Problems of Social Hygiene, Public Health and History of MedicineProblems of Social Hygiene, Public Health and History of Medicine0869-866X2412-2106Joint-Stock Company Chicot15910.32687/0869-866X-2019-27-si1-608-622Научная статьяUnique Experience of Cherubism Targeted TherapyKugushevA. Yu.drkugushev@gmail.comLopatinA. V.-YasonovS. A.-Russian Children's Clinical Hospital of Pirogov Russian National Research Medical UniversityRUDN University151220192760862206042021Copyright © 2019,2019The family form of giant cell reparative granuloma or cherubism is a rare benign lesion of the jaws which causes face deformation reminiscent of the cherubs portrayed in Renaissance art. Radical surgery, especially in children before puberty, is impossible or irrational, because it leads to disablement. For four years, a child with cherubism was undergoing an outpatient supervision in the Department of Maxillofacial Surgery in Russian Children Clinical Hospital. During the observation period it was noted that tumor masses were slowly progressing leading to exoorbitism. The child had a diagnosis histological verification; a treatment using human monoclonal antibodies to RANKL was developed, adapted and approved by the ethical committee. The clinical effect was observed from the third month of therapy - jaws corners sharpened, the volume reduced. The control biopsy material taken at the end of the 6-month course did not reveal any giant cells which meant complete pathomorphism. Computed tomography showed that at the end of the therapy bone density increased by 6-7 times in the affected zones and was additionally growing over the next 6 months of observation. Such dynamics allowed making effective contouring surgery of excessive bone tissues. Inoperable and early stages of cherubism require a combined treatment which includes a course of monoclonal antibodies followed by alendronic acid therapy that increases osteoblasts survival. After the treatment, if it is necessary to improve the appearance, contouring surgery of excessive bone tissue is performedgiant cell reparative granulomacherubismdenosumabchildrenalendronic acidbisphosphonatesгигантоклеточная репаративная гранулемахерувизмденозумабдетиалендроновая кислотабисфосфонаты1.Pulse C. L., Moses M. S., Greenman D., Rosenberg S. N., Zegarelli D. J. Cherubism: case reports and literature review. Dent. Today. 2001;20(11):100-3.2.Jaffe H. L. Giant-cell reparative granuloma, traumatic bone cyst, and fibrous (fibro-osseous) dysplasia of the jawbones. Oral Surg. Oral Med. Oral Pathol. 1953;6:159.3.Hershkovitz I., Spigelman M., Sarig R., et al. A possible case of cherubism in a 17th-century Korean mummy. PLoS One. 2014;9(8):e102441. doi: 10.1371/journal.pone.0102441. Pub. 2014 Aug 5.4.Hyckel P., Berndt A., Schleier P., Clement J. H., Beensen V., Peters H., Kosmehl H. Cherubism-new hypothesis on pathogenesis and therapeutic consequences. J. Cranio-Maxillofac. Surg. 2005;33(1):61-8. doi: 10.1016/j.jcms.2004.07.0065.Lo B., Faiyaz-Ul-Haque M., Kennedy S., Aviv R., Tsui L. C., Teebi A. S. Novel mutation in the gene encoding c-Abl-binding protein SH3BP2 causes cherubism. Am. J. Med. Genet. A. 2003;121A(1):37-40. doi: 10.1002/ajmg.a.202266.Meng X. M., Yu S. F., Yu G. Y. Clinico-pathological study of 24 cases of cherubism. Int. J. Oral Maxillofac. Surg. 2005;34(4):350-6. doi: 10.1016/j.ijom.2004.09.0067.Anderson D. E., McClendon J. L. Cherubism-hereditary fibrous dysplasia of the jaws; I genetic considerations. Oral Surg. Oral Med. Oral Pathol. 1962;15 Suppl 2:5-16.8.Tiziani V., Reichenberger E., Buzzo C. L., Niazi S., Fukai N., Stiller M., Peters H., Salzano F. M., Raposo do Amaral C. M., Olsen B. R. The gene for cherubism maps to chromosome 4h16. Am. J. Hum. Genet. 1999;65:158-66.9.Ueki Y., Tiziani V., Santanna C., Fukai N., Maulik C., Garfinkle J., Ninomiya C., doAmaral C., Peters H., Habal M., Rhee-Morris L., Doss J. B., Kreiborg S., Olsen B. R., Reichenberger E. Mutations in the gene encoding c-Abl-binding protein SH3BP2 cause cherubism. Nat. Genet. 2001;28:125-6.10.Lietman S. A., Kalinchinko N., Deng X., Kohanski R., Levine M. A. Identification of a novel mutation of SH3BP2 in cherubism and demonstration that SH3BP2 mutations lead to increased NFAT activation. Hum. Mutat. 2006;27: 717-8. doi: 10.1002/humu.943311.Mehrotra D., Kesarwani A., Nandlal. Cherubism: case report with review of literature. J. Oral Maxillofac. Surg. 2011;10(1):64-70. doi: 10.1007/s12663-010-0164-y12.Wolvius E. B., de Lange J., Smeets E. E., van der Wal K. G., van den Akker H. P. Noonan-like/multiple giant cell lesion syndrome: report of a case and review of the literature. J. Oral Maxillofac. Surg. 2006;64(8):1289-92. doi: 10.1016/j.joms.2006.04.02513.Pérez-Sayáns M., Barros-Angueira F., Suárez-Peñaranda J. É., García-García A. Variable expressivity familial cherubism: woman transmitting cherubism without suffering the disease. Head Face Med. 2013;9:33. doi: 10.1186/1746-160X-9-33. Pub. 2013 Nov 5.14.O’Connell J. E., Bowe C., Murphy C., et al. Aggressive giant cell lesion of the jaws: A review of management options and report of a mandibular lesion treated with denosumab. Oral Surg. Oral Med. Oral Pathol. Oral Radiol. 2015;120:e191.15.Skubitz K. M., Cheng E. Y., Clohisy D. R., et al. Gene expression in giant-cell tumors. J. Lab. Clin. Med. 2004;144:193-200.16.Rutkowski P., Ferrari S., Grimer R. J., Stalley P. D., Dijkstra S. P., Pienkowski A., Vaz G., Wunder J. S., Seeger L. L., Feng A., Roberts Z. J., Bach B. A. Surgical downstaging in an open-label phase II trial of denosumab in patients with giant cell tumor of bone. Ann. Surg. Oncol. 2015 Sep;22(9):2860-8. doi: 10.1245/s10434-015-4634-9. Epub. 2015 Jun 2.17.Branstetter D. G., Nelson S. D., Manivel J. C., et al. Denosumab induces tumor reduction and bone formation in patients with giant-cell tumor of bone. Clin. Cancer Res. 2012;18:4415-24.18.Karras N. A. Denosumab treatment of metastatic giant-cell tumor of bone in a 10-year-old girl. J. Clin. Oncol. 2013 Apr 20;31(12):e200-e202. doi: 10.1200/JCO.2012.46.4255. Pub. online 2013 Mar 18.19.Kobayashi E., Setsu N. Osteosclerosis induced by denosumab. Lancet. 2015 Feb 7;385(9967):539. doi: 10.1016/S0140-6736(14)61338-6. Epub 2014 Oct 28.20.Bredell M., Rordorf T., Kroiss S., Rücker M., Fritz Zweifel D., Rostetter C. Denosumab as a treatment alternative for central giant cell granuloma: A long-term retrospective cohort study. J. Oral Maxillofac. Surg. 2017;1-10. doi: 10.1016/j.joms.2017.09.01321.Balke M., Ahrens H., Streitbuerger A., et al. Treatment options for recurrent giant cell tumors of bone. J. Cancer Res. Clin. Oncol. 2009;135:149-58.22.Raposo-Amaral C. E., de Campos G. M., Warren S. M., Almeida A. B., Amstalden E. M., Tiziane V., Raposo-Amaral C. M. Two-stage surgical treatment of severe cherubism. Ann. Plast. Surg. 2007;58(6):645-51. doi: 10.1097/01.sap.0000248141.36904.1923.Papadaki M. E., Lietman S. A., Levine M. A., Olsen B. R., Kaban L. B., Reichenberger E. J. Cherubism: best clinical practice. Orphanet. J. Rare Dis. 2012;7(Suppl 1):S6-1172-7-S1-S6. Epub 2012 May 24.24.Shah N., Handa K. K., Sharma M. C. Malignant mesenchymal tumor arisingfrom cherubism: a case report. J. Oral Maxillofac. Surg. 2004;62(6):744-9.25.Dukart R. C., et al. Cherubism: report of case. J. Oral Surg. 1974;32(10):782-5.26.Von Wowern N. Cherubism: a 36-year long-term follow-up of 2generations in different families and review of the literature. Oral Surg. Oral Med. Oral Pathol. Oral Radiol. Endod. 2000;90(6):765-72.27.Roginsky V. V., et al. Familial cherubism: the experience of the Moscow Central Institute for Stomatology and Maxillo-Facial Surgery. Int. J. Oral Maxillofac. Surg. 2009;38(3):218-23.28.Koury M. E., Stella J. P., Epker B. N. Vascular transformation in cherubism. Oral Surg. Oral Med. Oral Pathol. 1993;76(1):20-7.29.Lannon D. A., Earley M. J. Cherubism and its charlatans. Br. J. Plast. Surg. 2001;54(8):708-11.30.Harris M. Central giant cell granulomas of the jaws regress with calcitonin therapy. Brit. J. Oral Maxillofac. Surg. 1993;31(2):89-94.31.Southgate J. Study of the cell biology and biochemistry of cherubism. J. Clin. Pathol. 1998;51(11):831-7.32.De Lange J., et al. A new mutation in the SH3BP2 gene showing reducedpenetrance in a family affected with cherubism. Oral Surg. Oral Med. Oral Pathol. Oral Radiol. Endod. 2007;103(3):378-81.33.Kaban L. B., Dodson T. B. Management of giant cell lesions. Int. J. Oral Maxillofac. Surg. 2006;35(11):1074-5, author reply 1076.34.Pogrel M. A. Calcitonin therapy for central giant cell granuloma. J. Oral Maxillofac. Surg. 2003;61(6):649-53, discussion 53-4.35.Kaban L. B. Antiangiogenic therapy of a recurrent giant cell tumor ofthe mandible with interferon alfa-2a. Pediatrics. 1999;103(6 Pt 1):1145-9.36.Thomas D., Henshaw R., Skubitz K., et al. Denosumab in patients with giant-cell tumour of bone: An open-label, phase 2 study. Lancet Oncol. 2010;11:275-80.37.Lipton A., Jacobs I. Denosumab: Benefits of RANK ligand inhibition in cancer patients. Curr. Opin. Support Palliat. Care. 2011;5:258-64.38.Rostetter C., Rordorf T., Essig H., et al. New approach to treatment of giant granula with denosumab. A case example. Swiss Dent. J. 2017;127:520 (in German).39.Tarsitano A., Del Corso G., Pizzigallo A., et al. Aggressive central giant cell granuloma of the mandible treated with conservative surgical enucleation and interferon-alpha-2a: Complete remission with long-term follow-up. J. Oral Maxillofac. Surg. 2015;73:2149.40.Naidu A., Malmquist M. P., Denham C. A., et al. Management of central giant cell granuloma with subcutaneous denosumab therapy. J. Oral. Maxillofac. Surg. 2014;72:2469.41.Schreuder W. H., Coumou A. W., Kessler P. A. et al. Alternative pharmacologic therapy for aggressive central giant cell granuloma: Denosumab. J. Oral Maxillofac. Surg. 2014;72:1301.42.Gupta B., Stanton N., Coleman H., et al. A novel approach to the management of a central giant cell granuloma with denosumab: A case report and review of current treatments. J. Craniomaxillofac. Surg. 2015;43:1127.43.Pham Dang N., Longeac M., Picard M., et al. Central giant cell granuloma in children: Presentation of different therapeutic options. Rev. Stomatol. Chir. Maxillofac. Chir. Orale. 2016;117:142 (in French).44.Skubitz K. M. Giant cell tumor of bone: current treatment options. Curr. Treat. Options Oncol. 2014;15:507.45.Ruggiero S. L., Dodson T. B., Fantasia J., et al. American Association of Oral and Maxillofacial Surgeons position paper on medication-related osteonecrosis of the jaw - 2014 Update. J. Oral. Maxillofac. Surg. 2014;72:1938.46.Saad D., Saad P. Report of a jaw osteonecrosis possibly caused by denosumab. Eur. J. Oral Implantol. 2017;10(2):213-22.47.Panya S., Fliefel R., Probst F., et al: Role of microbiological culture and polymerase chain reaction (PCR) of actinomyces in medication-related osteonecrosis of the jaw (MRONJ). J. Craniomaxillofac. Surg. 2017;45:357.48.Tessaris D., Matarazzo P., Lala R., et al: Odontoiatric perspectives and osteonecrosis of the jaw as a possible adverse effect of bisphosphonates therapy in fibrous dysplasia and McCune-Albright syndrome. J. Pediatr. Endocrinol. Metab. 2016;29:333.49.Demirel F., Esen I., Tunc B., et al. Scarcity despite wealth: Osteopetrorickets. J. Pediatr. Endocrinol. Metab. 2010;23:931-4.50.Mukai T., Ishida S., Ishikawa R., et al. SH3BP2 cherubism mutation potentiates TNF-α-induced osteoclastogenesis via NFATc1 and TNF-α-mediated inflammatory bone loss. J. Bone Miner. Res. 2014;29(12):2618-35. doi: 10.1002/jbmr.229551.Nakagawa T., Ohta K., Kubozono K., Ishida Y., Naruse T., Takechi M., Kamata N. Zoledronate inhibits receptor activator of nuclear factor kappa-B ligand-induced osteoclast differentiation via suppression of expression of nuclear factor of activated T-cell c1 and carbonic anhydrase 2. Arch. Oral Biol. 2015 Apr;60(4):557-65. doi: 10.1016/j.archoralbio.2014.09.012. Epub 2014 Oct 18.