Cherubism Combined with Epilepsy, Mental Retardation and Gingival Fibromatosis (Ramon

Syndrome): A Case Report

J. Suhanya,1 Chakshu Aggarwal,2 Khadijah Mohideen,2 S. Jayachandran,1 and I. Ponniah 2
1
Department of Oral Medicine and Radiology, Tamil Nadu Government Dental College and
Hospital, Chennai, 600 003 India
2
Department of Oral and Maxillofacial Pathology, Tamil Nadu Government Dental College and
Hospital, Chennai, 600 003 India
I. Ponniah, Email: salivaryduct@yahoo.co.uk .
Corresponding author.
Received August 14, 2009; Accepted November 19, 2009.
Abstract
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.
Keywords: Cherubism, Central giant, Cell granuloma, Giant cell, Lesions, Gingival fibromatosis,
Ramon syndrome

• Other Sections▼
o Abstract
o Introduction
o Case Report
o Discussion
o References

Introduction
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 [1]. 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 [5]. 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 [7]. The association of cherubism with gingival fibromatosis, epilepsy,
mental retardation, stunted growth, and hypertrichosis was first described by Ramon et al. [8], in
1967, and subsequently by Pina-Neto et al. [9], in 1986, in 4 individuals in a family under the
term Ramon syndrome. Two other examples were also reported by Primdore et al. [10], in 1992.
We report a case of Ramon syndrome.
 • Other Sections▼
o Abstract
o Introduction
o Case Report
o Discussion
o References

Case Report
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).
Fig. 1
a Shows clinical appearance of the bilateral swelling. b and c, shows gingival
hypertrophy without defined interdental papilla

Fig. 1
a Shows clinical appearance of the bilateral swelling. b and c, shows gingival hypertrophy
without defined interdental papilla
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).
Fig. 2
Shows bilateral involvement of the mandible including neck of the condyle
(arrow) and hypoplasia of the head of the condyle. Multilocularity is also evident
in the maxilla (arrows)

Fig. 2
Shows bilateral involvement of the mandible including neck of the condyle (arrow) and
hypoplasia of the head of the condyle. Multilocularity is also evident in the maxilla (arrows)
Fig. 3
Shows bicortical expansion in the posterior region and interdental bone above
the cementoenamel junction in the anterior region

Fig. 3
Shows bicortical expansion in the posterior region and interdental bone above the
cementoenamel junction in the anterior region
Fig. 4
Axial view of the CT scan shows multilocular lesion with hypodense and
hyperdense regions

Fig. 4
Axial view of the CT scan shows multilocular lesion with hypodense and hyperdense regions
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.
Fig. 5
Shows mononuclear and multinuclear cellular proliferation in a vaguely
storiform pattern (H and E, ×100)

Fig. 5
Shows mononuclear and multinuclear cellular proliferation in a vaguely storiform pattern (H and
E, ×100)
Fig. 6
Shows immature bone formation among the lesional tissue (H and E, ×100)

Fig. 6
Shows immature bone formation among the lesional tissue (H and E, ×100)

• Other Sections▼
o Abstract
o Introduction
o Case Report
o Discussion
o References
Discussion
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 [5]. 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 [14].
It is well known that GF is known to be induced by certain drugs like phenytoin, cyclosporine
and nifidepine [15]. 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 [20], 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 [5], psychomotor retardation and
gingival fibromatosis [24], neurofibromatosis and multiple non-ossifying fibromas of the femoral
bone [25, 26], and Fragile X syndrome [27]. 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 [19]. In this context and in view of the varied and phased
phenotypic expression in the sibs reported by Ramon et al. [8], 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 [32]. 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 [7]. 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.
Table 1
Gingival fibromatosis associated with other conditions [20]

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 [2]. 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 [2]. 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 [33].
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 [37].
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.

• Other Sections▼
o Abstract
o Introduction
o Case Report
o Discussion
 o References

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