. Inserm-u1241, C. Service-de-rhumatologie, and . Pontchaillou, , p.35000

, Service de chirurgie orthopédique

, Service de chirurgie pédiatrique

, Groupe Études Remodelage Osseux et bioMatériaux (GEROM), 49100 Angers

C. Service-d'imagerie-médicale and . Pontchaillou, 35000 Rennes (6) Service d'anatomie et cytologie pathologiques

U. Inserm, . Rennes, . Inra, and N. Institut,

U. Inserm, . Rennes, C. Inra, and . Rennes,

L. Solomon, Hereditary multiple exostosis, Am J Hum Genet, vol.16, p.351, 1964.

G. A. Schmale, E. U. Conrad, and W. H. Raskind, The natural history of hereditary multiple exostoses, J Bone Joint Surg Am, vol.76, pp.986-92, 1994.

C. L. Wicklund, R. M. Pauli, D. Johnston, and J. T. Hecht, Natural history study of hereditary multiple exostoses, Am J Med Genet, vol.55, pp.43-46, 1995.

J. Bovée, J. Khurana, F. Abdul-karim, and . Osteochondroma, , 2002.

D. E. Porter and A. Simpson, The neoplastic pathogenesis of solitary and multiple osteochondromas, J Pathol, vol.188, pp.119-125, 1999.

L. Legeai-mallet, A. Munnich, P. Maroteaux, L. Merrer, and M. , Incomplete penetrance and expressivity skewing in hereditary multiple exostoses, Clin Genet, vol.52, pp.12-18, 1997.

M. Jäger, B. Westhoff, S. Portier, B. Leube, K. Hardt et al., Clinical outcome and genotype in patients with hereditary multiple exostoses, J Orthop Res, vol.25, pp.1541-51, 2007.

K. Woertler, N. Lindner, G. Gosheger, C. Brinkschmidt, W. Heindel et al., MR imaging of tumor-related complications, vol.10, pp.832-840, 2000.

J. Cottalorda, D. Louahem, P. Mazeau, A. Weiss, L. 'kaissi et al., La maladie des exostoses multiples: orientations nouvelles, E-Mém Académie Natl Chir, vol.14, pp.83-93, 2015.

A. Cook, W. Raskind, S. H. Blanton, R. M. Pauli, R. G. Gregg et al., Genetic heterogeneity in families with hereditary multiple exostoses, Am J Hum Genet, vol.53, p.71, 1993.

W. Wuyts, V. Hul, and W. , Molecular basis of multiple exostoses: mutations in the EXT1 and EXT2 genes, Hum Mutat, vol.15, pp.220-227, 2000.

C. Francannet, A. Cohen-tanugi, L. Merrer, M. Munnich, A. Bonaventure et al.,

, Genotype-phenotype correlation in hereditary multiple exostoses, J Med Genet, vol.38, pp.430-434, 2001.

L. Merrer, M. Legeai-mallet, L. Jeannin, P. M. Horsthemke, B. Schinzel et al., A gene for hereditary multiple exostoses maps to chromosome 19p, Hum Mol Genet, vol.3, pp.717-739, 1994.

K. B. Jones, V. Piombo, C. Searby, G. Kurriger, B. Yang et al., A mouse model of osteochondromagenesis from clonal inactivation of Ext1 in chondrocytes, Proc Natl Acad Sci, vol.107, pp.2054-2063, 2010.

P. K. Cheung, C. Mccormick, B. E. Crawford, J. D. Esko, F. Tufaro et al., Etiological point mutations in the hereditary multiple exostoses gene EXT1: a functional analysis of heparan sulfate polymerase activity, Am J Hum Genet, vol.69, pp.55-66, 2001.

C. Mccormick, G. Duncan, K. T. Goutsos, and F. Tufaro, 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, vol.97, pp.668-673, 2000.

M. Trebicz-geffen, D. Robinson, Z. Evron, T. Glaser, M. Fridkin et al., The molecular and cellular basis of exostosis formation in hereditary multiple exostoses: Hereditary multiple exostoses, Int J Exp Pathol, vol.89, pp.321-352, 2008.

J. Huegel, M. Enomoto-iwamoto, F. Sgariglia, E. Koyama, and M. Pacifici, Heparanase stimulates chondrogenesis and is up-regulated in human ectopic cartilage: a mechanism possibly involved in hereditary multiple exostoses, Am J Pathol, vol.185, pp.1676-1685, 2015.

J. Huegel, F. Sgariglia, M. Enomoto-iwamoto, E. Koyama, J. P. Dormans et al., Heparan sulfate in skeletal development, growth, and pathology: The case of hereditary multiple exostoses: Heparan Sulfate in Skeletal Dysplasia, Dev Dyn, vol.242, pp.1021-1053, 2013.

M. Zuntini, M. Salvatore, E. Pedrini, A. Parra, F. Sgariglia et al., MicroRNA profiling of multiple osteochondromas: identification of disease-specific and normal cartilage signatures, Clin Genet, vol.78, pp.507-523, 2010.

B. M. Zak, M. Schuksz, E. Koyama, C. Mundy, D. E. Wells et al., Compound heterozygous loss of Ext1 and Ext2 is sufficient for formation of multiple exostoses in mouse ribs and long bones, Bone, vol.48, pp.979-87, 2011.

U. Häcker, K. Nybakken, and N. Perrimon, Heparan sulphate proteoglycans: the sweet side of development, Nat Rev Mol Cell Biol, vol.6, pp.530-571, 2005.

D. J. Bornemann, Abrogation of heparan sulfate synthesis in Drosophila disrupts the Wingless, Hedgehog and Decapentaplegic signaling pathways, Development, vol.131, pp.1927-1965, 2004.

H. M. Kronenberg, Developmental regulation of the growth plate, Nature, vol.423, p.332, 2003.

L. Koziel, M. Kunath, O. G. Kelly, and A. Vortkamp, Ext1-dependent heparan sulfate regulates the range of Ihh signaling during endochondral ossification, Dev Cell, vol.6, pp.801-813, 2004.

D. Stickens, Mice deficient in Ext2 lack heparan sulfate and develop exostoses, Development, vol.132, pp.5055-68, 2005.

J. Huegel, C. Mundy, F. Sgariglia, P. Nygren, P. C. Billings et al., Perichondrium phenotype and border function are regulated by Ext1 and heparan sulfate in developing long bones: A mechanism likely deranged in Hereditary Multiple Exostoses, Dev Biol, vol.377, pp.100-112, 2013.

C. Reijnders, C. Waaijer, A. Hamilton, E. P. Buddingh, S. Dijkstra et al., No Haploinsufficiency but Loss of Heterozygosity for EXT in Multiple Osteochondromas, Am J Pathol, vol.177, pp.1946-57, 2010.

C. E. De-andrea, F. A. Prins, M. I. Wiweger, and P. C. Hogendoorn, Growth plate regulation and osteochondroma formation: insights from tracing proteoglycans in zebrafish models and human cartilage, J Pathol, vol.224, pp.160-168, 2011.

A. Clément, M. Wiweger, V. Der-hardt, S. Rusch, M. A. Selleck et al., Regulation of Zebrafish Skeletogenesis by ext2/dackel and papst1/pinscher, PLoS Genet, vol.4, p.1000136, 2008.

K. Matsumoto, F. Irie, S. Mackem, and Y. Yamaguchi, A mouse model of chondrocyte-specific somatic mutation reveals a role for Ext1 loss of heterozygosity in multiple hereditary exostoses, Proc Natl Acad Sci, vol.107, pp.10932-10939, 2010.

Y. Bellaiche, I. The, and N. Perrimon, Tout-velu is a Drosophila homologue of the putative tumour suppressor EXT-1 and is needed for Hh diffusion, Nature, vol.394, pp.85-93, 1998.

B. A. Alman, Multiple hereditary exostosis and hedgehog signaling: implications for novel therapies, JBJS, vol.91, pp.63-67, 2009.

U. Häcker, X. Lin, and N. Perrimon, The Drosophila sugarless gene modulates Wingless signaling and encodes an enzyme involved in polysaccharide biosynthesis, Dev Camb Engl, vol.124, pp.3565-73, 1997.

X. Lin and N. Perrimon, Role of heparan sulfate proteoglycans in cell-cell signaling in Drosophila, Matrix Biol J Int Soc Matrix Biol, vol.19, pp.303-310, 2000.

A. Cuellar, A. Inui, M. A. James, D. Borys, and A. H. Reddi, Immunohistochemical localization of bone morphogenetic proteins (BMPs) and their receptors in solitary and multiple human osteochondromas, J Histochem Cytochem, vol.62, pp.488-498, 2014.

D. Chappard, G. Mabilleau, D. Moukoko, N. Henric, V. Steiger et al., Aluminum and iron can be deposited in the calcified matrix of bone exostoses, J Inorg Biochem, vol.152, pp.174-183, 2015.
URL : https://hal.archives-ouvertes.fr/hal-01392283

N. Clement and D. Porter, Hereditary multiple exostoses: anatomical distribution and burden of exostoses is dependent upon genotype and gender, Scott Med J, vol.59, pp.35-44, 2014.

S. Pannier and L. Legeai-mallet, Hereditary multiple exostoses and enchondromatosis, Best Pract Res Clin Rheumatol, vol.22, pp.45-54, 2008.

C. Parlier-cuau, V. Bousson, C. M. Ogilvie, R. D. Lackman, and J. Laredo, When should we biopsy a solitary central cartilaginous tumor of long bones? Literature review and management proposal, Eur J Radiol, vol.77, pp.6-12, 2011.

D. E. Porter, L. Lonie, M. Fraser, C. Dobson-stone, J. R. Porter et al., Severity of disease and risk of malignant change in hereditary multiple exostoses. A genotype-phenotype study, J Bone Joint Surg Br, vol.86, pp.1041-1047, 2004.

C. M. Czajka and M. R. Dicaprio, What is the Proportion of Patients With Multiple Hereditary Exostoses Who Undergo Malignant Degeneration?, Clin Orthop Relat Res, vol.473, pp.2355-61, 2015.

L. B. Rozeman, I. De-bruijn, P. Bacchini, E. L. Staals, F. Bertoni et al., Dedifferentiated peripheral chondrosarcomas: regulation of EXT-downstream molecules and differentiation-related genes, Mod Pathol Off J U S Can Acad Pathol Inc, vol.22, pp.1489-98, 2009.

J. A. Perrone, Dysphagia, due to massive cervical exostoses, Arch Otolaryngol, vol.86, pp.346-347, 1967.

L. Zaijun, Y. Xinhai, W. Zhipeng, H. Wending, H. Quan et al., Outcome and prognosis of myelopathy and radiculopathy from osteochondroma in the mobile spine: a report on 14 patients, Clin Spine Surg, vol.26, pp.194-199, 2013.

D. Assefa, R. C. Murphy, K. Bergman, and A. B. Atlas, Three faces of costal exostoses: case series and review of literature, Pediatr Emerg Care, vol.27, pp.1188-1191, 2011.

A. L. Goud, J. De-lange, V. B. Scholtes, S. K. Bulstra, and S. J. Ham, Pain, Physical and Social Functioning, and Quality of Life in Individuals with Multiple Hereditary Exostoses in the Netherlands: A National Cohort Study, J Bone Jt Surg-Am, vol.94, pp.1013-1033, 2012.

H. Hosalkar, J. Greenberg, R. L. Gaugler, S. Garg, and J. P. Dormans, Abnormal scarring with keloid formation after osteochondroma excision in children with multiple hereditary exostoses, J Pediatr Orthop, vol.27, pp.333-337, 2007.

E. Pedrini, I. Jennes, M. Tremosini, A. Milanesi, M. Mordenti et al., Genotype-Phenotype Correlation Study in 529 Patients with Multiple Hereditary Exostoses: Identification of "Protective" and "Risk, Factors: J Bone Jt Surg-Am, vol.93, pp.2294-302, 2011.

G. Morvan, V. Vuillemin, H. Guerini, M. Wybier, P. Mathieu et al.,

. Imagerie, E. Le-système, and . E-mém, Académie Natl Chir, vol.12, pp.6-17, 2013.

W. Wuyts, R. Radersma, K. Storm, and L. Vits, An optimized DHPLC protocol for molecular testing of the EXT1 and EXT2 genes in hereditary multiple osteochondromas: Molecular analysis of the EXT genes, Clin Genet, vol.68, pp.542-549, 2005.

G. K. Deirmengian, N. M. Hebela, M. O?connell, D. L. Glaser, E. M. Shore et al., Proximal Tibial Osteochondromas in Patients with Fibrodysplasia Ossificans Progressiva, J Bone Jt Surg, vol.90, pp.366-74, 2008.

A. M. Passanise, C. T. Mehlman, E. J. Wall, and J. P. Dieterle, Radiographic evidence of regression of a solitary osteochondroma: a report of 4 cases and a literature review, J Pediatr Orthop, vol.31, pp.312-316, 2011.

S. A. Bernard, M. D. Murphey, D. J. Flemming, and M. J. Kransdorf, Improved differentiation of benign osteochondromas from secondary chondrosarcomas with standardized measurement of cartilage cap at CT and MR imaging, Radiology, vol.255, pp.857-865, 2010.

T. D. Tiet, S. Hopyan, P. Nadesan, N. Gokgoz, R. Poon et al., Constitutive Hedgehog Signaling in Chondrosarcoma Up-Regulates Tumor Cell Proliferation, Am J Pathol, vol.168, pp.321-351, 2006.