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
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