FD/MAS: To better define GH excess in FD, all reported cases of GH excess associated with MAS reported in the world literature up to January 2013 were reviewed. 112 patients were identified. Mean age at diagnosis was 24.4. Among the 40 pediatric patients, 57% had precocious puberty. GH excess was suggested by accelerated growth in 85% of pediatric cases. GH excess was almost always associated with skull base FD. An adenoma was present in 54% of the patients. Median GH levels and mean IGF-1 SD scores at diagnosis were 57 μg/L and 8, respectively. Hyperprolactinemia was present in 81% of the patients. Pituitary surgery, performed in 25 cases, rarely cured GH excess. Somatostatin analogs improved IGF-1 levels in most patients but achieved control of GH excess in only 30%. Pegvisomant achieved normal IGF-1 levels in 10 of 13 cases. To study the spectrum and progression of femoral deformities in FD, we developed a radiographic classification system, tested intra- and interobserver reliability, and characterized the radiographic progression in treated patients. 127 femurs from 84 adult subjects were reviewed. The radiographs were evaluated for neck-shaft angle and angular deformities. 70% of the femurs were available to evaluate for progression (mean 10 years). 6 reproducible patterns of deformity were identified: type 1 (24%), normal neck-shaft angle with altered shape of the proximal femur;type 2 (6%), isolated coxa valga with neck-shaft angle >140;type 3 (7%), isolated coxa vara with neck-shaft angle <120;type 4 (20%), lateral bowing of the proximal half of the femur associated with normal neck-shaft angle;type 5 (14%), like in type 4 but associated with coxa valga;and type 6 (29%), like in type 4 but associated with coxa vara. Interobserver and intraobserver kappa values ranged from 0.83 to 0.87. In 52% of the femurs, there was progressive worsening of the original deformity. While the pattern remained the same and did not progress in types 1 and 2, in types 3 to 6 progression was common. A study of 81 patients with FD was performed to determine the association between measures of disease severity, impairment, and ambulation ability. Subjects were scored on the Skeletal Disease Burden Score, 9-minute walk test, manual muscle testing (MMT), range of motion (ROM). It was found that subjects with more severe disease walked slower than those with less skeletal disease, with the exception of the youngest subjects. Walking velocity was faster in subjects with better hip strength and range of motion and slower in those with bilateral coxa vara. Those subjects with more severe disease had less range of motion, were weaker at the hips, and more likely to have leg length discrepancy. Skeletal disease severity was associated with hip weakness, leg length discrepancy, and loss of range of motion. In most cases, findings did not differ in the presence or absence of associated endocrinopathies. Skeletal disease severity, MMT and ROM each has an impact on walking efficiency in persons with FD. These findings suggest that treatment focused on strategies to improve or, at least, maintain hip strength and range of motion, correct leg length discrepancies and hip malalignment may help preserve ambulation ability in persons with FD and that treatment should begin at a young age. To determine the efficacy of alendronate for treatment of FD, a 2 year randomized, double-blind, placebo-controlled trial in 40 subjects randomized and stratified by age was conducted. Alendronate was administered over a 24 month period in 6 month cycles. Dosing was stratified: 40 mg daily for subjects >50 kg, 20 mg for 30-50 kg, 10 mg for 20-30 kg. Primary endpoints were bone turnover markers, including serum osteocalcin and NTX-telopeptides. Secondary endpoints included areal bone mineral density (aBMD), pain, skeletal disease burden score, and functional parameters including the 9-minute walk test and manual muscle testing. Clinical data were collected on 35 subjects who completed the study. There was a decline in NTX-telopeptides in the alendronate group (p = 0.006), but no significant difference in osteocalcin between groups. The alendronate group had an increase in areal BMD in normal bone at the lumbar spine (p = 0.006), and in pre-determined regions of FD (p <0.001). There were no significant differences in pain scores, skeletal disease burden scores, or functional parameters between the groups. Alendronate treatment led to a reduction in the bone resorption marker NTX-telopeptides, and improvement in aBMD, but had no significant effect on serum osteocalcin, pain, or functional parameters. Denosumab may have efficacy in the treatment of FD, however its safety in children has not been established. The objective of the study was to investigate the effects of denosumab treatment on skeletal growth and histology in a child with FD who received a 7 month course of denosumab and subsequently underwent a leg amputation. Growth was assessed and histological analyses performed on growth plates obtained before and 17 months after denosumab treatment. After denosumab, sclerotic metaphyseal bands appeared on radiographs. Post treatment radiographs revealed migration of the bands away from the growth plates, consistent with continued linear growth. Histologically, the bands were composed of horizontally arranged trabeculae containing calcified cartilage. This cartilage appeared to derive from unresorbed primary spongiosa as a result of osteoclast inhibition by denosumab, similar to what has been observed with bisphosphonates. By 17 months after treatment, active bone resorption and formation had returned, as evidenced by the presence of active osteoclasts in resorption pits and osteoid surfaces. While further studies are needed to determine the safety of denosumab on the growing skeleton, in this child there was continued epiphyseal activity both during and after treatment and reversal of bone turnover suppression after treatment discontinuation, suggesting that denosumab did not have significant adverse effects on growth. Mis-sense mutations in Gs alpha, lead to an increase in cellular cAMP and cause FD/MAS.
The aim of this study was to develop an assay that would allow for the identification of small molecule inhibitors specific for the mutant Gs alpha that may used to develop drugs to treat FD/MAS. Chinese hamster ovary cells were stably transfected with either wild-type (WT) or mutant Gsαproteins (R201C and R201H). Stable cell lines that had relatively lower (WT) or higher (R201C and R201H) cAMP levels were generated. These cell lines were used to develop a FRET-based cAMP assay in 1536-well format for high throughput screening. A small molecule library of 343,768 compounds was screened to identify modulators of mutant Gs. 1,356 compounds with inhibitory activity were identified. 686 molecules were selected for further analysis. These molecules were grouped by potency, efficacy, and structural similarities to yield 22 clusters with more than 5 of structurally similar members and 144 singleton molecules. Seven chemotypes of the major clusters were identified for further testing and analyses. FGF23: Elevated serum FGF23 levels can be found in association with mosaic cutaneous disorders that affect large proportions of the skin. We report 5 such cases with elevated serum FGF23 and bone lesions. Exome sequencing of blood and affected skin identified somatic activating mutations of HRAS or NRAS. The same mutation was present in dysplastic bone. The finding of somatic activating RAS mutation in bone provides the first evidence that elevated serum FGF23 levels, hypophosphatemia and osteomalacia are associated with pathologic Ras activation and may provide insight into the understanding of the regulation of FGF23.
Showing the most recent 10 out of 79 publications
