NON-MALIGNANT WBC

• Chédiak-Higashi syndrome


  • Rare autosomal recessive disease of immune dysregulation
  • Associated with a mutation in the CHS1 LYST gene on chromosome 1q42.1-2
  • Many types of cells in the body are affected and exhibit abnormally large lysosomes, which contain fused dysfunctional granules
  • Clinical manifestations begin in infancy with partial albinism and severe recurrent life-threatening bacterial infections
  • Hematologic findings include giant lysosomal granules in granulocytes, monocytes, and lymphocytes
  • Patients often have bleeding issues as a result of abnormal dense granules in platelets
  • Death occurs before the age of 10 years
• Pseudo-Chédiak-Higashi granules


  • Cytoplasmic inclusions that resemble the fused lysosomal granules in Chédiak-Higashi syndrome
  • Have been reported in patients with acute myeloid leukemia, chronic myeloid leukemia, and myelodysplastic syndrome (MDS)
• Congenital neutropenias (CNs)


  • Rare group of genetic diseases characterized by low neutrophil count, increased risk of infection, organ dysfunction, and a high rate of leukemic transformation
  • Usually present in the first year of life as recurrent fevers caused by bacterial and fungal infections, which are often life threatening
  • Improvements in treatment, including antibiotic prophylaxis and use of granulocyte colony-stimulating factor (G-CSF), have decreased morbidity and mortality rates
  • Higher doses of G-CSF have been associated with increased risk of malignant transformation
  • Twenty-four genes have been identified as causing CN
• Leukocyte adhesion disorders (LADs)

  • Rare autosomal recessive inherited conditions resulting in the inability of neutrophils and monocytes to move from circulation to outside-in signaling
  • LAD I: Patients suffer from recurrent infections, often affecting skin and mucosal infections, lymphadenopathy, splenomegaly, and neutrophilia
  • LAD II: Patients have recurring infections, neutrophilia, growth retardation, a coarse face, and other physical deformities
  • LAD II is caused by molecular defects in SLC35C1, which codes for a fucose transporter that moves fucose from the endoplasmic reticulum to the Golgi region
• LAD II


  Leukocyte adhesion deficiency type II, caused by molecular defects in SLC35C1 which codes for a fucose transporter
• In LAD II, selectin synthesis is compromised
• LAD II patients


  • Have recurring infections, neutrophilia, growth retardation, a coarse face, and other physical deformities
• In LAD II, the defective fucose transporter


  Leads to an inability to produce functional selectins and defective leukocyte recruitment, which leads to recurring infections
• Other clinical findings related to defective fucose transport in LAD II are absence of blood group H antigen, growth retardation, and neurologic defects
• Cells from a patient with Chédiak-Higashi Syndrome

  • Neutrophil with large dark lysosomal granules
  • Monocyte with large azure granules
  • Lymphocyte with one large azure granule
• Consequences of leukocyte adhesion deficiency disorders are recurrent severe bacterial and fungal infections
• Hematopoietic stem cell transplant is the only curative treatment for leukocyte adhesion deficiency disorders
• LAD III


  Caused by mutations in Kindlin-3, which along with talin are required for activation of β integrin and leukocyte rolling
• In LAD III, leukocytes and platelets have normal expression of integrins, however there is failure in response to external signals that normally results in leukocyte activation
• LAD III patients


  • Experience a mild LAD I-like immunodeficiency with recurrent infections, and decreased platelet integrin GPIIbβ3 resulting in bleeding similar to Glanzmann thrombasthenia
• LAD I


  Caused by a mutation in ITGB2, the gene encoding the CD18 subunit of β2 integrins, resulting in either a decreased or truncated form of the B2 integrin
• The B2 integrin is necessary for adhesion to endothelial cells, recognition of bacteria, and the site of inflammation (called extravasation)
• Shwachman-Diamond syndrome (SDS)


  A rare autosomal recessive disease caused by mutations in the SBDS gene, which affects the SBDS protein product that has an important role in ribosomal maturation, cell proliferation and bone marrow microenvironment
• SDS patients


  • Are usually diagnosed in infancy with exocrine pancreatic insufficiency associated malabsorption, malnutrition, chronic steatorrhea, and failure to thrive, have bone marrow failure including cytopenias, myelodysplasia, and increased risk of acute leukemia, and suffer from recurring infections, skeletal abnormalities, skin and dental problems, and cognitive issues
• Hematopoietic stem cell transplant is an option for SDS patients with bone marrow failure, myelodysplastic syndrome (MDS), and acute leukemia
• Chronic granulomatous disease (CGD)

  A rare condition caused by the decreased ability of neutrophils to undergo a respiratory burst after phagocytosis of foreign organisms
• Approximately 60% of CGD cases are X-linked recessive and 40% are autosomal recessive, with X-linked recessive patients experiencing a more severe disease course and shorter lifespans
• CGD


  Caused by mutations in genes responsible for proteins that make up the reduced form of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase
• Normal phagocytosis of foreign organism

  Leads to phosphorylation and binding of cytosolic p47 phos and p67 phos, migration of primary granules containing antibacterial neutrophil elastase and cathepsin G and secondary granules containing the cytochrome complex gp91 phox and gp22phox to the phagolysosome, and formation of NADPH oxidase when p47 phos, p67 phos, p40 phox and RAC2 combine with the cytochrome complex, generating superoxide in the phagolysosome
• Most cases of CGD are due to mutations in gp91phox or p47
• CGD patients


  • Experience life-threatening catalase-positive bacterial and fungal infections, but advancements in care including prophylactic antibiotics and azole antifungals have improved the clinical course and increased survival rates
• CGD diagnosis


  Uses a test that measures intracellular production of reactive oxygen species with a fluorescent probe dihydrorhodamine
• WHIM (warts, hypogammaglobulinemia, infections, and myelokathexis) syndrome

  Classified as a defect in intrinsic and innate immunity, caused by mutations in the CXCR4 gene which regulates movement of white blood cells between the bone marrow and peripheral blood
• WHIM syndrome


  • Results in neutrophils accumulating in the bone marrow (myelokathexis), leading to low numbers of circulating neutrophils, as well as lymphopenia, monocytopenia, and hypogammaglobulinemia, causing recurrent bacterial infections and susceptibility to human papillomavirus infection
• Treatment for WHIM syndrome consists of antibiotic prophylaxis, immunoglobulin replacement therapy, and G-CSF, with CXCR4 receptor antagonists proving effective at increasing neutrophil and lymphocyte counts
• Pelger-Huët anomaly (PHA)


  An autosomal dominant disorder characterized by decreased nuclear segmentation and distinctive coarse chromatin clumping pattern, caused by a mutation in the lamin B-receptor gene
• PHA


  • Affects all leukocytes, with morphologic changes most obvious in mature neutrophils, which may appear round, ovoid, peanut-shaped, or have a bilobed "pince-nez" appearance
• Virtually all identified cases of PHA are heterozygotes, in which greater than 68% of neutrophils exhibit PH morphology, while homozygous PHA is rare and may be associated with cognitive impairment, heart defects, and skeletal abnormalities
• Neutrophils in PHA appear to function normally
• Pseudo- or Acquired Pelger-Huët Anomaly


  Neutrophils with similar morphology to PHA can be seen in patients with MDS, acute myeloid leukemia, myeloproliferative neoplasm, severe bacterial infections, HIV, tuberculosis, mycoplasma pneumonia, and with certain drugs
• Pseudo-PHA neutrophils


  • May be misclassified as myelocytes, metamyelocytes, or band neutrophils, leading to unnecessary tests, misdiagnosis, and inappropriate treatment, but they maintain normal function and their presence is not associated with inflammation, infection, or other causes of a neutrophilic left shift
• Differentiating between true and pseudo-PHA can be challenging, but true PHA is characterized by a higher percentage of affected cells (>68% vs <35%), and involvement of all WBC lineages, while pseudo-PHA is restricted to neutrophils except in MDS
• Neutrophil hypersegmentation


  Neutrophils with more than five lobes, most often associated with megaloblastic anemia but also seen in MDS
• Alder-Reilly anomaly (AR)


  A rare inherited disorder characterized by granulocytes (and sometimes monocytes and lymphocytes) with large, darkly staining metachromatic cytoplasmic granules containing partially digested mucopolysaccharides
• Leukocyte function is not affected in AR, and the characteristic Reilly bodies can differentiate it from toxic granulation in neutrophils