McCune-Albright syndrome (MAS) is a rare genetic disorder defined by the classic triad of polyostotic fibrous dysplasia (PFD), precocious puberty, and café-au-lait spots. Its prevalence in the general population is estimated at 1 in 100,000 to 1 in 1,000,000. It appears between ages 3 and 15, and about 75% are detected by age 30. It is more common in females, with a female-to-male ratio of 3:1.
This disease is caused by a post-zygotic mutation in the GNAS gene, resulting in somatic mosaicism. Craniofacial fibrous dysplasia is one of the clinical manifestations of MAS, with head lesions accounting for about 25% of all lesions, second only to the ribs. Fibrous dysplasia of the sphenoid bone can compress the optic canal, leading to compressive optic neuropathy.
It may be accompanied by various endocrine disorders such as hyperthyroidism, Cushing syndrome, and acromegaly.
QHow rare is McCune-Albright syndrome?
A
The incidence is extremely rare, occurring in 1 in 100,000 to 1 in 1,000,000 people. It often develops between ages 3 and 15, and about 75% are diagnosed by age 30. It is more common in females, with a female-to-male ratio of 3:1.
The clinical presentation of optic neuropathy in MAS ranges from asymptomatic to severe visual impairment.
Facial swelling and asymmetry: Facial bone deformity due to fibrous dysplasia is often the initial symptom. As it progresses, a leonine facies may appear.
Vision loss: Can range from acute onset to slowly progressive. Unilateral, slowly progressive visual impairment is common.
Bone pain and deformity: Pain in the affected bone.
Facial pain and headache: The main complaint in 81% of cases with sinus involvement.
Clinical Findings (Findings Confirmed by Physician Examination)
Proptosis and ocular deviation: Caused by lesions in the frontal, sphenoid, and ethmoid bones.
Hypertelorism: Increased interocular distance due to bone expansion of the medial orbital wall.
Optic neuropathy: Visual impairment and visual field constriction due to narrowing of the optic canal. Initially, optic disc swelling is observed, and if treatment is delayed, it progresses to optic atrophy.
Restricted eye movement: Strabismus occurs due to compression of extraocular muscles or bone deformity.
Eyelid closure disorder: Incomplete eyelid closure due to orbital bone deformity.
Systemic findings
Café-au-lait spots: Pigmented spots with irregular borders (described as “coast of Maine”).
Precocious puberty: Manifests as early menstruation in girls and testicular enlargement in boys.
Polyostotic bone lesions: Lesions are found in multiple bones, such as the skull, ribs, and femur.
Endocrine disorders: Hyperthyroidism, Cushing syndrome, growth hormone excess, etc.
Other findings may include epiphora due to nasolacrimal duct obstruction, trigeminal neuralgia or cranial nerve palsy due to skull base lesions, and hearing loss due to narrowing of the external and internal auditory canals.
MAS is caused by a postzygotic missense mutation in the GNAS gene. Because it occurs as a somatic mosaic, the earlier the mutation arises, the more extensive the affected tissues and the more severe the symptoms.
Fibrous dysplasia of the sphenoid bone: The optic canal passes through the sphenoid bone, and abnormal bone growth can narrow the optic canal.
Excess growth hormone: In cases with acromegaly, craniofacial bone enlargement is accelerated, increasing the risk of optic neuropathy.
Progression of the lesion: Bone lesions are usually not present immediately after birth but become noticeable several years later.
QWhy is the optic nerve damaged?
A
The optic canal passes through the sphenoid bone. In MAS, fibrous dysplasia occurs in the sphenoid bone, and the abnormally proliferated bone tissue narrows the optic canal, compressing the optic nerve. The risk is further increased if there is concomitant excess growth hormone.
The diagnosis of MAS is based on clinical symptoms. The classic triad of polyostotic fibrous dysplasia, precocious puberty, and café-au-lait spots serves as a clue.
GNAS gene testing: Useful for definitive diagnosis, but false negatives may occur due to mosaic mutations.
OCT (Optical Coherence Tomography): Measurement of retinal nerve fiber layer thickness can predict visual field changes. It is also considered useful for evaluating postoperative outcomes in children.
Histopathology: Characterized by excessive osteoid, decreased cells and blood vessels in bone trabeculae, and fibrous replacement. Bone biopsy is considered in diagnostically challenging cases, but when biopsy is not possible, diagnosis is made comprehensively based on history, examination, and imaging findings.
Endocrine screening: Active screening for endocrine disorders such as thyroid function, growth hormone, and cortisol is recommended.
Management of optic neuropathy in MAS is recommended to involve a multidisciplinary team (ophthalmology, neurosurgery, otorhinolaryngology, and endocrinology).
Optic nerve decompression is indicated in cases with visual impairment.
Surgical timing: If the lesion is stable, it is generally recommended to postpone surgery until after skeletal maturity. Approximately one-quarter of cases recur within 3 years after surgery.
Endoscopic decompression: Useful as a minimally invasive approach.
Surgical Treatment
Optic nerve decompression: Indicated when visual impairment is present. Meta-analysis reports visual improvement in 67.4% of cases.
Determination of surgical indication: Performed when progression of vision loss is confirmed.
Postoperative recurrence: Approximately 25% recur within 3 years, so long-term follow-up is necessary.
Conservative Treatment
Observation: For asymptomatic optic nerve stenosis, observation is a reasonable option.
Treatment of growth hormone excess: Early treatment of growth hormone excess may help prevent optic neuropathy.
Bisphosphonates: Used for pain relief of bone pain, but their effect on reducing bone lesions themselves is limited.
QIs surgery unnecessary even if the optic canal is narrowed?
A
If there is no visual impairment despite optic canal stenosis, observation is recommended. Prophylactic decompression is not recommended, and the main cause of blindness is iatrogenic. Surgery is considered when progression of visual loss is confirmed.
In cases with growth hormone excess, early treatment of growth hormone excess may suppress craniofacial bone expansion and contribute to prevention of optic neuropathy. However, established evidence is still insufficient.
6. Pathophysiology and Detailed Mechanism of Onset
The molecular mechanism of MAS originates from GNAS gene mutations. The Gsα protein encoded by GNAS is constitutively activated, leading to excessive cAMP production via adenylyl cyclase. This dysregulation of intracellular signaling affects multiple organs.
The mechanism of bone lesion development is as follows.
Impaired differentiation of bone marrow stromal cells: Excess cAMP prevents stromal cells from differentiating into normal osteoblasts, leading to replacement by fibroblastic tissue.
Trabecular bone loss and fibrosis: Normal bone structure is lost, forming ground-glass fibrous bone lesions.
Cyst formation: Cystic changes may occur within the bone.
Since the optic canal passes through the sphenoid bone, progression of fibrous dysplasia of the sphenoid bone narrows the canal, compressing the optic nerve. This is the essence of compressive optic neuropathy.
7. Latest Research and Future Prospects (Research-Stage Reports)
DeKlotz et al. (2017) reported 4 cases (5 optic nerves) of compressive optic neuropathy due to fibrous dysplasia treated with endoscopic transnasal optic nerve decompression. All cases showed improvement in best-corrected visual acuity postoperatively, with no major complications.
Efficacy of Decompression Surgery in Meta-Analysis
In a meta-analysis of 27 studies (241 patients, 368 optic nerves) by Amit et al. (2011), decompression surgery for symptomaticoptic neuropathy associated with fibrous dysplasia resulted in visual improvement in 67.4% of cases. On the other hand, prophylactic decompression of asymptomatic optic nerves was shown to increase the risk of visual deterioration by approximately 4.89-fold.
In an NIH cohort study by Boyce et al. (2013), comparing 22 cases of MAS-associated growth hormone excess with 21 non-MAS controls, no optic neuropathy developed in the early intervention group that started treatment before age 18, while about 57% of those who started treatment after adulthood developed optic neuropathy. Since growth hormone excess promotes expansion of craniofacial bones, early control is thought to suppress progression of optic canal stenosis.
Boyce AM, Collins MT. Fibrous Dysplasia/McCune-Albright Syndrome: A Rare, Mosaic Disease of Gαs Activation.Endocr Rev. 2020;41(2):345-370. doi:10.1210/endrev/bnz011. PMID: 31673695
Cutler CM, Lee JS, Butman JA, et al. Long-term outcome of optic nerve encasement and optic nerve decompression in patients with fibrous dysplasia: risk factors for blindness and safety of observation.Neurosurgery. 2006;59(5):1011-1018. PMID: 17143235
Amit M, Collins MT, FitzGibbon EJ, Butman JA, Fliss DM, Gil Z. Surgery versus Watchful Waiting in Patients with Craniofacial Fibrous Dysplasia – a Meta-Analysis.PLOS ONE. 2011;6(9):e25179. doi:10.1371/journal.pone.0025179. PMID: 21966446
Boyce AM, Glover M, Kelly MH, et al. Optic neuropathy in McCune-Albright syndrome: effects of early diagnosis and treatment of growth hormone excess.J Clin Endocrinol Metab. 2013;98(1):E126-E134. doi:10.1210/jc.2012-2111. PMID: 23093488
DeKlotz TR, Stefko ST, Fernandez-Miranda JC, Gardner PA, Snyderman CH, Wang EW. Endoscopic Endonasal Optic Nerve Decompression for Fibrous Dysplasia.J Neurol Surg B Skull Base. 2017;78(1):24-29. doi:10.1055/s-0036-1584894. PMID: 28180039
Szymczuk V, Florenzano P, de Castro LF, Collins MT, Boyce AM. Fibrous Dysplasia / McCune-Albright Syndrome. GeneReviews® [Internet]. Seattle (WA): University of Washington; Last Update: February 8, 2024. NBK274564
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