Progressive Osseous Heteroplasia

• Published in: Journal of bone and mineral research 2000-11, Vol.15 (11), p.2084-2094
• Main Authors: Kaplan, Frederick S., Shore, Eileen M.
• Format: Article
• Language: English
• Subjects: Albright hereditary osteodystrophy; Biological and medical sciences; Diseases of the osteoarticular system; fibrodysplasia ossificans progressiva; Fibrous Dysplasia, Polyostotic - etiology; GNAS1; GTP-Binding Protein alpha Subunits, Gs - genetics; heterotopic ossification; Humans; Malformations and congenital and or hereditary diseases involving bones. Joint deformations; Medical sciences; Ossification, Heterotopic - etiology; Ossification, Heterotopic - pathology; Ossification, Heterotopic - therapy; Prognosis; progressive osseous heteroplasia; Self-Help Groups; Skin Diseases - etiology; Skin Diseases - pathology
• ISSN: 0884-0431; 1523-4681
• DOI: 10.1359/jbmr.2000.15.11.2084

Progressive osseous heteroplasia (POH) is a recently described genetic disorder of mesenchymal differentiation characterized by dermal ossification during infancy and progressive heterotopic ossification of cutaneous, subcutaneous, and deep connective tissues during childhood. The disorder can be distinguished from fibrodysplasia ossificans progressiva (FOP) by the presence 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 patterns of heterotopic ossification, and the predominance of intramembranous rather than endochondral ossification. POH can be distinguished from Albright hereditary osteodystrophy (AHO) by the progression of heterotopic ossification from skin and subcutaneous tissue into skeletal muscle, the presence of normal endocrine function, and the absence of a distinctive habitus associated with AHO. Although the genetic basis of POH is unknown, inactivating mutations 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 classic AHO, severe POH‐like features, and reduced levels of Gsα protein and one with mild AHO, severe POH‐like features, reduced levels of Gsα protein, and a mutation in GNAS1—suggests that classic POH also could be caused by GNAS1 mutations. This possibility is further supported by the identification of a patient with atypical but severe platelike osteoma cutis (POC) and a mutation in GNAS1, indicating that inactivating mutations in GNAS1 may lead to severe progressive heterotopic ossification of skeletal muscle and deep connective tissue independently of AHO characteristics. These observations suggest that POH may lie at one end of a clinical spectrum of 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.