Endocrine Abstracts

Progressive osseous heteroplasia (POH) is a rare autosomal dominant disorder of mesenchymal differentiation characterized by progressive heterotopic ossification (HO) of dermis, skeletal muscle and deep connective tissues. Initially HO occurs during infancy as osteoma cutis, then extends progressively into deep connective tissues during childhood. Most cases of POH are caused by paternally inherited mutations of GNAS gene. Maternal mutations as well as epigentic defects of the same gene lead to pseudohypoparathyroidism (PHP) and Albright’s hereditary osteodystrophy (AHO). Recently, some reports documented the existence of POH patients showing additional features characteristics of PHP/AHO. Thus, POH has been proposed to be part of the spectrum of HO disorders caused by inactivating GNAS mutations.

We investigated nine unrelated POH patients, one of whom also showed resistance to PTH and TSH, for GNAS genetic and epigenetic status by direct sequencing and MS-MLPA. In a subset of patients, we performed RNA segregation analysis in order to establish the parental origin of the mutated allele.

We detected Four GNAS mutations in five of nine patients, all de novo and predicting truncated proteins. In three mutated patients, we demonstrated that the mutation occurred on the paternal allele. No evident differences were observed among patients harboring different mutations, as well as between mutated and non-mutated patients. Thus, neither the presence/absence nor the type or the localization of the mutation allowed to predict a specific phenotype or the severity of progression within the spectrum of GNAS–related disorders. All tested POH patients resulted wild type for GNAS imprinting status and no copy number abnormalities were found.

In conclusion, our results support that POH belongs to a continuum of HO disorders associated with inactivating GNAS mutations and further expand the spectrum of associated genetic defects. Moreover, unlike PHP, methylation alterations at GNAS locus are absent or uncommon in POH.