Fibrous Dysplasia / McCune Albright syndrome (FD/MAS) represents a wide spectrum of diseases due to somatic gain-of-function mutations of the GNAS gene. The mutation leads to overactivity in the target tissues and to a wide phenotype of clinical features that vary in severity and age of onset. The rarity of the disease and its variable presentation to multiple specialities often leads to misdiagnosis and inappropriate variability in investigations and treatments. To address this, our international consortium of clinicians, researchers, and patients’ advocates has developed pragmatic clinical guidelines for best clinical practice for the definition, diagnosis, staging, treatment and monitoring for FD/MAS to empower patients and support clinical teams in both general and specialised healthcare settings. With the lack of strong evidence to inform care, the guidelines were developed based on review of published literature, long-standing extensive experience of authors, input from other healthcare professionals involved in the care of FD/MAS patients and feedback from patients and patient groups across the globe. This has led to the formulation of a set of statements to inform healthcare professionals, patients, their families, carers and patient groups of the best practice of care. It is anticipated the implementation of these recommendations will lead to improvement in the care of patients with FD/MAS internationally. Electronic supplementary material The online version of this article (10.1186/s13023-019-1102-9) contains supplementary material, which is available to authorized users.
Fibrous dysplasia (FD) is a skeletal disease caused by somatic activating mutations of the cAMP-regulating protein, Gsα. These mutations lead to replacement of normal bone by proliferative osteogenic precursors, resulting in deformity, fracture, and pain. Medical treatment has been ineffective in altering the disease course. RANK ligand (RANKL) is a cell surface protein involved in many cellular processes, including osteoclastogenesis, and is reported to be overexpressed in FD-like bone cells. Denosumab is a humanized monoclonal antibody to RANKL approved for treatment of osteoporosis and prevention of skeletal-related events from bone metastases. We present the case of a 9-year-old boy with severe FD who was treated with denosumab for a rapidly expanding femoral lesion. Immunohistochemical staining on a pre-treatment bone biopsy specimen revealed marked RANKL expression. He was started on monthly denosumab, with an initial starting dose of 1 mg/kg and planned 0.25 mg/kg dose escalations every three months. Over seven months of treatment he showed marked reduction in pain, bone turnover markers, and tumor growth rate. Denosumab did not appear to impair healing of a femoral fracture that occurred while on treatment. With initiation of treatment he developed hypophosphatemia and secondary hyperparathyroidism, necessitating supplementation with phosphorus, calcium and calcitriol. Bone turnover markers (BTM) showed rapid and sustained suppression. With discontinuation there was rapid and dramatic rebound of BTM) with CTX (reflecting osteoclast activity) exceeding pre-treatment levels, and accompanied by severe hypercalcemia. In this child, denosumab lead to dramatic reduction of FD expansion and FD-related bone pain. Denosumab was associated with clinically significant disturbances of mineral metabolism both while on treatment and after discontinuation. Denosumab treatment of FD warrants further study to confirm efficacy and determine potential morbidity, as well as to determine the mechanism of RANKL in the pathogenesis of FD and related bone marrow stromal cell diseases.
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.
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