6-month-old, male, domestic shorthair cat (Felis catus).This cat presented with lameness in right rear and left front legs. Radiographs revealed multiple old and
new fractures in several bones. The animal was maintained on a diet of Hills Science Diet-« for 1.5 months and
then became lame again with a new fracture.
All bones are brittle and fracture easily. Bone callus is present on several ribs, the left distal
femur and the left distal ulna. The right distal tibia has a fresh oblique fracture.
The radius and ulna are submitted. Both have a normal growth plate. The primary
spongiosa lack osteoid and are mostly cartilage. Cartilage is retained in the secondary spongiosa and the
metaphyseal bone. No osteoclast activity is seen. The radius has a healing fracture with a mixture of cartilage, bone
and fibrous tissue.
Osteogenesis imperfecta, probable.
The bones in this cat are failing to produce osteoid. The growth plate is normal and no
remodeling of bone by osteoclasts is seen. These features support a bone formation problem as the most likely
disease. Osteogenesis imperfecta is the most likely cause for the changes in this bone. Confirmation of the disease
as the cause would require examination of the teeth, which was not done in this case. The histologic appearance
does not support other metabolic bone diseases as causes, including rickets and osteodystrophy fibrosa.
Osteodystrophy fibrosa is characterized by bone resorption and fibrosis. Rickets has thick, abnormal growth plates
and widened osteoid seams in the primary spongiosa.
Osteogenesis imperfecta is an inherited disease caused by a genetic defect of the COL1A1 or COL1A2 genes, which encode the procollagen molecules of collagen type 1. This results in quantitative and qualitative abnormalities in type 1 collagen. Bone and teeth are affected, but other type 1 collagen-rich tissues, such as skin, are not affected. Osteogenesis imperfecta has been reported in dogs, cats, cattle, sheep, mice and tigers. Defects in the COL1A1 and COL1A2 genes have been found in the Golden retriever dog and mice.
1. Bone, distal radius and ulna: Osteopenia, epiphyseal, focally extensive, marked, with metaphyseal reactive woven bone formation (fracture callus), synoviocyte hyperplasia, and pannus.
2. Bone, proximal humerus: Osteosclerosis, epiphyseal and metaphyseal, focally extensive, marked, with growth retardation lattices, mild trabecular woven bone formation, mild marrow fibrosis and myxomatous metaplasia, and focally extensive periosteal granulation tissue.
In the distal radius and ulna, conference participants noted several changes in addition to
those described by the contributor, including proteoglycan loss in the articular cartilage with empty chondrocyte
lacunae (chondrocyte necrosis), synoviocyte hyperplasia, and proliferation of a layer of synoviocytes covering the
articular cartilage (pannus). The relationship of the additional observed changes to the underlying condition in this
kitten is unclear, but conference participants speculated that the radial fracture may have accounted for both the
osteopenia in the radial epiphysis (i.e. due to disuse) and secondary degenerative lesions in the joint (i.e. due to
instability). Joint laxity is a characteristic feature of osteogenesis imperfecta (OI), along with bone and tooth
fragility and blue sclerae, and therefore may also have contributed to secondary joint lesions in this animal.
Additionally, many conference participants received a section of bone interpreted as proximal humerus instead of the distal radius and ulna described by the contributor. In contrast to the epiphyseal osteopenia noted in the radius, the primary lesion in the proximal humerus is osteosclerosis attributed to the persistence of primary spongiosa with increased cross connections between cartilage spicules resulting from decreased osteoclasis (growth retardation lattices). Throughout the metaphysis, there are scattered trabeculae of woven bone, and within the metaphyseal bone marrow there is mild fibrosis and/or myxomatous metaplasia. In the adjacent periosteum, there is focally extensive granulation tissue.
Osteogenesis imperfecta, though well-described in humans, remains a rare diagnosis in animals. As mentioned by the contributor, most cases of OI stem from mutations in COL1A1 and/or COL1A2 genes that encode the α1 and α2 chains of type I collagen, respectively. Collagen in bone, dentin, ligaments, tendons, and the sclera is primarily type I, resulting in the characteristic confinement of lesions to these anatomic locations.(1-6) While type I collagen also predominates in the skin, OI usually does not produce cutaneous lesions,(6) although skin fragility has been reported in affected newborn New Zealand Romney lambs.(1)
Noteworthy, OI represents a heterogenous group of diseases, and defects in glycosaminoglycan and proteoglycan metabolism(2) or deficient osteonectin synthesis(6) may also account for some cases. This observation, combined with evidence that a wide variety of mutations in COL1A1 and/or COL1A2 have been demonstrated in humans with OI, explains the substantial phenotypic variation seen in the disease.(1) The conference moderator emphasized this point and noted that because mutations that produce OI can cause qualitative and/or quantitative collagen defects, the bone fragility that results is not necessarily related to bone mass, and thus a uniform set of pathognomonic microscopic findings cannot be relied upon for the diagnosis of OI. As a result, the definitive diagnosis of OI based solely on the tissues provided for histologic examination in this case is not possible, although the clinical history in combination with the gross and microscopic findings is certainly suggestive of the disease. As described by the contributor, the growth plates in this case are microscopically normal, an expected finding in OI since the collagen found in cartilage is primarily type II.(6)
The osteosclerotic lesions in the proximal humeral metaphysis and epiphysis led some participants to consider osteopetrosis in the differential diagnosis, and the conference moderator noted that osteopetrosis, like OI, may manifest as brittle bones prone to fracture. Osteopetrosis in cats has been associated with feline leukemia virus (FeLV) infection and chronic vitamin D toxicosis.(5) However, osteopetrosis classically results in a more severe failure of bone modeling than is present in this case. Additionally, although trabecular bone in OI is often described as microscopically normal or osteopenic, some cases, particularly those seen in lethal OI with skin fragility in New Zealand Romney lambs, result in persistent trabeculae of calcified cartilage that extend into long bone diaphyses and fill marrow cavities, accompanied by a paucity of osteoclasts, similar to osteopetrosis.(1,5)
Of note, some of the earliest cases of OI in dogs and cats were later shown to represent misdiagnoses of fibrous osteodystrophy (FOD) due to nutritional secondary hyperparathyroidism, with apparent familial susceptibility actually derived from exposure to common nutritional deficiencies.(2) The paucity of osteoclasts in this case argues against a diagnosis of FOD. Other considerations briefly discussed during conference included osteopenia secondary to protein calorie malnutrition and lack of osteoclasts due to inconsistent exposure to such antiosteoclastic agents as lead or bisphosphonates. In addition, the lesion in the distal metaphyses of the radius and ulna is somewhat reminiscent of the scorbutic lattice of vitamin C deficiency (scurvy). However, conference participants uniformly agreed that there is more osteoid deposition on the primary spongiosa than would be expected in scurvy. Furthermore, the growth retardation lattice noted in the proximal humeral metaphysis is not expected in scurvy, and this case lacks other classic findings of scurvy, such as microfractures or infractions with associated hemorrhage and fibrin.(5,6)
1. Arthur DG, Thompson KG, Swarbrick P: Lethal osteogenesis imperfecta and skin fragility in newborn New
Zealand Romney lambs. NZ Vet J 40:112-116, 1992
2. Denholm LJ, Cole WG: Heritable bone fragility, joint laxity and dysplastic dentin in Fresian calves: a bovine syndrome of osteogenesis imperfecta. Aust Vet J 60:9-17, 1983
3. Leeb F, Peters M, Brugmann M, Fehr M, Hewicker-Trautwein M: Osteogenesis imperfecta in two litters of dachshunds. Vet Pathol 40:530-539, 2003
4.Seeliger F, Leeb T, Peters M, Brugmann M, Fehr M, Hewicker-Trautwein M: Osteogenesis imperfecta in two litters of Dachshunds. Vet Pathol 40:530-539, 2003
5. Thompson K: Bones and joints. In: Jubb, Kennedy, and Palmers Pathology of Domestic Animals, ed. Maxie MG, 5th ed., vol. 1, pp. 33-38. Saunders Elsevier, Philadelphia, PA, 2007
6.Weisbrode SE: Bones and joints. In: Pathologic Basis of Veterinary Disease, eds. McGavin MD, Zachary JF, 4th ed., pp. 1065-1066. Mosby Inc., St. Louis, MO, 2007