Synchronous jawbone diseases: a multicenter retrospective study

Abstract The aim of this study is to report an original case series of synchronous jawbone diseases. Data of patients seen over 13 years were extracted from the files of three Oral Radiology and Pathology diagnostic centers in Brazil. The clinical, radiographic, and laboratory characteristics were tabulated and analyzed by the authors; the patients were described according to lesion type. Seventy-two synchronous jawbone diseases were included in this study. Florid osseous dysplasia, Gorlin-Goltz syndrome, and cherubism were the most frequent disorders reported in this case series. In addition, the posterior mandible area was the main site of manifestation. Florid osseous dysplasia and Gorlin-Goltz syndrome represented two-thirds of our samples. With the utilization of adequate demographic, clinical, and radiologic information, it is possible to diagnose most of the synchronous lesions of jawbones. Sometimes, however, we need complementary exams, such as histopathologic and biochemical analysis or dosing of calcium, phosphorus, and alkaline phosphatase.


Introduction
Two or more lesions are considered synchronous when they affect more than one site at the same time, or have a maximum of six months difference between diagnoses, and are referred to as metachronous when they occur at separate times (excluding the possibility of recurrence or metastasis). 1,2The diagnosis of these disorders can represent a challenge for radiologists due to the uncommon occurrence, heterogeneity, similar radiologic features, and the limited clinical and demographic information available about the patient at the time of imaging. 3Image exams can show a range of bone alterations including osteolytic, sclerotic, or mixed conditions in appearance. 4ynchronous jaw disorders have been rarely described in the literature and limited to the specific lesions.Therefore, we describe a case series of synchronous jawbone diseases (SJBD), emphasizing the importance of correlating the parameters of images with clinical, demographic, and in some cases, with histological and biochemical analysis to achieve the correct diagnosis.

Results
Over 13 years, 120 SJBD cases were identified at the study centers.A total of 48 cases were excluded because they represented inflammatory diseases, resulting in 72 case reports.The clinical and radiographic characteristics of each disorder included are summarized in Table 1.The most frequent diseases were florid cemento-osseous dysplasia (FCOD) (33 cases; 45.8%), Gorlin-Goltz syndrome (GGS) (11 cases; 15.2%), and cherubism (6 cases; 8.3%).The lesions were more prevalent in females, with a male:female ratio of 1:2.The mean age of the patients was 37.6 years (range: 5-84 years).
FCOD was identified in 33 cases, representing 45.8% of all cases.The mean age was 51 years (range: 11-84).This group demonstrated a higher prevalence in female patients, with a male:female ratio of 1:32.The main diagnostic criteria were clinical exam (CE), PR, and CT (21 cases; 63.3%).Under radiographic evaluation, the most common image was well-defined and dense radiopacities surrounded by radiolucent rims was demonstrated (23 cases, 69%).The patients were more affected in two quadrants for this disease (20 cases; 60.6%).The second most prevalent disease was GGS, with 11 cases (15.2%).The mean age was 23 years (range: 8-74).The male:female ratio was 8:3, demonstrating a higher prevalence in male patients.The lesions' diagnostic criteria included CE and PR in all 11 cases, and a clinical exam, PR, and CT in 6 cases (54.5%).The most observed radiographic aspects were well defined, unilocular, radiolucent image (eight cases; 72.7%).The lesion showed mainly two affected quadrants (9 cases; 81.8%) followed by four affected quadrants (3; 27.2%).
Cherubism was found in 6 cases (8.3%).Cherubism did not demonstrate any sex predominance, with a male:female ratio of 1:1 and a mean age of 14.6 years (range: 5-36).The main diagnostic criteria for this lesion were CE and PR (6 cases; 100%).Radiographically, all lesions were presented as multilocular radiolucencies (6 cases; 100%).Four quadrants were affected for this syndrome in 5 cases (83.4%).Brown tumor of hyperparathyroidism (BTH) corresponded to four cases (5.5%).BTH demonstrated a strong predominance for males (4 cases; 100%) at a mean age of 53 years (range: 29-64).CE, RP, CT, laboratory examination (LE), and biopsy were performed for diagnosis in all four cases.The most observed radiographic aspect was multiple radiolucencies (4 cases; 100%).BTH showed two affected quadrants in two cases and three quadrants in two cases.
Multiple myeloma was observed in four cases (5.5%).They were mainly seen in male patients with a mean age of 65 years old (range 54-84 years old).Diagnostic criteria was based on CE, PR, CT and biopsy in all cases.Radiographic aspects showed radiolucent multilocular lesions in all analyzed patients.MM evidenced four affected quadrants in four cases and two quadrants in two cases.Simple bone cyst (SBC) were found in three cases (4.1%).SBC was observed mainly in male patients (2 cases; 66.6%) and in one case, the sex was not reported; the mean age was 15 years (range: 13-19).In two cases, the diagnostic criteria were CE, PR, and CT (66.6%).The radiographic aspect was mainly a well-defined, Dentigerous cysts (DC) were seen in 2 cases (2.7%), both being male at a mean age of 8.5 years (range: 5-12).Radiographically, all cases presented were welldefined, unilocular, radiolucent images associated with the crowns of an unerupted permanent tooth, and the diagnostic criteria were CE and PR (two cases; 100%).The two cases had two affected quadrants.Langerhans cell histiocytosis (LCH) corresponded to 2 cases (2.7) in males at a mean age of 14.5 years (range: 11-18).Under the main diagnostic criteria, CE, PR, and biopsy were performed in both cases (100%) and both cases presented an ill-defined, radiolucent image, and had four affected quadrants.
Paget's disease (PD) were found in 2 cases (2.7%, one man, one woman, at a mean age of 49 years [range: 48-58]).The main diagnostic criteria were CE, PR, CT, and LC.When radiographically evaluated, all lesions showed cotton wool-like radiopacity.One case presented four affected quadrants, and the other case presented two quadrants that were affected.Gardner syndrome (GS) occurred in 2 cases in women (2.7%) at mean age 15.5 years (range: 13-18).In 1 case, the diagnostic criteria were CE and PR, and in the other, the criteria were CE, PR, and CT.Radiographically, the images presented well-defined, unilocular, and dense radiopacities in one of the cases and an illdefined, multilocular, radiolucent image in the other.Considering the affected quadrants, 1 case presented four affected quadrants (50%) and 1 case presented 2 affected quadrants (50%).
Central ossifying fibroma (OF) represented 1.38% (one case) of our sample: a 21-year-old woman, who underwent CE, PR, CT, LE, and biopsy.The radiographic aspect was a well-defined, unilocular,

Discussion
To the best of our knowledge, this is the first case series study with different types of synchronic jawbone diseases.It is well known that the diagnosis of SJBD must follow a holistic approach that combines demographic, biochemical, clinical, and radiologic information.The method proposed by us is to focus on image features with the other necessary data to complete the diagnosis of each disease shown in Table 2.
According to our study, the most prevalent SJBD was FCOD, representing almost 50% of all cases.This condition occurs above the inferior alveolar canal, surrounding the root apices or in edentulous areas. 5The process is confined to an alveolar process, including interdental and interradicular septa.Subsequently, the newly formed bone spreads to the periodontal space without compromising pulp vitality and radicular reabsorption or changes in dental position (Figure 1A). 6FCOD has a symmetrical pattern, affecting at least two and, in many cases, even four quadrants.In the early immature osteolytic stage, the radiographic features are entirely radiolucent with a round or ovoid configuration, mimicking an inflammatory periapical lesion.The intermediate stage is characterized by a mixed radiolucent and radiopaque appearance (cotton wool appearance).In the final stage, the lesion becomes a densely mineralized mass (radiopaque), usually with a radiolucent rim. 7When an SBC is associated with FOCD, multilocular radiolucency can be detected and may result in an expanded or perforated cortical bone, as seen in three cases in the present series. 5he FOCD diagnosis can be achieved by PR. 8 CT and cone-beam computed tomography (CBCT) should be performed in lesions in the maxilla due to the greater difficulty of diagnosis.Kato et al. 9 showed that on CT examination, FOCDs can present with the cortical bone intact, slight thinning, expansion, and is less frequently perforated.In addition, the mandible is always involved, especially in posterior areas, as observed in this study.
The OF image has an oval shape, generally unilocular, with corticated margins and without root resorption, and according to the degree of calcification, completely radiolucent or as mixed images (Figure 1B). 10 Expansion without perforation of cortical bone and displacement of teeth are associated with larger lesions. 11Synchronous OF tends to occur in the mandible and maxilla, with one lesion in each area.Simultaneous lesions in the mandible, as seen in our work, are unusual.It is noteworthy that synchronous OF can be a manifestation of hyperparathyroidism. 12 PD presents, in general, in polyostotic form involving many skeletal bones, with jawbones being involved in 15% of cases (Figure 2A-C). 13The upper jaw is more affected than the lower jaw.In the early phase (osteolytic phase), radiolucent areas predominate (ground glass appearance), leading to the loss of the lamina dura when the lesion involves migration and resorption of the roots of teeth.In the osteoblastic phase, the radiopacity spreads in most of the areas, leading to the enlargement of the jaws, with alveolar ridges become widened (cotton wool appearance).The focal loss of lamina dura and hypercementosis allows the differentiation of PD from hyperparathyroidism. 14 Bone scintigraphy (Figure 2D-H) is recommended to delineate the alteration of mandible bone (Lincoln`s sign). 13steopetrosis is an inherited metabolic bone disorder with a clinical spectrum ranging from mild to severe that shows uniform and generalized sclerosis of the skeleton due to a failure in bone resorption (impaired osteoclast activity or development).Parallel bands of dense bone in the vertebrae and long bones give the impression of 'bone-withinbone'.The condition causes obliteration of medullary spaces, especially in long bones, skull (macrocephaly, frontal bossing), and spine, with increased bony trabeculae and thickened cortices (Figure 3D). 15

Teens and those in their 20s
No sex predilection. None.
None.The condition in jawbones leads to micrognathia.Another important sign seen in our cases was a thickening of the lamina dura as an early sign and an alteration in the medullar bone, which masks the roots. 16Delayed tooth eruption, tooth agenesis, enamel hypoplasia, and osteomyelitis of the jaws after surgical procedure are common findings. 17ultiple odontogenic keratocysts (MOK) are one of the main clinical features of nevoid basalcell carcinoma syndrome (NBCCS) or GGS.MOK occurs in 75% to 90% of patients with NBCCS.The most common radiographic characteristics are multiple well-defined, unilocular radiolucencies, and the lower jaw is more affected than the upper jaw (Figure 1C). 3,18Abnormalities in vertebrae (fused or bifid) and ribs (fused, bifid, splayed, or missing) can be found, and calcification of falx cerebri is pathognomonic (Figure 3A).Also, there is frontal and temporoparietal bossing, prominent supra-orbital ridges, and increased occipitofrontal circumference (Figures 3B, 3C).It is noteworthy that the syndrome is associated with benign neoplasia and other comorbidities.For this reason, it is vital to establish an early diagnosis, for which it is important to keep in mind that MOKs represent the first sign of the syndrome in 75% of patients. 19y definition, DC is always associated with the crown of an unerupted permanent tooth at the cementoenamel junction, and almost all cases of synchronous DC described are associated with third  molars. 20Radiographically, DC shows a unilocular radiolucent lesion of corticated borders of more than 5 mm.Synchronous DCs are rare, often associated with cleidocranial dysplasia, basal cell nevus syndrome, or type IV mucopolysaccharidosis. 21,22In general, DCs are diagnosed in routine radiographic examination or while investigating an asymptomatic swelling.A pathological exam is fundamental for the correct diagnosis, because other cysts, like keratocysts, can mimic the image appearance of DC.MRI provides correct detail on the lesion contents helping in the identification of cyst fluid, with hypodense image on T1 and hyperdense on T2-weighted images. 22he face of children affected by cherubism resembles that of cherubs from the Renaissance due to expansion of the cortical bone and consequent swelling of the cheek.Although there are reports of a unilateral manifestation, these cases are not fully accepted as cherubism by the entire scientific community. 23Under radiographic evaluation, the images have a radiolucent, multilocular aspect and well-defined borders (soap bubble appearance) located in the posterior regions of the mandible more often than the maxilla.The anterior regions and the adjacent bones can also be affected in the most severe cases of the disease.Bone alterations start in the angle and ascending ramus, expanding from to the mandibular body.Complete obliteration of the sinus is expected in more aggressive cases, and involvement of the orbital cavity can occur (Figure 4A-B).In the mandible, the body, corpus, and angle are affected, with preservation of condylar regions. 24Tooth displacement, root resorption, or agenesis are common features.Tooth agenesis is associated with more advanced disease. 23,25CT is the gold standard for evaluating bone lesions of the jaws (Figure 4C-D).In our sample, the condition had an equal prevalence in men and women, and the four quadrants were equally affected.
BTH represents the third most common endocrine disorder after diabetes mellitus and thyroid disease. 26Radiographically, the condition presents as a multiple hypodense image or as a multiple well-defined, uni or multilocular radiolucency resembling soap bubbles, with the cortical bone expanded (ground-glass appearance) (Figure 1D). 27ntreated secondary hyperparathyroidism can  progress to renal osteodystrophy (RO), which can cause alterations in jawbones in the form of renal osteitis fibrosa (OFi).RO is present in 90% of patients undergoing dialysis. 28In PR, OFi shows a diffuse ill-defined ground glass appearance with poor corticomedullary distinction and expansion of the cortical bone (Figure 5).The early radiographic appearance of jawbone involvement in OFi are thinning of the cortices and loss of the lamina dura. 29oot reabsorption and obliteration of the inferior alveolar canal are commonly found. 30BC can occur in association with FOCD, and SBC can manifest synchronously in jawbones.An et al. 31 and Chrcanovic and Gomez 32 , in a systematic review on synchronous SBC, showed that most lesions were located in the posterior mandibular region (mandibular body) and had been diagnosed in routine radiographic analysis (asymptomatic lesions).Interradicular scalloping is a characteristic.In addition, the authors determined that the most usual radiographic appearance in multifocal SBC was a unilocular shape with well-demarcated borders.The expansion of bone without perforation is more frequent in synchronous lesions than in solitary disease. 32Moreover, root resorption and the absence of lamina dura can occur.33 Langerhans cell histiocytosis (LCH) is a disorder characterized by abnormal proliferation of bone marrow-derived histiocytes. Th condition can present focal or systemic manifestations.In jawbones, LCH manifests as solitary or multiple radiolucent circumscribed lesions affecting the alveolar or cortical bone, causing the appearance of floating teeth with disease evaluation.The overlying mucosa is ulcerated,  with gingival inflammation.Bleeding, necrosis, recession, dental mobility, and premature loss of teeth are common occurrences.In many cases, the diagnosis is established through oral lesions.34 A significant number of synchronous lesions in association or not with syndromes are described in the literature.Aristizabal Arboleda and collaborators 35 published a case of a 15-year-old female patient who was diagnosed with a calcifying odontogenic cyst associated with dentigerous cyst in the right maxillary sinus.In addition, Só et al. 36 reported a case series of synchronous calcifying epithelial odontogenic tumor of the mandible and maxilla.Moreover, Shao and colleagues 37 also reported the occurrence of odontogenic myxoma with multiple keratocyst odontogenic in the nevoid basal cell carcinoma syndrome.Interestingly, the presence of synchronous lesions with different histological types were not found in our study.
In conclusion, FOCD, GGS, cherubism, and BTH were the most frequent disorders associated with synchronous jaw lesions in this case series.Also, t he poster ior ma ndible a rea was t he main site of manifestation.The utilization of adequate demographic, clinical, and radiologic information allows the appropriate diagnosis of most synchronous jawbone lesions.Sometimes, however, we also need a histopathology exam and biochemical analysis of calcium, phosphorus, and alkaline phosphatase.

Figure 1 .Figure 2 .
Figure 1.(A) Panoramic radiograph of two ossifying fibromas.Well-delimited unilocular, primarily radiolucent lesion containing diffuse calcifications can be seen bilaterally in the mandibular body and downward bowing of the inferior cortex of the mandible on the right side.(B) Mixed density lesions (arrows) consistent with florid osseous dysplasia.Note that the epicenter of the mandibular lesions is above the inferior alveolar canal.(C) Radiographic findings observed in a patient diagnosed as Gorlin-Goltz syndrome demonstrating multiple well-defined radiolucent images in the posterior areas of the maxilla and mandible (white arrows), and a pathological mandibular fracture was also observed (yellow arrow).(D) Well-defined, radiolucent images (green arrows) extending from the roots of teeth 18-20 and the roots of teeth 30-31, diagnosed as brown tumor of hyperparathyroidism secondary to chronic kidney disease.

Figure 3 .
Figure 3. Patient with Paget disease.(A) Sagittal and (B) coronal CT images reveal widening and osteosclerosis involving skull and jaws bones.Complete obliteration of frontal, maxillary, and sphenoid sinuses, and also involving middle nasal turbinates.(B) Bilateral lytic areas involving the mandibular bone (yellow arrows).(C) 3D CT volume rendering characterized by areas of bone expansion and distortion, which leads to deformities.(D-H) Total body bone scintigraphy with 99mTc showing increased activity and uptake of the radiotracer detected in the skullcap (E), thoracic and lumbar spine (D-E), in the left pelvis (D-E), and femur bones (G-H).Skull (F) and femur in detail are shown (G-H).

Figure 4 .
Figure 4. CT findings observed in a patient diagnosed as cherubism.Sagittal (A) and coronal (B) images showing multiple bilateral osteolytic lesions located in both jaws and infiltration of the orbital cavities.Partial obliteration of left maxillary sinus.Tomographic changes during the case: at the beginning (C) the lesions are hypodense and later (D), appeared more mineralized.Axial CT image showing significant bilateral distension of the mandibular body (C and D).

Figure 5 .
Figure 5. Alteration caused by osteitis fibrosa/renal osteodystrophy.(A) Sagittal CT shows poorly delimitated hyperdense lesion, with a 'ground-glass' appearance in both jaws, sphenoid, frontal, and occipital bones, displaying overgrowth of the maxillary and mandibular bone.The distinct overgrowth of the maxillary bone was profoundly affected by diffuse bone abnormalities (B) which could be illustrated with 3D reconstruction.Other facial and cranial bones were affected.(C) T2 coronal magnetic resonance image demonstrating variable-intensity signals, especially high-intensity signals, in both jaws and maxillary sinus, which was a consequence of the heterogeneous nature of lesions.(D) 3D CT volume rendering depicting leontiasis ossea patient appearance.(E-F) Microscopic aspect of osteitis fibrosa/renal osteodystrophy showing a dense cellular lesion consisting of mesenchymal and multinucleated giant cells, with erythrocytes extravasation (H&E, 50X and 100X).

Table 1 .
Clinicopathological and radiographic characteristics of the synchronous jaw lesions analyzed in the present study.n(%) image, and two mandibular quadrants were affected.Osteitis fibrosa cystica (OFC) was found in one case (1.38%), a 27-years-old man.Radiographs showed multiple radiolucencies and the diagnostic criteria were CE, PR, CT, LE, and biopsy; four quadrants were affected.Idiopathic osteosclerosis was observed in one case (1.38%) in a 74-year-old male patient.PR showed a generalized irregular radiopacity.Diagnosis was based on CE and PR, and lesion affected four quadrants of the patient.

Table 2 .
Definitions, etiology, clinical features, and biochemical analysis of the synchronous jawbone lesions.