JPC SYSTEMIC PATHOLOGY
Signalment: (JPC #2314367): Angus calf
HISTOPATHOLOGIC DESCRIPTION: Long bone, longitudinal section: Extending from both the epiphyseal and metaphyseal surfaces of physis, are increased numbers of irregular, enlarged, anastomosing trabeculae of immature woven bone (primary spongiosa), that often have retained cartilage cores with retained hypertrophic chondrocytes, which fill the marrow cavity and extend into the diaphysis. Trabeculae form horizontal connections to adjacent trabeculae and contain a central cartilaginous core surrounded by variably thick layers of osteoid and mineralized bone. There are markedly reduced numbers of both osteoclasts and osteoblasts. Diffusely, there is an overall decrease in hematopoietic elements within medullary spaces and they often contain small amounts of loose fibrous connective tissue. Cortical bone thickens advancing toward the diaphysis.
MORPHOLOGIC DIAGNOSIS: Long bone: 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
- Encompasses a group of rare disorders characterized by defects in osteoclastic bone resorption and primary spongiosa accumulation in the marrow cavity
- Occurs in humans and domestic animals
- It is suspected to be autosomal recessive, but may be caused by viruses such as BVDV, feline leukemia virus, canine distemper and lead poisoning
- Most common in Aberdeen-Angus cattle, including red Angus, also occurs in Hereford, Simmental, Belgian blue and Holstein breeds
- 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 RANKL (receptor activator of nuclear factor kappa B ligand)
- Improper bone resorption by osteoclasts may be due to mutations:
- proton pump (ATP6i): osteoclasts are unable to resorb bone
- chloride channel (CLCN7): disruption of osteoclast acidification abilities
- RANKL: impacts differentiation of osteoclasts, which will be absent or very low in numbers
- Mutations at any point in this progression can lead to osteopetrosis
- Osteopetrosis in red Angus is due to a mutation in the SLC4A2 gene, which 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
- Similar appearance in Hereford and Simmental breeds
- Hereford frontal bones are thickened and contain cystic spaces; not to be confused with hydrocephalus
- Belgian blue cattle: Autosomal recessive missense mutation in the chloride/proton exchanger lysosomal anion transporter (CLCN7)
- BVDV in persistently infected (PI) cattle have reduced numbers of osteoclasts resulting in cyclic abnormal trabecular modeling > osteopetrosis
- PI with BVDV 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
- Horses with osteopetrosis have abnormal osteoclast function (no ruffled border and few lysosomes are present ultrastructurally), but normal to increased numbers of osteoclasts
- Similar appearance in Hereford and Simmental breeds
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
TYPICAL GROSS FINDINGS:
- Brachygnathia inferior, sloping forehead, impacted molars and protruding tongue
- Long bones have normal shapes but are shorter are easily fractured; vertebrae are compact
- Marrow cavities of endochondral bone are filled with primary spongiosa; unresorbed cones of primary spongiosa may be evident grossly extending from metaphysis into the diaphysis
- 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
- Dysplastic change in premolar and molar teeth comprised 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 abundant, dense, unresorbed primary spongiosa cones that span the metaphysis to the center of the diaphysis
- Decreased remodeling of mature bone; rare osteoclasts in long bones (osteoclasts in the skull may be numerous and may not be in contact with trabeculae)
- May see large numbers of osteoclasts that lack a ruffled border depending on species
- Skull bones: absence or hypoplasia of nutrient and cranial nerve foramina
- Cartilage of the growth plate is normal or increased in width
- Chondro-osseous dense tissue, composed of cartilage matrix with a thin lining of woven bone that also fills the medulla
- Teeth: dentin, enamel, cementum, and bone are interwoven
- Long bone trabeculae are thickened and fill the marrow cavity
- Normal cortical bone or may be osteopenic
- 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 Sylvius aqueduct; chromatolysis of cranial nerve nuclei; periventricular corpora amylacea in the thalamus, caudate nucleus, and midbrain
- Liver and spleen: Extramedullary hematopoiesis
- 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; eosinophilic intranuclear and cytoplasmic inclusion bodies in osteoclasts
- Multifocal osteopetrosis-like retention of primary spongiosa is associated with bovine pestivirus (BVD)
- 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
- Avian retroviral type C osteopetrosis is induced by avian leukosis virus which results in abnormal growth and differentiation of osteoblasts; osteoblasts are increased in number and size and osteoclasts are decreased in number
- Feline: Chronic vitamin D toxicosis and subsequent to infection with feline leukemia virus associated with medullary osteosclerosis; lymphoma and myeloproliferative disease may also cause osteosclerosis
- Horses: Peruvian Paso foals and an Appaloosa – have normal to increased numbers of osteoclasts but abnormal osteoclast function
- White-tail deer: Have brachygnathia inferior, impacted tooth and protruding tongue
- Polypay sheep in Oregon: Brachygnathia and osteopetrosis with multiple limb fractures; characterized by a large number of osteoclasts that lacked a ruffled border and were not in contact with bony trabeculae
- Dogs: Dachshund (littermates) – normal size, shape, but had increased fragility; Australian Shepherd and Pekingese – severe myelophthistic anemia
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