Nonmalignant hereditary disorders of leukocytes

PELGER-HUËT ANOMALY

Hyposegmentation of nucleus

HEREDITARY NEUTROPHIL HYPERSEGMENTATION

• Inheritance Pattern: Autosomal Dominant

• Neutrophils are hypersegmented.

• Mean of 4 lobes (N: 2-5 lobes; mean of 3)

• Rare; Not associated with disease

• Hypersegmentation is not necessarily attributable to Vitamin B12 or Folic Acid Deficiency.

MAY-HEGGLIN ANOMALY

• Inheritance Pattern: Autosomal Dominant

• Rare

• Leukopenia

• Thrombocytopenia

• Giant platelets: Large platelets may be hypogranular

ALDER-REILLY ANOMALY

• Inheritance Pattern: Autosomal Recessive

• Abnormally large azurophilic and basophilic granules called Alder Reilly Bodies.

• Found in storage diseases (eg. mucopolysaccharidoses)

• Resemble severe toxic granulation

• Toxic granulation is not found in all neutrophil forms.

HYPERIMMUNOGLOBULIN E (JOB’S SYNDROME)

• Mode of Inheritance: Autosomal Dominant

• Defect: neutrophil and monocyte chemotaxis

• Cells respond slowly to chemotactic stimuli

• Rapid multiplication of bacteria

• Patient suffers from persistent boils, and recurrent “cold” staphylococcal abscesses

• Mechanism: Increased level of IgE is the result of insufficient suppressor T-cell function.

• Release of chemotactic inhibitor by mononuclear cells = increased susceptibility to bacterial infections

LAZY LEUKOCYTE SYNDROME

• Mode of Inheritance: Unknown

• Random and directed movement of cells are defective.

• Bone marrow (BM) reserves of granulocytes are normal, but release of cells to peripheral blood (PB) is poor à which causes neutropenia

• Cells fail to respond to inflammatory stimuli à there is defect in neutrophil chemotaxis

• Normal phagocytic and bactericidal activity • Cells contain defective actin filaments

LEUKOCYTE ADHESION DEFICIENCY

• Mode of Inheritance: Rare Autosomal Recessive Disorder

• Recurrent skin and soft tissue infections; neutrophilia

• Neutrophils fail to migrate to inflammatory sites

• Poor wound healing Deficiency or total lack of leukocyte surface glycoproteins CD 11/18 complex or β2 integrins

CHÉDIAK-HIGASHI SYNDROME

• Inheritance Pattern: Autosomal Recessive

• Giant cytoplasmic granules in phagocytes and lymphocytes

• Basic defect: membrane fusion protein for the secretion of the lysosomal compartment of cells

• There is Partial albinism: Due to pigmentary dilution and photophobia

• Hemorrhagic tendencies

• Recurrent infections

CHRONIC GRANULOMATOUS DISEASE (CGD)

• Mode of Inheritance: Sex-linked or Autosomal Recessive (Defective gene in chromosome 16)

• Rare; Detected in childhood

• Recurrent life-threatening infection by catalase (+) organisms

• Happens when phagocytes ingest but cannot kill catalase (+) organisms

• Due to a lack of an appropriate respiratory burst caused by mutations in one of several genes encoding for respiratory burst oxidase proteins

Nitroblue-Tetrazolium Screening Test (NBT)

• Detects abnormal oxidase activity found in CGD

• Indirect test for respiratory burst power

• Result is negative for CGD

CONGENITAL C3 DEFICIENCY

• Inheritance Pattern: Autosomal Recessive

• Deficiency of complement component C3

• Heterozygous carriers have 1⁄2 the normal C3 activity (adequate for disease resistance)

• Homozygotes suffer from repeated severe infections with encapsulated bacteria

• Failure of opsonization by C3b causes poor

• Recognition and inefficient phagocytosis

MYELOPEROXIDASE DEFICIENCY

• Inheritance Pattern: Autosomal Recessive

• Bacterial killing is slowed but complete

• Patients rarely troubled by infections

ingestion and disposal of foreign substances, unwanted biosynthetic products of cells and their breakdown products including lipids, CHO, CHONs, and nucleotides

FUNCTION OF MMS

• Abnormal increase in catabolism causing overload in cellular breakdown products

• Lack of an enzyme needed to metabolize the substances

• Indigestibility of ingested particles

Mechanisms associated with abnormal accumulation of substances in macrophages:

MUCOPOLYSACCHARIDOSES (MPS)

• Due to a deficiency of specific enzymes involved in the degradation of mucopolysaccharides

• Cells in affected tissues are swollen and have ballooning and clearing of their cytoplasm.

LIPID STORAGE DISEASE (LIPIDOSES)

• Inheritance Pattern: Autosomal Recessive trait

• Macrophages of tissues become overloaded with lipid

• Due to lack of a functional enzyme needed for lipid breakdown

• Highest incidence in Ashkenazic Jews (except for Gaucher Disease Type II)

GAUCHER DISEASE

• Inheritance Pattern: Autosomal Recessive

• Most common of the lipidoses

• Deficiency of enzyme β-glucosidase resulting to macrophage accumulation of glucocerebrosides (lipids) in spleen, liver, and bone marrow

• Types I-III

GAUCHER CELL

• Large macrophage with small eccentrically located nucleus

• Cytoplasm distended with glucocerebrosides

• “Crinkled” appearance o (+) PAS

• Striations in cytoplasm

TYPE I

• Most common

• “adult” form

• Sx benign in childhood/early adulthood

• Splenomegaly, Diminished liver function, Bone involvement

• CNS not affected

• Ashkenazi Jews

• Death due to liver disease, bleeding, sepsis

TYPE II

• Infantile/cerebral form

• Neurologic deterioration

• CNS involvement

• No predilection for Jews

• Death within first few years of life

Death within first few years of life

• Juvenile form

• Early childhood, Adolescence, Early adulthood

• Liver, Spleen, Bone

• CNS occasionally involved

• Ashkenazi Jews

• Short life expectancy

NIEMANN-PICK DISEASE

• Abnormal accumulation of sphingomyelin and cholesterol in phagocytic and parenchymal cells

• There are 5 categories (A-E)

• Estrogen therapy

• Cytoplasm of BM macrophages is swollen by small uniform lipid droplets (“foam” cells)

Identification of sphingomyelin in tissue biopsies

Diagnosis of Niemann-Pick disease

SEA-BLUE HISTIOCYTE SYNDROME

Adult form of Niemann-Pick Type B

TYPE A (Neuropathic)

• Deficient activity of lysosomal hydrolase, acid sphingomyelinase

• Infancy Infancy Failure to thrive (up to 3 years old only)

• Marked hepatosplenomegaly

• Neurologic deterioration

TYPE B (Non-neuropathic)

• Same enzymes deficient

• Adult form

• Infancy

• Survive into adulthood

• Hepatosplenomegaly

• No neurologic involvement

X-LINKED (BRUTON) AGAMMAGLOBULINEMIA

• Failure of B-cell precursors to develop to mature B cells

• Due to mutations in cytoplasmic tyrosine kinase

• Transmitted from mother to male offspring (6 months)

• Recurrent bacterial infections

• All classes of immunoglobulins are low to absent

• T-cell system is normal à Immunity to viral infections

DiGeorge SYNDROME (CONGENITAL THYMIC APLASIA)

• T-cell deficiency

• Defective development of thymus and parathyroid glands due to abnormal development of 3rd and 4th pharyngeal pouches

• Thymic hypoplasia, hypoparathyroidism, and immunodeficiency

deletion of chromosome 22q11 region

Defect in DiGeorge syndrome

WISKOTT-ALDRICH SYNDROME

• Inheritance Pattern: Sex-linked Recessive

• Both B- and T-cell function are impaired

• Increased incidence of lymphoreticular malignancies in male survivors

• Eczema

• Thrombocytopenia

• Recurrent bacterial & viral infections

WAS is characterized by?