Congenital Macrocytic Anemia

1. Congenital Macrocytic Anemia Beng Fuh, MD Assistant Professor of Pediatrics Pediatric Hematology/oncology East Carolina University

2. No relevant financial relationships with the manufacturer(s) of any commercial products and/or provider(s) of services discussed in this CME activity. I do not intend to discuss an unapproved/investigative use of a commercial product/device in my presentation

3. Objectives • Demonstrate an approach to an anemic patient • Review the differential diagnosis of anemia • Discuss the etiologies of hypoproliferative anemia • Treatment options for Diamond Blackfan anemia

4. Case Presentation • 13 y/o female with anemia HPI • Worsening fatigue x ~1 yr • Headaches X ~6 mos • Sinusitis 4 wks ago treated X2 • Noted to have anemia • Poor diet (fast foods) • Started on Multivitamins • Referred to ECU for further evaluation

5. PMH, ROS and FH • PMH • Menarche at age 12 yrs (1 yr ago) • “Normal” CBC in the past • Hand surgery for deformity in infancy • ROS • As in HPI, no fever, no bone pain, no wt loss • FH • Sister with Anemia • Previously treated with Vit B12 • Most recently with Fe supplementation • Mother with hypertension and ? anemia

6. PE VSS Wt: 50kg Ht: 157cm HEENT: NL Chest: NL CVS: NL ( no Murmur) Abd: NL (no HSM) Extremities: Abnormal left thumb

7. 13 y/o with Anemia- Findings Abnormal left hand Normal right hand With Permission. Dr. Fuh image collection

8. Laboratory findings RBC: 2.8 m/uL (low) Hb: 9.1g/dL (low) MCV: 103fL (high) RDW: 16.9 (High) Retic: 1.6% Normal (Low for hemoglobin) WBC and plt: NL Folate: NL Vit B12: NL Hb electrophoresis: NL Erythropoietin level: NL Chromosome breakage (fanconi anemia): NL

9. Other Revelations Obtained past labs Several CBCs since age 2 yrs showed macrocytic anemia Hb ~ 10g/dL MCV ~ 103fL CBC on 16 y/o sister: Mild microcytic anemia Hb: 11.3g/dL MCV: 73fL

10. Pt’s marrow Dr. Fuh’s slide collection, used with permission

11. Normal marrow Dr. Fuh’s slide collection, used with permission Erythroid precursor

12. Childhood anemia Where to begin • Is it really anemia • Detailed history (HPI, PMH, FH) • Complete physical exam • Screening Labs • Complete Blood Count (CBC) • Attention to Hb, MCV, RDW • WBC & diff, Platelet count • Peripheral smear • Reticulocyte Count

13. Factors affecting Hb in children • Age • Race • Gender • Degree of sexual maturity • Altitude • Heredity

14. Signs and symptoms of anemia • Palor • Jaundice • Fatigue • Dizziness • Headache • Tachycardia • Hypotension • Tachypnea • SOB • HSM • Stool color changes

15. Our Patient • Long standing anemia • Skeletal abnormalities • Hb: 9.1g/dL • MCV 103fL • Retic: 1.6 • What does this indicate?

16. Our Patient • Long standing anemia • Skeletal abnormalities • Hb: 9.1g/dL • MCV 103fL • Retic: 1.6 • What does this indicate? • Macrocytic anemia with relatively low reticulocyte count

17. Morphologic classification. Microcytic Anemia NormocyticAnemia Macrocytic Anemia

18. Differential Diagnosis of Anemia • Defect in Production of Erythrocytes • Extrinsic Destruction of Erythrocytes • Defect in components of Erythrocytes • Enzyme deficiency • Membrane defect • Hemoglobin deficiency/ defect • Heme defect • Globin defect • Globin deficiency

19. Differential Diagnosis of Anemia Reproduced with permission from Dr. Ray Watts, UAB

20. Hemoglobinopathies • Thalassemia often presents with: • Microcytosis • Beta thal may have elevated Hb F and HbA2 • Our pt • No microcytosis • Normal Hb electrophoresis

21. Differential Diagnosis of Anemia Reproduced with permission from Dr. Ray Watts, UAB

22. Fe def Presents with: • microcytosis • Elevated RDW • Our pt • Has microcytosis • No relevant meds or toxins

23. Differential Diagnosis of Anemia Reproduced with permission from Dr. Ray Watts, UAB

24. Folate and B12 def present with • Microcytosis and • Low folate or low B12 • Our pt • NlFolate • NlVit B12

25. Differential Diagnosis of Anemia Reproduced with permission from Dr. Ray Watts, UAB

26. Hemolytic anemia presents with • Normocytosis • Elevated reticulocytosis • Elevated bilirubin • Our pt • Nl to low retic • Macrocytosis

27. Differential Diagnosis of Anemia Reproduced with permission from Dr. Ray Watts, UAB

28. Global bone marrow abnormalities • Marrow fibrosis • Marrow infiltration • Malignancy • >1 hematopoietic cell line affected • Infections • Positive titers • Usually Parvo B19 or EBV • Our pt • Only RBC line affected • Neg for Parvo and EBV titers

29. Differential Diagnosis of Anemia Reproduced with permission from Dr. Ray Watts, UAB

30. Aplastic Anemia • > 1 cell hematopoietic cell lines affected • Fanconi Anemia • > 1 cell hematopoietic cell lines affected • Chromosome breakage studies abn • Our pt • Only RBC line abn • Nl breakage studies

31. Differential Diagnosis of Anemia Reproduced with permission from Dr. Ray Watts, UAB

32. Differential Diagnosis of Anemia Reproduced with permission from Dr. Ray Watts, UAB

33. Pure Rd Blood Cell Aplasia • Diamond Blackfan Anemia vs • Transient Erythroblastopenia of Childhood

34. Diamond Blackfan Anemia (DBA • History • 1938 : L. Diamond and K. Blackfan described congenital hypoplasticanemia • 1997: RPS 19 mutation found in some pts with DBA • Today: 6 Mutations associated with DBA • 50% of pts have none of these mutations • Epidemiology • Rare congenital, anemia • Incidence: 5 per million • 25 – 50 % are familial with an autosomal dominant • inheritance

35. Diamond-Blackfan Anemia • Etiology/ Pathophysiology • An arrest in the maturation of red cells • Anemia frequently evident in infancy but may occur later • Frequently associated with dysmorphic features (50%) • Severity of anemia is variable • Increased risk of malignancy in pts with DBA • Laboratory Studies • Decreased hemoglobin, elevated MCV • Frequently low reticulocyte Count • Elevated ADA • Bone marrow including cytogenetics • Erythroidhypoplasia

36. Dysmorphologic Associations with Diamond-Blackfan Anemia • Thumb abnormalities • Craniofacial problem • Glaucoma • Short-webbed neck • Short stature • Urogenital defects • Hypogonadism • Congenital heart defects • Mental retardation

37. Evaluation Labs CBC with retic Bone marrow biopsy Chromosome breakage studies to r/o fanconi anemia Parvo/EBV titers Folate and Vit B12 studies Other studies Hearing evaluation Renal ultrasound Echocardiogram Skeletal survey Ophthalmologic evaluation Cognitive evaluation

38. Treatment Observation only if mild asymptomatic anemia PRBC transfusions as needed Steroids Bone marrow transplantation for pts with severe anemia

39. Distinguishing DBA VS TEC

40. DBA vs TEC

41. Our pt • Developed frequent symptomatic anemia • Several PRBCs transfusion • Sister found to be good HLA match • Moderate response to prednisone • Parents and pts desiring definitive treatment • MSBMT performed this Spring

42. References • Cross, Hannaman. Hematology. Pediatric Board Review. Med Study 2008-2009. • Oski, F. Transient Erythroblastopenia. Pediatrics in Review. 1982. Volume 4. pages 25-27. • Prassouli, A., et al. Classic Transient Erythroblastopenia of Childhood with Human Parvovirus B19 Genome Detection in the Blood and Bone Marrow. J PediatrHematolOncol. 2005. Volume 27. Number 6. pages 333-336. • Segel, G. et al. Managing Anemia in a Pediatric Office Practice: Parts 1 and 2. Pediatrics In Review. 2002. Volume 23. Numbers 3 and 4. pages 75-84; 111-122. • Shaw, J and Meeder, R. Transient Erythroblastopenia of Childhood in Siblings: Case Report and Review of the Literature. J. Pediatric HematolOncol. 2007. Volume 29. Number 9. pages 659-660. • Silverstein, S. Laughing your way to passing the pediatric boards. 4th edition. Pages • Skeppner, G, Kreuger, A, Elinder, G. Transient Erythroblastopenia of Childhood: Prospective Study of 10 Patients with Special Reference to Viral Infections. J of PediatrHematolOncol. 2002. Volume 24. Number 4. pages 294-298. • Watts, R. Anemia and Differentials. Verbal Discussion. University of Alabama. October 2009. • Nathan and Oskis: Hematoloy of Infancy and Childhood; sixth edition; Saunders 2003 • ASPHO image bank