Marlous Hagelstein

In this thesis, the prevalence of extraskeletal, GNAS mutation associated manifestations of FD/MAS have been addressed, alongside different aspects of the clinical manifestations of FD/MAS and the effect on patients’ quality of life. In this chapter, the main findings of this thesis are briefly summarized.

The first aim was to characterize the FD/MAS patient population, particularly focusing on extraskeletal manifestations and patients with craniofacial localizations of FD. In chapter 3, we demonstrate the clinical characteristics of a combined cohort of 30 patients diagnosed with MZB at the LUMC (The Netherlands), NIH (USA) and INSERM UMR 1033 (Lyon), Hôpital Edouard Herriot in Lyon (France). The majority of myxomas found in this cohort were located in the upper leg (67%) and in patients with PFD/MAS (87%), which is consistent with previous literature [8]. The presence of GNAS mutations in both skeletal FD, myxomas as well as in other extraskeletal FD/MAS manifestations in this cohort confirms earlier reports suggesting an overlapping causality [9]. In this MZB patient cohort, 87% of patients suffered from polyostotic FD and/or MAS, and 43% of patients had extraskeletal GNAS-related features of whom 30% other tumors than an endocrinopathy. Four patients had BC/DCIS, three patients had IPMN and two patients had liver adenomas. In our opinion, this merely reflects the fact that MZB is a manifestation of a more severe phenotype of the GNAS-mutation and that patients presenting with MZB should be examined for PFD and non-skeletal manifestations of the GNAS-mutation [8]. We conclude that although the prognosis of the myxoma by itself is benign, MZB is associated with the more severe phenotypes of FD/MAS as none of the MFD patients had other extraskeletal features. We therefore advocated that MZB patients should undergo a complete screening for extent of bone disease, including bone scintigraphy, but also extraskeletal GNAS-features of FD/MAS.

Continuing characterizing the clinical manifestations of FD/MAS in our epidemiological study in chapter 4, we report an increased prevalence of a number of histologically confirmed malignancies in patients with FD/MAS. This included an increased SMR for primary bone tumors, such as osteosarcomas, which are not GNAS mutation related. An increased risk for osteosarcoma has been reported in FD/MAS, varying from 0,5% in MFD, increasing in PFD, up to 4% in MAS [1]. However, osteosarcomas are known not to be GNAS related and in our study available material from the bone tumors tested was GNAS negative. Findings in this chapter also suggest that the prevalence of cervical cancer, thyroid cancer and melanoma, all malignancies reported to be associated with a GNAS-mutation [1-5], and prostate cancer are increased in FD/MAS patients compared to the general population. However, of the three GNAS-mutation associated malignancies, only thyroid cancer has been reported in direct connection with the GNAS mutation in FD/MAS [6]. There were no increased risks for pancreatic cancer and hepatocellular carcinoma, despite the reported high prevalence of (pre-malignant) IPMN and hepatobiliary abnormalities [7]. We also did not observe an increased risk for testicular cancer or ovarian cancer in this chapter, possibly due to low numbers of these malignancies.

In chapter 5 we have shown that patients with CFD come in a wide spectrum of clinical presentations, and that multidisciplinary approach is essential in the management of these patients. This cohort study on patients with CFD shows the importance of a proper diagnostical workup since more than a third of patients have extra cranial affected skeletal and extra skeletal manifestations of the disease. These have to be recognized in order to ensure a proper screening and diagnostic as well as treatment management of these patients.

In the final chapter of this section, chapter 6, the prospective cohort study we implemented in 2018 is described. This study aims to set up a database for patients with FD/MAS and to study this rare disease by collecting data on as many patients as possible. We evaluated the natural course of the disease, as well as treatment outcome of both surgical and medical therapies by assessing symptoms of pain, physical function, markers for bone turnover as determinants for disease activity, radiological aspects at time of diagnosis and skeletal burden score and disease quantification by nuclear imaging before and after treatment. In addition, we assessed GNAS mutation related morbidity like precocious puberty, myxomas, hepatobiliary neoplasms and intrapancreatic mucinous neoplasms, and mortality, as well as psychological function by using validated questionnaires.

The next section of this thesis focused on our second overall aim, to provide an insight in different aspects of QoL of patients with FD/MAS in general, and CFD in particular. In chapter 7, we demonstrated that patients with isolated CFD attribute potential symptoms less to their disease compared to patients with CFD in relation to PFD/MAS [10]. In this chapter we also showed that patients with isolated CFD reported better QoL on all domains of the SF-36 (except role emotional and mental health) compared to patients with CFD/PFD/MAS. Perceived QoL of patients with isolated CFD was also better compared to patients in the non-CFD groups (on three out of eight subscales). The findings in this chapter confirmed our hypothesis that, within the spectrum of FD/MAS, the presence of craniofacial involvement alone is not sufficient to affect illness perceptions and QoL, which appear to be largely influenced by the extent of extracranial skeletal and extraskeletal involvement. Therefore, we concluded that patients with isolated CFD should be considered a unique patient subtype within the spectrum of FD/MAS patients concerning the impact of FD/MAS on their QoL.

We examined coping strategies of patients with FD/MAS using the Utrecht Coping List in chapter 8. In this chapter we demonstrate that patients with FD/MAS tend to express less emotions compared to reference data of a random sample of Dutch women [11]. On the other hand, patients with FD/MAS reported more active coping, seeking more distraction and more social support compared to patients with chronic pain caused by various diseases. There were no differences in coping strategies between the three different types of FD/MAS (MFD, PFD and MAS). Furthermore, using more passive coping strategies and more avoidant coping strategies were associated with more impairments in several aspects of QoL, such as social functioning, mental health and vitality. In addition, seeking social support was used more often by patients with FD/MAS than by patients with chronic pain, possibly indicating that a diagnosis of FD comes with a greater sense of social acceptance and greater tendency to ask friends and family for help than is the case with patients with chronic pain due to an unknown cause. Findings in this chapter were in accordance with the theory of the CSM, as we observed that coping strategies of patients with FD/MAS affected their QoL, which is in keeping with observations in patients with other chronic disorders. Lastly, in this chapter we confirmed our hypothesis that, in patients with FD/MAS, less effective coping strategies are associated with more impairment in QoL.