Non Malignant Leukocyte Disorders

• NON MALIGNANT LEUKOCYTE DISORDERS


  • Not caused by clonal or neoplastic changes in hematopoietic precursor cells
  • Genetic or acquire involving: Neutrophils, Lymphocytes, Monocytes, Eosinophils, Basophils
• QUALITATIVE DISORDERS: PHAGOCYTIC ABNORMALITIES

  • LEUKOPENIA
  • ABNORMAL IN FUNCTION
• LEUKOPENIA


  • Decreased production- BM not creating/synthesizing much WBC: irradiation, drugs, viral infection, congenital, aplastic anemia
  • Ineffective production- can produce abnormal/immature cells: megaloblastic (deficiency in Vitamins, ex. B12, and folic acid) anemia, myelodysplastic syndromes
  • Increased destruction- isoimmune neonatal, autoimmune, complement activation induced hemolysis
  • Splenic sequestration - WBC low
  • Increased margination- low of white cell precursors in BM compared to RBC low WBC count
• ABNORMAL IN FUNCTION


  • Job's syndrome- normal random activity; abnormal chemotactic activity, chemotaxis- white cells move to the site of infection, chemotaxis = diapedesis
  • Lazy leukocyte syndrome- both abnormal
  • Chronic granulomatous disease (CGD) - inability to phagocytize microorganisms (can't fully phagocytize because the problem in "respiratory burst"
  • impaired NADPH oxidase (impaired oxidative organisms), normal WBC morphology, abnormal function of WBC
  • Nitroblue tetrazolium test- blue ppt appearance
• CONGENITAL DEFECTS OF LEUKOCYTES NUMBER AND FUNCTION

  • SEVERE COMBINED IMMUNE DEFICIENCY
  • WISKOTT-ALDRICH SYNDROME
  • 22sq11 SYNDROME
  • BRUTON TYROSINE KINASE DEFICIENCY
  • CHEDIAK -HIGASHI SYNDROME
  • CONGENITAL DEFECTS AND PHAGOCYTES
  • LEUKOCYTE ADHESION DISORDERS
  • LEUKOCYTE ADHESION DISORDER
  • CHRONIC GRANULOMATOUS DISEASE (CGD)
  • WHIM SYNDROME
• SEVERE COMBINED IMMUNE DEFICIENCY

  • Affects both cellular and humoral immunity
  • have a marked decrease in circulating T cells, poorly functioning B cells, hypogammaglobulinemia, and profound clinical manifestations
  • If untreated, patients die within the first 2 years of life
• Yc deficiency or X-linked SCID


  • most common form and is caused by mutations in the IL2RG gene located at Xq13.1
  • Symptomatic between 3 to 6 months of age
  • Circulating T and NK cells are nearly absent
  • B cells are adequate but dysfunctional
• ADA deficiency


  • 19 to 20 % of SCD due to mutations in ADA gene in chromosome 20q13.12
  • Result in an intra- and extracellular accumulation of adenosine which is lymphotoxin
• WISKOTT-ALDRICH SYNDROME


  • combined immunodeficiency
  • Decreased WASp protein caused by one or more than 400 mutations in the WAS gene
  • Decreased T cells, B cells, and NK cells, neutrophils, and monocytes are dysfunctional
  • Risk of bleeding due to thrombocytopenia
• 22sq11 SYNDROME


  • classified as combined immunodeficiency
  • DiGeorge syndrome
  • Autosomal dominant Opitz GBBB
  • Sedlackova syndrome
  • Caylor cardiofacial syndrome
  • Shprintzen syndrome
  • Conotruncal anomaly face syndrome
  • Due to the absence of decreased size of the thymus and low number of T lymphocytes
  • Due to microdeletion in chromosome band 22sq11.2
  • Cardiac defects
  • Distinctive facial features
  • Developmental delays
  • Phychiatrix dx
  • Kidney dx
  • Hypocalcemia
• BRUTON TYROSINE KINASE DEFICIENCY


  • X-lined agammaglobulinemia
  • Primary immunodeficiency dx characterized by reduction in all serum immunoglobulin isotypes and profoundly decreased or absent B cells
  • Produces recurring bacterial infections
  • Triad: Thrombocytopenia, Immunodeficiency, Eczema
• CHEDIAK -HIGASHI SYNDROME


  • rare autosomal recessive dx of immune dysregulation
  • Associated with mutation in the CHS1 LYST gene on chromosomes 1q42
  • Exhibits abnormally large lysosomes of granulocytes, monocytes and lymphocytes which contain fused dysfunctional granules (dense granules in platelets)
  • Clinical manifestation shows partial albinism with recurrent bacterial infection
• Pseudo/ Chediak Higashi syndrome

  • Granules are cytoplasmic inclusion that resemble the fused lysosomal granules
  • AML, CML, and MDS
• CONGENITAL DEFECTS AND PHAGOCYTES


  • Congenital Neutropenia
  • Elastase deficiency
  • Cyclic neutropenia
  • Kosann dx
  • X-lined neutropenia
  • Glycogen storage type 1b
• LEUKOCYTE ADHESION DISORDERS


  • Results in the inability of neutrophils and monocytes to adhere to endothelial cells that they are don't move form circulation to the site of inflammation
  • Causes recurrent severe bacterial and fungal infections
• Types of Leukocyte Adhesion Disorders


  • LAD I: mutation in ITGB2 resulting in either decrease or truncated form of the B2 integrin
  • LAD II: same as LAD I but have normal B2 integrins; molecular defects in SLC35C1; absence of blood group H antigen
  • LAD III: mutations in Kindlin- 3; failure to response to external signals; decreased platelet integrin GPIIb83 seen in Glanzmann thrombosthenia
• LEUKOCYTE ADHESION DISORDER


  • Shwachman-Bodian-Diamond Syndrome
  • Defects in leukocyte motility due to mutation in the SBDS gene located at 7q11.22
  • Affects the SBDS protein which has an important role in ribosomal maturation, cell proliferation and bone marrow microenvironment
• CHRONIC GRANULOMATOUS DISEASE (CGD)
• WHIM SYNDROME


  • Warts, hypogammaglobulinemia, infections and myelokathexis syndrome
  • Defects in intrinsic and innate immunity
  • Due to mutations in the CXCR4 gene located at 2q22
• MORPHOLOGIC ABNORMALITIES OF LEUKOCYTES WITHOUT ASSOCIATED IMMUNODEFICIENCY


  • PELGER-HUET ANOMALY
  • PSEUDO OR ACQUIRED PHA
  • NEUTROPHIL HYPERSEGMENTATION
  • ALDER-REILLY ANOMALY
  • MAY-HEGGLIN ANOMALY
  • ABNORMALITIES IN MACROPHAGES/MONOCYTES-LIPID ABNORMALITIES
• PELGER-HUET ANOMALY


  • True or congenital PHA
  • Autosomal dominant dx characterized by decreased nuclear segmentation and distinctive coarse chromatin clumping pattern. Affects all leukocytes
  • Mutation in laminated B receptor gene
  • Pelger-Huet nuclei appear round, ovoid or peanut-shaped
  • Bilobed forms (pince-nez) spectacle-like morphology with the nuclei attached by a thin filament
  • Heterozygous PHS: individuals are clinically normal
  • Homozygous PHS: individual has cognitive impairment, hear defects and skeletal abnormalities
• PSEUDO OR ACQUIRED PHA


  • associated with severe bacterial infections HIV, TB, and mucoplasma pneumonia
  • Immunosuppressants chemotherapy, valproate sulfisoxazole, fluconazole, ganciclovir, growth factors and ibuprofen
• Difference between true PHA vs Pseudo

  • True PHA: Number of infected cells >66%, All WBC lineage, Hereditary, Normal granulation
  • Pseudo PHA: Number of infected cells >35%, Restricted to neutrophils, Acquired, Hypo granular neutrophils
• NEUTROPHIL HYPERSEGMENTATION


  • Neutrophils with six or more lobes nucleus
  • Often associated with megaloblastic anemia, MDS, and hereditary neutrophil hypersegmentation
  • acquired (in megaloblastic erythropoiesis) or inherited (Undritz anomaly)
  • Found in pernicious anemia folic acid deficiency chronic infections
• ALDER-REILLY ANOMALY


  • Rare inherited disorder characterized by granulocytes with large, darkly staining metachromatic cytoplasmic granules
  • Initially reported in patients with gargoylism
  • Heavy, coarse blue black cytoplasmic granules (darkly staining metachromatic) found in WBCs of myelocyte series (granulocytes)
  • Inherited condition
  • Usually found in Hurler, Hunter syndrome, and Maroteaux-Lamypolydystrophic dwarfism
  • Defect on mucopolysaccharides
• MAY-HEGGLIN ANOMALY


  • Autosomal dominant infecting neutrophils and plts
  • Dohle like inclusion
  • Giant bizarre platelets may be present, and function may be abnormal
  • Mutation on MYH9 gene on chromosome 22q12-13
  • Disorder production of precipitated myosin heavy chain type IIA affect megakaryocyte maturation and plt fragmentation
• ABNORMALITIES IN MACROPHAGES/MONOCYTES-LIPID ABNORMALITIES


  after neutrophils, monocytes will attack next. Because of certain enzyme deficiency, there usually and accumulation of components within the cell
• LYSOSOMAL STORAGE DISEASE


  • Gaucher Disease
  • Niemann Pick Disease
  • Tay-Sach's
  • Sea blue histiocytes
  • Sandhoff disease
• Gaucher Disease


  • Most common
  • autosomal recessive disorder caused by a defect or deficiency in enzyme B-glucocerebrosidase
  • Wrinkled/crumpled cytoplasm
  • 1 in 17 Ashkemazi Jews are carrier
  • Triad: hepatomegaly, gaucher cells in BM and increased phosphate
  • TEST: PAS stain
  • chitotriosidase: useful in terms of determining of glucocerebrosidase in storage
  • biomarkers used in diagnosis and monitoring of dx
• Niemann Pick Disease


  • Accumulation of fat in cellular lysosomes of vital organs
  • foam cells and sea-blue histiocytes can be seen in the bone marrow
  • Deficiency: sphingomyelinase
  • Type A: infancy and death after 4 years; <5% of normal sphingomyelinase activity
  • Type B: more common 10 to 20% normal enzyme activity
  • Type C: mutations in NPC1nor NP2 gene with buildup of cholesterol in lysosomes
• Tay-Sach's


  accumulation of glycolipids and gangliocytes
• Sea blue histiocytes


  Lipids, Bluegreen cytoplasm
• Sandhoff disease


  Glycolipids, vacuolated cytoplasm
• MYELOPEROXIDASE DEFICIENCY


  Neutrophils and lysosomes monocytes inherited autosomal dominant defects chromosome 17
• ACUTE LEUKEMIA
• ACUTE LEUKEMIA


  • Leukos (white) and haima -(blood)
  • Refers to a rapid clonal proliferation of lymphoid and myeloid progenitor cell known as lymphoblasts and myeloblasts
  • Abnormal proliferation

  
• Symptoms of Acute Leukemia


  • Fever
  • Weight lost
  • Increase sweating
• Dominant cause of cancer, and death in children under 15
• Acute Lymphocytic Leukemia (ALL)


  • Most common in children
  • Most
• Iocytes


  Cells that can be seen in the bone marrow