Hereditary multiple exostosis in a practice of pediatric oncologist

Multiple exostosis disease is a rare genetic disorder manifesting in skeletal lesions with development of multiple progressing deformations of the bones and joints. This pathology is characterized by high risk of malignant tumors accompanying bony outgrowths, primarily, chondrosarcoma with onset at the age of 20–40 years. Development  of multiple exostosis disease is mediated by pathogenic variants in the EXT1, EXT2 and EXT3 genes which are inherited through autosomal dominant type of inheritance with high penetrance. During diagnosis in children, this pathology should be differentiated from progressing ossifying fibrodysplasia, metachondromatosis, Langer–Giedion syndrome and common malignant tumors of the bones, cartilage and soft tissues.

 The article presents 2 clinical observations of treatment of multiple exostosis disease. In the first case, familial form of the disease with transmission of pathogenic variant in the EXT1 gene from the father and development of chondrosarcoma in both sons  at the ages of 17 and 21 years is described. In the second case, previously not described pathogenic variant in the EXT1 gene identified de novo in a 12-year-old patient with Ewing sarcoma is presented. These observations demonstrate  the necessity of early oncological screening in patients with multiple exostosis disease.

1. Pacifici M. Hereditary multiple exostoses: new insights into pathogenesis, clinical complications, and potential treatments. Curr Osteoporos Rep 2017;15(3):142–52. DOI: 10.1007/s11914-017-0355-2

2. Francannet C., Cohen-Tanugi A., Le Merrer M. et al. Genotypephenotype correlation in hereditary multiple exostoses. J Med Genet 2001;38(7):430–4. DOI: 10.1136/jmg.38.7.430

3. Raskind W.H., Conrad E.U. 3rd, Matsushita M. et al. Evaluation of locus heterogeneity and EXT1 mutations in 34 families with hereditary multiple exostoses. Hum Mutat 1998;11(3):231–9. DOI: 10.1002/(SICI)1098-1004(1998)11:3<231::AID-HUMU8>3.0.CO;2-K

4. Yakovleva A.E., Danilova A.L., Gurinova E.E. et al. The study of multiple exostatic chondrodysplasia in the Republic of Sakha (Yakutia). Vestnik Severo-Vostochnogo federal’nogo universiteta im. M.K. Ammosova = Bulletin of the Northeastern Federal University named after M.K. Ammosov 2016;3(4):114–7. (In Russ.).

5. Yakovleva A.E., Petukhova D.A., Golikova P.I. et al. A case of multiple exostatic chondrodysplasia in a Yakut family caused by a rare mutation in the EXT2 gene. Medicinskaya genetika = Medical Genetics 2019;18(12):25–33. (In Russ.). DOI: 10.25557/2073-7998.2019.12.25-33

6. Boyer A. Trait des maladies chirurgicales et des operations qui leur conviennent. Paris: The author & Migneret, 1814. (In French).

7. Krooth R.S., Macklin M.T., Hilbish T.F. Diaphysial aclasis (multiple exostoses) on Guam. Am J Hum Genet 1961;13(3):340–7.

8. Jackson I., Mattiangeli V., Cassidy L.M. et al. Millennium-old pathogenic Mendelian mutation discovery for multiple osteochondromas from a Gaelic Medieval graveyard. Eur J Hum Genet 20023;31(2):248–51. DOI: 10.1038/s41431-022-01219-2

9. Bukowska-Olech E., Trzebiatowska W., Czech W. et al. Hereditary multiple exostoses-a review of the molecular background, diagnostics, and potential therapeutic strategies. Front Genet 2021;12:759129. DOI: 10.3389/fgene.2021.759129

10. Jaffe N., Ried H.L., Cohen M. et al. Radiation induced osteochondroma in long-term survivors of childhood cancer. Int J Radiat Oncol Biol Phys 1983;9(5):665–70. DOI: 10.1016/0360-3016(83)90232-8

11. Masino F., Montatore M., Carpentiere R. et al. Hereditary multiple exostoses with a giant osteochondroma degenerated into chondrosarcoma. Radiol Case Rep 2024;19(8):2943–9. DOI: 10.1016/j.radcr.2024.04.012

12. Webber O. Zur Geschichte des Enchondroms namentlich in Bezug auf dessen hereditäres Vorkommen und secundäre Verbreitung in inneren Organen durch Embolie. Virchows Arch Path Anat 1866;35:501–24. (In German). DOI: 10.1007/BF01960750

13. Knight J.D. Sarcomatous change in three brothers with diaphysial aclasis. Br Med J 1960;1(5178):1013–5. DOI: 10.1136/bmj.1.5178.1013

14. Legeai-Mallet L., Munnich A., Maroteaux P. et al. Incomplete penetrance and expressivity skewing in hereditary multiple exostoses. Clin Genet 1997;52(1):12–6. DOI: 10.1111/j.1399-0004.1997.tb02508.x

15. Dahlin D.C., Unni K.K. Bone tumors: General aspects and data on 8,547 cases. 4th edn. Springfield: Charles C. Thomas Pub., 1986.

16. Willms R., Hartwig C.H., Böhm P. et al. Malignant transformation of a multiple cartilaginous exostosis – a case report. Int Orthop 1997;21(2):133–6. DOI: 10.1007/s002640050136

17. Zoccali C., Ferrraresi V., Rossi B. et al. Intermediate grade vertebral osteosarcoma in a patient affected by a sacral chondrosarcoma and hereditary multiple exostosis. Minerva Med 2015;106(2):115–7.

18. Matsuno T., Ichioka Y., Yagi T. et al. Spindle-cell sarcoma in patients who have osteochondromatosis. A report of two cases. J Bone Joint Surg Am 1988;70(1):137–41. DOI: 10.2106/00004623-198870010-00025

19. Marrero Barrera P.A., Marrero Ortiz P.V. Ewing sarcoma superimposed on a previous osteochondroma in multiple osteochondromatosis. Orthopedics 2014;37(4):e403–6. DOI: 10.3928/01477447-20140401-65

20. Wu Q., Xiao B.O., Li L.I., Feng L.I. Atypical teratoid/rhabdoid tumor with hereditary multiple exostoses in an 18-year-old male: a case report. Oncol Lett 2015;10(3):1561–4. DOI: 10.3892/ol.2015.3389

21. Neben K., Werner M., Bernd L. et al. A man with hereditary exostoses and high-grade non-Hodgkin’s lymphoma of the bone. Ann Hematol 2001;80(11):682–4. DOI: 10.1007/s002770100379

22. Sonne-Holm E., Wong C., Sonne-Holm S. Multiple cartilaginous exostoses and development of chondrosarcomas – a systematic review. Dan Med J 2014;61(9):A4895.

23. Fei L., Ngoh C., Porter D.E. Chondrosarcoma transformation in hereditary multiple exostoses: a systematic review and clinical and cost-effectiveness of a proposed screening model. J Bone Oncol 2018;13:114–22.

24. Inubushi T., Lemire I., Irie F. et al. Palovarotene inhibits osteochondroma formation in a mouse model of multiple hereditary exostoses. J Bone Miner Res 2018;33(4):658–66. DOI: 10.1002/jbmr.3341

25. Fusco C., Nardella G., Fischetto R. et al. Mutational spectrum and clinical signatures in 114 families with hereditary multiple osteochondromas: insights into molecular properties of selected exostosin variants. Hum Mol Genet 2019;28(13):2133–42. DOI: 10.1093/hmg/ddz046

26. Ihssan H.H., Kaoutar M., Chaimae L. et al. Hereditary exostosis: an unexpected malignant transformation in a pediatric patient. Radiol Case Rep 2024;20(1):722–6. DOI: 10.1016/j.radcr.2024.10.060

27. Gnoli M., Gambarotti M., Righi A. et al. Secondary peripheral chondrosarcoma in multiple osteochondromas: a retrospective single institution case series. Orphanet J Rare Dis 2024;19(1):63. DOI: 10.1186/s13023-023-03006-8