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CONSTITUTIONAL APLASTIC ANEMIA (FANCONİ ANEMIA)

CONSTITUTIONAL APLASTIC ANEMIA (FANCONİ ANEMIA) Characterized by defective DNA repair that is caused by a variety of genetic mutations Autosomal recessive Hematologic manifestations usually begin with thrombocytopenia or neutropenia Diagnosis is made between ages 2-10 years.

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CONSTITUTIONAL APLASTIC ANEMIA (FANCONİ ANEMIA)

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  1. CONSTITUTIONAL APLASTIC ANEMIA(FANCONİ ANEMIA) • Characterizedbydefective DNA repairthat is causedby a variety of geneticmutations • Autosomalrecessive • Hematologicmanifestationsusuallybeginwith thrombocytopeniaorneutropenia • Diagnosis is madebetweenages 2-10 years

  2. TypicalFeatures • Progressivepancytopenia • Macrocytosis • Multiplecongenitalanomalies • Increasedchromosomebreakage in peripheralblood Iymphocytes

  3. ClinicalFindings Thrombocytopenia : Purpura, petechiaeandbleeding Neutropenia : Severe orrecurrentinfections. Anemia : Weakness, fatigueandpallor. Congenitalanomalies : 50% of patients • Abnormalpigmentation of skin • Shortstature • Skelatalmalformations (hypoplasia, anomaliesorabsence of thethumbandradius) • Renalanomalies ( Aplasia, horseshoeanomalies, duplication of collectingsystem) • Microcephaly, micropthalmia, strabismus, earanomalies, hypoganitalism

  4. LaboratoryFindings • Thrombocytopenia, leukopenia, anemia • Macrocytosis, anisocytosis • HbFincreased • Bone marrow • Hypoplasiaoraplasia • Increasednumber of chromosomebreaks: confirmation of diagnosis.

  5. Differentialdiagnossis • ITP • Acquiredaplasticanemia • Acuteleukemia

  6. Complications • Relatedtothrombocytopeniaandneutropenia • Endocrinedysfuntion • GH deficiency, hypotiroidism, impairedglucosemetabolism • Increased risk of developingmalignancies • ANLL, headandneckCa, myelodysplasticsyndnomes

  7. Treatment • Supportivecare ( antibiotics, transfusion) • Oxymethalone (syntheticanabolicsteroid),androgentherapy: in completeresponse • Bone marrowtransplantation: an importanttreatmentoptionforchilren

  8. ACQUIRED APLASTIC ANEMIA • Characterizedbyperipheralpancytopeniawithhypocelluar bone marrow • 50% of cases in childhoodareidiopathic • Othercases : Secondarytoidiosyncraticreactionsto • Drugs • Phenylbutazone • Sulfonamides • Nonsteroidolantiinflammatorydrugs • Anticonvulsants • Toxiccauses • Benzene • Insecticides • Heavymetals • InfectiousCauses • Viralhapatitis • IM • HIV • Parvovirus B(19) Especially in immunocompromisedchildren

  9. ClinicalFindings • Weakness, fatigue, pallor • Anemia • Petechiae,purpura,bleeding • Thrombocytopenia • Fever, generalized,localizedinfection • Neutropenia • Hepatosplenomegalyandsignificantlymphadenopathyareunusual

  10. LaboratoryFinding • Normocyticanemia • Lowreticulocytecount • WBC count is low • Plateletcountbelow 50.000/mm3 • Bmaspirationandbiopsy • Hypocellularity

  11. Differentialdiagnosis • Acuteleukemia • StoragediseaseExamination of BM • Myelofibrosis Presence of hepatosplenomegaly *Newlydiagnosedaplasticanemiashould be studied forchromosomebreaksforthediagnosis of Fanconianemia

  12. Treatment • Supportivecare ( antibiotics, RBC transfusion • Platelettransfusion :manypatientsdevelopplateletalloantibodiesandbecomerefractory • BM transplantation • Antithymocyteglobulin • Cyclosporine

  13. Childrenreceivingearly BM transplantationfrom an • HLA identicalsiblinghave a longtermsurvival rate of greaterthan 80% • Completeremissionsmay be seen in 65-80 % of patientsreceivingimmunosuppressivetherapy • Boththerapiesareassociatedwith an increased risk of myelodysplasticsyndromes, acuteleukemiaandothermalignancies in longtermsurvivors

  14. CONGENITAL HYPOPLASTIC ANEMIA (DiamondBlackfanAnemia) • Rarecause of anemiathatusuallypresents in infancyorearlychildhood (birthto 1 year) • Treatmentwith CST results in increasederythropoiesis in about 2/3 of patients ( earlydiagnosis is important ) • Thecause is unclear, bothautosomal dominant andautosomalrecessivemodes of inheritanceoccur

  15. ClinicalFindings • Pallor, fatigue • Congestiveheartfailure • Shortstatureorothercongenitalanomaliesarepresent in 1/3 of patients ( affectinghead, faceandthumbs)

  16. LaboratoryFindings • Macrocyticanemia • Markedreticulocytopenia • Plateletcount is N/ ↑/↓ • Neutrophilcount is usually N/ slightly ↓ • BM → markeddecrease in erythroidprecursors but is otherwise normal • HbF is usuallyincreased → (persistent of fetalerythropoesis ) • Adenosinedeaminase in RBC is elevated

  17. DifferentialDiagnosis • Transienterythroblastopenia • Renalfailure • Hypothyroidism • Anemia of chronicdisease

  18. Treatment • Oral CST: ⅔ of patientsrespondtoprednisone 2 mg/kg/d • Transfusion:unresponsivepatients • BM transplantation:fortransfusiondependentpatients • Spontaneousremissionsoccur in up to20% of patients

  19. TRANSIENT ERYTHROBLASTOPENİA of CHILDHOOD • Commoncause of acquiredanemia in earlychildhood • Age : 6 monthsto 4 years • Normocyticanemiawithreticulocytopenia • Erythroidprecursorsinitiallyabsentfrom bone marrowAnemiadevelopsslowly, thecardiovascularsystem has time tocompensate

  20. Thedisorder is thoughtto be autoimmune in mostcases, becauseIgGfromsomepatients has beenshowntosuppresserythropoiesis in vitro. • Usuallyresolveswithin 6-8 weeks of diagnosis • Resolution of theanemiawithreticulocytosis • Not treatedwith CST because of itsshortcourse

  21. Althoughthere is an overlap in theage of presentation, Diamond-Blackfansyndromecommonlycausesanemiaduringthefirst 6 months of life, whereasTECoccursmorefrequentlyafterage of 1 year. TheRBCs in patientswithDiamond-BlackfansyndromehavefetalcharacteristicsthatareusefulfordistinguishingthisdisorderfromTEC, includingincreasedmeancellvolume, elevatedlevel of hemoglobin F, and presence of i antigen. Thelevel of adenosinedeaminasemay be elevated in patientswithDiamond-Blackfansyndrome but normal in childrenwithTEC. Twenty-fivepercent of whitepatientswithDiamond-Blackfananemiahavebeenfoundtohavemutations in the gene forribosomal protein S19, andmoleculardiagnosisforthesemutations ishelpfulwhenpositive. Recently, additional gene mutationshavebeenidentified in DiamondBlackfananemia.. In total, aboutthreefourths ofDiamond-Blackfanpatients can be identifiedbymutationalanalysis

  22. IRON DEFICIENCY ANEMIA • Themostcommoncause of anemia in pediatrics • Irondeficiency has decreasedsubstantially in incidenceduetoimprovednutritionandtheincreasedavailability of ironfortifiedinfantformulasandcereals. • Normal terminfantsarebornwithsufficientironstorestopreventirondeficiency is mostcommonbetween 6 and 24 months of life • Deficiencyearlierthan 6 months of agemayoccurifironstores at birtharereducedbyprematurily, smallbirthweight, neonatalanemia, perinatalbloodloss, hemorrhage • Irondeficientchildrenolderthan 24 months of ageshould be evaluatedforthebloodloss.

  23. Lowbirthweight • Consumption of wholecowmilkbeforetheage of 7 months • Use of formula not fortifiedwithiron • Lowsocioeconomicstatus • Exclusivebreastfeeding (withoutsolidorformulasupplementation) beyondtheage of 6 months • Perinatalbloodloss • Teenagefemales (ifmenstruation is heavyorifpregnant)

  24. ClinicalFindings • Mildirondeficiency • Usuallyasymptomatic • Severe irondeficiency • Pallor, fatigue,irritabilily, delayed motor development, concentrationdefects • A history of pica is common

  25. Pica is a more general termthatindicates a hungerformaterialthat is not normallyconsumed as food. • Geophagiareferstotheconsumption of dirtorclay, • Pagophagiareferstotheexcessiveconsumption of ice.

  26. LaboratoryFindings • Hb ↓ as low as 3-4 gr/dl • Microcytic ,hypochromic RBC • Low MCV, low MCH • RDW elevated • Reticulocytecount is usually normal orslightlyelevated • Decreased serum ferritin • Low serum iron • Elevated total ironbindingcapacity • Decreasedtransferrinsaturation • Peripheralbloodsmear • Microcytic, hypochromicRBCswithanisocytosis, occasionaltarget, teardrop, ellipticalandfragmentedredcells. • Leukocytesare normal,veryoftenplateletcount is increasedwith normal morphology

  27. DifferentialDiagnosis • Thalassemia • Elevatednumber of RBC soMentzerindex < 13 (βth.minor) high HbA2 • Leadpoisoning • Theanemia of chronicinflammationorinfection in latestages • Mildinfectionsduringinfancy → ideallyscreeningtestsforanemiashould not be obtainedwithin 3-4 wks of suchinfections

  28. Treatment • Oral dose of elementaliron 6 mg/kg/d in 3 divideddoses • Results in an increasedreticulocytecountwithin 3-5 dayswhentheirondeficiency is theonlycause of anemia, adequatetreatmentusuallyresults in a resolution of anemiawithin 4-6 wks. Treatment is generallycontinuedfor a fewadditionalmonthstoreplenishironstores.

  29. MEGALOBLASTIC ANEMIAS • Megaloblasticanemia is a macrocyticanemiathat is characterizedbylarge RBC precursors(megaloblasts) in the bone marrowandthat is usuallycausedbynutritionaldeficiencies of eitherfolicacidor vitamin B12 • RBCs: Elevated MCH andmeancellvolume (often 106 flormore), with normal MCHC;markedvariability in cell size (anisocytosis) andshape (poikilocytosis) • Neutrophils: Hypersegmentation (>5% of neutrophilswithfivelobesor a singleneutrophilwithsixlobes) • Platelets: Usually normal; thrombocytopenia in more severe anemia

  30. MEGALOBLASTIC ANEMIAS • Macrocyticanemiacausedbydeficiency of B12, folicacidorboth • B12 deficiencyduetodietarydeficiencymayoccur in infantswhoarebreast fed bymotherswhoarestrictvegeteriansorwhohavepernisiousanemia • B12 deficiencyduetointestinalmalabsorbtionmayoccur in childrenwithCrohndisease, chronicpancreatitis, bacterialovengrowth of thesmallbowel,infectionwiththefishtapeworm ( Diphylobothriumlatum) oraftersurgicalresection of the terminal ileum • B12 defeciencyduetoinbornerrors of metabolism (transcobalamindeficiencyandmethylmalonicaciduria) • Malabsorbtion of cobalaminduetodeficiency of IF (perniciousanemia) is rare in chilhood.

  31. Folicaciddeficiency • Inadequatedietaryintake ( goatmilk) • Malabsorbtion ( celiacdisease) • Increasedfolaterequirements • Anticonvulsanmedication ( phenobarbital, pheyntoin) • Cytotoxicdrugs ( methotrexate) • Prematurity

  32. ClinicalFindings • Pallor • Mildjaundice as a result of ineffectiveerythropoiesis • Thetongue is smoothandbeefyred • Infantswith B12 deficiencymay be irritable • Paresthesias, weakness • Unsteadygait • Decreasedvibratorysensation • Proprioception

  33. LaboratoryFindings • Elevated MCV, MCHb • Bloodsmear • Macroovalocyteswithanisocytosisandpoikilocytosis • Neutrophilsarelargeandhavehypensegmentednuclei • WBC andplateletcountsare normal withmilddeficiency, may be decreased in severe cases • BM → Erythroidhyperplasiawithenythroidandmyeloidprecursors • Serum indirectblrconcentrationmay be slightlyelevated • Low serum B12 (30 % of patientshavelow serum B12 withfolicaciddeficiency) • Low serum folicacid • Thelevel of redcellfolate is a betterreflection of folatestores • Elevatedmethylmalonicacid • Elevatedlevels of homocysteine

  34. DifferentialDiagnosis • Drugtherapy ( anticonvulsants, anti HIV nucleosideanalogues) • Downsyndrome • Fanconianemia • Diamond – Blackfananemia • Liverdisease • Hypothyroidism

  35. Treatment • Oral supplementation • Parentenaltreatment * Children at risk forthedevelopment of folicaciddeficienciessuch as prematureinfantsandthosewithchronichemolysisareoftengivenfolicacidprophylactically

  36. ANEMIA OF CHRONIC INFLAMMATION • MildtomoderateHb 8-12 gr/dl • Thereticulocytecount is low • Inflammatorycytokinesinhibiterythropoiesisshunting of ironintoandimpairedironreleasefrom RE cells. • Levels of erythropoietinarerelativelylow • Serum ironconcentration is low • Ironbindingcapasity is normal • Elevated serum ferritinlevel

  37. Chronicinfectionandotherinflammatorystatesimpairtherelease of ironfromreticuloendothelialcells, therebydecreasingtheamount of thisnecessaryingredientthatareavailableforRBCproduction. • Thelack of mobilizableironmay be theresult of theaction of proinflammatorycytokines (e.g., interleukin-1, tumornecrosisfactor-a). • Givingadditionalironunderthesecircumstancesfurtherincreasesreticuloendothelialironstoresanddoeslittletohelptheanemia. • Acuteinfectionmaycauseanemiathrough a variety of mechanisms, including bone marrowsuppression, shortened RBC life span, RBC fragmentation, andimmune-mediated RBC destruction

  38. ANEMIA of CHRONIC RENAL FAILURE • Normocyticanemia • BM → significanthypoplasia of theerythroidseries • Reticulocytecount is low • Deficiency of erytropoetin • Recombinanthumanerythropoietincorrectstheanemia

  39. ANEMIA of HYPOTHYROIDISM • Normocytic / macrocytic ( not megaloblastic) • Replacementtherapywiththyroidhormone is usuallyefective in correctingtheanemia

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