Abstract:

Fibrous dysplasia of the mandible typically begins during toddler years and culminates during puberty. These lesions may cause jaw disfigurement and may not be amendable to surgery. Imatinib successfully has treated cherubism associated with SH3BP2 mutations, but similar lesions can present in other conditions such as Noonan syndrome. We report diagnosis of Noonan syndrome caused by a PTPN11 activating mutation and successful treatment of the fibrous dysplasia of the mandible with imatinib.

Introduction:

Fibrous dysplasia of the mandible and maxilla, often referred to as cherubism, begins during toddler years and culminates with involution during puberty [1]. The presence of these lesions during the formative years of development leads to significant physical and psychological morbidity. In addition to physical disfigurement, these maxillary and mandibular lesions can cause difficulty with mastication, pain, and airway compromise [2]. Both jaw reconstruction following injury and cosmetic resection and reconstruction can potentiate further fibrous dysplasia and increase morbidity, though successful operative correction also is reported [3]. While intralesional corticosteroids, calcitonin, and alpha-interferon have been used, both response time and overall efficacy vary depending on the cohort studied [4, 5].

Cherubism classically is associated with SH3BP2 mutations, but similar lesions can be observed in Noonan syndrome, Fragile X syndrome, and neurofibromatosis type I and have been referred to as either cherubism-like lesions or giant cells lesions. MAP kinase pathway activation is implicated in these lesions, with BRAF, MEK, andSOS1 mutations reported [6]. Imatinib has been used successfully in three patients with SH3BP2 -associated cherubism [1]. We report successful use of empiric imatinib to resolve mandibular fibrous dysplasia in a single patient whose disease was later determined to be caused by Noonan syndrome with a confirmedPTPN11 activating mutation.

Results:

A 10-year-old male with short stature and mild conductive hearing loss presented to discuss use of imatinib to manage his worsening giant cell granulomas of the mandible that had been present for five years of age and consistent with cherubism on biopsy. He was suffering from difficulty with mastication, frequent bullying by peers, and inability to participate fully in athletics due to concern that any jaw injury would not be amenable to surgical correction. Targeted genetic testing for known SH3BP2 pathogenic mutations previously was negative, and additional genetic workup had been deferred since the patient phenotypically did not exhibit features of other disorders known to include similar lesions. Therapy was initiated with imatinib at 300 mg daily, rounding the usual pediatric dose to the nearest whole tablet [7]. The patient and his parents noted decreased mandibular size within two months of beginning treatment. He continued imatinib for 15 months with full resolution of the mandibular granulomas both clinically and on computed tomography of the jaw (Fig. 1). Imatinib then was discontinued at patient preference. Therapy was well tolerated with mild nausea, mild anorexia, and occasional headache. No dose reductions were required. The conductive hearing loss also resolved.

Integrative sequencing, including matched tumor/DNA and tumor/RNA sequencing confirmed a germline PTPN11 p.I56V mutation establishing a diagnosis of Noonan Syndrome. Subsequent cardiac evaluation was unremarkable, and the patient continues to follow with oncology, oral and maxillofacial surgery, and genetics. There is no evidence for recurrent disease 15 months post stopping imatinib.

Discussion:

While multiple giant cell lesion syndrome is a known characteristic of Noonan syndrome, its presentation without other phenotypic findings is rare [8]. While these lesions may involute during puberty, the benefit in reducing risk for dental malalignment, inoperable jaw injury, and perhaps most importantly, repeat suffering of adverse childhood experiences due to bullying cannot be understated [9]. We report for the first time the successful use of imatinib to treat giant cell granulomas associated with a PTPN11 activating mutation. Adverse effects were minor and similar to those experienced by pediatric patients receiving tyrosine kinase inhibitors to treat Philadelphia-chromosome-positive acute lymphoblastic leukemia. As Noonan syndrome features MAP kinase pathway activation, use of imatinib over additional agents studied in cherubism is attractive mechanistically since imatinib is known to inhibit downstream activity of the MAP kinase pathway through inhibition of cKIT [10].

It is unknown both whether the patient will require repeat therapy for recurrent disease and if a second course of imatinib will be effective. Recurrence could be mitigated by continuing maintenance imatinib through puberty, but prolonged therapy may not be desired by patients or families, especially for a self-limiting process. Additional reports on the use of imatinib with similar disease hopefully can address if imatinib should be offered to all patients with symptomatic fibrous dysplasia both due to SH3BP2 -associated cherubism or due to other underlying causes such as Noonan syndrome.

Ethics Statement:

All patient images and results were obtained with patient assent and parental consent, and both the patient and his parents support their publication.

Conflict of Interest:

All authors deny any conflicts of interest.

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Figure Legends

Figure 1.

A. Giant cell granulomas of the mandible (see example marked by arrow) were present as shown on computed tomography for five years upon patient presentation with clinical cherubism. B. Full resolution of the granulomas was noted both clinically and on computed tomography following 15 months of therapy with imatinib.