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CHERUBISM
Cherubism is a rare developmental jaw condition that is generally inherited as an autosomal
dominant trait with high penetrance but variable expressivity. Several investigators have
reported a higher disease penetrance in male than in females. Sporadic cases also can occur
and are thought to represent spontaneous mutations.
In two reports published simultaneously by laboratories on different continents, the gene for
cherubism was mapped to chromosome 4p16. Mutations subsequently were identified in the
SH3BP2 gene within this locus. The protein encoded by this gene is believed to function in
signal transduction pathways and to increase the activity of osteoclasts and osteoblasts during
normal tooth eruption. It has been suggested that mutations in the SH3BP2 gene may lead to
pathologic activation of osteoclasts and disruption of jaw morphogenesis. However, the
molecular pathogenesis of cherubism remains poorly understood.
The name cherubism was applied to this condition because the facial appearance is similar to
that of the plump-cheeked little angels (cherubs) depicted in Renaissance paintings. Although
cherubism also has been called familial fibrous dysplasia, this term should be avoided because
cherubism has no relationship to fibrous dysplasia of bone.
CLINICAL AND RADIOGRAPHIC FEATURES
Although some examples of cherubism may develop as early as 1 year of age, the disease
usually occurs between the ages of 2 and 5 years. In mild cases the diagnosis may not be made
until the patient reaches 10 to 12 years of age. The clinical alterations typically progress until
puberty. Then stabilize and slowly regress.
The cherublike facies arises from bilateral involvement of the posterior mandible that produces
angelic chubby cheeks. In addition, there is an “eyes upturned to heaven” appearance that is
due to a vide rim of exposed sclera noted below the iris. This latter feature is due to
involvement of the infraorbital rim and orbital floor that tilts the eyeballs upward, as well as to
stretching of the upper facial skin that pulls the lower lid downward. On occasion, affected
patients also reveal marked cervical lymphadenopathy.
The mandibular lesions typically appear as a painless, bilateral expansion of the posterior
mandible that tends to involve the angles and ascending rami. The bony expansion is usually
bilaterally symmetrical; in severe cases, most of the mandible is involved. Milder maxillary
involvement occurs in the tuberosity areas; in severe cases, the entire maxilla can be affected.
Extensive bone involvement causes a marked widening and distortion of the alveolar ridges. In
addition to the aesthetic and psychologic effect, the enlargements may cause tooth
displacement or failure of eruption, impair mastication, crate speech difficulties, or rarely lead
to loss of normal vision or hearing. Although there have been rare reports of unilateral
cherubism, it is difficult to accept these as examples of this disease unless there is a strong
family history.
Radiographically, the lesions are typically multilocular, expansile radiolucencies. The
appearance is virtually diagnostic as a result of their bilateral location. Less commonly, the
lesions appear as unilocular radiolucencies. Although cherubism typically involves only the jaws,
involvement also has been reported rarely in other bones such as the ribs and humerus.
No unusual biochemical findings have been reported in patients with cherubism. If laboratory
results do not suggest the diagnosis of hyperparathyroidism, then most children with multiple
symmetrical giant cell granulomas represent examples of cherubism. However, multiple giant
cell lesions may be seen in association with other conditions, including Ramon syndrome, JaffeCampanacci syndrome, and a Noonan-like syndrome. It has been suggested that the bony
lesions of cherubism represent a phenotypic picture common to a number of disease processes
that the bony lesions of cherubism represent a phenotypic picture common to a number of
disease processes that arise from multiple, distinct, initiating pathogenetic events.
HISTOPATHOLOGIC FEATURES
The microscopic findings of cherubism are essentially similar to those of isolated giant cell
granulomas, and they seldom permit a specific diagnosis of cherubism in the absence of clinical
and radiologic information. The lesional tissue consists of vascular fibrous tissue containing
variable numbers of multinucleated giant cells. The giant cells tend to be small and usually
aggregated focally. Like the giant cells in central giant cell granulomas, the giant cells in
cherubism express markers suggestive of osteoclastic origin. Foci of extravasated blood are
commonly present. The stroma in cherubism often tends to be more loosely arranged than that
seen in giant cell granulomas. In some cases, cherubism reveals eosinophilic, cufflike deposits
surrounding small blood vessels throughout the lesion. The eosinophilic cuffing appears to be
specific for cherubism. However, these deposits are not present in many cases, and their
absence does not exclude a diagnosis of cherubism. In older, resolving lesions of cherubism, the
tissue becomes more fibrous, the number of giant cells decreases, and new bone formation is
seen.
TREATMENT AND PROGNOSIS
The prognosis in any given case is unpredictable. In most instances the lesions tend to show
varying degrees of remission and involution after puberty. By the fourth decade, the facial
features of most patients approach normalcy. In spite of the typical scenario, some patients
demonstrate very mild alterations, whereas other reveal grotesque changes that often are very
slow to resolve. In occasional patients, the deformity can persist.
The question of whether to treat or simply observe a patient with cherubism is difficult.
Excellent results have been obtained in some cases by early surgical intervention with curettage
of the lesions. Conversely, early surgical intervention sometimes has been followed by rapid
regrowth of the lesions and worsening deformity. A course limited only to observation may
result in extreme and sometimes grotesque facial deformity, with associated psychologic
problems and functional deformity that may necessitate extensive surgery. Several
investigators have suggested the use of calcitonin in severe cases, but such therapy is
contraindicated because of the risk of development of postirradiation sarcoma. The optimal
therapy for cherubism has not been determined.