McCune-Albright syndrome

McCune-Albright syndrome (MAS) is a rare, sporadic mosaic disorder caused by postzygotic somatic gain-of-function mutations in the GNAS gene, which encodes the α subunit of the stimulatory G protein (Gsα).[1][2] The mutations—concentrated at codons R201 (R201H, R201C) and Q227—result in constitutive Gsα activation and excessive intracellular cyclic adenosine monophosphate (cAMP) production.[3] In bone, this leads to impaired differentiation of skeletal stem cells and replacement of normal bone with disorganized fibro-osseous tissue (polyostotic fibrous dysplasia), while extraskeletal manifestations include café-au-lait skin macules and hyperfunctioning endocrinopathies.[1] Because the mutation arises postzygotically, the clinical phenotype is determined by the mosaic distribution of affected cells, producing a uniquely broad clinical spectrum.[3] Approximately 90% of MAS patients have craniofacial fibrous dysplasia (FD), frequently involving the maxilla and mandible, where the characteristic ground-glass radiographic pattern and progressive bony expansion are key imaging findings.[4][5] Management is multidisciplinary, centered on observation, endocrine control, and surgical contouring when functional or aesthetic impairment warrants intervention.[5]

Current Classification

Under the 5th edition WHO classification of head and neck tumours, fibrous dysplasia is classified among the fibro-osseous lesions of the jaws, alongside ossifying fibroma, cemento-osseous dysplasia, segmental odontomaxillary dysplasia, and familial gigantiform cementoma.[6] MAS represents the syndromic form of polyostotic FD.

Accepted Names and Aliases

• McCune-Albright syndrome (MAS) — the standard designation
• Albright syndrome / Albright's syndrome — older eponymous terms still encountered[7]
• Polyostotic fibrous dysplasia with endocrinopathy — descriptive synonym
• Jaffe-Lichtenstein syndrome — historically applied to polyostotic FD with café-au-lait macules but without endocrinopathy; now largely subsumed under the FD/MAS spectrum[8]

Obsolete Terms

• Osteitis fibrosa disseminata — an outdated histologic designation that should not be used in current practice[7]

• Prevalence: Estimated at 1 in 100,000 to 1 in 1,000,000. A Danish registry study reported a prevalence of 61 per million in 2018 for all FD/MAS combined; a French hospitalization-based study reported 5.4 per million for hospitalized cases.[2][9][10]
• Age: Skeletal lesions typically manifest in the first years of life; 90% of craniofacial FD lesions are detectable by age 3–4. Diagnosis peaks during adolescence.[5][9]
• Sex: No clear sex predominance for FD/MAS overall, though MAS with precocious puberty is more commonly recognized in girls.[8][9][11]
• Jaw involvement: Among MAS patients with craniofacial FD, the maxilla is more commonly affected than the mandible; approximately one-third have both jaws involved. Maxillary lesions frequently extend to contiguous bones (zygoma, sphenoid, ethmoid).[4][5][8]
• Skeletal distribution: Polyostotic FD characteristically shows unilateral or predominantly unilateral skeletal involvement; the lower extremities (especially the femur), craniofacial bones, ribs, and pelvis are the most commonly affected sites.[11]

Presentation and Symptoms

MAS classically presents with the triad of polyostotic FD, café-au-lait macules, and endocrine hyperfunction:[1][2]

• Skeletal: Painless, progressive bony swelling is the most common craniofacial presentation, producing facial asymmetry that may be the initial reason for clinical evaluation. Bone pain occurs in roughly half of FD patients and is a major determinant of quality of life. Pathologic fractures are common in the appendicular skeleton but rare in the jaws.[8][11][12]
• Cutaneous: Café-au-lait macules with irregular, jagged borders ("coast of Maine") typically appear ipsilateral to skeletal lesions and may be present from birth.[7][8]
• Endocrine: Gonadotropin-independent precocious puberty (most common, especially in girls), hyperthyroidism, growth hormone excess, hypercortisolism, and FGF23-mediated renal phosphate wasting.[1][11][13]

Craniofacial and Oral Findings

• Progressive expansion of the maxilla and/or mandible with alveolar ridge widening and hard palate involvement[4][5]
• Malocclusion and dental crowding or spacing secondary to alveolar expansion[5][14]
• Dental anomalies including taurodontism, enamel hypomineralization, dentin dysplasia, retained primary teeth, and elevated caries index[4][5][14]
• Obliteration or diminution of the maxillary sinus[5][15]

Complications and Red Flags

• Optic neuropathy from orbital canal narrowing (rare but serious)[5]
• Hearing impairment from auditory canal or ossicular involvement[5]
• Sarcomatous transformation occurs in fewer than 1% of FD lesions; rapid growth, severe pain, cortical destruction, or paresthesia should prompt urgent evaluation[5][7]

Location and Distribution

FD in MAS characteristically involves the posterior maxilla, often extending to contiguous craniofacial bones (zygoma, sphenoid, ethmoid, frontal) — a pattern termed craniofacial FD.[8] Mandibular involvement is less common and typically unilateral.[15] Bilateral jaw involvement occurs in approximately one-third of MAS patients with craniofacial disease.[4] Lesions are centered in the medullary bone and expand outward, maintaining continuity with the surrounding skeleton.[8]

Periphery and Shape

• Margins are characteristically ill-defined, blending imperceptibly into adjacent normal bone without a distinct radiolucent or radiopaque border — a hallmark that distinguishes FD from encapsulated neoplasms[8]
• The lesion produces fusiform expansion of the affected bone, maintaining the general contour of the jaw while increasing its volume[8]
• Buccal and lingual cortices become thinned but are rarely interrupted[8]

Internal Architecture

Four radiographic patterns have been described in the jaws of MAS patients on panoramic radiography:[15]

• Ground glass (granular/condensed trabeculae) — the most recognized pattern, producing a diffuse, homogeneous, finely granular opacity classically described as "orange-peel" or "fingerprint"[8][15]
• Radiolucent (lytic) — predominates in early or immature lesions where fibrous tissue exceeds mineralized matrix[8]
• Mixed radiolucent-radiopaque — common in older patients and those treated with bisphosphonates[5]
• Radiopaque (sclerotic) — seen in mature or treated lesions[15]

The radiographic appearance evolves with age: the homogeneous ground-glass pattern is most common during childhood and adolescence, whereas lesions become increasingly heterogeneous, mixed, and sclerotic with skeletal maturation.[5] No statistically significant association has been found between radiographic pattern and specific endocrinopathies or renal phosphate wasting.[15]

Effects on Teeth and Adjacent Structures

• Tooth displacement and rotation: Teeth within or adjacent to the lesion may be displaced, with root splaying around the expanding lesion; the overall arch form is typically preserved[5]
• Loss of lamina dura: The periodontal ligament space becomes indistinct and the lamina dura is obscured where teeth are embedded in dysplastic bone[5]
• Root changes: Splaying, dilaceration, and occasional blunting of roots have been described[5]
• Inferior alveolar canal displacement: Superior displacement of the mandibular canal is a characteristic finding and has been described as nearly pathognomonic for mandibular FD[8]
• Maxillary sinus: Displacement of the sinus floor superiorly, with progressive reduction in sinus volume up to complete obliteration, is common in maxillary lesions[8][15]

Extent and Cortical Involvement

Volumetric imaging demonstrates the full extent of craniofacial involvement, which frequently crosses suture lines into contiguous bones — a feature that distinguishes craniofacial FD from monostotic disease.[8] Cortical thinning with endosteal scalloping is characteristic; cortical breakthrough is uncommon and, when present, should raise concern for secondary pathology such as aneurysmal bone cyst or sarcomatous transformation.[5][8]

Variants and Age-Related Changes

• Cystic degeneration: Occasionally reported within gnathic FD lesions[8]
• Secondary aneurysmal bone cyst: Rare; presents as a rapidly expanding lytic component within a pre-existing FD lesion[5]
• Sclerosis of the cranial base: Common in craniofacial FD, particularly involving the sphenoid and skull base[8]

CT (Medical)

CT is the technique of choice for defining the margins and full extent of craniofacial FD.[8][16] Axial and coronal images demonstrate the characteristic ground-glass density of the expanded bone, the degree of sinus obliteration, and the relationship to the optic canal, auditory canal, and orbital structures.[17][18] On CT, FD typically appears as homogeneous ground-glass attenuation replacing the medullary space, with smooth expansion and cortical thinning.[19] Heterogeneous mixed-density lesions with both sclerotic and cystic components may be seen in extensive polyostotic disease.[20] CT differentiates FD from Paget disease of the skull by the presence of ground-glass density, sinus and orbital involvement, and thinner cortices in FD versus symmetric cranial thickening with thick cortices in Paget disease.[19][21]

MRI

MRI signal intensity in FD is variable: lesions are predominantly hypointense on T1-weighted images and show variable (often hyperintense) signal on T2-weighted sequences.[22] Contrast enhancement is common.[22] MRI is particularly valuable when hemorrhagic or cystic changes are suspected, and for evaluating potential sarcomatous transformation, which may show heterogeneous enhancement and soft-tissue extension.[8][22]

Nuclear Medicine

Technetium-99m bone scintigraphy demonstrates intense, homogeneous tracer uptake at FD sites and is useful for identifying subclinical lesions, confirming polyostotic involvement, and assessing lesion activity. ¹⁸F-sodium fluoride PET/CT provides quantitative assessment of lesion metabolic activity and has been used to monitor treatment response, particularly with denosumab.[8][17][23]

The differential diagnosis of jaw involvement in MAS centers on distinguishing polyostotic FD from other fibro-osseous and expansile lesions. The syndromic context (café-au-lait macules, endocrinopathies, polyostotic distribution) usually narrows the diagnosis, but individual jaw lesions may require differentiation from the following entities:

The highest-risk diagnostic pitfall is misidentifying an ossifying fibroma as FD (or vice versa), because ossifying fibroma requires complete surgical excision whereas FD is managed conservatively.[5][24] When histologic and radiographic overlap creates uncertainty, GNAS mutation analysis reliably distinguishes FD (mutation-positive) from ossifying fibroma and other mimics (mutation-negative).[25][28]

Microscopic Features

FD is characterized by a cellular fibroblastic stroma composed of bland, fusiform spindle cells without atypia, interspersed with irregularly shaped trabeculae of immature woven bone:[8][29]

• Bone trabeculae: Irregularly curved, branching, and serpentine — classically described as resembling "Chinese characters" or "alphabet soup". Osteoblastic rimming is typically absent or inconspicuous.[8][29]
• Artifactual peritrabecular clefting: A characteristic histologic finding that helps distinguish FD from ossifying fibroma.[8]
• Microscopic homogeneity: The ratio of fibrous tissue to bony trabeculae is relatively uniform throughout a given lesion, an important diagnostic feature.[8]
• Non-encapsulated margins: Lesional tissue merges with peripheral cortical bone without a capsule, correlating with the ill-defined radiographic margins.[8]

Site-Specific Histologic Patterns

Three distinct histologic patterns have been identified in FD, with site-specific predilection:[29]

• Chinese writing type — axial and appendicular skeleton
• Sclerotic/Pagetoid type — cranial bones
• Sclerotic/hypercellular type — gnathic (jaw) bones

In craniofacial FD, particularly in mature lesions, lamellar bone maturation may be seen, which is uncommon at other skeletal sites.[8][26]

Molecular Pathology

Activating missense mutations at GNAS codon R201 are detectable in approximately 50–88% of FD lesions using standard PCR-based methods; sensitivity can be enhanced with peptide nucleic acid clamping or pyrosequencing.[30][31] GNAS mutations are absent in ossifying fibroma, cemento-osseous dysplasia, and chronic diffuse sclerosing osteomyelitis, making mutation analysis a reliable discriminator.[25][28] Rare sarcomatous transformation (osteosarcoma) may retain the GNAS mutation.[30]

Workup and Referral

All patients with suspected MAS require comprehensive endocrine evaluation, including assessment for precocious puberty, hyperthyroidism, growth hormone excess, hypercortisolism, and FGF23-mediated renal phosphate wasting.[1][11] Serum alkaline phosphatase and bone turnover markers correlate with skeletal disease burden.[32] Baseline maxillofacial CT defines the extent of craniofacial involvement. Audiologic and ophthalmologic evaluation is indicated when the auditory canal or orbit is involved.[5]

Medical Treatment

• Bisphosphonates: Intravenous bisphosphonates (e.g., pamidronate) may reduce bone pain and bone resorption markers; oral bisphosphonates have not demonstrated significant pain reduction in randomized trials. Response to bisphosphonate therapy is more limited in MAS than in non-syndromic polyostotic FD, largely due to higher skeletal disease burden.[32][33]
• Denosumab: RANKL inhibition with denosumab has shown promising reductions in lesion activity (assessed by ¹⁸F-NaF PET/CT) and bone turnover markers. However, rebound hypercalcemia after discontinuation is a serious safety concern, particularly in patients with high disease burden.[23][34]
• Endocrine management: Treatment of underlying endocrinopathies (aromatase inhibitors for precocious puberty, somatostatin analogues or pegvisomant for growth hormone excess, antithyroid agents) is essential and should precede elective surgery, as untreated growth hormone excess is associated with increased postoperative regrowth.[5]

Surgical Management

Surgery remains the cornerstone of treatment for symptomatic craniofacial FD:[5][35]

• Conservative contouring/debulking is the most common procedure but carries a high rate of regrowth (reported at 68–82%)[5][36]
• Radical resection with reconstruction has a lower recurrence rate (~45%) but greater morbidity[5]
• Elective procedures are generally deferred until after skeletal maturity, when lesion growth tends to stabilize[5]
• Therapeutic optic nerve decompression is indicated for progressive visual loss; prophylactic decompression is not routinely recommended[5][35]

Prognosis

FD lesions typically become less active after skeletal maturity.[5] Sarcomatous transformation occurs in fewer than 1% of patients.[5][7] Long-term surveillance with periodic clinical examination and imaging is recommended to monitor for lesion reactivation, late complications, and the rare possibility of malignant transformation.[16]

Pediatric Issues

Most MAS patients present in childhood, and craniofacial FD lesions are among the earliest to manifest.[5] Dental developmental disturbances — including malocclusion, retained primary teeth, taurodontism, and enamel hypoplasia — are common and may require early orthodontic intervention.[5][14] Orthodontic treatment has shown long-term stability in most patients, though close monitoring for disease progression is essential.[14]

Growth Hormone Excess

Growth hormone excess, present in up to 20% of MAS patients, is associated with more severe craniofacial FD and increased postoperative regrowth.[5][13] Screening and treatment of growth hormone excess before elective craniofacial surgery is strongly recommended.[5]

Dental Treatment Considerations

Clinicians have historically expressed concern that dental surgery may activate quiescent jaw FD lesions; however, biopsies have not been associated with regrowth, in contrast to more extensive surgical procedures.[4][5] Loss of normal anatomic landmarks (lamina dura, inferior alveolar canal) complicates dental extractions and implant planning, necessitating advanced imaging before invasive procedures.[5]