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Cherubism is an inherited, autosomal dominant disorder that characteristically affects the jaws of children. The disease typically manifest as a bilateral swelling with associated submandibular lymph node enlargements and usually regresses as age advances. The disease is microscopically indistinguishable from other giant cell lesions and is essentially a clinical diagnosis. The association of cherubism with gingival fibromatosis, epilepsy, mental retardation, stunted growth, and hypertrichosis is referred as Ramon syndrome. We report a case of Ramon syndrome in an 8 year old girl.
Cherubism is a non-neoplastic, hereditary, jaw disease of the childhood characterized by painless, bilateral symmetrical enlargements [1–5]. The name cherubism was used to describe active and intelligent children with normal interests and social curiosity but their facial profile was characterized by a rounded appearance with an upward gaze . The upward gaze or ‘eyes to heaven’ results from lower lid retraction in relation to the diffuse enlargement of the lower half of the face or to an upward displacement of the eye from a mass involving the orbital floor [1, 6]. Although familial in onset, cherubism may also occur sporadically [2, 3]. Transmission may either be of maternal or paternal in origin, however, the disease manifest early in the former mode of transmission . Usually the disease is diagnosed between 6 and 10 years of age and progresses until puberty, then the lesion demonstrate arrest and often regress, leading to a normal adult appearance in most patients [2–5]. Cherubism have been described in association with other genetic disorders . The association of cherubism with gingival fibromatosis, epilepsy, mental retardation, stunted growth, and hypertrichosis was first described by Ramon et al. , in 1967, and subsequently by Pina-Neto et al. , in 1986, in 4 individuals in a family under the term Ramon syndrome. Two other examples were also reported by Primdore et al. , in 1992. We report a case of Ramon syndrome.
An 8-year old girl was accompanied by her parents for evaluation of a bilateral swelling of the face. Before presentation, she was initially evaluated with a panoramic radiograph and computed tomography (CT) scan at a primary health centre in her native village. The parents became concerned about the swelling only in the recent past and were not aware of the swelling earlier, as they did not think it was an anomaly although they noticed puffiness of her face at 3 years of age. They also reported decrease in the size of the swelling since they first noticed it. History revealed that the patient was suffering from epilepsy from one and half years of age. She was under phenytoin therapy until 6 years of age. Other than epilepsy she was not known to suffer from any other disease. Her family history was not contributory, none of her siblings or other members of the immediate family and relatives were found to suffer from the jaw anomaly or features of other syndromes.
General examination revealed that the patient was hyperactive and often fails to respond to verbal commands. Her IQ level was 65. Palpation showed mobile, painless and enlarged lymph nodes in the submandibular and submental region. No neck webbing was noted. A visual skeletal examination was normal. Pectus excavatum or valvular abnormality was not found. Examination revealed a bilateral swelling of the face extending between the lower border of the mandible and below the inferior orbital margins (Fig. 1a). The swelling was painless. No skin pigmentation or other pathology was evident. Intra orally, gingival hypertrophy without discernible interdental papilla was evident, obscuring the visibility of certain teeth (Fig. 1b and c).
Panoramic radiograph showed a bilateral multilocular radioluceny involving the body, angle and ramus of the mandible and coronoid process. Both the condyles were hypoplastic with altered morphology of the condylar head. Mulilocular lesions were also evident in posterior regions of the right side of maxilla. Third molar tooth germ was absent and second molar tooth germ was mesially rotated on either side (Fig. 2). Occlusal radiograph revealed buccal and lingual expansion in the posterior region of the jaw with interdental bone above the CE junction in the mandibular anterior region (Fig. 3). Axial view of CT scan revealed a multilocular mixed, hypodense and hyper dense areas in the posterior regions of both jaws (Fig. 4).
Serum calcium, phosphorus and alkaline phosphatase were within normal limits. Acid phosphatase showed slight increase. Assay for parathormone and its related hormones were normal. Hematological evaluation was within normal limits. ESR was 20 mm/h.
After exclusion of hyperparathyroidism based on serum chemistry and central giant cell granuloma due to bilateral lesions, cherubism was clinically considered. Microscopic examination of an incisional sample showed spindle cell proliferation in short fascicles and storiform pattern containing scattered multinucleate giant cells (Figs. 5 and and6).6). Hemosiderin pigments were noted. Atypia or mitosis was not identified in the cellular proliferation. Vascularity or hemorrhage was minimal. Perivascular cuffing was evident focally. Immature bone formation with osteoblast lining was noted on the periphery of the section. A diagnosis of giant cell granuloma-like proliferation consistent with cherubism was rendered.
Cherubism in its classic presentation produce a bilateral swelling, widening of alveolar ridge, high arched palate, missing second and third molars, and cervical lymphadenopathy [1, 2, 4]. These features are required for a diagnosis of cherubism in conjunction with its characteristic radiographic features—see below. Other useful signs include teeth malposition, enamel hypoplasia and gingival fibromatosis . Radiologically, cherubism present as a multilocular radiolucency with thinning of the overlying cortex, but as the lesion enlarge, the cysts display a ground-glass appearance and eventually might regress and evolve into normal appearing bone [3, 11]. Routine light microscopic appearance of cherubism is indistinguishable to other conditions showing similar microscopic features [2, 3, 11–13].
The present case was characterized by GF, epilepsy, mental retardation, and cherubism. With regard to cherubism, the present case meets the clinical and radiological characteristics of cherubism though condylar involvement considered to be rare in cherubism was also noted . It is well known that GF is known to be induced by certain drugs like phenytoin, cyclosporine and nifidepine . The use of phenytoin therapy until 6 years of age would appear circumstantial to attribute GF in the present case. However, it is difficult to establish whether GF was an adverse manifestation of phenytoin therapy in view of discontinuation of phenytoin therapy 2 years prior to reporting. In such situations GF would be expected to regress from within 3 months of discontinuation although it may persist in some cases [16–18]. Furthermore, GF may also occur as part of syndromes or conditions unrelated to the use of drugs and its severity peaks during eruption of permanent incisors, sometimes at birth or during eruption of the primary dentition [8, 15, 18, 19]. The onset of GF was not known in the present case. GF is often familial but may lack familial affect in some cases [8, 19].
As evident from the Table 1 , Ramon syndrome is characterized by hypertrichosis, epilepsy, mental retardation and gingival fibromatosis, but other syndromes also share more or less features. However, as mentioned in the Table 1, cherubism occurring as part of other syndromes has not been reported. Thus, the presence of cherubism in combination with the features mentioned distinguish Ramon syndrome from the rest. In the present case, features such as epilepsy, GF, mental retardation in the setting of cherubism may well relate to Ramon syndrome though hypertrichosis was not a feature [8–10]. Review of literature revealed that cherubism have been reported in association with gingival fibromatosis , psychomotor retardation and gingival fibromatosis , neurofibromatosis and multiple non-ossifying fibromas of the femoral bone [25, 26], and Fragile X syndrome . Others have reported diabetes mellitus, vascular skin lesions and ocular abnormalities as part of Ramon syndrome [12, 21, 22]. Interestingly, the combination of epilepsy, mental retardation, hypertrichosis and GF are defined as idiopathic or HGF [8, 18, 19, 28–31]. Other phenotypic expressions like giant cell tumor and osteofibrosis are also known to occur in HGF . In this context and in view of the varied and phased phenotypic expression in the sibs reported by Ramon et al. , it is interesting to speculate whether HGF represents incomplete expression when it did not manifest cherubism and complete expression when cherubism was part of the disease complex. This possibility seems unlikely since the chromosome defect in cherubism (4p16.3) is different from HGF [7, 20]—see Table 1. However, there is also a view that gene dosage effect or alteration in multiple genes may be responsible for the syndromic form of GF . It was also surmised in the past that cherubism occurring as part of syndromes may have different mode of genetic inheritance compared to the classic disease . In the present case, there is no family history for HGF or cherubism. The reported case seems to represent a spontaneous mutation, however, genetic analysis of the patient and her family was not performed and therefore familial history cannot be completely ruled out.
Microscopically, [2, 3] cherubism show a highly vascular fibrous stroma with unevenly distributed osteoclastic-like multinucleated giant cells that tend to cluster near hemorrhagic foci and deposits of hemosiderin. Vascular channels are well formed with large endothelial lining. These histological features are reminiscent of giant cell granuloma [3, 11, 12]. The number of osteoclast-like cells, inflammatory component and cystic structures varies with the stage of the disease . The current case showed less number of multinucleated giant cells and vascularity but hemosiderin pigment was found in abundance in certain fields of the section. The presence of eosinophilic perivascular cuffing, albeit focally, was identified in the present case; this feature is generally considered pathognomonic of cherubism . The stroma was more cellular and showed spindle cell proliferation arranged in a storiform pattern but neither showed pleomorphism nor abnormal mitosis. However, caution should be exercised when highly cellular spindle cell background is encountered in a case of cherubism in view of the possibility of transformation to leiomyosarcoma .
As noted above, there is general consensus that cherubism and central giant cell granuloma share identical microscopic features [2, 12, 34]. However, studies on SH3BP2 gene involvement in central giant cell granuloma have failed to identify germ line mutations in exon 9 as in cherubism though the former lesion found to show sporadic mutation in exon 11 flanking SH3BP2 gene [34–36]. These data indicate that both are distinct entities at least with regard to hereditary affect. Nevertheless, in recent years interesting hypotheses have been drawn in connection with the pathogenesis of cherubism in that mutation of SH3BP2 gene function cause negative regulation of genes associated with odontogenesis, leading to disruption of normal control of odontogenesis manifested by absence of third molar germs and altered development of second molars. Since the PTH/PTHrP gene is downstream of SH3BP2 gene but upstream of tooth developmental genes, mutation of SH3BP2 or PTH/PTHrP cause defects in the normal spatial control of tooth development and dysregulation of mesenchymal bone building tissue areas with the resultant development of giant cell granulomas .
The decision to treat cherubism or not is a subject of controversy [3, 7]. Regression usually follows puberty but in some cases the disease may persist into adulthood [2, 3, 5, 38]. Studies involving long term follow-up of patients with cherubism show contradictory results. In some cases remission of the disease without any treatment was achieved while it may be aggressive in other instance [4, 38]. In view of the reported regression of the size of the swelling as narrated by the patients’ parents, it was decided to observe the patient until therapeutic intervention is required.
In conclusion, we report the 8th case of Ramon syndrome.