Fibrous Dysplasia/McCune-Albright Syndrome: A Rare, Mosaic Disease of Gα s Activation

Abstract

Fibrous dysplasia/McCune-Albright syndrome (FD/MAS) is a rare disorder of striking complexity. It arises from somatic, gain-of-function mutations in GNAS, leading to mosaic Gα s activation and inappropriate production of intracellular cyclic adenosine monophosphate (cAMP). The clinical phenotype is largely determined by the location and extent of affected tissues, and the pathophysiological effects of Gα s activation within these tissues. In bone, Gα s activation results in impaired differentiation of skeletal stem cells, leading to discrete skeletal lesions prone to fracture, deformity, and pain. Extraskeletal manifestations include a variable combination of hyperpigmented macules and hyperfunctioning endocrinopathies. Distinctive age-related changes in disease development has key effects on histologic, radiographic, and clinical features. FD/MAS thus presents along a uniquely broad clinical spectrum, and the resulting challenges in diagnosis and management can be difficult for clinicians. This review presents FD/MAS in the context of a mosaic disorder of Gα s activation, providing an intellectual framework within which to understand, evaluate, and treat this interesting disease. It includes a comprehensive summary of current understanding of FD/MAS pathogenesis, and a detailed discussion of clinical presentation and management. Critical areas of unmet need are highlighted, including discussion of key challenges and potential solutions to advance research and clinical care in FD/MAS.

Keywords: fibroblast growth factor 23; growth hormone excess; metabolic bone disease; precocious puberty; skeletal stem cells; somatic mosaicism.

Graphical Abstract

Figure 1.

G_s G-protein-coupled signaling dysregulation in FD/MAS. In the inactive state, the αβγ-heterotrimer is bound to GDP. After ligand binding, the GTP-bound α-subunit dissociates from the βγ-complex and activates adenylyl cyclase, leading to production of intracellular cyclic AMP and activation of protein kinase A and other downstream signaling pathways. Activating GNAS mutations in FD/MAS results in loss of GTPase activity in the α-subunit, resulting in constitutive Gα _s protein signaling. Alternatively, the mutant GDP-bound Gα _s may also interact with adenylyl cyclase to generate cAMP. ATP indicates adenosine triphosphate; cAMP, cyclic adenosine monophosphate; CREB, cyclic adenosine monophosphate response element-binding protein; FD/MAS, fibrous dysplasia/McCune-Albright syndrome; GDP, guanosine diphosphate; GPCR, G-coupled protein receptor; GTP, guanosine triphosphate.

Figure 2.

Representative histological features of fibrous dysplasia (FD). A and B show low-power and high-power views of an FD lesion with classic dense, irregular trabeculae and marrow fibrosis (ft). Massive de novo bone formation is apparent throughout, including areas of woven bone (wb) with prominent unmineralized osteoid (o). Collagen fibers are perpendicularly oriented along forming bone surfaces, also termed Sharpey fibers (black arrows). An osteoclastic giant cell is actively resorbing an area of abnormal bone (white arrow). Note the presence of high vascularity with a red blood cell-filled vessel coursing through the lesion adjacent to an area of venous pooling (black arrowhead).

Figure 3.

Skeletal deformities and radiographic findings in patients with fibrous dysplasia (FD). A, Images of a patient with a bowing deformity of the proximal upper extremity. Radiographs reveal extensive FD involvement, including an expansile humeral lesion demonstrating severe cortical thinning and a characteristic “ground-glass” appearance. B, A patient with coxa vara deformity proximally (at the hip) and genu valgum deformity distally (at the knees). Note the leg length discrepancy with the resulting asymmetry of the knees apparent in the photograph. This patient’s radiographs demonstrate diffuse FD involvement of the lower extremities with cortical thinning and “ground-glass” radiolucency. Plate and nail implants have been placed in the bilateral proximal femurs to correct shepherd’s crook deformities (yellow arrows). Note the presence of an 8-plate initially implanted in the distal femoral epiphyses, which has migrated proximally during skeletal growth (yellow star). This implant was intended to treat leg length discrepancy by slowing growth in the left leg, which is unfortunately now shorter than the right. C, Posterior view of a patient with severe spinal curvature, resulting in shortening of the torso and asymmetry of the shoulders and scapulae. This patient’s radiographs demonstrate severe thoracic scoliosis with loss of lung volumes bilaterally. Reproduced with permission from Hartley I et al. (24).

Figure 4.

Progression of craniofacial fibrous dysplasia (FD) in a patient with uncontrolled growth hormone excess. A, B, and C, Upper panels show computed tomography (CT) images at age 4 years. Note mild expansion of the left mandible (red arrows) and zygomatic bone (green arrows) visible on A and B, 3-dimensional (3D) reconstruction. C, An axial view demonstrates the characteristic homogenous. A patent optic canal surrounded by FD is visible on the right (white arrow). The left optic canal (not depicted) is also patent. D, E, and F lower panels show images from the same patient at age 17 after 13 additional years of uncontrolled growth hormone excess. D and E, On 3D reconstruction the left mandible has massively expanded (red arrows), leading to severe malocclusion and distorted dentition. The zygomatic bones are now expanded bilaterally (green arrows) with resulting orbital asymmetry. E, Note the severe macrocephaly with enlargement of the posterior cranium leading to a scaphocephalic appearance. F, An axial view demonstrates typical age-related changes with increased heterogeneity and areas of radiolucency. The left optic canal is visible and severely narrowed (white arrow), and the patient is unfortunately now blind.

Figure 5.

Radiographic features of endocrine disease in patients with McCune-Albright syndrome. A, Testicular ultrasound images show extensive right-sided involvement with mixed radiolucent and radio-opaque lesions involving most of the testis (red arrowheads). The left side is unaffected and demonstrates a normal homogeneous echotexture. B, A thyroid ultrasound shows diffuse involvement with heterogeneous mixed radiolucent and radio-opaque lesions, resulting in a spongiform appearance. C, A pelvic ultrasound from a 2-year-old girl shows a complex ovarian cyst (white arrow). Note the enlarged, mature-appearing uterus (blue arrowheads) that has grown under the influence of hyperestrogenism. D, An MR image from a patient with growth hormone excess shows pituitary enlargement and a hypoechoic area (white arrow) consistent with an adenoma. Note the expanded skull base involved with fibrous dysplasia (yellow star).

Figure 6.

Typical café-au-lait macules in patients with McCune-Albright syndrome. A, Lesions in a young child involving the lower back and buttocks approach but do not cross the midline of the body. Note the relatively even borders on the back lesions, whereas the buttock lesions show irregular borders. An osteotomy scar related to a femoral fixation procedure is visible on the right lateral buttock. B, A lesion involving the neck and shoulder of a young adult terminates sharply at the midline, with serpiginous borders involving the lateral aspects. C, An extensive lesion involving the neck and upper trunk of a young child extends past the midline. A port visible in the right lower chest was placed to facilitate intravenous access during a period of neonatal hypercortisolism. D, A lower extremity lesion in an adolescent extends downward from the upper medial thigh to the calf area.

Figure 7.

Radiographic features of fibrous dysplasia (FD). A, B, and C, Upper panels demonstrate age-related radiographic changes in 3 patients with diffuse femoral involvement. A, In a 6-month-old patient, FD appears heterogeneous with streak-like features. Note the irregular metaphyses resulting from uncontrolled FGF23-mediated hypophosphatemia (yellow arrowhead). B, Radiograph from a 6-year-old demonstrates the classic “ground-glass” homogeneity. C, In a 31-year-old, FD again appears heterogeneous, with sclerotic areas interspersed with areas of radiolucency. D and E, Lower panels depict nuclear medicine scan images used to evaluate total skeletal FD burden. D, Technetium-99 scintigraphy scan in a young child with near panostotic disease shows increased tracer uptake in most of the skeleton, including the skull, spine, and long bones (red arrows). Note the symmetric increased uptake at the metaphyses in this growing child. E, ¹⁸F-NaF PET/CT scan in an adult with mild disease shows tracer uptake in areas of FD involving the skull, ribs, and left tibia (red arrows). Note the superior resolution and anatomical characterization of ¹⁸F-NaF in comparison to technetium.