1. Marrow Failure Kathryn Scharbach 2005

2. Marrow failure syndromes & diseases Multilineage Failure Fanconi anemia Fanconi anemia dyskeratosis congenita dyskeratosis congenita Pearson syndrome Pearson syndrome Failure of a Single Lineage Diamond-Blackfan anemia Diamond-Blackfan anemia Shwachman-Diamond syndrome Shwachman-Diamond syndrome Kostman disease Kostman disease cyclic neutropenia cyclic neutropenia

3. Fanconi anemia Hematologic/Oncologic features progressive bone marrow failure progressive bone marrow failure –affects platelets first –followed by loss of other lineages increased risk of malignancy (>15%) increased risk of malignancy (>15%) –AML, myelodysplasia –gastrointestinal, gynecological, liver

4. Fanconi anemia Constitutional features radial & thumb defects radial & thumb defects short stature short stature genito-urinary abnormalities genito-urinary abnormalities abnormal skin pigmentation abnormal skin pigmentation –café au lait spots –hyperpigmentation micro-ophthalmia micro-ophthalmia microcephaly microcephaly

5. Fanconi anemia Clinical presentation & course majority of patients initially present between 4 and 14 years of age majority of patients initially present between 4 and 14 years of age –younger → characteristic physical findings or positive family history –10% diagnosed after 16 years of age principal presentation is hematopoietic failure principal presentation is hematopoietic failure highly variable clinical course highly variable clinical course

6. Fanconi anemia Diagnosis increased number of chromosomal breaks in blood lymphocytes cultured in presence of diepoxybutane (DEB) or mitomycin C (MMC) increased number of chromosomal breaks in blood lymphocytes cultured in presence of diepoxybutane (DEB) or mitomycin C (MMC)

7. Fanconi anemia Treatment supportive supportive androgenic steroids androgenic steroids cytokine treatment cytokine treatment –G-CSF, GM-CSF –erythropoietin bone marrow transplantation bone marrow transplantation gene therapy gene therapy ProgressionProgression

8. Dyskeratosis congenita Hematologic/Oncologic features progressive bone marrow failure progressive bone marrow failure increased risk of malignancy increased risk of malignancy –AML –myelodysplasia –epithelial malignancies

9. Dyskeratosis congenita Constitutional features reticulate skin pigmentation reticulate skin pigmentation nail dystrophy nail dystrophy mucosal leukoplakia mucosal leukoplakia epiphora epiphora developmental delay & short stature developmental delay & short stature pulmonary disease pulmonary disease esophageal webs esophageal webs dental caries & tooth loss dental caries & tooth loss premature grey hair & hair loss premature grey hair & hair loss

10. Dyskeratosis congenita

11. Pearson’s syndrome refractory sideroblastic anemia refractory sideroblastic anemia exocrine pancreatic deficiency exocrine pancreatic deficiency variably includes: variably includes: –Kearns-Sayre syndrome – ophthalmoplegia, pigmentary retinopathy, ataxia & heart block –metabolic acidosis –renal tubular acidosis –diabetes mellitus

12. Diamond-Blackfan anemia usually presents early in infancy usually presents early in infancy rare congenital hypoplastic anemia rare congenital hypoplastic anemia –moderate-severe macrocytic anemia –occasional neutropenia &/or thrombocytosis –normocellular BM with erythroid hypoplasia 25-47% of patients have associated congenital anomalies 25-47% of patients have associated congenital anomalies 75% respond to prednisone 75% respond to prednisone

13. Shwachman-Diamond syndrome neutropenia neutropenia exocrine pancreatic insufficiency exocrine pancreatic insufficiency metaphyseal dysostosis metaphyseal dysostosis increased risk of MDS & AML increased risk of MDS & AML treatment treatment –supportive care –pancreatic enzyme replacement –G-CSF for severe neutropenia –matched sibling stem cell transplantation

14. Kostmann syndrome severe congenital neutropenia severe congenital neutropenia –neutrophil count <200 –increase in eosinophils &/or eosinophils –bone marrow normal erythroid & platelet precursors normal erythroid & platelet precursors absence or marked decrease in myeloid cells absence or marked decrease in myeloid cells frequent bacterial infections frequent bacterial infections increased risk of MDS & AML increased risk of MDS & AML

15. Cyclic neutropenia oscillation of circulating blood counts (21 day periodicity) oscillation of circulating blood counts (21 day periodicity) –neutrophils oscillate between 0 and near normal levels –monocytes cycle out of phase with neutrophils cycling may occur in other lineages cycling may occur in other lineages vulnerable to opportunistic infections during neutropenic phase vulnerable to opportunistic infections during neutropenic phase