Non-Malignant Leukocyte Disorders Overview

Non-Malignant Leukocyte Disorders

• These disorders are not caused by cancerous changes in immature blood cells
• Causes can be genetic or acquired
• They affect one or more lineages (neutrophils, lymphocytes, monocytes, eosinophils, and basophils)
• The number of circulating cells, their morphology, or both can be altered
• Many of these disorders correlate with significant clinical manifestations, though some are benign

Qualitative Non-Malignant Leukocyte Disorders

• These are characterized by morphological abnormalities involving neutrophils
• Defects in leukocyte motility/movement are possible
• Defective respiratory burst is a common issue
• Lysosomal storage disorders may occur, and inherited disorders of lymphocytes can be seen
• Defects in neutrophils are relevant (hypersegmentation, Alder-Reilly anomaly, May-Hegglin anomaly, Chédiak-Higashi syndrome, Pelger-Huet anomaly)

Pelger-Huet Anomaly (PHA)

• This is an autosomal dominant disorder characterized by distinctive coarse, decreased nuclear segmentation, and chromatin clumping
• Affects all leukocytes, but the morphological changes are most pronounced in mature neutrophils
• Mutations in the lamin B-receptor gene
• The lamin B receptor in the inner nuclear membrane is critical to leukocyte nuclear shape changes
• Heterozygous PHA is normal; homozygous PHA can lead to cognitive impairment, heart defects, and skeletal abnormalities

Alder-Reilly Anomaly

• A rare disorder marked by granulocytes (monocytes and lymphocytes) with large, darkly staining metachromatic cytoplasmic granules
• Initially noted in patients with gargoylism, it can also appear in otherwise healthy individuals
• Granulations are sometimes seen in mucopolysaccharidoses (MPSs)

May-Hegglin Anomaly

• An autosomal dominant disorder characterized by variable thrombocytopenia, giant platelets, and large Dohle body-like inclusions in neutrophils, eosinophils, basophils, and monocytes
• Results from a mutation in the MYH9 gene, disrupting myosin heavy chain type IIA production, affecting megakaryocyte maturation and platelet fragmentation

Chédiak-Higashi Syndrome

• A rare autosomal recessive immune dysregulation disease resulting from a CHS1 LYST gene mutation
• Affects many cell types, causing unusually large lysosomes containing dysfunctional granules
• Initial symptoms usually occur in infancy, marked by partial albinism and severe recurrent life-threatening bacterial infections
• Patients often have bleeding problems due to abnormal dense granules in platelets, and death typically occurs before age 10

Defective Leukocyte Motility/Movement

• Job's Syndrome: Abnormal chemotaxis/directional motility resulting in persistent boils and recurrent staphylococcal abscesses
• Lazy leukocyte syndrome: Cells fail to respond to inflammatory stimuli, but phagocytic and bactericidal activity remain normal

Leukocyte Adhesion Disorders (LADs)

• Rare autosomal recessive inherited conditions
• Characterized by an inability of neutrophils and monocytes to move from circulation to the site of inflammation (extravasation)
• Consequences include recurrent severe bacterial and fungal infections
• Hematopoietic stem cell transplant is the only curative treatment
• Types include LAD I, II, III, and others (e.g., Shwachman-Bodian-Diamond syndrome)

WHIM Syndrome

• Characterized by warts, hypogammaglobulinemia, infections and myelokathexis
• A defect in intrinsic and innate immunity related to mutations in the CXCR4 gene. The CXCR4 protein regulates the movement of white blood cells
• Neutrophils accumulate in the bone marrow (myelokathexis), resulting in low circulating neutrophils
• Patients experience recurrent bacterial infections and have a high susceptibility to human papillomavirus (HPV) infection, which can cause warts

Defective Respiratory Burst

• Chronic Granulomatous Disease (CGD): This is a rare condition caused by decreased ability of neutrophils to undergo the respiratory burst after phagocytosis of foreign organisms
• This results from mutations in genes involved in the reduced form of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. This leads to life-threatening catalase-positive bacterial and fungal infections
• Congenital C3 Deficiency: Defects result in the inability to produce a respiratory burst.
• G-6-PD Deficiency: Impairs the production of NADPH oxidase, leading to defects in bactericidal activity.
• Myeloperoxidase (MPO) Deficiency: Low or absent MPO in neutrophils and monocytes leads to reduced bactericidal killing activity

Lysosomal Storage Diseases (LSDs)

• These are due to inherited enzyme deficiencies leading to the buildup of undigested materials in lysosomes
• The effect is to cause cell dysfunction, cell death, and a range of clinical symptoms that affect cells containing lysosomes
• Classified according to the accumulated macromolecule
• Examples: Lipid storage disease/sphingolipidoses and mucopolysaccharidoses

Lipid Storage Disorders (Sphingolipidoses)

• Qualitative disorders involving monocytes and macrophages, which accumulate undegraded lipid products, expanding reticuloendothelial tissue
• Examples are Gaucher's disease and Niemann-Pick disease

Gaucher's Disease

• Most common of the lysosomal lipid storage diseases
• Autosomal recessive disorder related to a defect or deficiency in the catabolic enzyme beta-glucocerebrosidase
• Accumulation of sphingolipid glucocerebroside in macrophages throughout the body
• Includes osteoclasts in bone and microglia in the brain
• Bone marrow replacement leads to anemia and thrombocytopenia
• Pseudo-Gaucher cells may be present in bone marrow in some patients with specific cancers

Niemann-Pick Disease

• Results from a deficiency in the enzyme acid sphingomyelinase, leading to the accumulation of sphingomyelin in cellular lysosomes
• Three subtypes: A, B, and C
• Type A is an acute neuronopathic form, primarily affecting Eastern European Jewish populations
• Type C is a non-neuronopathic form, more common in individuals of Northern African descent

Other Lipid Storage Diseases

• Includes detailed descriptions of differing enzyme deficiencies and the resultant accumulated substances in relevant diseases.

Inherited Disorders of Lymphocytes

• Describes various B-cell and T-cell deficiencies including Bruton-Tyrosine Kinase deficiency, Common Variable Immunodeficiency, 22q11 Syndromes, Severe Combined Immunodeficiency (SCID) , X-linked SCID, Adenosine deaminase deficiency, and Wiskott-Aldrich syndrome

Quantitative Non-Malignant Leukocyte Disorders

• Covers conditions related to increased or decreased counts of specific leukocytes (e.g., neutrophils, eosinophils, basophils, monocytes, lymphocytes).
• Provides associated causes and conditions for each leukocyte category