Progressive osseous heteroplasia

Progressive osseous heteroplasia (POH) is a recently described genetic diso rder of mesenchymal differentiation characterized by dermal ossification du ring infancy and progressive heterotopic ossification of cutaneous, subcuta neous, and deep connective tissues during childhood. The disorder can be di stinguished from fibrodysplasia ossificans progressiva (FOP) by the presenc e of cutaneous ossification, the absence of congenital malformations of the skeleton, the absence of inflammatory tumorlike swellings, the asymmetric mosaic distribution of lesions, the absence of predictable regional pattern s of heterotopic ossification, and the predominance of intramembranous rath er than endochondral ossification. POH can be distinguished from Albright h ereditary osteodystrophy (AHO) by the progression of heterotopic ossificati on from skin and subcutaneous tissue into skeletal muscle, the presence of normal endocrine function, and the absence of a distinctive habitus associa ted with AHO. Although the genetic basis of POH is unknown, inactivating mu tations of the GNAS1 gene are associated with AHO. The report in this issue of the JBMR of 2 patients with combined features of POH and AHO-one with c lassic AHO, severe POH-like features, and reduced levels of G(s)alpha prote in and one with mild AHO, severe POH-like features, reduced levels of G(s)a lpha protein, and a mutation in GNAS1-suggests that classic FOR also could be caused by GNAS1 mutations. This possibility is further supported by the identification of a patient with atypical but severe platelike osteoma cuti s (POC) and a mutation in GNAS1, indicating that inactivating mutations in GNAS1 may lead to severe progressive heterotopic ossification of skeletal m uscle and deep connective tissue independently of AHO characteristics. Thes e observations suggest that POH may lie at one end of a clinical spectrum o f ossification disorders mediated by abnormalities in GNAS1 expression and impaired activation of adenylyl cyclase. Analysis of patients with classic POH (with no AHO features) is necessary to determine whether the molecular basis of POH is caused by inactivating mutations in the GNAS1 gene.