Inherited human diseases of heterotopic bone formation

Nat Rev Rheumatol. 2010 Sep;6(9):518-27. doi: 10.1038/nrrheum.2010.122. Epub 2010 Aug 10.


Human disorders of hereditary and nonhereditary heterotopic ossification are conditions in which osteogenesis occurs outside of the skeleton, within soft tissues of the body. The resulting extraskeletal bone is normal. The aberration lies within the mechanisms that regulate cell-fate determination, directing the inappropriate formation of cartilage or bone, or both, in tissues such as skeletal muscle and adipose tissue. Specific gene mutations have been identified in two rare inherited disorders that are clinically characterized by extensive and progressive extraskeletal bone formation-fibrodysplasia ossificans progressiva and progressive osseous heteroplasia. In fibrodysplasia ossificans progressiva, activating mutations in activin receptor type-1, a bone morphogenetic protein type I receptor, induce heterotopic endochondral ossification, which results in the development of a functional bone organ system that includes skeletal-like bone and bone marrow. In progressive osseous heteroplasia, the heterotopic ossification leads to the formation of mainly intramembranous bone tissue in response to inactivating mutations in the GNAS gene. Patients with these diseases variably show malformation of normal skeletal elements, identifying the causative genes and their associated signaling pathways as key mediators of skeletal development in addition to regulating cell-fate decisions by adult stem cells.

Publication types

  • Review

MeSH terms

  • Activin Receptors, Type I / genetics
  • Fibrous Dysplasia, Polyostotic / complications
  • Fibrous Dysplasia, Polyostotic / genetics*
  • Genetic Linkage
  • Humans
  • Myositis Ossificans / complications
  • Myositis Ossificans / genetics*
  • Ossification, Heterotopic / etiology
  • Ossification, Heterotopic / genetics*


  • ACVR1 protein, human
  • Activin Receptors, Type I