骨髓衰竭综合征.ppt

Click to edit Master title style,Click to edit Master text styles,Second Level,Third Level,Fourth Level,Fifth Level,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,*,*,骨髓衰竭综合征,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/,m,L,WBC 2000/,m,L(20%neutrophils),Next Step,Look at blood smear,R/o circulating blasts,Do a bone marrow,Aspirate,Cell types,Cytogenetics,Biopsy,Cellularity,Pancytopenia with Hypocellular Marrow,Acquired aplastic anemia,Inherited bone marrow failure syndrome,Hypocellular Myelodysplastic Syndrome,Aleukemic leukemia,Marrow lymphoma,Pancytopenia with Cellular Marrow,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,Neutropenia,infections,Severity of Aplastic Anemia,Severe,2 of the following 3:neutrophils 500/,m,L,platelets 20,000/,m,L,reticulocytes 20,000/,m,L,BM cellularity 25%with 30%hematopoietic cells,Very severe,Neutrophils 13 genes,FANC Genes,Adapted from Joenje,2006,D1=,BRCA2,*,J and N interact with BRCA1 and BRCA2,FA Complementation Groups/Genes,Group,Locus,cDNA,Exons,AA,%,A,16q24.3,5.5,43,1455,70,B,Xp22.31,2.8,10,859,Rare,C,9q22.3,4.6,14,558,10,D1/BRCA2,13q12.3,11.4,27,3418,Rare,D2,3p25.3,5,44,1451,Rare,E,6p21-22,2.5,10,536,5,F,11p15,1.3,1,374,Rare,G/XRCC9,9p13,2.5,14,622,10,I,/,KIAA1794,15q25-26,4.5,38,1328,Rare,J/BACH1/BRIP1,17q22.3,4.6,20,1249,Rare,L/PHF9/POG,2p15-16.1,1.7,14,375,Rare,M/Hef,14q21.3,6.5,22,2014,Rare,N/PALB2,16p12.1,3.5,13,1186,Rare,BRIP1,is“BRCA1 interacting protein”;,PALB2,is“partner and localizer of,BRCA2,”,FA DNA Repair Pathway,B,D2,DNA Repair,DNA Damage,C,E,F,I,G,M,L,A,PCNA,NBS1,RAD51,J/BACH1,BRCA1,D2,Ub,D1/BRCA2,D2,Ub,N/PALB2,Who Should be Tested for FA?,Characteristic birth defects(eg thumbs,kidneys,poor growth,etc),Aplastic Anemia(AA),Myelodysplastic Syndrome(MDS),Acute Myeloid Leukemia(AML),Decreased fertility,Early characteristic cancer,Siblings of FA patients,What are the Tests for FA?,Blood chromosome breakage(DEB or MMC),Skin fibroblast chromosome breakage,Flow cytometry for G2 arrest,Western blot for ubiquitinated D2,Retroviral FA gene correction of FA phenotype,FA gene sequencing,D2 Ubiquitination,Shimamura et al,Blood,2002,L,I,J(BRIP1,),B,M,Retrovirus-mediated Correction of TA 0252s T-cells analyzed by flow cytometry after five days of MMC-Incubation,0,20,40,60,80,100,1,10,100,1000,c(MMC)nM,cells alive%,S11EG,SFA,S11FCIEG,S11FEIEG2,S11FFIEG,S11FG,FANCA,Retrovirus-mediated Correction of FA Cells,FA Complications,Aplastic Anemia,Acute Leukemia,Myelodysplastic Syndrome,Solid Tumors,Liver tumors,FA Aplastic Anemia,Adapted from,Kutler et al,Blood,2003,80%by age 15,90%overall,FA Literature:Cancer 1927-2007,179 solid tumors and 163 leukemias in 330/1865 patients;29 had 2-4 cancers,AML,Liver,HNSCC,Brain,Vulva,Wilms,ALL,Esophagus,Shifted median age to 16 years younger;,All Solid Tumors,New modalities,e.,Blood 2006;108:2509-2519,Infection,e.,Literature:Physical Findings,IBMFS:Adults and Older Children,*J and N interact with BRCA1 and BRCA2,FA chromosome breakage,Sequence candidate genes,patient consent,Clonal evolution,Improve transplant preparation to reduce graft vs host disease.,Dale:Blood,2006),Acquired aplastic anemia,Risk of Cancer in FA by O/E Ratio,FA Cohorts,Parameter,NAS,GEFA,ISFAR,NCI,Number of Patients,145,182,Person-Years,2000,2818,All Cancers,52x,44x,All Solid Tumors,51x,26x,Oral Cavity/Pharynx,706x,240 x,Vulvar,4317x,2411x,AML,785x,868x,MDS,8559x,4559x,North American Survey;,German FA Registry;,Israeli FA Registry;,National Cancer Institute,NCI FA Cumulative Incidence and Cause-specific Hazards,Competing Risks of Cancer,Fanconi Anemia:Phenotype/Outcome,Rosenberg,Huang,Alter,Blood 2004,Phenotype predicts age and incidence of marrow failure and solid tumors.,Normal Phenotype,Abnormal Phenotype,Abnormal phenotype=radii,plus abnormal development,heart or lung,kidney,hearing,and head.Competing risk analyses.,Transplant and Head and Neck Cancer in Fanconi Anemia,BMT,No BMT,DATA,:,Transplant increased,cancer by,;,Shifted median age to,16 years,younger;,All cancer patients had graft vs host disease.,Paris,Rosenberg,Socie,Gluckman,Alter:Blood,2005;Biol Blood&Marrow Transpl,2005,LESSON,:,Improve transplant preparation to reduce graft vs host disease.,USA,Diagnosis of FA after Cancer,Tongue SCC age 30,Skin SCCs age 33,Short,80 lbs,hearing aids,menopause age 30,XRT side effects,Normal blood counts,PB chromosomes no breaks;skin breaks,Exon 8:790 C T;Q264X;Gln264Stop,Exon 27:2585delCT;Frameshift,Cys846fsX20,Skin,Gene conversion,loss of exon 27 frameshift 2585delCT,Blood,Somatic Mosaicism,FANCA,Alter,Joenje,Oostra,Pals,Arch Otolaryngol,2005,Hematopoietic Mosaicism,Mosaicism from Recombination,a,A,A,a,a,A,A,a,a,A,A,a,FANCD1/BRCA2,Proband;Adult,FANCA,Photos with,parental and,patient consent,Odds Ratios for Complications in FA and,FANCD1,/,BRCA2,General Population,FA,FA vs Genl,FA-D1,FA-D1 vs FA,FA-D1 vs Genl,VATER,2.6/10,6,5/100,19,000,5/27,3.7,71,000,AML,1/10,5,9/145,800,10/27,8.9,7,000,Any Cancer,10/10,5,23/145,50,25/27,66,3300,FANCD1/BRCA2,is associated with extremely high incidences of VACTERL-H association,AML,and specific Solid Tumors(Wilms,medulloblastoma).,Alter,Brody,Rosenberg:J Med Genet 2007,Genotype/Phenotype/Outcome:27 FA with Biallelic Mutations in,BRCA2,Alter:Br J Haematol,2006,Alter,Brody,Rosenberg:J Med Genet,2007,78%by age 10,(AML,ALL),HR 7.7(CI 2-29),p=0.003,83%by age 7,(Wilms,Medulloblastoma),97%by age 6,FANCD1/BRCA2,Mutations,Mutations,Uniformity,1,Cluster,2,Missense,No,p=0.01,Yes,p=0.001,Deleterious,Yes,p=0.6,No,p=0.3,What is the risk of cancer in carriers of these missense mutations?,1,Chi square of expected frequency across the gene.,2,Permutation test of range between the extremes.,Alter,Brody,Rosenberg:J Med Genet,2007,Why do patients with biallelic deleterious/deleterious or deleterious/missense mutations in,BRCA2,both develop FA and cancer?,FA:When to Treat,Cytopenias,Hb 8 g/dL or symptoms,Platelets 30,000/mm,3,WBC 20%blasts in marrow,Solid tumors or liver tumors,When detected,FA:Guidelines for Diagnosis and Management,FA:How to Treat,Hematologic disease(benign or malignant),Stem cell transplant,Androgens,Hematopoietic growth factors(G-CSF,Ep),Chemotherapy,Folic acid,Blood products:not family;leukodeplete;irradiate,Gene therapy?,Liver tumors,Stop androgens,Solid tumors,Conservative/focused radiation,Chemotherapy that does not cross-link DNA,New modalities,e.g.cetuximab,FA:Guidelines for Diagnosis and Management,FA Surveillance:Cancer,Hematopoiesis AA,MDS,aML,Blood counts every 3-4 months,Bone marrow aspirate,biopsy,cytogenetics annually,Oral cavity and pharynx-role of HPV vaccine?,Age 10 years,BMT 1 year,Gynecologic-role of HPV vaccine?,Age 16 years,Menarche,Liver,Liver enzymes every 3-4 months,Liver ultrasound every 6-12 months,Skin,Annual exam,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/,m,L,WBC 2000/,m,L(20%neutrophils),Diagnosis:Fanconi Anemia,newly diagnosed in an adolescent,Dyskeratosis Congenita,Dyskeratosis Congenita-Kids,2 yo,HH,1.5 yo,HH,6 yo,TINF2,10 yo,TINF2,Dyskeratosis Congenita-Adults,22 yo,DKC1,48 and 16 yo,TERC,27 yo,TINF2,24 yo,TINF2,Physical Findings in DC,Dystrophic nails*,Lacey pigmentation*,Leukoplakia*,Epiphora,blepharitis,Developmental delay,Pulmonary disease,Short stature,Dental caries,Liver disease,Esophageal stricture,Early grey hair,hair loss,sparse eyelashes,Hyperhidrosis,Cerebellar hypoplasia,Hypogonadism,Microcephaly,Urethral stricture,Osteoporosis,avascular necrosis,*,Diagnostic Triad(need 2/3),.Or,1 of the triad,+hypoplastic bone marrow,+2 of the other findings.,X-linked recessive(XLR),Autosomal dominant(AD),Autosomal recessive(AR),Mutations in telomerase and shelterin pathways:,DKC1,(XLR),TERC,(AD),TERT,(AD,AR),TINF2,(AD),DC Inheritance,NOLA2,(AR),NOLA3,(AR),Others(50%),Major Complications in DC,Hematologic,Bone marrow failure,Myelodysplastic syndrome,Leukemia,Solid tumors,Head and neck,Anogenital,Pulmonary fibrosis,44 cancers in 36/425 patients,DC Literature:Cancer 1910-2007,HNSCC,Rectal,Stomach,What is the End of the Shoelace?,The aglet,Telomeres and Chromosomal Instability,Long TTAGGG repeats,Shorten with each cell division,Many proteins interact to regulate telomere length and stabilize structure,Lack of telomere maintenance leads to erosion of chromosome ends,genomic instability,cell crisis and cell death,FISH:telomeres,Courtesy of Peter Lansdorp,Telomere Biology Pathway,Armanios,Annu Rev Genomics Hum Genet,Kirwan and Dokal,BBA,Laboratory,Diagnostic Test:Telomere Length by flow-FISH,Alter,Baerlocher,Savage,Lansdorp:Blood,2007,Almost all patients with DC have very short telomeres in blood cells,including 3 silent carriers and 6 lacking the triad.,Most patients with other IBMFS have normal telomeres.,Telomere Length in Multiplex Family,Ethics:Denny et al:AJMG,Gene discovery:Savage et al:AJHG,TINF2,is Mutated in DC,Arg 282 Ser,Lys 280 Glu,Arg 282 His,Hoyeraal-Hreidarsson Syndrome,Revesz Syndrome,Savage et al:AJHG,NCI IBMFS Cohort:Relative Risk of Cancer(O/E Ratio),Parameter,FA,DC,Number,Person-Years,All Cancers,All Solid Tumors,Tongue,AML,MDS,NCI DC,Compared with All FA,DC Surveillance and Treatment,Similar to Fanconi Anemia,Role of HPV vaccine?,Stem cell transplant complicated by pulmonary disease,No role for immunosuppression,Features unique to DC:,Androgen sensitive,Splenic peliosis and rupture on androgens+G-CSF,Pulmonary fibrosis,Hepatic fibrosis,cirrhosis,Telomere length assay:diagnosis of patients,silent carriers;surveillance and genetic counseling,Diamond-Blackfan Anemia,Diamond-Blackfan Anemia,Normochromic,usually macrocytic anemia,developing in infancy,Reticulocytopenia,Marrow erythroblastopenia,Normal or slightly decreased leukocytes,Normal or increased platelets,Increased fetal hemoglobin(Hb F),Increased red cell adenosine deaminase(ADA),25%with physical findings:short,abnormal thumbs,etc,DBA Literature :Physical Findings,Finding,Number,%,Any abnormality including short stature,224,25,Any abnormality other than short stature,153,21,Short stature only,35,4,Thumb anomaly,57,6,Triphalangeal thumb,24,3,Cleft palate,24,3,Denominator=900,but no data in many reports.,DBA Inheritance,Autosomal dominant,25%,RPS19,2%,RPS24,1%,RPS17,40s ribosome biogenesis,Haploinsufficiency,7%,RPL5,5%,RPL11,2%,RPL35a,30 cancers in 30/899 patients;3 MDS not included,DBA Literature:Cancer 1936-,DBA Surveillance and Treatment,Monitor blood counts,Annual bone marrows(no consensus),Treat when Hb 8 g/dL,or symptoms,Corticosteroids,Transfuse during first year and puberty(no consensus),Cyclosporin A(rare),Metoclopramide(rare),Shwachman-Diamond Syndrome,Exocrine pancreatic insufficiency,Decreased trypsinogen and isoamylase(age-dependent),Pancreas small or fatty on imaging,Bone marrow failure,Neutropenia:1500/,m,L,Anemia:Macrocytosis,Thrombocytopenia,Myelodysplastic syndrome/acute leukemia,Bones,Metaphyseal dysostosis,Autosomal recessive,SBDS,=Shwachman-Bodian-Diamond Syndrome,60s ribosome biogenesis,SDS Literature:Leukemia 1949-2007,36 leukemias in 36/510 patients,AML,ALL,SDS Surveillance and Treatment,Similar to Fanconi Anemia,G-CSF-neutropenia,Stem cell transplant-cardiotoxicity from cyclophosphamide?,Features unique to SDS:,Malabsorption-pancreatic enzymes,ADEK,Metaphyseal dysostosis-surgery as needed,Cytogenetic clones-monitor,Severe Congenital Neutropenia,No physical phenotype,ANC 500/,m,L,Pyogenic infections,Rx G-CSF,Autosomal dominant,ELA2,GFI1,Autosomal recessive(Kostmann Syndrome),HAX1,X-linked recessive,WAS,SCN and Leukemia,(Rosenberg,Alter,.Dale:Blood,2006),High Dose,Poor ANC,Low Dose,Good ANC,Years on G-CSF,Years on G-CSF,Poor responders to G-CSF have a higher risk of leukemia.,These may have a more severely abnormal stem cell.,Early bone marrow transplantation should be considered for the poor responders.,3 cases of AML prior to the G-CSF era;44 since.,Does G-CSF cause leukemia?,Amegakaryocytic Thrombocytopenia,Neonatal thrombocytopenia,Decreased megakaryocytes,No anomalies,Evolution to aplastic anemia and/or leukemia,AR:1p,mpl,thrombopoietin receptor,Type I:nonsense mutations,severe,Type II:missense mutations,milder,Thrombocytopenia Absent Radii,Neonatal thrombocytopenia,Absent radii,thumbs present,Megakaryocytes absent,reduced,hypoplastic,immature,4 cases of leukemia,2 mo;1,5,41 yrs,No gene identified,Microdeletion 200 kb at 1q21.1;digenic,Treatment and Outcome,Inherited BMFS,Acquired AA,Support(txs,abx),Yes,not family,Yes,Immunosuppression,No,Yes,Androgens,Yes,No,G-CSF,Epo,Yes,Adjunct,Clonal evolution,MDS,AML,MDS,AML,PNH,Stem cell transplant,Yes,Yes,Solid tumors,Yes,inc p-BMT,p-BMT,Summary/Conclusions,Patients known to have an IBMFS have a high risk of neoplasia,Patients with atypical presentations of neoplasms may have an undiagnosed IBMFS,The molecular mechanisms depend on the IBMFS,The magnitude of these problems merits further study,FA chromosome breakage,DC telomere length,DBA red cell ADA,SD trypsinogen,isoamylase,SCN,Amega,TAR clinical diagnoses,Sequence candidate genes,Screening Tests for Suspected IBMFS,FA DNA Repair Pathway,Developmental delay,Transfusions,FA:How to Treat,Overlapping Syndromes,Reticulocytopenia,XRT side effects,Low Birth Weight,FA-D1 vs FA,Or,1 of the triad,+hypoplastic bone marrow,+2 of the other findings.,Revesz Syndrome,Acquired aplastic anemia,DC Surveillance and Treatment,Treat when Hb 8 g/dL,or symptoms,Cytogenetics,BMT donor,55,Gene conversion,loss of exon 27 frameshift 2585delCT,Dale:Blood,2006),And,Next,谢谢观看！,