NEUROMUSCULAR CASE OF THE MONTH - FEBRUARY 2000

Fibrodysplasia ossificans progressiva in a
15 month old female spayed DSH cat
Contributed by Dr. K. Ruth Youmans and Urlicha Walker
Franklin Veterinary Services Referral Centre
PO Box 145 Papakura, Auckland
New Zealand

Physical and Neurological Examination
Both stifles were found to be grossly thickened from mid femur to the proximal tibia. The hind limbs were "bowed" and the cat was unable to bear weight normally. The range of motion in the stifles was reduced, with the left extending only to 100º, and the right to 110º. Both patellas were luxated medially. The thickened soft tissue was firm and non-compressible, and extended into the inguinal area bilaterally. Both hind limbs were painful on palpation and manipulation. The right elbow joint was thickened with a reduced range of motion, and was painful on palpation. The cat was neurologically normal apart from abnormal hind limb reflexes, presumably due to the restrictive tissue. Voluntary movement and pain perception were present in both hind limbs.

Diagnostic Tests

Routine laboratory tests
CBC - No abnormalities

Serum biochemistry profile
         Calcium and phosphate levels - no abnormalities
         Serum CK - 362 IU/L (reference range 0-220 IU/L
         Cholesterol - 4.2 mmol/l (reference range 1.9-3.9 mmol/l
         Urea - 4.6 mmol/l (reference range 7.1-10.7 mmol/l)
         Creatinine - 71 µmol/l (reference range 88-177 µmol/l)

Radiographic evaluation Radiographs showed extensive soft tissue mineralization adjacent to both the right and left proximal tibia (Figures 1 and 2). Opacities in the gastrocnemius and other muscles tended to be ovoid and aligned in the direction of muscle fiber orientation. There was no evidence of a local periosteal reaction. Similar mineralized densities were seen in the proximal scapular musculature on both sides, extending towards the dorsal spinous processes of the T2-T5 vertebrae. A mineralized mass projected medially from the right medial humeral epicondylar periosteum, and there were also small periarticular mineralized foci adjacent to the left elbow. Patchy areas of mineralization were also seen lateral to the right ilium on a ventrodorsal view of the pelvis, and to a lesser extent adjacent to the left ilium. Foci of mineralization were identified periarticular to both stifles, and adjacent to the proximal femurs. Based on the radiographic findings, a diagnosis of  fibrodysplasia ossificans progressiva (generalized myositis ossificans) was suspected. Due to the extensive nature of the lesions, surgical excision of the affected tissue was not recommended. The cat responded poorly to further prednisone therapy and pain relief (buprenorphine injections), and was euthanitized for humane reasons. Samples of affected muscles (left scapula and popliteal regions) were placed in 10% formalin and submitted for histopathologic evaluation.

Figure 1. Ventrodorsal view of the pelvis, femurs, and proximal tibias showing multifocal mineralized densities Figure 2. Lateral view showing similar mineralized densities

Histological evaluation Fixed muscle specimens showed collagen proliferation, focal areas of lymphocytic infiltration (Fig 3), and areas of cartilage and ectopic bone formation within the muscle tissue (Fig 4). The pathological abnormalities appeared to have originated from the fascial connective tissue. The histologic findings supported the radiographic diagnosis.

Figure 3. H&E stain of muscle specimen showing foci of lymphocytic cellular infiltration and collagen proliferation Figure 4. H&E stain of muscle specimen showing ectopic bone formation surrounded by collagen proliferation.

Conclusions and Discussion
The clinical, radiographic, and histopathological findings in this case support a diagnosis of fibrodysplasia ossificans progressiva. Although Norris described a similar case as generalized myositis ossificans in 1980, because the changes are primarily seen in connective tissue it is more commonly described as a fibrodysplasia. This is a rare disorder in humans, and a limited number of feline cases have been previously reported (Norris et al, 1980; Warren and Carpenter, 1984; Waldron et al, 1985; Bradley, 1992; Valentine et al, 1992; Gannon et al, 1998). The basic defect resulting in fibrodysplasia ossificans progressiva has not been identified. However, defective inhibitors of mineralization, primary collagen abnormalities, increased fibroblast alkaline phosphatase or abnormal vasculature have been proposed as initiating factors (Valentine et al, 1992). In a recent report (Gannon et al, 1998), early intense lymphocytic perivascular infiltration into skeletal muscle is described in a child and an affected cat. Foci of lymphocytic infiltration were also observed in the cat of this report. It is thought that lymphocytes may have a role in the pathogenesis of heterotopic ossification. Fibrodysplasia ossificans progressiva is heritable in humans, and probably in pigs (Valentine et al, 1992). As yet there is little evidence that the disease is inherited in the cat, however, genetic studies and breeding trials have not been done.

In humans, treatments including surgical excision of lesions, radiotherapy, corticosteroids, dietary management and diphosphonates have no proven benefit (Valentine et al, 1992). Although diphosphonate-etidronate disodium inhibits calcification it does not prevent the formation of ectopic bone matrix which is also disabling. It can also inhibit calcification in normal bone (Bradley, 1992). Progressive involvement of the respiratory muscles in humans can result in respiratory insufficiency, pneumonia and death (Norris et al, 1980). Until the mechanisms that regulate osteogenic activity in mesenchymal cells are better understood, the pathogenesis of this disorder may remain elusive. Genetic studies and biochemical tissue analysis may better define the etiology of this condition in both the cat and man.

Acknowledgements
The contributors would particularly like to thank C. Honour for supporting the further study of this condition, and Ian Robertson, Nicola Wilson, Joanne Harrison, Bronwyn Smits, and Noeline Champion for their contributions to this report. The assistance of the Comparative Neuromuscular Laboratory is gratefully acknowledged.

References
Bradley WA (1992). Fibrodysplasia ossificans in a Himalayan cat. Aust Vet Pract 22: 154-158.

Gannon FH, Valentine BA, Shore EM et al (1998). Acute lymphocytic infiltration in an extremely early lesion of fibrodysplasia ossificans progressiva. Clin Orthop 346: 19-25.

Norris AM, Pallet L, Wilcock B (1980). Generalized myositis ossificans in a cat. J Am Anim Hosp Assoc 16:659-662.

Valentine VA, George C, Randolph JE et al (1992). Fibrodysplasia ossificans progressiva in the cat. A case report. J Vet Int Med 6:335-340.

Waldron D, Turk M, Turk P et al (1985). Progressive ossifying myositis in a cat. J Am Vet Med Assoc 187:64-65.

Warren HB, Carpenter JL (1984). Fibrodysplasia ossificans in three cats. Vet Pathol 21:495-499.

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