JPC SYSTEMIC PATHOLOGY
Signalment (JPC #2333663): Newborn, male Romney lamb
HISTORY: This lamb was one of approximately 50 lambs stillborn from a flock of 450 ewes. Six other lambs had similar connective tissue abnormalities including skin fragility, joint laxity, blue sclera, soft bones, brittle teeth, multiple bone fractures and long bones with thickened diaphyses without distinct medullary cavities.
HISTOPATHOLOGIC DESCRIPTION: Slide B (H&E): Alveolar bone, tooth and mucosal surface: Diffusely there is marked osteopenia characterized by a lack of cortical bone and markedly thin trabeculae of woven bone that are irregular, basophilic and multifocally lined by variably thick layers of flattened osteoblasts with decreased osteoid production and rare osteoclasts. Trabecular (woven) bone is often hypercellular with increased numbers of haphazardly arranged osteocytes within enlarged and multifocally coalescing lacunae. Trabeculae are widely separated by abundant, loosely arranged mesenchymal tissue admixed with multifocal variably dense areas of fibrous connective tissue. Multifocally there are trabecular microfractures and areas of hemorrhage, fibrin, and edema. The tooth has a disorderly arrangement of odontoblasts with piling up and loss of polarity and diffuse irregularity in the thickness of predentin. The dentin is thin, irregular, and scalloped with many parallel wavy basophilic lines (mineralization fronts) and marked reduction and loss of dentin tubules (dysplasia). Enamel is multifocally absent (lost during processing).
Slide A (van Gieson): Alveolar bone, tooth and mucosal surface: There is a diffuse decrease in collagen (red staining) content, characterized by osteopenia with thin trabeculae and lack of cortical bone and irregularity of dentin.
- Alveolar bone: Osteopenia, diffuse, moderate, with trabecular dysplasia, Romney, ovine.
- Tooth: Dentin dysplasia, diffuse, marked.
CONDITION: Osteogenesis and dentinogenesis imperfecta
SYNONYM: Brittle bone disease
- Osteogenesis imperfecta (OI) is a rare inherited autosomal dominant connective tissue disorder characterized by osteopenia and excessive bone fragility resulting in spontaneous fractures; fragile, opalescent teeth (dentinogenesis imperfecta); joint laxity; and blue sclera
- Four different forms have been identified in human patients; up to 9 forms have been described
- OI types 1 to 4 are inherited (autosomal dominant) due to mutations in either the COL1A1 or COL1A2 genes
- These genes code for α1 and α2 collagen (i.e. type I collagen)
- The other forms of OI are less common with autosomal recessive inheritance
- In animals the majority of cases are in calves and lambs and outbreaks may occur associated with new dominant mutations occurring in a sire
- Type I collagen is the predominant collagen in bone, dentin, ligaments, tendons and ocular sclera
- Normal process of type I collagen formation: Collagen alpha chains are synthesized on ribosomes of endoplasmic reticulum of osteoblasts > enzymatic cleavage through hydroxylation of proline & lysine (vitamin C-dependent step) > procollagen chains align in Golgi complex to form triple helix > cleaved by procollagen peptidases in extracellular space > forms tropocollagen > cross linked by lysyl hydroxylysyl oxidation to stabilize collagen & give it tensile strength
- OI is caused by defective COL1A1 or COL1A2 genes in osteoblasts that code for alpha 1 and alpha 2 chains of the procollagen molecule resulting in qualitative and quantitative type I collagen formation defects
- “Outbreaks” of disease can result from new dominant mutations in germ cell lines of a sire
- Most reports are in lambs or calves (similar to the severe human form, type II) but not breed-related (occurs in crossbred animals)
TYPICAL CLINICAL FINDINGS:
- Bone fractures (some in utero, evidenced by callus formation at birth)
- Tendon hypoplasia; joint hypermobility (often unable to stand)
- Animals that are born alive often cannot stand
- Blue-tinged sclera as a result of scleral thinning, revealing underlying choroid
- Teeth are fragile, small, misshapen, and translucent pink (dentinogenesis imperfecta)
- Usually no clinical lesions observed in skin, although type I collagen is major structural collagen in skin
TYPICAL GROSS FINDINGS:
- Generalized osteopenia: Thin cortex, reduced cancellous bone, wide marrow cavity
- Bones normal shape but extremely brittle
TYPICAL LIGHT MICROSCOPIC FINDINGS:
- Primary lesion is osteopenia of trabecular and cortical bone
- Osteoblast number and activity varies depending on age of animal
- Paucity of endochondral and intramembranous ossification
- Abrupt failure of secondary spongiosa & lamellar bone formation
- Trabeculae may be lined by woven bone but infractions and microfractures common; less normal appearing lamellar bone
- Long fragile primary spongiosa lined by thin layer of basophilic matrix
- Minimal osteoclastic resorption
- Cortices composed of woven bone containing large empty vascular spaces (delay in compaction)
- Less trabecular bone than normal without osteoclasis or fibrous tissue proliferation
- May have normal amount of bone with fracture disease (bone fragility)
- Growth plate is not affected (type II collagen)
- Marrow cavity contains loose mesenchymal tissue
- Dentin is thin and lacks a tubular pattern; has an undulating margin with the pulp cavity
- Sclera is thin (1/5 normal thickness)
- Defective collagen does not stain red with van Gieson stain
- Collagen fibrils in tendons, dentin, sclera, and skin are narrower than normal
- Osteoid apposition on bone surfaces reduced; few osteoblasts contain few large cytoplasmic vacuoles
- Belgian calves with dermatosparaxis have defect in activity of procollagen N-peptidase thus have skeletal abnormalities in which bones are not prone to fracture unless processed (bones are brittle)
- Italian Brown, Simmental, German Fleckvieh, and Brown Swiss cattle with lethal defect (autosomal recessive inheritance), arachnomelia, have bone fragility, arthrogryposis, long & distorted limbs with narrow diaphysis, vertebral column distortion, brachygnathia inferior with turning up of nose & cardiovascular abnormalities
Conditions with abnormal metaphyseal bone (abnormal, thin spongiosa):
- Vitamin C deficiency / scurvy: Also results in defective type I collagen; naked spicules of mineralized cartilage in the primary spongiosa, no osteoid, few osteoblasts; microfractures and periosteal hemorrhage
- Metaphyseal osteopathy: The physis is normal; trabeculae of primary spongiosa are composed of basophilic calcified calcified cartilage with absence of osteoid and osteoblasts; but this condition has abundant neutrophils, +/- necrosis between primary spongiosa
Causes of osteoporosis (reduced bone density/mass):
- Disuse: Loss of skeletal mass from inactivity & decreased weight bearing
- Senile: Physiologic loss of skeletal mass with age
- Severe intestinal parasitism: Trichostrongylus colubriformis; Ostertagia circumcincta
- Inflammatory bowel disease: Reported in dogs with malabsorption syndrome
- Corticosteroid-induced: Catabolic effect on skeleton by decreasing apposition rate by both inhibiting synthesis of collagen by pre-existing osteoblasts and differentiation of osteoblasts from their precursors; stimulating osteoclastic bone resorption
- Phosphorous deficiency (rickets in young animals; osteomalacia in adults)
- Copper deficiency: Collagen defects due to decrease in activity of lysyl oxidase; involves growth plates
- Primary or secondary hyperparathyroidism: Resorption of bone with replacement by fibrous connective tissue
- Humoral hypercalcemia of malignancy (HHM) or pseudohyperparathyroidism: Increased osteoclastic bone resorption distant to site of neoplasm causing metabolic acidosis
- Vitamin A imbalances: Toxicity is associated with decreased osteoblasts & teratogenic effects in utero; Deficiency results in defective remodeling of membranous bone due to decreased osteoclastic stimulation; in young animals there is an asynchrony of developing nervous & skeletal systems
- Hyperthyroidism: Thyroid hormones stimulate bone resorption
Causes of tooth lesions:
- Fluoride toxicosis: Chalky, opaque enamel with increased susceptibility to chipping
- Holstein-Friesian bulls in Australia, the United States, and Denmark
- May be autosomal dominant in this cattle breed
- Charolais calves in Denmark
- Angus calves in Brazil
- Hereford calf (single crossbred) in New Zealand
- Holstein-Friesian bulls in Australia, the United States, and Denmark
- Ovine: Reported in Romney in UK and New Zealand; Clun Forest in UK; Barbados Blackbelly as inherited as autosomal recessive & less severe disease than in cattle; marked skin fragility in Romneys
- Canine: Reported in dachshund, golden retrievers, beagles, standard poodles, collies, Bedlington terriers
- In dachshunds an autosomal recessive missense mutation in SERPINH1 gene has been reported; SERPINH1 binds to and stabilizes triple helix of newly-formed collagens
- Feline: Single report of an OI-like syndrome in a 12-week-old domestic longhair kitten
- Mice: Multiple mouse models, including Oim, Brtl, Fragilitas ossium (fro) and transgenic mice
- Barnes A, Carter E. Lack of cyclophilin B in osteogenesis imperfect with normal collagen folding. N Engl J Med. 2010; 362: 1940-1941.
- Craig LE, Dittmer KE, Thompson KG. Bones and joints. In: Maxie MG, ed. Jubb, Kennedy, and Palmer’s Pathology of Domestic Animals. Vol 1. 7th ed. St. Louis, MO: Elsevier; 2016:46-50.
- Eckardt J, Kluth S. Population screening for the mutation associated with osteogenesis imperfect in dachshunds. Vet Rec. 2013; 172: 364-366.
- Kamoun-Goldrat AS, Le Merrer MF. Animal models of osteogenesis imperfecta and related syndromes. J Bone Miner Metab. 2007; 25(4):211-218.
- Laine CM, Joeng KS, Campeau PM, Kiviranta R, et al. WNT1 mutations in early-onset osteoporosis and osteogenesis imperfecta. N Engl J Med. 2013; 368(19):1809-1816.
- Olson EJ, Carlson CS. Bones, joints, tendons and ligaments. In: McGavin MD, Zachary JF, eds. Pathologic Basis of Veterinary Disease. 6th ed. St. Louis, MO: Elsevier; 2017: 973-974.
- Seeliger F, Leeb T, Peters M, Brugmann M, Fehr M, Hewicker-Trautwein M. Osteogenesis imperfecta in two litters of Dachshunds. Vet Pathol. 2003; 40:530-539.
- Van Dijk FS, Zllikens MC, Micha D, Riessland M, et al. PLS3 mutations in X-linked osteoporosis with fractures. N Engl J Med. 2013; 369(16):1529-1536.