医学骨髓衰竭综合征培训课件.ppt

1、骨髓衰竭综合征骨髓衰竭综合征 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)Lo

2、ok at blood smear R/o circulating blasts Do a bone marrow AspirateCell typesCytogenetics BiopsyCellularity Acquired aplastic anemia Inherited bone marrow failure syndrome Hypocellular Myelodysplastic Syndrome Aleukemic leukemia Marrow lymphoma Primary marrow disease Leukemia Myelodysplastic syndrome

3、 Paroxysmal nocturnal hemoglobinuria Systemic disease Lupus Hypersplenism Infection,e.g.brucellosis,sarcoidosis,tuberculosisNormalAplastic Anemia fatigue,lassitude,dyspnea Thrombocytopenia bruises,petechiae serious bleeding Neutropenia infections Severe 2 of the following 3:neutrophils 500/mL,platel

4、ets 20,000/mL,reticulocytes 20,000/mL BM cellularity 25%with 30%hematopoietic cells Very severe Neutrophils 13 genesAdapted from Joenje,2006D1=BRCA2*J and N interact with BRCA1 and BRCA2GroupLocuscDNAExonsAA%A16q24.35.543145570BXp22.312.810859RareC9q22.34.61455810D1/BRCA213q12.311.4273418RareD23p25.

5、35441451RareE6p21-222.5105365F11p151.31374RareG/XRCC99p132.51462210I/KIAA179415q25-264.5381328RareJ/BACH1/BRIP117q22.34.6201249RareL/PHF9/POG2p15-16.11.714375RareM/Hef14q21.36.5222014RareN/PALB216p12.13.5131186RareBRIP1 is“BRCA1 interacting protein”;PALB2 is“partner and localizer of BRCA2”BD2DNA Rep

6、airDNA DamageCEFIGMLAPCNANBS1RAD51J/BACH1BRCA1D2D1/BRCA2D2N/PALB2 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 Blood chromosome breakag

7、e(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 sequencingShimamura et al,Blood,2002LIJ(BRIP1)BMRetrovirus-mediated Correction of TA 0252s T-cells analyzed by flow cytometry after fi

8、ve days of MMC-Incubation0204060801001101001000c(MMC)nMcells alive%S11EGSFAS11FCIEGS11FEIEG2S11FFIEGS11FGFANCAAplastic AnemiaAcute LeukemiaMyelodysplastic SyndromeSolid TumorsLiver tumorsAdapted fromKutler et al,Blood,200380%by age 15,90%overallAMLLiverHNSCCBrainVulvaWilmsALLEsophagusFA CohortsParam

9、eterNASGEFAISFARNCINumber of Patients145182Person-Years20002818All Cancers52x44xAll Solid Tumors51x26xOral Cavity/Pharynx706x240 xVulvar4317x2411xAML785x868xMDS8559x4559xNorth American Survey;German FA Registry;Israeli FA Registry;National Cancer InstituteRosenberg,Huang,Alter,Blood 2004Phenotype pr

10、edicts age and incidence of marrow failure and solid tumors.Normal PhenotypeAbnormal PhenotypeAbnormal phenotype=radii,plus abnormal development,heart or lung,kidney,hearing,and head.Competing risk analyses.BMTNo BMTDATA:Transplant increased cancer by 4.4-fold;Shifted median age to 16 years younger;

11、All cancer patients had graft vs host disease.ParisRosenberg,Socie,Gluckman,Alter:Blood,2005;Biol Blood&Marrow Transpl,2005LESSON:Improve transplant preparation to reduce graft vs host disease.USA Tongue SCC age 30 Skin SCCs age 33 Short,80 lbs,hearing aids,menopause age 30 XRT side effects Normal b

12、lood counts PB chromosomes no breaks;skin breaksExon 8:790 C T;Q264X;Gln264StopExon 27:2585delCT;Frameshift,Cys846fsX20SkinGene conversion,loss of exon 27 frameshift 2585delCTBloodSomatic Mosaicism,FANCAAlter,Joenje,Oostra,Pals,Arch Otolaryngol,2005aAAaaAAaaAAaPhotos with parental andpatient consent

13、General PopulationFAFA vs GenlFA-D1FA-D1 vs FAFA-D1 vs GenlVATER2.6/1065/10019,0005/273.771,000AML1/1059/14580010/278.97,000Any Cancer10/10523/1455025/27663300FANCD1/BRCA2 is associated with extremely high incidences of VACTERL-H association,AML,and specific Solid Tumors(Wilms,medulloblastoma).Alter

14、,Brody,Rosenberg:J Med Genet 2007Alter:Br J Haematol,2006Alter,Brody,Rosenberg:J Med Genet,20070.000.250.500.751.00Probability051015202530Age in YearsA:Leukemia78%by age 10(AML,ALL)0.000.250.500.751.00Probability051015202530Age in YearsC:Probability of AML+/-IVS7 MutationHR 7.7(CI 2-29),p=0.0030.000

15、.250.500.751.00Probability051015202530Age in YearsB:Solid Tumor83%by age 7(Wilms,Medulloblastoma)0.000.250.500.751.00Probability051015202530Age in YearsC:Any Cancer97%by age 6MutationsUniformity1Cluster2MissenseNo,p=0.01Yes,p=0.001DeleteriousYes,p=0.6No,p=0.3What is the risk of cancer in carriers of

16、 these missense mutations?1Chi square of expected frequency across the gene.2Permutation test of range between the extremes.Alter,Brody,Rosenberg:J Med Genet,2007Why do patients with biallelic deleterious/deleterious or deleterious/missense mutations in BRCA2 both develop FA and cancer?Cytopenias Hb

17、 8 g/dL or symptoms Platelets 30,000/mm3 WBC 20%blasts in marrow Solid tumors or liver tumors When detectedFA:Guidelines for Diagnosis and Management,2008 Hematologic disease(benign or malignant)Stem cell transplant Androgens Hematopoietic growth factors(G-CSF,Ep)Chemotherapy Folic acid Blood produc

18、ts: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.cetuximabFA:Guidelines for Diagnosis and Management,2008 Hematopoiesis AA,MDS,aML Blood counts every 3-4 months Bone

19、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 16 year old male Seen by family doctor becau

20、se 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)Diagnosis:Fanconi Anemia,newly diagnosed in an adolescent2 yo

21、,HH1.5 yo,HH6 yo,TINF210 yo,TINF222 yo,DKC148 and 16 yo,TERC27 yo,TINF224 yo,TINF2 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 Hype

22、rhidrosis 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 an

23、d shelterin pathways:DKC1(XLR)TERC(AD)TERT(AD,AR)TINF2(AD)NOLA2(AR)NOLA3(AR)Others(50%)Hematologic Bone marrow failure Myelodysplastic syndrome Leukemia Solid tumors Head and neck Anogenital Pulmonary fibrosisHNSCCRectalStomach The aglet Long TTAGGG repeats Shorten with each cell division Many prote

24、ins interact to regulate telomere length and stabilize structure Lack of telomere maintenance leads to erosion of chromosome ends,genomic instability,cell crisis and cell deathFISH:telomeresCourtesy of Peter LansdorpArmanios,Annu Rev Genomics Hum Genet,2009Kirwan and Dokal,BBA,2009Alter,Baerlocher,S

25、avage,Lansdorp:Blood,2007Almost 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.Ethics:Denny et al:AJMG,2008Gene discovery:Savage et al:AJHG,2008Lys 280 GluSavage et al:AJHG,2008Par

26、ameterFADCNumberPerson-YearsAll CancersAll Solid TumorsTongueAMLMDS 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 fib

27、rosis Hepatic fibrosis,cirrhosis Telomere length assay:diagnosis of patients,silent carriers;surveillance and genetic counseling Normochromic,usually macrocytic anemia,developing in infancy Reticulocytopenia Marrow erythroblastopenia Normal or slightly decreased leukocytes Normal or increased platel

28、ets Increased fetal hemoglobin(Hb F)Increased red cell adenosine deaminase(ADA)25%with physical findings:short,abnormal thumbs,etcFindingNumber%Any abnormality including short stature22425Any abnormality other than short stature15321Short stature only354Thumb anomaly576Triphalangeal thumb243Cleft pa

29、late243Denominator=900,but no data in many reports.Autosomal dominant 25%RPS19 2%RPS24 1%RPS17 40s ribosome biogenesis Haploinsufficiency 7%RPL5 5%RPL11 2%RPL35a30 cancers in 30/899 patients;3 MDS not included Monitor blood counts Annual bone marrows(no consensus)Treat when Hb 8 g/dL,or symptoms Cor

30、ticosteroids Transfuse during first year and puberty(no consensus)Cyclosporin A(rare)Metoclopramide(rare)Exocrine pancreatic insufficiency Decreased trypsinogen and isoamylase(age-dependent)Pancreas small or fatty on imaging Bone marrow failure Neutropenia:1500/mL Anemia:Macrocytosis Thrombocytopeni

31、a Myelodysplastic syndrome/acute leukemia Bones Metaphyseal dysostosis Autosomal recessive SBDS=Shwachman-Bodian-Diamond Syndrome 60s ribosome biogenesis36 leukemias in 36/510 patientsAMLALL Similar to Fanconi Anemia G-CSF-neutropenia Stem cell transplant-cardiotoxicity from cyclophosphamide?Feature

32、s unique to SDS:Malabsorption-pancreatic enzymes,ADEK Metaphyseal dysostosis-surgery as needed Cytogenetic clones-monitor No physical phenotype ANC 500/mL Pyogenic infections Rx G-CSF Autosomal dominant ELA2 GFI1 Autosomal recessive(Kostmann Syndrome)HAX1 X-linked recessive WAS(Rosenberg,Alter,.Dale

33、:Blood,2006)High Dose,Poor ANCLow Dose,Good ANCYears on G-CSFYears on G-CSFPoor 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

34、 since.Does G-CSF cause leukemia?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 Neonatal thrombocytopenia Absent radii,thumbs present Meg

35、akaryocytes absent,reduced,hypoplastic,immature 4 cases of leukemia 2 mo;1,5,41 yrs No gene identified Microdeletion 200 kb at 1q21.1;digenicInherited BMFSAcquired AASupport(txs,abx)Yes,not familyYesImmunosuppressionNoYesAndrogensYesNoG-CSF,EpoYesAdjunctClonal evolutionMDS,AMLMDS,AML,PNHStem cell tr

36、ansplantYesYesSolid tumorsYes,inc p-BMTp-BMT 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