A. FD/MAS. Our work in FD/MAS is focused on two broad areas: 1) the pathophysiology and natural history of the disease, and 2) treatment. (40% effort) To better understand the underlying pathophysiology and best treatment of pituitary disease in FD/MAS, we studied the pituitary glands for 4 patients with FD/MAS and GH excess who underwent hypophysectomy. We identified widespread and diffuse pituitary gland disease. The primary pathologic changes were characterized by hyperplastic and neoplastic change, and overrepresentation of somatotroph cells in structurally intact tissue areas. Genetic analysis of multiple microdissected samples revealed identical Gs alpha mutations in individual patients. The only desirable surgical outcome was in a patient who received complete hypophysectomy. These findings indicate developmental effects of Gs alpha mutation on the pituitary gland. Since the underlying change in MAS patients is somatotroph hyperplasia involving the entire pituitary gland, successful clinical management must target the entire pituitary, not just the adenomas evident on imaging. The gonadal phenotype in males with McCune-Albright syndrome (MAS) is not well characterized. Relative to girls, boys have a relatively low incidence of precocious puberty. To characterize the biochemical, radiologic, and histologic spectrum and clinical management of testicular pathology in males with MAS, we conducted a retrospective analysis of the 54 males followed prospectively in the NIH cohort. We found, 44 (81%) presented with ultrasound abnormalities including hyperechoic lesions (49%), hypoechoic lesions (30%), microlithiasis (30%), heterogeneity (47%), and focal calcifications (11%). Eight subjects underwent orchiectomy revealing large foci of Leydig cell hyperplasia (LCH). Because no subjects developed malignancy, a conservative approach was instituted and subsequent subjects were followed with serial imaging. Testosterone and gonadotropins were normal in subjects without precocious puberty (PP) or pituitary disease. Eleven (21%) subjects presented with PP. A combination of aromatase inhibitors, androgen receptor blockers, and leuprolide resulted in improved predicted adult height. In addition, the first cases of testicular adrenal rest and bilateral germ cell tumors in association with MAS were presented. These data made clear that contrary to prevailing thinking, the incidence of gonadal pathology in MAS is equal in males and females. The predominant histopathological finding was LCH, which carries a low risk of malignant transformation and can be managed conservatively. To date medical treatment of FD 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. To better understand the role of RANKL in the underlying pathophysiology of FD, as well as to develop a better treatment for FD, we treated a 9-year-old boy with severe FD and a rapidly expanding FD lesion with denosumab. Immunohistochemical staining on a pre-treatment bone biopsy specimen revealed marked RANKL expression. He was treated monthly, with an initial 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 resorption markers exceeding pre-treatment levels. This was accompanied by severe hypercalcemia. Denosumab lead to dramatic reduction of FD expansion and FD-related bone pain. Treatment was associated with clinically significant disturbances of mineral metabolism both on treatment and after discontinuation. Denosumab treatment of FD warrants further study. Studies in the pathophysiology of RANKL are ongoing. B. FGF23. The work in FGF23 is currently focused on the molecular biology of FGF23 in terms of transcription, translation and processing, and the study and treatment of patients with disorders of FGF23 excess. (40% effort) FGF23 circulates in both active (intact, iFGF23) and inactive (C-terminal, cFGF23) forms. O-glycosylation by ppGalNAcT3 and differential cleavage by furin have been shown to be involved in regulating the ratio of active to inactive FGF23. FD is associated with increased total FGF23 levels (cFGF23 + iFGF23);however, classic hypophosphatemic rickets is uncommon. This could be explained by increased FGF23 cleavage leading to an increase in inactive cFGF23 relative to active iFGF23. Given the fact that FD is caused by activating mutations in Gs alpha that results in increased cAMP levels, we postulated that there may be altered FGF23 cleavage in FD and that the mechanism may involve alterations in cAMP levels, and ppGalNacT3 and furin activities. Analysis confirmed that the elevated total FGF23 levels are due to proportionally increased cFGF23 levels, consistent with less glycosylation and enhanced cleavage by furin. Analysis of primary cell lines of FD and normal bone marrow stromal cells (BMSCs) demonstrated that BMSCs harboring the causative Gs alpha mutation had higher cAMP levels, lower ppGalNAcT3 and higher furin activity. These data support the model wherein glycosylation by ppGalNAcT3 inhibits FGF23 cleavage by furin, and suggest that FGF23 processing is a regulated process that controls overall FGF23 activity in FD patients. This finding has important implications for the treatment of disorders of FGF23 excess. C. Hypoparathyroidism. Skeletal findings in hypoparathyroidism (and its treatment with PTH) are a reflection of the loss and gain of activation of the GPCR/cAMP/PKA pathway in bone. Study of bone from untreated and PTH-treated patients offers an opportunity to better understand this pathway in bone. (20% effort) We treated five hypoparathyroid patients with synthetic human PTH 1-34 (hPTH 1-34), and collected blood and iliac crest biopsy specimens. hPTH 1-34 significantly increased bone markers to supranormal levels. Histomorphometry revealed that hPTH 1-34 significantly increased cancellous bone volume and trabecular number and further decreased trabecular separation. Trabecular width did not change, suggesting that the increase in trabecular number was due to intratrabecular tunneling. Cortical porosity/cortical area also significantly increased. Cancellous bone remodeling was decreased at baseline but increased above normal after hPTH 1-34. Similar changes were seen in endocortical and intracortical remodeling. BMD Z-scores did not change at the lumbar spine or femoral neck. Total hip Z-scores increased over the 18 months of treatment, however, total body BMD Z-scores decreased during the first 6 months of treatment and then stabilized, remaining significantly decreased compared to baseline. Radial Z-scores also decreased gradually with treatment. Daily hPTH 1-34 therapy for hypoparathyroidism stimulated bone turnover, increased bone volume, and altered bone structure in the iliac crest. The increased cortical porosity and decreased BMD Z-scores in the radius and total body suggest that replacement hPTH 1-34 may have varying effects in the different compartments of bone in hypoparathyroidism.

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National Institute of Dental & Craniofacial Research
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