JPC SYSTEMIC PATHOLOGY
Signalment (JPC# 86-950): A 4-month-old calf
HISTORY: Tissue from a calf euthanized because of necrotizing glossitis and abscessation of the mandible
HISTOPATHOLOGIC DESCRIPTION: Kidney, periodic acid-Schiff stain (PAS) stain: Diffusely, cortical tubular epithelial cells contain single to multiple, irregularly round, intracytoplasmic, variably PAS-positive (bright pink to red) bodies that measure up to 15um in diameter. Multifocally, medullary tubular epithelial cells occasionally contain similar intracytoplasmic, PAS-positive material. There is mild diffuse subcapsular tubular ectasia. Focally, the interstitium is minimally expanded by few lymphocytes and plasma cells.
MORPHOLOGIC DIAGNOSIS: Kidney, tubular epithelium: Intracytoplasmic PAS-positive bodies, diffuse, moderate, breed unspecified, bovine.
ETIOLOGIC DIAGNOSIS: Hereditary renal tubule hypergranulation
CONDITION: Chédiak-Higashi Syndrome (CHS)
- Autosomal recessive disorder of Aleutian mink; Hereford, Japanese Black, and Brangus cattle; blue smoke Persian cats; beige rats and mice; killer whales; blue and silver foxes; white tigers; bison; and man
- Results in the accumulation of abnormally large granules in a variety of cell types including leukocytes, platelets, hepatocytes, renal tubular epithelium, neurons, endothelial cells, and melanocytes
- Granules are:
- Melanosomes (melanocytes)
- Lysosomes (many cell types)
- Cytoplasmic granules (e.g. fused primary and secondary granules of neutrophils)
- Affected animals have an increased susceptibility to infection (a common cause of death of animals with CHS), partial oculocutaneous hypopigmentation, photophobia, and bleeding tendencies
- Autosomal recessive genetic defect (LYST gene, some sources also indicate Beige gene) resulting in reduced or absent formation, migration, and exocytosis of lysosomes with resultant abnormal granule formation in many cells (e.g. lysosomes, cytolytic granules, platelet granules, and melanosomes)
- LYST gene (cattle, mink, mice, some humans): membrane-associated lysosomal trafficking regulator gene
- Beige gene (beige mice, Japanese black cattle, rats, and somehumans)
- The fusion of pre-existing normal granules results in the formation of giant granules within the cytoplasm of neutrophils, eosinophils, basophils, monocytes, lymphocytes, thrombocytes, and other cells types, including hepatocytes, renal tubule epithelial cells, neurons, endothelial cells, and melanocytes
- Immune dysfunction:
- Leukocytes exhibit defective motility and chemotactic response
- Impaired fusion of lysosomes with phagosomes results in decreased bactericidal activity with normal neutrophil counts; phagocytosis is unaffected
- Loss of CD8 T-cell and natural killer cell cytotoxic activity, resulting in increased susceptibility to neoplasia (especially lymphoproliferative tumors) and viral infection
- Hypopigmentation: Partial albinism (color dilute effect) due to the formation of giant melanosomes that are passed only with difficulty from melanocytes to keratinocytes
- Bleeding tendencies: Platelet dense (delta) granules are either absent or indistinct with defective storage of ADP (ADP normally promotes platelet adherence and aggregation), resulting in deficient platelet clumping especially in response to exposed collagen
- Dense granules contain serotonin, histamine, epinephrine, Mg++, ATP/ADP, Ca++, GTP/GDP
- Coagulation is normal in Japanese black cattle and cats with CHS
TYPICAL CLINICAL FINDINGS:
- Skin: Hypopigmentation
- Eyes: Photophobia, lacrimation, cataract (cats)
- Bleeding disorders: Platelet numbers are normal but have impaired function resulting in prolonged hemorrhage from minor wounds, hematomas at injection sites, and death from acute hemorrhage; prolonged buccal mucosal bleeding time test
- Leukocyte dysfunction: Recurrent infections
TYPICAL GROSS FINDINGS:
- Skin: Hypopigmentation
- Eyes: Abnormal ocular pigmentation (pseudoalbinism); cataracts (cats)
- Occasionally cutaneous abscesses, oral ulcers, and subcutaneous hematomas secondary to leukocyte and platelet defects
TYPICAL LIGHT MICROSCOPIC FINDINGS:
- Hallmark of the disease is the presence of enlarged granules within melanocytes, neutrophils, eosinophils, and monocytes
- Haired skin: Irregular clumping of melanin within hair shafts, decreased number of melanin granules within the pigmented layer of the epidermis
- Eyes: Hypopigmentation of the iris and fundus
- Kidney: Variably sized, irregular, PAS-positive granules within the tubule epithelial cells
- Giant granules in all granule-containing cells
- Marked decrease of osmiophilic dense bodies and cytoplasmic vesicles
ADDITIONAL DIAGNOSTIC TESTS:
- Cytology: Detection of leukocytes containing giant granules on blood smear or hair shafts with enlarged melanosomes are convenient methods of diagnosis
- Enlarged intracytoplasmic granules: None
- Cats: CHS is the cause of the blue-smoke color of certain Persian cats; it is frequently associated with cataracts and increased susceptibility to respiratory infections and neonatal septicemia
- Mink: CHS is the cause of the blue-grey fur color of Aleutian mink; although all mink are susceptible to Aleutian mink disease parvovirus, mink with the Aleutian trait are particularly susceptible to severe and fatal disease (U-V05, P-V14)
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