Categories: Skeleton phene (incl. short stature & teeth)

Possibly relevant human trait(s) and/or gene(s)s (MIM numbers): 133701 (trait) , 608210 (gene)

Links to MONDO diseases: No links.

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal dominant

Considered a defect: yes

Key variant known: yes

Year key variant first reported: 2018

Species-specific name: also called: multiple osteochondromas, multiple hereditary exostoses, multiple cartilaginous exostoses, diaphyseal aclasis and hereditary deforming chondrodysplasia

Molecular basis: Friedenberg et al. (2018) reported a likely de novo causal variant in American Staffordshire Terriers as "One heterozygous variant (c.969C > A) is predicted to result in a stop codon in exon 5 of the [EXT2] gene. Sanger sequencing identified the identical mutation in all affected offspring. The mutation was absent in the unaffected offspring, both parents, all available grandparents, and 26 healthy unrelated American Staffordshire Terriers." These same authors note that "Because this mutation arose de novo, the identical mutation is unlikely to be the cause of osteochondromatosis in other dogs. However, de novo mutations in EXT2 are common in humans with osteochondromatosis, and by extension, it is possible that dogs with osteochondromatosis could be identified by sequencing the entire EXT2 gene."

Genetic engineering: Unknown
Have human generated variants been created, e.g. through genetic engineering and gene editing

Clinical features: Osteochondromatosis is a skeletal developmental disorder that results in exostoses (cartilage capped bone outgrowths) that develop during the growth period (Pacifici, 2017). Depending on the location and size of the exostoses, osteochondromatosis can clinically present asymptotically, or can cause pain, lameness, paresis and paralysis (Czerwik et al. 2019). Clinical signs often occur due to compression of nearby tissues, including nerve root compression (causing pain) or spinal cord compression (causing paralysis) (Friedenberg et al., 2018). [IT thanks DVM student Lilli Wilhelm, who provided the basis of this contribution in April 2022]

Pathology: Whilst the pathophysiology and progression of the condition remains unclear, the disease is associated with abnormal migration of chondrocytes from the epiphyseal growth plates towards the bony cortex (Czerwik et al., 2019). The heterotopic cartilage cells that become ossified causes irregular bone formation on bone surfaces (Doige, 1987). The exostoses mainly occur on tissues that undergo endochondral ossification, including long bones, ribs and spinous processes of vertebrae (Doige, 1987). Growth of osteochondromas ceases at the time of physeal closure, known as skeletal maturity (Mozos et al., 2002). [IT thanks DVM student Lilli Wilhelm, who provided the basis of this contribution in April 2022]

Breed: American Staffordshire Terrier.
Breeds in which the phene has been documented. For breeds in which a likely causal variant has been documented, see the variant table below

Associated gene: