Fibrous Dysplasia/McCune-Albright Syndrome:? ? Two studies examined the clinical spectrum and natural history of FD. The first, by Hart el al, characterized the onset, progression, and plateau of skeletal lesions in FD, and how the extent of disease correlated with functional outcomes. The second, by Kelly et al, examined pain in FD; the extent and natural history of painful skeletal disease, and which treatments were effective. ? ? In the study by Hart et al, we evaluated 109 subjects with FD who had been studied at the NIH for up to 32 years. We found that 90% of the skeletal disease burden was established by age 15. Disease was established in a region-specific pattern: 90% of the lesions were established in the craniofacial region by 3.4 years, in the extremities by age 13.7, and in the axial skeleton by age 15.5. Twenty-five out of 103 subjects eventually required ambulatory aids. The median age at which assistance was required was 7 (range 1-43). The median bone scan score for subjects requiring assistance was 64.3 (range 18.6-75) compared to 23.1 (range 0.5-63.5) in the unassisted subjects (p<0.0001). Amongst subjects requiring assistance with ambulation, 92% demonstrated this need by 17 yr. This study established that the majority of skeletal lesions and the associated functional disability in FD occur within the first decade of life. The implication is that the window of time for preventative therapies is narrow, and that studies designed to do so must begin treating subjects at an early age. In addition, these data also allow clinicians to reassure most parents that their children will not progress to significant dysfunction. ? ? While pain was known to be associated with FD, its prevalence and severity, and which skeletal sites are most likely to be painful was not known. In this study, we set out to determine prevalence, severity, and distribution of painful skeletal lesions, what the natural history of the pain was, and what treatments were effective. This was a cross sectional, retrospective review of the NIH cohort of patients with FD. We studied 35 children and 43 adults, and found that pain at sites of FD was common, reported by 67% of the population. Pain was more common and severe in adults than in children (81% and 49%, respectively p<0.005, severity 4.1/10, and 2.8/10, respectively, p<0.01). Surprisingly, there was no correlation between pain severity and skeletal disease burden. A disturbing finding was that children were more likely than adults to be untreated for pain (44% vs. 26%). We concluded that pain, which was sometimes severe, was common in FD and was often under-treated, especially in children. The prevalence and severity of pain was greater in adults, but was unrelated to the burden of FD. The increase in pain is neither due to more fractures, which are more common in children, nor to the development of new FD lesions, which was not a significant feature of aging.? ? In a study by Celi et al, we set out to define the clinical characteristics and molecular etiology of thyroid disease in MAS. To do this, we retrospectively examined the clinical data on 100 patients with MAS, and performed a series of ex vivo and in vitro experiments. Using abnormal ultrasound findings as the most sensitive test for thyroid involvement, we found the prevalence of thyroid disease in this cohort was 54%. Patients with thyroid disease had a higher ratio of the active thyroid hormone triiodothyronine (T3) relative to its precursor, thyroxine (T4). A possible mechanism of this finding is the intrathyroidal conversion of T4 to T3 by 5-deiodinase, likely driven by higher intracellular levels of cAMP due to mutations in GNAS. To test this hypothesis, we performed ex vivo experiments in which we measured 5-deiodinase activity in thyroid tissue from patients with MAS and controls. We found that the tissue had both higher type-1 (D1) and type-2 (D2) deiodinase activity; D1 control enzymatic activity was 5.9 +/- 4.5 fmol/min/mg vs. MAS 41.7 +/- 26.8, p<0.001; D2 control enzymatic activity was 28.3 +/- 13.8 fmol/min/mg vs. MAS 153.1 +/- 43.7, p<0.001. We further studied this by performing reconstitution experiments in which we established a stable HEK-293 cell line that carried a cAMP-dependent type-2 5-deiodinase that was transfected with wild type and disease-causing R201H or R201C Gs-alpha mutants. The basal transcriptional activity of the D2 promoter was significantly increased in both mutants (C and H) (R 10733 +/- 2855, vs. C 18548 +/- 4514, vs. H 19032 +/- 4410 RLU +/- SD, p<0.001), indicating that the shift in T3/T4 ratio is at least in part secondary to a cAMP-mediated intrathyroidal activation of D2 and to elevated D1 activity. While it remains to be tested, a therapeutic implication of these data is that propylthiouracyl, which, unlike methimazole is a potent inhibitor of D1, would offer an advantage over methimazole in the treatment of MAS-associated thyroid disease. ? ? ? ? Disorders of mineral metabolism? ? Studies of diseases manifested by hypo- and hyperphosphatemia have been informative in efforts to dissect the molecular pathways involved in FGF23 production and activity. Hyperphosphatemia caused by low levels of intact FGF23 may be due to mutations in FGF23, N-acetylgalactosaminyltransferase 3 (GALNT3), or KLOTHO. The diseases caused by these mutations are either familial tumoral calcinosis (FTC) or hyperostosis-hyperphosphatemia syndrome (HHS). Phenotypically, these two disorders have been distinguished by the fact that FTC is associated with subcutaneous calcific masses, and HHS with painful diaphyseal hyperostosis. While it has been shown that FTC can be due to mutations in FGF23, GALNT3, or KLOTHO, those cases that have been phenotypically characterized as HHS have only been shown to be caused by mutations in GALNT3. We described a new case of FTC/HHS that revealed a phenotype with aspects of both FTC and HHS, as well as several novel findings. Serum phosphorus was 7.3 mg/dl (normal, 2.5-4.8), and elevated renal phosphate reabsorption (TmP/GFR 6.99 mg/100 ml, normal 2.97-4.45). Radiographs revealed tooth anomalies, thyroid cartilage calcification, calcific masses in vertebral spaces, calcification of the interstitial septae of the soft tissue in the lower extremities, and cortical thickening of the long bones. Bone density was elevated with a total hip Z-Score of 1.9. C-terminus serum FGF23 was elevated at 1210 RU/ml (normal, 20-108), but intact FGF23 was low at 7.4 pg/ml (normal, 10-50). DNA sequencing determined the patient was a compound heterozygote for mutations in GALNT3. Since we have previously demonstrated the dependence of FGF23 action on parathyroid hormone (PTH), which signals through cAMP, we tested the effect of two medications known to increase renal tubule intracellular cAMP on phosphate metabolism. Treatment with niacinamide and acetazolamide decreased TmP/GFR and serum phosphate, which was paralleled by a decrease in serum C-terminus FGF23. This case broadens the spectrum of phenotypic and genotypic features of FTC/HHS, and suggests treatments to decrease renal phosphate reabsorption in the setting of a low intact FGF23.
| 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 |
| Chong, William H; Andreopoulou, Panagiota; Chen, Clara C et al. (2013) Tumor localization and biochemical response to cure in tumor-induced osteomalacia. J Bone Miner Res 28:1386-98 |
| Theman, Todd A; Collins, Michael T; Dempster, David W et al. (2009) PTH(1-34) replacement therapy in a child with hypoparathyroidism caused by a sporadic calcium receptor mutation. J Bone Miner Res 24:964-73 |
| Applbaum, Arthur Isak; Tilburt, Jon C; Collins, Michael T et al. (2008) A family's request for complementary medicine after patient brain death. JAMA 299:2188-93 |
| Celi, Francesco S; Coppotelli, Giuseppe; Chidakel, Aaron et al. (2008) The role of type 1 and type 2 5'-deiodinase in the pathophysiology of the 3,5,3'-triiodothyronine toxicosis of McCune-Albright syndrome. J Clin Endocrinol Metab 93:2383-9 |
| Kuznetsov, Sergei A; Cherman, Natasha; Riminucci, Mara et al. (2008) Age-dependent demise of GNAS-mutated skeletal stem cells and ""normalization"" of fibrous dysplasia of bone. J Bone Miner Res 23:1731-40 |
| Dumitrescu, Claudia E; Collins, Michael T (2008) McCune-Albright syndrome. Orphanet J Rare Dis 3:12 |
| Kelly, M H; Brillante, B; Collins, M T (2008) Pain in fibrous dysplasia of bone: age-related changes and the anatomical distribution of skeletal lesions. Osteoporos Int 19:57-63 |
| Michienzi, Stefano; Cherman, Natasha; Holmbeck, Kenn et al. (2007) GNAS transcripts in skeletal progenitors: evidence for random asymmetric allelic expression of Gs alpha. Hum Mol Genet 16:1921-30 |
| Khosravi, Azarmindokht; Cutler, Carolee M; Kelly, Marilyn H et al. (2007) Determination of the elimination half-life of fibroblast growth factor-23. J Clin Endocrinol Metab 92:2374-7 |
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