JPC SYSTEMIC PATHOLOGY
CARDIOVASCULAR SYSTEM
February 2022
M-M02

Signalment: (JPC #2314367):  Angus calf

 

HISTORY:  None

 

HISTOPATHOLOGIC DESCRIPTION:  Long bone, longitudinal section:  Extending from both the epiphyseal and metaphyseal surfaces of the physis, filling the marrow cavity, and extending into the diaphysis are increased numbers of irregular, enlarged, anastomosing trabeculae of immature woven bone (primary spongiosa) that form horizontal connections to adjacent trabeculae and often have retained cartilage cores containing hypertrophic chondrocytes.  The central cartilaginous cores are surrounded by variably thick layers of osteoid and mineralized bone.  There are markedly reduced numbers of both osteoclasts and osteoblasts. Diffusely, there is a marked decrease in hematopoietic elements within medullary spaces; medullary spaces often contain a small amount of loose fibrous connective tissue.

 

MORPHOLOGIC DIAGNOSIS:  Long bone, epiphysis, metaphysis, and diaphysis:  Persistent primary spongiosa with osteoclastopenia, failure of chondroclasis, and diffuse medullary osteosclerosis (osteopetrosis), Angus, bovine.

 

CONDITION:  Bovine congenital osteopetrosis

 

SYNONYMS:  Marble bone disease, Albers-Schonberg disease

 

GENERAL DISCUSSION:

• Osteopetrosis encompasses a group of rare disorders characterized by defects in osteoclastic bone resorption with resultant primary spongiosa accumulation in the marrow cavity; there are no primary lesions in the growth plate; cortical bone is either too thin or inadequately compacted in animals with laminar (plexiform) cortical bone growth resulting in pathological fractures ( rapidly growing cattle and small ruminants)
• Occurs in humans and domestic animals (cattle, dogs, cats, sheep, horses, rats, mice); most affected animals are stillborn
  • Most common in Aberdeen-Angus cattle including red Angus, also occurs in Hereford, Simmental, Belgian blue, and Holstein breeds

 

PATHOGENESIS:

• In animals, the condition is suspected to be autosomal recessive but may be caused by viruses (acquired or infectious forms of osteopetrosis) such as bovine viral diarrhea virus (BVDV), feline leukemia virus, avian leukosis virus, canine distemper, Gibbon ape leukemia virus (GALV) or lead poisoning
• Normal osteoclast production and activity:
  • Pluripotential stem cell > colony forming unit-granulocyte/monocyte (CFU-GM) > macrophage > osteoclast
  • Osteoclastogenesis is dependent on stromal cell production of macrophage colony stimulating factor (M-CSF) and osteoblast/osteoclast production of RANKL (receptor activator of nuclear factor kappa B ligand)
• Causes of improper bone resorption by osteoclasts (irrespective of number of osteoclasts present):
  • Genetic mutations impairing osteoclast production or function:
    • Proton pump (ATP6i): Osteoclasts are unable to resorb bone
    • Chloride channel (CLCN7, chloride/proton exchanger lysosomal anion transporter): Disruption of osteoclast acidification abilities; autosomal recessive missense mutation in Belgian blue cattle in Europe which have osteopetrosis, abnormal skull formation, and mandibular gingival hamartomas
    • RANKL: Impacts differentiation of osteoclasts, which will be absent or very low in numbers
    • SLC4A2: Osteopetrosis in Red Angus is due to a mutation in the gene, which normally exports bicarbonate ions in exchange for chloride ions (preventing toxic buildup of bicarbonate ions during acidification); mutation results in defective osteoclasts and reduced numbers; affected calves can be homo- or heterozygous
    • Undetermined genetic defect resulting in similar appearance in Hereford and Simmental breeds: Hereford frontal bone are thickened and contain cystic spaces (may also be present inmetaphyseal areas of long bones); not to be confused with hydrocephalus
  • Virus: Cattle persistently infected (PI) with BVDV have reduced numbers of osteoclasts resulting in cyclic abnormal trabecular modeling > osteopetrosis
    • BVDV persistent infection may impair osteoclast differentiation either due to a direct effect of viral infection on precursor cells or as a secondary effect as a result of the action of cytokines

TYPICAL CLINICAL FINDINGS:

• Usually stillborn, undersized, and premature (250-275 days gestation)
• In red Angus calves, dorsoventral compression of the medulla oblongata and degeneration of cranial nerves combined with cerebellar herniation and compression of the parietal cortex is the likely basis for abortion, stillbirth, and perinatal death
• Severe cases: Insufficient hematopoiesis due to improper bone marrow cavities can cause thrombocytopenia, nonregenerative anemia, and susceptibility to infections

TYPICAL GROSS FINDINGS:

• Marrow cavities of endochondral bone are filled with unresorbed primary spongiosa that may be evident grossly as cone-shaped bony material extending from metaphysis into the diaphysis
• Brachygnathia inferior, sloping forehead, impacted molars, and protruding tongue
• Long bones have normal shapes but are shorter are easily fractured; vertebrae are compact
• Intramembranous bones of the skull are dense and thick
• Diploe (spongy bone separating the two layers of compact bone of the skull) of the occipital, frontal, and parietal bones are absent, leading to flattened cerebral hemispheres and partial cerebellar herniation
• Many nutrient and cranial nerve foramina throughout the skeleton are hypoplastic or absent
• Optic nerves are hypoplastic, neurological complications and blindness secondary to compression of brainstem and cranial nerves
• Red Angus: Severe atrophy of optic nerves, craniofacial lesions
• Dysplastic changes in premolar and molar teeth: intra-alveolar intermingling of dentin, enamel, cementum, and bone contributing to dental ankyloses
• Liver: Enlargement due to extramedullary hematopoiesis

 

TYPICAL LIGHT MICROSCOPIC FINDINGS:

• Bones: metaphyses and diaphyses contain cones of abundant dense, unresorbed primary spongiosa that span the metaphysis to the center of the diaphysis
  • Decreased remodeling of mature bone
  • Depending on species, osteoclasts are either:
    • Rare in long bones
    • Present in high numbers but either lack a ruffled border depending on species or may not be in contact with trabeculae, may have scant to vacuolated cytoplasm
  • Skull bones: absence or hypoplasia of nutrient and cranial nerve foramina
  • Physis: Normal or increased in width
  • Primary spongiosa/trabeculae: Chondro-osseous dense tissue composed of cartilage matrix with a thin lining of woven bone fills the medulla
  • Cortical bone: normal or may be osteopenic
• Teeth: Dentin, enamel, cementum, and bone are interwoven (dysplastic)
• Eyes: Loss of retinal ganglion cells with severe atrophy of optic nerves
• Brain: Mineralized vessel walls and/or neurons in thalamus, cerebellum, meninges, choroid plexuses, and on the periphery of mesencephalic aqueduct; chromatolysis of cranial nerve nuclei; periventricular corpora amylacea in the thalamus, caudate nucleus, and midbrain
• Liver and spleen: Extramedullary hematopoiesis

 

DIFFERENTIAL DIAGNOSIS:

• Osteopetrosis-like osteosclerosis can be induced in young animals by treatment with parathyroid hormone, estrogen, diphosphonates, and hypercalcemia; affected animals have persistence of secondary spongiosa with normal primary spongiosa and growth plates
• Lead toxicity: Metaphyseal osteosclerosis extending toward the diaphysis;  acid-fast eosinophilic intranuclear and cytoplasmic inclusion bodies in osteoclasts
  • Characteristic lesion on radiographs in the metaphysis of immature long bones - lead line (a band of sclerosis)
  • Ultrastructurally – Excessive mineralized cartilage matrix in the cytoplasm of osteoclasts (suggests defect in intracellular processing of the matrix)
• Multifocal osteopetrosis-like retention of primary spongiosa is associated with bovine pestivirus (BVDV); maternal infections known to cause zones of metaphyseal sclerosis parallel to the growth plate (growth retardation lattices)

 

COMPARATIVE PATHOLOGY:

• Mice:
  • Op/op mice and knock-out c-src mice are models of osteopetrosis and have failure of tooth eruption, hair abnormalities, retardation of growth, and hepatosplenomegaly due to extraskeletal hematopoiesis; odontomas near unerupted incisors in c-src mice obliterate airways causing suffocation
  • Clcn7 ^–/– mice show diffuse osteopetrosis accompanied by severe retinal and neuronal degeneration although a recently developed mutant Clcn7-/- mouse did not develop osteopetrosis, but still developed lethal neural and retinal degeneration
• Chickens: Avian leukosis virus (M-V03) induces avian retroviral type C osteopetrosis (of long bone or boot shanks) which results in abnormal growth and differentiation of osteoblasts; osteoblasts are increased in number and size and osteoclasts are decreased in number
• Pet birds: Osteopetrosis is caused by chronic fluorine toxicity
• Felines: Chronic vitamin D toxicosis and subsequent to infection with feline leukemia virus associated with medullary osteosclerosis; lymphoma and myeloproliferative disease may also cause osteosclerosis
• Cats: Diffuse osteosclerosis (a type of osteopetrosis) secondary to lymphoma, myeloproliferative disease, or systemic lupus erythematosus
• Horses: Peruvian Paso foals and an Appaloosa - Abnormal osteoclast function (no ruffled border and few lysosomes are present ultrastructurally), but normal to increased numbers of osteoclasts
• White-tail deer: Have brachygnathia inferior, impacted teeth, and protruding tongue
• Polypay sheep in Oregon: Brachygnathia inferior and osteopetrosis with multiple limb fractures; microscopic lesions are similar to what is seen in bovine characterized by a large number of osteoclasts that lacked a ruffled border and were not in contact with bony trabeculae
• Dogs:
  • Canine distemper virus causes growth retardation lattices; experimental infections in puppies resulted in transient lesions that resolved once viral antigen disappeared
  • Dachshund (littermates) – normal size, shape, but had increased bone fragility
  • Australian Shepherd and Pekingese – severe myelophthistic anemia
  • Newfoundland dogs – Can have sclerosing dysplasia of the radial and ulnar metaphyses
• Apes: Osteopetrosis in one of many lesions associated with Gibbon ape leukemia virus (GALV); other lesions include malignant lymphoma, lymphoblastic leukemia, myelogenous (granulocytic) leukemia
• Humans: Two forms:
  • Malignant - Recessively inherited and lethal
  • Benign – Dominant and manifest in adolescence or adults

 

REFERENCES:

1. Lowenstine LJ McManamon R, Terio KA. Apes. In: Terio KA, McAloose D, Judy St. Leger J, ed. Pathology of Wildlife and Zoo Animals, Cambridge, MA: Academic Press; 2018:391.
2. Craig LE, Dittmer KE, Thompson KG. Bones and joints. In: Maxie MG, ed. Jubb, Kennedy and Palmer’s Pathology of Domestic Animals. Vol 1. 6th ed. Philadelphia, PA: Elsevier; 2016:50-52, 86, 87, 104, 105, 320.
3. Olson EJ, Carlson CS. Bones, joints, tendons, and ligaments. In: McGavin MD, Zachary JF, eds. Pathologic Basis of Veterinary Disease. 6th ed. St. Louis, MO: Elsevier; 2017:973-974.
4. Schmidt RE, Reavil DR, Phalen DN. Musculoskeletal System. Pathology of Pet and Aviary Birds. 2^nd Ames, IA: John Wiley & Sons, Inc.; 2015:212-213.
5. Stockham SL, Scott MA. Fundamentals of Veterinary Clinical Pathology. 2nd ed., Ames, IA: Blackwell Publishing Professional; 2008:160, 163, 234, 237, 338, 342.

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