Osteochondromatosis, EXT2-related

Gene: EXT2

Transmission: Autosomal, dominant

The animal only has to have one copy of the mutation to be at risk of developing hypertrophic cardiomyopathy. Animals with two copies of the mutation generally have more severe symptoms and an earlier onset of the disease than animals with just one copy of the mutation. Offspring are potentially at risk of developing the disease if at least one parent carries the mutation. Alternatively, the disease is caused by a de novo mutation.

Mutation: Substitution, EXT2 gene (nonsense); c.925C>A, p.(Tyr308 STOP), exon5, chromosome 18.

Breed: American Staffordshire Terrier/Amstaff

Medical system: Skeletal

Age of onset of symptoms: By 4 months of age.

Osteochondrosis in dogs, also called hereditary multiple exostoses, has been reported incidentally in multiple breeds. It is a rare genetic disease of skeletal development that occurs during endochondral bone growth. Exostoses are benign boney tissue masses covered by a cartilaginous layer that develop on the surface of the bone near the growth plates. The exostoses growths can be asymptomatic, but most dogs with osteochondrosis show symptoms of lameness, difficulty in movement and pain due to compression of surrounding tissues and/or nerves by the exostoses.

Osteochondrosis in humans is an autosomal dominant genetic disease caused by mutations in the EXT1, EXT2 or EXT3 genes. The EXT proteins are enzymes involved in the synthesis of heparan sulfate proteoglycans (extracellular matrix polysaccharides) that can contribute to normal chondrocyte function. A dominant mutation in the EXT1 gene has been reported as one cause of synovial osteochondromatosis in cats.

Osteochondromatosis was diagnosed in 3 young siblings from a litter of American Staffordshire Terriers that displayed clinical lameness and boney growths on radiographs. DNA analysis identified a heterozygous (dominant) nonsense mutation in the EXT2 that was considered causal for the clinical findings. The mutation was not seen in the parents and was judged de novo. The identification of this mutation is the first molecular characterization for osteochondromatosis in dogs. Although it is of academic interest, it is not of clinical concern to veterinarians or to breeders of American Staffordshire Terriers, due to its incidental and self-limiting occurrence within a single litter of animals. Osteochondromatosis as is occasionally reported in other dog breeds must await additional molecular characterizations.

References:

OMIA link: [1214-9615]

Friedenberg SG, Vansteenkiste D, Yost O, et al. (2018) A de novo mutation in the EXT2 gene associated with osteochondromatosis in a litter of American Staffordshire Terriers. J Vet Intern Med 32:986-992. [pm/29485212]

Contributed by: Rose Patenaude and Sarah Théorêt, Class of 2029, Faculté de médecine vétérinaire, Université de Montréal. (Translation DWS)