled around the Mediterranean Sea, with increased frequency also in southern Asian populations and American Indians. G6PD deficiency occurs in approximately 12% of African American males; in Southeast Asia the incidence is approximately 6%. Northern Europeans have the lowest incidence of G6PD deficiency among the populations listed.

11. (A) G6PD deficiency is an X-linked disorder. Affected males have a single mutated copy of the G6PD gene; affected females are usually compound heterozygotes with 2 different mutant G6PD gene alleles. Deficiency of G6PD in African Americans is most commonly the result of a mutation that renders the enzyme unstable, leaving new red blood cells with relatively normal enzyme levels but old red blood cells with nearly absent enzyme levels and with increased susceptibility to oxidant stress. The mutations in the G6PD gene that occur in other populations, particularly the Mediterranean and Middle Eastern populations, generally result in absent G6PD expression. These patients are more susceptible to oxidant-induced red blood cell lysis and are also susceptible to hemolysis induced by fava beans (termed favism).

12. (A) Heinz bodies (see Figure 87-2) are intracellular inclusions of oxidized and degenerated hemoglobin seen in red blood cell enzyme deficiencies such as G6PD deficiency. The inclusions are often attached to the red blood cell membrane and can be “eaten” by splenic macrophages, resulting in the characteristic “bite cells” of red blood cell enzyme deficiencies. Autoimmune hemolytic anemia is characterized by microspherocytosis, but there are no intracellular inclusions. Neonatal alloimmune thrombocytopenia has no unusual red blood cell features. Sickle cell disease has sickled red blood cells and often has Howell-Jolly bodies from splenic hypofunction, but it is not associated with Heinz bodies.

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FIGURE 87-2. Heinz bodies. Blood mixed with hypotonic solution of crystal violet. Precipitates of denatured hemoglobin within the cells. (Reproduced, with permission, from Lichtman MA, Beutler E, Kipps TJ, et al. Williams Hematology, 7th ed. New York: McGraw-Hill; 2006: Plate IV-4.)

13. (D) Hemolysis in patients with G6PD deficiency is stimulated by oxidative stress, which can be caused by stress from infections, diabetic ketoacidosis, or by medications and chemicals such as primaquine, sulfa drugs, and methylene blue. Other chemicals that can trigger hemolysis include dapsone, nitrofurantoin, trinitrotoluene, naphthalene, and acetanilid. Fava beans can stimulate hemolysis in certain populations with specific forms of G6PD mutations, such as those that occur in Mediterranean populations. Acetaminophen is not associated with hemolytic crises in patients with G6PD deficiency.

14. (C) Hemolytic crises in patients with G6PD deficiency and other hemolytic anemias are characterized by fatigue, pallor, scleral icterus and jaundice, splenomegaly, and hemoglobinuria. Laboratory findings include anemia with increased free plasma hemoglobin and decreased plasma haptoglobin. Pulmonary infiltrates are not associated with hemolytic crises.

15. (B) Hereditary spherocytosis is the most common structural red blood cell defect and affects approximately 1 in 5000 people. The most common cause of hereditary spherocytosis is a defect in spectrin, a protein responsible for the structural integrity of the red blood cell membrane. Defects in associated proteins, such as band 3, protein 4.2, and ankyrin, can also play a role in the defect but act via a relative spectrin deficiency. Hereditary spherocytosis is most common in northern Europeans and is characterized by anemia, jaundice, and splenomegaly. Most cases are inherited in an autosomal dominant fashion, but approximately 10% are inherited as a recessive trait. Hemoglobin deficiencies do not cause spherocytosis, and pyruvate kinase is a red blood cell enzyme that is unrelated to the structural features of the red cell membrane.

16. (B) The osmotic fragility test is the most specific test for the diagnosis of hereditary spherocytosis. Red blood cells are incubated in the presence of varying degrees of hypotonic solutions, and the red blood cell lysis is measured. Spherocytes, as a result of their decreased surface area, will be more susceptible to hypotonic lysis compared with normal red blood cells. The Coombs test detects the presence of antibodies in cases of autoimmune hemolytic anemia, which can be associated with spherocytes visualized on a peripheral smear but will be negative in cases of hereditary spherocytosis. Platelet aggregation studies and hemoglobin electrophoresis are not useful in the diagnosis of spherocytosis.

17. (B) Splenectomy should be an option for any patient with hereditary spherocytosis who requires frequent transfusions, has severe symptoms of anemia such as cardiac dysfunction or poor growth, has severe splenomegaly with significantly increased risk of rupture, or has persistent symptoms of hypersplenism such as leukopenia or thrombocytopenia. Splenectomy usually results in a persistently elevated baseline hemoglobin. Patients undergoing splenectomy should receive immunizations against H influenzae and S pneumoniae if possible before surgery, and they should be started on penicillin prophylaxis as soon as possible after splenectomy. Furthermore, splenectomy should be avoided if possible until patients are older than 5 years to reduce the incidence of severe bacterial infections that can occur in younger children. Exchange transfusions are not indicated for the treatment of spherocytosis, and steroids have no effect. Spectrin replacement is not yet a viable treatment option (see Figure 87-3).

18. (C) S pneumoniae, H influenzae type b, and E coli can all be encapsulated organisms, and patients with either splenic hypofunction or those undergoing splenectomy are at increased risk for infections from these and other encapsulated organisms. M pneumoniae is not an encapsulated organism, and splenectomized patients are not at a higher risk of mycoplasma infections. Patients who need a splenectomy should receive H influenzae and pneumococcal vaccines before the splenectomy, and then they should receive penicillin prophylaxis postsplenectomy to reduce the incidence of bacteremia and sepsis from encapsulated organisms.

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FIGURE 87-3. Sickle cell anemia, dactylitis. Note the swelling of the right thumb and first and second fingers. There is a high frequency of dactylitis in children with sickle cell anemia between the time of birth and four years of age with a mode at about one year. This swelling is associated with limited vascular necrosis of marrow and may affect the hands and feet. (Reproduced, with permission, from Lichtman MA, Beutler E, Kipps TJ, et al. Williams Hematology, 8th ed. New York: McGraw-Hill; 2006: Fig. 48-10.)

SUGGESTED READING

Cashore WJ. Neonatal hyperbilirubinemia. In: McMillan JA, DeAngelis CD, Feigin RD, et al, eds. Oski’s Pediatrics: Principles and Practice. 4th ed. Philadelphia, PA: Lippincott Williams and Wilkins; 2006.

Committee on Infectious Diseases, American Academy of Pediatrics. Immunization in special circumstances. In: Pickering LK, Baker CJ, Kimberlin DW, Long SS, eds. Red Book 2009 Report of the Committee on Infectious Diseases. 28th ed. Elk Grove Village, IL: American Academy of Pediatrics; 2009.

Gallagher PG, Jarolin P. Red cell membrane disorders. In: Hoffman R, Benz EJ, Shattil SJ, et al, eds. Hematology: Basic Principles and Practice. 5th ed. Philadelphia, PA: Churchill Livingstone; 2008.

Prchal JT, Gregg XT. Red cell enzymopathies. In: Hoffman R, Benz EJ, Shattil SJ, et al, eds. Hematology: Basic Principles and Practice. 5th ed. Philadelphia, PA: Churchill Livingstone; 2008.

Tabbara IA. Hemolytic anemias: diagnosis and management. Med Clin North Am. 1992;76(3):649-668.

Watchko JF. Identification of neonates at risk for hazardous hyperbilirubinemia: emerging clinical insights. Pediatr Clin North Am. 2009;56:671-687.

CASE 88: AN 18-MONTH-OLD GIRL WITH ANEMIA

An 18-month-old Hispanic girl is brought to your office for routine evaluation. A screening hemoglobin level was noted to be 4.6 g/dL. The child does appear pale and has a “cranky” disposition, according to the parents. On further history, the child’s parents inform you that her diet consists of approximately 36 ounces of cow’s milk per day. There is no prior history of anemia and no history of pica, trauma, or recent blood loss. The child is the product of a full-term, uncomplicated pregnancy and has been doing well, with no other medical problems and normal growth and development to date. There is no family history of blood disorders.

Her physical examination is notable for mild pallor and a 2/6 systolic ejection murmur at the left sternal border.

SELECT THE ONE BEST ANSWER

1. The most likely diagnosis for this child is

(A) acute lymphoblastic leukemia

(B) iron deficiency anemia

(D) anemia of chronic disease

(E) G6PD

2. The most useful diagnostic test at this point would be

(A) complete blood count with smear

(B) serum ferritin level

(D) direct and indirect Coombs test

(E) G6PD screen

3. The differential diagnosis of a child with microcytic anemia includes all of the following except

(A) lead intoxication

(B) folate deficiency

(D) anemia of chronic disease

(E) thalassemia

4. Most of the body’s iron is located in the

(A) erythrocytes

(B) splenic histiocytes

(D) hepatocytes

(E) skeletal myocytes

5. Which of the following compounds does not inhibit iron absorption from the gastrointestinal (GI) tract?

(A) ascorbic acid

(B) phytates

(D) sodium bicarbonate

(E) antacids

6. Which of the following is the least likely cause of iron deficiency in adolescents?

(A) menorrhagia

(B) pregnancy

(D) sedentary lifestyle

(E) diet

7. Which of the following is not a complication of iron deficiency anemia?

(A) geophagia (compulsive dirt eating)

(B) cognitive delay

(D) short stature

(E) rapid or irregular heartbeat

8. Which of the following is a laboratory finding associated with iron deficiency?

(A) increased serum TIBC (total iron-binding capacity)

(B) increased serum ferritin

(D) increased serum iron

(E) decreased red blood cell red distribution width (RDW)

9. Treatment options for children with iron deficiency anemia include all of the following except

(A) red blood cell transfusion

(B) oral ferrous sulfate

(D) oral folic acid

(E) iron-rich diet

10. Beta-thalassemia is found most commonly among which of the following ethnic groups?

(A) Southeast Asian

(B) northern European

(D) American Indian

(E) Japanese

11. Which of the following is not a physical feature among patients with thalassemia major?

(A) frontal bossing

(B) splenomegaly

(D) tibial bowing

(E) growth failure

12. Hemoglobin H disease is associated with how many alpha-globin gene deletions?

(A) 0

(B) 1

(D) 3

(E) 4

13. Which of the following is not a complication of transfusion-associated hemochromatosis?

(A) dilated cardiomyopathy

(B) diabetes mellitus

(D) hypogonadism

(E) osteoporosis

14. Which of the following is a normal childhood hemoglobin electrophoresis pattern?

(A) 96% A, 3% A2, 1% F

(B) 90% A, 8% A2, 2% F

(D) 80% A, 10% A2, 10% F

(E) 80% A, 2% A2, 18% F

15. Which of the following statements regarding Diamond-Blackfan anemia is false?

(A) Diamond-Blackfan anemia is usually microcytic

(B) reticulocyte count in patients with Diamond-Blackfan anemia is low

(D) Diamond-Blackfan anemia is usually diagnosed in patients before their first birthday

(E) small “i” antigens are present on red blood cells

16. Which of the following anemic patients is most likely to have transient erythroblastopenia of childhood?

(A) 2-month-old boy with macrocytic anemia

(B) 11-month-old girl with increased fetal hemoglobin levels

(D) 35-month-old girl with failure to thrive

(E) newborn with anemia and jaundice

17. Which of the following is not a symptom of lead toxicity?

(A) recurrent emesis

(B) constipation

(D) polyuria

(E) anemia

ANSWERS

1. (B) The most likely diagnosis is iron deficiency anemia, based on the patient’s age and her history of cow’s milk intake. Iron deficiency is a common cause of anemia in children, with a peak incidence between 6 months and 3 years of age. Iron stores initially are accumulated during the last 3 months of pregnancy, and so iron deficiency in neonates and early infancy is due either to prematurity, early blood losses, or hemolysis. In contrast, iron deficiency in older infants and toddlers is usually a result of dietary deficiency, most commonly a result of excessive cow’s milk intake. Cow’s milk is a poor source of iron, with only 0.5-1 mg/L of iron and with only 10% of the iron bioavailable. Furthermore, excessive intake of cow’s milk is associated with decreased intake of other, more iron-rich, foods. Cow’s milk also frequently causes mucosal irritation in the GI tract, leading to chronic lowgrade blood loss. As iron deficiency develops slowly, over months to years, even severe anemia is relatively well tolerated by children with few symptoms. After correction of the iron deficiency, however, parents often note that children are less pale, have more energy, and are less “cranky.” Management of diet-associated iron deficiency involves decreasing or eliminating cow’s milk intake and increasing the intake of other iron-rich foods such as meats and leafy green vegetables, in addition to added oral iron supplements as needed.

Children with acute leukemias usually present with other cytopenias in addition to anemia and are commonly symptomatic from their cytopenias, with fevers, fatigue, petechiae, and bleeding. Anemia of chronic disease occurs in patients with a history of chronic inflammation, such as those with collagen vascular diseases, chronic infections (particularly osteomyelitis and tuberculosis), or renal insufficiency. The anemia of chronic disease is generally mild and of slow onset and is secondary to poor utilization of iron stores and suboptimal bone marrow responsiveness to erythropoietin. Management involves treatment of the underlying disease, as additional iron will not be used by the bone marrow or be effective in raising the hemoglobin level. Lead poisoning can be associated with microcytic anemia and is also frequently associated with iron deficiency. The latter results in increased lead absorption and toxicity. Anemia because of lead poisoning is usually a late finding and, fortunately, is rare in modern times because of the removal of lead from previously common sources such as paint and gasoline.

2. (A) The complete blood count with peripheral smear is the single most useful diagnostic test for iron deficiency. The complete blood count not only details the magnitude of anemia but also reports on red blood cell features, including the MCV and RDW, which will help to differentiate the anemia of iron deficiency (characterized by a low MCV and high RDW) from anemia because of thalassemia (characterized by a low MCV with a normal RDW). Furthermore, the peripheral smear will demonstrate the characteristic microcytosis with hypochromia and poikilocytosis of iron deficiency. The serum ferritin level is normally decreased with iron deficiency but can be falsely normal or high with any concurrent systemic inflammation. A hemoglobin electrophoresis would be useful to diagnose beta-thalassemia or other hemoglobinopathies but is not helpful in the diagnosis of iron deficiency. Electrophoresis in patients with thalassemia can be falsely normal in the presence of iron deficiency. The Coombs tests look for antibodies to red blood cells in the patient’s serum (indirect) or bound directly to the patient’s red blood cells (direct), and are useful to diagnose autoimmune hemolytic anemias but would not be useful in this case.

3. (B) Folate deficiency is a cause of macrocytic anemia and is also associated with hypersegmentation of neutrophils on the peripheral smear. The differential diagnosis of microcytic anemia in children includes lead poisoning, alpha- and beta-thalassemia, iron deficiency, anemia of chronic disease, and sideroblastic anemia. Iron deficiency is by far the most common, occurring in up to 10% of children in the United States. The anemia of chronic disease is also common but can be normocytic in more than half of the cases. Anemias due to hemoglobinopathies such as sickle cell disease, red blood cell enzyme defects or structural defects, and autoimmune hemolytic anemias are all generally normocytic. Macrocytic anemias can result from folate deficiency, vitamin B₁₂deficiency, or myelodysplastic or aplastic anemias.

4. (A) The average adult man has approximately 5 g of total body iron, and most (60-80%) of the body’s total iron is bound to erythrocyte hemoglobin. Approximately 10-30% of the total body iron stores are located in the reticuloendothelial cells of the liver and spleen. The heart and liver have only minimal amounts of iron under normal conditions, but they can contain large amounts of iron in states of iron overload. Only 0.1% of the total body iron stores can be found in the plasma, bound to transferrin. Only 1 mg of the total body iron is lost each day through sloughed skin and enteric mucosal cells and therefore must be replaced through the diet. The human body, unfortunately, has no other mechanism for selective iron excretion.

5. (A) Dietary iron is generally absorbed in the duodenum, and the absorption is regulated both in the form of the dietary iron as well as by the local intestinal environment. At neutral pH, iron is primarily in the ferric (Fe+3) form, which is poorly absorbed. In the stomach and duodenum, the acidic pH converts iron to the ferrous (Fe+2) form, which is more readily absorbed. Furthermore, iron found in heme moieties (from meat sources) is more readily absorbed compared with free elemental iron. Ascorbic acid and citric acid increase the absorption of iron from the intestine by reducing the iron from the ferric to the ferrous state. Phytates (found in soy-based formulas) and phosphates (found in cow’s milk) both bind to free iron in the GI tract and inhibit its absorption. Bicarbonate increases the gastric pH, which also inhibits conversion of iron to its ferrous form and reduces its absorption.

6. (D) The activity level of adolescents is unrelated to their iron stores. However, any cause of chronic blood loss, such as heavy menstrual bleeding, or any period of increased physiologic iron demand, such as pregnancy or growth spurts, can lead to iron deficiency. Dietary causes of iron deficiency are extremely rare in adolescents but can occur with unusual dietary patterns, such as strict vegetarianism or anorexia nervosa.

7. (C) Cardiomyopathy is generally not a complication of iron deficiency, although children with severe long-standing anemia of any etiology can have cardiac dysfunction as a result of excessive workload. Geophagia, a form of pica, along with cognitive delays, delayed growth, and irritability, are all associated with iron deficiency. The cognitive delays, unfortunately, may not be totally reversible with correction of the iron deficiency. Iron deficiency has also been associated with breath-holding spells, febrile seizures, proteinlosing enteropathy (because of the loss of enteric mucosal cells), and, rarely, thromboembolic strokes hypothesized to be secondary to a decrease in red blood cell membrane fluidity and flexibility that occurs with iron deficiency.

8. (A) The presence of iron deficiency is associated with a variety of laboratory abnormalities, including abnormalities in the blood count and abnormalities of other serum proteins. The features of iron deficiency in the complete blood count include a low MCV, an increased RDW, and associated hypochromia and poikilocytosis. Laboratory values consistent with iron deficiency include decreased ferritin, increased TIBC, decreased serum transferrin saturation, increased free erythrocyte protoporphyrin, and decreased serum iron. Anemia of chronic disease, by comparison, is characterized by a decreased TIBC and a normal serum ferritin level, whereas beta-thalassemia is generally associated with normal to increased serum iron, normal TIBC, and normal to increased serum ferritin levels.

9. (D) Folic acid therapy is not indicated for treatment of iron deficiency except in those cases of combined iron and folate deficiency, such as with severe malnutrition. Although oral ferrous sulfate at 3-6 mg/kg of elemental iron per day is the usual first option for treatment, intravenous iron therapy is an option for those patients with extremely low iron stores or those who would not absorb or tolerate oral iron. Red blood cell transfusions can be used for patients with very severe anemia, and the iron from the transfused red blood cells can then be recycled by the body for future red blood cell production as well. Responses to treatment for iron deficiency anemia are generally rapid, with an increase in reticulocytes occurring within 7 days and increased hemoglobin levels by 1 month.

Iron deficiency anemia develops slowly over time and progresses through several stages. Initially, depletion of the total body iron stores results in low serum ferritin levels but unchanged hemoglobin and serum iron levels. Upon complete iron store depletion, the serum iron level drops, associated with an increase in the serum TIBC. Further loss of iron then results in “iron deficiency anemia,” with development of the microcytic, hypochromic anemia characteristic of iron deficiency. Repletion of iron, either by oral, intravenous, or transfusion therapy, initially replaces the red blood cell iron, with normalization of the hemoglobin level and red blood cell MCV. However, in the absence of further aggressive iron repletion, the serum iron and ferritin levels remain low, and the patient remains in a state of “iron-limited erythropoiesis.” Therefore, it is crucial that iron replacement therapy be continued for several months after the normalization of the red blood cell parameters to ensure adequate replacement of the total body iron stores.

10. (A) Thalassemias are blood disorders characterized by decreased alpha- or beta-globin chain production, and they have a wide spectrum of clinical symptoms based on the relative levels of the alpha- and betaglobin chains. beta-thalassemia is most commonly found in persons of Mediterranean, northeast African, Indian, Indonesian, and Southeast Asian descent. The gene frequency can be as high as 20% in these populations. In contrast, beta-thalassemia is extremely rare in populations from northern Europe and the far East (Korea, China, and Japan). Alphathalassemia can be found primarily in Mediterranean, West African, and southwestern Pacific populations, with a gene frequency of up to 70% in some southwestern Pacific populations. It is extremely rare in populations from Great Britain, Iceland, and Japan.

11. (C) Beta-thalassemia patients are subdivided based on clinical severity into thalassemia carriers and those with thalassemia trait, thalassemia intermedia, or thalassemia major. Beta-thalassemia carriers are asymptomatic, with only mild microcytosis; patients with thalassemia trait have a mild microcytic anemia but generally are otherwise well. Patients with thalassemia intermedia and thalassemia major both have moderate to severe anemia and require transfusion therapy. Red blood cells produced by the bone marrow in patients with more severe thalassemia are poorly functional, stimulating further red blood cell production. This ineffective erythropoiesis eventually results in bone marrow hyperplasia and extramedullary hematopoiesis, which cause the clinical features of thalassemia major (also called Cooley anemia) that occur in the absence of regular transfusions. These features of thalassemia major include severe anemia with massive hepatosplenomegaly and growth failure. Bone marrow hyperplasia results in frontal bossing, maxillary prominence, a “hair-on-end” appearance of the skull on radiograph, and long bone changes including severe osteoporosis and cortical thinning from medullary expansion. The thin bony cortices leave the bones susceptible both to bowing and to fractures. Scleral icterus and jaundice are not features of thalassemia.

Laboratory features of beta-thalassemia include an increased concentration of hemoglobin A2, although hemoglobin F, or fetal hemoglobin, is usually normal. The red blood cells in patients with thalassemia are microcytic, with hypochromia and basophilic stippling. The presence of target cells and ovalocytes is also consistent with thalassemia.

12. (D) The alpha-globin chains in hemoglobin are produced by 4 separate alpha-globin gene alleles. A single allele deletion results in an asymptomatic carrier state, with microcytosis but no anemia. Two alpha-globin allele deletions cause alpha-thalassemia trait with mild anemia but marked hypochromia and microcytosis. Deletion of 3 alleles results in more severe hemoglobin H disease, characterized by moderate anemia, with hemoglobin levels of 7-10 g/dL, associated with jaundice and hepatosplenomegaly. Hemoglobin H is composed of 4 beta-globin chains and comprises 5-30% of the total hemoglobin in hemoglobin H disease patients. Hemoglobin H unfortunately has no oxygendelivering capacity and precipitates within the red blood cell, forming Heinz bodies and inducing splenic sequestration and destruction.

Deletion of all 4 alpha-globin alleles results in hydrops fetalis with severe intrauterine microcytic anemia and hepatosplenomegaly. The hemoglobin present is exclusively Bart hemoglobin, or gamma4, which is composed of 4 fetal gamma-globin chains. Bart hemoglobin, like hemoglobin H, has no oxygen-delivering capacity, and so hydrops fetalis is invariably fatal (either in utero or perinatally) in the absence of transfusion therapy.

13. (C) Transfusion therapy for patients with thalassemia frequently results in hemochromatosis, or “iron overload.” Although many organs are affected by iron overload, the kidneys are relatively spared. Iron overload is associated with dilated cardiomyopathy because of excessive iron deposition in cardiac myocytes, diabetes mellitus because of pancreatic iron deposition, and hypogonadism from pituitary failure secondary to iron deposition. Other complications of iron overload include growth failure, hypothyroidism, hypoparathyroidism, and hepatic fibrosis with an increased risk of hepatocellular carcinoma.

Treatment of iron overload in cases of hereditary hemochromatosis consists of regular phlebotomy to withdraw iron and reduce the body’s iron stores. In cases of transfusion-induced iron overload, iron reduction is accomplished with desferrioxamine chelation. Desferrioxamine, which must be given either intravenously or subcutaneously, binds to iron in the bloodstream and is then excreted in the urine. The success of chelation can be measured by serum ferritin levels or by liver biopsy, the most sensitive measure of total body iron stores.

14. (A) Normal red blood cells have a mixture of predominantly hemoglobin A (α2β2), with small amounts of hemoglobins A2 (α2δ2) and F (α2γ2). Normally hemoglobin A comprises at least 95% of the total hemoglobin, with hemoglobin A2 ranging from 2% to 4% and hemoglobin F from 0.5% to 1%. Increasing amounts of hemoglobin F relative to hemoglobin A are found in fetuses and neonates, before the conversion of the erythrocyte precursors to adult hemoglobin A production. Increased levels of hemoglobin F can be found in cases of hereditary persistence of fetal hemoglobin; increased levels of hemoglobin A2 are found in patients with beta-thalassemia.

15. (A) Diamond-Blackfan anemia (DBA) is one of a rare group of genetic disorders known as the “inherited bone marrow failure syndromes.” These disorders have in common proapoptotic hematopoietic, bone marrow failure, birth defects, and in most, a predisposition to cancer. The diagnostic criteria for DBA published in 1976 consist of presentation of anemia before the first birthday with near normal or slightly decreased neutrophil counts, variable platelet counts, reticulocytopenia, macrocytosis, and normal marrow cellularity with a paucity of red cell precursors. The incidence of DBA is approximately 5 in 1 million births. Ninety percent of the cases initially present in the first 6 months of life. DBA does not have any race or sex predilection. Several ribosomal protein genes are mutated in patients with DBA, and mutations in these genes account for approximately 50% of DBA cases. With the discovery of these mutated genes in DBA, it became evident that the penetrance of autosomaldominant DBA is quite variable with regard to both hematologic and nonhematologic manifestations. It is estimated that the incidence of familial autosomal-dominant DBA is 15-45%. Physical examination findings of DBA occur in approximately a third of cases and include craniofacial abnormalities such as microcephaly, microphthalmia, hypertelorism, micrognathia, growth failure (either intrauterine or postnatal), and abnormal thumbs, which can be bifid, duplicated, subluxed, hypoplastic, absent, or triphalangeal. The laboratory features include macrocytic anemia, decreased or absent reticulocytes, and an otherwise normal blood count. DBA is also characterized by an increase in hemoglobin F and the presence of the i antigen on red blood cells, which is normally only found on fetal red blood cells. Treatment of DBA involves blood transfusions as needed, but approximately 25% of patients respond to steroid treatment with an increased hemoglobin level. A bone marrow transplant is often required, particularly in cases that do not respond to steroid therapy, and is the only currently available curative therapy.

16. (C) TEC, or transient erythroblastopenia of childhood, is most frequently confused with other forms of congenital anemia such as DBA. The features most consistent with TEC include a normocytic anemia in a patient older than 2 years, often with a history of a preceding viral upper respiratory infection. Reticulocytes are also decreased in patients with TEC, as are the red blood cell precursors in the bone marrow. Features that would suggest DBA include age of onset younger than 1 year, abnormal physical features (particularly abnormal thumbs) or growth failure, and elevations in MCV, adenosine deaminase levels, fetal hemoglobin, and i antigen (a red blood cell antigen normally only found on fetal red blood cells). The most significant characteristic feature of TEC is spontaneous recovery in the absence of treatment, whereas anemias because of DBA or other congenital red cell aplasias will not resolve without other therapy.

17. (D) Lead toxicity is a cause of microcytic anemia in children that must be ruled out with initial screening because of potentially severe and irreversible complications. Sources of lead poisoning include leaded gasoline, lead smelters, paint chips from houses with lead-based paint, old batteries, magazine color pages, and lead-glazed pottery. Lead toxicity is associated with abdominal pain, emesis, constipation, peripheral neuropathy, renal disease, and can eventually result in encephalopathy with decreased IQ, altered behavior, ataxia, and seizures. Decreased hemoglobin levels from lead toxicity are a product of inhibition of heme synthesis, resulting in accumulation of heme precursors and causing an elevation in the serum-free erythrocyte protoporphyrin levels.

SUGGESTED READING

Abshire TC. Sense and sensibility: approaching anemia in children. Contemp Pediatr. 2001;18(9):104-113.

Brittenham GM. Disorders of iron metabolism: iron deficiency and overload. In: Hoffman R, Benz EJ, Shattil SJ, et al, eds. Hematology: Basic Principles and Practice. 5th ed. Philadelphia, PA: Churchill Livingstone; 2008.

Chisolm JJ Jr. Lead poisoning. In: McMillan JA, DeAngelis CD, Feigin RD, et al, eds. Oski’s Pediatrics: Principles and Practice. 4th ed. Philadelphia, PA: Lippincott Williams and Wilkins; 2006.

Cunningham MJ. Update on thalassemia: clinical care and complications. Pediatr Clin North Am. 2008;55(2):447-460.

Forget BG. Thalassemia syndromes. In: Hoffman R, Benz EJ, Shattil SJ, et al, eds. Hematology: Basic Principles and Practice. 5th ed. Philadelphia, PA: Churchill Livingstone; 2008.

Lipton JM, Ellis SR. Diamond-Blackfan anemia: diagnosis, treatment, and molecular pathogenesis. Hematol Oncol Clin North Am. 2009;23(2):261-282.

Martin PL, Pearson HA. Hypoplastic and aplastic anemias. In: McMillan JA, DeAngelis CD, Feigin RD, et al, eds. Oski’s Pediatrics: Principles and Practice. 4th ed. Philadelphia, PA: Lippincott Williams and Wilkins; 2006.

Recht M, Pearson HA. Nutritional anemias. In: McMillan JA, DeAngelis CD, Feigin RD, et al, eds. Oski’s Pediatrics: Principles and Practice. 4th ed. Philadelphia, PA: Lippincott Williams and Wilkins; 2006.

Walters MC, Abelson HT. Interpretation of the complete blood count. Pediatr Clin North Am. 1996;43(3):599-622.

CASE 89: A 16-YEAR-OLD WITH SICKLE CELL DISEASE AND RESPIRATORY DISTRESS

A mother brings her 16-year-old son, who is known to have sickle cell disease, to the emergency department with “difficulty breathing.” He was well until approximately 1 week ago when he began having bilateral leg and arm pain, which are his usual sites for sickle cell pain. He was taking ibuprofen and codeine at home with some relief. The past evening the pain worsened, and he also began having fevers to 101.6°F (38.6°C). This morning he also began having some chest pain and difficulty taking deep breaths, and so his mother brought him to the emergency department. The patient has had several past admissions for his sickle cell disease for vaso-occlusive crisis pain management. He has never received a blood transfusion.

On physical examination, the patient is awake and alert but clearly in pain. His sclerae are icteric bilaterally. He has a 3/6 systolic ejection murmur, and he has decreased breath sounds in his right lung base. The remainder of his examination is noncontributory.

His white blood cell count is 16,500/μL, with a hemoglobin of 6.5g/dL and a platelet count of 426,000/μL. His differential has 65% neutrophils, 25% lymphocytes, 8% monocytes, and 2% eosinophils. His reticulocyte count is 18.6%. A chest radiograph reveals a small fluffy infiltrate in the right lower lobe of the lung.

SELECT THE ONE BEST ANSWER

1. At this time, the patient most likely has which of the following complications of sickle cell disease?

(A) splenic sequestration

(B) aplastic crisis

(D) acute chest syndrome

(E) splenic infarction

2. The most common symptoms associated with acute chest syndrome in pediatric patients with sickle cell disease include all of the following except

(A) hemoptysis

(B) temperature higher than 101.3°F (38.5°C)

(D) chest pain

(E) bone pain

3. The management of acute chest syndrome should include all of the following except

(A) opioids for pain control

(B) broad-spectrum antibiotics

(D) incentive spirometry

(E) acetaminophen for fever

4. Which of the following antibiotics is the best initial choice in the management of a patient with sickle cell disease and fever?

(A) ceftriaxone

(B) clindamycin

(D) metronidazole

(E) penicillin

5. Which of the following is not a side effect of the opioids used for pain management in children with sickle cell disease?

(A) constipation

(B) nausea

(D) hematuria

(E) fatigue

6. Acute chest syndrome is most common in patients with which of the following hemoglobin genotypes?

(A) AS

(B) SS

(D) beta-thalassemia

(E) hemoglobin E disease

7. Recurrent acute chest syndrome is associated with all of the following complications except

(A) chronic hypoxia

(B) pulmonary hypertension

(D) cor pulmonale

(E) anoxic brain injury

8. Which of the following is the most likely result of neonatal hemoglobin electrophoresis for patients with sickle cell trait?

(A) FS

(B) FSC

(D) FAS

(E) FC

9. Which of the following is the approximate hemoglobin S gene carrier frequency in the U.S. African American population?

(A) 4%

(B) 8%

(D) 32%

(E) 48%

10. Which of the following findings on the peripheral blood smear is a feature of decreased splenic function in patients with sickle cell disease?

(A) Auer bodies

(B) basophilic stippling

(D) polychromasia

(E) blasts

11. Renal complications of patients with sickle cell anemia include all of the following except

(A) hyposthenuria

(B) hematuria

(D) glucosuria

(E) renal failure

12. Gallstones found in patients with sickle cell anemia are composed primarily of which of the following compounds?

(A) calcium oxalate

(B) calcium bilirubinate

(D) xanthine oxide

(E) cholesterol

13. Acute hemiparesis in patients with sickle cell disease is best managed by which of the following?

(A) red blood cell transfusion

(B) red blood cell exchange transfusion

(D) hyperbaric oxygen

(E) heparin

14. All of the following are neurologic complications of strokes in pediatric patients with sickle cell disease except

(A) recurrent stroke

(B) cognitive delay

(D) seizure disorder

(E) moyamoya

15. Which of the following has been shown to be most effective in preventing recurrence of strokes in patients with sickle cell disease?

(A) aspirin

(B) low molecular weight heparin

(D) regular red blood cell transfusions

(E) heparin

16. Aplastic crises in patients with sickle cell disease are most commonly associated with which of the following infections?

(A) Epstein-Barr virus

(B) adenovirus

(E) cytomegalovirus

17. Which of the following complications of sickle cell disease is most likely to occur during infancy?

(A) priapism

(B) transient ischemic attack

(D) dactylitis

(E) stroke

18. Which of the following antibiotics is most effective for prophylaxis against S pneumoniae in patients with sickle cell disease?

(A) trimethoprim-sulfamethoxazole

(B) penicillin

(D) fluconazole

(E) azithromycin

19. Which of the following statements about hydroxyurea treatment in patients with sickle cell disease is false?

(A) beneficial effects of hydroxyurea can begin in the first few weeks after commencing therapy

(B) hydroxyurea can decrease elevated transcranial Doppler velocities

(C) hydroxyurea induces erythroid regeneration and the premature commitment of erythroid precursors, with resulting increased production of hemoglobin F

(D) hydroxyurea treatment has been shown to reduce vaso-occlusive pain crises in patients with sickle cell disease

(E) the dose of hydroxyurea is titrated according to the patient’s renal function.

ANSWERS

1. (D) Sickle cell disease is characterized by a mutation in the hemoglobin beta chain, where a valine is substituted for a glutamic acid at the β6 position. This amino acid substitution predisposes the hemoglobin molecule to polymerization, particularly under hypoxic or acidic conditions, with hemoglobin polymerization resulting in “sickling” of the red blood cell. Symptoms of sickle cell disease can occur with hemoglobin genotypes including homozygous hemoglobin SS and combinations of hemoglobin S with other mutant beta-globin chains, such as hemoglobin SC, Sβ⁰ thalassemia, or Sβ+ thalassemia. The disease severity varies to some degree with the genotype because patients with SS and Sβ⁰ genotypes tend toward more severe disease. Red blood cell sickling and the resulting microvascular obstruction is the cause of the wide range of complications associated with sickle cell disease.

In a patient with sickle cell disease of any genotype, the combination of respiratory symptoms, fever, chest pain, and an infiltrate on chest radiograph after an episode of vaso-occlusive pain are all consistent with the diagnosis of acute chest syndrome. Acute chest syndrome occurs at least once in up to 50% of patients with sickle cell disease. The etiology of acute chest syndrome in patients with sickle cell disease is unclear but may include components of both pulmonary infection and infarction in addition to fat embolism from infarcted bone marrow. Therefore, any combination of the symptoms just listed should be treated as acute chest syndrome. Patients who have had prior episodes of acute chest syndrome are more likely to have recurrent episodes.

2. (A) The most common symptoms in pediatric acute chest syndrome are fever and cough, with approximately 70% also having some degree of hypoxia. Chest pain, dyspnea, and wheezing can be seen less commonly. Up to 60% of patients, however, will have a normal pulmonary examination. Although hemoptysis occurs frequently in adult sickle cell patients with acute chest syndrome, it is rare in pediatric sickle cell patients. Other associated findings with acute chest syndrome include a drop in hemoglobin and an elevation in the baseline white blood cell count. Acute chest syndrome, if not appropriately treated, can rapidly progress to respiratory insufficiency and acute respiratory distress syndrome (ARDS) and can be fatal.

3. (C) The management of acute chest syndrome requires multiple interventions. Pain control to prevent respiratory “splinting” is important because the inability to take deep breaths will lead to further lung collapse and worsening of the acute chest syndrome. However, oversedation with respiratory depression should also be avoided, and so the opioid dose in patients with acute chest syndrome must be carefully titrated. Intravenous hydration is also important because dehydration contributes to further intravascular sickling. Overhydration with potential pulmonary edema and worsening symptoms must also be avoided. Antibiotics to cover the possible infectious etiologies (which include S pneumoniae, H influenzae, N meningitidis, Chlamydophila [Chlamydia] pneumoniae, and M pneumoniae, as well as many other bacteria and viruses) are important in the management of acute chest syndrome. Incentive spirometry to maintain alveolar patency is also important, and bronchodilator therapy can be a useful adjunct as well. Intubation for severe respiratory distress may also be required. Nitrous oxide therapy is not recommended for the management of acute chest syndrome.

Red blood cell transfusions are the most effective therapy for acute chest syndrome. Patients with sickle cell disease generally have baseline hemoglobin values of 7-9 g/dL, and transfusions that raise the hemoglobin well above this range can lead to hyperviscosity and further sickle cell complications such as strokes. Those patients with baseline hemoglobin values higher than 10 g/dL should undergo exchange transfusion rather than simple transfusion to avoid hyperviscosity complications. The goal for blood transfusion or exchange transfusion should be to lower the percentage of sickled cells in the blood while avoiding further complications.

4. (A) Children with sickle cell disease are at increased risk for severe bacterial infections because of splenic hypofunction, secondary to slowly progressive autoinfarction of splenic tissue. The average age of complete splenic infarction is approximately 2-4 years old in patients with hemoglobin SS but can be delayed to 6-8 years of age in patients with hemoglobin SC or Sβ⁺ thalassemia. Even before this age, however, children with sickle cell disease are more susceptible to encapsulated organism infection and rapidly progressive sepsis in the absence of treatment. Potential organisms include S pneumoniae, H influenzae, N meningitidis, Salmonella species, and E coli. Therefore, children with sickle cell disease should receive all recommended vaccines on time, and those who have fevers should always be evaluated by a physician. They should undergo laboratory evaluation including complete blood count with a reticulocyte count, blood culture, urinalysis, urine culture, and chest radiograph.

Ceftriaxone, a broad-spectrum third-generation cephalosporin, is the antibiotic most likely to cover most of the potential pathogens in children with sickle cell disease, and particularly S pneumoniae, the most common cause of infections and infectious morbidity in sickle cell patients. Other thirdgeneration cephalosporins are also acceptable options. A macrolide such as azithromycin is frequently added to cover possible Chlamydia and Mycoplasma pulmonary infections. Although clindamycin and vancomycin are effective against most gram-positive bacteria, including S aureus, they are not effective against the encapsulated gramnegative bacteria that are potential causes of infections and therefore are not optimal choices for initial management. Anaerobic infections are not more frequent in patients with sickle cell disease, and so metronidazole is not an appropriate initial choice.

5. (D) Opiates have several common side effects, including impaired GI motility and constipation, nausea and vomiting, hypotension, respiratory depression, lowered seizure threshold, and pruritus, which must be managed to maximize the pain management in children with sickle cell crises. Hematuria is not a side effect of opiates but does occur commonly in patients with sickle cell disease.

6. (B) Patients with hemoglobin SS and Sβ⁰ thalassemia tend to have the most severe complications from sickle cell disease, including more frequent episodes of acute chest syndrome. Patients with hemoglobins SC and Sβ⁺thalassemia generally have milder symptoms, although the range of severity is wide and patients with hemoglobins SC or Sβ⁺ thalassemia can have very severe complications. Patients with beta-thalassemia do not have complications from red blood cell sickling, such as acute chest syndrome. Other factors, such as the amount of fetal hemoglobin (hemoglobin F), the presence of coexisting alpha-thalassemia or other unknown factors may play a role in modifying sickle cell disease severity. People with hemoglobin AS, or sickle cell trait, do not experience acute chest syndrome and have virtually no symptoms, but they should receive genetic counselling regarding the risks of sickle cell disease in their offspring.

7. (C) Recurrent acute chest syndrome results in pulmonary injury with intimal hyperplasia and fibrosis. Chronic pulmonary infiltrates, chest pain, hypoxia, and the eventual development of pulmonary hypertension and cor pulmonale can all ensue. Emphysema does not occur as a result of recurrent acute chest syndrome.

8. (D) The results of neonatal hemoglobin electrophoresis are reported in order of decreasing amounts of the expressed hemoglobin molecules. For example, patients with normal hemoglobin, or hemoglobin AA, will have more fetal hemoglobin (hemoglobin F) than hemoglobin A at birth, and they will have a neonatal hemoglobin electrophoresis result of “FA.” Patients with homozygous hemoglobin SS will still have more fetal hemoglobin at birth than sickle hemoglobin, and so their neonatal electrophoresis result will be “FS.” Patients with hemoglobin SC disease will have a neonatal electrophoresis result of “FSC.” Patients with sickle cell trait have more hemoglobin A than hemoglobin S, because A is more stable than S, and so the correct result for patients with sickle trait is “FAS.” Patients with hemoglobin Sβ⁺ thalassemia will have some hemoglobin A but not as much as the hemoglobin S, and therefore the result will be “FSA.”

9. (B) Approximately 8% of U.S. African Americans carry the hemoglobin S gene, resulting in a sickle cell disease frequency of approximately 1 in 600 African Americans. By comparison, approximately 4% of African Americans in the United States carry the hemoglobin C gene, 1% carry a gene mutation for beta-thalassemia, and 1-3% carry a gene mutation for alpha-thalassemia. Sickle cell disease can also be found in Middle Eastern, Indian, and Central and South American populations; the hemoglobin S gene mutation is extremely rare in whites. The prevalence of sickle cell disease has been linked to protection from malaria infection, with those patients with sickle cell trait or disease relatively spared from the severe complications of malaria.

10. (C) Howell-Jolly bodies are intracellular collections of precipitated hemoglobin that, under normal circumstances, cause the red blood cell to be trapped in the spleen, either to be totally destroyed or to have the Howell-Jolly body “removed” by splenic macrophages, resulting in smaller, more fragile red blood cells that leave the spleen. The presence of red blood cells with these bodies in the peripheral circulation suggests the loss of the splenic filtration function, either because of surgical splenectomy or functional splenectomy from progressive infarction that occurs in patients with sickle cell disease. The average age of complete splenic infarction is approximately 2-4 years old for patients with hemoglobin SS but is delayed to 6-8 years of age in patients with hemoglobin SC. Auer bodies are white blood cell inclusions found in patients with acute promyelocytic leukemia. Basophilic stippling is seen in lead poisoning and represents residual ribosomal material within the red blood cells precipitated as a result of the presence of toxins. Polychromasia refers to the presence of reticulocytes on the peripheral smear, which appear more purplish than the mature red blood cells. Although patients with sickle cell disease do have an increase in reticulocytes and have significant polychromasia on their peripheral smears, it is not associated with their splenic function.

11. (D) Renal disease is a common complication of patients with sickle cell disease. The kidney is particularly susceptible to injury in patients with sickle cell disease because of the relatively hypoxic environment of the renal medulla and the high oxygen requirements of the renal parenchyma. Renal disease occurs in up to 25% of adolescents with sickle cell disease. Also, up to 40% of adults with sickle cell disease have renal insufficiency, with many progressing to end-stage renal disease requiring dialysis and possibly renal transplant. Components of “sickle cell nephropathy” include hyposthenuria, hematuria, proteinuria, renal cortical infarction, papillary necrosis, pyelonephritis, and, rarely, renal cell carcinoma. Glucosuria is not a complication seen in patients with sickle cell disease.

Hyposthenuria refers to the inability of patients with sickle cell disease to concentrate their urine because of the infarction of and damage to the renal medulla. The presence of hyposthenuria can be found in sickle cell patients by 5-10 years of age and becomes irreversible by 15 years of age. Hyposthenuria can cause significant dehydration, particularly in patients experiencing complications of their sickle cell disease. Hematuria can be microscopic or gross and primarily arises from the left kidney (80% of cases), although in approximately 10% of cases, hematuria arises from both kidneys. Proteinuria can range from microalbuminuria to nephrotic syndrome.

12. (B) The gallstones of patients with chronic hemolytic anemias (including sickle cell disease) are composed of bilirubin, a breakdown product of hemoglobin. Cholelithiasis with or without associated cholecystitis occurs in up to 70% of patients with sickle cell disease, and it can occur in children as young as 4 years of age. Approximately a third of children with gallstones have an underlying hemolytic anemia. Recurrent or severe abdominal pain is common in patients with sickle cell disease and frequently is a result of cholelithiasis or cholecystitis, although hepatitis, pancreatitis, and other intra-abdominal processes must be considered, in addition to abdominal vaso-occlusive pain crises. Recurrent or severe abdominal pain in sickle cell patients with gallstones or episodes of acute cholecystitis are indications for cholecystectomy.

13. (B) Acute stroke in patients with sickle cell disease is one of the indications for emergent exchange transfusion. Approximately 10% of children with sickle cell disease have at least one stroke episode by the mean age of 7-8 years. Symptoms can range from headaches, changes in vision, cranial nerve palsies, hemiparesis, seizures, coma, or death. The diagnosis is made with magnetic resonance imaging (MRI), although urgent computed tomography (CT) scanning to rule out intracranial hemorrhage (rare in children but more common in adults with sickle cell disease) can also be performed. The use of emergent exchange transfusion in a patient with sickle cell disease and acute neurologic symptoms decreases the percent of hemoglobin S to less than 30% and results in decreased symptom severity and decreased incidence of long-term complications. Simple red blood cell transfusions are not effective in the treatment of stroke in patients with sickle cell disease, and nonsteroidal anti-inflammatory agents and hyperbaric oxygen have no role in stroke management in these cases.

14. (C) Patients with sickle cell disease who have strokes have similar symptoms to other patients with acute cerebrovascular injuries, including the acute onset of cranial nerve palsies, hemiparesis, and, possibly, seizures or coma. Although most sickle cell patients have a complete neurologic recovery from their strokes, complications such as residual neurologic dysfunction, persistent seizure disorder, cognitive delay, behavioral changes, and recurrent strokes can occur. Optic neuritis is not a neurologic complication of strokes in patients with sickle cell disease. Stroke recurrence in patients with sickle cell disease can occur in up to 60% of patients within 3 years of the initial stroke in the absence of treatment. Slowly progressive cognitive delay because of recurrent, otherwise asymptomatic strokes is a common problem in children with sickle cell disease and requires early identification and intervention. Neovascularization occurs in the areas of the brain that are left underperfused by the stroke. The network of small, delicate vessels that appear as cloud-like puffs on an arteriogram are called moyamoya. The name derives from a disorder described most often in people of Japanese ancestry in which a similar network of vessels develops idiopathically. The network of vessels in moyamoya has a propensity to rupture. Hemorrhage produces additional neurologic deficits. Bleeds from moyamoya can be extremely debilitating and even fatal in patients with sickle cell disease.

15. (D) Regular blood transfusions to maintain a baseline hemoglobin level of 8-10 g/ dL and a hemoglobin S fraction of less than 30% is the only proven therapy that can prevent stroke recurrence in children with sickle cell disease. The incidence of stroke recurrence can be decreased from 60% within 3 years of an initial stroke without treatment to less than 10% with regular blood transfusions. However, the hemoglobin should be maintained less than 10 g/dL to avoid hyperviscosity associated with higher hemoglobin levels and an increase in stroke risk.

16. (D) Parvovirus B19 infections are associated with aplastic crises in any patient with shortened red blood cell lifespan. Therefore, patients with sickle cell disease, red blood cell enzyme deficiencies, or red blood cell structural defects are susceptible to aplastic crises from parvovirus B19. Parvovirus infects the erythroid precursors within the bone marrow, temporarily halting new red blood cell production. The otherwise normal patient, with a red blood cell lifespan of 120 days, will suffer a small, likely asymptomatic fall in total hemoglobin, followed by bone marrow recovery and new red blood cell production. Patients with a decreased red blood cell lifespan because of the inability of the marrow to produce new red blood cells appropriately have severe, possibly life-threatening falls in hemoglobin levels. Infections with bacteria and other viruses, such as Epstein-Barr virus (EBV) or adenovirus, do not commonly have bone marrow toxicity and generally do not cause aplastic crises.

17. (D) Dactylitis, or hand-foot syndrome, is a complication of sickle cell disease that most commonly occurs in infants younger than 1 year of age. Dactylitis is characterized by painful nonpitting edema of the dorsal surfaces of the hands and feet bilaterally, without other locations of pain or swelling. Dactylitis is also frequently accompanied by a low-grade fever. The etiology is not completely understood but most likely involves vaso-occlusion within the distal extremities. Management is similar to other types of vaso-occlusive pain crises. Priapism is a condition of prolonged, painful erection that occurs in up to 40% of adolescent males with sickle cell disease and requires urgent intervention with intravenous fluids, pain control, and either medical or surgical interventions to reduce the erection. Priapism rarely occurs in children younger than 10 years of age and never occurs in infancy. The erections of priapism can last for 30 minutes to several days, and recurrence can lead to eventual impotence. Acute chest syndrome and transient ischemic attacks can both occur in infancy but are more common in older children and adults. The average age of the initial cerebral vascular accidents in children with sickle cell disease is 7-8 years.

18. (B) Penicillin is the first choice for pneumococcal prophylaxis in patients with sickle cell disease, which is required because of the decreased splenic function and increased risk of sepsis from encapsulated organisms. Trimethoprim-sulfamethoxazole, rifampin, and fluconazole are not effective agents against S pneumoniae. In patients who are allergic to penicillin, erythromycin provides an option for prophylactic therapy.

19. (D) In patients with sickle cell disease, hydroxyurea induces erythroid regeneration and increased production of HbF. The drug is classified as an antimetabolite and antineoplastic agent. The exact mechanism of its antineoplastic activity has not been fully elucidated but is believed to be S-phase specific. The dose is titrated according to the patient’s blood counts, in particular the absolute neutrophil count. Beneficial effects of hydroxyurea can begin in the first few weeks after commencing therapy, and studies have shown that treatment can result in significantly fewer hospitalizations for pain, with shorter lengths of stay, compared with those receiving placebo. The role of hydroxyurea in the prevention of stroke in sickle cell disease is an area of active investigation. High transcranial flow velocities are associated with an increased risk of stroke in patients with sickle cell disease, and hydroxyurea therapy has been shown to decrease elevated transcranial flow velocities, suggesting it might serve as an alternative to chronic erythrocyte transfusions for primary stroke prophylaxis. Hydroxyurea is also an alternative to chronic transfusions for secondary stroke prophylaxis in children for whom transfusions cannot be continued safely (eg, erythrocyte allosensitization). The role of hydroxyurea in preserving organ function in sickle cell disease is not yet determined. Although the long-term risks and benefits of hydroxyurea are not known, current clinical experience has not identified any clear detrimental effects or safety concerns.

SUGGESTED READING

American Academy of Pediatrics. Health supervision for children with sickle cell disease. Pediatrics. 2002;109(3):526-535.

Embury SH, Vichinsky EP. Sickle cell disease. In: Hoffman R, Benz EJ, Shattil SJ, et al, eds. Hematology: Basic Principles and Practice. 5th ed. Philadelphia, PA: Churchill Livingstone; 2008.

Heeney MM, Ware RE. Hydroxyurea for children with sickle cell disease. Pediatr Clin North Am. 2008;55(2):483-501.

Lane PA. Sickle cell disease. Pediatr Clin North Am. 1996;43(3): 639-662.

CASE 90: A 14-YEAR-OLD BOY WITH A PAINFUL LEFT THIGH

A 14-year-old boy is brought to your office by his father for left leg pain. He had injured his left leg several weeks earlier playing football. He was not seen by a physician at the time of injury. The pain has persisted despite minimal activity since that time, and the pain has not been relieved with the use of ibuprofen.

He has been seen in your office since he was an infant, and he has no history of any medical problems. The family history is also negative for any significant medical problems. He has been doing well in school and had been active in sports before this injury, with no history of prior leg injuries.

On physical examination, he is well appearing with normal vital signs. His left leg appears grossly normal but is tender above the left knee. Radiographs reveal a lytic bone lesion in the distal left femur, with no fracture.

SELECT THE ONE BEST ANSWER

1. The differential diagnosis of painful bony lesions in children includes all of the following except

(A) osteosarcoma

(B) Ewing sarcoma

(D) nonossifying fibroma

(E) osteomyelitis

2. Which of the following sites within bones is the most common primary site for osteosarcoma?

(A) metaphysis

(B) diaphysis

(D) epiphysis

(E) osteoblast

3. The peak incidence of osteosarcoma occurs in which age range?

(A) 1-4 years

(B) 5-8 years

(D) 13-17 years

(E) first year of life

4. Which of the following is not a risk factor for osteosarcoma?

(A) history of bilateral retinoblastoma

(B) history of prior radiation exposure

(D) family history of leukemia

(E) Li-Fraumeni syndrome

5. Which of the following is the peak age range for diagnosis of patients with Ewing sarcoma?

(A) 1-5 years

(B) 5-10 years

(D) 20-30 years

(E) first year of life

6. Which of the following is the least common site of Ewing sarcoma?

(A) femur

(B) ilium

(D) skull

(E) fibula

7. Which of the following clinical features is least likely to distinguish osteosarcoma from Ewing sarcoma?

(A) fever

(B) tumor location

(D) age of onset

(E) family history

8. Which of the following is not a clinical feature of Langerhans cell histiocytosis?

(A) diabetes mellitus

(B) seborrheic dermatitis

(D) pancytopenia

(E) diabetes insipidus

9. Which of the following is the least likely laboratory finding in patients with hemophagocytic lymphohistiocytosis?

(A) thrombocytopenia

(B) elevated alkaline phosphatase

(D) low serum fibrinogen

(E) anemia

10. Which of the following blood products should not be used in pediatric patients with malignancies who are receiving chemotherapy?

(A) platelet apheresis units

(B) blood-type matched FFP

(D) leuko-reduced or leuko-filtered red blood cells

(E) cryoprecipitate

11. In which of the following clinical situations is a platelet transfusion least likely to be effective?

(A) correction of thrombocytopenia in a patient with acute idiopathic thrombocytopenia purpura (ITP)

(B) control of bleeding in a patient with Fanconi anemia

(D) treatment of an intracranial hemorrhage in a patient with Wiskott-Aldrich syndrome

(E) control of bleeding following chemotherapy

12. In which of the following clinical situations is the use of FFP the most effective treatment option?

(A) persistent hemorrhage in a patient with hepatic insufficiency

(B) presurgical prophylaxis in a patient with hypofibrinogenemia

(D) treatment of a hemarthrosis in a patient with hemophilia A

(E) patient with bleeding following chemotherapy

13. Which of the following microorganisms cannot be acquired via blood product transfusions?

(A) cytomegalovirus

(B) hepatitis B virus

(D) human immunodeficiency virus

(E) Plasmodium vivax

14. Features of patient reactions to red blood cell transfusions include all of the following except

(A) temperature higher than 101.3°F (38.5°C)

(B) myoglobinuria

(D) dyspnea

(E) rash

15. Long-term complications of radiation therapy include all of the following except

(A) diabetes mellitus

(B) secondary amenorrhea

(D) restrictive lung disease

(E) growth retardation

16. Which of the following types of chemotherapy is not matched correctly with one of its side effects?

(A) doxorubicin and pulmonary fibrosis

(B) cisplatin and high-frequency hearing loss

(D) corticosteroids and avascular necrosis

(E) vincristine and neuropathy

ANSWERS

1. (D) Osteosarcoma and Ewing sarcoma are both primary bone malignancies that occur in children and young adults and most commonly present with pain localized to the tumor site. Osteosarcoma (also known as osteogenic sarcoma) is a relatively common pediatric malignancy, with approximately 400 cases per year in children younger than 20 years of age in the United States. Ewing sarcoma and a related tumor, peripheral primitive neuroectodermal tumor (PPNET), are similar entities with similar tissues of origin that can arise within either bone or soft tissues and are members of a group of tumors called the “small round blue cell tumors of childhood,” a group that also includes neuroblastoma, lymphoma, and rhabdomyosarcoma. Ewing sarcoma is one of the few solid tumors for which the underlying molecular genetic abnormality has been described: rearrangement of the EWS gene on chromosome 22q12 with an ETS gene family member. In 95% of cases, a t(11;22)(q24;q12) translocation is detected. These translocations define the Ewing sarcoma family of tumors (ESFT) and provide a valuable tool for their accurate and unequivocal diagnosis. They also represent ideal targets for the development of tumor-specific therapeutics. Ewing sarcoma accounts for approximately 100 cases of pediatric malignancy per year in the United States. Osteoid osteoma is a common benign bony lesion that generally occurs in the lower extremities and presents with night-time pain that is relieved with nonsteroidal anti-inflammatory medications. Nonossifying fibromas (also called fibrous cortical defects) are benign developmental defects in ossification that are painless, usually only detected incidentally, and require no therapy (see Figure 90-1).

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FIGURE 90-1. X-ray imaging of osteosarcoma, Ewing sarcoma, and chondrosarcoma. A. The typical “sunburst” appearance of osteosarcoma. B. The “onionskin” appearance often seen in Ewing sarcoma. C. The lobulated appearance of chondrosarcoma. (Reproduced, with permission, from Kantarjian HM, Wolff RA, Koller CA. MD Anderson Manual of Medical Oncology. New York: McGraw-Hill; 2006: Fig 33-7A-C.)

2. (A) Osteosarcoma most commonly occurs in the metaphyses of long bones but can spread into the diaphyses and epiphyses via local invasion. Bone marrow involvement with osteosarcoma is extremely rare.

The most common sites of osteosarcoma are at those sites with the most rapid bone growth: the distal femur, proximal tibia, and proximal humerus. Approximately 65% of all osteosarcomas occur in the femur, and more than 80% of femoral osteosarcomas occur in the distal end. The second most common site is the proximal tibia; the third most common site is the proximal humerus. Approximately 20% of osteosarcomas occur in the arms. In general, the outcomes for localized osteosarcoma are good, with 60-80% long-term survival with current treatments. Children with metastatic osteosarcoma, however, do significantly worse, with only a 20-30% survival rate. Osteosarcoma can also rarely occur in flat bones such as the skull, ribs, and pelvis, where it also has a much poorer outcome.

3. (D) The peak incidence of osteosarcoma occurs in the second decade of life, particularly during the pubertal growth spurt, and tends to occur slightly earlier in girls (who have an earlier onset of puberty). The development of osteosarcoma may in part be associated with the rapid bone growth that occurs during these times. Osteosarcoma is very rare in children younger than 5 years of age and uncommon in adults older than 30 years of age.

4. (C) Down syndrome is associated with an increased incidence of hematologic malignancies but does not have an increased incidence of osteosarcoma or other sarcomas. Children with cases of bilateral retinoblastoma almost always have germ-line mutations in the Rb gene, which are also associated with an increased incidence of secondary malignancies, approximately 50% of which are osteosarcomas. The risk of osteosarcoma in patients with Rb gene mutations is approximately 500 times that of the general population.

Prior radiation exposure, including radiation therapy for childhood malignancies, is also associated with an increased incidence of osteosarcoma. Radiation exposure has been linked to up to 5% of osteosarcoma cases, and osteosarcoma can occur up to 40 years after exposure to radiation.

A family history of sarcomas, leukemias, adrenocortical carcinomas, and breast and bone cancers can be found in families with hereditary mutations in the p53 gene, termed the Li-Fraumeni syndrome, which also is associated with an increased incidence of osteosarcoma. Other syndromes associated with increased osteosarcoma incidence include Paget disease and Ollier disease (enchondromatosis), both of which more commonly are associated with adult-onset osteosarcoma.

5. (C) Ewing sarcoma is most common during the second decade of life but can occur in younger and older populations as well. Approximately 70% of the cases occur in children younger than 20 years of age, and half of the cases occur between 10 and 20 years of age. Ewing sarcoma is extremely rare in adults older than 30 years of age. Ewing sarcomas are also extremely rare in African Americans and Asians, occurring most commonly in white populations. There is no apparent connection between the onset of Ewing sarcoma and the occurrence of puberty, and there are no associated syndromes or exposures that increase the risk of Ewing sarcoma.

6. (D) Ewing sarcoma can present in a wide variety of locations, and, although most arise from within the skeleton, some Ewing sarcomas can arise in soft tissues as well. The primary sites for Ewing sarcoma are the pelvis and lower extremities, with approximately 20% of cases in the pelvis, 20% in the femurs, and 10% each in the tibias and fibulas. Approximately 9% of cases occur in the chest wall and are sometimes known as Askin tumors. Ewing sarcomas are more common in the axial skeleton than osteosarcomas, but approximately 3% of cases occur in the skull.

7. (D) Ewing sarcoma and osteosarcoma both occur predominantly in the same age range of patients (between 10 and 20 years of age). However, Ewing sarcoma and osteosarcoma have distinct features that can assist in the diagnosis before biopsy. Ewing sarcoma tends to be associated with systemic symptoms such as fever and weight loss, whereas osteosarcoma usually presents with local symptoms such as pain and swelling. Ewing tumors are more commonly located in the axial skeleton and are usually diaphyseal, as opposed to osteosarcomas that are more commonly metaphyseal and more likely to occur in the extremities. Furthermore, Ewing sarcoma classically has associated reactive bone formation (described as “onion skin” or “hair-on-end” periosteal reaction visible on x-rays) that is not usually found in osteosarcomas, which typically present with lytic bony lesions. A family history of other sarcomas, leukemias, breast cancers, or adrenal cancers suggests the possibility of Li-Fraumeni syndrome, a tumor predisposition syndrome which occurs as a result of mutations in the p53 gene. It is associated with an increase in the incidence of osteosarcoma but is not associated with Ewing sarcoma.

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FIGURE 90-2. Extensive Langerhans cell histiocytosis. Radiograph of the skull shows well-circumscribed osteolytic areas with a typical “map” appearance. (Reproduced, with permission, from Wolff K, Goldsmith LA, Katz SI, et al. Fitzpatrick’s Dermatology in General Medicine, 7th ed. New York: McGraw-Hill; 2008: Fig. 148-11.)

8. (A) Langerhans cell histiocytosis (LCH) is a monoclonal disorder of histiocytes with a wide variety of clinical presentations that affects approximately 4 children per million per year (see Figure 90-2). Previously recognized entities such as histiocytosis X, Letterer-Siwe disease, Hand-Schüller-Christian syndrome, and eosinophilic granuloma are now all classified as subtypes of LCH. The most benign form of LCH is eosinophilic granuloma, which consists of isolated lytic bony lesions, most commonly in the skull but also occurring in the vertebrae, mandible, ribs, ilium, scapula, and long bones. The bony lesions can be asymptomatic or can cause localized pain and swelling. Hand-Schüller-Christian disease is multifocal LCH characterized by skull lesions, diabetes insipidus, and exophthalmos. Other less common features include other pituitary hormonal abnormalities, gingival ulcerations with premature tooth eruption, chronic otitis media, and persistent seborrheic rashes. Letterer-Siwe disease is the most severe form of LCH and usually has an onset before 2 years of age. Letterer-Siwe disease is characterized by more severe visceral involvement, including lung, liver, intestinal, and marrow disease, with persistent fevers, irritability, failure to thrive, malabsorption, pancytopenia, and other symptoms related to diffuse organ involvement. Letterer-Siwe disease only accounts for 15% of LCH cases but has the worst prognosis and is the least responsive to therapy.

9. (B) Hemophagocytic lymphohistiocytosis (HLH) is a histiocytic syndrome that can be either primary or secondary to infection or neoplasia. Proliferation of activated macrophages results in the symptoms of HLH, which can involve the liver, spleen, bone marrow, and central nervous system. Symptoms include fever, hepatosplenomegaly, skin rashes, and meningeal inflammation with meningismus and, potentially, seizures. Laboratory features include pancytopenia, hypertriglyceridemia, hypofibrinogenemia, hyperferritinemia, and hypoproteinemia. Depressed T-cell and NK-cell activity can also be demonstrated. Alkaline phosphatase levels are generally normal. Diagnosis of HLH requires the presence of fever, splenomegaly, peripheral cytopenias of at least 2 cell lines, hypertriglyceridemia or hypofibrinogenemia, and evidence of hemophagocytosis either in the bone marrow or in a lymph node biopsy specimen.

10. (C) Blood products for patients receiving chemotherapy should be leuko-reduced and irradiated to decrease the transmission rate of cytomegalovirus (carried by donor white blood cells) and to decrease the incidence of graft-versushost disease (mediated by viable donor lymphocytes). Exposure of the patient to blood products from relatives should be avoided to prevent alloimmunization of the patient to potential bone marrow donor antigens. Furthermore, patients receiving chemotherapy often require frequent blood product transfusions, and so exposure to unrelated donors should be minimized as much as possible. Therefore, platelet apheresis units, which are isolated from single donors, are preferred over units pooled from multiple donors. FFP should be given to replace coagulation factors when needed and should be blood-type matched to reduce the incidence of immune-mediated reactions from the antibodies carried in the transfused plasma.

11. (A) Platelet transfusions are necessary both for control of active bleeding and for prevention of spontaneous hemorrhages in patients with decreased or dysfunctional platelets. Platelet transfusions should be given to prevent spontaneous hemorrhages when the platelet count is lower than 10,000/μL. In most cases, a lumbar puncture can be performed safely with platelet counts higher than 10,000/μL. Intramuscular injections should be avoided when platelet counts are less than 20,000/μL. To prevent intracranial hemorrhages in patients with brain tumors, the platelet count should be higher than 30,000-50,000/μL.

Platelet transfusions are most useful in states of platelet hypoproduction, such as for patients receiving chemotherapy, in conditions of bone marrow hypoplasia such as Fanconi anemia, aplastic anemia, and in conditions with intrinsic platelet dysfunction, such as Wiskott-Aldrich syndrome, Bernard-Soulier syndrome, or Glanzmann thrombasthenia. Platelet transfusions are less likely to increase platelet counts in cases of increased platelet consumption, such as ITP, disseminated intravascular coagulation (DIC), Kasabach-Merritt syndrome, or in cases of platelet sequestration from hypersplenism. The transfused platelets in cases of increased consumption or sequestration will be rapidly consumed or sequestered. Correction of thrombocytopenia in these cases requires treatment for the underlying condition rather than platelet transfusions.

12. (A) FFP is a plasma product isolated from whole blood by centrifugation. Rapid freezing is used to preserve the plasma proteins, which include clotting factors II, V, VII, VIII, IX, X, XI, XII, and other proteins such as protein C, protein S, antithrombin III, complement factors, and immunoglobulins. FFP contains small amounts of fibrinogen, factor XIII, and von Willebrand factor, but these factors can be found in higher concentrations in cryoprecipitate, generated from rapid thawing of FFP.

Clotting factors are predominantly synthesized in the liver, and so hepatic insufficiency is associated with clotting factor deficiencies that result in prolongation of the PT and PTT. Replacement of these factors with FFP is frequently necessary to control bleeding. Because FFP is a poor source of fibrinogen, it should not be used as a source of fibrinogen replacement for a patient with hypofibrinogenemia; instead, cryoprecipitate should be used as needed. For patients with single factor deficiencies, such as in patients with hemophilia, replacement of factor with FFP would require large volumes and exposures to large numbers of donors, each with added risk of transfusion-related infections. Therefore, factor replacement with purified or recombinant products, which have lower risks of transmission of viral infections because of postsynthetic processing, is preferred for treatment of any bleeding episodes in these patients.

In patients receiving anticoagulant therapy, reversal of the anticoagulant action is frequently required, either to control excessive bleeding or before surgical procedures. Heparin functions as an anticoagulant by inhibiting serine proteases in the coagulation cascade, including thrombin-mediated generation of fibrin. The effects of heparin can be reversed rapidly by administration of protamine, a mixture of polypeptides that binds to heparin and neutralizes its inhibitory effect on the coagulation proteases. FFP is less effective in reversing the effects of heparin because the excess heparin will inhibit FFP-derived factors as well. In patients being treated with warfarin sodium, the vitamin K– dependent clotting factors (factors II, VII, IX, and X) are depleted and can be replaced on an emergent basis for severe bleeding with FFP. However, for control of nonemergent bleeding or to reverse the effects of warfarin sodium, vitamin K replacement is the preferred method of treatment, with rapid synthesis of the factors by the liver occurring in the presence of vitamin K to correct the deficiency.

13. (C) Blood transfusions are associated with a small risk of viral transmission and infection, with potential blood-borne pathogens including human immunodeficiency virus (HIV), hepatitis B and C viruses, cytomegalovirus (CMV), and EBV. Other viruses that are primarily spread via respiratory droplets, such as influenza, respiratory syncytial virus, and varicella zoster, are not spread by blood transfusions. Blood products are aggressively screened, both by donor history and serologic testing, to decrease the chances of a transfusion-related infection. Non-blood cell containing blood products are treated further to decrease the transmission rate of viruses. The current risks of viral transmission (per units of blood transfused) are approximately 1 in 2 million units for HIV and 1 in 500,000 units for hepatitis C. Approximately a third of packed red blood cell units are CMV-positive and can cause CMV infection in recipients who are CMV-negative. The viral transmission rates for products such as FFP and cryoprecipitate are much lower because of the extra treatment, but they are still not completely risk free.

14. (B) Reactions to blood product transfusions occur in 1-10% of transfusions and can range from mild fever and chills to anaphylaxis and shock. Reactions occur more commonly in patients who have received prior transfusions. Acute reactions occur within 24 hours of the transfusion and can have a variety of presentations. Acute hemolytic transfusion reactions because of ABO blood type mismatch are generally the most severe, with clinical features that include fevers, chills, anxiety, nausea, vomiting, shortness of breath, hypotension, hemoglobinemia, hemoglobinuria, renal failure, and DIC. Simple febrile reactions to the presence of donor cytokines can also be associated with fevers, chills, nausea, vomiting, and headaches but are not associated with hemoglobinemia or hemoglobinuria. Allergic reactions because of host antibodies to donor plasma proteins can also occur, and can range from minor urticaria to anaphylaxis. Chronic transfusion reactions can also occur from 4 days to several weeks posttransfusion. Delayed hemolytic reactions are usually a result of alloimmunization to minor blood group antigens from prior blood transfusions, and they are usually less severe than acute reactions. Delayed transfusion reactions are usually associated with mild fevers, fatigue, and weakness and laboratory features of hemolysis such as increased reticulocytes, increased indirect bilirubin, decreased haptoglobin, and peripheral spherocytosis. Hemoglobinuria is rare in delayed transfusion reactions. Myoglobinuria is not a feature of either acute or chronic transfusion reactions.

15. (A) Radiation therapy is associated with a wide range of complications, which vary depending on the radiation site and dose. Central nervous system radiation is associated with cognitive delays, hormonal abnormalities (such as growth hormone deficiency and thyroid dysfunction), and increased risk of cerebrovascular disease. Thoracic radiation is associated with cardiac damage (ranging from cardiomyopathy to restrictive pericarditis to myocardial infarction from increased atherosclerosis) and with lung damage (fibrosis or restrictive lung disease). Abdominal irradiation is associated with injury to abdominal organs, primarily gonadal failure and infertility. Furthermore, radiation therapy is associated with an increased risk of secondary malignancies at the sites of radiation. Diabetes mellitus is not a common complication of radiation therapy.

16. (A) Anthracyclines such as doxorubicin are associated with cardiac toxicity and can cause both acute and delayed cardiomyopathy with congestive heart failure. Anthracyclines are not associated with any pulmonary complications. Platinum compounds such as cisplatin are associated with renal toxicity and ototoxicity with high-frequency hearing loss. Cyclophosphamide, a commonly used alkylating agent, is also associated with renal toxicity, and its metabolites can irritate the bladder wall, resulting in hemorrhagic cystitis. High-dose steroid therapy has a long list of side effects and complications, including hypertension, hyperglycemia, behavioral changes, and growth delay but can also cause avascular necrosis, particularly of the femoral head. Adverse reactions to vincristine include neuritic pain, constipation, hair loss, sensory loss, paresthesia, difficulty in walking, slapping gait, loss of deep-tendon reflexes, and muscle wasting. Generalized sensorimotor dysfunction may become progressively more severe with continued treatment.

SUGGESTED READING

Arico M, Egeler RM. Clinical aspects of Langerhans cell histiocytosis. Hematol Oncol Clin North Am. 1998;12(2):247-258.

Chintagumpala MM, Mahoney DH Jr. Malignant bone tumors. In: McMillan JA, DeAngelis CD, Feigin RD, et al, eds. Oski’s Pediatrics: Principles and Practice. 4th ed. Philadelphia, PA: Lippincott Williams and Wilkins; 2006.

Copley L, Dormans JP. Benign pediatric bone tumors. Pediatr Clin North Am. 1996;43(4):949-966.

Heare T, Hensley MA, Dell’Orfano S. Bone tumors: osteosarcoma and Ewing’s sarcoma. Curr Opin Pediatr. 2009;21(3):365-372.

Himelstein BP, Dormans JP. Malignant bone tumors of childhood. Pediatr Clin North Am. 1996;43(4):967-984.

Quirolo KC. Transfusion medicine for the pediatrician. Pediatr Clin North Am. 2002;49:1211-1238.

CASE 91: A 6-YEAR-OLD WITH FEVERS, FATIGUE, AND BRUISING

A 6-year-old child is brought to your clinic by her parents for recurrent fevers, extreme fatigue, and bruising on her legs. She was a previously well child with no past medical history but was noted by her parents to be “very tired” starting about 1 week ago. Her activity level dropped significantly and she seemed to be “sleeping all the time,” according to her mother. She also began having daily fevers 3 days ago, and yesterday was noted to have large bruises on her legs bilaterally, despite no history of trauma. Her parents deny any medication use or any ingestions. The family history is negative for any significant medical problems. Before the past week she had been going to school and doing well.

On physical examination, the child is pale and tiredappearing. Her temperature is 102°F (38.9°C) orally. She has a few petechiae in her oropharynx and diffuse cervical lymphadenopathy. She has a 2/6 systolic ejection murmur. Her liver and spleen are both palpable 1 cm below the costal margin. Her legs have multiple large ecchymoses.

Her complete blood count revealed a white blood cell count of 65,000/μL, a hemoglobin of 6.4 g/dL, and a platelet count of 18,000/μL. The differential has 84% large white blood cells with minimal agranular pale blue cytoplasm and large nuclei with very fine chromatin and large nucleoli.

SELECT THE ONE BEST ANSWER

1. The patient’s most likely diagnosis is which of the following?

(A) aplastic anemia

(B) acute lymphoblastic leukemia

(D) hemolytic-uremic syndrome

(E) Fanconi anemia

2. Which of the following studies is not indicated for this patient at this time?

(A) chest radiograph

(B) bone marrow aspirate

(D) spinal MRI

(E) CT of head

3. Which of the following interventions is indicated for this patient at this time?

(A) intravenous antibiotics

(B) intravenous erythropoietin

(D) subcutaneous heparin

(E) intravenous gammaglobulin

4. Which of the following features of this patient’s presentation places her at highest risk for treatment failure?

(A) gender

(B) white blood cell count

(D) physical examination

(E) platelet count

5. What is the likelihood of a child with standard-risk acute lymphoblastic leukemia entering remission after the first month of induction therapy?

(A) 5-10%

(B) 20-30%

(D) 50-60%

(E) 90-95%

6. Which of the following increased serum laboratory values is not a feature of tumor lysis syndrome?

(A) uric acid

(B) calcium

(D) potassium

(E) phosphorus

7. Measures to prevent the complications of tumor lysis syndrome include all of the following except

(A) intravenous hydration

(B) urine alkalinization

(D) intravenous potassium phosphate

(E) intravenous uricase

8. Which of the following is not a risk factor for development of childhood leukemia?

(A) previous treatment with chemotherapy

(B) ataxia-telangiectasia

(D) Down syndrome

(E) Li-Fraumeni syndrome

9. Which of the following is the least likely site of leukemia relapse?

(A) bone marrow

(B) cerebrospinal fluid (CSF)

(D) liver

(E) ovaries

10. The best option for Pneumocystis jiroveci prophylaxis in this patient is which of the following?

(A) intravenous dapsone

(B) intravenous pentamidine

(D) intramuscular penicillin

(E) aerosolized pentamidine

11. Which of the following immunizations is contraindicated in patients receiving chemotherapy?

(A) measles-mumps-rubella (MMR)

(B) tetanus-diphtheria (Td)

(D) inactivated poliomyelitis vaccine (IPV)

(E) varicella vaccine

12. Which of the following white counts represent neutropenia?

(A) WBC 8500; 51% neutrophils

(B) WBC 2000; 89% neutrophils

(D) WBC 5000; 15% neutrophils

(E) WBC 9000; 30% neutrophils

13. Which of the following intravenous antibiotic regimens is least effective empiric therapy for febrile patients with neutropenia?

(A) ceftazidime

(B) vancomycin

(D) meropenem

(E) vancomycin and ceftazidime

14. Which of the following is the least common type of infection in patients with an absolute neutrophil count less than 500?

(A) gingivitis

(B) cellulitis

(D) bacterial meningitis

(E) typhlitis

15. Features of Shwachman-Diamond syndrome include all of the following except

(A) protein malabsorption

(B) cyclic neutropenia

(D) elevated risk of aplastic anemia

(E) pancreatic deficiency

16. Which of the following procedures is contraindicated in patients with severe neutropenia?

(A) lumbar puncture

(B) peripheral venous blood sampling

(D) rectal temperature

(E) bone marrow aspiration and biopsy

17. Which of the following is not an acceptable management option for the management of a varicellanaive patient receiving chemotherapy who develops a new varicella infection?

(A) intravenous immunoglobulin

(B) intravenous acyclovir

(D) isolation precautions

(E) hospitalization

ANSWERS

1. (B) The presence of cytopenias with blast forms on the peripheral smear is characteristic of acute leukemia. Leukemias are the most common form of childhood cancer and account for approximately a third of all pediatric malignancies. There are approximately 3000 new cases of pediatric leukemia each year in the United States, which occur in all races and equally in boys and girls. Approximately 75% of new leukemias are acute lymphoblastic leukemia; approximately 20% are acute myeloid leukemia. The peak age of onset of acute leukemia in children is between 2 and 5 years of age. The underlying etiology of acute leukemias in children is generally unknown, although there is an increased risk of acute leukemia in children with syndromes such as Down syndrome, Bloom syndrome, Fanconi syndrome, and ataxia-telangiectasia. Symptoms of acute leukemias in children are generally related to the cytopenias with bleeding, easy bruising, and petechiae from thrombocytopenia, pallor and fatigue from anemia, and fevers and infections from functional neutropenia. Children with acute leukemia also frequently have diffuse lymphadenopathy, hepatosplenomegaly, and bone pain with limping or refusal to walk.

Aplastic anemia can present with the acute onset of pancytopenia but does not have associated peripheral white blood cell blasts. Aplastic anemia can be either acquired or congenital, such as with Fanconi syndrome. Potential causes of acquired aplastic anemia include environmental toxins, infections, and prior radiation therapy or chemotherapy. Treatment requires either immunosuppression or bone marrow transplantation. ITP is characterized by isolated thrombocytopenia with no other blood count abnormalities, whereas hemolytic uremic syndrome, or HUS, is usually secondary to a prodromal diarrheal illness, followed by renal failure, anemia, and thrombocytopenia.

2. (D) The initial workup of a patient with leukemia includes a chest radiograph to rule out an underlying mediastinal mass with the possibility of airway compromise. Furthermore, bone marrow evaluation and a lumbar puncture are required for evaluation of the patient’s disease status. In general, the bone marrow in cases of acute leukemia is filled with more than 80% leukemic blasts and severely decreased numbers of precursors for other types of blood cells. In the absence of peripheral neurologic symptoms, a spinal MRI is not indicated. Approximately 5-10% of new cases of acute leukemia have leukemic blasts present in the CSF at diagnosis and rarely can have symptoms such as headache or cranial nerve palsies; but the presence or absence of leukemic blasts in the spinal fluid cannot be determined by imaging.

3. (A) Any patient with fever and neutropenia requires urgent intravenous antibiotic therapy. A patient with new acute leukemia, although potentially having a normal absolute neutrophil count, likely has few functional neutrophils and is therefore functionally neutropenic and at high risk for serious bacterial infections. This patient would benefit from blood and platelet transfusions at this time, but there is no indication for starting erythropoietin. Furthermore, diuresis and anticoagulation are not indicated at this time.

4. (B) Initial risk groups for pediatric leukemia are based on patient age and total white blood cell count. The patient’s white blood cell count of more than 50,000/μL places her in the high-risk category for acute lymphoblastic leukemia (ALL). Girls with ALL tend to have a slightly higher survival rate than boys, although gender is not a feature used to determine the initial risk groups for treatment purposes. Patients younger than 1 year of age or older than 10 years of age are considered “high risk” and require more intensive therapy. Physical examination features have no prognostic significance for ALL outcomes. Other prognostic features include cellular ploidy (with hypodiploid leukemias having a worse outcome) and other chromosomal abnormalities, such as the Philadelphia chromosome [t(9;22) bcr-abl translocation], which are associated with a worse outcome.

5. (E) The likelihood of remission after induction therapy for standard risk ALL in a child is more than 90%. The current likelihood of a long-term “cure” is approximately 70-80%, with lower survival for higher risk patients, patients with relapsed disease, and for those with acute myeloid leukemia.

6. (B) Tumor lysis syndrome, which most commonly occurs in leukemias and rapidly growing lymphomas, can occur both before and after therapy is initiated. The rapid cellular turnover in these types of tumors results in the release of large amounts of intracellular breakdown products and electrolytes into the blood. Features of tumor lysis include increases in serum uric acid, potassium, phosphorus, lactate dehydrogenase (LDH), and aspartate aminotransferase (AST). Calcium levels are frequently low because of the elevated phosphorus levels and can result in anorexia, vomiting, muscle cramps or spasms, tetany, and seizures. Uric acid and calcium phosphate can precipitate in renal tubules and cause renal insufficiency, resulting in elevation of the serum creatinine level.

7. (D) The management of tumor lysis syndrome includes aggressive hydration with intravenous fluids, urine alkalinization, and decreasing uric acid levels. The goals of hydration and alkalinization are to maintain good urine output and prevent precipitation of uric acid within the renal tubules. Inhibition of xanthine oxidase (which generates uric acid from nucleic acid metabolism) with allopurinol or direct metabolism of uric acid with intravenous urate oxidase decreases the serum levels of uric acid and decreases the risk of renal obstruction. Uricase is an alternative to allopurinol and reserved for patients who are at high risk for developing tumor lysis syndrome. It is a synthetic urate oxidase enzyme and acts by degrading uric acid. Treatment of increases in potassium and phosphorus with diuretics or medications such as insulin, calcium gluconate, or sodium polystyrene are also indicated as needed. Potassium and phosphorus should not be added to intravenous fluids because of the already increased levels in patients with tumor lysis syndrome and the potential for associated renal insufficiency. Dialysis for severe renal insufficiency may be required in some cases.

8. (C) Risk factors for the development of childhood leukemia include prior chemotherapy with either alkylating agents or topoisomerase inhibitors, both of which increase the incidence of secondary malignancies. Alkylating agents such as cyclophosphamide are associated with an increased risk of leukemias, usually within 5 years of exposure. Topoisomerase inhibitors such as etoposide are associated with an increased risk of myeloid malignancies, usually within 2 years. Ataxia-telangiectasia is a tumor predisposition syndrome associated with an increased risk of leukemias. Down syndrome is associated with a risk of transient myeloproliferative disorder (TMD), a neonatal leukemia-like proliferation of white blood cells that will spontaneously resolve without therapy. Unfortunately, in 20% of cases of TMD, true leukemia develops later in childhood, and patients with Down syndrome have a 500-fold increased risk of the M7 subtype of acute myelogenous leukemia compared with normal children. No linkage has been demonstrated between maternal illicit drug use during pregnancy and an increased incidence in childhood leukemia.

9. (D) Leukemia relapses most commonly occur in the bone marrow but can also occur in the CSF and testes, both sanctuary sites where chemotherapy penetration is limited by the blood-brain and bloodtestes barriers, respectively. Leukemia relapses can occur in solid organs such as the liver or spleen but are extremely rare.

10. (C) Pneumocystis jiroveci infections are common in patients with malignancies receiving chemotherapy and occur in up to 50% of these patients in the absence of prophylactic therapy. Pneumocystis jiroveci pneumonia is characterized by fever, nonproductive cough, tachypnea, hypoxia, and bilateral diffuse interstitial infiltrates seen on chest radiograph. Acute, fulminant P jiroveci pneumonia (PJP) is more common in patients with malignancies than in patients with other forms of immunodeficiency in those settings, whereas PJP is a more chronic, indolent infection. Diagnosis of PJP requires either sputum cultures or bronchoalveolar lavage to look for characteristic cysts and trophozoites of Pneumocystis jiroveci.

Oral trimethoprim-sulfamethoxazole is the most effective prophylactic agent for Pneumocystis jiroveci pneumonia, with a less than 5% failure rate. Side effects of trimethoprim-sulfamethoxazole include neutropenia and skin rashes, which can progress to Stevens-Johnson syndrome. Dapsone and aerosolized pentamidine are secondary options for PJP prophylaxis; each has a 20% failure rate. Intravenous pentamidine has not been demonstrated to be an effective prophylactic regimen but is pressed into action when the other regimens become impractical. Penicillin has no role in PJP prophylaxis. Patients with new diagnoses of hematologic malignancies and all patients receiving chemotherapy should receive some form of prophylactic therapy. Furthermore, prophylaxis should continue for up to 6 months after therapy has finished because the immune system requires several months for full recovery.

11. (A) Live virus vaccines such as oral polio vaccine (OPV) and MMR are contraindicated in patients receiving chemotherapy. Varicella vaccine, although also a live virus vaccine, has been shown to be safe and somewhat effective in patients receiving chemotherapy. Furthermore, although other vaccines are not strictly contraindicated, the relative immunodeficiency in patients receiving chemotherapy impedes the development of protective immunity from the vaccine, and so titers must be checked after completion of chemotherapy to determine whether booster immunizations are needed. In general, vaccinations should be withheld during chemotherapy and should be restarted approximately 3-6 months after chemotherapy treatment has been completed.

12. (D) Neutropenia is defined as an absolute neutrophil count (ANC) of less than 1500, with the ANC calculated by multiplying the total white blood cell count by the percentage of neutrophils. Mild neutropenia, with an ANC between 1000 and 1500, is associated with an increased risk of bacterial infections; moderate (between 500 and 1000) and severe (<500) neutropenias are associated with much higher risks of infections. Decreased numbers of neutrophils also decrease or eliminate the signs and symptoms associated with infections and inflammation, with decreased or absent pyuria, minimal CSF pleocytosis, normal chest radiographs, and minimal redness or swelling of skin. Fever is often the only sign of infection in these patients and should be treated urgently. Pseudoneutropenia is a condition common in African Americans in the United States, characterized by an ANC of 1000-1500 but with no increased risk of infections. Neutrophils are generally present within the bloodstream or attached to the vascular endothelial surfaces (a process called margination). Neutrophils can be induced to be released from vascular endothelial cell surfaces by treatment with corticosteroids or epinephrine. Pseudoneutropenia is a result of increased margination of neutrophils, and therefore the true neutrophil count is normal and the patient will have normal responses to infections.

13. (B) Antibiotic coverage for patients with fevers and neutropenia needs to provide coverage for the most common and the most serious infections. Historically, gram-negative bacterial infections predominated in patients with neutropenia and were frequently fatal. More recently, with the increased use of central venous catheters, there has been a dramatic increase in the prevalence of gram-positive bacterial infections.

Gram-negative infections most commonly arise from endogenous enteric bacteria that can penetrate mucosal barriers as a result of the neutropenia. They are both common and serious and can cause rapid decompensation and death if not treated. Treatment regimens for patients with fever and neutropenia must therefore include broad-spectrum gram-negative coverage. Infections because of Pseudomonas aeruginosa are particularly dangerous in neutropenic patients, and any antibiotic regimen used must provide antipseudomonal coverage. For patients with fever and neutropenia, vancomycin, which only covers gram-positive organisms, is therefore not a good option. Gram-positive organisms from endogenous skin flora or enteric flora can also frequently cause infections but are less likely to be rapidly fatal. Targeted gram-positive coverage, eg vancomycin, is generally not provided as initial therapy. The other antibiotics or antibiotic combinations provide adequate gram-negative and grampositive coverage for initial therapy.

14. (D) Patients with an ANC less than 500 are most susceptible to infections from endogenous flora, which are prominent in the GI tract and mucous membranes. The neutropenia results in impaired mucosal barrier defenses, allowing for infections to develop. Therefore, the most common infections include skin infections (cellulitis), respiratory infections (upper and lower), and GI infections (oral infections such as stomatitis or gingivitis and rectal infections such as perirectal abscesses). Bacterial meningitis is infrequent among patients with neutropenia, although it can be severe.

15. (B) Features of Shwachman-Diamond syndrome include persistent neutropenia with recurrent skin and respiratory bacterial infections, pancreatic insufficiency with malabsorption, failure to thrive, and metaphyseal chondrodysplasia (most commonly at the hips, knees, shoulders, and wrists). Pancreatic insufficiency and recurrent infections generally begin before the patient reaches 10 years of age. Aplastic anemia occurs in up to 25% of cases of Shwachman-Diamond syndrome, as well as short stature, cleft palate, microcephaly, and thrombocytopenia. There is also an associated increased risk of progression to acute leukemia.

16. (D) Rectal temperatures and any procedures that involve potential injury to the perirectal tissues, such as administration of rectal contrast, should be avoided in patients with neutropenia because of the risk of mucosal surface disruption and localized or disseminated infection. Other procedures such as peripheral blood sampling and placement of intravenous lines or a lumbar puncture, if performed with sterile technique, are acceptable to perform on patients with neutropenia. Oral procedures such as tooth brushing or throat cultures are also acceptable but should be done carefully to avoid mucosal injury. Extensive dental work, however, should be avoided if possible.

17. (C) Urgent management of varicella exposure in a patient receiving chemotherapy is crucial to avoid potentially life-threatening complications associated with active varicella. Primary varicella has a mortality rate of up to 20% in patients receiving chemotherapy, with disseminated varicella affecting the lungs, liver, and CNS. Varicella-naive children who are exposed to varicella while on chemotherapy should receive varicella immune globulin within 72 hours of exposure. In the absence of varicella immune globulin, intravenous immune globulin is used instead. High-dose intravenous acyclovir should also be given for those patients who develop varicella. Ribavirin is not efficacious against varicella and should not be used.

SUGGESTED READING

Jeha S. Tumor lysis syndrome. Semin Hematol. 2001;38(4 suppl 10): 4-8.

Mahoney DH Jr. Acute lymphoblastic leukemia. In: McMillan JA, DeAngelis CD, Feigin RD, et al, eds. Oski’s Pediatrics: Principles and Practice. 4th ed. Philadelphia, PA: Lippincott Williams and Wilkins; 2006.

Mahoney DH Jr. Quantitative granulocyte disorders. In: McMillan JA, DeAngelis CD, Feigin RD, et al, eds. Oski’s Pediatrics: Principles and Practice. 4th ed. Philadelphia, PA: Lippincott Williams and Wilkins; 2006.

Pieters R, Carroll WL. Biology and treatment of acute lymphoblastic leukemia. Pediatr Clin North Am. 2008;55(1):1-20.

Rubnitz JE, Gibson B, Smith FO. Acute myeloid leukemia. Pediatr Clin North Am. 2008;55(1):21-51.

Viscoli C, Castagnola E. Treatment of febrile neutropenia: what is new? Curr Opin Infect Dis. 2002;15:377-382.

CASE 92: A 5-YEAR-OLD WITH PETECHIAE

A 5-year-old boy was brought to the emergency department for evaluation of a new rash. The patient awoke this morning covered in “red dots,” according to his mother. He had a “cold” approximately 2 weeks ago but otherwise has been well. He takes no medications and has had no sick contacts. There is no history of toxin ingestion. The family history is noncontributory.

On physical examination, the child is well appearing and afebrile. He has diffuse petechiae covering his face, neck, chest, back, stomach, arms and legs. He also has large bruises on his forearms and upper and lower legs. He has no palpable lymphadenopathy or hepatosplenomegaly.

A complete blood count done in the emergency department is within normal limits except for a platelet count of 8000/μL.

SELECT THE ONE BEST ANSWER

1. The differential diagnosis for a petechial rash of acute onset includes all of the following except

(A) ITP

(B) Rocky Mountain spotted fever

(D) ALL

(E) Fanconi anemia

2. Which of the following laboratory abnormalities is most commonly associated with the development of petechiae?

(A) thrombocytopenia

(B) prolonged PT

(D) low factor VIII level

(E) prolonged PTT

3. The most likely diagnosis for this child is

(A) ALL

(B) ITP

(D) thrombocytopenia with absent radii (TAR) syndrome

(E) Wiskott-Aldrich syndrome

4. Which of the following tests is not indicated in the initial evaluation of a patient with a suspected bleeding disorder?

(A) platelet function analysis

(B) direct Coombs test

(D) complete blood count

(E) international normalized ratio (INR) test

5. Which of the following medications is not associated with immune-mediated thrombocytopenia?

(A) erythromycin

(B) penicillin

(D) chloroquine

(E) ceftazidime

6. Which of the following is not an indication for a bone marrow evaluation in cases of thrombocytopenia?

(A) fever

(B) concurrent neutropenia

(D) history of upper respiratory infection

(E) concurrent anemia

7. The most common age range for the presentation of acute ITP is

(A) 0-1 years

(B) 2-10 years

(D) 15-20 years

(E) older than 20 years

8. Which of the following is the least common complication of ITP?

(A) intracranial hemorrhage

(B) epistaxis

(D) melena

(E) gingival hemorrhage

9. Which of the following is the best initial treatment for patients with ITP?

(A) intravenous immune globulin

(B) ibuprofen

(D) platelet transfusion

(E) FFP

10. Which of the following is not a feature of Wiskott-Aldrich syndrome?

(A) eczematous rash

(B) thrombocytopenia

(D) recurrent infections

(E) small platelet size

11. Which of the following syndromes is not associated with an increased incidence of neonatal thrombocytopenia?

(A) Glanzmann thrombasthenia

(B) Kasabach-Merritt syndrome

(D) Fanconi anemia

(E) TAR syndrome

12. What is the inheritance pattern for factor VIII deficiency?

(A) autosomal recessive

(B) autosomal dominant

(D) mitochondrial

(E) autosomal dominant with variable penetrance

13. Which of the following procedures is contraindicated in a patient with uncorrected severe factor IX deficiency?

(A) peripheral intravenous line placement

(B) femoral central line placement

(D) brain CT scan

(E) blood cultures

14. Laboratory findings associated with hemophilia A include which of the following?

(A) prolonged PT

(B) prolonged PTT

(D) prolonged fibrin time

(E) prolonged INR

15. Which of the following is not a useful treatment option for control of bleeding in a patient with hemophilia B?

(A) recombinant factor IX

(B) recombinant factor VIII

(D) aminocaproic acid

(E) topical human recombinant thrombin

16. Which of the following is the least likely to occur in patients with vWD?

(A) gingival hemorrhage

(B) menorrhagia

(D) hemarthrosis

(E) bleeding with central line placement

17. Which of the following is the best treatment for a patient with severe bleeding and type 1 vWD?

(A) intranasal desmopressin (DDAVP)

(B) FFP

(D) platelet transfusion

(E) recombinant factor IX

18. Which of the following statements regarding vWD is true?

(A) incidence of vWD is higher in males than in females

(B) vWD is the most common hereditary bleeding disorder in the United States

(D) type 3 vWD is the most common subtype

(E) there are 5 hereditary types of vWD

ANSWERS

1. (C) Petechial rashes are uncommon in pediatrics but are a presenting symptom of severe systemic illness. The differential diagnosis of acute-onsetpetechiae includes infectious and noninfectious causes. Infections caused by the meningococcus, rickettsia, and several congenital infections, for example, toxoplasmosis, rubella, CMV, herpes simplex, and sepsis from any organism causing DIC can be associated with petechial rashes. Infectious mononucleosis is generally not associated with petechiae. Noninfectious causes of petechial rashes include ITP, a common cause of acute thrombocytopenia and petechiae, as well as drug-induced immune thrombocytopenia, HUS, and Henoch-Schönlein purpura. Bone marrow suppression of platelet production in diseases such as ALL and aplastic anemia also can be associated with thrombocytopenia and petechiae.

2. (A) Petechiae are the result of capillary hemorrhages and/or abnormal platelet function, caused by either decreased platelet number or intrinsic platelet dysfunction. Abnormal platelet function or number can also be associated with purpura, easy bruising, and mucocutaneous bleeding such as epistaxis and menorrhagia. Therefore, in the patient with petechiae, the most likely abnormality is thrombocytopenia. Although abnormal PTs and PTTs are associated with bleeding disorders, the symptoms generally do not include petechiae. Low factor VIII or IX levels in particular are associated with intraarticular and deep muscle hemorrhages rather than petechiae. An increased level of fibrin degradation products is associated with activation of the coagulation cascade, such as that which occurs in deep venous thromboses or DIC, and it is not directly related to the presence or absence of petechiae.

3. (B) The most likely diagnosis for an otherwise healthy child with the acute onset of petechiae with thrombocytopenia is ITP, particularly in toddlers with a history of a recent upper respiratory infection and no family history of other disorders. ITP is generally associated with a history of a viral illness 1-3 weeks before the onset of thrombocytopenia. Characteristically, children have diffuse petechiae with purpura and ecchymoses, but they are otherwise well, with no fevers, weight loss, bone pain, organomegaly, with an otherwise normal physical examination and no history of medication use. Other less common bleeding complications of ITP include epistaxis, GI hemorrhage, and hematuria. Less than 1% of cases experience an intracranial hemorrhage, but the associated morbidity and mortality from intracranial hemorrhage is significant. The peripheral smear will show characteristic scant, large platelets, with the remainder of the complete blood count and peripheral smear being normal.

ALL occurs in children in the same age range as ITP but is associated with other findings such as fever, organomegaly, and other abnormalities in the complete blood count. vWD generally is not associated with petechiae, although type 2B, a rare subtype, is associated with thrombocytopenia and can present with petechiae. In general, vWD does not have an acute onset and most commonly is associated with a positive family history. TAR syndrome is a rare autosomal recessive syndrome characterized by congenital thrombocytopenia, with neonatal onset of petechiae and purpura and associated limb anomalies, including absent radii bilaterally but normal thumbs. The normal thumbs distinguish TAR syndrome from Fanconi anemia, which can also have cytopenias and limb anomalies but is associated with abnormal thumbs.

4. (B) The initial evaluation of a child with easy bruising, bleeding, and/or petechiae should include a complete blood count with differential and evaluation of the peripheral smear to assess the platelet count and morphology. In addition, the PT and PTT should be measured to assess the function of the coagulation cascade. The result of a PT determination performed on a normal individual will vary depending on what type of analytical system is used. This is due to the differences between batches of manufacturer’s tissue factor used in the reagent to perform the test. The INR was devised to standardize the results. Each manufacturer assigns an ISI (International Sensitivity Index) value for any tissue factor they manufacture. The ISI value indicates how a particular batch of tissue factor compares with an internationally standardized sample. The ISI is usually between 1.0 and 2.0. The INR is the ratio of a patient’s PT to a normal (control) sample, raised to the power of the ISI value for the analytical system. A screening test for platelet function such as a platelet function analysis is also indicated. A bleeding time should not be performed as a screening test in children for possible bleeding disorders because of the limited expertise in correctly performing the test and the poor sensitivity and specificity of the results. The thrombin time can be useful in addition for evaluating a patient for a fibrinogen defect. A direct Coombs test will not be helpful in assessing the status of the coagulation system. Further testing can then focus on any abnormalities found in the initial screen, such as measuring factor levels in patients with prolonged PT or PTT or platelet aggregation studies for patients with abnormal platelet function analyses.

5. (A) Many types of medications, including many antimicrobials, can induce immune-mediated thrombocytopenia. Some medications, such as valproic acid and chemotherapeutic agents, cause thrombocytopenia via myelosuppression in a dosedependent fashion. Other types of medications, including antibiotics such as the penicillins, sulfonamides, and quinines, as well as nonsteroidal anti-inflammatory medications, anticonvulsants, diuretics, and acetaminophen, are associated with immune-mediated thrombocytopenias. Macrolides such as erythromycin do not generally cause these immune-mediated reactions. Other medications associated with immune-mediated thrombocytopenia include heparin and gold, which can both be associated with the development of antiplatelet antibodies.

Medications that induce immune-mediated thrombocytopenia can do so via 2 mechanisms. Heparin and gold induce antibodies in 1-3% of uses, and the antibodies act through platelet activation, leading to platelet consumption and a combination of thrombosis from platelet activation and bleeding from thrombocytopenia. Other medications, such as chloroquine, can induce antibodies that bind to platelet surface proteins only in combination with the drug itself. These antibody-drug coated platelets could then be sequestered in the reticuloendothelial system, resulting in severe thrombocytopenia and potentially severe bleeding.

6. (D) The history of an upper respiratory infection is most consistent with the diagnosis of acute ITP, and a bone marrow evaluation is not required for those patients with characteristic features of ITP. The presence of fever, other cytopenias, lymphadenopathy, or organomegaly is more likely to be associated with other diagnoses, such as acute leukemia, and therefore patients with these features should undergo a bone marrow evaluation.

7. (B) The peak age of onset of ITP is 2-6 years old. It is much less common in infants younger than 1 year of age and in adolescents. About 80-90% of pediatric ITP cases are self-limited and have complete recovery of platelet counts within 6 months, independent of the type of treatment used. ITP that occurs in patients younger than 1 year of age or in those older than 10 years of age is more likely to be chronic, with persistent and possibly lifelong thrombocytopenia that is often less responsive to treatment. Children with chronic ITP can also have other associated autoimmune diseases or immunodeficiencies, such as systemic lupus erythematosus or common variable immunodeficiency, with immune-mediated thrombocytopenia as the presenting feature.

8. (C) Platelet disorders with thrombocytopenia or platelet dysfunction are associated with petechiae, purpura, and mucocutaneous bleeding, including epistaxis, gingival hemorrhage, and GI bleeding (see Figure 92-1). Spontaneous intracranial hemorrhage is a rare but severe complication of ITP, with an estimated incidence between 0.1 and 0.5% of ITP cases. Joint bleeding is a common complication of clotting factor deficiencies such as factor VIII or factor IX deficiency (hemophilia A and B, respectively) but is almost never seen in patients with platelet disorders.

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FIGURE 92-1. Idiopathic thrombocytopenic purpura. Nonpalpable purpura in ITP. (Reproduced, with permission, from Knoop KJ, Stack LB, Storrow AS, et al. Atlas of Emergency Medicine, 3rd ed. New York: McGraw-Hill; 2010:362. Photo contributor: Lawrence B. Stack, MD.)

9. (A) The most frequently used initial treatment for ITP is either intravenous immune globulin (IVIG) or anti-Rho-D immune globulin. Corticosteroids can also be effective, but bone marrow evaluation should be performed before steroid use to rule out the presence of underlying leukemia. Platelet transfusions are generally not indicated for ITP treatment because the platelets will be rapidly destroyed by the immune-mediated platelet consumption occurring in ITP. Nonsteroidal anti-inflammatory medications, such as ibuprofen, should also be avoided, because they inhibit platelet function. Anti-Rho-D immune globulin acts via binding to red blood cells and inducing red blood cell sequestration in the spleen, thereby displacing platelets to be released back into the bloodstream. Therefore, one of the side effects of anti-Rho-D treatment is anemia, and its use should be avoided in patients who are anemic before treatment. The mechanism of IVIG action is poorly understood.

The use of IVIG, anti-Rho-D, or corticosteroids will not have any effect on the natural course of the disease but can temporarily increase the platelet count to reduce the incidence of bleeding complications. Because approximately 80-90% of cases of ITP resolve spontaneously regardless of the treatment used, careful observation can also be a therapeutic option, with later intervention as needed. For emergent cases with severe bleeding unresponsive to other therapies, splenectomy can reduce platelet consumption and sequestration and lead to an increased platelet count but should not be used as the primary therapy. Splenectomy is generally reserved for cases of chronic ITP unresponsive to other therapies with reduced quality of life because of bleeding complications.

10. (C) Wiskott-Aldrich syndrome is a rare X-linked disorder that is characterized by neutropenia, thrombocytopenia, and an eczematous skin rash (see Figure 92-2). Anemia is not a feature of the syndrome. The immune deficiency of Wiskott-Aldrich syndrome results in increased infections of all types, including viral, bacterial, and fungal. The thrombocytopenia is characterized by small platelets and an increased risk of bleeding, with a significant risk of intracranial hemorrhage. Wiskott-Aldrich syndrome can also be associated with other autoimmune disorders such as Coombs positive hemolytic anemia, arthritis, and vasculitis. Patients with Wiskott-Aldrich syndrome have more than a 100-fold increased risk of malignancies, including lymphomas and brain tumors. Splenectomy can result in an increased platelet count, reduced risk of bleeding complications, and increased patient survival, but bone marrow transplantation is the only currently available curative therapy.

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FIGURE 92-2. Severe atopic dermatitis in a boy with WiskottAldrich syndrome. Note the serosanguineous crusting. (Reproduced, with permission, from Wolff K, Goldsmith LA, Katz SI, et al. Fitzpatrick’s Dermatology in General Medicine, 7th ed. New York: McGraw-Hill; 2008: Fig. 144-7.)

11. (A) Neonatal thrombocytopenia is a relatively common finding and can be the result of a variety of underlying conditions. Maternal antibodies can cross the placenta to cause alloimmune thrombocytopenia in the fetus, and maternal use of certain medications can also cause neonatal thrombocytopenia. Neonatal infections, sepsis, DIC, and thrombosis can all also be associated with thrombocytopenia.

Neonates with large hemangiomas or vascular malformations can have associated consumptive coagulopathy with DIC and thrombocytopenia, termed the Kasabach-Merritt syndrome. Other congenital causes of thrombocytopenia include syndromes such as TAR syndrome, congenital amegakaryocytic thrombocytopenia, Bernard-Soulier syndrome, and Wiskott-Aldrich syndrome. Fanconi anemia is an autosomal recessive, aplastic disorder associated with chromosomal instability that can have isolated neonatal thrombocytopenia or pancytopenia as well as skeletal anomalies. However, the most common age of onset of cytopenias in patients with Fanconi’s anemia is 3-14 years of age, with only 5% of cases diagnosed in infancy. Neonates with a chromosomal disorder such as trisomy 13, 18, or 21 can also frequently have isolated thrombocytopenia of unknown etiology. Glanzmann thrombasthenia is a rare autosomal recessive disorder associated with defective platelet adhesion and bleeding but with normal platelet counts.

12. (C) Factor VIII deficiency, or hemophilia A, is inherited in an X-linked pattern. Factor IX deficiency, or hemophilia B, is also X-linked, whereas factor XI deficiency (sometimes called hemophilia C) is inherited in an autosomal recessive manner. Hemophilia A occurs in approximately 1 in 4000 newborn boys; hemophilia B occurs in approximately 1 in 30,000. Both are associated with an increased risk of bleeding. Possible neonatal complications include umbilical stump bleeding, bleeding from circumcision sites, and intracranial hemorrhage. Children with hemophilia can have mucocutaneous bleeding and purpura, but deep soft tissue hemorrhages and intra-articular joint hemorrhages (termed hemarthroses) are the hallmarks of the disease. Hemarthrosis can occur at any age but most commonly occurs with increased (but still uncoordinated) ambulation in late infancy and early toddlerhood. Hemarthroses are characterized by acute joint warmth, swelling, and tenderness, and, if recurrent, can result in chronic arthritis and joint destruction. Other bleeding complications in patients with hemophilia include oral hemorrhages (particularly after dental procedures), GI bleeding, and hematuria.

The severity of bleeding symptoms is related to the level of factor in the blood, with mild cases having more than 5% of factor levels, moderate cases having 1-5% normal factor levels, and severe cases having less than 1% normal factor levels. Normal factor levels range from 60% to 150%, with female heterozygotes having levels between 20% and 50% of normal with no bleeding symptoms.

13. (B) Placement of central lines or arterial lines, lumbar punctures, intramuscular injections, and any surgical procedures should be avoided in patients with hemophilia (severe factor VIII or IX deficiency) until after factor replacement therapy has been given. Peripheral venipuncture can be done, although repeated traumatic efforts should be avoided. Hemophilia patients who have suffered head trauma should receive factor replacement therapy before any brain imaging is performed because any intracranial hemorrhage that has occurred will continue bleeding until factor replacement is given.

14. (B) Factor VIII deficiency results in a prolonged PTT, with a normal PT and thrombin time. Fibrin time is not a true test. Factor VIII is involved in the intrinsic coagulation cascade, which is initiated by factor XII interaction with high molecular weight kinins or kallikrein. This interaction results in serial activation of factors XI and IX. Factor VIII acts as a cofactor with activated factor IX for activation of factor X. The PTT measures the function of the intrinsic cascade and is therefore prolonged in cases of factor VIII or IX deficiency. The PT measures the extrinsic clotting cascade, with factor VII interacting with tissue factor to activate factor X. Activated factor X can then activate factor V, which then activates thrombin (factor II). Thrombin cleaves fibrinogen to form fibrin. Factor XIII is then required for fibrin cross-linking to form a stable blood clot.

15. (B) Therapy for bleeding in a patient with hemophilia B, or factor IX deficiency, includes local control measures such as ice and direct pressure but can also include topical thrombin and oral aminocaproic acid, an antifibrinolytic agent. For more severe bleeding, replacement of the deficient factor is required. With mild mucocutaneous bleeding, the goal of factor replacement should be to increase the factor level to approximately 20-30%. With more severe bleeding, the target factor level is much higher. Patients with hemarthroses should receive factor replacement to attain a 60-80% factor level; patients with suspected or documented intracranial hemorrhages should attain a 100% factor level. The replacement factor used is specific for the underlying defect because factor VIII will not suffice for treatment of patients with factor IX deficiency and vice versa. However, for patients with hemophilia who have developed inhibitory antibodies against the replacement factor treatments, the need for replacement factor can be bypassed with the use of preactivated downstream clotting proteins, such as activated factor VII, which directly activates factor X and promotes clot formation in the absence of either factors VIII or IX.

16. (D) vWD is characterized by deficiencies or dysfunction of von Willebrand factor (vWF), a large serum protein involved in platelet interactions with each other and with the forming blood clot. vWD can be divided into 3 types, depending on the underlying defect in von Willebrand factor. Type 1 vWD is caused by decreased amounts of von Willebrand factor, type 3 is caused by its complete absence. Type 2 is composed of 4 subtypes, each a result of a different mutation that affects the function of the protein. Each type of vWD is associated with increased bleeding, particularly bleeding from mucous membranes (epistaxis and menorrhagia) and postoperative bleeding after surgical procedures such as dental extraction or tonsillectomy/adenoidectomy. Chronic blood loss can be severe enough to cause iron deficiency anemia, and vWD should always be suspected in older children or adolescents who develop iron deficiency anemia.

17. (A) Type 1 vWD is caused by decreased production of vWF, which is produced and stored in both platelets and vascular endothelial cells, and DDAVP can stimulate the release of available vWF in most patients to increase the serum levels and assist in clot formation. Side effects of DDAVP include hyponatremia. Serum sodium levels should be monitored in patients receiving frequent DDAVP doses. FFP has very small amounts of vWF and would not be an effective therapy for severe bleeding. Cryoprecipitate, however, contains large amounts of vWF and can be used for replacement. Endogenous vWF in the bloodstream is bound to factor VIII and protects factor VIII from degradation. So the best treatment option for bleeding patients with decreased vWF, or for those who do not respond to DDAVP, is replacement with partially purified factor VIII products, which also contain large amounts of vWF. Recombinant factor VIII products are composed solely of purified factor VIII and do not contain any vWF. Except in cases of type IIB vWD that are associated with thrombocytopenia, platelet counts are generally normal in vWD patients, and so transfusions would not be of benefit to control bleeding.

18. (B) As mentioned, vWD is a group of heterogenous disorders with an underlying defect in vWF abundance or function. vWD is an autosomal dominant disorder that occurs equally in males and females in approximately 1% of the general population, making it the most common inherited bleeding disorder in the United States. Type 1 vWD, due to decreased vWF production, is the most common subtype of vWD, accounting for approximately 80% of cases. Types 2 and 3 vWD are much less common, the result of either a defect in the vWF protein or absent vWF production, respectively. Bleeding symptoms in patients with vWD are generally mild to moderate, and they predominantly involve mucocutaneous sites, with prolonged epistaxis, menorrhagia, and prolonged bleeding after dental procedures being common. Deep soft tissue hemorrhages and hemarthroses (intra-articular joint hemorrhages) that characterize patients with hemophilia are extremely rare in patients with vWD.

SUGGESTED READING

Allen GA, Glader B. Approach to the bleeding child. Pediatr Clin North Am. 2002;49:1239-1256.

Blanchette V, Bolton-Maggs P. Childhood immune thrombocytopenic purpura: diagnosis and management. Pediatr Clin North Am. 2008;55(2):393-420.

Casella JF, Bowers DC, Pelidis MA. Disorders of coagulation. In: McMillan JA, DeAngelis CD, Feigin RD, et al, eds. Oski’s Pediatrics: Principles and Practice. 4th ed. Philadelphia, PA: Lippincott Williams and Wilkins; 2006.

Ewenstein BM. von Willebrand’s disease. Annu Rev Med. 1997;48:525-542.

Furie B, Furie BC. Molecular basis of blood coagulation. In: Hoffman R, Benz EJ, Shattil SJ, et al, eds. Hematology: Basic Principles and Practice. 5th ed. Philadelphia, PA: Churchill Livingstone; 2008.

Rodriguez NI, Hoots WK. Advances in hemophilia: experimental aspects and therapy. Pediatr Clin North Am. 2008; 55(2): 357-376.

CASE 93: A 3-YEAR-OLD GIRL WITH AN ABDOMINAL MASS

A mother brings in her 3-year-old daughter for evaluation after feeling a “lump” in her abdomen while giving her a bath. The child has been healthy and has no significant past medical history. She has had normal growth and development to date. There is no family history of significant medical problems.

On physical examination, the child is well appearing, laughing and playing on her mother’s lap. Her physical examination is notable for a large, firm mass palpable on the left side of her abdomen.

SELECT THE ONE BEST ANSWER

1. Which of the following is the least likely cause of abdominal masses in children?

(A) teratoma

(B) neuroblastoma

(D) renal cell carcinoma

(E) hepatoblastoma

2. Which of the following clinical features is not associated with an increased incidence of Wilms tumor?

(A) hemihypertrophy

(B) renal insufficiency

(D) atrial septal defect

(E) hypospadias

3. Children with Beckwith-Wiedemann syndrome are at increased risk for which of the following pediatric malignancies?

(A) medulloblastoma

(B) hepatoblastoma

(D) retinoblastoma

(E) brainstem glioma

4. Which of the following is the most common extracranial solid tumor in children?

(A) Wilms tumor

(B) hepatoblastoma

(D) rhabdomyosarcoma

(E) non-Hodgkin lymphoma

5. Which of the following age ranges has the highest incidence of Wilms tumor?

(A) 0-1 months

(B) 6-12 months

(D) 8-10 years

(E) 10-15 years

6. Which of the following is the most common presentation of children with Wilms tumor?

(A) asymptomatic abdominal mass

(B) hypertensive crisis

(D) unilateral headache

(E) bone pain

7. What percentage of Wilms tumors are bilateral (ie, present in both kidneys) at initial diagnosis?

(A) 1%

(B) 10%

(D) 50%

(E) 90%

8. Presenting features of children with neuroblastoma can include all of the following except

(A) periorbital ecchymoses

(B) unilateral miosis

(D) elevated alpha-fetoprotein levels

(E) elevated vasoactive intestinal peptide levels and diffuse diarrhea

9. Which of the following laboratory values is most likely to be abnormal in children with neuroblastoma?

(A) white blood cell count

(B) serum ALT and AST (alanine/aspartase aminotransferase) levels

(D) PT

(E) platelet count

10. Stage 4S neuroblastoma is characterized by disease at all of the following sites except

(A) liver

(B) bone marrow

(D) skin

(E) adrenal gland

11. Which of the following is the least common site of neuroblastoma metastatic disease?

(A) bones

(B) bone marrow

(D) liver

(E) lymph nodes

12. Which of the following syndromes is not associated with an increased risk of pediatric malignancies?

(A) ataxia-telangiectasia

(B) Li-Fraumeni syndrome

(D) osteogenesis imperfecta

(E) Down syndrome

13. Which of the following neoplasms does not have an increased incidence in patients with type I neurofibromatosis?

(A) plexiform neurofibroma

(B) pheochromocytoma

(D) optic glioma

(E) brainstem glioma

14. Which of the following is the most common neonatal solid tumor?

(A) teratoma

(B) hepatoblastoma

(D) medulloblastoma

(E) retinoblastoma

15. Which of the following tumors is least likely to arise in the anterior mediastinum?

(A) non-Hodgkin lymphoma

(B) germ cell tumor

(D) neuroblastoma

(E) teratoma

16. Which of the following pediatric tumors is associated with increased beta-human chorionic gonadotropin (hCG) levels?

(A) neuroblastoma

(B) seminoma

(D) teratoma

(E) adrenal-cortical carcinoma

ANSWERS

1. (D) The differential diagnosis of pediatric abdominal masses includes neoplastic and nonneoplastic causes. Potential pediatric neoplasms that can present as abdominal masses include germ cell tumors, neuroblastomas, Wilms tumors, lymphomas, and rhabdomyosarcomas, among others. Renal cell carcinoma can occur in children but is extremely rare. Other nonneoplastic causes of palpable pediatric abdominal masses to be considered include impacted stool, distended bladder, intraabdominal abscesses, ovarian cysts, pyloric stenosis, enlarged kidneys secondary to polycystic kidney disease, hydronephrosis, or renal vein thrombosis.

2. (D) Several syndromes and physical features are associated with an increased incidence of Wilms tumor. Beckwith-Wiedemann syndrome, WAGR syndrome (Wilms tumor, aniridia, genitourinary malformations, and mental retardation), and Denys-Drash syndrome (renal failure, pseudohermaphroditism, and Wilms tumor) are associated with an increased incidence of Wilms tumor. Patients with hemihypertrophy or aniridia also have an increased risk and should be screened regularly for abdominal malignancies. Patients with aniridia associated with a chromosome 11p13 deletion have up to a 50% incidence of Wilms tumor by 4 years of age. There is no increased incidence in Wilms tumor associated with the presence of cardiac defects.

Nephrogenic rests are sites of abnormal persistent embryonal nephroblastic tissue that are more commonly found in patients with syndromes that predispose to Wilms tumor, such as WAGR syndrome, Beckwith-Wiedemann syndrome, and Denys-Drash syndrome. Nephrogenic rests are renal parenchymal lesions that are precursors to Wilms tumor development. They occur in 1% of the general population, but in 35% of patients with unilateral Wilms tumors and in nearly 100% of patients with bilateral Wilms tumors. If present, particularly if multiple (called nephroblastomatosis), patients should undergo regular abdominal screening to monitor for progression of the lesions to Wilms tumor.

3. (B) Beckwith-Wiedemann syndrome occurs in approximately 1 in 15,000 infants and is associated with abnormal imprinting on chromosome 11p15. The normally imprinted (and thus inactive) maternal allele is lost, resulting in unipaternal disomy and Beckwith-Wiedemann syndrome. The syndrome is characterized by macrosomia, macroglossia, organomegaly, neonatal hypoglycemia, and abdominal wall defects such as omphalocele, diastasis recti, and umbilical hernia. Other common features include linear earlobe creases, macrocephaly, advanced bone age, and absent gonads. Beckwith-Wiedemann syndrome is also associated with an increased risk of hepatoblastoma, gonadoblastoma, Wilms tumor, and adrenal tumors, but not leukemias. Children with Beckwith-Wiedemann syndrome should be followed with abdominal ultrasounds and serum alpha-fetoprotein levels every 6 months until they are at least 6 years of age to monitor for these tumors.

4. (C) Neuroblastoma is the most common extracranial solid tumor in children and the third most common overall (after leukemias and brain tumors), with approximately 600 new cases in the United States each year. Wilms tumor is the fifth most common (with approximately 450 new cases in the United States each year); rhabdomyosarcoma and other soft tissue sarcomas are the sixth most common. Hepatoblastoma accounts for approximately 100 cases per year in the United States.

5. (C) Wilms tumor in children occurs most commonly at 2-4 years of age, and more than 80% of cases present before 5 years of age with 98% of cases by the age of 7 years. Bilateral and familial cases of Wilms tumor and those associated with tumor-predisposition syndromes tend to occur earlier than sporadic cases. Wilms tumor can occur both in infants and in adolescents, but infants have a higher incidence of other renal tumors such as congenital mesoblastic nephroma and rhabdoid kidney tumors, whereas adolescents have a higher incidence of renal cell carcinomas.

6. (A) Wilms tumor most commonly presents as an asymptomatic abdominal mass, with more than twothirds of children with Wilms tumor having masses detected incidentally by parents or physicians. Symptoms of Wilms tumor can include abdominal pain, which occurs in approximately 33% of cases, hypertension, which occurs in approximately 25% of cases and is rarely emergent, hematuria (gross or microscopic), which occurs in 20% of cases. and other symptoms of abdominal mass compression such as intestinal obstruction. Furthermore, anemia because of intratumoral hemorrhage can occur, although usually the onset of anemia is acute and associated with a rapid increase in apparent tumor size because of the hemorrhage. Constitutional symptoms such as fevers, fatigue, and weight loss are rare in cases of Wilms tumor; headaches are not generally associated with Wilms tumor.

7. (B) Approximately 5-10% of Wilms tumor cases are bilateral at diagnosis, although the frequency is much higher among those cases of Wilms tumor associated with genetic syndromes.

Approximately 10-15% of Wilms tumor cases are metastatic at diagnosis, most commonly to the lungs and lymph nodes. The tumor can also be identified in the contralateral kidney. Brain, bone, and liver metastases do occur, but they are rare. Local invasion into the renal vasculature, which can progress up the inferior vena cava to the right atrium, can also occur and can lead to hypertension and abdominal vein distention. Evaluation of any child for a suspected Wilms tumor should always include an abdominal ultrasound to evaluate the presence of a tumor thrombus in the renal vasculature and a chest CT scan to rule out pulmonary metastatic disease.

The survival of children with localized Wilms tumor is good, with a more than 90% long-term expected survival rate. Survival for children with stage 4 Wilms tumor is more than 85%.

8. (D) Neuroblastoma is a relatively common pediatric neoplasm and the most common extracranial solid tumor in children. Approximately 75% of cases occur in children younger than 2 years of age, and more than 90% occur in children younger than 5 years of age.

Neuroblastoma arises from primordial neural crest cells, and its primary sites are either abdominal or thoracic. Presenting symptoms of neuroblastoma can include bilateral periorbital ecchymoses (“raccoon eyes”), Horner syndrome (unilateral ptosis, miosis, and anhidrosis), or rapid eye movements (opsoclonus-myoclonus syndrome). Elevated alphafetoprotein levels are more commonly found in hepatoblastomas and some germ cell tumors but not in patients with neuroblastoma. Other presenting symptoms of neuroblastoma include fever, palpable abdominal mass, hypertension, respiratory distress, superior vena cava (SVC) syndrome, spinal cord compression, weight loss, bone pain, watery diarrhea as a result of vasoactive intestinal peptide secretion, and paraneoplastic ataxia.

9. (C) Elevation of urine catecholamines homovanillic acid (HVA) and vanillylmandelic acid (VMA) are found in almost all (approximately 95%) cases of neuroblastoma, and they are also elevated in most cases of pheochromocytoma. HVA and VMA are by-products of catecholamine metabolism and are increased in cases of neuroblastoma as a result of excessive production from adrenergic tissue. Although neuroblastoma can metastasize to the bone marrow in some cases, blood cell production is rarely impaired, although anemia and thrombocytopenia are more common than leukopenia. Furthermore, neuroblastoma that involves the liver can also cause elevated liver enzyme (AST and ALT) levels and prolonged coagulation tests, but these features are much less common than elevations in urine catecholamines.

10. (C) Stage 4S neuroblastoma is a form of neuroblastoma that occurs only in infants younger than 1 year of age, with metastatic disease limited exclusively to the liver, bone marrow (with <10% involvement), and skin. Bony disease is a feature of stage 4 neuroblastoma but not stage 4S. Outcomes for stage 4S neuroblastoma, as opposed to stage 4 disease, are extremely good, and can include complete disease resolution in the absence of any therapy.

11. (C) Neuroblastoma can metastasize to almost anywhere in the body but is most commonly found in the bone marrow, bones, and liver. Lung and CNS metastases can occur but are very rare and portend worse outcomes.

Treatment for neuroblastoma is stratified according to the patient’s age, stage, and the biology of the tumor. Age older than 18 months and widely disseminated disease are unfavorable clinical prognostic factors. Genetic aberrations including MYCN amplification, loss of chromosome 1p and 11q, and gain of chromosome 17q are associated with a worse prognosis. Patients classified as high risk are treated with intensive multimodality therapy. Infants with a specific pattern of metastatic disease (limited to the skin, liver, and bone marrow; stage 4S) who have tumors with favorable biology have a high incidence of spontaneous regression and favorable prognosis.

12. (D) Osteogenesis imperfecta is not associated with an increase in pediatric malignancies, whereas each of the other listed syndromes have an increased incidence of pediatric cancers. Ataxia-telangiectasia is a syndrome characterized by DNA repair defects and presents with cerebellar ataxia and oculocutaneous telangiectasias. Malignancies occur in approximately 15% of cases and include non-Hodgkin lymphomas and carcinomas. Li-Fraumeni syndrome is associated with mutations in the p53 gene, which is important in cell cycle regulation. Patients with Li-Fraumeni syndrome are predisposed to a variety of malignancies, including soft tissue sarcomas, leukemias and lymphomas, adrenocortical carcinomas, and breast and bone cancers. Bloom syndrome is a rare syndrome most commonly found in patients of Ashkenazi Jewish heritage and is characterized by intrauterine growth retardation, abnormal facies, facial telangiectasias, and other skin lesions. Patients with Bloom syndrome are predisposed to all types of leukemias, and they occur in approximately a fourth of patients.

13. (C) Neurofibromatosis is an autosomal dominant syndrome with an incidence of approximately 1 in 2500 children in the United States. Mutations in the neurofibromin gene are responsible for neurofibromatosis. The features include café-au-lait spots, cutaneous neurofibromas, axillary and inguinal freckling, Lisch nodules, sphenoid dysplasia, tibial bowing, and other skeletal anomalies such as short stature and scoliosis. Other features can also include renovascular hypertension, seizures, and developmental delay. Type 1 neurofibromatosis is also associated with an increased incidence of malignancies, including plexiform neurofibromas and neurofibrosarcomas, pheochromocytomas, and brain tumors such as meningiomas, astrocytomas, acoustic neuromas, and optic gliomas. Patients with neurofibromatosis are not at increased risk for the development of medulloblastoma.

14. (A) Teratomas are the most common neonatal solid tumor, accounting for up to a third of all neonatal tumors. Teratomas are generally benign masses composed of tissues from at least 2 of the 3 embryonic germ layers: endoderm, mesoderm, and ectoderm. The tissues within a teratoma can be fully differentiated (resulting in a “mature” teratoma), partially differentiated (resulting in an “immature” teratoma), or malignant. Immature teratomas account for 30% of neonatal teratomas; malignant teratomas account for less than 10% (but up to 50% of teratomas in older children). The primary sites include the sacrococcygeal region, the anterior mediastinum, and the CNS. Treatment of teratomas is complete surgical excision, and metastases in mature and immature cases are extremely rare. Malignant teratomas require excision and chemotherapy to treat the type of malignant tissue present within the mass.

15. (D) The anterior mediastinum is a common site for pediatric tumors, with presenting symptoms ranging from cough or dysphagia to hoarseness, wheezing, dyspnea, or SVC syndrome. The most common anterior mediastinal tumors include lymphomas (particularly T-cell lymphomas), teratomas and other germ cell tumors, and thymic tumors. Neuroblastomas generally arise from sympathetic ganglia, and cases of thoracic neuroblastoma are more likely to be located in the posterior mediastinum. Cases of thoracic neuroblastoma are adjacent to the spinal cord and often are associated with spinal canal invasion and spinal cord compression, requiring urgent medical and/or surgical intervention. More than 50% of thymomas are asymptomatic, but approximately a third are associated with myasthenia gravis.

16. (C) Tumors that contain components of syncytiotrophoblastic tissue, such as choriocarcinomas, express high amounts of beta-hCG protein. Other germ cell tumors more commonly express high levels of alpha-fetoprotein (AFP) but not beta-hCG. Neuroblastomas express high levels of catecholamines but neither AFP nor beta-hCG. Mature teratomas also do not express AFP or beta-hCG, and so the presence of elevated AFP or beta-hCG levels indicates a malignant component to a teratoma.

SUGGESTED READING

Chintagumpala MM, Steuber CP. Wilms tumor. In: McMillan JA, DeAngelis CD, Feigin RD, et al, eds. Oski’s Pediatrics: Principles and Practice. 4th ed. Philadelphia, PA: Lippincott Williams and Wilkins; 2006.

Dreyer ZE, Fernbach DJ. Neuroblastoma. In: McMillan JA, DeAngelis CD, Feigin RD, et al, eds. Oski’s Pediatrics: Principles and Practice. 4th ed. Philadelphia, PA: Lippincott Williams and Wilkins; 2006.

Golden CB, Feusner JH. Malignant abdominal masses in children: quick guide to evaluation and diagnosis. Pediatr Clin North Am. 2002;49:1369-1392.

Park JR, Eggert A, Caron H. Neuroblastoma: biology, prognosis, and treatment. Pediatr Clin North Am. 2008;55(1):97-120.

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