Disorders of myelopoiesis.ppt

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Information about Disorders of myelopoiesis.ppt

Published on September 26, 2018

Author: AbdulKaderSouid

Source: slideshare.net

1. Abdul-Kader Souid ↓ Neutrophil Count (Neutropenia) • Inherited (bone marrow examination is necessary): • Neutropenia, severe congenital, 1, AD; SCN1 (MIM#202700); mutations in ELANE (MIM#130130) • Cyclic neutropenia, AD (MIM#162800); mutations in ELANE (MIM#130130) • Neutropenia, severe congenital, 3, AR; SCN3 (MIM#610738); mutations in HAX1 (MIM#605998) • Acquired: Viral infection (common), drug-induced (common), bone marrow failure syndrome (rare) ↓ Neutrophil Function • Granulomatous disease, chronic, X-linked (XLR); CDGX (MIM#306400): A primary immunodeficiency (defective microbial killing); mutations in CYBB (MIM#300481). • Hyper-IgE recurrent infection syndrome (HIES), AD (MIM#147060): A primary immunodeficiency characterized by chronic eczema, recurrent Staphylococcal infections, ↑serum IgE, and eosinophilia due to STAT3 (MIM#102582) mutations. Disorders of MyelopoiesisMust know AD, autosomal dominant; AR, autosomal recessive; XLR, X-linked recessive

2. Myelopoiesis • Hematopoiesis: Hematopoietic multipotent (stem) cells can differentiate to → erythrocytes, megakaryocytes, neutrophils, eosinophils, basophils, monocytes, T lymphocytes, B lymphocytes, natural killer cells, dendritic cells, and mast cells. • Myelopoiesis I: Multipotent (stem) cell → CFU-GEMM (CD34+/ HLA-DR+). • Myelopoiesis II: CFU-GEMM → CFU-GM (CD34+/ HLA-DR+/ CD-64+). – CFU-GM is driven by the growth factors c-kit ligand, IL-3, IL-6, and GM-CSF. • Myelopoiesis III: CFU-GM → CFU-G (CD34+/ HLA-DR+/ CD-64+). – CFU-G is driven by the growth factor G-CSF. CFU: Colony forming units that grow at 37ºC in semisolid medium as pure colonies in 7 days. CFU-GEMM: Colony forming units of precursor to granulocytes, erythrocytes, macrophages (monocytes), and megakaryocytes. CFU-GM: Colony forming units of precursor to granulocytes and monocytes/macrophages. CFU-G: Colony forming units of precursor to granulocytes. GM-CSF: Granulocyte-macrophage colony-stimulating factor. G-CSF: Granulocyte colony-stimulating factor. CFU-GEMM CFU-GM CFU-G Reading

3. Neutrophil Function (1) Neutrophil entrance from marrow to circulation. (2) Rolling & tethering (adherence, mediated by selectins). (3) Adhesion: Activated endothelial cells express intercellular adhesion molecules (ICAM), which serve as ligands for neutrophil β2 integrins (impaired in ‘leukocyte adhesion deficiency’, LAD). (4) Invasion through the vascular basement membrane with release of proteases and reactive oxidative intermediates, destructing extracellular matrix and allowing migration into tissue (impaired in chronic granulomatous disease). (5-6) Uptake of pathogens into the phagocytic vacuole with concomitant degranulation both into the phagocytic vacuole and to the exterior (impaired in Chédiak-Higashi). (7) Chemokines [IL-8, monocyte chemoattractant protein (MCP)-1, macrophage inflammatory protein (MIP)-1α, and IL-1β] recruit cells of the immune system (impaired in hyper-IgE syndrome). (8) Extracellular traps are extrusions of chromatin and cationic bactericidal granule proteins. Reading

4. Neutrophil Function Chemotaxis → Motility → Adhesion→ Ingestion → Killing 9/26/2018 Lysis of the cytoplasmic granule (G) against two ingested zymosan particles (Z). The dense body of the granule disappears from view in the interval of 5 sec. (J Exp Med 1962;116:827) Taxis = motion or orientation Zymosan = a glucan of repeating glucose units found on surface of fungi. This degranulation process is impaired in Chédiak-Higashi disease Must know

5. Neutrophil “Respiratory Burst” Most homes have a bottle of hypochlorite (Ocl-) in the kitchen or bathroom (Domestos, Chlorox, etc.); as advertised, these products kills all household germs. These reactions are impaired in chronic granulomatous disease (↓killing of catalase- positive bacteria) Chronic granulomatous disease → infections with catalase-positive organisms (Staphylococcus aureus, Serratia marcescens, Acinetobacter anitratus, Salmonella, Burkholderia cepacia, Aspergillus, Nocardia) → necrotizing granulomas. Initial diagnosis is made by the oxidative burst flow cytometry test (phagocytes fail to oxidize rhodamine). Must know Bacterial Catalase ((catalase-positive bacteria) H2O + ½O2

6. 6 Hyper-IgE recurrent infection syndrome (HIES), AD (MIM#147060): A primary immunodeficiency characterized by chronic eczema, recurrent Staphylococcal infections, ↑ serum IgE, and eosinophilia due to STAT3 (MIM#102582) mutations. (impaired chemotaxis and cytokine production) This patient (Malaysian) had severe, persistent atopic dermatitis (intense itching), severe atopy (asthma and allergic rhinitis), and a recent invasive infection (right hip joint and bone). One year ago, Staphylococcus aureus and varicella-zoster virus (VZV) infections. He had a significant history of food allergy, such as crab and shrimps which severely flare his skin disease. The father has similar moderate-to-severe atopic dermatitis and allergic rhinitis. His sister has a much milder atopic dermatitis. His maternal grandfather has asthma and maternal aunt has atopic dermatitis. Must know

7. Mutations in LYST (MIM#606897), which encodes a lysosomal trafficking regulator protein ↓Neutrophil chemotaxis + ↓Degranulation → ↓Bactericidal activity ↓Platelet storage pool → Bleeding ↓Melanosomes → Albinism 7 Union of lysosomal (giant) granules in Chédiak-Higashi Albinism Optional Degranulation Abnormality Chédiak-Higashi Syndrome (CHS, OMIM#214500, AR)

8. 8 Leukocyte adhesion deficiency, type I; LAD, AR (MIM#116920) Mutations in ITGB2 (MIM#600065; integrin, beta-2) (recurrent bacterial infections; impaired pus formation and wound healing) Lack of CD18/CD11 surface adhesive glycoproteins (β2 integrins) on neutrophil membranes → neutrophilia + pyogenic infections without pus. Infections in a toddler with leukocyte adhesion deficiency Optional

9. Severe Congenital Neutropenia • Recurrent otitis, gingivitis, pneumonia, enteritis, and bacteremia in early infancy. • Neutrophil count is <0.2 ×109/L with monocytosis, anemia, and thrombocytosis. • Bone marrow shows neutrophil maturation arrest at the myeloblast (no mature neutrophils). • Patients are at risk for developing acute myelogenous leukemia (AML). • G-CSF is effective (↑increasing neutrophil counts & ↓infections). • Hematopoietic transplantation is the only curative therapy. 9/26/2018 9 Must know • Neutropenia, severe congenital, 1, AD; SCN1 (MIM#202700); mutations in ELANE (MIM#130130) • Neutropenia, severe congenital, 3, AR; SCN3 (MIM#610738); mutations in HAX1 (MIM#605998)

10. • Recurrent neutropenia, with a cycle period of about 21 days. • The diagnosis is established by measuring the neutrophil count twice a week for eight consecutive weeks. • Supportive care includes regular dental care, prompt antibacterial therapy as needed, and genetic counseling. • Granulocyte colony-stimulating factor (G-CSF) is given at the nadir of the neutrophil counts. Note: Mutations in the elastase gene are associated with both cyclic neutropenia and severe congenital neutropenia. Cyclic neutropenia, AD (MIM#162800); mutations in ELANE (MIM#130130) Must know

11. • Neutropenia due to proliferative defect and ↑apoptosis of early myeloid progenitor cells. • Clinical findings begins in the neonatal period and include short stature, inadequate weight gain, skeletal abnormalities, infections (otitis media, sinusitis, pneumonia), and large stools (steatorrhea, malabsorption, pancreatic exocrine deficiency), and marrow failure. – Imaging confirms extensive fatty replacement of the pancreas. – The presentation resembles cystic fibrosis (sweat chloride is normal in Shwachman syndrome and high in cystic fibrosis). • The risk of evolution to myelodysplastic syndrome and acute myelogenous leukemia is at least 20%. • G-CSF raises the neutrophil counts. • Hematopoietic stem cell transplantation is curative. 11 Shwachman-Diamond Syndrome 1; SDS1, AR (MIM#260400); mutations in SBDS (MIM#607444) Optional

12. 1. Neutrophil respiratory burst defect + XLR + catalase-positive pathogens 2. Giant neutrophil granules + albinism 3. Negative CD11/CD18 expression + neutrophilia 4. Eczema + infections + Stat 3 mutation 5. Pancreatic insufficiency + neutropenia + SBDS mutation 6. Elastase gene (ELANE) 7. Risks of developing AML 8. Treatment with G-CSF 9. Hematopoietic stem cell transplantation A. Severe congenital neutropenia B. Shwachman-Diamond Syndrome C. Cyclic neutropenia D. Chronic granulomatous disease E. Chédiak-Higashi syndrome F. Leukocyte adhesion deficiency G. Hyper IgE syndrome Fever with neutropenia is best treated with monotherapy (meropenem, cefepime or ceftazidime). Although these regimens do not cover methicillin-resistant Staphylococcus aureus and coagulase-negative staphylococci, vancomycin should be withheld in low-risk patients pending cultures in an effort to prevent vancomycin-resistant enterococci. Must Know Pearls Freifeld AG, et al. Infectious Diseases Society of America. Clinical practice guideline for the use of antimicrobial agents in neutropenic patients with cancer: 2010 update by the Infectious Diseases Society of America. Clin Infect Dis. 2011;52:e56-93. doi: 10.1093/cid/cir073.

13. Two brothers present to the clinic for evaluation of recurrent neutropenia. They suffer from regular episodes of mucositis, sinusitis, otitis media, pharyngitis and tonsillitis. Their maternal grandfather, mother, maternal aunt and her son all have neutropenia. 9/26/2018 13 0 500 1000 1500 2000 0 10 20 30 40 50 ANC days CBC on the 5-year-old boy reveals absolute neutrophil count (ANC) of 300/mL (0.3 x109/L). The results of his ANC over 45 days are shown. Blood smear shows normal neutrophil morphology. Which of the following is the most likely diagnosis? A. Chédiak-Higashi syndrome B. Leukocyte adhesion deficiency C. Hyper IgE syndrome D. Severe congenital neutropenia E. Cyclic neutropenia

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