Orbital, Mandible, and Jaw Enlargement in Noonan Syndrome

FIGNoonan syndrome is among the conditions linked to pathogenic variants in several genes encoding RAS proteins. These conditions, collectively known as RASopathies, are characterized by hyperactivity in the RAS/mitogen-activated protein kinase pathway. Clinical features of Noonan syndrome encompass a predisposition to cancer, short stature, undescended testicles, and craniofacial abnormalities, including giant cell lesions of the jaws. Rarely, giant cell lesions of the jaws may occur in other RASopathies such as NF1, oculoectodermal, and cardiofaciocutaneous syndromes. Due to the similar presentation of syndromic giant cell lesions of the jaws with cherubism, questions have arisen about its pathological mechanisms—specifically, whether giant cell lesions of the jaws represent an overlap with cherubism or a phenotypic variation within these syndromes. However, molecular analyses have shown that cherubism is different from RASopathies, because it is caused only by variants of the SH3-domain binding protein 2 gene, and the affected patients do not exhibit any other systemic abnormalities. In a recent review of the literature, 25 of 34 patients with Noonan syndrome had bilateral giant cell lesions of the jaws mischaracterized as cherubism. We present a 21-year-old boy, initially diagnosed with cherubism, with multiple cystic lesions affecting both the mandible and maxilla, as well as the orbital walls (panels A, B). Upon a thorough clinical examination, he was found to have Noonan syndrome, with the SOS1 gene in heterozygosity, and no mutations in the cherubism gene. The patient was scheduled for craniofacial surgery and medical treatment with imatinib. This case underscores the importance of comprehensive clinical analysis for patients who may initially appear to have cherubism but present with a distinct systemic disease.