Deficiency of the α‐Subunit of the Stimulatory G Protein and Severe Extraskeletal Ossification

• Published in: Journal of bone and mineral research 2000-11, Vol.15 (11), p.2074-2083
• Main Authors: Eddy, Mark C., Jan de beur, Suzanne M., Yandow, Suzanne M., McAlister, William H., Shore, Eileen M., Kaplan, Frederick S., Whyte, Michael P., Levine, Michael A.
• Format: Article
• Language: English
• Subjects: Adult; Biological and medical sciences; Child; cyclic adenosine monophosphate; Diseases of the osteoarticular system; Endocrinopathies; Exons; Female; Fibrous Dysplasia, Polyostotic - diagnostic imaging; Fibrous Dysplasia, Polyostotic - metabolism; Fibrous Dysplasia, Polyostotic - pathology; GTP-Binding Protein alpha Subunits, Gs - deficiency; GTP-Binding Protein alpha Subunits, Gs - genetics; Hand Deformities, Congenital - diagnostic imaging; heterotopic bone; Humans; Leg - abnormalities; Leg - diagnostic imaging; Malformations and congenital and or hereditary diseases involving bones. Joint deformations; Medical sciences; Mutation; Non tumoral diseases. Target tissue resistance. Benign neoplasms; Ossification, Heterotopic - genetics; Ossification, Heterotopic - metabolism; Ossification, Heterotopic - pathology; osteodystrophy; Parathyroids. Parafollicular cells. Cholecalciferol. Phosphocalcic homeostasis (diseases); Pregnancy; Progressive osseous heteroplasia; Protein Subunits; pseudohypoparathyroidism; Radiography; Skin - pathology
• ISSN: 0884-0431; 1523-4681
• DOI: 10.1359/jbmr.2000.15.11.2074

Progressive osseous heteroplasia (POH) is a rare disorder characterized by dermal ossification beginning in infancy followed by increasing and extensive bone formation in deep muscle and fascia. We describe two unrelated girls with typical clinical, radiographic, and histological features of POH who also have findings of another uncommon heritable disorder, Albright hereditary osteodystrophy (AHO). One patient has mild brachydactyly but no endocrinopathy, whereas the other manifests brachydactyly, obesity, and target tissue resistance to thyrotropin and parathyroid hormone (PTH). Levels of the α‐subunit of the G protein (Gsα) were reduced in erythrocyte membranes from both girls and a nonsense mutation (Q12X) in exon 1 of the GNAS1 gene was identified in genomic DNA from the mildly affected patient. Features of POH and AHO in two individuals suggest that these conditions share a similar molecular basis and pathogenesis and that isolated severe extraskeletal ossification may be another manifestation of Gsα deficiency.