Open Access

Multiple Osteochondromas: Clinicopathological and Genetic Spectrum and Suggestions for Clinical Management

  • Liesbeth Hameetman1,
  • Judith VMG Bovée1,
  • Antonie HM Taminiau2,
  • Herman M Kroon3 and
  • Pancras CW Hogendoorn1Email author
Hereditary Cancer in Clinical Practice20042:161

DOI: 10.1186/1897-4287-2-4-161

Received: 18 August 2004

Accepted: 15 November 2004

Published: 15 November 2004

Abstract

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.

Keywords

bone neoplasm multiple osteochondromas genetics clinical management chondrosarcoma exostosis

Introduction

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.

Incidence

Osteochondromas represent about 50% of all surgically treated primary benign bone tumours [1]. Approximately 15% of the osteochondroma patients have multiple lesions [1, 3] of which 62% have a positive family history [4].

The incidence for Multiple Osteochondromas has been estimated at 1:50,000 in the general population [5], with a higher prevalence in males (male:female ratio of 1.5:1) [4, 6], which is partly due to incomplete penetrance in females [4].

Osteochondroma

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 [79]. 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 [3].

Multiple Osteochondromas

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, 46, 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

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 [13]. 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 [15]. 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 [15]. 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 [18] and is the most important predictor of clinical behaviour and thus prognosis of patients with chondrosarcomas [15]. Chondrosarcomas secondary to osteochondromas are usually low-grade tumours resulting in a reasonably fair prognosis for these patients [15].

In the remaining 6% of the cases with malignant progression tumours arise in the bony stalk of the osteochondroma, including osteosarcomas and spindle cell sarcomas [1922].

Genetics

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 [2325]. 44-66% of the Multiple Osteochondroma families show linkage at the EXT1 region [26, 27], compared to 27% for EXT2 [27]. Germline mutations of EXT1 and EXT2 have been described in Multiple Osteochondroma patients from Caucasian [23, 25, 2831] and Asian populations [3234].

Most mutations (80%) found in EXT1 and EXT2 (Fig. 2) are either nonsense, frameshift or splice-site mutations leading to premature terminations of the EXT proteins (reviewed by Zak et al [35]). Mutations in EXT1 occur in all parts of the gene, while mutations in EXT2 concentrate towards the N-terminus of the gene, implying that this part of the protein may have special functions. This seems contradictive, since only the C-terminal region is highly conserved, implicating some functional importance for this part of the protein [24, 25]. In the literature, only one somatic mutation in the EXT1 gene has been described in a sporadic chondrosarcoma [29].
Figure 2

Mutation spectrum of the EXT1 and EXT2 genes in MO patients described so far [106].

Loss of the remaining wild-type allele has been demonstrated in hereditary osteochondromas [31], 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 [36].

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 [38].

The existence of a third EXT gene on chromosome 19p, EXT3 [39], 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 [4042]. EXTL1, EXTL2 and EXTL3 are located at 1p36.1 [40], 1p11-p12 [41] and 8p12-p22 [42], respectively. No linkage with Multiple Osteochondromas or other bone diseases has been documented for these genes [43].

EXT1

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) [44], where patients carry a deletion of 8q24 [45]. Besides multiple osteochondromas the Langer Gideon syndrome is characterised by craniofacial dysmorphism and mental retardation [44, 45].

In the early nineties Cook et al found linkage to the 8q24.11-q24.13 region in Multiple Osteochondroma families [46] and two years later the EXT1 gene was identified by positional cloning [23].

The EXT1 gene, composed of 11 exons, spans approximately 350kb of genomic DNA (Fig. 3) [47] with a promoter region that has the characteristics of a house keeping gene [47]. EXT1 mRNA is ubiquitously expressed and has a coding sequence of 2238 bp [23]. In mouse embryos, high mRNA levels of the EXT1 homologue have been found in the developing limb buds [48, 49]. EXT1 homologues have also been identified in Drosophila melanogaster (tout-velu, Ttv) and Caenorhabditis elegans [50, 51].
Figure 3

Genomic DNA structures of the EXT1 and EXT2 genes.

EXT2

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 [51]. 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) [55]and Caenorhabditis elegans [51].

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].

EXT function

The gene products of human EXT1 and EXT2 are endoplasmic reticulum localised type II transmembrane glycoproteins. In vivo they form a stable hetero-oligomeric complex that accumulates in the Golgi apparatus, where it is involved in heparan sulphate proteoglycan (HSPG) biosynthesis (reviewed by Esko et al [58]) (Fig. 4). The EXT1/EXT2 complex catalyses the elongation of the HS chain [5962], which is subsequently deacetylated, sulphated and epimerised resulting in a large spectrum of structural heterogenic HS chains. The sulphation pattern of HS chains is critical for binding specific proteins [58]. Several growth factors have conserved patterns of basic amino acids for binding to HSPGs, which is crucial for proper signalling [63, 64].
Figure 4

The mode of action of the EXT-proteins in heparan sulphate biosynthesis. After a tetrasaccharide linker is synthesised on conserved serine residues of the core protein, EXTL2 and/or EXTL3 initiate the polymerisation of the heparan sulphate chain by the addition of N-acetylglucosamine [60, 107]. The EXT1/EXT2 complex subsequently catalyses further elongation of the heparan sulphate chain by adding alternating units of N-acetylglucosamine and glucuronic acid [5962]. Subsequent deacetylation and sulphation of most N-acetylglucosamines, epimerisation of the glucoronic into iduronic acid and further sulphation result in a large spectrum of structural heterogenic heparan sulphate chains [58, 108]. Adapted from Couchman et al [109] and Nybakken et al [110].

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 [65]). 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 [66]. In mouse and chick, syndecan-2 and -3 have shown to be involved in signalling pathways in proliferating chondrocytes [6770].

The six glypican family members encode proteins attached to the cell membrane with a glycosylphosphati-dylinositol (GPI)-anchor. They predominantly function as co-receptors [66]. Expression of several glypicans has been found in the perichondrium, the developing limb and mesenchymal tissues of the developing mouse embryo [71].

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 [72]. 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 [73]). CD44 isoforms containing variable exon 3 (v3) have been shown to bind growth factors through HS side chains, thereby regulating cell growth and motility [74].

In Drosophila, the EXT1 homologue Ttv (tout-velu), also involved in HS synthesis, is required for the diffusion of Hedgehog (Hh), an important segment polarity protein (homologue of mammalian IHh) [50]. Remarkably, in Ttv mutants only the IHh signalling is affected, while other HSPG-dependent pathways, like FGF and WNT signalling, are not. This indicates a specificity in the regulation of the distribution of extracellular signals by HSPGs in Drosophila [75, 76].
Figure 5

Growth plate signalling. EXT1 and EXT2 are expressed in the proliferative and transition zone [77] (Fig. 5). The HSPGs, expressed in all zones of the growth plate [6772]. A. In the embryonic growth plate chondrocytes in the transition zone secrete IHh protein, which diffuses to its receptor Patched (Ptc) in the lateral perichondrium. Subsequently, via a yet incompletely understood mechanism, increased secretion of ParaThyroid Hormone related Protein (PTHrP, PTHlP) is induced at the apical perichondrium, which diffuses to its receptor expressed in the late proliferating chondrocytes [80]. Terminal differentiation is inhibited by direct or indirect upregulation of Bcl-2, prolonging cell survival [78]. In this way, PTHrP regulates chondrocyte differentiation by delaying the progression of chondrocytes towards the hypertrophic zone and allowing longitudinal bone growth. B. In the post-natal growth plate the signalling is confined to the growth plate [79].

Growth Signalling

Indian Hedgehog (IHh)/PTHrP signalling in the growth plate

In the growth plate EXT1 and EXT2 are expressed in the proliferative and transition zone [77] (Fig. 5). The HSPGs, expressed in all zones of the growth plate [6772], 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 [78]. 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 [79].

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 [84] inhibits chondrocyte proliferation via phosphorylation of STAT-1 and subsequent upregulation of p21WAF/CIP1, which can inhibit the cell cycle [85]. FGFR3 activation also leads to repression of IHh signalling [80, 81, 86].

Histogenesis and secondary sarcoma formation

In the past, many have considered the histogenesis of osteochondroma as a perversion in the direction of normal bone growth resulting from aberrant epiphyseal development with displacement of epiphyseal cartilage. However, several research groups have demonstrated using different techniques that both sporadic and hereditary osteochondromas are true neoplasms [31, 87, 88], resulting in a multi-step genetic model for peripheral cartilaginous tumorigenesis (Fig. 6) [89].
Figure 6

Peripheral Cartilaginous Tumorigenesis.

Although some believe that the severity of the angular deformity is correlated with the number of sessile osteochondromas [37], 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 [31] 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 [31]. 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 [94] 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 [94]. Upregulation of Bcl-2 characterised malignant transformation of osteochondroma towards grade I secondary peripheral chondrosarcoma [94]. 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 [94].

The process of malignant transformation is genetically represented by chromosomal instability [95], probably caused by defects in spindle formation. The LOH found in osteochondroma was restricted to 8q24 [31], whereas in secondary peripheral chondrosarcomas LOH was found in virtually all loci tested [95]. 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 [31], whereas more severe aneuploidy [9799], including near-haploidy [95], 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 [89], and overexpression of p53 [95].

Near-haploidy was not found in osteochondromas [87, 88] or in high grade peripheral chondrosarcomas [95] and can be considered a progression marker towards a low malignant phenotype [89].

Patient management

Diagnosis

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 [30] and/or two-colour multiplex ligation-dependent probe amplification (MLPA) [105]. 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 [105]. 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.

Follow-up

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.

The process of making a Multiple Osteochondroma diagnosis and patient follow-up is summarized in a flowchart (Fig. 7).
Figure 7

Overview of systematic steps to screen and follow-up (suspected) Multiple Osteochondroma patients.

Conclusion

With all new developments and discoveries in the genetic, pathological and radiologic behaviour of osteochondromas and secondary peripheral chondrosarcomas, it has become possible to screen and carefully monitor Multiple Osteochondroma patients and their families. This will enable us to provide patients with more adequate care and treatment strategies.
Figure 1

Specimen radiographs and histology. A pedunculated osteochondroma shown in a macroscopic whole mount section (A) and specimen radiograph (B); C, whole mount section of a sessile osteochondroma. Note the presence of a small cartilage cap in both osteochondromas (< 0.5 cm); D, radiograph of the forearm of a Multiple Osteochondroma patient. Several osteochondromas can be seen at the ends of the ulna and radius. Note that the ulna is shortened, which caused subsequent bowing of the radius; E and F, gross specimen and whole mount section of secondary peripheral chondrosarcoma. The cartilage cap is thicker than 2 cm and in the whole mount section the lobules are clearly visible.

Authors’ Affiliations

(1)
Department of Pathology, Leiden University Medical Centre
(2)
Department of Orthopaedic Surgery, Leiden University Medical Centre
(3)
Department of Radiology, Leiden University Medical Centre, L1-Q

References

  1. Mulder JD, Schütte HE, Kroon HM, Taconis WK: Radiologic Atlas of Bone Tumors. 2nd edition. Elsevier, Amsterdam; 1993.Google Scholar
  2. 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
  3. Dahlin's Bone Tumors General Aspects and Data on 11,087 Cases 5th edition. Lippincott-Raven Publishers, Philadelphia; 1996.
  4. 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
  5. Schmale GA, Conrad EU, Raskind WH: The natural history of hereditary multiple exostoses. J Bone Joint Surg [Am] 1994, 76A: 986–992.Google Scholar
  6. 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
  7. 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
  8. Huvos AG: Bone tumors. Diagnosis, treatment, and prognosis. 2nd edition. W.B. Saunders Company, Philadelphia; 1991.Google Scholar
  9. Cooper A: Exostosis. In Surgical Essays. Edited by: Cooper A, Travers B. Cox&Son, London; 1818.Google Scholar
  10. Crandall BF, Field LL, Sparkes RS, Spence MA: Hereditary multiple exostoses; report of a family. Clin Orthop 1983, 190: 217–219.Google Scholar
  11. Boyer A: Traite des Maladies Chirurgicales. Ve. Migneret, Paris; 1814.Google Scholar
  12. 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
  13. 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
  14. Springfield DS, Gebhardt MC, McGuire MH: Chondrosarcoma: a review. J Bone Joint Surg [Am] 1996, 78A: 141–149.Google Scholar
  15. 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
  16. 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
  17. 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
  18. 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
  19. 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
  20. 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
  21. 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
  22. 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
  23. 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
  24. 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
  25. 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
  26. 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
  27. 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
  28. 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
  29. 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
  30. 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
  31. 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
  32. 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
  33. 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
  34. 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
  35. Zak BM, Crawford BE, Esko JD: Hereditary multiple exostoses and heparan sulfate polymerization. Biochim Biophys Acta 2002,1573(3):346–355.PubMedView ArticleGoogle Scholar
  36. 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
  37. 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
  38. 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
  39. 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
  40. 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
  41. 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
  42. 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
  43. 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
  44. 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
  45. 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
  46. 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
  47. 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
  48. 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
  49. 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
  50. 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
  51. 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
  52. 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
  53. 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
  54. 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
  55. 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
  56. 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
  57. 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
  58. 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
  59. 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
  60. 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
  61. 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
  62. 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
  63. Rubin JB, Choi Y, Segal RA: Cerebellar proteoglycans regulate sonic hedgehog responses during development. Development 2002,129(9):2223–2232.PubMedGoogle Scholar
  64. Cardin AD, Weintraub HJ: Molecular modeling of protein-glycosaminoglycan interactions. Arteriosclerosis 1989,9(1):21–32.PubMedView ArticleGoogle Scholar
  65. Knudson CB, Knudson W: Cartilage proteoglycans. Semin Cell Dev Biol 2001,12(2):69–78. 10.1006/scdb.2000.0243PubMedView ArticleGoogle Scholar
  66. 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
  67. 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
  68. Zimmermann P, David G: The syndecans, tuners of transmembrane signaling. FASEB J 1999,13(Suppl):S91-S100.PubMedGoogle Scholar
  69. 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
  70. 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
  71. 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
  72. 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
  73. 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
  74. 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
  75. 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
  76. 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
  77. 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
  78. 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
  79. 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
  80. 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
  81. 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
  82. Kato Y, Iwamoto M: Fibroblast growth factor is an inhibitor of chondrocyte terminal differentiation. J Biol Chem 1990,265(10):5903–5909.PubMedGoogle Scholar
  83. 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
  84. 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
  85. 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
  86. 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
  87. 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
  88. 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
  89. 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
  90. 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
  91. 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
  92. 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
  93. 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
  94. 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
  95. 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
  96. 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
  97. 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
  98. 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
  99. 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
  100. Bassett GS, Cowell HR: Metachondromatosis. Report of four cases. J Bone Joint Surg Am 1985,67(5):811–814.PubMedGoogle Scholar
  101. Maroteaux P: Metachondromatosis. Z Kinderheilkd 1971,109(3):246–261. 10.1007/BF00442274PubMedView ArticleGoogle Scholar
  102. 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
  103. Fairbank TJ: Dysplasia epiphysialis hemimelica (tarso-ephiphysial aclasis). J Bone Joint Surg Br 1956,38-B(1):237–257.PubMedGoogle Scholar
  104. Ollier M: Dyschondroplasie. Lyon Med 1900, 93: 23–25.Google Scholar
  105. 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
  106. 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
  107. 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
  108. Esko JD, Lindahl U: Molecular diversity of heparan sulfate. J Clin Invest 2001,108(2):169–173.PubMed CentralPubMedView ArticleGoogle Scholar
  109. Couchman JR: Syndecans: proteoglycan regulators of cell-surface microdomains. Nat Rev Mol Cell Biol 2003,4(12):926–937. 10.1038/nrm1257PubMedView ArticleGoogle Scholar
  110. Nybakken K, Perrimon N: Heparan sulfate proteoglycan modulation of developmental signaling in Drosophila. Biochim Biophys Acta 2002,1573(3):280–291.PubMedView ArticleGoogle Scholar

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