We investigated the efficacy, safety, and clinical significance of trafermin, a recombinant human fibroblast growth factor (rhFGF)‐2, for periodontal regeneration in intrabony defects in Phase III trials. Study A, a multicenter, randomized, double‐blind, placebo‐controlled study, was conducted at 24 centers. Patients with periodontitis with 4‐mm and 3‐mm or deeper probing pocket depth and intrabony defects, respectively, were included. A total of 328 patients were randomly assigned (2:1) to receive 0.3% rhFGF‐2 or placebo, and 323 patients received the assigned investigational drug during flap surgery. One of the co‐primary endpoints, the percentage of bone fill at 36 weeks after drug administration, was significantly greater in the rhFGF‐2 group at 37.131% (95% confidence interval [CI], 32.7502 to 41.5123; n = 208) than it was in the placebo group at 21.579% (95% CI, 16.3571 to 26.8011; n = 100; p < 0.001). The other endpoint, the clinical attachment level regained at 36 weeks, was not significantly different between groups. Study B, a multicenter, randomized, blinded (patients and evaluators of radiographs), and active‐controlled study was conducted at 15 centers to clarify the clinical significance of rhFGF‐2. Patients with 6‐mm and 4‐mm or deeper probing pocket depth and intrabony defects, respectively, were included. A total of 274 patients were randomly assigned (5:5:2) to receive rhFGF‐2, enamel matrix derivative (EMD), or flap surgery alone. A total of 267 patients received the assigned treatment during flap surgery. The primary endpoint, the linear alveolar bone growth at 36 weeks, was 1.927 mm (95% CI, 1.6615 to 2.1920; n = 108) in the rhFGF‐2 group and 1.359 mm (95% CI, 1.0683 to 1.6495; n = 109) in the EMD group, showing non‐inferiority (a prespecified margin of 0.3 mm) and superiority of rhFGF‐2 to EMD. Safety problems were not identified in either study. Therefore, trafermin is an effective and safe treatment for periodontal regeneration in intrabony defect, and its efficacy was superior in rhFGF‐2 compared to EMD treatments. © 2015 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research (ASBMR).
We demonstrate that individuals with the NF1 p.Met992del pathogenic variant have a mild NF1 phenotype lacking clinically suspected plexiform, cutaneous, or subcutaneous neurofibromas. However, learning difficulties are clearly part of the phenotypic presentation in these individuals and will require specialized care.
IntroductionHypophosphatasia, a metabolic bone disease caused by a tissue-nonspecific alkaline phosphatase deficiency, leads to undermineralization of bone and/or teeth, impaired vitamin B6 metabolism, and a spectrum of disease presentation. At the mild end of the spectrum, it presents as pathologic fractures in later adulthood. Patients with isolated dental manifestations, typically presenting as premature loss of primary teeth, are classified as having odontohypophosphatasia (odontoHPP). A subset of patients diagnosed with odontoHPP in childhood can later develop extra-dental manifestations that constitute childhood- or adult-onset hypophosphatasia.Case reports: methods/resultsRetrospective data related to onset, detailed clinical course, and method of diagnosis were collected as part of a natural history of adult patients with hypophosphatasia.Of 9 initial patients, all had low serum alkaline phosphatase levels for their age and gender at adult presentation (Table 2). The majority (8/9) demonstrated childhood dental signs of hypophosphatasia as the initial clinical manifestation: premature loss of primary teeth (7/9), absent primary teeth (1/9), and delayed loss of primary teeth (1/9). Despite childhood dental presentation and/or other signs/symptoms, diagnosis of hypophosphatasia was delayed 20–54 years (median = 46) since the primary tooth problems and 8–45 years (median = 27) since the first fracture or onset of a major adult tooth problem.ConclusionPatients with primary tooth loss in childhood were often diagnosed with hypophosphatasia later in life. Pediatric patients classified as having odontoHPP under present practice can manifest significant disease burden later in life.
Purpose: We studied galactose supplementation in SLC35A2-congenital disorder of glycosylation (SLC35A2-CDG), caused by mono-allelic pathogenic variants in SLC35A2 (Xp11.23), encoding the ER and Golgi UDP-galactose transporter. Patients present with epileptic encephalopathy, developmental disability, growth deficiency, and dysmorphism. Methods: Ten patients with SLC35A2-CDG were supplemented with oral D-galactose for 18 weeks in escalating doses up to 1.5 g/kg/day. Outcome was assessed using the Nijmegen Pediatric CDG Rating Scale (NPCRS, ten patients) and by glycomics (eight patients). Results: SLC35A2-CDG patients demonstrated improvements in overall NPCRS ( P =0.008), the current clinical assessment ( P =0.007) and the system specific involvement ( P =0.042) domains. Improvements were primarily in growth and development with five patients resuming developmental progress, that included postural control, response to stimuli, chewing and swallowing amelioration. Additionally, there were improvements in gastrointestinal symptoms and epilepsy. One patient in our study did not show any clinical improvement. Galactose supplementation improved patients’ glycosylation with decreased ratios of incompletely formed to fully formed glycans (M-gal/di-sialo, P =0.012 and mono-sialo/di-sialo, P =0.017) and increased levels of a fully galactosylated N-glycan ( P =0.05). Conclusion: Oral D-galactose supplementation results in clinical and biochemical improvement in SLC35A2-CDG. Galactose supplementation may partially overcome the Golgi UDP-galactose deficiency and improves galactosylation. Oral galactose is well-tolerated and shows promise as dietary therapy.
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