|Year : 2018 | Volume
| Issue : 3 | Page : 59-64
Unilateral cherubism in a family with a history of bilateral cherubism: Confirmed by SH3BP2 mutation
John J Frazier1, Shyam Kishor Sah2, Ernst J Reichenberger2, Hui Liang3
1 Department of Diagnostic Sciences, Oral and Maxillofacial Radiology, Louisiana State University Health, School of Dentistry, New Orleans, Louisiana, USA
2 Department of Reconstructive Sciences, Center for Regenerative Medicine and Skeletal Development, Institute for Systems Genomics, UconnHealth, Farmington, Connecticut, USA
3 Department of Oral and Maxillofacial Radiology, Texas A & M University College of Dentistry, Dallas, Texas, USA
|Date of Web Publication||1-Feb-2019|
John J Frazier
School of Dentistry, Louisiana State University Health, 1100 Florida Ave., New Orleans 70119, Louisiana
Source of Support: None, Conflict of Interest: None
Cherubism is an autosomal dominant fibro-osseous disease of childhood that is more common in males and is characterized by a painless bilateral expansion of the mandible and/or maxilla. The disease progresses through puberty and then stabilizes or regresses. It has been mapped to chromosome 4p16.3 with a pathogenesis attributed to a mutation of the SH3BP2 gene. Heterozygous cherubism mutations occur either as de novo mutations or are inherited as an autosomal dominant trait. Except for extremely rare cases, cherubism is always bilateral. Treatment is generally “watchful waiting” but surgical intervention may be considered. We present a case of unilateral cherubism in a family with a history of bilateral cherubism. To the best of our knowledge, this is the first documented case of unilateral cherubism with the SH3BP2 mutation.
Keywords: Cherubism, SH3PB2, unilateral
|How to cite this article:|
Frazier JJ, Sah SK, Reichenberger EJ, Liang H. Unilateral cherubism in a family with a history of bilateral cherubism: Confirmed by SH3BP2 mutation. J Oral Maxillofac Radiol 2018;6:59-64
|How to cite this URL:|
Frazier JJ, Sah SK, Reichenberger EJ, Liang H. Unilateral cherubism in a family with a history of bilateral cherubism: Confirmed by SH3BP2 mutation. J Oral Maxillofac Radiol [serial online] 2018 [cited 2019 Feb 15];6:59-64. Available from: http://www.joomr.org/text.asp?2018/6/3/59/251375
| Introduction|| |
Cherubism was first described in 1933 by Jones. The name cherubism is derived from the resemblance of the facial features of affected individuals to the cherubs in baroque art. It is a rare, nonneoplastic, autosomal dominant disease characterized by painless swelling of the jaws in children., Affected individuals generally are normal at birth and begin to manifest the disease between 2 and 5 years of age. Cherubism is characterized by benign fibro-osseous lesions limited to the jaws with and without a family history. In the past, there was the notion that cherubism affects males to greater extent and more often than females (2:1) and has a penetrance in males of 100% and 50%–70% in females;, however, more recent evidence suggests that there is no sex difference. It is possible that cherubism lesions can be missed in some very mild cases when the patient does not have access to modern dental care, but full penetrance is assumed in cherubism patients with mutations in the autosomal dominant cherubism gene SH3BP2. The disease is self-limiting and begins stabilization and regression as the affected child enters puberty and continues into early adulthood. Cherubism is generally an isolated disease but maybe syndromic. Cherubism has been mapped to chromosome 4p16.3 with the affected gene being identified as the SH3-binding protein SH3BP2., Cherubism is almost exclusively described in the literature as affecting the jaws bilaterally.,,,,,,, A search of the databases: PubMed, Scopus, Embase, and Ovid Medline to September 2018 for unilateral cherubism only returned one case by Reade et al., but genetic confirmation for this patient is not available. In this paper, we present a rare case of unilateral cherubism in a family with a history of bilateral cherubism.
| Case Report|| |
An 8-year-old girl was referred to Texas A & M University College of Dentistry with a unilateral swelling of her right face. Clinical examination revealed an expansion of the right posterior mandible. No tenderness was noted. Medical history revealed asthma and a penicillin allergy, most importantly, the paternal grandfather, father, and uncle had documented bilateral cherubism when they were young. An initial panoramic radiograph demonstrated an expansile and multilocular radiolucent lesion of the right ramus distal to the first molar. No appreciable findings were present on the contralateral side [Figure 1]a. On the same day, the patient's 4-year-old brother (sibling II-3) had a panoramic radiograph obtained due to a similar condition which also revealed bilateral multilocular radiolucent lesions in the mandible [Figure 2]a and [Figure 2]b. The girl (II-1) had two other siblings, a younger brother (sibling II-2) and a younger sister (sibling II-4), neither of them had any clinical manifestations of the disease. The panoramic radiographs of the patient's father (I-1) at the age of 37 years, a younger brother (sibling II-2) at the age 8 years, and a younger sister (sibling II-4) at the age of 3 years are presented in [Figure 3]a, [Figure 3]b, [Figure 3]c. The unilateralism of the lesion in this 8-year-old girl was concerning, and other entities were considered. However, given the family history, clinical examination and radiographs were consistent with cherubism that the diagnosis was rendered. The treatment plan was to obtain a cone beam computed tomography (CBCT) for documentation of the extent of the lesion and to reevaluate in 6 months. An oral pathology consultation was in agreement with the diagnosis and treatment plan.
|Figure 1: Panoramic radiographs of the female proband (II-1) at age 8 (a) and 11 years (b) showing significant changes in an expansile multilocular radiolucent lesion of the right posterior mandible. Note the absence of a similar lesion on the contralateral side|
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|Figure 2: Panoramic radiographs of patient's younger brother (sibling II-3) at age 4 (a) and 6 years (b) showing stable, expansile, multilocular radiolucent lesions bilaterally. Note the anterior displacement of the second molars, which is characteristic for cherubism|
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|Figure 3: (a) Panoramic radiograph of the affected father (I-1) showing remnants of resolved bilateral cherubism with remodeling of the mandible and the cystic spaces becoming re-ossified and bilateral displacement of the mandibular canal inferior-posteriorly. (b and c) Panoramic radiographs of the unaffected younger brother at age 8 (sibling II-2) and sister at age 3 (sibling II-4), respectively, showing no radiographic features of cherubism|
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A subsequent CBCT study (iCAT, Hatfield, PA, USA) taken 3 days after the panoramic radiograph to document the extent of the lesion reported a large well-defined multilocular radiolucency of the right mandibular angle and ramus with buccal and lingual cortical expansion and perforation [Figure 4]a, [Figure 4]b, [Figure 4]c, [Figure 4]d. Follow-up in 6 months was recommended to monitor the progress of the lesion. The patient returned 2½s years later with the mother of the patient reporting the lesion had significantly increased in size and was rapidly growing. A follow-up panoramic radiograph demonstrated that the lesion had increased in size significantly with the involvement of the second premolar of the right mandible [Figure 1]b. Based on the size of the lesion, treatment options discussed were observation, surgical shave and sequela, and total resection. At that time, the treatment plan was observation with follow-up. Tissue was submitted for histopathological examination. Histopathology revealed a cellular, vascular stroma with scattered multinucleated giant cells and areas of hemorrhage, findings that are consistent with cherubism [Figure 5]. Due to the rarity of unilateral cherubism and other entities that have similar radiographic and histopathological findings (i.e., central giant cell granuloma), genetic testing for the unilateral case as well as for the father and siblings was conducted.
|Figure 4: Cone beam computed tomography study of (a) axial, (b) sagittal, and (c) coronal views showing an expansile multilocular radiolucent lesion in the right posterior mandible. Note the lack of expansion on the contralateral side. (d) Three-dimensional rendering showing extensive destruction of the mandible and ramus with no disease in the condyle or coronoid process|
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|Figure 5: H and E staining showing (a) multiple scattered, multinucleated giant cells, and hemosiderin deposits and (b) a cellular, vascular, and hemorrhagic stroma characteristic for cherubism|
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The study was approved by the Institutional Review Board of Texas A & M University (IRB #094-CD-EXP) and the Institutional Review Board of the University of Connecticut Health (IRB #03-008). Informed written consent, assent, and HIPPA were obtained from participating family members; and saliva samples were collected using an Oragene DNA self-collection kit (DNA Genotek, Ottawa, Ontario, Canada) including the patient's father and three other siblings. The isolated genomic DNA from saliva was analyzed. Exon 9 of the SH3BP2 gene was amplified by polymerase chain reaction with primers 9F: 5'-CTTGCCGTCCTCACACAGAG-3' and 11R: 5'-TTAGGAACTGTGGAGTCCTG-3', designed with Primer 3 (http://primer3.sourceforge.net). Sequencing on an ABI PRISM 3730 automated sequencer was performed. Electropherograms were visualized by Chromas (Technelysium, South Brisbane, Australia), and resulting sequencing data were compared to GenBank reference sequence NM_003023.4.
Five family members were tested for the SH3BP2 mutation and consisted of the father with a history of bilateral cherubism, the female proband (II-1) with unilateral cherubism, the brother with bilateral cherubism (sibling II-3), the unaffected brother (sibling II-2), and the unaffected sister (sibling II-4). All affected family members had a mutation in exon 9 of SH3BP2, with a proline at position 418 replaced by a threonine (NM_003023.4 (SH3BP2): C.1252C>A; NM_003023.4 (SH3BP2): P. Pro418Thr). The pedigree chart and electropherogram of the mutant sequence are shown in [Figure 6]a and [Figure 6]b.
|Figure 6: (a) Mutations in SH3BP2 (c.1252C>A) were found in affected family members, including the father, the present case of unilateral cherubism, and the affected younger brother (sibling II-3). (b) Mutant sequence (left) and normal sequence (right)|
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| Discussion|| |
Cherubism was first described in 1933 by Jones in three children aged 6, 5, and 4 years old in the same family. These children began around the age of 2 years to develop swellings in the jaws bilaterally that progressed into marked swelling of the maxilla and mandible. On radiographs, the lesions showed multiple cystic spaces that were symmetric bilaterally. Jones observed that the lesions in the oldest child remained stable for the past 2 years and postulated that the disease may be self-limiting. Originally, Jones called the condition “familial multilocular cystic disease of the jaws.” He latter coined the term cherubism as he initially described the fullness in the cheeks and the upward gaze of the eyes revealing white sclera as having a cherubic appearance. Clinically, cherubism begins to appear around the ages of 2–5 years but has been reported to be diagnosed as late as 7–10 years., It is generally a bilateral, symmetric enlargement that usually affects the mandible and maxilla that tends to regress at puberty with remodeling of the jaws into the third decade with the cystic spaces becoming re-ossified and giving a “ground-glass” appearance., With maxillary involvement, the skin of the lower eyelid can be pulled downward revealing the white sclera and giving the patient an “eye-to-the-heavens” appearance. Cervical and submandibular lymphadenopathy is a common finding.,, The World Health Organization states that cherubism is a fibro-osseous disease that affects only the jaws; however, on rare occasion, other extragnathic bones such as the humerus, ribs, femur, metacarpal bones, pelvis, and tibia have been documented.,
Cherubism can be familial or isolated. Meng et al. reviewed 24 cases of cherubism and revealed that 14 of the patients had a positive family history of cherubism. Cherubism has been associated with Noonan syndrome, Ramon syndrome, Fragile X, and neurofibromatosis., Recent advances in the molecular biology of cherubism have substantially increased our understanding of the pathogenesis of the disease. In 1999, Mangion et al. localized the gene to a region on chromosome 4p16.3 in an interval between D4S127 and 4p-telomere., In 2001, Ueki et al. studied 12 families using haplotype and linkage analysis and localized the cherubism locus to a 1.5 megabase region on 4p16 between the markers D4S127 and D4S115. Further sequencing studies located a point mutation on the SH3-binding protein SH3BP2 as the cause of cherubism. Jones believed that the etiology of cherubism was related to the development of the permanent teeth and this may be a correct assumption as signaling pathways involving the SH3BP2 may be involved in osteoblastic and osteoclastic regulation in tooth eruption.,, In a study by de Lange et al., 11 members of a Turkish family with a history of bilateral cherubism had genetic analysis. Five family members had a SH3BP2 point mutation that consisted of an amino acid substitution at position 418 in exon 9 were proline was replaced by threonine (p. P418T c.1513C>A). A male and a female adult participant had the point mutation but did not manifest the disease. The authors concluded that either the disease was subclinical and that clinical signs and symptoms were not revealed or that the disease never presented. Expressivity of cherubic lesions is highly variable, and it is quite possible that bone lesions are missed in patients with a mild progression of cherubism. Once the cystic lesions have filled in with bone in adults, radiographic analysis may fail to detect physical evidence of cherubim. In our presented case, the affected family members (father [I-1], the patient [II-1], and the boy sibling [II-3]) had a mutation in exon 9 of SH3BP2, with a proline at position 418 replaced by a threonine. The unaffected family members (the younger brother sibling II-2 and the younger sister sibling II-4) did not have the mutation in exon 9 of SH3BP2, and they have not had any clinical and radiographic presentation of cherubism at ages 11 and 6.
The classic panoramic radiographic features of cherubism of a bilateral, expansile, symmetric multilocular radiolucency in the ramus and posterior mandible with inferior displacement of the mandibular canal and anterior displacement of the so-called “floating tooth” of the developing second molar are well known., Our patient's sibling II-3 presents the classic panoramic radiographic features of bilateral cherubism [Figure 2]. The regression of the disease was demonstrated by the panoramic radiograph of the patient's father, showing remnants of resolved bilateral cherubism with remodeling of the mandible and the cystic spaces becoming re-ossified and bilateral displacement of the mandibular canal inferior-posteriorly [Figure 3]a. If, however, the radiographs are acquired at a time when one side manifest itself sooner than the other or a true unilateral presentation is present, a diagnosis of cherubism is generally difficult and a radiographic differential diagnosis must be rendered. As in the present case, the radiographic features on the affected side are a classic radiographic presentation for cherubism and if both sides were affected similarly, the diagnosis of cherubism would be made-based solely on the imaging. The differential diagnosis for a multilocular radiolucency of the posterior mandible includes other lesions that are multilocular and/or contain giant cells such as giant cell tumor, central giant cell granuloma, hyperparathyroidism, fibrous dysplasia, ameloblastoma, and cherubism., Although panoramic radiography is generally adequate in establishing a diagnosis in cherubism, multidetector computed tomography, or CBCT scans are now being considered essential to the diagnosis, assessment of extent and damage, progression of disease, and surgical planning.
The typical histopathology of cherubism is one of a cellular, fibrous, vascular stroma with abundant multinucleated giant cells and hemorrhage. The histopathological findings in the present unilateral case fit the criteria for cherubism, and with the clinical and radiographic correlation, strongly suggest the diagnosis. However, these findings are not distinct and can also be seen in giant cell tumor, central giant cell granuloma, brown tumor of hyperparathyroidism, and aneurysmal bone cyst., One histopathological clue in identifying cherubism is identifying perivascular eosinophilic cuffing which is specific for cherubism but is not always present and was found in only 10 of the 20 patients examined by Meng et al., In the absence of eosinophilic cuffing like our case presented here, clinical and radiographic correlation is needed to make a diagnosis. Biochemical analysis is not useful in identifying cherubism as no markers exist. The analysis of alkaline phosphatase, parathyroid hormone, and calcium can be used to differentiate hyperparathyroidism from cherubism, as they are elevated in hyperparathyroidism and normal in cherubism.,
Several different grading systems have been developed by Fordyce, Arnott, Motamedi, and Seward and Hankey that base the grading on the bilateral regions involved and extent of the lesions.,,,,, These systems have been used in some studies but do not appear to be widely adopted. Treatment options for cherubism range from “watchful waiting,” pharmacological treatment, surgery, and radiotherapy. A philosophy espoused by Laskin may be used in deciding on treatment and should be based on knowledge of the biological course of the disease and the clinical behavior of the individual case. A conservative approach is most appropriate until functional or emotional imbalances demand surgical intervention. The surgical treatment of choice is curettage with or without bone grafting. Exacerbation of the disease after surgery has been reported by some authors; however, others suggest that ultimately, it enhances the involution process.,, In extensive lesions of the mandible with pathological fracture risk, mandibulectomy with reconstruction is recommended. Calcitonin, an effective treatment for giant cell granuloma, has been tried with variable degrees of success in cherubism.,, The impact of calcitonin is unclear as some patients were already older and lesions may have regressed spontaneously. Radiation therapy, once a treatment option for cherubism, is now contraindicated because of the risk of osteoradionecrosis, malignant transformation, and osteosarcoma.,,
In the present case, an extremely rare occurrence of unilateral cherubism is seen in an 8-year-old girl with a family history of the disease. The rarity of unilateral cherubism can be assessed as to its documentation in the literature. A search of PubMed until September 27, 2018, for “cherubism” yielded 493 results; a search for “unilateral” and “cherubism” yielded 7 results. Of those 7 results, 5 were not about unilateral cherubism.,,,, Of the remaining 2 search results, one was an initial unilateral presentation that subsequently became bilateral, and the other, published in 1984, was a documented case of unilateral cherubism., A search of other databases: Scopus, Embase, and Ovid Medline for unilateral cherubism returned the same case by Reade et al. In that case, a 16-year-old affected male was presented. The boy had an unaffected sister and a familial history of bilateral cherubism affecting his mother's two brothers and one of the brother's sons. Radiography revealed an expansile multilocular radiolucent lesion in the posterior mandible and ramus. No other jaw abnormalities were detected. A biopsy revealed typical histology consistent with cherubism. The comparison of our patient with that presented in Reade et al., our patient was female, younger, had a more extensive lesion that was not stable, and had one affected sibling and two unaffected siblings. In both cases, cherubism was inherited with all of the other affected individuals being male. Comparing the unilateral cases to the literature on bilateral cherubism, the patients were older at presentation than the average of 2–5 years. The radiographic and histological features are consistent with bilateral cases., Given the scant literature on unilateral cherubism, assessment of is clinical management, biological behavior, and its treatment options cannot be made. The importance of the knowledge that this entity exists is in clinicians considering this in a differential diagnosis when the clinical and radiographic features are those of “classic” cherubism without a bilateral distribution. The differential diagnosis of a unilateral, multilocular radiolucent lesion is extensive and making the correct diagnosis is vital as the treatment options are different.
| Conclusion|| |
Unilateral cherubism is an extremely rare event. Its presentation can prove a diagnostic dilemma to clinicians, radiologists, and pathologists. It should be considered in the differential diagnosis when the classic radiographic and histopathological features of cherubism are present but confined to one quadrant of the jaws. Unilateral cherubism presence in the literature is anemic, and therefore, little can be stated about its biological behavior and clinical management. Here, we present the first documentation of unilateral cherubism that is supported by genetic confirmation with a point mutation in SH3BP3. This finding underscores the role of genetic confirmation as the correct diagnosis affects the management and treatment of unilateral multilocular lesions.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
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Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6]