Signalment:  

Stillborn, late-term, male Red Angus calf (Bos taurus).A registered Red Angus seedstock and cow-calf operation in northern Wyoming recognized a distinctive syndrome of late-term abortions/stillbirths in 2008. It occurred after genetic disease was recognized in progeny of one bulls full brother on a property in Kansas. The Wyoming rancher was concerned the bull he owned had the same trait, and bred one bull, BUF CRK Romeo L081, to 25 of his daughters. The goal was to establish that this valuable bull was free of the trait. Unfortunately, of 25 calves born to Romeo and his daughters in 2008, 5 were identical to malformed calves born to the bulls full brother in Kansas. All five were stillborn or premature (7 months term). 


Gross Description:  

This calf had a flat skull, impacted molars, short mandible (brachygnathia inferior), and a protuberant tongue. Gestational age was approximately 8 months. 


Histopathologic Description:

Rib; persistent primary spongiosa, with empty resorption lacunae and scant osteoclasts.


Morphologic Diagnosis:  

Osteopetrosis. 


Lab Results:  

Negative for bovine viral diarrhea virus by attempted virus isolation.


Condition:  

Osteopetrosis


Contributor Comment:  

Osteopetrosis has been recognized in the Angus breed since the 1960s, when a series of studies by Dr. Horst Leipold and colleagues documented the condition following an initial case report from New York.(2,5,6) The gross appearance of calves is distinctive. It is one of the few abortifacient inherited diseases in cattle that can be diagnosed with confidence over the telephone when concerned ranchers phone veterinarians or their diagnostic laboratory. 

Gross diagnosis is established by splitting long bones and demonstrating persisting primary spongiosa in the medullary cavity. Histologically, osteoclasts are markedly reduced in number, in spite of the presence of resorption lacunae. In this section of rib there are scant osteoclasts. Where present, they are lightly stained with washed out vesicular nuclei. 

The basis for the defect is a mutation in the anion exchanger protein coded for by SLC4A2 on chromosome 4. A similar mutation causes osteopetrosis in mice.(1,7) To date, no comparable mutation has been recognized in severe forms of osteopetrosis in children. Human osteopetrosis is classified morphologically into forms with reduced, normal or excessive numbers of osteoclasts. In Angus cattle it is likely that absence of the anion exchanger results in alkalinized cytoplasm, resulting in death of osteoclasts.(3) Death in utero is due to compression of the cerebral cortex with posterior herniation of cerebellum as a result of osseous crowding in the cranial vault.(4) An important diagnostic rule out is osteopetrosis due to in utero infection with bovine viral diarrhea virus. In this instance this and other calves sired by the bull were negative for BVDV.


JPC Diagnosis:  

Bone, rib: Persistent primary cartilaginous spongiosa with osteoclastopenia. 


Conference Comment:  

The contributors published an excellent report of the calves in this case, with gross and histopathologic descriptions as well as comparisons with osteopetrosis conditions in humans.4 Although, as the contributor explains, osteopetrosis can be caused by several genetic mutations, all affected individuals share similar clinical characteristics (increased skeletal mass, increased likelihood of fractures and neurological complications).(4)

The distinctive gross appearance of affected calves identified by the contributor are:
Distinctive histologic findings are: Interestingly, 4 of the 10 affected calves in this report were heterozygous for the SLC4A2 mutation. The heterozygous calves were born alive, survived 1-7 days post birth and had milder brain lesions than the homozygous calves.(4)

Conference participants noted that the cortex in the examined sections appears thin. Since we are unclear as to the level at which these sections were taken, we cannot fully evaluate this cortical thinning. It was speculated that the sections may be through the cutback zone, in which case the cortex would be expected to be discontinuous and thin. 


References:

1. Josephsen K, Praetorius J, Frische S, et al. Targeted disruption of the Cl-/HCO3- exchanger Ae2 results in osteopetrosis in mice. Proc Natl Acad Sci USA. 2009;106:1638-1641.
2. Leipold HW, Huston K, Dennis SM, Guffy MM. Hereditary osteopetrosis in Aberdeen Angus Calves. I. Pathological changes. Ann G+â-¬n+â-¬t S+â-¬l Anim. 1971;3:245-253.
3. Meyers SN, McDaneld TG, Swist SL, et al. A deletion mutation in bovine SLC4A2 is associated with osteopetrosis in Red Angus cattle. BMC Genomics. 2010;11:337.
4. OToole D, Swist S, Steadman L, Johnson GC. Neuropathology and craniofacial lesions of osteopetrotic Red Angus calves. Vet Pathol. 2012;49:746.
5. Thompson K. Diseases of bones and joints. In: Maxie MG, ed. Pathology of Domestic Animals. 5th ed. Vol. 1. Edinburgh, Scotland: WB Saunders; 2007:38-40.
6. Thomson RG. Failure of bone resorption in a calf. Vet Pathol. 1966;3:234-246.
7. Wu J, Glimcher LH, Aliprantis AO. HCO3-/Cl- anion exchanger SLC4A2 is required for proper osteoclast differentiation and function. Proc Natl Acad Sci USA. 2008;105:16934-16939.


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1-1


1-2. Rib


1-3 Rib


1-4. Rib



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