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Orthopeadic Resources


The Connection Corner Guide Book to MHE/MO/HME:   Click here


MHE/MO/HME Pain and Exostoses Tracker:  Click here


MHE/MO/HME School needs check list:  Click here


MHE Center Paley Institute:  Click here


Research Publications


The MHE Research Foundation would like to Thank Dr. Paley and Dr. Lee for all their efforts on behalf of all MHE families around the world. This research on MHE hip reconstruction is a long term follow up study, the procedures Dr. Paley performs on the hip offers a "noteworthy improvement in the quality of life for patients”  


Citation: Lee, D.H.; Paley, D.

Reconstruction of the Hip in Multiple Hereditary Exostoses.

Children 2021, 8, 490. 

A complete holistic overview for how each area of the body is impacted by MHE.  This publication was written by Dror Paley and David Feldman; founding members of the medical and scientific advisory board for The MHE Research Foundation published in March 2020. 


The impact of hereditary multiple exostoses on quality of life, satisfaction, global health status, and pain.

D'Ambrosi R, Ragone V, Caldarini C, Serra N, Usuelli FG, Facchini RM.

Arch Orthop Trauma Surg. 2017 Feb;137(2):209-215. doi: 10.1007/s00402-016-2608-4. Epub 2016 Dec 8.

PMID: 27933382

Unsuspected osteochondroma-like outgrowths in the cranial base of Hereditary Multiple Exostoses patients and modeling and treatment with a BMP antagonist in mice.

Sinha S, Mundy C, Bechtold T, Sgariglia F, Ibrahim MM, Billings PC, Carroll K, Koyama E, Jones KB, Pacifici M.

PLoS Genet. 2017 Apr 26;13(4):e1006742. doi: 10.1371/journal.pgen.1006742. eCollection 2017 Apr.

PMID: 28445472


Hereditary Multiple Exostoses: New Insights into Pathogenesis, Clinical Complications, and Potential Treatments.

Pacifici M.

Curr Osteoporos Rep. 2017 Jun;15(3):142-152. doi: 10.1007/s11914-017-0355-2. Review.

PMID: 28466453


Aberrant perichondrial BMP signaling mediates multiple osteochondromagenesis in mice.

Inubushi T, Nozawa S, Matsumoto K, Irie F, Yamaguchi Y.

JCI Insight. 2017 Aug 3;2(15). pii: 90049. doi: 10.1172/jci.insight.90049. [Epub ahead of print]

PMID: 28768899


Retinoid roles and action in skeletal development and growth provide the rationale for an ongoing heterotopic ossification prevention trial.

Pacifici M.

Bone. 2018 Apr;109:267-275. doi: 10.1016/j.bone.2017.08.010. Epub 2017 Aug 19. Review.

PMID: 28826842


Is Routine Spine MRI Necessary in Skeletally Immature Patients With MHE? Identifying Patients at Risk for Spinal Osteochondromas.

Jackson TJ, Shah AS, Arkader A.

J Pediatr Orthop. 2017 Oct 9. doi: 10.1097/BPO.0000000000001084. [Epub ahead of print]

PMID: 29016429


Advances in the pathogenesis and possible treatments for multiple hereditary exostoses from the 2016 international MHE conference.

Phan AQ, Pacifici M, Esko JD.

Connect Tissue Res. 2018 Jan;59(1):85-98. doi: 10.1080/03008207.2017.1394295. Epub 2017 Nov 3.

PMID: 29099240


Palovarotene Inhibits Osteochondroma Formation in a Mouse Model of Multiple Hereditary Exostoses.

Inubushi T, Lemire I, Irie F, Yamaguchi Y.

J Bone Miner Res. 2018 Apr;33(4):658-666. doi: 10.1002/jbmr.3341. Epub 2017 Nov 30.

PMID: 29120519


The pathogenic roles of heparan sulfate deficiency in hereditary multiple exostoses.

Pacifici M.

Matrix Biol. 2017 Dec 24. pii: S0945-053X(17)30362-1. doi: 10.1016/j.matbio.2017.12.011. [Epub ahead of print] Review.

PMID: 29277722


Heparan sulfate antagonism alters bone morphogenetic protein signaling and receptor dynamics, suggesting a mechanism in hereditary multiple exostoses.

Mundy C, Yang E, Takano H, Billings PC, Pacifici M.

J Biol Chem. 2018 May 18;293(20):7703-7716. doi: 10.1074/jbc.RA117.000264. Epub 2018 Apr 5.

PMID: 29622677


Ulnar Distraction Osteogenesis in the Treatment of Forearm Deformities in Children With Multiple Hereditary Exostoses.

Refsland S, Kozin SH, Zlotolow DA.

J Hand Surg Am. 2016 Sep;41(9):888-95. doi: 10.1016/j.jhsa.2016.06.008. Epub 2016 Aug 1.

To read full text publication Click here



Radiographic Analysis of the Pediatric Hip Patients With Hereditary Multiple Exostoses (HME).
Duque Orozco MD1, Abousamra O, Rogers KJ, Thacker MM.
J Pediatr Orthop. 2016 Jun 18.


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Imaging of benign complications of exostoses of the shoulder, pelvic girdles and appendicular skeleton.

Gavanier M1, Blum A2.
Diagn Interv Imaging. 2016 Jun 14. pii: S2211-5684(16)30094-8. doi: 10.1016/j.diii.2015.11.021.


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Correction of ankle valgus by hemiepiphysiodesis using the tension band principle in patients with multiple hereditary exostosis.
van Oosterbos M1, van der Zwan AL1, van der Woude HJ2, Ham SJ3.
J Child Orthop. 2016 Jun;10(3):267-73. doi: 10.1007/s11832-016-0742-8. Epub 2016 May 27.


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HhAntag, a Hedgehog Signaling Antagonist, Suppresses Chondrogenesis and Modulates Canonical and Non-Canonical BMP Signaling. 
Mundy C1, Bello A2, Sgariglia F1, Koyama E1, Pacifici M1.
J Cell Physiol. 2016 May;231(5):1033-44. doi: 10.1002/jcp.25192. Epub 2015 Sep 22.


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Magnetic Resonance Imaging in Symptomatic Children With Hereditary Multiple Exostoses of the Hip.
Duque Orozco MD1, Abousamra O, Rogers KJ, Thacker MM.
J Pediatr Orthop. 2016 Apr 30.


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Gradual ulnar lengthening in children with multiple exostoses and radial head dislocation: results at skeletal maturity.
D'Ambrosi R1,2, Barbato A3, Caldarini C3, Biancardi E3, Facchini RM3.
J Child Orthop. 2016 Apr;10(2):127-33. doi: 10.1007/s11832-016-0718-8. Epub 2016 Feb 24.


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Surgical hip dislocation according to Ganz for excision of osteochondromas in patients with multiple hereditary exostoses.
Sorel JC1, Façee Schaeffer M2, Homan AS2, Scholtes VA2, Kempen DH3, Ham SJ3.
Bone Joint J. 2016 Feb;98-B(2):260-5. doi: 10.1302/0301-620X.98B2.36521.


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Multiple Hereditary Exostoses. (Basic characteristics of MHE)
DuBose CO.
Radiol Technol. 2016 Jan-Feb;87(3):305-21. quiz 322-5.


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Multiple osteochondroma of the hand: initial and long-term follow-up study.
Woodside JC1, Ganey T2, Gaston RG3.
Hand (N Y). 2015 Dec;10(4):616-20. doi: 10.1007/s11552-015-9775-6. Epub 2015 Jun 3.


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Preoperative Computer Simulation and Patient-specific Guides are Safe and Effective to Correct Forearm Deformity in Children.
Bauer AS1, Storelli DA, Sibbel SE, McCarroll HR, Lattanza LL.
J Pediatr Orthop. 2015 Oct 21.


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Skeletal maturity of children with multiple osteochondromas: is diminished stature due to a systemic influence?
Staal HM1, Goud AL2, van der Woude HJ3, Witlox MA4, Ham SJ5, Robben SG6, Dremmen MH6, van Rhijn LW4.
J Child Orthop. 2015 Oct;9(5):397-402. doi: 10.1007/s11832-015-0680-x. Epub 2015 Sep 1.


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Outcomes of Hemiepiphyseal Stapling for Genu Valgum Deformities in Patients With Multiple Hereditary Exostoses:
A Comparative Study of Patients With Deformities of Idiopathic Cause.
Kang S1, Kim JY, Park SS.
J Pediatr Orthop. 2015 Aug 20.


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Beam Projection Effect in the Radiographic Evaluation of Ankle Valgus Deformity Associated With Fibular Shortening.
Jang WY1, Park MS, Yoo WJ, Chung CY, Choi IH, Cho TJ.
J Pediatr Orthop. 2015 Aug 20.


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Interactions of signaling proteins, growth factors and other proteins with heparan sulfate: 
mechanisms and mysteries.
Billings PC1, Pacifici M.
Connect Tissue Res. 2015;56(4):272-80. doi: 10.3109/03008207.2015.1045066.


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Scoliosis in patients with multiple hereditary exostoses.
Matsumoto Y1, Matsumoto K, Harimaya K, Okada S, Doi T, Iwamoto Y.
Eur Spine J. 2015 Jul;24(7):1568-73. doi: 10.1007/s00586-015-3883-4. Epub 2015 Mar 21.


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Developmental pattern of the hip in patients with hereditary multiple exostoses.
Wang YZ1, Park KW2, Oh CS3, Ahn YS4, Kang QL5, Jung ST6, Song HR7.
BMC Musculoskelet Disord. 2015 Mar 15;16:54. doi: 10.1186/s12891-015-0514-5.


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Heparanase stimulates chondrogenesis and is up-regulated in human ectopic cartilage: a mechanism possibly involved in hereditary
multiple exostoses.
Huegel J1, Enomoto-Iwamoto M1, Sgariglia F1, Koyama E1, Pacifici M2.  
Am J Pathol. 2015 Jun;185(6):1676-85. doi: 10.1016/j.ajpath.2015.02.014. Epub 2015 Apr 8.


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Loss of Function in Heparan Sulfate Elongation Genes EXT1 and EXT 2 Results in Improved Nitric Oxide Bioavailability and Endothelial Function.
Mooij HL, Cabrales P, Bernelot Moens SJ, Xu D, Udayappan SD, Tsai AG, van der Sande MA, de Groot E, Intaglietta M, Kastelein JJ,
Dallinga-Thie GM, Esko JD, Stroes ES, Nieuwdorp M.
J Am Heart Assoc. 2014 Dec 2;3(6). pii: e001274. doi: 10.1161/JAHA.114.001274.


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Chest wall osteochondroma in children: a case series of surgical management.
Bakhshi H1, Kushare I, Murphy MO, Gaynor JW, Dormans JP.
J Pediatr Orthop. 2014 Oct-Nov;34(7):733-7. doi: 10.1097/BPO.0000000000000153.


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Hip joint osteochondroma: systematic review of the literature and report of three further cases.
Makhdom AM1, Jiang F2, Hamdy RC2, Benaroch TE2, Lavigne M3, Saran N2.
Adv Orthop. 2014;2014:180254. doi: 10.1155/2014/180254. Epub 2014 May 20.


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Multiple hereditary exostoses (MHE): elucidating the pathogenesis of a rare skeletal disorder through interdisciplinary research.
Jones KB1, Pacifici M, Hilton MJ. Connect Tissue Res. 2014


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Possible effects of EXT2 on mesenchymal differentiation - lessons from the zebrafish
Malgorzata I Wiweger, Carlos E de Andrea, Karel W Scheepstra, Zhe Zhao and Pancras C Hogendoorn
Orphanet Journal of Rare Diseases 2014, 9:35  doi:10.1186/1750-1172-9-35


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Perichondrium phenotype and border function are regulated by Ext1 and heparan sulfate in developing long bones:
A mechanism likely deranged in Hereditary Multiple Exostoses.
Huegel J, Mundy C, Sgariglia F, Nygren P, Billings PC, Yamaguchi Y, Koyama E, Pacifici M.
Dev Biol. 2013 Feb 28. pii: S0012-1606(13)00087-0. doi: 10.1016/j.ydbio.2013.02.008.


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Validation of a new multiple osteochondromas classification through Switching Neural Networks.
Mordenti M, Ferrari E, Pedrini E, Fabbri N, Campanacci L, Muselli M, Sangiorgi L.
Am J Med Genet A. 2013 Mar;161(3):556-60. doi: 10.1002/ajmg.a.35819. Epub 2013 Feb 8.


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Pathophysiology of heparan sulphate: many diseases, few drugs.
Lindahl U1, Kjellén L.
J Intern Med. 2013 Jun;273(6):555-71. doi: 10.1111/joim.12061. Epub 2013 Mar 12.


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Loss of β-Catenin Induces Multifocal Periosteal Chondroma-Like Masses in Mice.
Cantley L, Saunders C, Guttenberg M, Candela ME, Ohta Y, Yasuhara R, Kondo N, Sgariglia F, Asai S, Zhang X, Qin L, Hecht JT, Chen D,
Yamamoto M, Toyosawa S, Dormans JP, Esko JD, Yamaguchi Y, Iwamoto M, Pacifici M, Enomoto-Iwamoto M.
Am J Pathol. 2013 Mar;182(3):917-27. doi: 10.1016/j.ajpath.2012.11.012.  


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Multiple Hereditary Exostoses: Its Burden on Childhood and Beyond: Commentary on an article by A.L. Goud, MD, et al.:  
“Pain, Physical and Social Functioning, and Quality of Life in Individuals with Multiple Hereditary Exostoses in the Netherlands. A
National Cohort Study”. Arkader A.
J Bone Joint Surg Am. 2012 Jun 6;94(11):e811-1


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Autism-like socio-communicative deficits and stereotypies in mice lacking heparan sulfate.
Irie F, Badie-Mahdavi H, Yamaguchi Y.
Proc Natl Acad Sci U S A. 2012 Mar 12.


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HSPG-Deficient Zebrafish Uncovers Dental Aspect of Multiple Osteochondromas.
Wiweger MI, Zhao Z, van Merkesteyn RJ, Roehl HH, Hogendoorn PC.
PLoS One. 2012;7(1):e29734. Epub 2012 Jan 11.


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Epiphyseal growth plate and secondary peripheral chondrosarcoma the neighbours matter.
J Pathol. 2012 Jan;226(2):219-28. doi: 10.1002/path.3003. Epub 2011 Nov 23.
de Andrea CE, Hogendoorn PC.


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Identification and functional characterization of the human EXT1 promoter region.
Jennes I, Zuntini M, Mees K, Palagani A, Pedrini E, De Cock G, Fransen E, Vanden Berghe W, Sangiorgi L, Wuyts W.

Gene. 2012 Jan 15;492(1):148-59. Epub 2011 Oct 19.

Compound heterozygous loss of Ext1 and Ext2 is sufficient for formation of multiple exostoses in mouse ribs and long bones.
Zak BM, Schuksz M, Koyama E, Mundy C, Wells DE, Yamaguchi Y, Pacifici M, Esko JD.
Bone. 2011 May 1;48(5):979-87. Epub 2011 Feb 15.


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Breakpoint characterization of large deletions in EXT1 or EXT2 in 10 Multiple Osteochondromas families.
Jennes I, de Jong D, Mees K, Hogendoorn PC, Szuhai K, Wuyts W.
BMC Med Genet. 2011 Jun 26;12(1):85.


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Growth plate regulation and osteochondroma formation: insights from tracing proteoglycans in zebrafish models and human cartilage.
de Andrea CE, Prins FA, Wiweger MI, Hogendoorn PC.

J Pathol. 2011 Jun;224(2):160-8. doi: 10.1002/path.2886. Epub 2011 Apr 19.


Glycobiology and the Growth Plate: Current Concepts in Multiple Hereditary Exostoses
Jones, Kevin B.
Journal of Pediatric Orthopaedics. 31(5):577-586, July/August 2011.

Publications from the press release above
Conditional ablation of the heparan sulfate-synthesizing enzyme Ext1 leads to dysregulation of BMP signaling and severe skeletal defects.
Matsumoto Y, Matsumoto K, Irie F, Fukushi JI, Stallcup WB, Yamaguchi Y.
Sanford-Burnham Medical Research Institute, United States.
J Biol Chem. 2010 Jun 18;285(25):19227-34. Epub 2010 Apr 19.


To read full text publication Click Here

A mouse model of chondrocyte-specific somatic mutation reveals a role for Ext1 loss of heterozygosity in multiple hereditary exostoses.
Matsumoto K, Irie F, Mackem S, Yamaguchi Y.

Proc Natl Acad Sci U S A. 2010 Jun 15;107(24):10932-7. Epub 2010 Jun 1.

Roles of heparan sulfate in mammalian brain development current views based on the findings from Ext1 conditional knockout studies.
Yamaguchi Y, Inatani M, Matsumoto Y, Ogawa J, Irie F.

Prog Mol Biol Transl Sci. 2010;93:133-52.

Tiling resolution array-CGH shows that somatic mosaic deletion of the EXT gene is causative in EXT gene mutation negative multiple 
osteochondromas patients.
Szuhai K, Jennes I, de Jong D, Bovée JVWiweger MWuyts WHogendoorn PC.

Hum Mutat. 2010 Dec 7 (full text link)

Multiple osteochondromas in the archaeological record:  a global review
E.M. Murphy, C.J. McKenzie
Journal of Archaeological Science 37 (2010) 2255e2264


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No Haploinsufficiency but Loss of Heterozygosity for EXT in Multiple Osteochondromas
Reijnders CM, Waaijer CJ, Hamilton A, Buddingh EP, Dijkstra SP, Ham J, Bakker E, Szuhai K, Karperien M, Hogendoorn PC, Stringer SE, Bovée JV.

Am J Pathol. 2010 Sep 2. PMID: 20813973

Genetic models of osteochondroma onset and neoplastic progression: evidence for mechanisms alternative to EXT genes inactivation.
Zuntini M, Pedrini E, Parra A, Sgariglia F, Gentile FV, Pandolfi M, Alberghini M, Sangiorgi L.

Oncogene. 2010 Jul 1;29(26):3827-34.

Primary cilia organization reflects polarity in the growth plate and implies loss of polarity and mosaicism in osteochondroma
de Andrea CE, Wiweger M, Prins F, Bovée JV, Romeo S, Hogendoorn PC.
International Journal of Laboratory Investigation (April issue)

Sugars, bones, and a disease called multiple hereditary exostoses
Henry H. RoehlMaurizio Pacifici
Journal of Developmental Dynamics May 2010 issue

EXTra hit for mouse osteochondroma
Judith V. M. G. Bovée

10.1073/pnas.0914431107 PNAS published February 2, 2010 vol. 107 no. 5 1813-1814

Biological Sciences - Developmental Biology:
A mouse model of osteochondromagenesis from clonal inactivation of Ext1 in chondrocytes
Kevin B. Jones, Virginia Piombo, Charles Searby, Gail Kurriger, Baoli Yang, Florian Grabellus, Peter J. Roughley, Jose A. Morcuende, 
Joseph A. Buckwalter, Mario R. Capecchi, Andrea Vortkamp, and Val C. Sheffield

PNAS published online doi:10.1073/pnas.0910875107

Mutation in the heparan sulfate biosynthesis enzyme Ext1 influences growth factor signaling and fibroblast interaction with the 
extracellular matrix.
Cecilia Österholm, Malgorzata M. Barczyk, Marta Busse, Mona Grønning, Rolf K. Reed, and Marion Kusche-Gullberg
J. Biol. Chem. 2009 284: 34935-34943. First Published on October 22, 2009, doi:10.1074/jbc.M109.005264


To read this Full Text publication Click here

Multiple osteochondromas: mutation update and description of the multiple osteochondromas mutation database (MOdb).
Jennes I, Pedrini E, Zuntini M, Mordenti M, Balkassmi S, Asteggiano CG, Casey B, Bakker B, Sangiorgi LWuyts W.

Hum Mutat. 2009 Oct 6

Involvement of the Spine in Patients with Multiple Hereditary Exostoses
James W. Roach, Joshua W.B. Klatt, and Nathan D. Faulkner

The Journal of Bone and Joint Surgery. Am., Aug 2009; 91: 1942 - 1948.

Multiple Hereditary Exostosis and Hedgehog Signaling: Implications for Novel Therapies
Benjamin A. Alman

The Journal of Bone and Joint Surgery. Am., Jul 2009; 91: 63 - 67.

Research on rare bone disorder reveals new insights into autism:  Click Here

Genetic Publications


Genetics Home Reference is a service of the National Library of Medicine (NLM), which is part of the National Institutes of Health, an agency of the U.S. Department of Health and Human Services.


NCBI Gene Review

Hereditary Multiple Osteochondromas

Synonyms: Diaphyseal Aclasis, Multiple Cartilaginous Exostoses, Hereditary Multiple Exostoses

Wim Wuyts, PhD, Gregory A Schmale, MD, Howard A Chansky, MD, and Wendy H Raskind, MD, PhD.


Disease Data Base

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