Multiple Osteochondromas: Clinicopathological and Genetic Spectrum and Suggestions for Clinical Management
© The Author(s) 2004
Received: 18 August 2004
Accepted: 15 November 2004
Published: 15 November 2004
Multiple Osteochondromas is an autosomal dominant disorder characterised by the presence of multiple osteochondromas and a variety of orthopaedic deformities. Two genes causative of Multiple Osteochondromas, Exostosin-1 (EXT1) and Exostosin-2 (EXT2), have been identified, which act as tumour suppressor genes. Osteochondroma can progress towards its malignant counterpart, secondary peripheral chondrosarcoma and therefore adequate follow-up of Multiple Osteochondroma patients is important in order to detect malignant transformation early.
This review summarizes the considerable recent basic scientific and clinical understanding resulting in a multi-step genetic model for peripheral cartilaginous tumorigenesis. This enabled us to suggest guidelines for clinical management of Multiple Osteochondroma patients. When a patient is suspected to have Multiple Osteochondroma, the radiologic documentation, histology and patient history have to be carefully reviewed, preferably by experts and if indicated for Multiple Osteochondromas, peripheral blood of the patient can be screened for germline mutations in either EXT1 or EXT2. After the Multiple Osteochondroma diagnosis is established and all tumours are identified, a regular follow-up including plain radiographs and base-line bone scan are recommended.
Keywordsbone neoplasm multiple osteochondromas genetics clinical management chondrosarcoma exostosis
Osteochondroma is the most common benign bone tumour, which occurs as sporadic (solitary) or multiple, usually in the context of the hereditary syndrome, Multiple Osteochondromas (MO) [1, 2]. Considerable understanding obtained through research on the genetic, pathological and radiologic background of these tumours, has provided insights into the tumorigenesis of Multiple Osteochondromas resulting in the optimisation of clinical management, including radiologic and mutational screening.
Osteochondromas represent about 50% of all surgically treated primary benign bone tumours . Approximately 15% of the osteochondroma patients have multiple lesions [1, 3] of which 62% have a positive family history .
The incidence for Multiple Osteochondromas has been estimated at 1:50,000 in the general population , with a higher prevalence in males (male:female ratio of 1.5:1) [4, 6], which is partly due to incomplete penetrance in females .
Osteochondroma (osteocartilaginous exostosis), according to the 2002 WHO definition, is a cartilage capped benign bony neoplasm on the outer surface of bones preformed by endochondral ossification [7–9]. They develop and increase in size in the first decade of life and cease to grow at skeletal maturation or shortly thereafter. The most common site of involvement is the metaphyseal region of the long bones of the limbs, like the distal femur, upper humerus, upper tibia and fibula [1, 8]. However, osteochondromas also occur in flat bones, in particular the ilium and scapula. An important differential diagnostic feature as compared to e.g. metachondromatosis or parosteal and periosteal osteosarcoma, is the extension of the medullar cavity into the lesion and the continuity of the cortex with the underlying bone. The perichondrium, the outer layer of osteochondroma, is continuous with the periosteum of the underlying bone.
Many osteochondromas are cauliflower shaped and can be divided on macroscopical grounds to often long slender pendunculated osteochondromas and flat sessile ones.
In the cartilage cap the chondrocytes are arranged in a similar fashion as in the epiphyseal growth plate. As a typical benign tumour the chondrocytes have small single nuclei. Binucleated chondrocytes may be seen during active growth.
The stalk may fracture, which may result in reactive fibroblastic proliferation and new bone formation, erroneously leading to interpretation as the formation of secondary sarcoma. Attached to the perichondrium a secondary bursa may develop and simulate the growth of the underlying tumour. This bursa is lined by synovium and may show inflammatory changes .
Multiple Osteochondromas (hereditary multiple exostoses, diaphyseal aclasis) are characterised by the presence of multiple osteochondromas [2, 4, 6, 10, 11] the number of which can vary significantly between and within families. Most Multiple Osteochondroma patients also suffer from a variety of orthopaedic deformities like shortening of the ulna with secondary bowing of the radius (39-60%), inequality of the limbs (10-50%), varus or valgus angulation of the knee (8-33%), deformity of the ankle (2-54%) and disproportionately short stature [2, 4–6, 12]. It has been a matter of debate whether these deformities are a result of skeletal dysplasia or a result of local effects on the adjacent growth plate caused by developing osteochondromas.
No well-documented association between Multiple Osteochondromas and other non-bone related disorders has been described so far.
Malignant transformation of osteochondroma is estimated to be less than 1% in patients with solitary lesions and 0.5-3% in patients with Multiple Osteochondromas [2, 7]. In 94% of the cases with malignant progression a secondary peripheral chondrosarcoma has developed within the cartilage cap of an osteochondroma . Secondary peripheral chondrosarcoma is a hyaline cartilage producing tumour and constitutes approximately 15% of all chondrosarcomas [1, 14], which is the third most frequent malignant bone tumour after myeloma and osteosarcoma . Increasing pain, functional disability and/or a growing mass, specifically after maturation of the skeleton, may indicate malignant transformation. Radiologic features show irregular mineralisation and increased thickness (over 2 cm) of the cartilage cap of an osteochondroma. The cap shows lobules of hyaline cartilage that are separated by bands of fibrous tissue . With (dynamic) contrast enhanced magnetic resonance (MR) imaging this can be seen as septal enhancement whereas osteochondromas only display peripheral enhancement. High-grade peripheral chondrosarcomas are characterised by inhomogeneous and homogeneous enhancement patterns on gadolinium-enhanced MR images [16, 17].
The histological grading of chondrosarcoma is based on nuclear size and chromasia and cellularity  and is the most important predictor of clinical behaviour and thus prognosis of patients with chondrosarcomas . Chondrosarcomas secondary to osteochondromas are usually low-grade tumours resulting in a reasonably fair prognosis for these patients .
Multiple Osteochondromas is an autosomal dominant disorder for which two genes have been isolated, Exostosin-1 (EXT1; OMIM 133700) located at 8q24 and Exostosin- 2 (EXT2; OMIM 133701) located at 11p11-p12 [23–25]. 44-66% of the Multiple Osteochondroma families show linkage at the EXT1 region [26, 27], compared to 27% for EXT2 . Germline mutations of EXT1 and EXT2 have been described in Multiple Osteochondroma patients from Caucasian [23, 25, 28–31] and Asian populations [32–34].
Loss of the remaining wild-type allele has been demonstrated in hereditary osteochondromas , indicating that the EXT genes act as tumour suppressor genes in Multiple Osteochondromas. This is consistent with Knudson's two-hit model for tumour suppressor genes .
Not many genotype-phenotype correlation studies have been described to draw definitive conclusions [37, 38]. There seems to be a slightly higher risk of malignant transformation in patients with an EXT1 mutation as compared to EXT2 .
The existence of a third EXT gene on chromosome 19p, EXT3 , has been suggested, however no gene has been identified, nor has this locus been implicated by other researchers.
Based on their homology with EXT1 and EXT2, three other members of the EXT-family of genes, the EXT-like genes (EXTL1-3), have been identified [40–42]. EXTL1, EXTL2 and EXTL3 are located at 1p36.1 , 1p11-p12  and 8p12-p22 , respectively. No linkage with Multiple Osteochondromas or other bone diseases has been documented for these genes .
Before linkage to Multiple Osteochondromas, osteochondromas were already known to be involved in a contiguous gene deletion syndrome, the Langer Gideon syndrome (LGS or trichorhinophalangeal syndrome type II; OMIM150230) , where patients carry a deletion of 8q24 . Besides multiple osteochondromas the Langer Gideon syndrome is characterised by craniofacial dysmorphism and mental retardation [44, 45].
In two large Multiple Osteochondroma pedigrees not linked to 8q24, linkage was found to a 3 cM region located at 11p11-p12, excluding the pericentrometric region [52, 53]. In 1996, the EXT2 gene was identified by positional cloning by two groups independently [24, 25].
The EXT2 gene contains 16 exons (Fig. 3) and spans approximately 108 kb of genomic DNA . The mRNA consists of approximately 3kb, with a single open reading frame of 2154 bp in which the C-terminal region shows high similarity with EXT1 [24, 25]. The mRNA shows alternative splicing in exon 1a and 1b and is ubiquitously expressed [24, 25]. Homologues of EXT2 have been found in mouse (chromosome 2) [51, 54], Drosophila melanogaster (sister of tout-velu, sotv) and Caenorhabditis elegans .
Like EXT1, EXT2 has been implicated in a contiguous gene deletion syndrome, Potocki-Shaffer syndrome (DEFECT11; OMIM 601224), where patients carry a deletion of 11p11.2-p12 [56, 57]. Patients with this syndrome demonstrate multiple osteochondromas, enlarged parietal foramina (FPP), craniofacial dysostosis and mental retardation [56, 57].
Heparan Sulphate Proteoglycans (HSPG)
HSPGs are large multifunctional macromolecules involved in several growth signalling pathways, anchorage to the extracellular matrix and sequestering of growth factors (reviewed by Knudson ). Four HSPG families have been identified: syndecan, glypican, perlecan and CD44 isoforms.
The syndecan family consists of four members, encoding type I transmembrane polypeptides involved in the anchorage of cells to the extracellular matrix and binding of growth factors . In mouse and chick, syndecan-2 and -3 have shown to be involved in signalling pathways in proliferating chondrocytes [67–70].
The six glypican family members encode proteins attached to the cell membrane with a glycosylphosphati-dylinositol (GPI)-anchor. They predominantly function as co-receptors . Expression of several glypicans has been found in the perichondrium, the developing limb and mesenchymal tissues of the developing mouse embryo .
The largest HSPG, perlecan, is the most common proteoglycan of the basement membrane. It is expressed in hyaline cartilage and in all zones of the rat growth plate during endochondral ossification . Perlecan, syndecan and glypican are reported to be involved in FGF-signalling [65, 66].
The fourth HSPG family is specific isoforms of the type I transmembrane glycoproteins CD44. The CD44 gene consists of 20 exons of which 10 (so-called variable exons) can be alternatively spliced (reviewed by Ponta et al ). CD44 isoforms containing variable exon 3 (v3) have been shown to bind growth factors through HS side chains, thereby regulating cell growth and motility .
Indian Hedgehog (IHh)/PTHrP signalling in the growth plate
In the growth plate EXT1 and EXT2 are expressed in the proliferative and transition zone  (Fig. 5). The HSPGs, expressed in all zones of the growth plate [67–72], are presumed to be involved in the diffusion of IHh to its receptor in the perichondrium. During normal embryonic growth IHh, expressed in the transition zone, is involved in a paracrine feedback loop regulating proliferation and differentiation of chondrocytes and bony collar formation in the growth plate (Fig. 5A). In this feedback loop PTHrP regulates chondrocyte differentiation by delaying progression of chondrocytes towards the hypertrophic zone, allowing longitudinal bone growth . In the rat post-natal growth plate the feedback loop is confined to the growth plate itself (Fig. 5B), in particular to the transition zone .
Fibroblast Growth Factor (FGF) signalling in the growth plate
The FGF-signalling pathway is dependent on HSPGs for the high affinity binding capacity of the FGF receptor (FGFR), allowing receptor dimerisation and subsequent cell signalling [80, 81]. The most potent mitogen for chondrocytes, FGF-2 (basic FGF), inhibits differentiation of chondrocytes via stimulation of extracellular matrix synthesis [82, 83]. In contrast, activation of FGFR3 in the proliferative zone (Fig. 5), by FGF18  inhibits chondrocyte proliferation via phosphorylation of STAT-1 and subsequent upregulation of p21WAF/CIP1, which can inhibit the cell cycle . FGFR3 activation also leads to repression of IHh signalling [80, 81, 86].
Histogenesis and secondary sarcoma formation
Although some believe that the severity of the angular deformity is correlated with the number of sessile osteochondromas , several studies in mice have shown that haploinsufficiency of EXT1 or EXT2 causes severe skeletal deformities [90, 91]. Loss of the remaining wild-type allele of EXT1 in hereditary osteochondromas  indicated that inactivation of both copies of the EXT1 gene in cartilaginous cells of the growth plate is required for osteochondroma formation, thereby acting as a tumour suppressor gene . Two studies have shown diminished HSPG expression in either osteochondromas or cultured EXT1-/- cells [92, 93]. This is hypothesised to affect the negative feedback loop by disturbing IHh diffusion to Ptc and by preventing high-affinity binding of FGF to its receptor (Fig. 5). Immunohistochemical studies have already shown that molecules involved in the IHh/PTHrP and FGF/FGFR signalling (PTHrP, PTHrP-R1, Bcl-2, FGF2, FGFR1, FGFR3 and p21) are absent in osteochondromas  suggesting that growth signalling is indeed disturbed in osteochondroma.
At the protein level, re-expression of several of these signalling molecules (FGF2, FGFR1, p21, PTHrP and Bcl-2) was found in secondary peripheral chondrosarcoma and the expression increased with increasing histological grade . Upregulation of Bcl-2 characterised malignant transformation of osteochondroma towards grade I secondary peripheral chondrosarcoma . Signalling may now occur in an autocrine fashion or in a paracrine one in which IHh acts on cells in its near vicinity, having to diffuse over only a few cell diameters and thereby avoiding HSPG-dependent diffusion .
The process of malignant transformation is genetically represented by chromosomal instability , probably caused by defects in spindle formation. The LOH found in osteochondroma was restricted to 8q24 , whereas in secondary peripheral chondrosarcomas LOH was found in virtually all loci tested . Also a broad range in DNA ploidy including near-haploidy and non-specific chromosomal alterations were found [95, 96]. DNA-flow cytometry of the cartilaginous cap of osteochondromas showed mild aneuploidy , whereas more severe aneuploidy [97–99], including near-haploidy , was seen in grade I secondary peripheral chondrosarcomas.
Further progression towards high-grade secondary peripheral chondrosarcomas is characterised by polyploidisation, which is thought to be evolved from near-haploid precursor clones , and overexpression of p53 .
With the identification of EXT1 and EXT2 as the genes causative of Multiple Osteochondromas, it has become possible to screen patients with multiple lesions for germline mutations in either EXT gene in a diagnostic setting. However this procedure is time consuming and costly and therefore it is important to select patients carefully on the basis of family history, radiologic documentation and, if available, review of histology of resected lesions.
The diagnosis of Multiple Osteochondromas is based on the combination of two or more radiologically documented osteochondromas originating from the juxta-metaphyseal region of the long bones [2, 4], with or without a positive family history. Radiologically, Multiple Osteochondroma patients have a typical phenotype, easy to recognise by the expert eye. This can exclude the differential diagnoses of other skeletal disorders like metachondromatosis [100, 101], dysplasia epiphysealis hemimelica [102, 103] or non-hereditary syndromes that occur in multiple bones such as enchondromatosis (Ollier's disease) [102, 104]. Given the specific radiologic and histological expertise needed, it is recommended to seek for an expert opinion from a bone tumour specialist or from a national bone tumour registry consisting of clinicians, radiologists and pathologists, before screening for germline mutations.
If the typical Multiple Osteochondroma radiologic phenotype is present, it is important to evaluate the patient's family history to see whether other relatives are (possibly) affected. From these family members radiologic studies and, if available, histology of resected lesions can be examined. If there are other affected family members, Multiple Osteochondromas can be clinically established.
Then subsequent EXT mutation analysis is optional. However it can be useful to screen for germline mutations in family members presenting a mild or no phenotype and this will also give insight into the inheritance pattern (penetrance) of the specific mutation. A known EXT mutation can also be used for prenatal diagnostics. If there is no positive family history, Multiple Osteochondromas cannot be excluded, since it is possible that the patient is the founder of a new Multiple Osteochondroma family and these index patients should be screened for EXT mutations.
Mutation analysis for EXT1 and EXT2 can be performed on peripheral blood of the patient. This can be established through PCR and subsequent sequencing of all exons of EXT1 and EXT2  and/or two-colour multiplex ligation-dependent probe amplification (MLPA) . When a mutation in either gene is found, the Multiple Osteochondromas diagnosis can be confirmed. If there is no mutation the diagnosis of Multiple Osteochondromas cannot be excluded, since there is a small possibility that the mutation could not be detected due to technical limitations. With the currently used methods it is possible to detect point mutations or gross deletions in 75-88% of the Multiple Osteochondroma patients . These methods cannot detect positional changes, like translocations, inversions, insertions or transpositions. These changes affect the structure of the gene without changing the sequence or dosage of exons.
When the diagnosis of Multiple Osteochondromas is established, patients should have a regular follow-up to discover potential malignant transformation at an early stage and enable adequate treatment to be implemented. To our knowledge, the literature does not mention a specific clinical and/or radiologic consensus about the most proper method for the follow-up of patients with proven Multiple Osteochondromas. The following pathways for both clinical and radiologic follow-up can be followed. Localisation of all, relatively larger, osteochondromas can be established with a base-line bone scan, which shows increased bone activity within the skeleton at sites of increased bone turnover, like at the sites of osteochondromas, but also at the epiphysis and apophyses of growing bones. Since secondary peripheral chondrosarcomas are extremely rare before puberty, this is, therefore, only recommended for patients who have reached skeletal maturation. Regular follow-up before that time is not necessary unless the patient presents with clinical complaints. A number of osteochondromas will demonstrate a normal uptake of the radiopharmacon, demonstrating complete maturation, while others may still show an increased activity of the radiopharmacon. This finding, at the baseline, does not immediately and specifically imply malignant transformation, but can well be explained by, as yet, incomplete maturation of the osteochondroma or just by its distinct size. Furthermore, base-line plain radiographic examinations of areas that are not accessible to palpation, like the chest, pelvis and scapula are recommended, because in these areas of the body late detection of malignant transformation of an osteochondroma towards peripheral chondrosarcoma is most common.
After these base-line examinations, patients with Multiple Osteochondromas could routinely be seen, each year or every two years, in the outpatient clinic for clinical and radiologic follow-up. It should be emphasised to the patients to come at an earlier time if changes in their clinical condition occur, such as pain or growth of a known lesion. It is also important to realise that no new osteochondromas develop after skeletal maturation.
Radiologic follow-up could consist of both plain radiographs of the pelvis, chest and scapulae in combination with follow-up bone scans. Changes in the clinical history and findings, in combination with changes on the plain radiographs or bone scans, should be regarded with suspicion. As to changes in the uptake of the radiopharmacon on bone scans however, it should be considered that increase of the uptake does not always indicate malignant transformation. It can also be a result of trauma or the formation of an overlying bursa or inflammatory reaction. Nevertheless, these changes warrant further examination through plain radiographs and dedicated magnetic resonance (MR) imaging, including contrast-enhanced MR sequences. Also the thickness of the cartilage cap can be monitored with MR imaging.
Radiologic skeletal surveys, as a means of follow-up, do not seem to be of additional value. The role of ultrasound, in the follow-up of lesions, is still controversial and needs further studies.
The entire purpose of adequate follow-up is aimed at the early detection of malignant transformation, which enables adequate surgical treatment consisting of en-bloc resection of the lesion and its pseudo-capsule with tumour-free margins, preferably in an oncology centre with experience in treating bone sarcomas. Inadequate primary surgery of a secondary peripheral chondrosarcoma will inevitably result in recurrences and can eventually result in the death caused by local problems or even metastases.
- Mulder JD, Schütte HE, Kroon HM, Taconis WK: Radiologic Atlas of Bone Tumors. 2nd edition. Elsevier, Amsterdam; 1993.Google Scholar
- Bovee JVMG, Hogendoorn PCW: Multiple osteochondromas. In World Health Organization Classification of Tumours. Pathology and Genetics of Tumours of Soft Tissue and Bone. Edited by: Fletcher CDM, Unni KK, Mertens F. IARC Press, Lyon; 2002.Google Scholar
- Dahlin's Bone Tumors General Aspects and Data on 11,087 Cases 5th edition. Lippincott-Raven Publishers, Philadelphia; 1996.
- Legeai-Mallet L, Munnich A, Maroteaux P, Le Merrer M: Incomplete penetrance and expressivity skewing in hereditary multiple exostoses. Clin Genet 1997, 52: 12–16.PubMedView ArticleGoogle Scholar
- Schmale GA, Conrad EU, Raskind WH: The natural history of hereditary multiple exostoses. J Bone Joint Surg [Am] 1994, 76A: 986–992.Google Scholar
- Wicklund LC, Pauli RM, Johnston D, Hecht JT: Natural history study of hereditary multiple exostoses. Am J Med Genet 1995, 55: 43–46. 10.1002/ajmg.1320550113PubMedView ArticleGoogle Scholar
- Khurana J, Abdul-Karim F, Bovee JVMG: Osteochondroma. In World Health Organization Classification of Tumours. Pathology and Genetics of Tumours of Soft Tissue and Bone. Edited by: Fletcher CDM, Unni KK, Mertens F. IARC Press, Lyon; 2002.Google Scholar
- Huvos AG: Bone tumors. Diagnosis, treatment, and prognosis. 2nd edition. W.B. Saunders Company, Philadelphia; 1991.Google Scholar
- Cooper A: Exostosis. In Surgical Essays. Edited by: Cooper A, Travers B. Cox&Son, London; 1818.Google Scholar
- Crandall BF, Field LL, Sparkes RS, Spence MA: Hereditary multiple exostoses; report of a family. Clin Orthop 1983, 190: 217–219.Google Scholar
- Boyer A: Traite des Maladies Chirurgicales. Ve. Migneret, Paris; 1814.Google Scholar
- Shapiro F, Simon S, Glimcher MJ: Hereditary multiple exostoses. Anthropometric, roentgenographic, and clinical aspects. J Bone Joint Surg Am 1979,61(6A):815–824.PubMedGoogle Scholar
- Willms R, Hartwig C-H, Böhm P, Sell S: Malignant transformation of a multiple cartilaginous exostosis - a case report. Int Orthop 1997, 21: 133–136. 10.1007/s002640050136PubMed CentralPubMedView ArticleGoogle Scholar
- Springfield DS, Gebhardt MC, McGuire MH: Chondrosarcoma: a review. J Bone Joint Surg [Am] 1996, 78A: 141–149.Google Scholar
- Bertoni F, Bacchini P, Hogendoorn PCW: Chondrosarcoma. In World Health Organization Classification of Tumours. Pathology and Genetics of Tumours of Soft Tissue and Bone. Edited by: Fletcher CDM, Unni KK, Mertens F. IARC Press, Lyon; 2002.Google Scholar
- Geirnaerdt MJ, Bloem JL, Eulderink F, Hogendoorn PC, Taminiau AH: Cartilaginous tumors: correlation of gadolinium-enhanced MR imaging and histopathologic findings. Radiology 1993,186(3):813–817.PubMedView ArticleGoogle Scholar
- Geirnaerdt MJ, Hogendoorn PC, Bloem JL, Taminiau AH, Woude HJ: Cartilaginous tumors: fast contrast-enhanced MR imaging. Radiology 2000,214(2):539–546.PubMedView ArticleGoogle Scholar
- Evans HL, Ayala AG, Romsdahl MM: Prognostic factors in chondrosarcoma of bone. A clinicopathologic analysis with emphasis on histologic grading. Cancer 1977, 40: 818–831. 10.1002/1097-0142(197708)40:2<818::AID-CNCR2820400234>3.0.CO;2-BPubMedView ArticleGoogle Scholar
- Lamovec J, Spiler M, Jevtic V: Osteosarcoma arising in a solitary osteochondroma of the fibula. Arch Pathol Lab Med 1999,123(9):832–834.PubMedGoogle Scholar
- Matsuno T, Ichioka Y, Yagi T, Ishii S: Spindle-cell sarcoma in patients who have osteochondromatosis. A report of two cases. J Bone Joint Surg [Am] 1988, 70: 137–141.Google Scholar
- Bovee JVMG, Sakkers RJB, Geirnaerdt MJA, Taminiau AHM: Intermediate grade osteosarcoma and chondrosarcoma arising in an osteochondroma. A case report of a patient with hereditary multiple exostoses. J Clin Pathol 2002, 55: 226–229. 10.1136/mp.55.4.226PubMed CentralPubMedView ArticleGoogle Scholar
- Tsuchiya H, Morikawa S, Tomita K: Osteosarcoma arising from a multiple exostoses lesion: case report. Jpn J Clin Oncol 1990, 20: 296–298.PubMedGoogle Scholar
- Ahn J, Ludecke H-J, Lindow S, Horton WA, Lee B, Wagner MJ, Horsthemke B, Wells DE: Cloning of the putative tumour suppressor gene for hereditary multiple exostoses (EXT1). Nature Genet 1995, 11: 137–143. 10.1038/ng1095-137PubMedView ArticleGoogle Scholar
- Wuyts W, Van Hul W, Wauters J, Nemtsova M, Reyniers E, Van Hul EV, De Boulle K, de Vries BB, Hendrickx J, Herrygers I, Bossuyt P, Balemans W, Fransen E, Vits L, Coucke P, Nowak NJ, Shows TB, Mallet L, Ouweland AM, McGaughran J, Halley DJ, Willems PJ: Positional cloning of a gene involved in hereditary multiple exostoses. Hum Mol Genet 1996,5(10):1547–1557. 10.1093/hmg/5.10.1547PubMedView ArticleGoogle Scholar
- Stickens D, Clines G, Burbee D, Ramos P, Thomas S, Hogue D, Hecht JT, Lovett M, Evans GA: The EXT2 multiple exostoses gene defines a family of putative tumour suppressor genes. Nature Genet 1996, 14: 25–32. 10.1038/ng0996-25PubMedView ArticleGoogle Scholar
- Raskind WH, Conrad EU III, Matsushita M, Wijsman EM, Wells DE, Chapman N, Sandell LJ, Wagner M, Houck J: Evaluation of locus heterogeneity and EXT1 mutations in 34 families with hereditary multiple exostoses. Hum Mutat 1998,11(3):231–239. 10.1002/(SICI)1098-1004(1998)11:3<231::AID-HUMU8>3.0.CO;2-KPubMedView ArticleGoogle Scholar
- Legeai-Mallet L, Margaritte-Jeannin P, Lemdani M, Le Merrer M, Plauchu H, Maroteaux P, Munnich A, Clerget-Darpoux F: An extension of the admixture test for the study of genetic heterogeneity in hereditary multiple exostoses. Hum Genet 1997, 99: 298–302. 10.1007/s004390050361PubMedView ArticleGoogle Scholar
- Philippe C, Porter DE, Emerton ME, Wells DE, Simpson AH, Monaco AP: Mutation screening of the EXT1 and EXT2 genes in patients with hereditary multiple exostoses. Am J Hum Genet 1997, 61: 520–528. 10.1086/515505PubMed CentralPubMedView ArticleGoogle Scholar
- Hecht JT, Hogue D, Wang Y, Blanton SH, Wagner M, Strong LC, Raskind W, Hansen MF, Wells D: Hereditary multiple exostoses (EXT): mutational studies of familial EXT1 cases and EXT-associated malignancies. Am J Hum Genet 1997, 60: 80–86.PubMed CentralPubMedGoogle Scholar
- Wuyts W, Van Hul W, De Boulle K, Hendrickx J, Bakker E, Vanhoenacker F, Mollica F, Ludecke HJ, Sayli BS, Pazzaglia UE, Mortier G, Hamel B, Conrad EU, Matsushita M, Raskind WH, Willems PJ: Mutations in the EXT1 and EXT2 genes in hereditary multiple exostoses. Am J Hum Genet 1998, 62: 346–354. 10.1086/301726PubMed CentralPubMedView ArticleGoogle Scholar
- Bovee JVMG, Cleton-Jansen AM, Wuyts W, Caethoven G, Taminiau AHM, Bakker E, Van Hul W, Cornelisse CJ, Hogendoorn PC: EXT-mutation analysis and loss of heterozygosity in sporadic and hereditary osteochondromas and secondary chondrosarcomas. Am J Hum Genet 1999,65(3):689–698. 10.1086/302532PubMed CentralPubMedView ArticleGoogle Scholar
- Xu L, Xia J, Jiang H, Zhou J, Li H, Wang D, Pan Q, Long Z, Fan C, Deng HX: Mutation analysis of hereditary multiple exostoses in the Chinese. Hum Genet 1999, 105: 45–50. 10.1007/s004390051062PubMedView ArticleGoogle Scholar
- Park KJ, Shin K-H, Ku J-L, Cho T-J, Lee SH, Choi IH, Phillipe C, Monaco AP, Porter DE, Park JG: Germline mutations in the EXT1 and EXT2 genes in Korean patients with hereditary multiple exostoses. J Hum Genet 1999, 44: 230–234. 10.1007/s100380050149PubMedView ArticleGoogle Scholar
- Shi YR, Wu JY, Hsu YA, Lee CC, Tsai CH, Tsai FJ: Mutation screening of the EXT genes in patients with hereditary multiple exostoses in Taiwan. Genet Test 2002,6(3):237–243. 10.1089/109065702761403441PubMedView ArticleGoogle Scholar
- Zak BM, Crawford BE, Esko JD: Hereditary multiple exostoses and heparan sulfate polymerization. Biochim Biophys Acta 2002,1573(3):346–355.PubMedView ArticleGoogle Scholar
- Knudson AG Jr: Mutation and cancer: statistical study of retinoblastoma. Proc Natl Acad Sci USA 1971,68(4):820–823. 10.1073/pnas.68.4.820PubMed CentralPubMedView ArticleGoogle Scholar
- Carroll KL, Yandow SM, Ward K, Carey JC: Clinical correlation to genetic variations of hereditary multiple exostoses. J Pediatr Orthop 1999, 19: 785–791. 10.1097/00004694-199911000-00017PubMedGoogle Scholar
- Francannet C, Cohen-Tanugi A, Le Merrer M, Munnich A, Bonaventure J, Legeai-Mallet L: Genotype-phenotype correlation in hereditary multiple exostoses. J Med Genet 2001,38(7):430–434. 10.1136/jmg.38.7.430PubMed CentralPubMedView ArticleGoogle Scholar
- Le Merrer M, Legeai-Mallet L, Jeannin PM, Horsthemke B, Schinzel A, Plauchu H, Toutain A, Achard F, Munnich A, Maroteaux P: A gene for hereditary multiple exostoses maps to chromosome 19p. Hum Mol Genet 1994, 3: 717–722. 10.1093/hmg/3.5.717PubMedView ArticleGoogle Scholar
- Wise CA, Clines GA, Massa H, Trask BJ, Lovett M: Identification and localization of the gene for EXTL, a third member of the multiple exostoses gene family. Genome Res 1997,7(1):10–16. 10.1101/gr.7.1.10PubMedView ArticleGoogle Scholar
- Wuyts W, Van Hul W, Hendrickx J, Speleman F, Wauters J, De Boulle K, Van Roy N, Van Agtmael T, Bossuyt P, Willems PJ: Identification and characterization of a novel member of the EXT gene family, EXTL2. Eur J Hum Genet 1997, 5: 382–389.PubMedGoogle Scholar
- Van Hul W, Wuyts W, Hendrickx J, Speleman F, Wauters J, De Boulle K, Van Roy N, Bossuyt P, Willems PJ: Identification of a third EXT-like gene (EXTL3) belonging to the EXT gene family. Genomics 1998, 47: 230–237. 10.1006/geno.1997.5101PubMedView ArticleGoogle Scholar
- Arai T, Akiyama Y, Nagasaki H, Murase N, Okabe S, Ikeuchi T, Saito K, Iwai T, Yuasa Y: EXTL3/EXTR1 alterations in colorectal cancer cell lines. Int J Oncol 1999,15(5):915–919.PubMedGoogle Scholar
- Hall BD, Langer LO, Giedion A, Smith DW, Cohen MM Jr, Beals RK, Brandner M: Langer-Giedion syndrome. Birth Defects Orig Artic Ser 1974,10(12):147–164.PubMedGoogle Scholar
- Ludecke H-J, Johnson C, Wagner MJ, Wells DE, Turleau C, Tommerup N, Latos-Bielenska A, Sandig KR, Meinecke P, Zabel B, Horsthemke B: Molecular definition of the shortest region of deletion overlap in the Langer-Giedion syndrome. Am J Hum Genet 1991, 49: 1197–1206.PubMed CentralPubMedGoogle Scholar
- Cook A, Raskind W, Blanton SH, Pauli RM, Gregg RG, Francomano CA, Puffenberger E, Conrad EU, Schmale G, Schellenberg G, Wijsman E, Hecht JT, Wells D, Wagner MJ: Genetic heterogeneity in families with hereditary multiple exostoses. Am J Hum Genet 1993, 53: 71–79.PubMed CentralPubMedGoogle Scholar
- Ludecke H-J, Ahn J, Lin X, Hill A, Wagner MJ, Schomburg L, Horsthemke B, Wells DE: Genomic organization and promotor structure of the human EXT1 gene. Genomics 1997, 40: 351–354. 10.1006/geno.1996.4577PubMedView ArticleGoogle Scholar
- Lohmann DR, Buiting K, Ludecke H-J, Horsthemke B: The murine Ext1 gene shows a high level of sequence similarity with its human homologue and is part of a conserved linkage group on chromosome 15. Cytogenet Cell Genet 1997, 76: 164–166. 10.1159/000134536PubMedView ArticleGoogle Scholar
- Lin X, Wells D: Isolation of the mouse cDNA homologous to the human EXT1 gene responsible for hereditary multiple exostoses. DNA Seq 1997,7(3–4):199–202. 10.3109/10425179709034035PubMedView ArticleGoogle Scholar
- Bellaiche Y, The I, Perrimon N: Tout-velu is a drosophila homologue of the putative tumour suppressor EXT1 and is needed for Hh diffusion. Nature 1998, 394: 85–88. 10.1038/27932PubMedView ArticleGoogle Scholar
- Clines GA, Ashley JA, Shah S, Lovett M: The structure of the human multiple exostoses 2 gene and characterization of homologs in mouse and caenorhabditis elegans. Genome Res 1997, 7: 359–367.PubMed CentralPubMedGoogle Scholar
- Wu Y-Q, Heutink P, De Vries BBA, Sandkuijl LA, Ouweland AMW, Niermeijer MF, Galjaard H, Reyniers E, Willems PJ, Halley DJ: Assignment of a second locus for multiple exostoses to the pericentromeric region of chromosome 11. Hum Mol Genet 1994, 3: 167–171. 10.1093/hmg/3.1.167PubMedView ArticleGoogle Scholar
- Wuyts W, Ramlakhan S, Van Hul W, Hecht JT, Ouweland AMW, Raskind WH, Hofstede FC, Reyniers E, Wells DE, de Vries B, Conrad EU, Hill A, Zalatayev D, Weissenbach J, Wagner MJ, Bakker E, Halley DJJ, Willems PJ: Refinement of the multiple exostoses locus (EXT2) to a 3-cM interval on chromosome 11. Am J Hum Genet 1995, 57: 382–387.PubMed CentralPubMedGoogle Scholar
- Stickens D, Evans GA: Isolation and characterization of the murine homolog of the human EXT2 multiple exostoses gene. Biochem Mol Med 1997, 61: 16–21. 10.1006/bmme.1997.2588PubMedView ArticleGoogle Scholar
- Han C, Belenkaya TY, Khodoun M, Tauchi M, Lin X, Lin X: Distinct and collaborative roles of Drosophila EXT family proteins in morphogen signalling and gradient formation. Development 2004,131(7):1563–1575. 10.1242/dev.01051PubMedView ArticleGoogle Scholar
- Potocki L, Shaffer LG: Interstitial deletion of 11(p11.2p12): a newly described contiguous gene deletion syndrome involving the gene for hereditary multiple exostoses (EXT2). Am J Med Genet 1996, 62: 319–325. 10.1002/(SICI)1096-8628(19960329)62:3<319::AID-AJMG22>3.0.CO;2-MPubMedView ArticleGoogle Scholar
- Bartsch O, Wuyts W, Van Hul W, Hecht JT, Meinecke P, Hogue D, Werner W, Zabel B, Hinkel GK, Powell CM, Shaffer LG, Willems PJ: Delineation of a contiguous gene syndrome with multiple exostoses, enlarged parietal foramina, craniofacial dysostosis, and mental retardation, caused by deletions on the short arm of chromosome 11. Am J Hum Genet 1996, 58: 734–742.PubMed CentralPubMedGoogle Scholar
- Esko JD, Selleck SB: Order out of chaos: assembly of ligand binding sites in heparan sulfate. Annu Rev Biochem 2002, 71: 435–471. 10.1146/annurev.biochem.71.110601.135458PubMedView ArticleGoogle Scholar
- Lind T, Tufaro F, McCormick C, Lindahl U, Lidholt K: The putative tumor suppressors EXT1 and EXT2 are glycosyltransferases required for the biosynthesis of heparan sulfate. J Biol Chem 1998,273(41):26265–26268. 10.1074/jbc.273.41.26265PubMedView ArticleGoogle Scholar
- Kitagawa H, Shimakawa H, Sugahara K: The tumor suppressor EXT-like gene EXTL2 encodes an alpha1, 4-N-acetylhexosaminyltransferase that transfers N-acetylglucosamine to the common glycosaminoglycan-protein linkage region. J Biol Chem 1999,274(20):13933–13937. 10.1074/jbc.274.20.13933PubMedView ArticleGoogle Scholar
- McCormick C, Duncan G, Tufaro F: New perspectives on the molecular basis of hereditary bone tumours. Mol Med Today 1999, 5: 481–486. 10.1016/S1357-4310(99)01593-2PubMedView ArticleGoogle Scholar
- McCormick C, Duncan G, Goutsos KT, Tufaro F: The putative tumor suppressors EXT1 and EXT2 form a stable complex that accumulates in the Golgi apparatus and catalyzes the synthesis of heparan sulfate. Proc Natl Acad Sci USA 2000,97(2):668–673. 10.1073/pnas.97.2.668PubMed CentralPubMedView ArticleGoogle Scholar
- Rubin JB, Choi Y, Segal RA: Cerebellar proteoglycans regulate sonic hedgehog responses during development. Development 2002,129(9):2223–2232.PubMedGoogle Scholar
- Cardin AD, Weintraub HJ: Molecular modeling of protein-glycosaminoglycan interactions. Arteriosclerosis 1989,9(1):21–32.PubMedView ArticleGoogle Scholar
- Knudson CB, Knudson W: Cartilage proteoglycans. Semin Cell Dev Biol 2001,12(2):69–78. 10.1006/scdb.2000.0243PubMedView ArticleGoogle Scholar
- Liu W, Litwack ED, Stanley MJ, Langford JK, Lander AD, Sanderson RD: Heparan sulfate proteoglycans as adhesive and anti-invasive molecules. Syndecans and glypican have distinct functions. J Biol Chem 1998,273(35):22825–22832. 10.1074/jbc.273.35.22825PubMedView ArticleGoogle Scholar
- David G, Bai XM, Schueren B, Marynen P, Cassiman JJ, Berghe H: Spatial and temporal changes in the expression of fibroglycan (syndecan-2) during mouse embryonic development. Development 1993,119(3):841–854.PubMedGoogle Scholar
- Zimmermann P, David G: The syndecans, tuners of transmembrane signaling. FASEB J 1999,13(Suppl):S91-S100.PubMedGoogle Scholar
- Seghatoleslami MR, Kosher RA: Inhibition of in vitro limb cartilage differentiation by syndecan-3 antibodies. Dev Dyn 1996,207(1):114–119. 10.1002/(SICI)1097-0177(199609)207:1<114::AID-AJA11>3.0.CO;2-0PubMedView ArticleGoogle Scholar
- Shimo T, Gentili C, Iwamoto M, Wu C, Koyama E, Pacifici M: Indian hedgehog and syndecans-3 coregulate chondrocyte proliferation and function during chick limb skeletogenesis. Dev Dyn 2004,229(3):607–617. 10.1002/dvdy.20009PubMedView ArticleGoogle Scholar
- Veugelers M, De Cat B, Ceulemans H, Bruystens AM, Coomans C, Durr J, Vermeesch J, Marynen P, David G: Glypican-6, a new member of the glypican family of cell surface heparan sulfate proteoglycans. J Biol Chem 1999,274(38):26968–26977. 10.1074/jbc.274.38.26968PubMedView ArticleGoogle Scholar
- SundarRaj N, Fite D, Ledbetter S, Chakravarti S, Hassell JR: Perlecan is a component of cartilage matrix and promotes chondrocyte attachment. J Cell Sci 1995,108(Pt 7):2663–2672.PubMedGoogle Scholar
- Ponta H, Sherman L, Herrlich PA: CD44: from adhesion molecules to signalling regulators. Nat Rev Mol Cell Biol 2003,4(1):33–45. 10.1038/nrm1004PubMedView ArticleGoogle Scholar
- Voort R, Taher TE, Wielenga VJ, Spaargaren M, Prevo R, Smit L, David G, Hartmann G, Gherardi E, Pals ST: Heparan sulfate-modified CD44 promotes hepatocyte growth factor/scatter factor-induced signal transduction through the receptor tyrosine kinase c-Met. J Biol Chem 1999,274(10):6499–6506. 10.1074/jbc.274.10.6499PubMedView ArticleGoogle Scholar
- The I, Bellaiche Y, Perrimon N: Hedgehog movement is regulated through tout velu - dependant synthesis of a heparan sulfate proteoglycan. Mol Cell 1999,4(4):633–639. 10.1016/S1097-2765(00)80214-2PubMedView ArticleGoogle Scholar
- Bornemann DJ, Duncan JE, Staatz W, Selleck S, Warrior R: Abrogation of heparan sulfate synthesis in Drosophila disrupts the Wingless, Hedgehog and Decapentaplegic signaling pathways. Development 2004,131(9):1927–1938. 10.1242/dev.01061PubMedView ArticleGoogle Scholar
- Stickens D, Brown D, Evans GA: EXT genes are differentially expressed in bone and cartilage during mouse embryogenesis. Dev Dyn 2000,218(3):452–464. 10.1002/1097-0177(200007)218:3<452::AID-DVDY1000>3.0.CO;2-PPubMedView ArticleGoogle Scholar
- Amling M, Neff L, Tanaka S, Inoue D, Kuida K, Weir E, Philbrick WM, Broadus AE, Baron R: Bcl-2 lies downstream of parathyroid hormone related peptide in a signalling pathway that regulates chondrocyte maturation during skeletal development. J Cell Biol 1997, 136: 205–213. 10.1083/jcb.136.1.205PubMed CentralPubMedView ArticleGoogle Scholar
- Eerden BCJ, Karperien M, Gevers EF, Lowik CWGM, Wit JM: Expression of Indian Hedgehog, PTHrP and their receptors in the postnatal growth plate of the rat: evidence for a locally acting growth restraining feedback loop after birth. J Bone Miner Res 2000,15(6):1045–1055. 10.1359/jbmr.2000.15.6.1045PubMedView ArticleGoogle Scholar
- Erlebacher A, Filvaroff EH, Gitelman SE, Derynck R: Toward a molecular understanding of skeletal development. Cell 1995, 80: 371–378. 10.1016/0092-8674(95)90487-5PubMedView ArticleGoogle Scholar
- Goldfarb M: Functions of fibroblast growth factors in vertebrate development. Cytokine and Growth Factor Reviews 1996,7(4):311–325. 10.1016/S1359-6101(96)00039-1PubMedView ArticleGoogle Scholar
- Kato Y, Iwamoto M: Fibroblast growth factor is an inhibitor of chondrocyte terminal differentiation. J Biol Chem 1990,265(10):5903–5909.PubMedGoogle Scholar
- Iwamoto M, Shimazu A, Nakashima K, Suzuki F, Kato Y: Reduction of basic fibroblasts growth factor receptor is coupled with terminal differentiation of chondrocytes. J Biol Chem 1991,266(1):461–467.PubMedGoogle Scholar
- Liu Z, Xu J, Colvin JS, Ornitz DM: Coordination of chondrogenesis and osteogenesis by fibroblast growth factor 18. Genes Dev 2002,16(7):859–869. 10.1101/gad.965602PubMed CentralPubMedView ArticleGoogle Scholar
- Sahni M, Ambrosetti D-C, Mansukhani A, Gertner R, Levy D, Basilico C: FGF signaling inhibits chondrocyte proliferation and regulates bone development through the STAT-1 pathway. Genes Dev 1999, 13: 1361–1366. 10.1101/gad.13.11.1361PubMed CentralPubMedView ArticleGoogle Scholar
- Naski MC, Colvin JS, Coffin JD, Ornitz DM: Repression of hedgehog signaling and BMP4 expression in growth plate cartilage by fibroblast growth factor receptor 3. Development 1998, 125: 4977–4988.PubMedGoogle Scholar
- Bridge JA, Nelson M, Orndal C, Bhatia P, Neff JR: Clonal karyotypic abnormalities of the hereditary multiple exostoses chromosomal loci 8q24.1 (EXT1) and 11p11–12 (EXT2) in patients with sporadic and hereditary osteochondromas. Cancer 1998, 82: 1657–1663. 10.1002/(SICI)1097-0142(19980501)82:9<1657::AID-CNCR10>3.0.CO;2-3PubMedView ArticleGoogle Scholar
- Mertens F, Rydholm A, Kreicbergs A, Willen H, Jonsson K, Heim S, Mitelman F, Mandahl N: Loss of chromosome band 8q24 in sporadic osteocartilaginous exostoses. Genes Chromosomes Cancer 1994, 9: 8–12. 10.1002/gcc.2870090103PubMedView ArticleGoogle Scholar
- Bovee JVMG, Royen MV, Bardoel AFJ, Rosenberg C, Cornelisse CJ, Cleton-Jansen AM, Hogendoorn PC: Near-haploidy and subsequent polyploidization characterize the progression of peripheral chondrosarcoma. Am J Pathol 2000,157(5):1587–1595.PubMed CentralPubMedView ArticleGoogle Scholar
- Lin X, Wei G, Shi Z, Dryer L, Esko JD, Wells DE, Matzuk MM: Disruption of gastrulation and heparan sulfate biosynthesis in EXT1-deficient mice. Dev Biol 2000,224(2):299–311. 10.1006/dbio.2000.9798PubMedView ArticleGoogle Scholar
- Koziel L, Kunath M, Kelly OG, Vortkamp A: Ext1-dependent heparan sulfate regulates the range of Ihh signaling during endochondral ossification. Dev Cell 2004,6(6):801–813. 10.1016/j.devcel.2004.05.009PubMedView ArticleGoogle Scholar
- Hecht JT, Hall CR, Snuggs M, Hayes E, Haynes R, Cole WG: Heparan sulfate abnormalities in exostosis growth plates. Bone 2002,31(1):199–204. 10.1016/S8756-3282(02)00796-2PubMedView ArticleGoogle Scholar
- Yamada S, Busse M, Ueno M, Kelly OG, Skarnes WC, Sugahara K, Kusche-Gullberg M: Embryonic fibroblasts with a gene trap mutation in EXT1 produce short heparan sulphate chains. J Biol Chem 2004,279(31):32134–32141. 10.1074/jbc.M312624200PubMedView ArticleGoogle Scholar
- Bovee JVMG, Broek LJCM, Cleton-Jansen AM, Hogendoorn PCW: Up-regulation of PTHrP and Bcl-2 expression characterizes the progression of osteochondroma towards peripheral chondrosarcoma and is a late event in central chondrosarcoma. Lab Invest 2000, 80: 1925–1933. 10.1038/labinvest.3780202PubMedView ArticleGoogle Scholar
- Bovee JVMG, Cleton-Jansen AM, Kuipers-Dijkshoorn N, Broek LJCM, Taminiau AHM, Cornelisse CJ, Hogendoorn PC: Loss of heterozygosity and DNA ploidy point to a diverging genetic mechanism in the origin of peripheral and central chondrosarcoma. Genes Chromosomes Cancer 1999, 26: 237–246. 10.1002/(SICI)1098-2264(199911)26:3<237::AID-GCC8>3.0.CO;2-LPubMedView ArticleGoogle Scholar
- Bovee JVMG, Sciot R, Cin PD, Debiec-Rychter M, Zelderen-Bhola SL, Cornelisse CJ, Hogendoorn PC: Chromosome 9 alterations and trisomy 22 in central chondrosarcoma: a cytogenetic and DNA flow cytometric analysis of chondrosarcoma subtypes. Diagn Mol Pathol 2001,10(4):228–235. 10.1097/00019606-200112000-00004PubMedView ArticleGoogle Scholar
- Xiang JH, Spanier SS, Benson NA, Braylan RC: Flow cytometric analysis of DNA in bone and soft-tissue tumors using nuclear suspensions. Cancer 1987, 59: 1951–1958. 10.1002/1097-0142(19870601)59:11<1951::AID-CNCR2820591119>3.0.CO;2-XPubMedView ArticleGoogle Scholar
- Helio H, Karaharju E, Nordling S: Flow cytometric determination of DNA content in malignant and benign bone tumours. Cytometry 1985, 6: 165–171. 10.1002/cyto.990060213PubMedView ArticleGoogle Scholar
- Mandahl N, Baldetorp B, Ferno M, Akerman M, Rydholm A, Heim S, Willen H, Killander D, Mitelman F: Comparative cytogenetic and DNA flow cytometric analysis of 150 bone and soft-tissue tumors. Int J Cancer 1993, 53: 358–364. 10.1002/ijc.2910530303PubMedView ArticleGoogle Scholar
- Bassett GS, Cowell HR: Metachondromatosis. Report of four cases. J Bone Joint Surg Am 1985,67(5):811–814.PubMedGoogle Scholar
- Maroteaux P: Metachondromatosis. Z Kinderheilkd 1971,109(3):246–261. 10.1007/BF00442274PubMedView ArticleGoogle Scholar
- Murphey MD, Flemming DJ, Boyea SR, Bojescul JA, Sweet DE, Temple HT: From the archives of the AFIP. Enchondroma versus chondrosarcoma in the appendicular skeleton: differentiating features. Radiographics 1998,18(5):1213–1237.PubMedView ArticleGoogle Scholar
- Fairbank TJ: Dysplasia epiphysialis hemimelica (tarso-ephiphysial aclasis). J Bone Joint Surg Br 1956,38-B(1):237–257.PubMedGoogle Scholar
- Ollier M: Dyschondroplasie. Lyon Med 1900, 93: 23–25.Google Scholar
- White SJ, Vink GR, Kriek M, Wuyts W, Schouten J, Bakker B, Breuning MH, den Dunnen JT: Two-color multiplex ligation-dependent probe amplification: detecting genomic rearrangements in hereditary multiple exostoses. Hum Mutat 2004,24(1):86–92. 10.1002/humu.20054PubMedView ArticleGoogle Scholar
- Stenson PD, Ball EV, Mort M, Phillips AD, Shiel JA, Thomas NS, Abeysinghe S, Krawczak M, Cooper DN: Human Gene Mutation Database (HGMD): 2003 update. Hum Mutat 2003,21(6):577–581. 10.1002/humu.10212PubMedView ArticleGoogle Scholar
- Kim BT, Kitagawa H, Tamura J, Saito T, Kusche-Gullberg M, Lindahl U, Sugahara K: 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. Proc Natl Acad Sci USA 2001,98(13):7176–7181. 10.1073/pnas.131188498PubMed CentralPubMedView ArticleGoogle Scholar
- Esko JD, Lindahl U: Molecular diversity of heparan sulfate. J Clin Invest 2001,108(2):169–173.PubMed CentralPubMedView ArticleGoogle Scholar
- Couchman JR: Syndecans: proteoglycan regulators of cell-surface microdomains. Nat Rev Mol Cell Biol 2003,4(12):926–937. 10.1038/nrm1257PubMedView ArticleGoogle Scholar
- Nybakken K, Perrimon N: Heparan sulfate proteoglycan modulation of developmental signaling in Drosophila. Biochim Biophys Acta 2002,1573(3):280–291.PubMedView ArticleGoogle Scholar