JPC SYSTEMIC PATHOLOGY
CARDIOVASCULAR SYSTEM
February 2022
M-M03

SIGNALMENT (JPC #1758202):  6-month-old Suffolk lamb

 

HISTORY:  This lamb had multiple marked angular limb deformities.

 

HISTOPATHOLOGIC DESCRIPTION:  Vertebrae: Growth plates are diffusely markedly irregular and disorganized, forming nodules and anastomosing cartilaginous islands and irregular trabeculae of variable length that extend deep into the vertebral body and form multiple ossification centers.  Within the cartilaginous trabeculae, zones of proliferation and hypertrophy contain disorganized chondrocytes arranged in irregular clusters and cords.  The chondroid matrix frequently demonstrates abrupt changes in staining character including pallor, deep basophilia, and eosinophilia.  Diffusely, there are decreased numbers of primary and secondary spongiosa, and the few remaining bony trabeculae are thin (osteopenia), widely spaced, and occasionally contain small foci of cartilage (retention of cartilaginous cores). The cortical bone is thin and multifocally discontinuous (osteopenia).  Diffusely the bone marrow is hypocellular with abundant adipose tissue, and there is a paucity of both osteoblasts and osteoclasts. 

 

MORPHOLOGIC DIAGNOSIS: Bone, vertebrae: Osteochondrodysplasia with multiple ossification centers, Suffolk, ovine.

 

ETIOLOGIC DIAGNOSIS: Hereditary chondrodysplasia

 

CONDITION: Spider lamb syndrome

 

SYNONYMS: Spider lamb chondrodysplasia, ovine hereditary chondrodysplasia, inherited arachnomelia

 

GENERAL DISCUSSION:

• Congenital skeletal abnormalities may be genetic, teratogenic, or nutritional and it may be difficult to distinguish between these
• Chondrodysplasias: hereditary disorders of bone growth due to primary lesions in growth cartilage including physeal cartilage (longitudinal bone growth) and epiphyseal cartilage (epiphyseal development); can result in disproportionate dwarfism often with short legs and normal-sized heads (versus primordial dwarfism e.g. due to decreased growth hormone)
• Spider lamb syndrome: the most common hereditary chondrodysplasia of sheep, results in abnormalities in multiple axial and appendicular bones; semi-lethal condition of Suffolk and Hampshire sheep, commonly reported as autosomal recessive inheritance with complete penetrance; heterozygotes were selected for due to enhancement of long bone growth

 

PATHOGENESIS:

• Single-base point mutation in tyrosine kinase II domain of fibroblast growth factor receptor 3 (FGFR3) à decreased FGFR3 inhibition of chondrocytes entering the hypertrophic phase à increased length of long bones and presence of multiple secondary centers of ossification in the epiphyses (especially abnormal ossification centers of those that develop around the time of birth) à variation in size, shape, and orientation of bones
  • FGFs and FGFRs are essential in the formation and growth of the endochondral skeleton
  • FGFR3 is expressed by resting and proliferating chondrocytes NOT hypertrophic chondrocytes; acts as an inhibitor of chondrocyte proliferation and terminal differentiation
• Absence of subchondral bone predisposes to degenerative arthropathy
• Variation in clinical features and severity may be related to differential bone stresses caused by in utero positioning, high fetal numbers, rate of weight gain, nutrition, exercise, sex, and inherited conformation

 

TYPICAL CLINICAL FINDINGS:

• Lambs may be aborted, stillborn, or born alive with variably severe skeletal abnormalities, some may appear normal at birth and then develop clinical signs 4-6 weeks of age
• Deformities of the limbs and spinal column progressively worsen with age
• Lambs rarely survive > 12 weeks of age, except in research settings

 

TYPICAL GROSS FINDINGS:

• Multiple disorganized ossification centers, predominantly affected are those that form at the time of birth (those that developed in utero appear relatively normal, e.g. proximal metatarsal, proximal metatarsal physes)
• Vertebrae (thoracic, cervical): scoliosis and/or kyphosis, wedge-shaped vertebral bodies and dorsal deviation, misshapen vertebrae with abundant irregular cartilaginous centers; neck is disproportionally long
• Sternebrae: sternum concavity (pectus excavatum), variably sized sternebrae, misalignment
• Limbs: Disproportionately long, valgus deformity of the below the carpus (“knock-kneed” appearance), +/- pelvic limb deformities
  • Retained cartilage cores on the metaphyseal side of affected growth plates
  • Olecranon, distal scapula: Lateral or medial deviation of the radius and ulna; excess cartilage surrounding islands of ossification; thickened, irregular growth plates
  • Eroded joint cartilage and secondary degenerative arthropathy
• Skull: Small heads with Roman nose (shortening of the maxilla with dorsal rounding), craniocaudal elongation and angulation of the occipital condyles

 

TYPICAL LIGHT MICROSCOPIC FINDINGS:

• Increased width of the zone of proliferation and hypertrophy, unevenness of growth cartilage, and failure to form/maintain orderly chondrocyte columns
• Multiple irregular islands of ossification in nodules of hypertrophic cartilage
  • Ossification centers fail to coalesce and expand in normal fashion toward the articular surfaces
• Chondrocytes are disorganized and often vacuolated, with multiple sites and irregular patterns of ossification
  • Articular cartilage is thickened with microfractures and flap formation or thinned with eburnation of underlying bone in more severely affected joints
  • Nodules or tongues of poorly organized cartilage extend from the growth plate into the metaphysis and/or epiphysis

 

ADDITIONAL DIAGNOSTIC TESTS:

• DNA testing: Mutation identified, can detect homozygous and heterozygous animals
• Radiographs (best confirmatory test): Characteristic changes in the elbow, sternum, and shoulder including multiple irregular islands of ossification (anconeal area, olecranon, distal humerus), sternebral malalignment, wedge-shaped vertebral bodies, and craniocaudal elongation of occipital condyles

 

DIFFERENTIAL DIAGNOSIS:

Other chondrodysplastic syndromes in sheep (uncommon):

• Ancon mutant is a now-extinct breed characterized by disproportionate dwarfism, although recent mesomelic (short-limbed) mutants have reappeared in different breeds
• Texel sheep (New Zealand) have an autosomal recessive trait of dwarfism and varus forelimb deformity with wide-based stance, flaccid trachea with partially flattened rings; due to mutation in SLC13A1 gene
• Merino sheep (Australia) develop disproportionate dwarfism in the autosomal recessive brachygnathia, cardiomegaly, and renal hypoplasia syndrome
• Cabugi breed (Brazil) develop a syndrome of skeletal dysplasia, craniofacial abnormalities, and dwarfism

Other conditions causing scoliosis, kyphosis, or arthrogryposis in sheep:

• Cache Valley virus (g. Bunyavirus)
• Akabane virus (g. Bunyavirus)
• Bluetongue virus (Reoviridae, g. Orbivirus)
• Border disease virus (g. Pestivirus)
• Wild lupine ingestion by the dam at 40-70 days gestation
• Veratrum californicum ingestion by dam
• Conium maculatum (poison hemlock) ingestion by dam
• Astragalus, Oxytropis sp. (locoweed) ingestion by pregnant ewes
• Trachymene (wild parsnip) ingestion by pregnant ewes ("bent-leg" syndrome)
• Parbendazole overdose at 12-24 days gestation

 

COMPARATIVE PATHOLOGY:

• Cattle:
  • Chondrodysplasia similar to spider lamb syndrome: Simmental, brown Swiss, other European breeds; excessively long, thin, distal extremities, fragile bones, scoliosis, shortened mandible
  • Chondrodysplasia resulting in disproportionate dwarfism:
    • Dexter bulldog type: Dexter, Charolais, Jersey, Holstein breeds; usually aborted before 7^th month; short limbs, cranial base, and vertebral column; tongue protrudes; absent hard palate; umbilical hernia; absence of growth plates, irregular maturation and/or degeneration of resting cartilage; mutation in aggrecan (ACAN) gene
    • Telemark type: Telemark cattle with the lethal form of chondrodysplasia die of suffocation shortly after birth; domed cranium, brachygnathic face, palatoschisis, protruding tongue, short neck, short and bulky rotated limbs; Jerseys have a similar disorder, but have a wider phenotypic variability with some calves being viable
    • Brachycephalic ("snorter") type: Beef cattle (especially Herefords and Angus); brachycephalic with bulging forehead, shortened maxilla, protruding mandible, malocclusion; laterally displaced eyes; longitudinally compressed vertebrae; distal long bones proportionally shorter than proximal
    • Ellis-van Crevald syndrome: Japanese brown and Tyrolean Grey cattle with mutation in EVC2 gene results in a disorder of chondrocyte differentiation leading to chondrodysplastic dwarfism including severely reduced length of long bones, genital defects, and heart defects; similar to equivalent human disease
    • Intrauterine zinc or manganese deficiency
• Goats:
  • Akabane virus (g. Bunyavirus)
  • Conium maculatum, Nicotiana, lupines (during gestation)
• Horses:
  • Miniature horses: Four distinct types of dwarfism associated with four different mutations in the ACAN gene; one form similar to the Dexter “bulldog” cattle
  • Sudan grass (Sorghum sudanense) and hybrid sorghum ingestion
  • Wooly loco (Astragalus mollisimus) grazing during gestation
• Pigs:
  • Danish landrace: Autosomal recessive inherited chondrodysplasia in 3 litters with lesions limited to the long bones of the limbs
  • Yorkshire: A single progeny of a sow appeared normal following parturition but developed shorter, wider long bones with age analogous to Schmid metaphyseal chondrodysplasia of humans; determined to be autosomal dominant  inheritance with a missense mutation in the alpha-1 chain of type X collagen (COL10A1)
  • Conium maculatum (poison hemlock)
  • Nicotiana (tobacco)
• Chickens, ducks, turkeys: Tibial dyschondroplasia (M-T06); very common, multifactorial, affects fast growing meat-type birds; persistence of growth plate cartilage most commonly noted in the proximal tibiotarsal metaphysis; may cause lameness or pathologic fracture if lesion is large
• Rabbits: Chondrodysplasia can occur with homozygous Pelger-Huet anomaly
• Dogs:
  • Chondrodysplastic breeds: dachshund, Pekingese, and Bassett hounds; display atypical expression of FGF4 in chondrocytes from retrogene on chromosome 18, resulting in inappropriate activation of FGFRs (e.g. FGFR3)
  • Primordial dwarfism (AKA pseudoachondroplastic dysplasia): Miniature poodles, miniature Schnauzers, miniature pinschers
  • Multiple epiphyseal dysplasia: Beagles
  • Chondrodysplasia: Alaskan malamute, Norwegian elkhounds, English pointer, Great Pyrenees, cocker spaniel
  • Osteochondrodysplasia: Scottish deerhounds
  • Chondrodystrophy: Nova Scotia duck tolling retrievers; exhibit shortened long bones in addition to premature degeneration of the nucleus pulposus of the intervertebral discs; linked to an FGF4 retrogene insertion on canine chromosome 12 that has a 20-fold higher expression of FGF4 (Murphy, Vet Pathol. 2019)
• Cats: Osteochondrodysplasia of Scottish fold cats with defective maturation and function of cartilage in distal limbs, ears, and tail
• Mice: A similar syndrome to spider lamb syndrome has been reported

 

REFERENCES:

1. Andrade DGA, Basso RM, Castiglioni MCR, et al. Description of the D4/D4 genotype in Miniature horses with dwarfism. J Vet Diagn Invest. 2020;32(1):99-102.
2. Craig LE, Dittmer KE, Thompson KG. Bones and joints. In: Maxie MG, ed. Jubb, Kennedy, and Palmer’s Pathology of Domestic Animals. Vol 1. 6th ed. St. Louis, MO: Elsevier; 2016:37-46.
3. Murphy BG, Dickinson P, Marcellin-Little DJ, et al. Pathologic Features of the Intervertebral Disc in Young Nova Scotia Duck Tolling Retrievers Confirms Chondrodystrophy Degenerative Phenotype Associated With Genotype. Vet Pathol. 2019;56(6):895-902.
4. 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; 2017:975.
5. Shrivaprasad HL. Miscellaneous diseases.  In: Boulianne M., ed. Avian Disease Manual. 8^th Jacksonville, FL: American Association of Avian Pathologists; 2019:172-3.

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