Paternally inherited inactivating mutations of the GNAS1 gene in progressive osseous heteroplasia.
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BACKGROUND: Progressive osseous heteroplasia (POH), an autosomal dominant disorder, is characterized by extensive dermal ossification during childhood, followed by disabling and widespread heterotopic ossification of skeletal muscle and deep connective tissue. Occasional reports of mild heterotopic ossification in Albright's hereditary osteodystrophy (AHO) and a recent report of two patients with AHO who had atypically extensive heterotopic ossification suggested a common genetic basis for the two disorders. AHO is caused by heterozygous inactivating mutations in the GNAS1 gene that result in decreased expression or function of the alpha subunit of the stimulatory G protein (Gsalpha) of adenylyl cyclase. METHODS: We tested the hypothesis that GNAS1 mutations cause POH, using the polymerase chain reaction to amplify GNAS1 exons and exon-intron boundaries in 18 patients with sporadic or familial POH. RESULTS: Heterozygous inactivating GNAS1 mutations were identified in 13 of the 18 probands with POH. The defective allele in POH is inherited exclusively from fathers, a result consistent with a model of imprinting for GNAS1. Direct evidence that the same mutation can cause either POH or AHO was observed within a single family, in which the phenotype correlated with the parental origin of the mutant allele. CONCLUSIONS: Paternally inherited inactivating GNAS1 mutations cause POH. This finding extends the range of phenotypes derived from haplo insufficiency of GNAS1, provides evidence that imprinting is a regulatory mechanism for GNAS1 expression, and suggests that Gsalpha is a critical negative regulator of osteogenic commitment in nonosseous connective tissues. (+info)
Impaired angiogenesis and endochondral bone formation in mice lacking the vascular endothelial growth factor isoforms VEGF164 and VEGF188.
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Vascular endothelial growth factor (VEGF)-mediated angiogenesis is an important part of bone formation. To clarify the role of VEGF isoforms in endochondral bone formation, we examined long bone development in mice expressing exclusively the VEGF120 isoform (VEGF120/120 mice). Neonatal VEGF120/120 long bones showed a completely disturbed vascular pattern, concomitant with a 35% decrease in trabecular bone volume, reduced bone growth and a 34% enlargement of the hypertrophic chondrocyte zone of the growth plate. Surprisingly, embryonic hindlimbs at a stage preceding capillary invasion exhibited a delay in bone collar formation and hypertrophic cartilage calcification. Expression levels of marker genes of osteoblast and hypertrophic chondrocyte differentiation were significantly decreased in VEGF120/120 bones. Furthermore, inhibition of all VEGF isoforms in cultures of embryonic cartilaginous metatarsals, through the administration of a soluble receptor chimeric protein (mFlt-1/Fc), retarded the onset and progression of ossification, suggesting that osteoblast and/or hypertrophic chondrocyte development were impaired. The initial invasion by osteoclasts and endothelial cells into VEGF120/120 bones was retarded, associated with decreased expression of matrix metalloproteinase-9. Our findings indicate that expression of VEGF164 and/or VEGF188 is important for normal endochondral bone development, not only to mediate bone vascularization but also to allow normal differentiation of hypertrophic chondrocytes, osteoblasts, endothelial cells and osteoclasts. (+info)
Preoperative, single-fraction irradiation for prophylaxis of heterotopic ossification after total hip arthroplasty.
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We gave a single fraction of 750 cGy preoperatively (within 16 h of surgery) to 143 patients prior to total hip arthroplasty. The patients were evaluated for heterotopic ossification at 1, 3 and 6 months. The preoperative radiation did not affect the surgical procedure. After a median follow-up of 12 (6-24) months we encountered six patients with heterotopic ossifications of Brooker grade I-II. Potential late risks from ionising radiation should be considered when treating younger patients. (+info)
Nerve cell markers in ossifying fibromyxoid tumour of soft parts.
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Reported herein are two benign ossifying fibromyxoid tumors (OFMTs) of the soft tissues in axilla and terminal phalanx respectively. Both cases on immunohistochemistry (IHC) showed reactivity for vimentin, S-100 protein and glial fibrillary acidic protein (GFAP) antibodies. In addition, a focal/diffuse strong positivity for neurofilament (NF) and neuron specific enolase (NSE) was observed. Electron microscopy in one instance revealed abundant intermediate filaments, primitive cell junctions and a focally present external lamina. In the light of nerve cell differentiation of these tumors and the similarity of IHC profile and EM features of OFMT to a poorly differentiated malignant peripheral nerve sheath tumor (MPNST); it is suggested that OFMT is a variably differentiated PNST rather than a simple Schwannian neoplasm as is believed. (+info)
Heterotopic ossification.
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Heterotopic ossification (HO) is the presence of bone in soft tissue where bone normally does not exist. The acquired form of HO most frequently is seen with either musculoskeletal trauma, spinal cord injury, or central nervous system injury. For example, patients who have recently undergone total hip arthroplasty or have paraplegia after spinal cord injury are at risk for HO. The fever, swelling, erythema, and occasional joint tenderness seen in early HO can be difficult to distinguish from cellulitis, osteomyelitis, or thrombophlebitis. Bone scanning and other imaging tests frequently are used to distinguish between these diagnostic possibilities. As treatment or prophylaxis for HO, either a nonsteroidal antiinflammatory drug (such as indomethacin), a diphosphonate (such as ethane-1-hydroxy-1,1-diphosphate), or local radiation therapy is recommended. Before therapy begins, bone scanning may be requested to confirm the diagnosis of HO. In addition, surgical resection of HO is used to preserve joint mobility; however, HO is likely to recur and possibly progress if resection is undertaken before the lesion has become mature. With a view toward avoiding recurrent HO and other operative complications, serial quantitative bone scans are used as an aid to time surgical intervention. (+info)
Ossifying malignant mixed epithelial and stromal tumor of the liver: a case report of a previously undescribed tumor.
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BACKGROUND: Malignant mixed tumors of the liver in adults are rare. To the authors' knowledge, twenty-four cases of primary malignant mixed hepatic tumors have been reported in the literature since the first description by Walter in 1896. Many of the previously reported cases are now considered mixed hepatoblastoma, primary hepatocellular carcinomas with focal sarcomatous metaplasia, or epithelioid hemangioendothelioma. METHODS: Clinical, radiologic, histologic and immunohistochemic methods were used to characterize an unusual example of a mixed malignant tumor of the adult liver that the authors descriptively refer to as "ossifying malignant mixed epithelial and stromal tumor" of the liver. RESULTS: In contrast to previously reported cases, the tumor in question was morphologically distinct. It was composed of three distinct neoplastic phenotypes: malignant spindle cells, with adenocarcinomatous differentiation, and extensive osteoid formation. The tumor was treated by partial hepatectomy. The patient was alive 8 years postoperatively as of December 2001. The distinctive combination of morphologic features and prolonged survival are much different from previously reported cases of mixed malignant hepatic tumors, which were typically rapidly fatal. CONCLUSIONS: The authors believe that the clinical and pathologic features of this patient's tumor are sufficiently distinctive to exclude it from the well-established categories of hepatic neoplasms. Histologically, the authors suggest the descriptive name "ossifying malignant mixed epithelial and stromal tumor of the liver" as a preliminary description for this tumor until the origin and relationship to other hepatic neoplasms are further characterized. (+info)
Abnormal collagen fibrils in tendons of biglycan/fibromodulin-deficient mice lead to gait impairment, ectopic ossification, and osteoarthritis.
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Small leucine-rich proteoglycans (SLRPs) regulate extracellular matrix organization, a process essential in development, tissue repair, and metastasis. In vivo interactions of biglycan and fibromodulin, two SLRPs highly expressed in tendons and bones, were investigated by generating biglycan/fibromodulin double-deficient mice. Here we show that collagen fibrils in tendons from mice deficient in biglycan and/or fibromodulin are structurally and mechanically altered resulting in unstable joints. As a result, the mice develop successively and progressively 1) gait impairment, 2) ectopic tendon ossification, and 3) severe premature osteoarthritis. Forced use of the joints increases ectopic ossification and osteoarthritis in the double-deficient mice, further indicating that structurally weak tendons cause the phenotype. The study shows that mutations in SLRPs may predispose to osteoarthritis and offers a valuable and unique animal model for spontaneous osteoarthritis characterized by early onset and a rapid progression of the disease. (+info)
Early surgical management for heterotopic ossification about the elbow presenting as limited range of motion associated with ulnar neuropathy.
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BACKGROUND: The formation of heterotopic ossification (HO) about the elbow after traumatic injury has been well documented in the literature. The optimal treatment, however, for ectopic bone associated with restricted range of motion and ulnar nerve entrapment syndrome has not been established. METHODS: Seven elbows with HO in 7 patients admitted to Chang Gung Memorial Hospital from April 1998 to January 1999 presented with limited range of motion and associated ulnar nerve neuropathy. All of these patients received early surgical excision of HO combined with release of the encased ulnar nerve and anterior transposition, followed by early gentle passive physical therapy and active exercise within the pain-free range of motion postoperatively. RESULTS: Almost full range of motion and complete functional ability following surgery were recovered in 6 of the 7 patients, while I patient who suffered from multiple traumatic injuries had limited improvement from 45 degrees ankylosis to 10 degrees approximately 90 degrees of a flexion-extension motion arc. CONCLUSION: Our results suggest that early surgical management combined with gentle physical therapy postoperatively is a feasible modality for treating patients with post-traumatic HO about the elbow presenting as limited range of motion and associated ulnar nerve compression syndrome. (+info)