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PubMedDate not supplied

Tuberoplasty: creation of an acromiohumeral articulation-a treatment option for massive, irreparable rotator cuff tears.

This article reports the results of treatment for irreparable tears of the rotator cuff with a new procedure that we have termed a tuberoplasty. The tuberoplasty procedure involves removal of exostoses on the humerus followed by reshaping of the greater tuberosity to create a smooth, congruent acromiohumeral articulation. The coracoacromial ligament is preserved, and an acromioplasty is not performed. Twenty patients underwent this procedure with a minimum 27-month follow-up. All patients had significant disabling pain and weakness preoperatively. On the basis of the modified UCLA rating scale, the overall score increased from 9.3 to 27.7, with 12 excellent results, 6 good results, and 1 fair result (95% satisfactory). Pain relief was most dramatic, with 13 patients (68%) completely pain-free. All patients were able to perform activities of daily living, and 9 of 11 who were employed preoperatively returned to work. All patients had residual weakness in external rotation. There were no poor results and no complications.

Acromion↗
PubMed2000

Pseudoaneurysm of the popliteal artery caused by exostosis of the femur: case report and review of the literature.

A 13-year-old boy with a solitary exostosis of the left femur was seen with a pseudo-aneurysm of the popliteal artery. When left leg pain occurred 3 months earlier, radiographic examination revealed an exostosis with a cartilage cap. Serial radiographic examination demonstrated gradual disruption of the cartilage cap of the exostosis as the pseudoaneurysm developed. An exostosis with an irregular surface was found at surgery. A literature review disclosed 39 similar cases in which loss of the cartilage cap was considered as one of the causes of the aneurysm formation. Considering the clinical course of our patient, however, we believe that exostoses lose their cartilage caps by pressure destruction due to the aneurysms. It is highly probable that loss of the cartilage does not cause the aneurysms.

Adolescent↗
PubMed2001

Human tumor suppressor EXT gene family members EXTL1 and EXTL3 encode alpha 1,4- N-acetylglucosaminyltransferases that likely are involved in heparan sulfate/ heparin biosynthesis.

The tumor suppressors EXT1 and EXT2 are associated with hereditary multiple exostoses and encode bifunctional glycosyltransferases essential for chain polymerization of heparan sulfate (HS) and its analog, heparin (Hep). Three highly homologous EXT-like genes, EXTL1-EXTL3, have been cloned, and EXTL2 is an alpha1,4-GlcNAc transferase I, the key enzyme that initiates the HS/Hep synthesis. In the present study, truncated forms of EXTL1 and EXTL3, lacking the putative NH2-terminal transmembrane and cytoplasmic domains, were transiently expressed in COS-1 cells and found to harbor alpha-GlcNAc transferase activity. EXTL3 used not only N-acetylheparosan oligosaccharides that represent growing HS chains but also GlcAbeta1-3Galbeta1-O-C2H4NH-benzyloxycarbonyl (Cbz), a synthetic substrate for alpha-GlcNAc transferase I that determines and initiates HS/Hep synthesis. In contrast, EXTL1 used only the former acceptor. Neither EXTL1 nor EXTL3 showed any glucuronyltransferase activity as examined with N-acetylheparosan oligosaccharides. Heparitinase I digestion of each transferase-reaction product showed that GlcNAc had been transferred exclusively through an alpha1,4-configuration. Hence, EXTL3 most likely is involved in both chain initiation and elongation, whereas EXTL1 possibly is involved only in the chain elongation of HS and, maybe, Hep as well. Thus, their acceptor specificities of the five family members are overlapping but distinct from each other, except for EXT1 and EXT2 with the same specificity. It now has been clarified that all of the five cloned human EXT gene family proteins harbor glycosyltransferase activities, which probably contribute to the synthesis of HS and Hep.

Adult↗
PubMed2000

rib-2, a Caenorhabditis elegans homolog of the human tumor suppressor EXT genes encodes a novel alpha1,4-N-acetylglucosaminyltransferase involved in the biosynthetic initiation and elongation of heparan sulfate.

The proteins encoded by the EXT1, EXT2, and EXTL2 genes, members of the hereditary multiple exostoses gene family of tumor suppressors, are glycosyltransferases required for the heparan sulfate biosynthesis. Only two homologous genes, rib-1 and rib-2, of the mammalian EXT genes were identified in the Caenorhabditis elegans genome. Although heparan sulfate is found in C. elegans, the involvement of the rib-1 and rib-2 proteins in heparan sulfate biosynthesis remains unclear. In the present study, the substrate specificity of a soluble recombinant form of the rib-2 protein was determined and compared with those of the recombinant forms of the mammalian EXT1, EXT2, and EXTL2 proteins. The present findings revealed that the rib-2 protein was a unique alpha1,4-N-acetylglucosaminyltransferase involved in the biosynthetic initiation and elongation of heparan sulfate. In contrast, the findings confirmed the previous observations that both the EXT1 and EXT2 proteins were heparan sulfate copolymerases with both alpha1,4-N-acetylglucosaminyltransferase and beta1,4-glucuronyltransferase activities, which are involved only in the elongation step of the heparan sulfate chain, and that the EXTL2 protein was an alpha1,4-N-acetylglucosaminyltransferase involved only in the initiation of heparan sulfate synthesis. These findings suggest that the biosynthetic mechanism of heparan sulfate in C. elegans is distinct from that reported for the mammalian system.

Animals↗
PubMed2000

Structural analysis of glycosaminoglycans in animals bearing mutations in sugarless, sulfateless, and tout-velu. Drosophila homologues of vertebrate genes encoding glycosaminoglycan biosynthetic enzymes.

Mutations that disrupt developmental patterning in Drosophila have provided considerable information about growth factor signaling mechanisms. Three genes recently demonstrated to affect signaling by members of the Wnt, transforming growth factor-beta, Hedgehog, and fibroblast growth factor families in Drosophila encode proteins with homology to vertebrate enzymes involved in glycosaminoglycan synthesis. We report here the biochemical characterization of glycosaminoglycans in Drosophila bearing mutations in sugarless, sulfateless, and tout-velu. We find that mutations in sugarless, which encodes a protein with homology to UDP-glucose dehydrogenase, compromise the synthesis of both chondroitin and heparan sulfate, as would be predicted from a defect in UDP-glucuronate production. Defects in sulfateless, a gene encoding a protein with similarity to vertebrate N-deacetylase/N-sulfotransferases, do not affect chondroitin sulfate levels or composition but dramatically alter the composition of heparin lyase-released disaccharides. N-, 6-O-, and 2-O-sulfated disaccharides are absent and replaced entirely with an unsulfated disaccharide. A mutation in tout-velu, a gene related to the vertebrate Exostoses 1 heparan sulfate co-polymerase, likewise does not affect chondroitin sulfate synthesis but reduces all forms of heparan sulfate to below the limit of detection. These findings show that sugarless, sulfateless, and tout-velu affect glycosaminoglycan biosynthesis and demonstrate the utility of Drosophila as a model organism for studying the function and biosynthesis of glycosaminoglycans in vivo.

Amidohydrolases↗
PubMed2002

Demonstration of a novel gene DEXT3 of Drosophila melanogaster as the essential N-acetylglucosamine transferase in the heparan sulfate biosynthesis: chain initiation and elongation.

Hereditary multiple exostoses gene (EXT) family members encode glycosyltransferases required for heparan sulfate (HS) biosynthesis in humans as well as in Drosophila. In the present study, we identified a novel Drosophila EXT protein with a type II transmembrane topology and demonstrated its glycosyltransferase activities. The truncated soluble form of this new homolog designated DEXT3 transferred N-acetylglucosamine (GlcNAc) through an alpha1,4-linkage not only to N-acetylheparosan oligosaccharides that represent growing HS chains (alpha-GlcNAc transferase II activity) but also to GlcUAbeta1-3Galbeta1-O-C(2)H(4)NHCbz, a synthetic substrate for alpha-GlcNAc transferase I that determines and initiates HS biosynthesis. The results suggest that DEXT3 is the ortholog of human EXTL3 and Caenorhabditis elegans rib-2. Semiquantitative reverse transcriptase-PCR analysis revealed ubiquitous expression of the DEXT3 mRNA. Based on the findings of the present study and those of a recent study where a fly mutant, deficient in the botv gene identical to DEXT3, affected HS proteoglycan-mediated developmental signalings, it is suggested that DEXT3 with the revealed glycosyltransferase activities is critically involved in HS formation in Drosophila. These results suggest the essential roles of DEXT3, its human ortholog EXTL3, and the C. elegans ortholog rib-2 in the biosynthesis of heparan sulfate and heparin, if present, in the respective organisms.

Amino Acid Sequence↗
PubMed2003

In vitro heparan sulfate polymerization: crucial roles of core protein moieties of primer substrates in addition to the EXT1-EXT2 interaction.

Heparan, the common unsulfated precursor of heparan sulfate (HS) and heparin, is synthesized on the glycosaminoglycan-protein linkage region tetrasaccharide GlcUA-Gal-Gal-Xyl attached to the respective core proteins presumably by HS co-polymerases encoded by EXT1 and EXT2, the genetic defects of which result in hereditary multiple exostoses in humans. Although both EXT1 and EXT2 exhibit GlcNAc transferase and GlcUA transferase activities required for the HS synthesis, no HS chain polymerization has been demonstrated in vitro using recombinant enzymes. Here we report in vitro HS polymerization. Recombinant soluble enzymes expressed by co-transfection of EXT1 and EXT2 synthesized heparan polymers with average molecular weights greater than 1.7 x 105 using UDP-[3H]GlcNAc and UDP-GlcUA as donors on the recombinant glypican-1 core protein and also on the synthetic linkage region analog GlcUA-Gal-O-C2H4NH-benzyloxycarbonyl. Moreover, in our in vitro polymerization system, a part time proteoglycan, alpha-thrombomodulin, that is normally modified with chondroitin sulfate served as a polymerization primer for heparan chain. In contrast, no polymerization was achieved with a mixture of individually expressed EXT1 and EXT2 or with acceptor substrates such as N-acetylheparosan oligosaccharides or the linkage region tetrasaccharide-Ser, which are devoid of a hydrophobic aglycon, suggesting the critical requirement of core protein moieties in addition to the interaction between EXT1 and EXT2 for HS polymerization.

Animals↗
PubMed2004

Embryonic fibroblasts with a gene trap mutation in Ext1 produce short heparan sulfate chains.

Mutational defects in either EXT1 or EXT2 genes cause multiple exostoses, an autosomal hereditary human disorder. The EXT1 and EXT2 genes encode glycosyltransferases that play an essential role in heparan sulfate chain elongation. In this study, we have analyzed heparan sulfate synthesized by primary fibroblast cell cultures established from mice with a gene trap mutation in Ext1. The gene trap mutation results in embryonic lethality, and homozygous mice die around embryonic day 14. Metabolic labeling and immunohistochemistry revealed that Ext1 mutant fibroblasts still produced small amounts of heparan sulfate. The domain structure of the mutant heparan sulfate was conserved, and the disaccharide composition was similar to that of wild type heparan sulfate. However, a dramatic difference was seen in the polysaccharide chain length. The average molecular sizes of the heparan sulfate chains from wild type and Ext1 mutant embryonic fibroblasts were estimated to be around 70 and 20 kDa, respectively. These data suggest that not only the sulfation pattern but also the length of the heparan sulfate chains is a critical determinant of normal mouse development.

Animals↗
PubMed1985

Otitis externa. A common, often self-inflicted condition.

Otitis externa can be caused by trauma to the ear canal, skin disorders, and viral and bacterial infections. Often the disease is self-inflicted; insertion of an object into the canal in an attempt to clean the ear interferes with the ear's own cleansing mechanism and causes inflammation and infection. Swimmers, persons who wear a hearing aid, and persons who have had an ear disorder are especially prone to infection and may need to take special precautions. Appropriate treatment, including instillation of drops, cleansing of the canal, and drug therapy, usually prevents recurrence. Surgical intervention may be necessary to enlarge a tiny canal or remove exostoses and osteomas. A rare form of otitis externa is "malignant" external otitis, which usually affects diabetic patients and has a high mortality.

Adolescent↗
PubMedDate not supplied

The vertebral artery: a review of anatomical, histopathological and functional factors influencing blood flow to the hindbrain.

An uncompromised blood flow to the brain is essential for normal neurological function. If the blood supply to the hindbrain, via the paired vertebral arteries, is reduced sufficiently, signs and symptoms of tertebrobasilar ischaemia may result. There are several factors that may cause a reduction in vertebral artery blood flow. These include exostoses, such as the retroarticular canal and lateral bridge of the atlas vertebra that may cause compression of the related part of the vertebral artery; or atherosclerosis of the artery wall occluding the vessel lumen. Functional factors, such as sustained end-of-range rotation of the cervical spine, may cause distortion of the vertebral artery in the suboccipital region, which may be reflected as decreased blood flow in the suboccipital and intracranial parts of the artery. A combination of such factors is likely to cause reduced blood flow to the hindbrain. It is the purpose of this review to highlight some of the factors that may compromise vertebral artery blood flow and, therefore, to provide some evidence on which to base our professional practice.

Cervical Vertebrae↗
PubMed1984

Effect of dog food containing 460 ppm fluoride on rat reproduction.

A one-generation, two-litter rat reproduction study was done in a kennel in Allegan County, Michigan, as part of an investigation of reproductive problems in Shetland sheepdogs (shelties). Since 1970, at least 115 sheltie litters at this kennel have been grossly deformed and/or have died, generally within 3 d of birth. The causative factor(s) appears to be associated with the environment, as the shelties have had successful pregnancies elsewhere. There was some concern that a potential threat to human reproduction also might exist in this area. After it was discovered that fluoride in the dog food had apparently caused mottled teeth and bony exostoses in dogs at this and at least two other kennels, dog-food fluoride content and local well water were investigated as possible causes of the reproductive problems. A two-way factorial statistical design allowed assessment of dietary fluoride content and water source and interaction between the two. UPj:TUC(SD)spf rats, 9 males and 18 females in each group, were assigned to treatment with high-fluoride dog food (460 ppm) and well water; high-fluoride dog food and distilled water; low-fluoride dog food (56 ppm) and well water; and low-fluoride dog food and distilled water. After 60 d in the kennel, the rats were mated. Even after two litters, the only adverse effect was dental fluorosis in the high-fluoride groups. The results indicated that rats cannot be used in the search for the cause(s) of reproductive problems in dogs in this kennel.

Abnormalities, Drug-Induced↗
PubMed1999

EXT-mutation analysis and loss of heterozygosity in sporadic and hereditary osteochondromas and secondary chondrosarcomas.

Osteochondromas occur as sporadic solitary lesions or as multiple lesions, characterizing the hereditary multiple exostoses syndrome (EXT). Approximately 15% of all chondrosarcomas arise within the cartilaginous cap of an osteochondroma. EXT is genetically heterogeneous, and two genes, EXT1 and EXT2, located on 8q24 and 11p11-p12, respectively, have been cloned. It is still unclear whether osteochondroma is a developmental disorder or a true neoplasm. Furthermore, it is unclear whether inactivation of both alleles of an EXT gene, according to the tumor-suppressor model, is required for osteochondroma development, or whether a single EXT germline mutation acts in a dominant negative way. We therefore studied loss of heterozygosity and DNA ploidy in eight sporadic and six hereditary osteochondromas. EXT1- and EXT2-mutation analysis was performed in a total of 34 sporadic and hereditary osteochondromas and secondary peripheral chondrosarcomas. We demonstrated osteochondroma to be a true neoplasm, since aneuploidy was found in 4 of 10 osteochondromas. Furthermore, LOH was almost exclusively found at the EXT1 locus in 5 of 14 osteochondromas. Four novel constitutional cDNA alterations were detected in exon 1 of EXT1. Two patients with multiple osteochondromas demonstrated a germline mutation combined with loss of the remaining wild-type allele in three osteochondromas, indicating that, in cartilaginous cells of the growth plate, inactivation of both copies of the EXT1 gene is required for osteochondroma formation in hereditary cases. In contrast, no somatic EXT1 cDNA alterations were found in sporadic osteochondromas. No mutations were found in the EXT2 gene.

Adolescent↗
PubMed2000

Genotypic and phenotypic spectrum in tricho-rhino-phalangeal syndrome types I and III.

Tricho-rhino-phalangeal syndrome (TRPS) is characterized by craniofacial and skeletal abnormalities. Three subtypes have been described: TRPS I, caused by mutations in the TRPS1 gene on chromosome 8; TRPS II, a microdeletion syndrome affecting the TRPS1 and EXT1 genes; and TRPS III, a form with severe brachydactyly, due to short metacarpals, and severe short stature, but without exostoses. To investigate whether TRPS III is caused by TRPS1 mutations and to establish a genotype-phenotype correlation in TRPS, we performed extensive mutation analysis and evaluated the height and degree of brachydactyly in patients with TRPS I or TRPS III. We found 35 different mutations in 44 of 51 unrelated patients. The detection rate (86%) indicates that TRPS1 is the major locus for TRPS I and TRPS III. We did not find any mutation in the parents of sporadic patients or in apparently healthy relatives of familial patients, indicating complete penetrance of TRPS1 mutations. Evaluation of skeletal abnormalities of patients with TRPS1 mutations revealed a wide clinical spectrum. The phenotype was variable in unrelated, age- and sex-matched patients with identical mutations, as well as in families. Four of the five missense mutations alter the GATA DNA-binding zinc finger, and six of the seven unrelated patients with these mutations may be classified as having TRPS III. Our data indicate that TRPS III is at the severe end of the TRPS spectrum and that it is most often caused by a specific class of mutations in the TRPS1 gene.

Adolescent↗
PubMed1995

Molecular dissection of a contiguous gene syndrome: localization of the genes involved in the Langer-Giedion syndrome.

The Langer-Giedion syndrome (tricho-rhino-phalangeal syndrome type II, TRPS II) is characterized by craniofacial dysmorphism and skeletal abnormalities. It combines the clinical features of TRPS I and multiple cartilaginous exostoses (EXT). We have used YAC cloning, Southern blotting, PCR analysis, and fluorescence in situ hybridization to study chromosome 8 deletions, translocations, an inversion, and an insertion in patients with TRPS I, TRPS II or EXT. Our results indicate that the TRPS gene maps more than 1,000 kb proximal to the EXT1 gene and that both genes are affected in TRPS II. We conclude that TRPS II is not due to pleiotropic effects of mutations in a single gene, but that it is a true contiguous gene syndrome.

Base Sequence↗
PubMed1996

Fibrodysplasia (myositis) ossificans progressiva: clinicopathological features and natural history.

Patients with fibrodysplasia (myositis) ossificans progressiva (FOP) (n = 28) were studied for up to 24 years. All had characteristic short big toes potentially recognizable at birth; there were radiographic changes in the toes, thumbs, cervical spine and metaphyses of the long bones, including exostoses. Ossification in the large skeletal muscles began from birth to 16 years (mean age 4.6 years) initially in 25 patients in the neck and upper spinal muscles, and later around the hips, major joints and jaw. The rate and extent of disability was unrelated to the time of onset. There was no evidence that any form of treatment produced consistent benefit. Despite the unique combination of skeletal abnormalities and ectopic ossification, the first diagnosis in patients with FOP was often wrong and usually delayed after ectopic ossification began (mean 2.7 years, range 0-14). Except where presentation was unusual, such as progressive stiffness, this delay was mainly due to failure to recognize the significance of the abnormal toes. The most frequent erroneous histological diagnoses were soft tissue sarcoma or fibromatosis. This series emphasizes the usually incorrect initial diagnosis, the misinterpretation of the histology, the unpredictable prognosis and the failure of current treatment. Despite its extreme rarity, there is a need for wider knowledge of this condition both to avoid clinical errors and to stimulate research.

Abnormalities, Multiple↗
PubMed1984

Forensic aspects of aboriginal skeletal remains in Australia.

The assessment of Aboriginal skeletal remains and their distinction from whites is an area of major importance to the Australian forensic pathologist. The Aborigines, the indigenous people of Australia, are a distinct racial group with many characteristic anthropological features. The assessment of race is best made from an examination of cranial traits, 20 which are of value. A characteristic pattern of attrition of the teeth provides a method for establishing a skeleton as pre-European contact Aboriginal or postcontact tribal Aboriginal. The limb proportions of Aborigines differ significantly from other races and provide a useful adjunct to other racial discriminants. Quantifiable sex discriminants in the Aboriginal pelvis and femur differ in their ranges of values from other races. The humerus and shoulder girdle are of no value in making a racial distinction and are of limited value in sexing Aboriginal skeletons. Some pathological changes seen in Aboriginal skeletons are of value in corroborating race. These pathological changes include evulsion of incisor teeth, healed "parry fractures" of the ulnae, tibial squatting facets, treponemal changes, and auditory exostoses. The place and manner of burial together with related artefacts, features, and ecofacts may also provide corroboration.

Australia↗
PubMed1979

Premalignant tumors and conditions of bone.

Most bone sarcomas arise in apparently normal bone. However, some sarcomas arise in preexisting benign bone tumors or in nonneoplastic conditions. Some of the lesions, such as multiple exostoses and Ollier's disease, have a propensity to develop chondrosarcoma. Rarely does a benign giant cell tumor become malignant without prior irradiation, malignant transformation of other benign tumors, such as osteoblastoma and chondroblastoma, is a medical curiosity. Among nonneoplastic conditions, radiation changes, long-standing chronic osteomyelitis, and Paget's disease have definite premalignant connotations. However, the risk of developing cancer in these conditions is still low.

Adult↗
PubMed1985

Bursa formation in secondary chondrosarcoma with intrabursal chondrosarcomatosis.

Osteocartilaginous exostoses (osteochondromata) are rather common bone tumors. Although most are straightforward lesions, one may occasionally encounter one of a number of well-recognized complications. In the current case, secondary malignant transformation and bursal sac formation were present. Additionally, numerous malignant chondroid nodules were shed into the attached bursa, giving rise to a large soft tissue mass, a situation which we feel is both remarkable and, to our knowledge, unique.

Aged↗