Deficiency of the alpha-subunit of the stimulatory G protein and severe extraskeletal ossification.
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 alpha-subunit of the G protein (Gsalpha) 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 Gsalpha deficiency.
Eddy
M C
MC
Center for Metabolic Bone Disease and Molecular Research, Shriners Hospital for Children, St. Louis, Missouri 63131, USA.
Jan De Beur
S M
SM
Yandow
S M
SM
McAlister
W H
WH
Shore
E M
EM
Kaplan
F S
FS
Whyte
M P
MP
Levine
M A
MA
D000328:Adult; D002648:Child; D005091:Exons; D005260:Female; D005359:Fibrous Dysplasia, Polyostotic / Q000000981:diagnostic imaging / Q000378:metabolism / Q000473:pathology; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000172:deficiency* / Q000235:genetics*; D006228:Hand Deformities, Congenital / Q000000981:diagnostic imaging; D006801:Humans; D007866:Leg / Q000002:abnormalities / Q000000981:diagnostic imaging; D009154:Mutation; D009999:Ossification, Heterotopic / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D011247:Pregnancy; D021122:Protein Subunits; D011859:Radiography; D012867:Skin / Q000473:pathology
D021122:Protein Subunits; D019205:GTP-Binding Protein alpha Subunits, Gs