Abstract

Case Report

A case of cherubism in a 9-year-old Caucasian girl is reported. The particularity of the case is the incomplete penetrance of the disease caused by a mutation in 2 female members of the same family and the possibility to under-diagnose the condition without molecular genetic testing.

The patient was first seen in the Department of Maxillo-Facial Surgery in January 2009. She complained of painless, progressive and disfiguring enlargement of the lower face, speech and swallowing problems.

The mother told us that the patient is her third daughter. The girl had been born as a full-term normal delivery, with a birth weight of 3.100 kg, following an uneventful but painful pregnancy. At birth, the baby girl showed normal facial appearance and no abnormalities were noticed throughout the next years. The girl was about 5 years old when her mother noticed the first signs of cherubism: the teeth were not in the right place on the mandible and, furthermore, there was an enlargement of the lower face. The enlargement was slow and progressive. The face became deformed, especially over the angles of the mandible.

Clinical examination revealed swellings at the angles of the mandible, a little asymmetrical enlargement of the mandible and chubbiness of the face (fig. ​(fig.1).1). Mixed dentition and poor occlusion were noticed. No ocular, respiratory or cardiovascular problems were found. Except her facial appearance, bad alignment of the teeth and malocclusion, the patient did not exhibit any physical abnormality and showed no signs of mental retardation.

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Fig. 1

Facial appearance of the patient shows asymmetrical enlargement of the mandible.

Panoramic radiograph showed clearly that the facial enlargement is the result of bone changes. Radiological examination revealed bilateral multilocular areas of diminished density in the mandible and congenitally missing 2nd and 3rd lower molars. The maxillary dentition was not affected (fig. ​(fig.22).

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Fig. 2

Orthopantomogram of the patient shows bilateral multicystic lesions and dental abnormalities (agenesis of dental buds of 2nd and 3rd lower permanent molars); no similar lesions are seen in the maxilla.

Biopsy of the mandible was obtained. Histological examination demonstrated the replacement of the normal bony structure with proliferating fibrous tissue containing numerous multinucleated acidophilic giant cells randomly distributed in a fibrovascular stroma of nuclear spindle-shaped cells [Cionca et al., 2009].

Family history was negative indicating no other members with similar findings (fig. ​(fig.3).3). Both parents and their first 2 daughters are normal. The 2nd daughter (age 14) of the couple had complications with the eruption of secondary teeth.

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Fig. 3

Pedigree of the family.

Cherubism was suspected based on suggestive clinical, radiological and histological findings.

The previous family history suggested a non-familial case of cherubism and a patient with an apparent de novo mutation. Diagnostic investigations were completed by molecular genetic detection for a SH3BP2 mutation. Informed consent for DNA analysis was obtained from all members of the family. Analysis consisted of PCR amplification and direct sequencing of exon 9 of the SH3BP2 gene, including the intron-exon boundaries. Of 5 family members, abnormal results were obtained for the patient and her mother. A c.1244G>A mutation was identified in exon 9 of the SH3BP2 gene. Following the results, the 39-year-old mother was clinically and radiographically investigated. Facial appearance was unremarkable (fig. ​(fig.4).4). Panoramic radiograph showed normal appearance of maxilla and mandible with no radiologic evidence of an earlier manifestation of cherubism in the jaws (fig. ​(fig.5).5). There were no retrospective medical records or personal memories of any signs or symptoms of cherubism in her earlier years.

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Fig. 4

Facial appearance of the asymptomatic mother.

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Fig. 5

Recent orthopantomogram of the mother shows normal radiological appearance without any remnants.

No operative treatment was undertaken. The patient was scheduled for regular follow-up (including clinical, radiographic, dental, orthodontic, and ophthalmologic evaluations).

Discussion

Despite a negative family history, genetic analysis was useful for the detection of familial mutation. Direct sequencing of exon 9 of the SH3BP2 gene identified an A-to-G transition, resulting in an arg415-to-gln (R415Q) substitution. This mutation was first reported by Ueki et al. [2001] in a family with a classical cherubic phenotype. It is described in the well-known mutation hotspot at amino acid number 415 to 420 [Ueki et al., 2001; Lo et al., 2003; de Lange et al., 2007; Carvalho et al., 2009]. All 11 missense mutations identified so far are in exon 9 and affect 4 amino acids within a 6-amino acid sequence (RSPPDG) located 31 to 36 amino acids upstream of the SH2 domain and 205 to 210 downstream of the SH3-binding domain [Ueki et al., 2001; Lo et al., 2003; Lietman et al., 2006]. These results indicate an essential role of this domain of the gene in the development of cherubism.

Both patient and her mother carried the disease-causing mutation. The patient inherited the mutation from her mother in an autosomal dominant manner. The mother failed to express the clinical symptoms of cherubism whereas her youngest daughter expressed a mild cherubic phenotype with no sign of involvement of the maxilla or of the floor of the orbits. The effect of the lesions on permanent tooth development was manifested by absence of 2nd molars and delay eruption of 1st molars in the mandible. This means that the SH3BP2 gene is linked to tooth development and eruption [Ueki et al., 2001; Hyckel et al., 2005]. The lack of signs in the carrier mother and the difference in clinical presentation between the patient and her carrier mother are consistent with incomplete penetrance in females and variable expression of the c.1244G>A mutation in the SH3BP2 gene. We suggest that the mother was never afflicted by cherubism and did not develop the feature of the disorder in her youth based on recent jaw radiography and her information about her childhood. Radiological appearance was normal without any remnants. More than that, reduced penetrance in females is often observed in cherubism [Anderson and McClendon, 1962; Peters, 1979]. Recent studies demonstrated that even penetrance in males, thought to be close to 100%, is incomplete [Petschler et al., 2003; de Lange et al., 2007]. Lietman et al. [2006] describe a c.1255G>A mutation within exon 9 of SH3BP2 in a patient with cherubism. The patient's father and 2 siblings were carriers of the mutation but lacked clinical features of cherubism. Incomplete penetrance and variable expressivity of the mutation are explained by action of unidentified genes or other factors which may modulate the effect(s) of this mutation on the development of cherubism [Lietman et al., 2006].

We suggest genetic counseling/molecular genetic testing for all patients with cherubism, but especially for those with non-familial or sporadic forms.

Acknowledgements

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