Marrow Marrow FailureFailureKathryn ScharbachKathryn Scharbach

20052005

Marrow failureMarrow failuresyndromes & diseasessyndromes & diseases

Multilineage Multilineage FailureFailure

Fanconi anemiaFanconi anemia dyskeratosis dyskeratosis

congenitacongenita Pearson Pearson

syndromesyndrome

Failure of a Single Failure of a Single LineageLineage

Diamond-Blackfan Diamond-Blackfan anemiaanemia

Shwachman-Shwachman-Diamond syndromeDiamond syndrome

Kostman diseaseKostman disease cyclic neutropeniacyclic neutropenia

Fanconi anemiaFanconi anemiaHematologic/Oncologic featuresHematologic/Oncologic features

progressive bone marrow failureprogressive bone marrow failure– affects platelets firstaffects platelets first– followed by loss of other lineagesfollowed by loss of other lineages

increased risk of malignancyincreased risk of malignancy (>15%) (>15%)– AML, myelodysplasiaAML, myelodysplasia

– gastrointestinal, gynecological, livergastrointestinal, gynecological, liver

Fanconi anemiaFanconi anemiaConstitutional featuresConstitutional features

radial & thumb defectsradial & thumb defects short statureshort stature genito-urinary abnormalities genito-urinary abnormalities abnormal skin pigmentationabnormal skin pigmentation

– café au lait spotscafé au lait spots– hyperpigmentationhyperpigmentation

micro-ophthalmiamicro-ophthalmia microcephalymicrocephaly

Fanconi anemiaFanconi anemiaClinical presentation & Clinical presentation &

coursecourse majority of patients initially majority of patients initially

present between 4 and 14 years present between 4 and 14 years of ageof age– younger younger → → characteristic physical characteristic physical

findings or positive family historyfindings or positive family history– 10% diagnosed after 16 years of age10% diagnosed after 16 years of age

principal presentation is principal presentation is hematopoietic failurehematopoietic failure

highly variable clinical coursehighly variable clinical course

Fanconi anemiaFanconi anemiaDiagnosisDiagnosis

increased number of increased number of chromosomal breaks in blood chromosomal breaks in blood lymphocytes cultured in presence lymphocytes cultured in presence of diepoxybutane (DEB) or of diepoxybutane (DEB) or mitomycin C (MMC)mitomycin C (MMC)

Fanconi anemiaFanconi anemiaTreatment Treatment

supportive supportive androgenic steroidsandrogenic steroids cytokine treatmentcytokine treatment

– G-CSF, GM-CSFG-CSF, GM-CSF– erythropoietinerythropoietin

bone marrow transplantationbone marrow transplantation gene therapygene therapy

Progression

Dyskeratosis Dyskeratosis congenitacongenita

Hematologic/Oncologic Hematologic/Oncologic featuresfeatures progressive bone marrow failureprogressive bone marrow failure

increased risk of malignancyincreased risk of malignancy– AML AML – myelodysplasiamyelodysplasia– epithelial malignanciesepithelial malignancies

Dyskeratosis Dyskeratosis congenitacongenita

Constitutional featuresConstitutional features reticulate skin pigmentationreticulate skin pigmentation nail dystrophynail dystrophy mucosal leukoplakiamucosal leukoplakia epiphoraepiphora developmental delay & short staturedevelopmental delay & short stature pulmonary diseasepulmonary disease esophageal websesophageal webs dental caries & tooth lossdental caries & tooth loss premature grey hair & hair losspremature grey hair & hair loss

Dyskeratosis Dyskeratosis congenitacongenita

Pearson’s syndromePearson’s syndrome

refractory sideroblastic anemiarefractory sideroblastic anemia exocrine pancreatic deficiencyexocrine pancreatic deficiency variably includes:variably includes:

– Kearns-Sayre syndrome Kearns-Sayre syndrome – – ophthalmoplegia, pigmentary retinopathy, ophthalmoplegia, pigmentary retinopathy, ataxia & heart blockataxia & heart block

– metabolic acidosismetabolic acidosis– renal tubular acidosisrenal tubular acidosis– diabetes mellitusdiabetes mellitus

Diamond-Blackfan Diamond-Blackfan anemiaanemia

usually presents early in infancyusually presents early in infancy rare congenital hypoplastic anemiarare congenital hypoplastic anemia

– moderate-severe macrocytic anemiamoderate-severe macrocytic anemia– occasional neutropenia &/or thrombocytosisoccasional neutropenia &/or thrombocytosis– normocellular BM with erythroid hypoplasianormocellular BM with erythroid hypoplasia

25-47% of patients have associated 25-47% of patients have associated congenital anomaliescongenital anomalies

75% respond to prednisone75% respond to prednisone

Shwachman-Diamond Shwachman-Diamond syndromesyndrome

neutropenianeutropenia exocrine pancreatic insufficiencyexocrine pancreatic insufficiency metaphyseal dysostosismetaphyseal dysostosis increased risk of MDS & AMLincreased risk of MDS & AML treatmenttreatment

– supportive caresupportive care– pancreatic enzyme replacementpancreatic enzyme replacement– G-CSF for severe neutropeniaG-CSF for severe neutropenia– matched sibling stem cell transplantationmatched sibling stem cell transplantation

Kostmann syndromeKostmann syndrome

severe congenital neutropeniasevere congenital neutropenia– neutrophil count <200neutrophil count <200– increase in eosinophils &/or eosinophilsincrease in eosinophils &/or eosinophils– bone marrowbone marrow

normal erythroid & platelet precursorsnormal erythroid & platelet precursors absence or marked decrease in myeloid absence or marked decrease in myeloid

cellscells

frequent bacterial infectionsfrequent bacterial infections increased risk of MDS & AMLincreased risk of MDS & AML

Cyclic neutropeniaCyclic neutropenia

oscillation of circulating blood counts oscillation of circulating blood counts (21 day periodicity)(21 day periodicity)– neutrophils oscillate between 0 and near neutrophils oscillate between 0 and near

normal levelsnormal levels– monocytes cycle out of phase with monocytes cycle out of phase with

neutrophilsneutrophils cycling may occur in other lineagescycling may occur in other lineages vulnerable to opportunistic infections vulnerable to opportunistic infections

during neutropenic phaseduring neutropenic phase