A variety of inherited osteochondrodysplasias causing disturbances in cartilage and bone growth and development have been identified in humans. Some of these conditions have also been identified in dogs, and in some specific breeds, these conditions are considered normal characteristics. As an example, achondroplasia is considered a normal characteristic in Bulldogs, Boston Terriers, and Pekingese, and hypochondroplasia is considered a normal characteristic in Dachshunds and Beagles.1 In addition, certain infectious diseases, toxins, dietary deficiencies, and hormonal deficiencies may cause bone lesions similar to those seen with inherited osteochondrodysplasias.1
One of the less well known of the osteochondrodysplasias in dogs is MED. In 1956, Cotchin and Duce2 reported a single case of epiphyseal dysplasia involving a male Miniature Poodle, and other authors reported 3 similar cases over the next 10 years.3,4 In a report of MED involving a litter of Beagles, Rasmussen5 indicated that 4 of the 8 puppies in the litter had delayed bone formation in the epiphyses with stippled or punctate calcification.
Rasmussen and Reiman6 later bred 2 of the affected dogs from this litter, resulting in 5 diseased puppies, suggesting that the condition had an autosomal recessive mode of inheritance. Johnson et al7 reported a case of MED involving a Golden Retriever mixed-breed dog that had severe clinical signs and in which radiography of the epiphyses of the humeral and femoral heads and the vertebrae revealed severely delayed bone formation. Saunders and Jezyk8 reported on a litter of dogs with similar-appearing lesions that had congenital hypothyroidism.
Because of the limited number of cases of MED in dogs that have been published, more information is needed on this condition. The purpose of the study reported here, therefore, was to determine clinical, radiographic, and pathologic abnormalities in dogs with MED.
Materials and Methods
Case selection criteria—Case records of the Radiology Section at the Norwegian School of Veterinary Science for 1991 through 2005 were searched to identify dogs in which MED had been diagnosed on the basis of results of radiography of the shoulder region and vertebral column.
Medical records review—Information obtained from the medical records of dogs included in the study consisted of signalment, history, clinical findings, radiographic abnormalities, and results of necropsy when available. In addition, information was obtained on results of hematologic, serum biochemical, and thyroid function testing, when available.
Results
Nineteen dogs from 10 litters met the criteria for inclusion in the study. There were 11 Hygenhund, 6 Dunker, 1 Golden Retriever, and 1 English Pointer (the Hygenhund and Dunker are hound breeds from Norway). The 11 Hygenhund were from 4 litters (2 litters of 8 with 2 affected puppies each, a litter of 9 with 4 affected puppies, and a litter of 6 with 3 affected puppies), and the 6 Dunker were from 4 litters (2 litters of 3 with 1 affected puppy each, a litter of 4 with 1 affected puppy, and a litter of 8 with 3 affected puppies). Litter size was not known for the other 2 dogs. Eleven of the affected dogs were male, and 8 were female. Fourteen of the 19 dogs were initially examined because of lameness. The remaining 5 dogs were identified as a result of radiographic examination at 8 weeks of age of all dogs in 2 litters of Hygenhund puppies (a litter of 8 with 2 affected puppies and a litter of 6 with 3 affected puppies). One of these litters had been produced by parents proven to be carriers of the condition; the breeder of this litter had failed to follow a recommendation to avoid breeding proven carriers. The other litter had been produced by parents that were closely related to proven carriers of the condition; the breeder was unaware of this fact at the time of mating. One affected puppy from the first litter was euthanatized at 9 weeks of age following radiography and underwent necropsy; the remaining affected puppy from this litter underwent periodic reevaluation until 30 weeks of age. This puppy was euthanatized at 7 months of age and underwent necropsy. The 3 unaffected puppies in the other litter were examined at 9 and 21 weeks of age. The 3 affected puppies in this litter were reexamined each week for the first month after the diagnosis was made, every other week for the subsequent 2 months, and every month thereafter. Affected puppies in both litters were euthanatized if they had clinically important lameness lasting > 4 days that did not fully respond to nonspecific treatment. Blood samples were collected from the 6 puppies in the second litter at the time radiographs were obtained and submitted for standard hematologic and serum biochemical testing. In addition, blood samples collected at 6 months of age from the 3 affected puppies were submitted for determination of plasma total thyroxine, free thyroxine, and thyroid-stimulating hormone concentrations. Thyroid hormone concentrations were assayed with a chemiluminescent competitive immunoassay.a
Clinical findings—All 19 affected dogs appeared normal at birth. In 13 of the 14 dogs examined because of lameness, clinical signs of sufficient severity and duration to warrant investigation were first evident at 5 to 8 months of age. In the remaining dog, severe clinical signs developed at 13 months of age, although the dog had had multiple episodes of lameness prior to this time. Many owners reported incidents of mild lameness from the age of 2 or 3 months when questioned. In addition, 4 affected puppies from a single litter all developed bilateral valgus deformities of the tibiae with external rotation of approximately 30° by 4 months of age.
For the 2 litters of puppies examined at 8 weeks of age, affected puppies seemed to move less gracefully than the unaffected puppies even at this age, and all of the affected puppies in these 2 litters had persistent lameness involving 1 or more joints by 7 months of age and were euthanatized. Results of hematologic, serum biochemical, and thyroid function testing performed in 3 affected dogs at 5 months of age were unremarkable.
Radiographic findings—In general, a pronounced failure of the ossification process involving the epiphyses, apophyses, and cuboidal bones of the appendicular skeleton and the epiphyses of the vertebrae was evident on radiographs of the affected dogs. The patellae and fabellae were also affected. Radiographically, the metaphyses and diaphyses of the long bones and vertebrae seemed normal with normal length. The diagnosis was easily made on radiographs obtained at 8 weeks of age (Figure 1).
Lateral radiographic views of a forelimb and hind limb and the vertebral column in a 9-week-old dog with MED (A, C, E) and in an unaffected littermate (B, D, F). Notice the delay in bone formation in all epiphyses (including vertebral epiphyses), apophyses, and cuboidal bones in the affected dog. Appearance and length of the diaphyses and metaphyses were similar in the affected and unaffected dogs.
Citation: Journal of the American Veterinary Medical Association 233, 4; 10.2460/javma.233.4.600
In dogs for which follow-up radiographs were available, the epiphyses retained an abnormal appearance throughout the growth period, even though bone formation appeared to proceed and the size of the ossification center increased with age (Figure 2). Bone developed from the normal ossification centers and not from scattered centers in the epiphyses, except that the distal epiphyses of the tibia had a stippled or multifocal appearance on radiographs.
Lateral radiographic views of the shoulder joints obtained at 9 (A), 14 (B), 20 (C), and 27 (D) weeks of age in a dog with MED and obtained at 9 (E) and 20 (F) weeks of age in an unaffected littermate.
Citation: Journal of the American Veterinary Medical Association 233, 4; 10.2460/javma.233.4.600
Radiographic abnormalities seen in littermates seemed identical. Severity of radiographic abnormalities varied substantially among affected dogs from different litters (Figure 3).
Lateral radiographic views of the shoulder and stifle joints obtained at 8 months of age in 2 dogs with MED (dog 1, A and C; dog 2, B and D). The 2 dogs were from different litters, although they had the same sire. Notice the difference in severity of the lesions between the 2 dogs.
Citation: Journal of the American Veterinary Medical Association 233, 4; 10.2460/javma.233.4.600
For 2 unaffected and 3 affected female dogs in a single litter, the distance between the proximal and distal physes of the radius was measured on lateral radiographic projections obtained at 9 weeks and 21 weeks of age. There was no significant difference in length of the radius between unaffected and affected dogs at either time.
Pathologic findings—Ten of the affected dogs underwent a necropsy. At necropsy, the proximal aspect of the humerus and the distal aspect of the femur appeared to be the most severely affected. However, abnormalities were evident in all epiphyses, including those in the vertebrae, and in the apophyses and cuboidal bones. On gross examination, the epiphyses had a whitish appearance, and in some joints, small loose fragments of apparent cartilaginous origin were found. When bones were cut sagittally, it could be seen that most of the epiphyses consisted of a whitish tissue, and the ossification centers were substantially smaller than could be expected (Figure 4).
Gross appearance of the femur and humerus (sagittal sections) from a dog euthanatized at 9 weeks of age because of MED. Large parts of the epiphyses consist of cartilaginous tissue (y); the ossification centers (x) are substantially smaller than normal.
Citation: Journal of the American Veterinary Medical Association 233, 4; 10.2460/javma.233.4.600
On histologic examination of the epiphyses in dogs euthanatized at the time severe lameness was evident, the ossification centers were smaller than expected and contained poorly developed bone tissue (Figure 5). The hypertrophic zone surrounding the ossification center was irregular and poorly developed. Reduced ingrowth of vascular channels was evident on the periphery of the ossification center, and there were few vacuoles in the neighboring chondroid tissue. The cartilaginous tissue occupying the large space between the ossification center and the articular cartilage consisted of a homogenous matrix containing numerous lacunae with large, often vacuolated chondrocytes that had round, moderately dark nuclei. No or very few blood vessels could be seen. The cartilaginous tissue was unevenly stained with pale areas, indicating abnormal matrix or possible necrosis.
Histologic section of the proximal epiphysis of the humerus in a dog euthanatized at 8 months of age because of MED. Notice that the ossification center (a) is smaller than normal, contains poorly developed bone tissue, and is surrounded by a large quantity of cartilaginous tissue that varies in color, suggesting that the cartilage matrix is abnormal. There is reduced ingrowth of vascular channels and few vacuoles in cartilaginous tissue on the edge of the ossification center (b), and the resting zone in the cartilaginous tissue has a large number of chondrocytic lacunae with small, dark nuclei (c). The metaphysis (d) appears normal.
Citation: Journal of the American Veterinary Medical Association 233, 4; 10.2460/javma.233.4.600
In the shoulder and stifle joints of an affected dog euthanatized at 14 months of age, portions of the articular cartilage and underlying cartilaginous tissue had separated from the rest of the epiphyses, forming what resembled enormous osteochondritis dissecans lesions (Figure 6).
Gross appearance and lateral radiographic views of the shoulder and stifle joints in a dog euthanatized at 14 months of age because of MED. Radiographically, the physes appear closed, but endochondral bone formation in the epiphyses is less than normal. In the shoulder joint, a large part of the epiphysis is separated from the articular surface, and this part is swollen and pale. In the stifle joint, a large part of the articular surface was opaque and elevated from the rest of the surface with a rupture around it and deeply under it.
Citation: Journal of the American Veterinary Medical Association 233, 4; 10.2460/javma.233.4.600
Discussion
Results of the present study suggested that MED is a rare condition in dogs characterized by a deficiency in ossification of the epiphyses of the long bones, the epiphyses of the vertebrae, the cuboidal bones, and the apophyses. Radiographic abnormalities were evident in dogs examined as young as 8 weeks of age, and most dogs had developed a severe lameness by 5 to 8 months of age. Disease severity was consistent among littermates, but varied among dogs from different litters. The condition most likely had an autosomal recessive mode of inheritance, although genetic studies of mode of inheritance could not be performed.
Comparison of findings for dogs in the present study with findings provided in previous reports suggested that the Miniature Poodle described by Cotchin and Duce2 did not have MED. For this dog, the figures and text suggested that the metaphyses and diaphyses of the long bones were as severely affected as the epiphyses and that the frontal bones of the skull were seriously deformed. On the other hand, it is possible that the Beagles described by Rasmussen5 had the same condition as did the dogs described in the present report, given the similarity in appearance and location of the lesions. Rasmussen and Reiman6 indicated that there were no radiographic changes in the proximal aspects of the tibiae in these Beagles and stated that similar findings have been reported for human patients with some forms of MED. We suggest that the radiographs provided by Rasmussen and Reiman6 clearly show dysplasia of the epiphyses of the tibia in these dogs and that lesions involving the epiphyses, cuboidal bones, and apophyses were similar to those seen in the present study. The dog described by Johnson et al7 had radiographic abnormalities similar to those seen in the present study and likely had the same disease.
On histologic examination of epiphyses from dogs in the present study, we did not find any signs of separate, punctate centers of ossification or of dystrophic calcification. Some epiphyses, especially the distal tibial epiphysis, seemed to have a stippled appearance on radiographs that gave an appearance of multiple centers of ossification. However, histologic examination revealed poorly and unevenly developed bone tissue in the center of ossification, and this may explain the stippled appearance on radiographs.
In humans with MED, the vertebrae are typically not involved, although some forms of this condition may be associated with irregularity of the vertebral endplates.9 The genetics of MED have been extensively studied in humans, with most forms having a dominant pattern of inheritance. Numerous mutations causing this condition have been identified in the genes coding for cartilage oligometric matrix protein, all 3 protein chains of collagen IX, and matrilin-3.9–11 Even so, a cause has been identified for only about 50% of the dominant forms of MED in humans.12 Forms of MED with a recessive pattern of inheritance in humans have also been identified and have been attributed to various mutations in the gene coding for the diastrophic dysplasia sulfate transporter.13 Other related inherited skeletal disorders in humans, such as pseudoachondroplasia9 and spondyloepiphyseal dysplasia,14 are characterized by severe dwarfism and thus involve the physes and metaphyses, but otherwise cause radiographic abnormalities similar to those seen in the dogs in the present study.
Radiographic abnormalities in dogs in the present study were similar to those described in a report8 of dogs with congenital hypothyroidism. Thyroid hormones are essential for the normal development of endochondral and intramembranous bone and plays an important role in the linear growth and maintenance of bone mass. However, given that results of thyroid function testing (total thyroxine, free thyroxine, and thyroid-stimulating hormone concentrations) were within reference limits in 3 affected dogs in the present study that were old enough to be tested, it is not likely that these dogs had hypothyroidism.
Surprisingly, even though the severity of lesions varied among affected dogs from different litters in the present study, lesions in affected littermates were identical or nearly so. The reason for this is not clear. If the variation between litters could be explained by variations in genetic penetrance, there should also have been variations between littermates within affected litters. Two or more inherited mutations causing similar or related changes are often present in humans with MED,9 and it is possible that 2 or more genes were also involved in these dogs. Expression of a disease could also be affected by the general genetic background. However, it is likely that the genetic background would vary between affected siblings, resulting in variations in lesion severity. Environmental factors such as toxins, drugs, and nutritional deficiencies may facilitate penetrance of a disease.
All 4 affected puppies in 1 litter in the present study had a uniform malformation of the tibiae (ie, moderate valgus deformity combined with external torsion of the bone of approximately 30°) that was evident by 4 months of age. This deformity most likely was a result of unequal growth within the physes of the tibiae and probably was primary. These puppies also had by far the most severe epiphyseal lesions, compared with other puppies in the study, and they were the only ones with radiographically detectable changes in the metaphyses at 8 months of age. These changes were evident in the caudal part of the proximal end of the humerus and might have been secondary. Nevertheless, their appearance in these dogs suggested that moderate involvement of the physes and metaphyses should not be excluded in dogs with MED. Similarly, although the Golden Retriever described in the present report did not have radiographic evidence of metaphyseal or diaphyseal involvement, the forelimbs in this dog appeared slightly shorter than normal, and histologic examination revealed signs of slightly severe abnormal endochondral ossification in the proximal physes of the humerus.
Dogs in the present study reportedly had episodes of mild lameness beginning at approximately 2 to 3 months of age. During this early stage of the disease, pain might have been a result of pressure on cartilaginous tissue and poorly developed bone in the epiphyses. Severe clinical signs likely developed later when the degenerate cartilage in the epiphyses started to fail. In the dog that survived to 14 months of age, severe destruction of the stifle and shoulder joints was evident at necropsy. Changes in this dog might represent the probable outcome or end stage with increasing age, as the extensive destruction seen in the shoulder and stifle joints would probably have occurred in all affected joints as the thick layer of cartilaginous tissue became necrotic and failed as a result of loading. Our experience indicates that shoulder, stifle, and hip joints are the most vulnerable in dogs with this disease, possibly reflecting development of lesions in those joints bearing the greatest weight. It is the authors' opinion that dogs with MED should be euthanatized, as there currently is no treatment that can make these dogs pain free.
Outcome for the dogs in the present study indicated a poorer prognosis than that described previously for a litter of Beagles,5 in that those dogs survived long enough to be bred. There may have been a difference in clinical signs simply because of differences in size of the affected dogs, resulting in lesser total impact on the joints in the smaller dogs. This might possibly have been combined with the fact that the tolerance for pain in the experimental animals was higher at that time. Alternatively, it may be that these Beagles had a different, less painful disease.
At present, MED in dogs may be understood as an inherited condition diagnosed on the basis of characteristic clinical, radiographic, and pathologic findings in combination with a lack of deficiency in thyroid function. Changes were limited to the epiphyses, apophyses, cuboidal bones, and patellae, whereas the metaphyses and diaphyses of the long bones had a normal or near normal appearance. Further genetic studies may lead to a more accurate description of this condition and may help in identifying the underlying mutation.
ABBREVIATIONS
| MED | Multiple epiphyseal dysplasia |
Immulite 2000, Diagnostics Product Corp, Roche Norway, Oslo, Norway.
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