骨髓衰竭综合征PPT

1、关于骨髓衰竭综合征第一张，PPT共八十三页，创作于2022年6月Case Presentation16 year old maleSeen by family doctor because tennis instructor noticed that he was tiring easilyHistory of trip outside the USA 5 months earlierNoted to have pallor and a large bruise on arm (where hit by tennis ball)CBC: Hb 8.5 g/dL, platelets 40,00

2、0/mL, WBC 2000/mL (20% neutrophils)第二张，PPT共八十三页，创作于2022年6月Next StepLook at blood smearR/o circulating blastsDo a bone marrowAspirateCell typesCytogeneticsBiopsyCellularity第三张，PPT共八十三页，创作于2022年6月Pancytopenia with Hypocellular MarrowAcquired aplastic anemiaInherited bone marrow failure syndromeHypocel

3、lular Myelodysplastic SyndromeAleukemic leukemiaMarrow lymphoma第四张，PPT共八十三页，创作于2022年6月Pancytopenia with Cellular MarrowPrimary marrow diseaseLeukemiaMyelodysplastic syndromeParoxysmal nocturnal hemoglobinuriaSystemic diseaseLupusHypersplenismInfection, e.g. brucellosis, sarcoidosis, tuberculosis第五张，

4、PPT共八十三页，创作于2022年6月Bone Marrow (BM) BiopsyNormalAplastic第六张，PPT共八十三页，创作于2022年6月Aplastic Anemia: Signs and SymptomsAnemiafatigue, lassitude, dyspneaThrombocytopeniabruises, petechiaeserious bleedingNeutropeniainfections第七张，PPT共八十三页，创作于2022年6月Severity of Aplastic AnemiaSevere2 of the following 3: neut

5、rophils 500/mL, platelets 20,000/mL, reticulocytes 20,000/mLBM cellularity 25% with 30% hematopoietic cellsVery severeNeutrophils 13 genes第二十三张，PPT共八十三页，创作于2022年6月FANC GenesAdapted from Joenje, 2006D1 = BRCA2*J and N interact with BRCA1 and BRCA2第二十四张，PPT共八十三页，创作于2022年6月FA Complementation Groups/Gen

6、esGroupLocuscDNAExonsAA%A16q24.35.543145570BXp22.312.810859RareC9q22.34.61455810D1/BRCA213q12.311.4273418RareD23p25.35441451RareE6p21-222.5105365F11p151.31374RareG/XRCC99p132.51462210I/KIAA179415q25-264.5381328RareJ/BACH1/BRIP117q22.34.6201249RareL/PHF9/POG2p15-16.11.714375RareM/Hef14q21.36.5222014R

7、areN/PALB216p12.13.5131186RareBRIP1 is “BRCA1 interacting protein”; PALB2 is “partner and localizer of BRCA2”第二十五张，PPT共八十三页，创作于2022年6月FA DNA Repair PathwayBD2DNA RepairDNA DamageCEFIGMLAPCNANBS1RAD51J/BACH1BRCA1D2UbD1/BRCA2D2UbN/PALB2第二十六张，PPT共八十三页，创作于2022年6月Who Should be Tested for FA?Characteristi

8、c birth defects (eg thumbs, kidneys, poor growth, etc)Aplastic Anemia (AA)Myelodysplastic Syndrome (MDS)Acute Myeloid Leukemia (AML)Decreased fertilityEarly characteristic cancerSiblings of FA patients第二十七张，PPT共八十三页，创作于2022年6月What are the Tests for FA?Blood chromosome breakage (DEB or MMC)Skin fibro

9、blast chromosome breakageFlow cytometry for G2 arrestWestern blot for ubiquitinated D2Retroviral FA gene correction of FA phenotypeFA gene sequencing第二十八张，PPT共八十三页，创作于2022年6月D2 UbiquitinationShimamura et al, Blood, 2002LIJ (BRIP1)BM第二十九张，PPT共八十三页，创作于2022年6月Retrovirus-mediated Correction of TA 0252s

10、T-cells analyzed by flow cytometry after five days of MMC-Incubation0204060801001101001000c (MMC) nMcells alive %S11EGSFAS11FCIEGS11FEIEG2S11FFIEGS11FGFANCARetrovirus-mediated Correction of FA Cells第三十张，PPT共八十三页，创作于2022年6月FA ComplicationsAplastic AnemiaAcute LeukemiaMyelodysplastic SyndromeSolid Tum

11、orsLiver tumors第三十一张，PPT共八十三页，创作于2022年6月FA Aplastic AnemiaAdapted fromKutler et al,Blood, 200380% by age 15,90% overall第三十二张，PPT共八十三页，创作于2022年6月FA Literature: Cancer 1927-2007179 solid tumors and 163 leukemias in 330/1865 patients; 29 had 2-4 cancersAMLLiverHNSCCBrainVulvaWilmsALLEsophagus第三十三张，PPT共

12、八十三页，创作于2022年6月Risk of Cancer in FA by O/E RatioFA CohortsParameterNASGEFAISFARNCINumber of Patients145182Person-Years20002818All Cancers52x44xAll Solid Tumors51x26xOral Cavity/Pharynx706x240 xVulvar4317x2411xAML785x868xMDS8559x4559xNorth American Survey;German FA Registry;Israeli FA Registry; Natio

13、nal Cancer Institute第三十四张，PPT共八十三页，创作于2022年6月NCI FA Cumulative Incidence and Cause-specific Hazards第三十五张，PPT共八十三页，创作于2022年6月Competing Risks of Cancer第三十六张，PPT共八十三页，创作于2022年6月Fanconi Anemia: Phenotype/OutcomeRosenberg, Huang, Alter, Blood 2004Phenotype predicts age and incidence of marrow failure and

14、 solid tumors.Normal PhenotypeAbnormal PhenotypeAbnormal phenotype = radii, plus abnormal development, heart or lung, kidney, hearing, and head. Competing risk analyses.第三十七张，PPT共八十三页，创作于2022年6月Transplant and Head and Neck Cancer in Fanconi AnemiaBMTNo BMTDATA:Transplant increased cancer by 4.4-fold

15、; Shifted median age to 16 years younger;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第三十八张，PPT共八十三页，创作于2022年6月Diagnosis of FA after CancerT

16、ongue SCC age 30Skin SCCs age 33Short, 80 lbs, hearing aids, menopause age 30XRT side effectsNormal blood countsPB chromosomes no breaks; skin breaksExon 8: 790 C T; Q264X; Gln264StopExon 27: 2585delCT; Frameshift, Cys846fsX20SkinGene conversion, loss of exon 27 frameshift 2585delCTBloodSomatic Mosa

17、icism, FANCAAlter, Joenje, Oostra, Pals, Arch Otolaryngol, 2005第三十九张，PPT共八十三页，创作于2022年6月Hematopoietic Mosaicism 第四十张，PPT共八十三页，创作于2022年6月Mosaicism from RecombinationaAAaaAAaaAAa第四十一张，PPT共八十三页，创作于2022年6月FANCD1/BRCA2 Proband; Adult FANCAPhotos with parental andpatient consent第四十二张，PPT共八十三页，创作于2022年6月Od

18、ds Ratios for Complications in FA and FANCD1/BRCA2General 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, an

19、d specific Solid Tumors (Wilms, medulloblastoma).Alter, Brody, Rosenberg: J Med Genet 2007第四十三张，PPT共八十三页，创作于2022年6月Genotype/Phenotype/Outcome: 27 FA with Biallelic Mutations in BRCA2Alter: Br J Haematol, 2006Alter, Brody, Rosenberg: J Med Genet, 200778% by age 10(AML, ALL)HR 7.7 (CI 2-29), p = 0.003

20、83% by age 7(Wilms, Medulloblastoma)97% by age 6第四十四张，PPT共八十三页，创作于2022年6月FANCD1/BRCA2 MutationsMutationsUniformity1Cluster2MissenseNo, p = 0.01Yes, p = 0.001DeleteriousYes, p = 0.6No, p = 0.3What is the risk of cancer in carriers of these missense mutations?1Chi square of expected frequency across t

21、he 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?第四十五张，PPT共八十三页，创作于2022年6月FA: When to TreatCytopeniasHb 8 g/dL or symptomsPla

22、telets 30,000/mm3WBC 20% blasts in marrowSolid tumors or liver tumorsWhen detectedFA: Guidelines for Diagnosis and Management, 2008第四十六张，PPT共八十三页，创作于2022年6月FA: How to TreatHematologic disease (benign or malignant)Stem cell transplantAndrogensHematopoietic growth factors (G-CSF, Ep)ChemotherapyFolic

23、acidBlood products: not family; leukodeplete; irradiateGene therapy?Liver tumorsStop androgensSolid tumorsConservative/focused radiationChemotherapy that does not cross-link DNANew modalities, e.g. cetuximabFA: Guidelines for Diagnosis and Management, 2008第四十七张，PPT共八十三页，创作于2022年6月FA Surveillance: Ca

24、ncerHematopoiesis AA, MDS, aMLBlood counts every 3-4 monthsBone marrow aspirate, biopsy, cytogenetics annuallyOral cavity and pharynx - role of HPV vaccine?Age 10 yearsBMT 1 yearGynecologic - role of HPV vaccine?Age 16 yearsMenarcheLiverLiver enzymes every 3-4 monthsLiver ultrasound every 6-12 month

25、sSkinAnnual exam第四十八张，PPT共八十三页，创作于2022年6月Case Presentation16 year old maleSeen by family doctor because tennis instructor noticed that he was tiring easilyHistory of trip outside the USA 5 months earlierNoted to have pallor and a large bruise on arm (where hit by tennis ball)CBC: Hb 8.5 g/dL, platel

26、ets 40,000/mL, WBC 2000/mL (20% neutrophils)Diagnosis: Fanconi Anemia, newly diagnosed in an adolescent第四十九张，PPT共八十三页，创作于2022年6月Dyskeratosis Congenita第五十张，PPT共八十三页，创作于2022年6月Dyskeratosis Congenita - Kids2 yo, HH1.5 yo, HH6 yo, TINF210 yo, TINF2第五十一张，PPT共八十三页，创作于2022年6月Dyskeratosis Congenita - Adults

27、22 yo, DKC148 and 16 yo, TERC27 yo, TINF224 yo, TINF2第五十二张，PPT共八十三页，创作于2022年6月Physical Findings in DCDystrophic nails*Lacey pigmentation*Leukoplakia*Epiphora, blepharitisDevelopmental delayPulmonary diseaseShort statureDental cariesLiver diseaseEsophageal strictureEarly grey hair, hair loss, sparse

28、eyelashesHyperhidrosisCerebellar hypoplasiaHypogonadismMicrocephalyUrethral strictureOsteoporosis, avascular necrosis*Diagnostic Triad (need 2/3). Or, 1 of the triad, + hypoplastic bone marrow, + 2 of the other findings. 第五十三张，PPT共八十三页，创作于2022年6月X-linked recessive (XLR), Autosomal dominant (AD), Aut

29、osomal 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%)第五十四张，PPT共八十三页，创作于2022年6月Major Complications in DCHematologicBone marrow failureMyelodysplastic syndromeLeukemiaSolid tumorsHead and neckAno

30、genitalPulmonary fibrosis第五十五张，PPT共八十三页，创作于2022年6月44 cancers in 36/425 patientsDC Literature: Cancer 1910-2007HNSCCRectalStomach第五十六张，PPT共八十三页，创作于2022年6月What is the End of the Shoelace?The aglet第五十七张，PPT共八十三页，创作于2022年6月Telomeres and Chromosomal InstabilityLong TTAGGG repeatsShorten with each cell di

31、visionMany proteins interact to regulate telomere length and stabilize structureLack of telomere maintenance leads to erosion of chromosome ends, genomic instability, cell crisis and cell deathFISH: telomeresCourtesy of Peter Lansdorp第五十八张，PPT共八十三页，创作于2022年6月Telomere Biology PathwayArmanios, Annu Re

32、v Genomics Hum Genet, 2009Kirwan and Dokal, BBA, 2009第五十九张，PPT共八十三页，创作于2022年6月Laboratory Diagnostic Test: Telomere Length by flow-FISHAlter, Baerlocher, Savage, Lansdorp: Blood, 2007Almost all patients with DC have very short telomeres in blood cells, including 3 silent carriers and 6 lacking the tr

33、iad. Most patients with other IBMFS have normal telomeres.第六十张，PPT共八十三页，创作于2022年6月Telomere Length in Multiplex FamilyEthics: Denny et al: AJMG, 2008Gene discovery: Savage et al: AJHG, 2008第六十一张，PPT共八十三页，创作于2022年6月TINF2 is Mutated in DCArg 282 SerLys 280 GluArg 282 HisHoyeraal-Hreidarsson SyndromeRev

34、esz SyndromeSavage et al: AJHG, 2008第六十二张，PPT共八十三页，创作于2022年6月NCI IBMFS Cohort: Relative Risk of Cancer (O/E Ratio)ParameterFADCNumberPerson-YearsAll CancersAll Solid TumorsTongueAMLMDS第六十三张，PPT共八十三页，创作于2022年6月NCI DC Compared with All FA第六十四张，PPT共八十三页，创作于2022年6月DC Surveillance and TreatmentSimilar to

35、 Fanconi AnemiaRole of HPV vaccine?Stem cell transplant complicated by pulmonary diseaseNo role for immunosuppressionFeatures unique to DC:Androgen sensitiveSplenic peliosis and rupture on androgens + G-CSFPulmonary fibrosisHepatic fibrosis, cirrhosisTelomere length assay: diagnosis of patients, sil

36、ent carriers; surveillance and genetic counseling第六十五张，PPT共八十三页，创作于2022年6月Diamond-Blackfan Anemia第六十六张，PPT共八十三页，创作于2022年6月Diamond-Blackfan AnemiaNormochromic, usually macrocytic anemia, developing in infancyReticulocytopeniaMarrow erythroblastopeniaNormal or slightly decreased leukocytesNormal or in

37、creased plateletsIncreased fetal hemoglobin (Hb F)Increased red cell adenosine deaminase (ADA)25% with physical findings: short, abnormal thumbs, etc第六十七张，PPT共八十三页，创作于2022年6月DBA Literature 2008: Physical FindingsFindingNumber%Any abnormality including short stature22425Any abnormality other than sho

38、rt stature15321Short stature only354Thumb anomaly576Triphalangeal thumb243Cleft palate243Denominator = 900, but no data in many reports.第六十八张，PPT共八十三页，创作于2022年6月DBA InheritanceAutosomal dominant25% RPS192% RPS241% RPS1740s ribosome biogenesisHaploinsufficiency7% RPL55% RPL112% RPL35a第六十九张，PPT共八十三页，创

39、作于2022年6月30 cancers in 30/899 patients; 3 MDS not includedDBA Literature: Cancer 1936-2008第七十张，PPT共八十三页，创作于2022年6月DBA Surveillance and TreatmentMonitor blood countsAnnual bone marrows (no consensus)Treat when Hb 8 g/dL, or symptomsCorticosteroidsTransfuse during first year and puberty (no consensus)

40、Cyclosporin A (rare)Metoclopramide (rare)第七十一张，PPT共八十三页，创作于2022年6月Shwachman-Diamond SyndromeExocrine pancreatic insufficiencyDecreased trypsinogen and isoamylase (age-dependent)Pancreas small or fatty on imagingBone marrow failureNeutropenia: 1500/mLAnemia: MacrocytosisThrombocytopeniaMyelodysplasti

41、c syndrome/acute leukemiaBonesMetaphyseal dysostosisAutosomal recessiveSBDS = Shwachman-Bodian-Diamond Syndrome60s ribosome biogenesis第七十二张，PPT共八十三页，创作于2022年6月SDS Literature: Leukemia 1949-200736 leukemias in 36/510 patients AMLALL第七十三张，PPT共八十三页，创作于2022年6月SDS Surveillance and TreatmentSimilar to Fan

42、coni AnemiaG-CSF - neutropeniaStem cell transplant - cardiotoxicity from cyclophosphamide?Features unique to SDS:Malabsorption - pancreatic enzymes, ADEKMetaphyseal dysostosis - surgery as neededCytogenetic clones - monitor第七十四张，PPT共八十三页，创作于2022年6月Severe Congenital NeutropeniaNo physical phenotypeAN

43、C 500/mLPyogenic infectionsRx G-CSFAutosomal dominantELA2GFI1Autosomal recessive (Kostmann Syndrome)HAX1X-linked recessiveWAS第七十五张，PPT共八十三页，创作于2022年6月SCN and Leukemia(Rosenberg, Alter, .Dale: 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 f