Progressive osseous heteroplasia caused by a novel nonsense mutation in the GNAS1 gene

Progressive osseous heteroplasia (POH), characterized by progressive heterotopic ossifications of the dermis, skeletal muscle and deep connective tissues, is caused by inactivating mutations of GNAS1 of a paternally transmitted allele. We report a novel GNAS1 mutation in a patient with POH. The patient is a 6-year-old boy, whose short stature came to medical attention in infancy. He was diagnosed with growth hormone (GH) deficiency, and subsequent GH therapy resulted in catch-up growth. He developed soft tissue masses in the right heel and right elbow that were calcified or ossified on plain radiographs. MR imaging raised a suspicion of heterotopic ossification; thus, GNAS1 was analyzed. A novel nonsense mutation p.R342X was observed in the patient, but not in his parents. Single nucleotide polymorphism analysis revealed paternal transmission of the mutant allele. RT-PCR analysis demonstrated expression of both normal and mutant GNAS1 transcripts in the patient. Thus, the patient is considered to have developed POH because of the non-functioning truncated Gs(alpha) protein.