Deficiency of the alpha-subunit of the stimulatory G protein and severe extraskeletal ossification

Progressive osseous heteroplasia (POH) is a rare disorder characterized by derm;pl ossification beginning in infancy followed by increasing and extens ive bone formation in deep muscle and fascia, We describe two unrelated gir ls with typical clinical, radiographic, and histological features of POH wh o also have findings of another uncommon heritable disorder, Albright hered itary osteodystrophy (AHO). One patient has mild brachydactryly but no endo crinopathy, whereas the other manifests brachydactyly, obesity, and target tissue resistance to thyrotropin and parathyroid hormone (PTH). Levels of t he alpha -subunit of the G protein (G(s)alpha) were reduced in erythrocyte membranes from both girls and a nonsense mutation (Q12X) in exon 1 of the G NAS1 gene was identified in genomic DNA from the mildly affected patient. F eatures of POH and AHO in two individuals suggest that these conditions sha re a similar molecular basis and pathogenesis and that isolated severe extr askeletal ossification may be another manifestation of G deficiency.