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Progressive osseous heteroplasia
1Department of Orthopaedic Surgery, The University of Pennsylvania School of Medicine, Philadelphia, USA.
Insights
Progressive osseous heteroplasia (POH) may be caused by GNAS1 gene mutations, linking it to a spectrum of ossification disorders. Further analysis of POH patients is needed to confirm the genetic basis.
Area of Science:
- Genetics
- Molecular Biology
- Developmental Biology
Background:
- Progressive osseous heteroplasia (POH) is a genetic disorder causing abnormal bone formation.
- POH is distinct from fibrodysplasia ossificans progressiva (FOP) and Albright hereditary osteodystrophy (AHO) based on clinical features.
- The genetic cause of POH remains unknown, though GNAS1 mutations are linked to AHO.
Purpose of the Study:
- To investigate the potential role of GNAS1 gene mutations in Progressive osseous heteroplasia (POH).
- To explore the relationship between POH, AHO, and GNAS1 gene expression.
- To determine if POH falls within a spectrum of ossification disorders related to GNAS1 abnormalities.
Main Methods:
- Clinical case study analysis of patients with POH and AHO features.
- Genetic analysis to identify mutations in the GNAS1 gene.
- Biochemical assessment of Gsalpha protein levels.
Main Results:
- Two patients with combined POH and AHO features showed reduced Gsalpha protein levels, with one having a GNAS1 mutation.
- A patient with atypical osteoma cutis and a GNAS1 mutation demonstrated severe heterotopic ossification.
- These findings suggest GNAS1 mutations can cause severe ossification independently of AHO.
Conclusions:
- Progressive osseous heteroplasia (POH) may be caused by inactivating GNAS1 mutations.
- POH could represent one end of a clinical spectrum of ossification disorders linked to GNAS1.
- Further studies on classic POH patients are required to confirm the GNAS1 mutation link.
Abstract:
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 Gsalpha protein and one with mild AHO, severe POH-like features, reduced levels of Gsalpha 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.