Optic Neuropathy in McCune-Albright Syndrome with Craniofacial Fibrous Dysplasia
McCune-Albright Syndrome (MAS) is a rare genetic disease that is defined by the triad of polyostotic fibrous dysplasia, precocious puberty, and café-au-lait skin spots . A variety of other symptoms may also be seen in patients with MAS, including hyperthyroidism, Cushing syndrome, and acromegaly. The prevalence of individuals affected by MAS in the general population is estimated to be from 1 in 100,000 to 1 in 1,000,000 .
MAS is due to a post-zygotic mutation in the guanine nucleotide binding protein (GNAS) gene during embryogenesis; thus, the severity and prevalence of symptoms are largely impacted by when the spontaneous mutation occurs . This phenomenon is known as somatic mosaicism, in which post-zygotic mutations affect only portions of the body and are not transmitted to future offspring . Fibrous dysplasia of the craniofacial region is a manifestation of MAS and is sometimes associated with a compressive optic neuropathy . This complication of MAS may present with acute vision loss, necessitating immediate surgical intervention . Early diagnosis and treatment of growth hormone excess in MAS may help prevent craniofacial expansion and subsequent optic neuropathy .
MAS results from a postzygotic missense mutation in the GNAS gene during embryogenesis . This gene encodes the alpha-subunit of stimulatory heterotrimeric G protein (Gsα) and is found in various tissues including bone . The mutation leads to constitutive Gs signaling which results in elevated activity of adenylyl cyclase and dysregulated Cyclic adenosine monophosphate (cAMP) production . In bones, this irregular activation impairs the ability for bone marrow stromal cells to differentiate normally. The affected bone becomes replaced by these highly proliferative cells and results in fibroblastic tissue lesions seen in fibrous dysplasia. These lesions can grow and compress adjacent tissue. These lesions are not usually seen immediately after birth but rather become noticeable after a few years . Due to its somatic mosaic pattern, fibrous dysplasia from MAS can occur throughout the appendicular, axial, and/or craniofacial skeleton. General clinical signs and symptoms include bone pain, deformities, and increased risk of fractures . Because the optic canal is transmitted through the sphenoid bone, fibrous dysplasia of the craniofacial skeleton with involvement of the sphenoid bone can result in a compressive optic neuropathy with vision loss .
The diagnosis of MAS is usually based on clinical symptoms. The dermatologic findings of café-au-lait skin spots represent the somatic mosaicism in the disease process and present as patches of hyperpigmentation with jagged borders, commonly referred to as “coast of Maine”; these dermatologic findings are typically found more medially . Although genetic testing of the GNAS gene is available, its somatic mosaicism pattern may lead to false negative test results . Patients with MAS often present with initial symptoms due to fibrous dysplasia or precocious puberty . In fibrous dysplasia, X-Ray and Computed Tomography (CT) may help to identify lesions and possible surrounding tissue compression. Due to undermineralization of the bone in fibrous dysplasia, these lesions on X-Ray are shown to have a “ground-glass” and radiolucent pattern . This can be further evidenced by histopathology of the bone showing an overabundance of osteoid . In patients with MAS, baseline vision evaluation and yearly visits with a neuro-ophthalmologist are recommended. Craniofacial fibrous dysplasia of the temporal bone has also been known to impact hearing; thus, audiology evaluations may be warranted .
Treatment and Management
The treatment and management of craniofacial fibrous dysplasia in MAS remains ill defined . However, craniofacial fibrous dysplasia causing compression of the optic nerve and subsequent vision loss may require surgical management. Recently in 2019, the Fibrous Dysplasia/McCune-Albright Syndrome International Consortium released an article that summarized best practice management guidelines. In their assessment of craniofacial fibrous dysplasia lesions that compress surrounding structures, they recommended coordination of a multidisciplinary team that included ophthalmology, ENT, neurosurgery, craniofacial surgery, plastic surgery, maxillofacial surgery, and audiology. They also recommended advanced imaging techniques and 3D analysis for surgical planning . A retrospective cross-sectional analysis was performed on patients with growth hormone excess in the setting of MAS. This study observed that early diagnosis and treatment of growth hormone excess in MAS might prevent the progression of optic neuropathy. These interventions included octreotide, transsphenoidal surgery (when indicated), pegvisomant, and radiotherapy .
There has also been discussion regarding whether patients with neuroimaging demonstrating fibrous dysplasia of the sphenoid bone should receive prophylactic decompression of the optic nerve. A study analyzed patients with optic canal encasement and found that neuro-ophthalmologic examination was normal in most of these patients, thus suggesting that prophylactic decompression of the optic nerve is likely not indicated based on imaging alone and that diagnostic imaging does not correlate with vision loss . Endoscopic endonasal optic nerve decompression has been performed on patients with optic nerve compression with decreased visual acuity. In the 2017 study by DeKlotz et al., 5 decompression surgeries in 4 patients resulted in improvements in visual acuity post-surgically for all 5 surgeries, and no complications were identified . A meta-analysis of 27 studies analyzed patients with craniofacial dysplasia and impaired optic nerves. All optic nerves that were clinically impaired underwent decompression, and 67.4% of these patients reported improvement in vision after the surgical intervention. This study also analyzed prophylactic surgery in patients with no symptoms and found that this prophylactic surgical correction resulted in visual deterioration . Thus, in addition to the study observing that prophylactic surgery may not benefit the patient in the future, the study showed that this procedure may actually worsen vision in asymptomatic patients.
Bisphosphonates treatment for fibrous dysplasia has had varying results in terms of clinical effectiveness and remains an area of further investigation . The current indication for bisphosphonates in fibrous dysplasia is for pain relief, but its effectiveness in reducing fibrous dysplasia lesions remains unclear . Treatments of other manifestations of MAS include bromocriptine (hyperprolactinemia), gonadotropin-releasing hormone analogs (central precocious puberty), and antithyroid medications and/or radioablation (hyperthyroidism) .
McCune-Albright Syndrome is a genetic disease that is defined by the triad of polyostotic fibrous dysplasia, precocious puberty, and coast of Maine café-au-lait skin spots. Polyostotic fibrous dysplasia may affect the craniofacial skeleton, and more specifically the sphenoid bone near the optic nerve. Progression of craniofacial fibrous dysplasia may lead to compression of the optic nerve and subsequent vision loss. Surgical intervention by a multidisciplinary team is often indicated in these events, but prophylactic surgery based on imaging for asymptomatic patients is not supported by the literature.
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