骨髓衰竭综合征
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Stem cell transplant ATG/CsA Cyclophosphamide Support
Transfusions Platelets ?G-CSF
OverlapC, TERT, DC TINF2
PNH
AA
Acquired
Bone Marrow Failure
Blanche P Alter, MD, MPH Clinical Genetics Branch Division of Cancer Epidemiology and Genetics Bethesda, MD
Case Presentation
16 year old male Seen by family doctor because tennis instructor noticed that he was tiring easily History of trip outside the USA 5 months earlier Noted to have pallor and a large bruise on arm (where hit by tennis ball) CBC: Hb 8.5 g/dL, platelets 40,000/mL, WBC 2000/mL (20% neutrophils)
Primary marrow disease
Leukemia Myelodysplastic syndrome Paroxysmal nocturnal hemoglobinuria
Systemic disease
Lupus Hypersplenism Infection, e.g. brucellosis, sarcoidosis, tuberculosis
Bone Marrow (BM) Biopsy
Normal Aplastic
Aplastic Anemia: Signs and Symptoms
Anemia
fatigue, lassitude, dyspnea
Thrombocytopenia
bruises, petechiae serious bleeding
Next Step
Look at blood smear
R/o circulating blasts
Do a bone marrow
Aspirate
»Cell types »Cytogenetics
Biopsy
»Cellularity
Pancytopenia with Hypocellular Marrow
Evidence for Immune Disease
Autologous recovery after immunosuppression for transplant Even syngeneic transplants require conditioning Response to immunosuppression (ATG/CsA; Cp) Oligoclonal expansion of Vb subfamilies Activated T cells
Increased frequency of HLA-DR2
Increased apoptosis
Immune Pathophysiology of Acquired Aplastic Anemia
PNH,
Inciting event (virus or drug), aberrant immune response, oligoclonal expansion of cytotoxic T cells, destroys stem cells. BMT or IST eradicate or suppress pathogenic T-cell clones. Immune response recurs, selection of PNH, MDS, or AML cells.
Acquired aplastic anemia Inherited bone marrow failure syndrome Hypocellular Myelodysplastic Syndrome Aleukemic leukemia Marrow lymphoma
Pancytopenia with Cellular Marrow
Fanconi syndrome): 1936 proteinuria, glucosuria, phosphaturia, aminoaciduria, citraturia, and proximal renal tubular acidosis
Fanconi Anemia - Children
All findings biased by under- or over-reporting!
Laboratory Findings in FA
Low blood counts (pancytopenia) Large red cells (macrocytosis) Increased fetal hemoglobin (Hb F) Chromosome breakage in lymphocytes or fibroblasts cultured with a DNA crosslinker, e.g. diepoxybutane (DEB) or mitomycin C (MMC)
AML
Other
MDS
Inherited Bone Marrow Failure Syndromes (IBMFS): Young Children
4 yo DBA 3 yo FA 2 yo SDS 1.5 yo SCN
NB TAR
10 yo DC
5 yo Amega
IBMFS: Adults and Older Children
23 FA 26 FA 16 SDS
21 DC
32 DBA
42 TAR
IBMFS: Benign Hematology Oncology
Syndrome Fanconi Anemia (FA) Dyskeratosis Congenita (DC) Diamond-Blackfan Anemia (DBA) Shwachman-Diamond Syndrome (SD) Severe Congenital Neutropenia (SCN) Amegakaryocytic Thrombocytopenia Hematology Aplastic Aplastic Pure anemia Neutropenia Neutropenia Thrombocytopenia Leukemia AML AML AML AML AML AML Solid Tumors SCC SCC Sarcomas -
Photos with permission
Fanconi Anemia: Adults
Aplastic anemia, 16 Absent radius, 0 ?, 6 Aplastic anemia, 5 Cancer, 30 BMT donor, 55
Literature: Physical Findings
Neutropenia
infections
Severity of Aplastic Anemia
Severe
2 of the following 3: neutrophils <500/mL, platelets <20,000/mL, reticulocytes <20,000/mL BM cellularity <25% with <30% hematopoietic cells
Fanconi Anemia (Fanconi
pancytopenia syndrome): 1927 - 3 brothers with pancytopenia and physical abnormalities, “perniziosiforme”
Fanconi Syndrome (renal
Thrombocytopenia Absent Radii (TAR) Thrombocytopenia
AML
-
These disorders are the major “Inherited Bone Marrow Failure Syndromes.”
History: Guido Fanconi
Fanconi Anemia - Definition
Autosomal recessive
(1 X-linked recessive gene)
Physical findings Aplastic anemia Leukemia Solid tumors Chromosome instability DNA repair defect >13 genes
Stem cell Immune
Acquired Aplastic Anemia
Radiation Drugs (cytotoxics, chloramphenicol, nonsteroidals, anticonvulsants, gold) Chemicals (benzene, insecticides, pesticides, fertilizer) Viruses (Epstein-Barr, hepatitis [non-A,B,C], human immunodeficiency) Genetic polymorphisms in detoxifying enzymes Paroxysmal nocturnal hemoglobinuria (PNH) Pregnancy Immune diseases (eosinophilic fasciitis, hypoimmunoglobulinemia, thymoma) IDIOPATHIC
Finding Low Birth Weight Short Skin hyperpigmented Skin café au lait Thumbs Radii Gonads male Gonads female Microcephaly % 52 45 31 18 32 7 26 1 22 Finding Eyes Renal Developmental delay Ears, deaf Legs, hips, feet Cardiopulmonary Gastrointestinal tract Brain/pituitary Short or skin only % 20 20 10 8 6 6 5 3 7
Copyright ©2006 American Society of Hematology. Copyright restrictions may apply.
Young, N.S. et al. Blood 2006;108:2509-2519
Treatment for Acquired Aplastic Anemia
FANC Genes
C B D1 D2 E F G I J* L M
N*
D1 = BRCA2 *J and N interact with BRCA1 and BRCA2
A
Adapted from Joenje, 2006
FA Complementation Groups/Genes
Very severe
Neutrophils <200/mL
Non-severe (moderate)
Better than severe
Nosology of Aplastic Anemia
Genetics
Acquired Inherited
Cell biology
Transfusions Platelets ?G-CSF
OverlapC, TERT, DC TINF2
PNH
AA
Acquired
Bone Marrow Failure
Blanche P Alter, MD, MPH Clinical Genetics Branch Division of Cancer Epidemiology and Genetics Bethesda, MD
Case Presentation
16 year old male Seen by family doctor because tennis instructor noticed that he was tiring easily History of trip outside the USA 5 months earlier Noted to have pallor and a large bruise on arm (where hit by tennis ball) CBC: Hb 8.5 g/dL, platelets 40,000/mL, WBC 2000/mL (20% neutrophils)
Primary marrow disease
Leukemia Myelodysplastic syndrome Paroxysmal nocturnal hemoglobinuria
Systemic disease
Lupus Hypersplenism Infection, e.g. brucellosis, sarcoidosis, tuberculosis
Bone Marrow (BM) Biopsy
Normal Aplastic
Aplastic Anemia: Signs and Symptoms
Anemia
fatigue, lassitude, dyspnea
Thrombocytopenia
bruises, petechiae serious bleeding
Next Step
Look at blood smear
R/o circulating blasts
Do a bone marrow
Aspirate
»Cell types »Cytogenetics
Biopsy
»Cellularity
Pancytopenia with Hypocellular Marrow
Evidence for Immune Disease
Autologous recovery after immunosuppression for transplant Even syngeneic transplants require conditioning Response to immunosuppression (ATG/CsA; Cp) Oligoclonal expansion of Vb subfamilies Activated T cells
Increased frequency of HLA-DR2
Increased apoptosis
Immune Pathophysiology of Acquired Aplastic Anemia
PNH,
Inciting event (virus or drug), aberrant immune response, oligoclonal expansion of cytotoxic T cells, destroys stem cells. BMT or IST eradicate or suppress pathogenic T-cell clones. Immune response recurs, selection of PNH, MDS, or AML cells.
Acquired aplastic anemia Inherited bone marrow failure syndrome Hypocellular Myelodysplastic Syndrome Aleukemic leukemia Marrow lymphoma
Pancytopenia with Cellular Marrow
Fanconi syndrome): 1936 proteinuria, glucosuria, phosphaturia, aminoaciduria, citraturia, and proximal renal tubular acidosis
Fanconi Anemia - Children
All findings biased by under- or over-reporting!
Laboratory Findings in FA
Low blood counts (pancytopenia) Large red cells (macrocytosis) Increased fetal hemoglobin (Hb F) Chromosome breakage in lymphocytes or fibroblasts cultured with a DNA crosslinker, e.g. diepoxybutane (DEB) or mitomycin C (MMC)
AML
Other
MDS
Inherited Bone Marrow Failure Syndromes (IBMFS): Young Children
4 yo DBA 3 yo FA 2 yo SDS 1.5 yo SCN
NB TAR
10 yo DC
5 yo Amega
IBMFS: Adults and Older Children
23 FA 26 FA 16 SDS
21 DC
32 DBA
42 TAR
IBMFS: Benign Hematology Oncology
Syndrome Fanconi Anemia (FA) Dyskeratosis Congenita (DC) Diamond-Blackfan Anemia (DBA) Shwachman-Diamond Syndrome (SD) Severe Congenital Neutropenia (SCN) Amegakaryocytic Thrombocytopenia Hematology Aplastic Aplastic Pure anemia Neutropenia Neutropenia Thrombocytopenia Leukemia AML AML AML AML AML AML Solid Tumors SCC SCC Sarcomas -
Photos with permission
Fanconi Anemia: Adults
Aplastic anemia, 16 Absent radius, 0 ?, 6 Aplastic anemia, 5 Cancer, 30 BMT donor, 55
Literature: Physical Findings
Neutropenia
infections
Severity of Aplastic Anemia
Severe
2 of the following 3: neutrophils <500/mL, platelets <20,000/mL, reticulocytes <20,000/mL BM cellularity <25% with <30% hematopoietic cells
Fanconi Anemia (Fanconi
pancytopenia syndrome): 1927 - 3 brothers with pancytopenia and physical abnormalities, “perniziosiforme”
Fanconi Syndrome (renal
Thrombocytopenia Absent Radii (TAR) Thrombocytopenia
AML
-
These disorders are the major “Inherited Bone Marrow Failure Syndromes.”
History: Guido Fanconi
Fanconi Anemia - Definition
Autosomal recessive
(1 X-linked recessive gene)
Physical findings Aplastic anemia Leukemia Solid tumors Chromosome instability DNA repair defect >13 genes
Stem cell Immune
Acquired Aplastic Anemia
Radiation Drugs (cytotoxics, chloramphenicol, nonsteroidals, anticonvulsants, gold) Chemicals (benzene, insecticides, pesticides, fertilizer) Viruses (Epstein-Barr, hepatitis [non-A,B,C], human immunodeficiency) Genetic polymorphisms in detoxifying enzymes Paroxysmal nocturnal hemoglobinuria (PNH) Pregnancy Immune diseases (eosinophilic fasciitis, hypoimmunoglobulinemia, thymoma) IDIOPATHIC
Finding Low Birth Weight Short Skin hyperpigmented Skin café au lait Thumbs Radii Gonads male Gonads female Microcephaly % 52 45 31 18 32 7 26 1 22 Finding Eyes Renal Developmental delay Ears, deaf Legs, hips, feet Cardiopulmonary Gastrointestinal tract Brain/pituitary Short or skin only % 20 20 10 8 6 6 5 3 7
Copyright ©2006 American Society of Hematology. Copyright restrictions may apply.
Young, N.S. et al. Blood 2006;108:2509-2519
Treatment for Acquired Aplastic Anemia
FANC Genes
C B D1 D2 E F G I J* L M
N*
D1 = BRCA2 *J and N interact with BRCA1 and BRCA2
A
Adapted from Joenje, 2006
FA Complementation Groups/Genes
Very severe
Neutrophils <200/mL
Non-severe (moderate)
Better than severe
Nosology of Aplastic Anemia
Genetics
Acquired Inherited
Cell biology