Purpose To quantify Na 18 F-PET/CT uptake in relation to clinical and biochemical parameters of fibrous dysplasia (FD) severity and healthy bone (HB) metabolism. Secondary aims: comparing normalization for volume of distribution and determining reproducibility of Na 18 F-PET/CT uptake parameters in HB and FD. Relating Na 18 F uptake to skeletal burden score (SBS), bisphosphonate therapy and pain measured by Brief Pain Inventory (BPI). Methods In a prospective cohort study (n = 20), Na 18 F-PET/CT parameters of HB and FD were assessed by two independent readers to determine the cutoff defining increased bone uptake, optimized normalization, and interobserver agreement (ICC) and were related to SBS, serum biomarkers, medication, and clinical parameters. Results Physiological bone standardized uptake value (SUV) was best normalized but displayed large interpatient variation (total range 4.1-13.7 g/mL), with very high interobserver agreement (ICC = 0.964). FD burden defined by patient-specific SUV cutoffs reached near-perfect agreement for SUVpeak (ICC = 0.994) and total lesion fluorination (TLF) (ICC = 0.999). TLF correlated weakly with SBS (R 2 = 0.384, p = 0.047). TLF correlated positively with serum alkaline phosphatase (R 2 = 0.571, p = 0.004) and procollagen type 1 N-terminal propeptide (R 2 = 0.621, p = 0.002), SBS did not (p > 0.06). SBS and TLF both correlated with increased fibroblast growth factor-23 (R 2 = 0.596, p = 0.007 and R 2 = 0.541, p = 0.015, respectively). TLF was higher in use of bisphosphonates (p = 0.023), SBS was not. Average BPI scores correlated to increased FGF-23 (R 2 = 0.535, p = 0.045), workrelated BPI scores to higher SBS (R 2 = 0.518, p = 0.024), higher TLF (R 2 = 0.478, p = 0.036), and higher levels of FGF-23 (R 2 = 0.567, p = 0.034). Conclusions Individualized Na 18 F-PET/CT SUV cutoffs reproducibly discriminated HB from FD and were well-normalized. The strong relations of bone formation serum markers with Na 18 F-PET/CT FD burden measurements suggest clinical relevance over SBS as an adjunct instrument in FD patients. The correlation of both imaging modalities with increased work-related BPI scores also indicates clinical applicability. Moreover, SBS is known to remain stationary irrespective of use of medication, whereas TLF on Na 18 F-PET/CT was higher in baseline patients using bisphosphonates. This makes Na 18 F-PET/CT a promising tool to quantitatively measure treatment efficacy in FD. KeywordsSodium fluoride PET/CT . Fibrous dysplasia . Reproducibility . Serum biomarkers . Bisphosphonates This article is part of the Topical Collection on Orthopedics * Wouter van der Bruggen

Purpose: Craniofacial fibrous dysplasia (CFD) is a subtype of fibrous dysplasia/McCune-Albright syndrome (FD/MAS) characterized by FD lesions in one or more of the skull bones. The orbit is often involved, with facial pain, facial deformity, and increased risk of compressive optic neuropathy as associated clinical manifestations possibly leading to altered illness perceptions and impairments in quality of life(QoL). The aim of this study was to evaluate illness perceptions and QoL in patients with CFD among our FD/MAS cohort. Methods: One hundred ninety-one patients were included. Illness perceptions and QoL were assessed by using validated questionnaires, that is, the Illness Perceptions Questionnaire–Revised and the Short-Form 36. Patients were first grouped as CFD versus non-CFD, a second selection was based on the presence of “Isolated CFD” versus “CFD+PFD/MAS.” Non-CFD patients were grouped as monostotic fibrous dysplasia “MFD” versus polyostotic “PFD/MAS.” Results: Patients with isolated CFD attributed less symptoms to their disease compared with patients with CFD+PFD/MAS (p < 0.05). Furthermore, patients with isolated CFD reported better QoL on all domains (except role emotional and mental health) compared with patients with CFD+PFD/MAS (p < 0.05). Patients with isolated CFD also reported better QoL compared with non-CFD groups (on 3 out of 8 subscales) (p < 0.05). Conclusions: Patients with isolated CFD attribute less symptoms to their disease and report better QoL compared with patients with CFD with extracranial involvement or FD without cranial involvement. These findings indicate that craniofacial involvement alone is not sufficient to cause negative illness perceptions and impairments in QoL. Therefore, it can be postulated that isolated CFD should be considered a unique patient subtype within the spectrum of FD/MAS patients.

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Background Fibrous dysplasia/McCune-Albright syndrome (FD/MAS) may cause pain, impaired ambulation and decreased quality of life (QoL). International guidelines advocate management of FD/MAS in a tertiary multidisciplinary care pathway, but no longitudinal data are available to support this recommendation. This multicenter prospective observational study aimed to evaluate effects of 1 year of treatment in the FD/MAS care pathway in 2 tertiary clinics on QoL and pain, assessed by change in Short Form 36 and Brief Pain Inventory between baseline and follow-up. Patients completing baseline questionnaires < 1 year after intake were classified as new referrals, others as under chronic care. Results 92 patients were included, 61 females (66%). 22 patients (24%) had monostotic disease, 16 (17%) isolated craniofacial FD, 27 (40%) polyostotic FD and 17 (19%) MAS. 26 were new referrals (28%) and 66 chronic patients (72%). Median age at baseline was 47 years (Q1–Q3 36–56). Skeletal burden correlated with baseline Physical Function (rs = − 0.281, p = 0.007). QoL was in all domains lower compared to the general population. New referrals reported clinically important differences (CID) over time in domains Physical Function (mean 67 ± SD24 to 74 ± 21, effect size (ES) 0.31, p = 0.020), Role Physical (39 ± 41 to 53 ± 43, ES 0.35, p = 0.066), Social Functioning (64 ± 24 to 76 ± 23, ES 0.49, p = 0.054), and Health Change (39 ± 19 to 53 ± 24, ES 0.76, p = 0.016), chronic patients in Physical Function (52 ± 46 to 66 ± 43, ES 0.31, p = 0.023) and Emotional Wellbeing (54 ± 27 to 70 ± 15, ES 0.59, p < 0.001). New referrals reported a CID of 1 point in maximum pain, average pain and pain interference, chronic patients reported stable scores. Change in pain interference and Role Physical were correlated (rs = − 0.472, p < 0.001). Patients with limited disease extent improved more than patients with severe disease. Patients receiving FD-related therapy had lower baseline scores than patients not receiving therapy and reported improvements in QoL after 1 year. Yet also patients without FD-related therapy improved in Physical Function. Conclusions All FD-subtypes may induce pain and reduced QoL. A multidisciplinary care pathway for FD/MAS may improve pain and QoL, mainly in new referrals without MAS comorbidities with low baseline scores. Therefore, we recommend referral of patients with all subtypes of FD/MAS to specialized academic centers.

Mazabraud's syndrome (MZB) is a rare condition in which fibrous dysplasia of bone/the McCune-Albright syndrome (FD/ MAS) co-exists with intramuscular myxomas. Both FD and the myxomas harbor the GNAS-mutation. Recent studies have shown that extraskeletal, GNAS-related features are associated with a more severe phenotype of FD/MAS. However, patients with MZB are often only seen by orthopedic surgeons. We therefore evaluated MZB patients seen in tertiary referral centers from the Netherlands (LUMC), USA (National Institutes of Health) and France (INSERM UMR 1033 (Lyos), Hôpital Edouard Herriot). All FD/MAS patients known in these centers with an additional diagnosis of a myxoma were included. Demographic information and data on disease extent and extraskeletal manifestations of FD/MAS such as precocious puberty (PP) or café-au-lait patches (CAL) were retrieved from patient's medical records. Thirty MZB patients were included: 20 women (67%) and 10 men (33%). Patients received a diagnosis of MZB (median 42 years, range 16-19) significantly later than the diagnosis of FD/MAS (median 30 years, range 0-60), p < 0.01. Twenty-six patients were diagnosed with polyostotic disease (87%). In 97% the myxoma was located near the skeletal FD lesion. The combination of MZB and MAS was made in 13 patients in whom PP (n = 7), CAL (n = 7), GH-excess (n = 3) and hyperthyroidism (n = 3) were present. Other extraskeletal features were (multinodular) goiter (n = 2) and thyroid cysts (n = 1). Furthermore, in this cohort of patients with MZB several (pre-)malignant tumors were observed; ductal carcinoma in situ of the breast in 3 patients (10%), breast cancer in 1 patient (3.3%), intra pancreatic mucinous neoplasms in 3 patients (10%) and liver adenomas in 2 patients (6.6%). A total of 47% of patients with MZB had an additional extraskeletal feature such as an endocrinopathy. In MZB, 87% of patients suffer from polyostotic FD, 43% of patients have extraskeletal GNAS-features such as an hyperfunctioning endocrinopathy and 30% (pre-)malignant tumors. We therefore advocate that MZB patients should undergo a complete screening and long-term follow-up for extent of bone disease, but also extraskeletal GNAS features of FD/MAS.