Fibrous dysplasia/McCune-Albright Syndrome

Filled Under: ATTI - XVI CONGRESSO NAZIONALE SIOMMMS 2016

Year: 2016

Number: 3/4

Author: and

Fibrous dysplasia/McCune-Albright Syndrome

Fibrous dysplasia (FD) is an uncommon skeletal disorder resulting in fractures, deformity, pain, and functional impairment. It may affect one bone (monostotic) or multiple (polyostotic) and may occur isolately or in combination with café-au-lait spots and hyperfunctioning endocrinopathies, termed McCune-Albright syndrome (MAS). FD/MAS is caused by somatic activating mutations in GNAS which induces the expression of α-subunit of the Gs stimulatory protein (Gsα). FD/MAS arises sporadically (postzygotic GNAS mutations with somatic mosaic disease state). Mosaicism is apparent in the clinical features of FD/MAS, including patchy bone disease occurring along a broad spectrum of distribution, which can range from an isolated, trivial lesion to severe disease involving nearly the entire skeleton. FD is a disease of post-natal skeletal stem cells. In bone, constitutive Gsα activation gives rise to bone marrow stromal cells (BMSCs) with impaired capacity to differentiate toward mature osteoblasts, adipocytes, and hematopoiesis-supporting stroma. Bone and bone marrow are thus replaced by proliferating BMSCs, resulting in fibro-osseous tissue devoid of hematopoietic marrow. Bone lesions are typically not apparent at birth and begin to manifest clinically during the first few years of life frequently with fractures in the appendicular skeleton. FD in the craniofacial region may cause facial deformity and rarely functional deficits, including vision and hearing loss. Evaluation and treatment of endocrinopathies are an important component of management in FD/MAS, because endocrine dysfunction can exacerbate skeletal disease. In particular, growth hormone excess (increasing bone turn over) as well as hypophosphatemia and rickets/osteomalacia, are associated with increased risk of fractures. Activating GNAS mutations in FD/MAS are weak oncogenes and may cause a small increased risk of malignant transformation in affected tissues including bone. Treatment for FD lesions is mainly palliative, with an emphasis on optimizing function and minimizing morbidity related to deformities and fractures. Surgical management in the craniofacial skeleton is complicated by frequent post-operative FD regrowth and should focus on correction of functional deformities (optic nerve decompression). Antiresorptive therapy with bisphosphonates has been advocated due to high levels of bone resorption frequently seen in FD tissue. Early, uncontrolled series reported improvements in bone pain, with variable effects on FD radiographic appearance. A 2-year randomized, placebo-controlled trial of alendronate did not demonstrate an improvement in FD- related bone pain, radiographic appearance, or skeletal disease burden. Based on these data, oral bisphosphonates are not likely to be effective in altering the disease course in FD; however, more potent intravenous formulations may be helpful for persistent, moderate to severe pain, although in our experience with only marginal effects on biochemical markers of bone turn over. Sporadic cases have been reported with the use of denosumab in FD/MAS. The rationale for using denosumab in FD does exist but controlled studies are need to establish its efficacy. When associated with MAS, diagnosis of acromegaly may be difficult due to pre(co)-existing skeletal deformities. Also, therapeutic approach can relevantly differ from what is reported in the available guidelines. In fact, neurosurgery are hampered by skull bone deformities, radiotherapy is not recommended due to the risk of osteo-sarcoma and MAS-associated acromegaly is apparently less responsive to somatostatin analogs (SRLs). The combination of SRLs with the growth hormone antagonist pegvisomant improves biochemical control without pituitary adenoma growth and may be suggested as primary treatment in these rare patients. However, in our experience it is necessary to progressively increase the dose of pegvisomant since the patients may develop resistance to the lower doses of the drug. Biochemical control of acromegaly in combination with intravenous bisphosphonates or denosumab may be advocated for an optimal management of increased bone turn over in MAS.

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