4-month-old male Newfoundland dog, Canis lupus familiarsThis dog had a history of being slow to get up and having trouble with the rear legs. The onset and duration of these clinical signs was not reported and could not be obtained. The referring veterinarian (rDVM) reported that the dog had swollen and thickened elbows and that the right elbow was worse than the left. The right elbow was possibly luxated. The dog also had severe pain in the hips and at the base of the tail. Additional clinical findings were not reported. Radiographs were reported to show white stippling due to decreased endochondral bone formation in all epiphyses of the limbs. The vertebrae were also affected. The owner elected euthanasia and declined a full necropsy. The rDVM removed the right front leg at the level of the scapula and the right rear leg at the level of the proximal femur and submitted them for examination. No other information could be obtained regarding status of littermates, diet, age of onset, etc.
The right front limb, including the scapula, and the entire right rear limb were submitted fresh. The soft tissues were removed so that the bones could be examined and sectioned. The articular surfaces of all bones were smooth with a characteristic mottled white appearance. The apophyses were the most affected. The trochlea of the humerus appeared thickened and flared. On cut section, the epiphyses contained increased amounts of cartilaginous tissue which was most evident and extensive in the humeral condyles and the apophyses of other bones; these regions also had much smaller ossification centers than less affected bones. Occasionally, the metaphyseal physes were irregular and there were tongues of cartilage that extended from the physis into the metaphysis. Small islands of cartilage were also present in the metaphysis.
Multiple longitudinal sections of bone, including the proximal and distal femur, the proximal and distal tibia, the proximal and distal humerus, and the proximal radius were decalcified and examined microscopically. The slide submitted contains a section of the distal femur. The articular-epiphyseal (AE) complex and areas of persistent epiphyseal cartilage are highly irregular with various staining patterns. There are multifocal to coalescing areas of eosinophilic cartilage alternating with increased amounts of basophilic hyaline cartilage creating a mosaic type appearance. The eosinophilic regions of cartilage are indicative of loss of proteoglycans suggesting degeneration. There are two adjacent irregular spaces within the hyaline cartilage that contain fragments of basophilic debris. The cartilage is irregularly organized and there are separate multifocal islands of cartilage within the epiphysis that are undergoing ossification. Some of these islands extend to, and merge with, the metaphyseal growth plate. There appears to be reduced ingrowth of vascular channels along the edges of the reduced ossification centers. The metaphyseal growth plate (not present in all submitted sections) varies from normal regions to multifocal irregular areas characterized by disorganization of the three cartilage zones (resting, proliferating and hypertrophic) as well as multifocal extensions of cartilage tongues into the metaphysis. In some of these irregular regions, islands of cartilage within the epiphysis merge with the metaphyseal growth plate causing marked disorganization.
Similar lesions of varying degrees were noted in all of the other bones examined histologically. In some bones the metaphyseal physes were more affected than in others, especially in the proximal radius and trochlea of the distal humerus.
Distal femur: Severe epiphyseal dysplasia and mild metaphyseal dysplasia
A variety of inherited osteochondrodysplasia have been described in dogs and some are considered normal characteristics of certain breeds. Those that cause disease may be present at birth or develop later in life, especially as weight-bearing increases.(5) Many bone dysplasias are breed specific, such as chondrodysplasias in: the Alaskan Malamute, the Norwegian Elkhound, the English Pointer, and in the Great Pyrenees.(5) In these types of chondrodysplasias, the main lesions are in the metaphyseal growth plates and are generally associated with dwarfism or short stature.(5) The growth plates are disorganized with tongues of cartilage often extending into the metaphysis.(5) There are specific differences among breeds in terms of which zones of cartilage, and which bones, are most affected. Pseudoachondroplastic dysplasia of miniature poodles is another type of dysplasia that was originally termed epiphyseal dysplasia. Affected dogs are smaller than their litter mates.(5) Enlarged costochondral junctions, long costal cartilages, shortened vertebrate, and abnormal formation of the trachea and nasal septum have been described.(1) The limb bones often have enlarged epiphyses that are sometimes flared over the metaphases.(1) The cartilage matrix is described as sparse with a lack of basophilia.(1) Chondrocytes have variable size and sometimes are clumped in large lacunae.(1) Radiographic findings show irregular multifocal development of ossification centers that create a stippled appearance.(1) Decreased sulfation of glycosaminoglycans despite normal collagen synthesis is proposed as a cause of these lesions.(1) Osteochondrodysplasia in the Scottish Deerhound is characterized by growth plates that are irregular in width and physeal-metaphyseal junctions that are uneven.(1) There is also a syndrome in Labrador Retrievers and Samoyeds that involves both ocular and skeletal dysplasia.(1) An autosomal recessive inheritance has been suggested for most of these breed specific conditions.(1)
Multiple epiphyseal dysplasia (MED) has been reported rarely in single dog case reports and in two case series. One case series included a litter of Beagle puppies(5) and the other included 19 dogs of various breeds.(6) MED has been described in dogs as a rare condition that involves a deficiency in ossification of the epiphyses of the long bones and vertebrate, the cuboidal bones, and the apophyses.(6) An autosomal recessive mode of inheritance has been suggested.(6) This is in contrast to the disease in humans which most commonly has a dominant pattern of inheritance. However, recessive forms of the disease in humans have been reported and have been linked to a mutation in the gene encoding the oligomeric cartilage matrix protein on chromosome 19 as well as mutations in genes encoding type IX collagen (COL9A2) and matrilin-3.(1) These mutations lead to an anomaly in the matrix of hyaline, articular, and physeal cartilage.(1) In dogs, specific causative mutations have not yet been identified and it has been suggested that environmental factors such as toxins, drugs, and nutritional deficiencies may aid penetrance.(6)
In the case series of 19 affected dogs, dogs were normal at birth, lesions were noted on radiographs as early as 8-weeks-old, mild clinical signs were reported at 2 to 3 months of age, and most dogs had severe lameness by 5 to 8 months of age.(6) Radiographic findings in that case series were reportedly similar to those described in dogs with congenital hypothyroidism.(6) Thyroid testing could not be performed in the present case. Radiographic findings include: a delay in ossification of the epiphyses, apophyses, and cuboidal bones of the appendicular skeleton, the patella, the fabellae, and the epiphyses of the vertebrae; normal appearing metaphyses and diaphyses of the long bones and vertebrae which also seemed normal in length; continued abnormal appearing epiphyses throughout the growth phase but bone formation proceeded from the normal ossification centers and the size of ossification centers increased with age; and a stippled appearance to the distal epiphysis of the tibia.(1)
The shoulder, stifle, and hip joints have been reported to be the most severely affected in dogs, likely due to greater weight bearing on these joints.(6) Reported gross lesions in dogs with MED include: a whitish appearance to all epiphyses, including those in the vertebrate, and in the apophyses and cuboidal bones; occasional loose fragments of cartilage in some joints; and smaller ossification centers noted in sagittal sections.(6) Histologic findings described in affected dogs include: smaller than normal ossification centers with poorly developed bone tissue and an irregular poorly developed hypertrophic zone in the epiphyses; decreased ingrowth of vascular channels at the periphery of ossification centers and few vacuoles in the adjacent chondroid tissue; cartilaginous tissue in the epiphyses with uneven staining, pale areas, and many lacunae with large, often vacuolated chondrocytes with round dark nuclei; and few or no blood vessels within the epiphyseal cartilage.(6) Flocculent accumulation of chondroitin sulfate and glycoprotein in chondrocyte lacunae is described as the initial lesion.(1) Adjacent lacunae then coalesce and liquefy to form cysts and their contents mineralize.(1)
As the epiphyses of multiple long bones were the most severely affected in the current case, a diagnosis of MED was made. The gross and histologic findings were similar to those described in other reports of MED.(1,5,6) Other differentials considered for this case included pseudoachondroplasia and spondyloepiphyseal dysplasia. The former condition has been described in humans and Miniature Poodles and the latter has been described in humans. These dysplasias are characterized by lesions in both the physes and metaphases, thus resulting in severe dwarfism.(5,1) In this case, the metaphyseal lesions were generally mild to moderate in most bones and dwarfism was not evident. In the 19 dog case series, some dogs had moderate lesions in the metaphyses, and the authors stated that MED should not be excluded in dogs with these lesions.(5) Nonetheless, another form, or multiple forms, of dysplasia cannot be entirely ruled out in the current case. As there is currently no treatment that can relieve the pain in affected dogs, euthanasia is recommended.(6)
Bone, distal femur: Epiphyseal/metaphyseal dysplasia (epiphyseal/metaphyseal (osteo)chondrodysplasia).
This is an interesting and complex entity in which pinpointing causation to a specific genetic anomaly has not been successful. The clinical, radiographic and morphologic abnormalities associated with skeletal dysplasias are heterogeneous with over 200 described disorders, and can be broadly divided into connective tissue disorders that disrupt formation of bone (osteodysplasia) or cartilage and endochondral ossification (chondrodysplasia).(3) The nomenclature is confusing and often terms such as dysplasia (processes involving generalized defects caused by intrinsic alterations), dysostosis (processes limited to a specific bone or bone segment), and dystrophy (defects caused by an extrinsic process) are often used interchangeably.(1) Often the term osteochondrodysplasia is applied when morphologically both cartilage as well as endochondral bone is altered; however given the complexity of bone development, in some disorders, tissues other than bone are affected, as this case in chondrodysplasia of the Alaskan Malamute. Several animal models of chondrodysplasia have been established.(8) In humans, several causative genes have been identified, which include cartilage matrix proteins (e.g. COL2A1, COMP), transcription factors (e.g. Hox and Pax genes) growth factor receptors (e.g. I), and chondrocyte maturation/hypertrophy factors (e.g. PTH/PTHrP, CBFA1).(3) Recently, single gene mutations associated with specific disorders have been identified, such as the chondrodysplastic breed-standard phenotypes of nineteen breeds of domestic dogs.(4) The underlying genetic mechanism presented in this case has not been determined.
Relevant to the discussion is the acquired atypical expression of FGF4 which manifests as the characteristic skeletal breed traits among chondrodysplastic breeds such as dachshunds and bassett hounds.(4) FGF4 induces the expression of sprouty genes which interfere with ubiquitin mediated degradation of FGF receptors, causing their over activation.(4) The receptor FGFR3 is a negative regulator of bone growth, thus chondrocyte proliferation is downregulated in these breeds leading to their short stature.(2) In contrast, spider lamb chondrodysplasia is caused by inhibition of FGFR3 leading to uncontrolled chondrocyte proliferation, resulting in the long, splayed legs of black-faced lambs.(2)
Conference participants preferred a morphologic diagnosis of epiphyseal and metaphyseal chondrodysplasia for this case to identify the histologic abnormalities of chondrocytes/cartilage matrix and disruption of normal ossification within both the epiphysis and metaphysis visible in most sections. However, the more general term osteochondrodysplasia would be appropriate as well. However, the conference participants recognize the difficulty involved in characterizing these complex abnormalities, and note the contributors diagnosis of MED correlates with previous case reports in dogs and people with the distinctive stippling of the epiphyses evident grossly, radiographically and histologically.(6)
The contributor provides an in-depth discussion on MED while contrasting other breed-specific osteochondrodysplasias. The diversity in causes and presentations of both osseous and chondrous dysplasias reveal the intricate and complex nature of osteogenesis both during development and in repair from injurious stimuli.
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