1 / 11

HEREDITARY MARROW FAILURE: STRATEGIC APPROACH.

HEREDITARY MARROW FAILURE: STRATEGIC APPROACH. Definition: IBMFS (Inherited Bone Marrow Failure Syndromes) are genetic disorders characterized by inadequate blood cell production. 1 Classification: IBMFS Pancytopenia Single cell line cytopenia

neka
Download Presentation

HEREDITARY MARROW FAILURE: STRATEGIC APPROACH.

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. HEREDITARY MARROW FAILURE: STRATEGIC APPROACH.

  2. Definition: IBMFS (Inherited Bone Marrow Failure Syndromes) are genetic disorders characterized by inadequate blood cell production.1 • Classification: • IBMFS • Pancytopenia Single cell line cytopenia • Fanconi’s anemia Red cellWhite cellPlatelet • Dyskeratosis congenita - Diamond -Kostmannsyn - TAR • Shwachman- Diamond Blacfansyn - CAMT • syndrome - Congenital • Cartilage Hair Hypoplasia Dyserythropoietic • Pearson’s syndrome anaemia • TAR- Thrombocytopenia Absent Radii • CAMT- Congenital Amegakaryocytic Thrombocytopenia.

  3. Pathogenesis: Abnormality in-- • DNA repair • Redox related pathway • Telomere maintenance • Ribosome biosynthesis. • Clinical approach: • Age: • Infancy: Pearson’s syn; Diamond- Blackfan syn.; Thrombocytopenia with Absent Radii; Congenital Amegakaryocytic Thrombocytopenia; Kostmann’s syndrome. • Late childhood: Fanconi’s anemia(median age 7 years), Dyskeratosis congenita, Shwachman- Diamond syn, Cartilage Hair Hypoplasia, Congenital dyserythropoieticanaemia.

  4. Other systemic involvement or congenital abnormalities: • Abnormal Mucocut. lesions Pancreatic Skeletal system • facies involvement • Fanconi’sDyskeratosis ---ShwachmanCartilage • Anemia(FA)Congenita(DC)Diamond syn.Hair • Broad nasal - reticulated skin (SDS)Hypoplasia(CHH) • bridge - nail dystrophy ---Pearson’s syn • Short stature - mucosal leukoplakia(PS) • Micrognathia • Café- au lait spots Skeletal(SDS) Systemic(PS) • Hypopigmentation-metaphyseal-IDDM • Epicanthal folds dysostosis-hepatic failure • Absent or Triphalangeal-rib cage abnormality-renal tubulopathy • thumb -osteopenia

  5. Laboratory investigations: • Peripheral smear • MacrocytosisNormocytic, Normochromic • FA (raised erythropoietin, thrombocytopenia, -- SDS • anaemia, raised HbF) -- Congenital dyserythropoie • Diamond Blacfansyn (DBA) (raised erythropoietin, tic anemia type II(CDA). • anaemia, thrombocytosis, raised HbF) • DC (Pancytopenia, raised HbF) • Pearson’s syn (Pancytopenia) • CHH (anemia less severe, lymphopenia) • Bone Marrow Examination • Decreased cellularityIncreased cellularity • FA DC, • DBA.

  6. Diagnostic tests: • Fanconi’s anemia: hypersensitivity of cultured fibroblasts to chromosomal breaking effect of diepoxybutane (DEB) or mitomycin C (MMC) and to Oxygen radicals & ionizing radiation. Cellular Phenotype: large no. of cells with 4N DNA s/o delay in G2 /M or late S phase of cell cycle. • Dyskeratosis Congenita: demonstration of shortened telomeres in peripheral blood cells. Cellular Phenotype: anaphase and telophase bridges, premature replicative senescence. • Shwachman Diamond syndrome: Diagnostic criteria– Pancreatic insufficiency— low trypsinogen(<3 years), low isoamylase(>3 years), elevated fecal fat excretion. Hematological- neutropenia, anemia, thrombocytopenia, MDS on bone marrow examination.

  7. Pearson’s syndrome: vacuolization of hematopoietic precursor cells in bone marrow, mitochondrial enzyme defect and mtDNA deletion establishes the diagnosis. • Diamond Blacfan syndrome: diagnostic criteria– age < 1 year, macrocytic anemia, reticulocytopenia, paucity of erythroid precursors in bone marrow. criteria- major– pathogenic mutations, positive family history, minor– elevated RBC ADA, elevated HbF, congenital anomalies of DBA, no e/o other IBMFS. • Congenital Dyserythropoietic Anemia: Type I- bone marrow internuclear chromatin bridges between nearly completely separated erythroblasts, electron microscopy shows spongy “Swiss cheese” appearance of heterochromatin. Type II- bone marrow normoblasticerythroid hyperplasia with binucleate or multinucleate late polychromatic normoblasts. Type III: bone marrow giant multinucleate and mononucleate erythroblasts with other changes basophilic stippling, nuclear lobulation and karyorrhexis.

  8. Predisposition to malignancy: All conditions predispose pt to MDS/AML . Fanconi’s due to abnormal hypersensitivity to chromosomal breakage and TNF- over production.

  9. Ribosomal protein abnormality leading these syndromes predispose to cancer.

  10. Treatment modalities available: • Hematopoietic stem cell transplant: • Curative- Kostman’s syndrome, Amegakaryocytic thrombocytopenia, congenital dyserythropoietic anemia, Diamond Blackfansydrome. • Curative but increased morbidity and mortality- Fanconi’s anemia, • dyskeratosiscongenita, Shwachman- Diamond syn., Cartilage Hair Hypoplasia with SCID. • G-CSF: • transient improvement– Fanconi’s, Pearson’s syn. • good results– SDS, dyskeratosiscongenitia, Kostmann’s syn. • Androgens: • Fanconi’s anemia, Diamond Blackfansyn, Dyskeratosis Congenita. • IL- 3: Abnormal sensitivity of Fanconi’s anemia pt. to IL 3.

  11. References: Nathan and Oski’s 7th edition: Textbook of Hematology in infancy and childhood. Ribosomes and marrow failure: coincidental association or molecular paradigm? Blood15 June 2006, Vol. 107, No. 12, pp. 4583-4588.

More Related