The diagnosis of cherubism is based on patient age, family history, clinical examination, radiographic findings, biochemical analyses and molecular analysis.
The classic clinical appearance of the cherubic face includes bilateral, symmetric, painless fullness of the cheeks and mandible in children at 2 to 7 years of age, when the diagnosis of cherubism is usually made. Retraction of the lower eyelids from bilateral mandibular and maxillary enlargement results in exposure of the sclera below the iris and an apparent upward gaze as described by Jones in 1933. However, this classic appearance is not infrequently absent and the patient may present with bilateral multicystic lesions which enlarge the mandible. These may be an incidental finding on radiographic examinations performed for other reasons such as trauma or during routine dental examinations.
Enlargement of the cervical lymph nodes that contribute to the patient’s full-faced appearance, a V-shaped palate with a high arch, early loss of primary teeth and displaced, impacted, supernumerary and missing teeth are common findings in patients with cherubism. Orbital involvement may appear late in affected individuals. This is manifest by osseous orbital expansion, globe displacement, proptosis, diplopia, optic neuropathy and loss of vision [18
There have been reported cases of cherubism with massive enlargement of the jaws and backward displacement of the tongue resulting in airway obstruction and obstructive sleep apnea, speech, mastication and swallowing problems [21
]. Some patients with severe cherubism report episodic pain [17
]. Patients with aggressive, rapidly progressing cherubism should be evaluated by a craniofacial team consisting of a surgeon (oral and maxillofacial surgeon, plastic surgeon, otolaryngologist), geneticist/genetic counselor, ophthalmologist, dentist/orthodontist and child psychologist/social worker and nurse.
At birth no signs of cherubism are present. Swelling of the jaws usually appears between 2 and 4 years of age. A rapid increase in size of the lesions and the affected jaws follows until the age of 7-8 years. After that, lesions remain unchanged or increase slowly until puberty (Figure ). Around the age of puberty, the condition begins to regress and facial deformity starts to improve, although lesions can be still seen on radiographs. By 30 years of age, lesions are frequently not detectable. In a follow-up study of 18 patients with cherubism, von Wowern found progressive new bone formation in the lesions of patients over 20 years of age [27
]. By 41 years of age, the bone structure in the affected areas was completely normal. Diagnosis in adults with a mild form of cherubism, not appreciated in childhood can be difficult as lytic bone cysts fill in with bone and may not be radiographically detectable. However, in rare instances actively expanding lesions in suspected cherubism may be diagnosed in adults [12
Figure 2 A. Photograph of a 10 year old girl with bilateral cheek and jaw swelling. Cherubism was confirmed with genetic testing that was positive for the SH3BP2 gene. The patient had genetic counseling and was followed longitudinally. B. Patient one year later (more ...)
Although not pathognomonic for cherubism, the radiographic findings of bilateral, multilocular, radiolucent areas within the mandible, usually located at the angles and rami, should raise the suspicion for the disease. The coronoid processes are commonly involved, whereas the condyles are rarely affected. Lesions in the mandible are usually symmetric, whereas those in the maxilla may be asymmetric [4
]. Imaging typically shows expansile remodeling of the involved bones, thinning of the cortices, and multilocular radiolucencies with a coarse trabecular pattern.
Biopsy and histopathologic examination are not required in most cases to establish the diagnosis of cherubism. However, when performed, numerous osteoclast-like multinucleated giant cells in a moderately loose fibrous stroma are present. Thus cherubism is considered to be a fibro-osseous disorder. Ovoid to spindle shaped cells within the fine fibrillar collagenous stroma, numerous small vessels with large endothelial cells and perivascular capillary cuffing are also present. Eosinophilic cuffing appears to be specific to cherubism. However, these deposits are not present in many cases, and their absence does not exclude the diagnosis of cherubism [53
]. The histological findings of cherubism are similar to those of aggressive or non-aggressive giant cell lesions, myxoma, aneurysmal bone cyst and hemangioma and other vascular lesions.
Gene testing is recommended to determine whether a mutation in the cherubism gene SH3BP2
is present [54
] and to confirm the clinical diagnosis of cherubism. For molecular analysis, genomic DNA from a blood sample or tissue from lesions is used for sequence analysis. Cherubism is an autosomal dominant disorder but most cases are due to de novo
mutations. Therefore, the absence of a positive family history does not rule out the possibility of cherubism.
An important component in the management of cherubism is the differential diagnosis which includes brown tumor of hyperparathyroidism, giant cell lesions, Noonan/multiple giant cell lesion syndrome, fibrous dysplasia, aneurysmal bone cyst and the hyperparathyroidism-jaw tumor syndrome (HPT-JT). The limited and symmetrical distribution of the cherubism lesions can often facilitate distinction of cherubism from these other conditions, and of course mutation analysis of SH3BP2 can confirm the diagnosis. If no mutation in SH3BP2 is found cherubism cannot be excluded because of possible genetic heterogeneity.
Hyperparathyroidism may be differentiated by analysis of parathyroid hormone levels, calcium, phosphorous and alkaline phosphatase. However, hyperparathyroidism is rare in children except in the setting of chronic renal failure (secondary hyperparathyroidism). Fibrous dysplasia [55
] and Noonan/multiple giant cell lesion syndrome [56
] can be also be identified by genetic testing.
Noonan syndrome was first described in 1963 and is characterized by short stature, hypertelorism, prominent posteriorly angulated ears, congenital heart defect, low normal intelligence or developmental delay, cryptorchidism in males, and bleeding disorders [59
]. In 1986, Chuong and colleagues published a series of 17 patients with giant cell lesions of the jaws studying the correlation of histologic appearance to biologic behavior [60
]. Two of these patients had Noonan syndrome and bilateral giant cell lesions of the mandible and the maxilla. Dunlap et al. first reported on the Noonan syndrome and cherubism association and presented 4 children at age 4 to 8 years old with the combination of the two entities [61
]. They considered the 2 patients with Noonan syndrome reported by Chuong et al. having cherubism as well. Later, in 1991, Cohen and Gorlin reviewed 15 cases with Noonan syndrome and giant cell lesions and proposed the name Noonan-like/multiple giant cell lesion syndrome and considered it to be separate from Noonan syndrome and cherubism [62
]. Following that, 5 more cases of the Noonan-like/multiple giant cell lesion syndrome were published [63
Later, mutations of the PTPN11
] and the SOS1
] were identified in patients with Noonan syndrome. These findings support the notion that the giant cell lesions in patients with Noonan syndrome are distinct from cherubism. Molecular analysis has led to the consideration of the Noonan syndrome with multiple giant cell lesions as a variant within the Noonan syndrome spectrum [57
] and the term Noonan-like/multiple giant cell lesion syndrome should no longer be used. Rather Noonan/multiple giant cell lesion syndrome is more appropriate. There has also been a report of bilateral mandibular lesions in association with neurofibromatosis and a mutation in the NF1
gene, which is associated with neurofibromatosis and with Noonan Syndrome [68
]. Differentiation between cherubism and Noonan/multiple giant cell lesion syndrome is important as giant cell lesions may behave aggressively in the latter and can lead to considerable morbidity if not treated appropriately [69
]. Giant cell lesions in Noonan patients can easily be mistaken for cherubism if the lesions appear symmetrically in maxilla and mandible (Figures &).
Figure 3 Noonan/multiple giant cell lesion syndrome. A 20-year old woman with Noonan/multiple giant cell lesion syndrome with bilateral involvement of the mandible and the maxilla. A and B. Frontal and submental photographs reveal prominent maxillary and mandibular (more ...)
Figure 4 Imaging studies of the patient in Figure pre-treatment (A, C, E) and post-treatment (B, D, F). A and B. Panoramic radiographs. C and D. Lateral cephalograms. E and F. 3D CT scans. Pre- and post-treatment images show improvement of the (more ...)
Cases of cherubism associated with other disorders such as fragile X syndrome, gingival fibromatosis with psychomotor retardation, neurofibromatosis type 1, and craniosynostosis have been published in the literature [15
]. Finally, cherubism has been reported to be associated with Ramon syndrome [73
] and Jaffe-Campanacci syndrome ([61
]. Ramon syndrome is extremely rare with only 8 cases reported in the literature and presents with mental retardation, short stature, gingival fibromatosis and epilepsy [73
]. Similarly rare is Jaffe-Campanacci syndrome [75
], which includes non-ossifying fibromas that can be localized in long bones and/or jaw bones, mental retardation, café au lait
spots, hypogonadism, ocular and cardiovascular anomalies (reviewed in [76
]. However, to our knowledge only eccentric or unilateral mandibular or maxillary lesions have been described in the literature for Jaffe-Campanacci syndrome [61