PEDIATRIC HEMATOLOGY BOARD REVIEW

1. PEDIATRIC HEMATOLOGY BOARD REVIEW Lakshmi Venkateswaran MD Assistant Professor Section of Hematology/Oncology Texas Children’s Hospital/Baylor College of Medicine June, 2010

2. RED CELL DISORDERS

3. NEONATAL ANEMIA • Hemorrhage: • Twin-twin / feto-maternal transfusion, overt/external hemorrhage • Hemolysis • Immune: ABO, Rh, minor blood group incompatibility • Infection: TORCH, sepsis, parvo virus • Red cell defects: membrane disorders, enzyme deficiencies, hemoglobinopathy, micro/macro-angiopathic hemolysis • Underproduction • Fanconi’s anemia • Diamond Blackfan anemia • Schwachman-Diamond syndrome • Aase syndrome • Pearson syndrome • Dyskeratosis congenita • Congenital Dyserythropoietic anemia

4. IRON DEFICIENCY ANEMIA • Cause: • Dietary (milk based diet - esp. toddlers), blood loss (Meckel’s diverticulum, GI ulcer, polyps, hemangioma, irritation by cow’s milk protein, worm infestation), inhibition of/decreased absorption (lead poisoning, celiac disease, tropical sprue) • Clinical Features: • Pica, pallor, tachycardia, heart murmur, epithelial changes; chronic – impaired growth, cognitive dysfunction, altered attention span, behavior, performance • Lab Features: • Microcytosis (low MCV), increased RDW, anisocytosis, poikilocytosis, normal / low reticulocyte count, thrombocytosis

6. IRON DEFICIENCY ANEMIA • Differential diagnosis of microcytic anemia: • Lead poisoning (coarse basophilic stippling, elevated blood lead level) • Thalassemia trait (MCV disproportionately low, elevated Hb A2, presence of Bart’s Hb in NB screen) • Anemia of chronic disease (low serum Fe, TIBC, nl or high ferritin) • Sideroblastic anemia • Congenital anemia with unstable Hb • Management: • Oral ferrous sulfate • Identify & correct cause • PRBC transfusion – only for severe anemia, with cardiac failure • Parenteral Fe - only in special cases

7. MEGALOBLASTIC ANEMIA • Vitamin B12 deficiency • Dietary – vegan diet (neonate with vegan mother) • Congenital disorders of absorption & metabolism • Intrinsic factor defect – gastrectomy, pernicious anemia • Disorders of ileum • Folic acid deficiency • Dietary deficiency (goat’s milk) • Defects in absorption – small bowel disorders • Inborn errors of absorption & metabolism • Drugs – anticonvulsants, methotrexate • Increased demand – pregnancy, lactation, hemolytic anemia, prematurity, alcoholism

9. MEGALOBLASTIC ANEMIA • Clinical features: • Macrocytic anemia (high MCV) • low/nl reticulocyte count • neutropenia, thrombocytopenia • hypersegmented neutrophil • megaloblastic bone marrow • Management: • Vitamin B12 supplementation (oral / parenteral) • Folate supplementation (often oral, rarely parenteral) • Identify and treat the cause

10. HEMOGLOBINOPATHIES • Sickle cell disease: • Beta globin mutation • Sickled RBCs with shortened survival • Lab Features: • Normocytic anemia • Increased reticulocyte count • Thrombocytosis • Leukocytosis • Peripheral smear: sickle cells, polychromasia, Howell-Jolly bodies • Hb profile: Hb SS (>50% Hb S); NB screen: FS

11. SICKLE CELL DISEASE

12. SICKLE CELL DISEASE • Clinical Features & management: • Hand foot syndrome – hydration, analgesics • Vaso-occlusive crisis – hydration, analgesics • Acute chest syndrome – hydration, analgesics, oxygen, PRBC transfusion, antibiotics • Splenic sequestration crisis – PRBC transfusion, splenectomy (for recurrent crises) • Aplastic crisis – PRBC transfusion • Splenic dysfunction, sepsis with encapsulated organisms – broad spectrum cephalosporins, +/- vancomycin, macrolides • Stroke – prevention-TCD screening, exchange transfusion • Priapism – hydration, PRBC transfusion, irrigation, surgery • Education about fever/pain management, spleen palpation

13. HEMOGLOBINOPATHIES • Hemoglobin C • Homozygous – mild anemia, microcytosis; target cells • Hemoglobin SC • Sickle cell disease; splenomegaly; microcytosis, target & sickle cells • Hb S / thalassemia • Beta zero, beta plus, alpha thalassemia • Hemoglobin E • South East Asia; microcytosis, mild to moderate anemia

14. THALASSEMIA • Beta thalassemia: quantitative beta globin defect • Thalassemia major • Severe anemia, transfusion dependent, hepatosplenomegaly, characteristic facies • Microcytic, hypochromic anemia, poikilocytes, target cells • Management – chronic transfusion / iron chelation, splenectomy, bone marrow transplantation • Thalassemia intermedia • Thalassemia minor

15. THALASSEMIA • Alpha thalassemia: quantitative alpha globin defect • One gene • Silent carrier • Two genes • Thalassemia trait (microcytosis, mild anemia, Hb Bart’s in NB screen) • Three genes • Hb H disease (moderate hemolytic anemia, Hb Bart’s in NB screen, Hb H in Hb profile) • Four genes • Hydrops fetalis

16. THALASSEMIA

17. HEMOLYTIC ANEMIA • Intrinsic • Hereditary spherocytosis • Mild, moderate, severe • Increased MCHC, spherocytes, increased osmotic fragility, reticulocytosis • Transfusion, splenectomy • Hereditary elliptocytosis • G6PD deficiency • Seen in African American, Asian, Arabic, Mediterranean population • Mild-severe; hemolysis triggered by food/drugs (fava beans, bactrim, naphthalene, anti-malarials), infections • Prevent exposure, transfusion • Pyruvate Kinase deficiency

18. HEMOLYTIC ANEMIA • Extrinsic • Paroxysmal cold hemoglobinuria • Autoimmune hemolytic anemia • Idiopathic or secondary • Often preceded by viral infection • Acute hemolysis, severe anemia, reticulocytosis, hyperbilirubinemia, hemoglobinuria • Mild splenomegaly • Coomb’s test positive • Steroids, transfusion

19. BONE MARROW FAILURE • Congenital disorders – Macrocytic anemia • Fanconi’s anemia - rash, skeletal (thumb), cardiac, renal anomalies; supportive care, BMT • Diamond-Blackfan anemia – pure red cell aplasia, macrocytic, reticulocytopenic; prednisone, BMT • Transient Erythroblastopenia of childhood • Normo/macrocytic anemia, reticulocytopenia; may follow viral infection; self-resolving • Acquired aplastic anemia • Macrocytic anemia, pancytopenia • Bleeding, infections • BMT, immunosuppressive therapy

20. POLYCYTHEMIA • Primary • Polycythemia vera • Familial polycythemia • Secondary • Pulmonary disease • Cardiac disease • Renal disorders • Tumors – Wilm’s, liver, adrenal gland, cerebellum, uterus, ovary • Endocrine imbalance – excess steroids, androgens, growth hormone

21. Q & A 1. On a routine-screening complete blood count, a 1-year-old is noted to have a microcytic anemia. A follow-up hemoglobin electrophoresis demonstrates an increased concentration of hemoglobin A2. The child is most likely to have a. Iron deficiency b. β-thalassemia trait c. Sickle cell anemia d. Chronic systemic illness e. Lead poisoning

22. Q & A 2. A 15 month old infant has been breast fed since birth. He now eats finger foods (carrot, peas etc) and some cereal. His mother is a strict vegan and plans to continue the child on a similar diet. A complete blood count documents anemia. What is the most likely cause of anemia? Niacin Folic acid Riboflavin Thiamine Vitamin B12

23. Q & A 3. A 4-year-old previously well boy develops pallor, dark urine, and jaundice. There has been no apparent exposure to a jaundiced person or to any toxins. He is taking trimethoprim-sulfamethoxazole for otitis media. You consider the possibility of a hemolytic crisis caused by glucose-6-phosphate dehydrogenase (G6PD) deficiency. In which of the following ethnic groups is the incidence lowest? a. African American b. Greek c. Chinese d. Middle Eastern e. Scandinavian

24. Q & A 4. On a routine newborn screen, a 2-week-old child in your clinic is noted to have sickle cell disease. As you discuss treatment options with this family, you recommend a. Monthly injections of vitamin B12 b. Tetracycline prophylaxis c. Meningococcal vaccine at 2, 4, and 6 months of age d. Education of parents regarding abdominal palpation and temperature taking e. Infusion of immunoglobulin every 6 weeks

25. Q & A 5. A preterm black male infant was found to be jaundiced 12 h after birth. At 36 h of age, his serum bilirubin was 18 mg/dL, hemoglobin concentration was 12.5 gm/dL, and reticulocyte count 9%. Many nucleated red cells and some spherocytes were seen in the peripheral blood smear. The differential diagnosis should include which of the following? a. Pyruvate kinase deficiency b. Hereditary spherocytosis c. Sickle cell anemia d. Rh incompatibility e. Polycythemia

26. Q & A 6. On a routine well-child examination, a 1-year-old boy is noted to be pale. He is in the seventy-fifth percentile for weight and the twenty-fifth percentile for length. Results of physical examination are otherwise normal. His hematocrit is 24%. Of the following questions, which is most likely to be helpful in making a diagnosis? a. What is the child’s usual daily diet? b. Did the child receive phototherapy for neonatal jaundice? c. Has anyone in the family received a blood transfusion? d. Is the child on any medications? e. What is the pattern and appearance of his bowel movements?

27. Q & A 7. Having performed a complete history and physical examination on the patient, you proceed with a diagnostic workup. Initial laboratory results are as follows: hemoglobin 8 gm/dL; hematocrit 24%; leukocyte count 11,000/Μl with 38% neutrophils, 7% bands, 55% lymphocytes; hypochromia on smear; lead level 7 μg/dL whole blood; platelet count adequate; reticulocyte count 0.5%; sickle cell preparation negative; stool guiac negative; and mean corpuscular volume (MCV) 65fl. You would most appropriately recommend a. Blood transfusion b. Oral ferrous sulfate c. Intramuscular iron dextran d. An iron-fortified cereal e. Calcium EDTA

28. Q & A 8. A 10 y/o girl c/o increasing fatigue several days after suffering from an URI. Findings on PE include obvious pallor, scleral icterus and spleen tip palpable 3 cm below costal margin. Laboratory studies reveal Hb of 6.3 gm/dl, retic count of 10% and indirect bilirubin of 2.8 mg/dl. Rest of the blood count is wnl. Past medical history is unremarkable. She has had a normal Hb at 1 year of age and has not had any lab tests until this visit. Of the following, in addition to the CBC, the most appropriate lab test to order in this patient is A. G6PD assay B. Direct Coomb’s test C. Osmotic fragility D. Haptoglobin concentration E. Hemoglobin electrophoresis

29. Q & A 9. A 2950-g black baby boy is born at home at term. On arrival at the hospital, he appears pale, but the physical examination is otherwise normal. Laboratory studies reveal the following: mother’s blood type A, Rh positive; baby’s blood type O, Rh positive; hematocrit 38%; reticulocyte count 5%. Which of the following is the most likely cause of the anemia? a. Fetomaternal transfusion b. ABO incompatibility c. Physiologic anemia of the newborn d. Sickle cell anemia e. Iron-deficiency anemia

30. Q & A 10. An 8-year-old patient with sickle cell anemia 11. A 7-month-old boy with severe anemia requiring transfusions, heart failure, hepatosplenomegaly, and weakness 12. A 3-day-old newborn with anemia and pathologic hyperbilirubinemia requiring phototherapy 13. A completely asymptomatic, healthy 1-year-old whose routine CBC reveals an abnormality.

31. Q & A – a,b

32. Q & A – c,d

33. WHITE CELL DISORDERS

34. NEUTROPENIA • Intrinsic defects: • Reticular dysgenesis • Cyclic neutropenia • Severe congenital neutropenia (Kostmann disease) • Myelokathexis and WHIM syndrome • Schwachman-Diamond syndrome • Chediak-Higashi syndrome • Familial benign neutropenia • Bone marrow failure syndromes (congenital 7 acquired)

35. CYCLICAL NEUTROPENIA • Sporadic or autosomal dominant • Regular, periodic oscillations (every 21 days; range 14-36 days) of neutrophils (rarely other cells as well) • Nadir <200cells/microL • S/s: fever, oral ulcers, gingivitis, periodontitis, pharyngitis, lymph node enlargement • Severe: mastoiditis, pneumonia, vaginal/rectal ulcers, peritonitis; ~10% mortality • Bone marrow: Hypoplasia or arrest at myelocyte stage • ELA-2 mutations • Management: GCSF

36. SEVERE CONGENITAL NEUTROPENIA • Autosomal recessive inheritance • Incidence 2 per million • ANC < 200 cells/microL • Recurrent infections (skin, stomatitis, pneumonia, peri-rectal abscess; Staph aureus, E. coli, Pseudomonas sepsis) • Bone marrow exam: arrest at promyelocyte / myelocyte stage • ELA-2 gene mutations • May develop MDS/ AML • Management: GCSF (risk for leukemia) / BMT

37. SCHWACHMAN-DIAMOND SYNDROME • Clinical features: • Neutropenia (moderate to severe), recurrent infections, exocrine pancreatic insufficiency (diarrhea), growth retardation / short stature, metaphysial chondrodysplasia / skeletal abnormalities • SDS gene mutation ~90% of patients • Bone marrow: • Decreased myeloid precursors • Cancer predisposition syndrome, can progress to bone marrow failure • Management: GCSF, BMT, pancreatic enzyme supplement

38. CHEDIAK-HIGASHI SYNDROME • Autosomal recessive inheritance • Clinical features: • Partial oculo-cutaneous albinism, recurrent infections, cranial & peripheral neuropathies; hepatosplenomegaly & pancytopenia in accelerated phase • Diagnosis: • Giant lysosomes in peripheral blood granulocytes & BM myeloid precursors cells • CHS gene mutations • Management: treat infections, ascorbic acid, BMT

39. NEUTROPENIA • Extrinsic defects: • Infection • Drugs • Autoimmune neutropenia • Chronic benign neutropenia of childhood • Associated with immune dysfunction • Associated with metabolic diseases • Nutritional deficiencies • Reticuloendothelial sequestration • Bone marrow infiltration • Chronic idiopathic neutropenia

40. CHRONIC BENIGN NEUTROPENIA OF CHILDHOOD • Most common cause • Median age 8-11 months (range 3-38 months) • ANC 0-500 • May last for several months (median 20; range 6-54 months) • Diagnosis: • Anti-neutrophil antibody usually positive • BM exam: Maturation arrest at earlier stages • Management: • Treat infections, counsel parents • Rarely GCSF • Reassurance - Self-resolving

41. NEONATAL ALLOIMMUNE NEUTROPENIA • Analogous to Rh hemolytic disease • May last for several weeks to 6 months • Diagnosis: • Mother - NA1 & NA2 antigen negative; antibody positive • Father & patient antigen positive • Self-resolving • Management: • Treat infections • May consider GCSF

42. NEUTROPHILIA • Acute / Chronic infection • Chronic inflammation • Tumors • Myeloproliferative disorders • Drugs (lithium, ranitidine, corticosteroids) • Leukemoid reactions • Post-neutropenia rebound • Chronic idioapthic neutrophilia • Familial cold urticaria • Splenectomy • Leukocyte adhesion deficiency • Stress, exercise, epinephrine • Hypoxia

43. Q & A 14. An otherwise healthy child has on his 1-year-old routine CBC the polymorphonuclear neutrophil shown in the following illustration. This child likely has a. Malignancy b. Iron deficiency c. Folic acid deficiency d. Dohle inclusion bodies e. The Pelger-Huet nuclear anomaly

44. Q & A 15. A 12 month old infant presents with 3 day history of rhinorrhea, decreased appetite and temperature of 101.5 C. On PE, the child is happy, playful and has no other findings except rhinorrhea. Since 8 months of age, the CBC has consistently shown WBC count of 2400 to 3000 (2.4 - 3x109/L), and ANC less than 400. A bone marrow exam at 11 months showed granulocytopenia with normal trilineage precursors. Besides occasional cold, the child has not had any serious infections. Of the following, the management strategy that is most appropriate is A. Allogenic BMT B. IVIG C. Prophylactic antibiotic therapy D. GCSF E. Symptomatic supportive care

45. EOSINOPHILIA • Allergic disorders: Asthma, hay fever, urticaria, drug reaction, acute bronchopulmonary aspergillosis • Dermatitis: Atopic dermatitis, pemphigus, pemphigoid • Infections: Invasive parasites, PCP, Toxoplasmosis, Malaria, Scabies, Coccidioidomycosis • Tumors: Brain tumors, Hodgkin / NHL, myeloproliferative disorders, eosinophilic leukemia • Hereditary eosinophilia • GI disorders: Regional enteritis, milk precipitin disease • Hypereosinophilic syndromes • Miscellaneous: Immunodeficiency disorders

46. MONOCYTOSIS • Hematologic disorders • Leukemia / lymphoma, neutropenia • Collagen vascular disorder • Granulomatous disease • Ulcerative colitis, regional enteritis, sarcoidosis • Infection • Subacute bacterial endocarditis, Tuberculosis, syphilis, protozoal / rickettsial infections; FUO • Post-splenectomy state

47. Q & A 16. During a routine-screening CBC, a 1-year-old is noted to have eosinophilia. Which of the following most likely will cause increased eosinophilia in the peripheral blood smear? a. Bacterial infections b. URI c. Fungal infections d. Invasive parasitic infestation e. Tuberculosis

48. CONGENITAL PLATELET DISORDERS • Quantitative • Thrombocytopenia absent radius syndrome • Neonate with absent radius, platelet count improves after 1 year • Amegakaryocytic thrombocytopenia • Bone marrow failure; isolated thrombocytopenia, may progress to pancytopenia / MDS; management – BMT • Wiskott-Aldrich syndrome • X-linked recessive; triad of immunodeficiency, eczema, thrombocytopenia (small platelets) • Congenital macrothrombocytopenia (MYH 9 disorder) • May-Hegglin & others; large to giant platelets; some have Dohle bodies; may have renal, eye (cataract), hearing defects

49. CONGENITAL PLATELET DISORDERS • Qualitative • Glanzmann thrombasthenia • Normal platelet count, bleeding since infancy; Gp IIb/IIIa defect; platelet transfusion for major bleeds / rF VIIa • Bernard-Soulier syndrome • Thrombocytopenia; Gp Ib/IX defect; platelet transfusion for major bleeds / rF VIIa • Gray platelet syndrome • Absence of platelet granules • Storage pool disorder • Platelet secretion defect

50. ACQUIRED PLATELET DISORDERS • Acquired thrombocytopenia • Immune thrombocytopenic purpura • Immune mediated, may follow viral infection, vaccination • Destruction of antibody coated platelets • Physical exam – normal except petechiae, bruises • Lab features: Isolated thrombocytopenia, mixture of normal and large platelets • Diagnosis of exclusion, BMA not necessary in typical cases • Management: steroids, IVIG; platelet transfusion only for life threatening bleeding