The Journal of Bone & Joint Surgery

The Journal of Bone & Joint Surgery, Volume 91, Issue Supplement 4

Multiple Hereditary Exostoses | July 01, 2009

Multiple Hereditary Exostosis and Hedgehog Signaling: Implications for Novel Therapies

Benjamin A. Alman, MD, FRCSC¹

¹ Division of Orthopaedic Surgery, The Hospital for Sick Children, 555 University Avenue, Toronto, ON M5G 1X8, Canada. E-mail address: Benjamin.alman@sickkids.ca

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Disclosure: In support of his research for or preparation of this work, the author received, in any one year, outside funding or grants in excess of $10,000 from the Canadian Institutes of Health Research. Neither he nor a member of his immediate family received payments or other benefits or a commitment or agreement to provide such benefits from a commercial entity.

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J Bone Joint Surg Am, 2009 Jul 01;91(Supplement 4):63-67. doi: 10.2106/JBJS.I.00301

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Extract

Multiple hereditary exostosis is an autosomal dominant condition in which osteochondromas develop at the metaphyseal portions of the bones. In addition, persons with this condition have short stature, asymmetric involvement of the bones, and a small risk of malignant degeneration of an osteochondroma into chondrosarcoma. The location of osteochondromas adjacent to the growth plate suggests that their origin is from growth-plate chondrocytes.

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Introduction

Growth-plate chondrocytes go through a coordinated process of differentiation, resulting in the longitudinal growth of bones. The Indian hedgehog-parathyroid hormone-related protein (Ihh-PTHrP) pathway regulates the rate at which chondrocytes within the growth plate proliferate and differentiate, thus controlling the longitudinal growth of bones. Linkage studies and mutational analysis show that multiple hereditary exostosis is caused by mutations in the EXT genes, the products of which play a role in the diffusion of hedgehog proteins; a mutation in an EXT gene causes abnormal Ihh diffusion, leading to an osteochondroma. Hedgehog signaling remains activated in osteochondromas. Pharmacologic agents that inhibit hedgehog signaling are under development, and these agents may be useful in the treatment of osteochondromas or of chondrosarcomas that develop from malignant degeneration.

Characteristics of Multiple Hereditary Exostosis

Cartilaginous tumors are the most common neoplasms affecting bone, and osteochondromas are the most common of the benign cartilaginous lesions^1,2. Osteochondromas are outgrowths of bone and cartilage that occur in the metaphyseal region of long bones, near the growth plate. The cortex of the bone is continuous with the outgrowth, which is capped by cartilage (Fig. 1). Osteochondromas can occur as solitary lesions or as multiple lesions, as seen in multiple hereditary exostosis.

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Fig. 1: Typical appearance of an osteochondroma. A T1-weighted spin-echo magnetic resonance image showing a cartilaginous cap (light signal) covering an outgrowth of bone, which includes a cortex (dark signal) and medullary canal, both of which are in continuity with the bone from which the osteochondroma arises.

Multiple hereditary exostosis is inherited in an autosomal dominant manner and has been associated with a prevalence of approximately one in 50,000³. The osteochondromas in multiple hereditary exostosis develop at a higher frequency adjacent to faster-growing growth plates. Affected individuals have short stature, and either the mesomelic segment or the distal segment of limbs are more severely affected. Because of variable penetrance, approximately 5% of individuals who have the ability to transmit the disease are clinically unaffected^4,5. Within the mesomelic portion of the limbs, the fibula and ulna are more affected than the tibia and radius are. This results in a common sequence of lower-extremity and upper-extremity deformity. In the upper extremity, the asymmetry in longitudinal growth causes a progressive relative shortening of the ulna, resulting in ulnar deviation of the wrist and, in severe cases, subluxation of the radial head (Fig. 2). The osteochondromas can also restrict supination and pronation by direct impingement or by causing a functional relative shortening of the interosseous ligament^6-9. The treatment of these deformities includes removal of exostoses, growth modulation by hemiepiphyseodesis and epiphyseodesis, and osteotomy. Many patients with this condition undergo multiple orthopaedic procedures during childhood and adolescence, and the results of surgical treatment are often suboptimal.

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Fig. 2: Typical radiographic appearance of the forearm in multiple hereditary exostosis. A: Osteochondromas are seen at the ends of the bones. B: The ulna is more affected by shortening than is the radius, resulting in radial-head subluxation and ulnar deviation at the wrist.

Osteochondromas grow as the affected individual grows. It is rare for osteochondromas to be identified at birth, but, in half of affected individuals, the tumor is readily apparent by the age of five years. When a person with multiple hereditary exostosis stops growing, the osteochondroma stops growing. The cartilaginous cap is usually <1 cm in thickness when growth is complete¹⁰. There is a chance of malignant progression in multiple hereditary exostosis, and progression is estimated to occur at a rate of <1%¹¹. Malignant change is usually to a low-grade chondrosarcoma, which can be clinically identified by an increase in size of the exostosis in an adult¹². There are no universally accepted surveillance protocols for malignant change in multiple hereditary exostosis; however, because malignant change most frequently occurs in the fourth decade¹², clinical vigilance in adults is important. The identification of a noninvasive method to identify malignant progression is an area of current research.

Relationship of Osteochondromas to the Growth Plate

Because of their location adjacent to the growth plate, it has long been thought that osteochondromas derive from growth-plate chondrocytes. Indeed, animal studies show that transplantation of a growth plate at an angle 90° to the usual axis of longitudinal growth will cause an exostosis to form¹³.

The growth plate, which is located between the cartilaginous epiphysis and the newly generated bone in the metaphysis, is responsible for longitudinal bone growth. The perichondrium is a layer of dense connective tissue that surrounds the growth plate. Within the growth plate, chondrocytes undergo differentiation, progressing through the resting, proliferation, prehypertrophic, and hypertrophic stages until eventually undergoing programmed cell death. Adjacent to the region where chondrocytes undergo apoptosis, blood vessels invade the cartilage matrix, presumably delivering osteoblasts that produce endochondral bone¹⁴. Chondrocytes develop from mesenchymal precursor cells (sometimes called mesenchymal stem cells), which differentiate into a common osteochondroprogenitor cell. Once cells become committed to a chondrocyte phenotype, they undergo a coordinated process of differentiation, with expression of various genes (e.g., SOX9, IHH, PTHrP, RUNX2, type X Collagen)^15-17 marking the states of differentiation.

The hedgehog signaling pathway is crucial in the regulation of chondrocyte fate in the growth plate. Prehypertrophic chondrocytes in the growth plate express the Hh ligand Indian hedgehog (Ihh)^18-20. Ihh serves as a key regulator of endochondral ossification, acting in a negative feedback loop with parathyroid hormone-related protein (PTHrP). Ihh regulates the onset of hypertrophic differentiation by signaling the periarticular chondrocytes to upregulate PTHrP, which inhibits the differentiation of proliferating chondrocytes. Ihh also regulates chondrocyte differentiation and induces ossification of the perichondrium in a PTHrP-independent manner (Fig. 3)²¹. The regulation of PTHrP by Ihh involves mediators such as bone morphogenetic proteins (BMPs), which also play a role in initiating the chondrocyte differentiation cascade; for instance, BMP2 upregulates the expression of Ihh in chondrocytes²².

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Fig. 3: Diagrammatic representation of the growth plate and the development of an osteochondroma. A: Growth-plate chondrocytes go through a coordinated differentiation process, regulated by Indian hedgehog and PTHrP, which act in a negative feedback loop to regulate differentiation. B: Mutations in an EXT gene cause abnormalities in hedgehog protein diffusion, resulting in the development of some growth-plate chondrocytes at an angle to the longitudinal bone growth and eventually development of an osteochondroma.

Genetic Etiology of Multiple Hereditary Exostosis

Since multiple hereditary exostosis occurs in an autosomal dominant inheritance pattern, several different investigators have searched for the causative gene. An initial clue came from individuals with Langer-Giedion syndrome, as affected individuals have multiple exostoses in addition to characteristic facial features and central nervous system abnormalities. Because this syndrome is caused by a large germ-line deletion in a region of chromosome 8, it was hypothesized that a causative gene for osteochondromas would be located in the area of this deletion²³. Genetic linkage analysis identified regions of DNA in which the causative gene would most likely be located. Two loci were identified initially, and, subsequently, mutations in genes in these regions have been identified²⁴. These two genes are termed EXT1 and EXT2, for exostosis^25-27. These same genes are also mutated in isolated osteochondromas, but only in the cells from the osteochondroma itself. There is mutation in one allele in an EXT gene in the germ-line of affected patients, but, in patients who have malignant tumor formation, there is usually loss of the second allele (loss of heterozygosity), which suggests that this gene functions as a tumor suppressor^11,28.

Molecular Etiology of Multiple Hereditary Exostosis

The EXT genes are the human homologues of the Drosophila gene Tout-velu (Ttv). Mutations in Ttv cause a similar phenotype in Drosophila as do mutations in hedgehog ligand, suggesting that Ttv either is a mediator in hedgehog signaling or regulates its expression. The protein product of Ttv was found to be involved in heparan sulfate proteoglycan biosynthesis. Heparan sulfate proteoglycan consists of a protein core to which heparan sulfate (HS) glycosaminoglycan (GAG) chains are attached. The formation of HS GAG chains is catalyzed by glycosyltransferases, which are encoded by Ttv in Drosophila and by members of the EXT family of genes in mammals. The Ext protein products are located on the endoplasmic reticulum, where they add the repeating GAG units to the heparan sulfate core protein^29-31.

How a disruption in heparan sulfate processing results in a phenotype similar to a hedgehog mutation in Drosophila is explained by the way in which heparan sulfate proteoglycan and hedgehog ligands interact. Heparan sulfate proteoglycan can bind to hedgehog ligands, and, in the extracellular environment, this binding can control the region in which hedgehog ligand can diffuse. EXT mutations cause abnormal heparan sulfate proteoglycan processing, and this results in an abnormal diffusion of hedgehog ligand in the extracellular environment because the protein is not as able to effectively bind and control the movement of the hedgehog protein^29-31. Since hedgehog ligand acts to pattern the terminal differentiation of growth-plate chondrocytes, the functional consequence of the mutation causes the growth-plate chondrocytes to pattern abnormally, with bone and cartilage growth occurring at an angle to the normal growth-plate direction (Fig. 3). An alternative explanation is that the abnormal heparan sulfate proteoglycan changes the deformation and differentiation potential of perichondrial cells, resulting in the development of growth-plate-like cells that differentiate in an abnormal direction³².

However, the situation is not nearly as simple as the growth-plate chondrocytes growing in the wrong direction. Unlike normal growth-plate chondrocytes, the cartilage at the end of the osteochondroma does not disappear at the end of growth but instead persists. As a result, the abnormal heparan sulfate proteoglycan plays a more general role in the regulation of chondrocyte differentiation, and hedgehog proteins play an important role in the development of a variety of other organs. Why EXT mutations primarily affect the bone and not other organs is not clear, although this finding suggests that the growth plate is more sensitive to hedgehog ligand diffusion abnormalities than other organs are.

An interesting clinical finding in multiple hereditary exostosis, which can also be partly explained by the EXT mutation, is the development of wider than expected scars after surgery³³, which is another reason that the results of surgical treatment are not always satisfactory. One possibility is that the EXT mutation plays a role in the diffusion of growth factors that are important to wound-healing, thus causing this phenotype. Another is that abnormal heparan sulfate proteoglycan causes a change in the extracellular matrix, resulting in a wider than expected scar or keloid.

There have been several genotype-phenotype studies of small numbers of patients with multiple hereditary exostosis. These studies suggest that patients with EXT1 mutations have more exostoses, more limb malalignment resulting in shorter limb segments and shorter height, and more pelvic and flat-bone involvement than do patients with EXT2 mutations³⁴.

Potential Molecular Therapeutic Target for Multiple Hereditary Exostosis

Normal growth-plate chondrocytes undergo a coordinated differentiation process that ends in terminal programmed cell death. In osteochondromas, a cartilaginous cap persists throughout adulthood. Indeed, secondary malignant change in this cartilage may be responsible for the progression to chondrosarcoma. Hedgehog signaling inhibits the terminal differentiation of chondrocytes, and it is possible that continued hedgehog signaling acts to maintain the cartilage cells in the cap in a less differentiated state. Gene expression studies suggest that this is the case, as osteochondromas express hedgehog ligands and target genes^14,35. Constitutive activation of hedgehog signaling is a common occurrence in the broad range of benign and malignant cartilage tumors, raising the possibility that therapeutic targeting of hedgehog signaling could be used as an approach to treat osteochondromas or perhaps chondrosarcomas. In human chondrosarcoma, organ cultures in vitro, and xenografts in non-obese diabetic severe combined immunodeficient (NOD/Scid) mice, treatment with the hedgehog blocking agent triparanol resulted in a substantial decrease in tumor volume, cellularity, and proliferation rate¹⁴. The hedgehog signaling pathway could be an ideal therapeutic target.

Cyclopamine, a drug derived from the plant Veratrum californicum, is known to block hedgehog signaling. This drug has a teratogenic effect in sheep; ingestion during pregnancy by ewes results in the birth of lambs with holoprosencephaly. Because this agent affects the developing fetus and not the mature sheep that is ingesting the plant, it could potentially inhibit hedgehog signaling in mature animals with minimal side effects. Hedgehog-inhibiting agents such as cyclopamine are under development for clinical use and may have a role in treating cartilage neoplasia³⁶.

Mutations in EXT alone are not sufficient to cause malignant progression. Thus, secondary events are necessary for these lesions to progress to chondrosarcoma. Data from cytogenetic and mutational analysis studies suggest that loss of a tumor-suppressor gene (such as p53 or Rb) plays a role in this progression^37,38. The role of tumor suppressors and other secondary genetic events in malignant progression is under investigation.

Conclusions

Multiple hereditary exostosis is associated with constitutive hedgehog signaling activation. New therapies aimed at modulating this signaling activation may pave the way for improved nonoperative approaches to cartilaginous neoplasia, potentially reducing deformity, obviating the need for multiple surgical procedures, and preventing malignant degeneration. Image Not Available

References

Spjut HJ, Dorfman HD, Fechner RE, Ackerman LV. Tumors of bone and cartilage. Washington, DC: Armed Forces Institute of Pathology; 1971. Tumors of cartilaginous origin; p 77-110. 1971

Levesque J, Marx R, Bell RS, Wunder JS, Kandel R, White L. A clinical guide to primary bone tumors. Baltimore: Williams and Wilkins; 1998. Enchondroma; p 98-107. 1998

Schmale GA, Conrad EU 3rd, Raskind WH. The natural history of hereditary multiple exostoses. J Bone Joint Surg Am.1994;76:986-92.76986 1994 [PubMed]

Wicklund CL, Pauli RM, Johnston D, Hecht JT. Natural history study of hereditary multiple exostoses. Am J Med Genet.1995;55:43-6.5543 1995 [CrossRef]

Legeai-Mallet L, Munnich A, Maroteaux P, Le Merrer M. Incomplete penetrance and expressivity skewing in hereditary multiple exostoses. Clin Genet.1997;52:12-6.5212 1997 [CrossRef]

Peterson HA. Multiple hereditary osteochondromata. Clin Orthop Relat Res.1989;239:222-30.239222 1989

Stieber JR, Dormans JP. Manifestations of hereditary multiple exostoses. J Am Acad Orthop Surg.2005;13:110-20.13110 2005

Akita S, Murase T, Yonenobu K, Shimada K, Masada K, Yoshikawa H. Long-term results of surgery for forearm deformities in patients with multiple cartilaginous exostoses. J Bone Joint Surg Am.2007;89:1993-9.891993 2007 [CrossRef]

Watts AC, Ballantyne JA, Fraser M, Simpson AH, Porter DE. The association between ulnar length and forearm movement in patients with multiple osteochondromas. J Hand Surg [Am].2007;32:667-73.32667 2007 [CrossRef]

Murphey MD, Choi JJ, Kransdorf MJ, Flemming DJ, Gannon FH. Imaging of osteochondroma: variants and complications with radiologic-pathologic correlation. Radiographics.2000;20:1407-34.201407 2000

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;60:80-6.6080 1997

Ahmed AR, Tan TS, Unni KK, Collins MS, Wenger DE, Sim FH. Secondary chondrosarcoma in osteochondroma: report of 107 patients. Clin Orthop Relat Res.2003;411:193-206.411193 2003 [CrossRef]

D'Ambrosia R, Ferguson AB Jr. The formation of osteochondroma by epiphyseal cartilage transplantation. Clin Orthop Relat Res.1968;61:103-15.61103 1968

Tiet TD, Hopyan S, Nadesan P, Gokgoz N, Poon R, Lin AC, Yan T, Andrulis IL, Alman BA, Wunder JS. Constitutive hedgehog signaling in chondrosarcoma up-regulates tumor cell proliferation. Am J Pathol.2006;168:321-30.168321 2006 [CrossRef]

Zou L, Zou X, Li H, Mygind T, Zeng Y, Lü N, Bünger C. Molecular mechanism of osteochondroprogenitor fate determination during bone formation. Adv Exp Med Biol.2006;585:431-41.585431 2006

Akiyama H, Kim JE, Nakashima K, Balmes G, Iwai N, Deng JM, Zhang Z, Martin JF, Behringer RR, Nakamura T, de Crombrugghe B. Osteo-chondroprogenitor cells are derived from Sox9 expressing precursors. Proc Natl Acad Sci U S A.2005;102:14665-70.10214665 2005 [CrossRef]

de Crombrugghe B, Lefebvre V, Nakashima K. Regulatory mechanisms in the pathways of cartilage and bone formation. Curr Opin Cell Biol.2001;13:721-7.13721 2001 [CrossRef]

Pathi S, Rutenberg JB, Johnson RL, Vortkamp A. Interaction of Ihh and BMP/Noggin signaling during cartilage differentiation. Dev Biol.1999;209:239-53.209239 1999 [CrossRef]

Lyons KM, Pelton RW, Hogan BL. Patterns of expression of murine Vgr-1 and BMP-2a RNA suggest that transforming growth factor-beta-like genes coordinately regulate aspects of embryonic development. Genes Dev.1989;3:1657-68.31657 1989 [CrossRef]

Bitgood MJ, McMahon AP. Hedgehog and Bmp genes are coexpressed at many diverse sites of cell-cell interaction in the mouse embryo. Dev Biol.1995;172:126-38.172126 1995 [CrossRef]

Kronenberg HM. Developmental regulation of the growth plate. Nature.2003;423:332-6.423332 2003 [CrossRef]

Minina E, Kreschel C, Naski MC, Ornitz DM, Vortkamp A. Interaction of FGF, Ihh/Pthlh, and BMP signaling integrates chondrocyte proliferation and hypertrophic differentiation. Dev Cell.2002;3:439-49.3439 2002 [CrossRef]

Bühler EM, Malik NJ. The tricho-rhino-phalangeal syndrome(s): chromosome 8 long arm deletion: is there a shortest region of overlap between reported cases? TRP I and TRP II syndromes: are they separate entities? Am J Med Genet.1984;19:113-9.19113 1984 [CrossRef]

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;53:71-9.5371 1993

Ahn J, Lüdecke HJ, Lindow S, Horton WA, Lee B, Wagner MJ, Horsthemke B, Wells DE. Cloning of the putative tumour suppressor gene for hereditary multiple exostoses (EXT1). Nat Genet.1995;11:137-43.11137 1995 [CrossRef]

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. Nat Genet.1996;14:25-32.1425 1996 [CrossRef]

Wuyts W, Van Hul W. Molecular basis of multiple exostoses: mutations in the EXT1 and EXT2 genes. Hum Mutat.2000;15:220-7.15220 2000 [CrossRef]

Hall CR, Cole WG, Haynes R, Hecht JT. Reevaluation of a genetic model for the development of exostosis in hereditary multiple exostosis. Am J Med Genet.2002;112:1-5.1121 2002 [CrossRef]

The I, Bellaiche Y, Perrimon N. Hedgehog movement is regulated through tout velu-dependent synthesis of a heparan sulfate proteoglycan. Mol Cell.1999;4:633-9.4633 1999 [CrossRef]

Dasgupta U, Dixit BL, Rusch M, Selleck S, The I. Functional conservation of the human EXT1 tumor suppressor gene and its Drosophila homolog tout velu. Dev Genes Evol.2007;217:555-61.217555 2007 [CrossRef]

McCormick C, Leduc Y, Martindale D, Mattison K, Esford LE, Dyer AP, Tufaro F. The putative tumour suppressor EXT1 alters the expression of cell-surface heparan sulfate. Nat Genet.1998;19:158-61.19158 1998 [CrossRef]

Hecht JT, Hayes E, Haynes R, Cole WG, Long RJ, Farach-Carson MC, Carson DD. Differentiation-induced loss of heparan sulfate in human exostosis derived chondrocytes. Differentiation.2005;73:212-21.73212 2005 [CrossRef]

Hosalkar H, Greenberg J, Gaugler RL, Garg S, Dormans JP. Abnormal scarring with keloid formation after osteochondroma excision in children with multiple hereditary exostoses. J Pediatr Orthop.2007;27:333-7.27333 2007 [CrossRef]

Alvarez C, Tredwell S, De Vera M, Hayden M. The genotype-phenotype correlation of hereditary multiple exostoses. Clin Genet.2006;70:122-30.70122 2006 [CrossRef]

Hameetman L, Rozeman LB, Lombaerts M, Oosting J, Taminiau AH, Cleton-Jansen AM, Bovée JV, Hogendoorn PC. Peripheral chondrosarcoma progression is accompanied by decreased Indian Hedgehog signalling. J Pathol.2006;209:501-11.209501 2006 [CrossRef]

Rubin LL, de Sauvage FJ. Targeting the Hedgehog pathway in cancer. Nat Rev Drug Discov.2006;5:1026-33.51026 2006 [CrossRef]

Yamaguchi T, Toguchida J, Wadayama B, Kanoe H, Nakayama T, Ishizaki K, Ikenaga M, Kotoura Y, Sasaki MS. Loss of heterozygosity and tumor suppressor gene mutations in chondrosarcomas. Anticancer Res.1996;16:2009-15.162009 1996

Röpke M, Boltze C, Meyer B, Neumann HW, Roessner A, Schneider-Stock R. Rb-loss is associated with high malignancy in chondrosarcoma. Oncol Rep.2006;15:89-95.1589 2006

Topics

signal transduction ; exostoses ; epiphysial cartilage ; erinaceidae ; osteochondroma

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Benjamin A. Alman; Multiple Hereditary Exostosis and Hedgehog Signaling: Implications for Novel Therapies. The Journal of Bone & Joint Surgery. 2009 Jul;91(Supplement_4):63-67.

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