JPC SYSTEMIC PATHOLOGY
CARDIOVASCULAR SYSTEM
February 2022
M-M04

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 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 that pile up and have loss of polarity, and there is 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 in bone and dentin, characterized by osteopenia with thin trabeculae and lack of cortical bone and irregular dentin.

 

MORPHOLOGIC DIAGNOSIS:  1. Alveolar bone:  Osteopenia, diffuse, moderate, with lack of lamellar bone formation (trabecular dysplasia), Romney, ovine.

2. Tooth: Dentin dysplasia, diffuse, marked.

 

CONDITION:  Osteogenesis and dentinogenesis imperfecta

 

SYNONYM:  Brittle bone disease

 

GENERAL DISCUSSION:

• 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
• Other forms of OI are less common with autosomal recessive inheritance
• Four different forms have been identified in human patients: OI types 1 through 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)
• In animals the majority of cases are in calves and lambs, most are similar to the severe human form (type 2)
• Outbreaks may occur associated with new dominant mutations occurring in a sire

 

PATHOGENESIS:

• 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

 

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 (result of scleral thinning, revealing underlying choroid)
• Teeth are fragile, small, misshapen, and translucent pink
• 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
• Paucity of endochondral and intramembranous ossification
• Abrupt failure of secondary spongiosa & lamellar bone formation
  • Trabeculae may be lined by woven bone
  • Infractions and microfractures are common
  • Long fragile primary spongiosa lined by thin layer of basophilic matrix
  • Minimal osteoclastic resorption +/- atrophic osteoblasts
• Cortices are composed of basophilic woven bone with loose mesenchymal tissue and large empty vascular spaces (delay in compaction)
• Occasionally bone mass may appear normal with evidence of fracture disease (bone fragility)
• Growth plate is not affected (type II collagen)
• Marrow cavity contains loose mesenchymal tissue
• Dentin is thin, irregular, and 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

 

ULTRASTRUCTURE

• 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

 

DIFFERENTIAL DIAGNOSIS:

Gross:

• Dermatosparaxis: Belgian blue calves with mutation in procollagen I N-proteinase gene have skeletal abnormalities in which bones are not prone to fracture unless processed (bones are brittle)
• Arachnomelia: Italian Brown, Simmental, German Fleckvieh, and Brown Swiss cattle with lethal autosomal recessive gene mutation resulting in bone fragility, arthrogryposis, long & distorted limbs with narrow diaphysis, vertebral column deformity, brachygnathia inferior with turning up of nose, & cardiovascular abnormalities

 

Conditions with abnormal metaphyseal bone (abnormal, thin spongiosa):

• Vitamin C deficiency / scurvy (M-M07): Nonhuman primates, guinea pigs, several other nondomestic species; 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 (M-M17): Canine condition; the physis is normal; trabeculae of primary spongiosa are composed of basophilic calcified cartilage with absence of osteoid and osteoblasts and has abundant neutrophils, +/- necrosis between primary spongiosa

 

Causes of osteopenia/osteoporosis (reduced bone density/mass):

• Starvation
• Disuse: Loss of skeletal mass from inactivity & decreased weight bearing (Wolff’s law)
• 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; inhibits synthesis of collagen by pre-existing osteoblasts and differentiation of osteoblasts from their precursors, and stimulates 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 asynchrony of developing nervous & skeletal systems
• Hyperthyroidism: Thyroid hormones stimulate bone resorption

 

Causes of tooth lesions:

• Fluoride toxicosis (M-T04): Chalky, opaque enamel with increased susceptibility to chipping

 

COMPARATIVE PATHOLOGY:

Osteogenesis imperfecta in other species:

• Bovine:
  • Holstein-Friesian bulls in Australia, the United States, and Denmark
  • Charolais calves in Denmark
  • Angus calves in Brazil
  • Hereford calf (single crossbred) in New Zealand
• Ovine:
  • Romney breed in UK and New Zealand – unique additional features of domed head with brachgnathia inferior and marked skin fragility; dominant inheritance
  • Clun Forest breed in UK and Barbados Blackbelly
• 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: Two case reports
• Mice: Multiple mouse models, including Oim, Brtl, Fragilitas ossium (fro) and transgenic mice

 

REFERENCES:

1. 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.
2. Kamoun-Goldrat AS, Le Merrer MF. Animal models of osteogenesis imperfecta and related syndromes. J Bone Miner Metab. 2007; 25(4):211-218.
3. 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.

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