True Unilateral Mandibular Cherubism: A Literature Review and Case Report

Journal Pre-proof True Unilateral Mandibular Cherubism: A Literature Review and Case Report Darin T. Johnston, DDS, J.W. Hudson, DDS, Nathaniel G. Wells, DMD, Jason D. Pickup, DMD PII:




YJOMS 58905

To appear in:

Journal of Oral and Maxillofacial Surgery

Received Date: 2 April 2019 Revised Date:

28 August 2019

Accepted Date: 30 August 2019

Please cite this article as: Johnston DT, Hudson JW, Wells NG, Pickup JD, True Unilateral Mandibular Cherubism: A Literature Review and Case Report, Journal of Oral and Maxillofacial Surgery (2019), doi: This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Published by Elsevier Inc on behalf of the American Association of Oral and Maxillofacial Surgeons

True Unilateral Mandibular Cherubism: A Literature Review and Case Report Darin T. Johnston, DDSa J.W. Hudson, DDSb Nathaniel G. Wells, DMDc Jason D. Pickup, DMDc a

Resident, Department of Oral and Maxillofacial Surgery, University of Tennessee Medical Center, 1930 Alcoa Highway, Knoxville, Tennessee, USA 37920 b

Professor, Department of Oral and Maxillofacial Surgery, University of Tennessee Medical Center, 1930 Alcoa Highway, Knoxville, Tennessee, USA 37920


Former Resident, Department of Oral and Maxillofacial Surgery, University of Tennessee Medical Center, 1930 Alcoa Highway, Knoxville, Tennessee, USA 37920

Corresponding Author: Dr. J.W. Hudson Department of Oral and Maxillofacial Surgery, University of Tennessee Medical Center, 1930 Alcoa Highway, Knoxville, Tennessee, USA 37920 Telephone: (865) 305-9022 Facsimile: (865) 305-9026 Email: [email protected]

True Unilateral Mandibular Cherubism: A Literature Review and Case Report Darin T. Johnston DDS J.W. Hudson DDS Nathaniel G. Wells DMD Jason D. Pickup DMD

Introduction Cherubism is a self-limiting fibro-osseous disorder that is classically characterized by bilateral mandibular swelling in the first or second decade. Three cases of unilateral cherubism have been described in the literature; however, only one case did not eventually develop bilateral involvement. Histopathologic variation and genetic heterogeneity complicate the diagnosis and treatment of a unilateral benign giant cell lesion of the jaws. This case report presents a 13-year-old male with unilateral posterior mandibular swelling that proved to be histologically and clinically consistent with unilateral cherubism. Involution of the unilateral lesion with no bilateral involvement occurred during eight years of serial examination.

Background Cherubism is a self-limiting fibro-osseous disorder that manifests in the first or second decade. It is typically bilateral and can present in the bimaxillary dental arches and zygoma, most commonly in the posterior mandible causing painless expansion and dental eruption abnormalities.1-3 With few reported exceptions, the condyles are always spared.2-4 Occasionally, the bony expansion can result in significant mandibular, maxillary, and periorbital orbital swelling resulting in mandibular protrusion, airway obstruction, and vision changes that can result in functional deficits and psychosocial disruption.1, 4-6 The spectrum of dental abnormalities includes tooth displacement, oligodontia, failed eruption, and root resorption. Reactive hyperplasia and fibrosis of submandibular lymph nodes is not an uncommon finding.4, 7 The disease course, divided into four stages, in generally accepted and well summarized by Holley et al.8 Between the second and third decade the lesions spontaneously regress resulting in near normal bony contours by the fourth decade.2-4, 7 Radiologic evaluation with orthopantomograms and computed tomography demonstrates well circumscribed multilocular radiolucent lesions.9 There is expansion with cortical perforation.1, 3-5, 7, 8 A grading system for location and severity of cherubism was suggested over 5 decades ago, followed by multiple modifications. Grade 1 classification involves only the mandible and has the best chance for spontaneous regression, especially in the posterior mandible. Grade 2 classification presents with full mandibular involvement and only bilateral maxillary tuberosity involvement. Grade 3 is a diffuse involvement of the bimaxillary skeleton.10

Considerable controversy has persisted for greater than four decades regarding the histologic distinguishability of cherubism from other giant cell lesions.10 Some have postulated that cherubism is histologically identical to a central giant cell lesion.2, 3 Others argue that eosinophilic perivascular collagen cuffing is specific for cherubism.5, 11 This histological finding, when evaluated, appears to occur in 50% of cherubism cases.4 The disease is autosomal dominant.2, 12 Penetrance is variable with females demonstrating 50-75% and males with nearly 100%.3 There are reports of less than 100% penetrance in males.4, 12 In many cases, cherubism is due to a genetic defect resulting from a mutation of the SH3BP2 gene from chromosome 4p16.3.13, 14 The genetic pathogenesis remains poorly understood, but is thought to involve parathyroid hormone receptor signaling and overexpression of Msx-1 that ultimately interrupts tooth bud development and interferes with jaw morphogenesis. This theory appears to explain the spatial and temporal development and eventual resolution of the disease.15 Genetic heterogeneity does exist as reported by Ueki et al., where 3 of 15 families with cherubism had no mutations in SH3BP2.14 Cherubism has also been found in combination with other genetic disorders including Noonan syndrome, Ramon syndrome, and Fragile X syndrome.16 Three cases of unilateral cherubism have been described in the literature.8, 10, 17 In 1978 Arnott reported a case of a 9-year-old boy who presented with unilateral cherubism in the right mandibular angle, yet subsequently developed bilateral disease within six months.10 Similarly, Holley reported a case of a 5-year-old boy who presented with unilateral cherubism in the left posterior mandibular body who likewise developed bilateral disease within 18 months.8 Only one case of unilateral cherubism that

spontaneously regressed without bilateral development has been reported. In 1984 Read reported a 16-year-old boy with left mandibular angle cherubism. The unilateral lesion resolved three years later.17 A differential diagnosis of a multilocular lytic lesion of midface and/or mandibular bones includes giant cell lesion of bone, odontogenic keratocyst, ameloblastoma, central giant cell granuloma, fibrous dysplasia, aneurysmal bone cyst, brown tumor of hyperparathyroidism, and cherubism. We present a case of unilateral cherubism.

Case Report A 13-year-old boy was referred to our clinic with a two year history of painless, left posterior mandibular swelling. The swelling was not associated with any regional dental or soft tissue pathology. The patient had a full complement of teeth except for an impacted left mandibular second molar and a congenitally missing lower left third molar. The patient and his family denied prior trauma to the area. The patient was living with his two siblings and their adoptive parents. Neither the patient nor the adoptive parents described any prior facial swelling or jaw deformity of the right posterior mandible. The two siblings had no history of jaw problems. Maxillofacial computed tomography and orthopantomograms (figures 1, 2A-B, 5A) showed a large multilocular mixed cystic-solid mass in the left mandibular ramus, which was associated with an impacted second molar on the left side. The lesion involved the majority of the left mandibular ramus and a portion of the left mandibular body. The condyle was spared. There was cortical disruption with no definite extra osseous soft tissue component. Possible differential

diagnoses included: ameloblastoma, dentigerous cyst, odontogenic keratocyst, fibrous dysplasia, browns tumor of hyperparathyroidism, and aneurysmal bone cyst. Laboratory findings were unremarkable, including normal parathyroid hormone and serum calcium. Two years prior to being referred to our clinic an outside provider performed an incisional biopsy of the left posterior mandible that demonstrated a benign giant cell lesion with the unique feature of perivascular cuffing (figures 3A-B). The slides were obtained and reviewed by a second oral-maxillofacial pathologist at our institution who offered a similar description, and likewise concluded the histopathologic features were highly suggestive of cherubism. Shortly after the patient’s first visit in our clinic, a second biopsy was performed of the left posterior mandible along with surgical removal of the impacted left mandibular second molar. The final diagnosis of the specimen was benign giant cell lesion of bone consistent with cherubism. The histologic finding of eosinophilic perivascular cuffing was again noted. The patient was referred for genetic testing which demonstrated no mutation in the SH3BP2 gene, a finding consistent with the established genetic heterogeneity of cherubism. During the eight year follow up period serial orthopantomograms and computed tomography scans were obtained that demonstrated involution of the unilateral lesion and no development of bilateral disease (figures 4, 5A-C).

Discussion Cherubism manifests in the first or second decades with facial swelling resulting from expansile lytic lesions of the facial bones. It almost always presents bilaterally,

however unilateral cherubism has been reported. The disease progress is believed to pass through four distinct stages. Histopathologically, it is generally indistinguishable from other giant cell lesions. However, a significant exception is the presence of perivascular eosinophilic cuffing, a feature unique to cherubism. Unfortunately, this finding is not consistently observed, perhaps due to microscopic changes as the disease progresses. This potentially confounding heterogeneity extends to the realm of genetics. While the SH3BP2 gene has been linked to cherubism, the genetic analysis of the autosomal dominant disease does not always reveal an SH3BP2 mutation. Specifically, 80% of patients with cherubism have a mutation in the SH3BP2 gene and 20% do not.14 Stated differently, 1 in 5 individuals with cherubism do not have an identifiable genetic mutation. Theoretically, a perfect storm could occur if a child presented with unilateral facial swelling related to an expansile osteolytic mass, an unremarkable or unavailable family history, and no mutation in the SH3BP2 gene. It would be very challenging to navigate the differential diagnosis and determine which, if any, medical/surgical intervention should be recommended. If present, perivascular cuffing may allow the surgeon to render a definitive, albeit rare, diagnosis of unilateral cherubism. This is important because the treatment modalities for other giant cell lesions differ significantly.18, 19 Initial surgical treatment for cherubism is generally limited to removal of impacted teeth affected by the lesion. Recontouring or debulking is reserved for the salvage of sight or psychosocial circumstances. Medical treatment modalities have been utilized over the years for treatment of giant cell lesions including the use of calcitonin,

interferon therapy, and RANK-L inhibition.20, 21 Radiotherapy was abandoned many years ago due to poor outcomes including midface and mandibular hypoplasia, soft palate incompetence, and fibrosarcoma.2

Conclusion Unilateral facial swelling resulting from an expansile osteolytic giant cell lesion in a child presents a unique challenge to the diagnostician due to the heterogeneity of histologic and genetic features. While extremely rare, unilateral cherubism must be included in the differential diagnosis. Automatic exclusion may lead the clinician to recommend ineffective or inappropriate treatment. It is possible to diagnose unilateral cherubism if a logical algorithm is employed. The above case of unilateral cherubism has been followed for eight years with involution of the lesion and no development of bilateral disease.

References 1. Roginsky VV, Ivanov AL, Ovtchinnikov IA, Khonsari RH: Familial cherubism: the experience of the Moscow Central Institute for Stomatology and Maxillo-Facial Surgery. Int J Oral Maxillofac Surg 38:218, 2009 2. Peters WJN: Cherubism: A study of twenty cases from one family. Oral Surgery, Oral Medicine, Oral Pathology and Oral Radiology 47:307, 1979 3. Penarrocha M, Bonet J, Minguez JM, Bagan JV, Vera F, Minguez I: Cherubism: a clinical, radiographic, and histopathologic comparison of 7 cases. J Oral Maxillofac Surg 64:924, 2006 4. Meng XM, Yu SF, Yu GY: Clinicopathologic study of 24 cases of cherubism. Int J Oral Maxillofac Surg 34:350, 2005 5. Papadaki ME, Lietman SA, Levine MA, Olsen BR, Kaban LB, Reichenberger EJ: Cherubism: best clinical practice. Orphanet J Rare Dis 7 Suppl 1:S6, 2012 6. Lannon DA, Earley MJ: Cherubism and its charlatans. Br J Plast Surg 54:708, 2001 7. Tsodoulos S, Ilia A, Antoniades K, Angelopoulos C: Cherubism: a case report of a three-generation inheritance and literature review. J Oral Maxillofac Surg 72:405 e1, 2014 8. Holley TJ, Giannini PJ, Narayana N, Desa VP: Early detection of cherubism with eventual bilateral progression: a literature review and case report. Oral Surg Oral Med Oral Pathol Oral Radiol, 2018 9. Jones WA: Familial Multilocular Cystic Disease of the Jaws. 17:946, 1933 10. Arnott DG: Cherubism--an initial unilateral presentation. Br J Oral Surg 16:38, 1978 11. Hamner JE, 3rd: The demonstration of perivascular collagen deposition IN CHERUBISM. Oral Surg Oral Med Oral Pathol 27:129, 1969 12. de Lange J, van Maarle MC, van den Akker HP, Redeker EJ: A new mutation in the SH3BP2 gene showing reduced penetrance in a family affected with cherubism. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 103:378, 2007 13. Mangion J, Rahman N, Edkins S, Barfoot R, Nguyen T, Sigurdsson A, Townend JV, Fitzpatrick DR, Flanagan AM, Stratton MR: The gene for cherubism maps to chromosome 4p16.3. Am J Hum Genet 65:151, 1999 14. Ueki Y, Tiziani V, Santanna C, Fukai N, Maulik C, Garfinkle J, Ninomiya C, doAmaral C, Peters H, Habal M, Rhee-Morris L, Doss JB, Kreiborg S, Olsen BR, Reichenberger E: Mutations in the gene encoding c-Abl-binding protein SH3BP2 cause cherubism. Nat Genet 28:125, 2001 15. Hyckel P, Berndt A, Schleier P, Clement JH, Beensen V, Peters H, Kosmehl H: Cherubism - new hypotheses on pathogenesis and therapeutic consequences. J Craniomaxillofac Surg 33:61, 2005 16. van Capelle CI, Hogeman PH, van der Sijs-Bos CJ, Heggelman BG, Idowu B, Slootweg PJ, Wittkampf AR, Flanagan AM: Neurofibromatosis presenting with a cherubism phenotype. Eur J Pediatr 166:905, 2007

17. Reade PC, McKellar GM, Radden BG: Unilateral mandibular cherubism: brief review and case report. Br J Oral Maxillofac Surg 22:189, 1984 18. de Lange J, van den Akker HP, van den Berg H: Central giant cell granuloma of the jaw: a review of the literature with emphasis on therapy options. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 104:603, 2007 19. Odell EW: Cawon's Essentials of Oral Pathology and Oral Medicine. (ed. 9). Elsevier, 2017 20. de Lange J, van den Akker HP, Scholtemeijer M: Cherubism treated with calcitonin: report of a case. J Oral Maxillofac Surg 65:1665, 2007 21. Schreuder WH, Coumou AW, Kessler PA, de Lange J: Alternative pharmacologic therapy for aggressive central giant cell granuloma: denosumab. J Oral Maxillofac Surg 72:1301, 2014

Figure Legend: Figure 1: Computerized tomography 3-D reformats showing obvious lytic lesion left posterior mandible. Initial presentation. Figure 2: Computerized tomography at initial presentation showing unilateral multilocular lytic lesion of the left mandibular body and ramus. The right mandible is unaffected with inferior alveolar nerve (dashed arrow). A, axial cut with impacted left mandibular second molar and impacted right mandibular third molar. B, coronal cut demonstrating spared left mandibular condyle. Figure 3: Histopathologic examination with hematoxylin and eosin (H&E) stain; magnification 200x. A, scattered giant cells. B, hyalinized angiopathy or perivascular cuffing (arrows). Figure 4: Computerized tomography eight years later showing involution of the unilateral lytic lesion of the left mandibular body and ramus (solid arrows). The right mandible remains unaffected. The right inferior alveolar canal is visible (dashed arrow). Figure 5: Serial orthopantomograms with arrows outlining the extension and eventual involution of the left mandible lesion. A, initial presentation. B, three year follow up with interval extraction of teeth #1, 16, 18,32. C, 8 year follow up with obvious involution and no contralateral involvement.