The Skeletal Clinical Studies Program studies human diseases as model systems through which physiologic mechanisms of skeletal and mineral metabolism can be elucidated. This is done through meticulous clinical studies of model human diseases that allow for the study of specific aspects of skeletal biology and mineral metabolism. Observations lead to testable clinical and translational hypotheses, and evidenced-based treatments for the diseases studied. These studies have focused on fibrous dysplasia (FD)/McCune-Albright syndrome (MAS), a disease of the bone marrow stromal cell and multiple endocrine organs, and more recently on patients with tumor-induced osteomalacia (TIO), and hypoparathyroidism ? disorders of phosphate, vitamin D, and FGF-23 metabolism. ? ? Studies in FD/MAS were carried out through several clinical protocols (98-D-0145, 98-D-0146, and 01-D-0197). FD is a rare skeletal disease, caused by somatic activating mutations in the G-protein, Gs-alpha, encoded by the GNAS gene. These mutations result in ligand-independent cAMP signaling in affected tissues. In the skeleton, this leads to replacement of normal bone by mechanically unsound fibroosseous tissue. FD can occur in isolation or as part of the MAS, defined clinically by some combination of FD, cafe-au-lait skin spots, and hyperfunctioning endocrinopathies. The skin and endocrine lesions are the tissue-specific manifestations of the GNAS mutations.? ? What specific aspects of FD in children, in terms of location, severity, etc. are related to, and perhaps cause, impairment in functional outcome are not known. Understanding these aspects of the disease may lead to better interventions or studies to test interventions. We studied bone scans, skeletal surveys, and medical records of FD patients and correlated these data to the Pediatric Outcomes Data Collection Instrument (PODCI), a validated instrument used for the study pediatric orthopedic diseases. Twenty-eight of 33 patients >16 years old and enrolled in a natural history study responded to the PODCI questionnaire. The mean standardized PODCI scales for all 28 patients were lowest for sports (62, range 14-100) and happiness (72, range 25-100). Adolescents and parents disagreed with each other over sports (the adolescents reported higher scores than their parents), and pain (parental scores were higher than adolescent scores). However, the overall global scales correlated well between the parents and adolescents. The femoral neck shaft angle correlated strongly with the PODCI scale for sports, but not for transfers. The SDBS for the lower extremity disease burden correlated to both transfers and sports. Neither deformity of the limbs, presence of scoliosis, prevalence of endocrine dysfunction, nor the number of fractures correlated with the PODCI scales. The loss of the normal neck shaft angle and the disease burden in the lower extremities appear to have the greatest effect on functional activity. Correction of the neck shaft angle may be a potential intervention to improve the quality of life in patients with FD. ? ? Growth hormone (GH) excess affects approximately 20% of the patients with McCune-Albright Syndrome (MAS), and untreated it is a major source of morbidity, especially in the craniofacial region. The best treatment for this group of patients is unknown. To see if there was an advantage to a newly developed medicinal that is an antagonist of the GH receptor in MAS patients with disease of this specific molecular etiology, we examined efficacy of the GH receptor antagonist, pegvisomant. Five MAS patients with GH excess were treated with pegvisomant for 12 weeks in a randomized, double blind placebo-controlled crossover study. The primary measure of efficacy was normalization of insulin growth factor I (IGF-I), and secondary outcome measures were reduction in serum IGF binding protein-3 (IGFBP-3), improvement of fatigue and sweating, and reduction in markers of bone metabolism and bone pain. Combined mean changes in serum IGF-I at 6 and 12 weeks were a decrease of 53% and 62%, respectively. IGF1BP-3 decreased by 24% and 37%, respectively. There were no significant changes in signs and symptoms of acromegaly, or markers of bone metabolism and bone pain, nor was there a significant change in pituitary size. Retrospective comparison of the degree of control achieved with pegvisomant versus other medications (long-acting octreotide ? dopamine agonist) in the same group showed the two regimens were similarly effective. We concluded that pegvisomant effectively reduced IGF-I and IGFBP-3 levels in GH excess caused by Gs-alpha mutations, but had no effect on FD. ? ? GH is becoming widely used clinically in adults for GH replacement. The long-term safety and efficacy remain to be established. Related to this is the long-debated association between growth hormone (GH) replacement and malignancy. We reported a case of Hodgkin lymphoma that developed in temporal association with the initiation of GH replacement in a 57-year-old woman with panhypopituitarism. Her treatment course included transphenoidal surgery, external beam radiation, bromocriptine, cabergoline, and eventually, GH replacement therapy. Approximately 2 years after GH replacement therapy, the diagnosis of Hodgkin lymphoma was made. Although the exact contribution of GH to development of Hodgkin disease in this patient is unclear and a causal effect cannot be concluded, the temporal association is suggestive, and warrants reporting as part of ongoing surveillance for potential complications of GH replacement. ? ? A major current focus of the Skeletal Clinical Studies Program, which arose out of the study of FD, is the study of FGF-23. FGF-23 is a recently-described hormone that has been demonstrated to be involved in the regulation of phosphate and vitamin D metabolism. The physiologic role of FGF-23 in mineral metabolism and how serum FGF-23 levels are regulated have yet to be elucidated. To better understand FGF-23 regulation, 3 patients with mineral metabolism defects were studied. Patient 1 had post surgical hypoparathyroidism and was treated with a pharmacologic dose of calcitriol. Patient 2 had post surgical hypoparathyroidism and FD. She was treated with increasing doses of calcitriol followed by synthetic PTH 1-34. Patient 3 had pseudohypoparathyroidism type 1B (a kidney-specific genetic defect in vitamin D metabolism) and tertiary hyperparathyroidism. She underwent parathyroidectomy that was followed by the development of hungry bone syndrome and hypocalcemia requiring treatment with calcitriol. Serum FGF-23 and serum and urine levels of mineral metabolites were measured in all 3 patients. Patient 1 had an acute and marked increase in serum FGF-23 (70-670 RU/ml, normal range 18-108) within 24 hours in response to high-dose calcitriol administration. Patient 2 demonstrated stepwise increases in serum FGF-23 (117-824 RU/ml) in response to increasing serum levels of 1,25-D. Finally, prior to parathyroidectomy, while hypercalcemic, euphosphatemic, with low levels of 1,25-D (10 pg/ml, normal 22-67), and very high serum PTH (863.7 pg/ml, normal 6.0-40.0), patient 3 had high serum FGF-23 levels (217 RU/ml). Following surgery, while hypocalcemic, euphosphatemic and with high serum levels of serum 1,25-D (140 pg/ml), FGF-23 levels were higher than preoperative levels (305 RU/ml). These data demonstrate the serum FGF-23 levels are regulated by serum 1,25-D (likely more so than by serum phosphorus), and that the phosphaturic effect of FGF-23 is, at least in part, modulated by PTH. These data also leave open the question of a role for either calcium and/or PTH in FGF-23 regulation and emphasize the need for further studies in appropriate human disease models to answer these questions.

National Institute of Health (NIH)
National Institute of Dental & Craniofacial Research (NIDCR)
Intramural Research (Z01)
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Dental & Craniofacial Research
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Robinson, Cemre; Estrada, Andrea; Zaheer, Atif et al. (2018) Clinical and Radiographic Gastrointestinal Abnormalities in McCune-Albright Syndrome. J Clin Endocrinol Metab 103:4293-4303
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