Osteogenesis imperfecta (OI) is a lethal heritable disorder of connective tissue characterised by varying degrees of congenital bone fragility and defects of dense connective tissue in tendons, ligaments and skin. Dysplastic dentin and abnormally thin (and therefore blue) sclera are seen in many OI syndromes. OI in cattle, as in other species, is phenotypically and genetically heterogeneous. For example, bone fragility in some OI syndromes is associated with reduced cortical thickness, the diaphyses of the long bones being gracile in appearance on radiology. In other OI syndromes however the cortical dimensions of the long bones are normal but the bones nonetheless fragile. Where there is dentinogenesis imperfecta (DI), the teeth are pink coloured due to the vascularised dental pulp being visible through the thinner than normal layer of dentin. Amelogenesis is normal although the enamel may be "crazed" due to multiple enamel fractures resulting from the lack of structural support from the underlying dentin. Radicular and coronal fractures of the incisor teeth are common in OI calves with DI.
Affected calves present with poor growth rates, spontaneous multiple fractures, congenital bone deformations, generalised joint laxity, dentinogenesis imperfecta, and light blue sclerae. Fractures may occur intrapartum (particularly rib fractures) or in the early postnatal period (typically long bone fractures). Clinical severity varies greatly between cases however, even in the same family pedigree, with some affected siblings presenting with joint laxity and DI but no spontaneous fractures. The digital flexor tendons of severely affected cases are palpably thin and soft, even through the skin. At necropsy the tendons are thin, less transluscent white, more pink than normal and often with intratendon haemorrhages associated with tendon connective tissue fragility. Visceral and vascular connective tissues with a significant content of Type III collagen do not however appear to be clinically affected.
Inheritance of OI can be recessive or dominant. In cattle, OI has been reported in several breeds including Holsteins, Charolais and Angus. In contrast to the recessive syndromes, each pedigree (family) with a dominant OI syndrome has its own unique spontaneous mutation. In dominant transmitted OI syndromes, the progenitor can be clinically normal but a germ cell line chimera, transmitting the causal mutation to progeny in proportion to the proportion of their germ cells that carry the mutation, and potentially may also be a somatic cell chimera but with sufficient normal somatic cells for structural integrity of connective tissue. Breeding trials may be necessary to distinguish between recesive and dominant inheritance.
The generalized fragility of bone and dentin and the joint laxity in OI is due to structural defects in the fibrillogenesis of collagen fibrils comprised of Type 1 collagen. Type I collagen is the most abundant structural protein found in the extracellular matrix of vertebrate bones and dense coneective tissues. It assembles into fibrils forming the structural scaffold of bone, skin and other connective tissues.
Diagnosis is based on presenting clinical signs, radiographic evidence of slender, thin-cortices of long bones and immunohistochemical identification of the disease using PCR and western blot techniques. However, contemporary DNA technologies now offer the best prospects for developing diagnostic tests for the control of recessively transmitted OI syndromes.
In many OI syndromes the molecular pathology involves a type 1 collagen dysplasia due to mutation of one of the two genes, COL1A1 and COL1A2 which encode the two related collagen propeptides that polymerise in the extracellular space to form the type 1 collagen fibrils. On this basis, OI has been characterised as a group of related type 1 collagenopathies. However, more recently the OI phenotype has been described in individuals with single gene mutations affecting non-collagenous proteins such as CRTAP and LEPRE1 that participate in or regulate type 1 collagen fibrillogenesis. In general terms, the causal mutations in dominantly transmitted OI syndromes are likely to be found in the COL1A genes and those in the recessive syndromes more likely to be in genes that encode proteins involved in post-translational modification of the type 1 procollagen propeptides or type 1 collagen fibrillogenesis. Defects of collagen fibrillogenesis can be detected ultrastructurally in the tendon and bones of OI affected calves. Reduced mean tendon collagen fibril diameters and failure to develop the normal bimodal distribution of collagen fibril diameters in tendon during post-natal growth are typical ultrastructural findings in OI, accompanied by dilation of the rough endoplasmic reticular cisternae of the tendon fibroblasts with abnormal fibrillar secretory product.
A differential diagnosis for OI would include rickets and other osteomalacias, contractural arachnodactyly, progressive degenerative myeloencephalopathy, arthrogryposis multiplex, palatoschisis, Congenital chondrodystrophy, syndactylism and epitheliogenesis imperfecta.
Mild cases of OI in calves may be reared to slaughter age without fractures occuring, but the great majority of cases will have an increasing incidence of long bone fractures. Although these fractures heal normally and rapidly, recumbency during recovery leads to increased osteoporosis and ultimately further fractures. Treatment of OI calves is therefore not recommended.
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