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The handle http://hdl.handle.net/1887/3185515 holds various files of this Leiden University dissertation.
Author: Hagelstein-Rotman, M.
Title: Fibrous dysplasia and the McCune-Albright syndrome: various aspects of a heterogeneous disease
Issue date: 2021-06-17
Part I
Introduction
CHAPTER 1
General Introduction
General introduction | 15
Chapter 1
Fibrous dysplasia/McCune–Albright syndrome (FD/MAS) is a genetic, non-inheritable rare disease caused by a post-zygotic mutation in the GNAS gene [1]. The manifestations of the disease range from asymptomatic, incidental, monostotic cases to severely invalidated patients who suffer from multiple skeletal lesions as well as endocrinopathies, skin lesions and even (pre-) malignant tumors [2].
PATHOPHYSIOLOGY OF FD/MAS
FD/MAS is caused by a post zygotic, activating mutation of the α subunit of the stimulatory G‐protein (Gsα) [3]. In the skeleton, this results in the overproduction of cAMP in affected cells of the osteogenic lineage, leading to the accelerated production of bone marrow stromal cells (BMSC), while inhibiting the differentiation of these progenitor cells into mature osteoblasts (figure 1). Despite expressing early osteoblast markers such as alkaline phosphatase (ALP), these immature cells are dysfunctional, leading to the laying down of fibro‐osseous tissue that is under‐mineralized, of poor quality and of disturbed micro‐architecture. In extensive disease, increased fibroblast growth factor 23 (FGF‐23) expression by the mass of osteogenic mutated cells leading to renal phosphate wasting and impaired 1.25 vitamin D production further exacerbate the mineralization defect [4].
The disturbed bone microarchitecture and mineralization defect decrease bone strength, resulting in increased risk for deformities and fractures [5].
Furthermore, FD lesions are characterized by an increased number of osteoclasts, leading to a local increase in bone resorption. This local increase in osteoclastogenesis is due to a significant up‐regulation of the receptor activator of nuclear factor κ‐B ligand (RANKL) and increased production of interleukin‐6 (IL‐6) by GNAS‐mutated osteogenic cells. The local increase results in a systemic increase as well, as serum measures of RANKL and IL-6 have been shown to be upregulated il-6 [6, 7]. The observed increase in number and clustering of osteoclasts exhibits a tunneling resorption pattern and endosteal fibrosis analogous to changes observed in hyperparathyroidism. It has been suggested that local increase in bone turnover would be associated with increased deposition of abnormal, under‐mineralized fibro‐osseous tissue, leading to pain, further expansion of FD lesions and increased risk for deformities and fractures.
Also, the local increase in osteoclastogenesis may be further promoted by increased parathyroid hormone-related protein (PTHrP) expression, amplifying the effects of mutated osteogenic cells to upregulate RANK-L and down-regulate OPG [8]. Increased bone resorption leads to increased abnormal bone formation by the mutated immature osteoblasts, perpetuating the vicious circle that leads to continuing formation of abnormal bone, lesion expansion, pain, and increasing risk for deformities and fractures (Figure 1).
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Figure 1. Pathophysiology of FD.
In fibrous dysplasia (FD), bone marrow stromal cells (BMSC) carrying the GNAS mutation fail to differentiate into healthy osteoblasts, leading to the formation of immature osteoblasts, which replace normal bone. The GNAS mutated osteoblasts and osteocytes are believed to produce increased levels of fibroblast growth factor-23 (FGF-23), further exacerbating the underlying mineralization defect. High levels of FGF-23 are associated with renal phosphate wasting, leading to hypophosphatemia and a decrease in production of active vitamin D. The increased abnormal bone formation and mineralization lead to a decrease in bone strength, which leads to the risk of deformity or fracture of affected bone. Bone resorption is also affected, as demonstrated by the presence of unusually high number of osteoclasts at the periphery of FD lesions leading to increased levels of interleukine-6 (IL-6) and receptor activator of nuclear factor kappa-Β ligand (RANK-L). This causes osteoblasts to upregulate osteoprotegerin (OPG) in order to inhibit osteoclastogenesis and bone resorption. Pain in FD is believed to be caused by a combination of the increase in local bone turnover, abnormal mineralization, directly via deformity or fractures, or as recently hypothesized via a neural element [9].
The somatic mosaicism associated with the postzygotic nature of the GNAS mutation results in a wide spectrum of clinical manifestations. The spectrum ranges from patients who are asymptomatic to patients who are suffering from multiple skeletal lesions, sometimes severely invalidated. In case of the McCune-Albright syndrome, skeletal lesions are accompanied by other GNAS-associated manifestations such as hyperfunctioning endocrinopathies [10].
General introduction | 17
Chapter 1
CLINICAL CHARACTERISTICS OF FD/MAS
FD/MAS is characterized by a wide spectrum of clinical presentations. Depending on the timing of the GNAS mutation during intra-uterine development, patients may present with a variety of manifestations of the disease.
On one side of the spectrum are patients with monostotic FD, who can be completely asymptomatic and in whom the diagnosis has been the result of an incidental finding on radiographic imaging. Polyostotic fibrous dysplasia (PFD) finds its origin earlier during prenatal development and is characterized by FD lesions on multiple sites in the skeleton.
Patients with PFD can have two localizations of FD but can also have involvement of almost the complete skeleton. Lastly, in patients with MAS, the GNAS mutation has occurred very early on during intra uterine embryonic development and affected all three germ layers.
This results in involvement of not only the bones, but the endocrine organs and the skin as well. By the age of 15 years the total skeletal burden and clinically significant lesions are usually detectable [1]. Apart from PP and neonatal Cushing, endocrine manifestations can arise throughout life.
MAS patients generally have the most severe clinical presentation with sometimes FD lesions throughout the complete skeleton, including craniofacial involvement, café au lait patches on the skin and a variety of endocrine manifestations. Most common is precocious puberty, but growth hormone excess and hyperthyroidism may develop, and neonatal Cushing’s disease might also be present in children of <12 months of age.
Craniofacial fibrous dysplasia (CFD) is a subtype of FD/MAS and is characterized by FD lesions in one or more of the skull bones, which are commonly affected sites in FD/MAS [11]. Clinical manifestations associated with involvement of craniofacial bones are facial pain, increased risk of compressive optic neuropathy and facial deformity [12]. In isolated CFD the skull bones are the only affected part of the skeleton, whereas in PFD/MAS craniofacial involvement can occur as part of polyostotic disease. The clinical spectrum of symptoms in patients ranges from completely asymptomatic, with CFD lesions discovered incidentally, to severely invalidating disease with patients suffering from a range of more or less severe symptoms depending on craniofacial localizations of FD lesions, such as headaches, vision loss, impaired hearing and facial deformity [11].
Mazabraud’s syndrome (MZB) is defined by the association of fibrous dysplasia of bone (FD) with intramuscular myxomas. It is a very rare syndrome with fewer than 200 reported cases in literature worldwide. In MZB, the GNAS-gene causes both skeletal FD lesions and soft-tissue myxomas [13]. The skeletal FD lesion generally located near the myxoma.
Myxomas can cause symptoms of pain, painless swelling or neurological complaints,
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CLINICAL VIGNETTE
Patient X is a woman of 41 years old with the McCune-Albright syndrome. When she was a couple of weeks old, she slowly developed skin hyperpigmentation on the right side of her body and precocious puberty. During this phase of her life, she suff ered from anovulatory menstrual cycles, breast development and clitoromegaly. At the age of 8 years, she started to have diffi culty walking and at the age of 9 years she suff ered from a femoral fracture. Radiological evaluation through x-rays showed multiple cystic lesions in the skeleton, fi tting the polyostotic fi brous dysplasia diagnosis. Combined with the endocrinopathies the diagnosis of McCune-Albright syndrome was established.
Because of coxa varum with instability, an uplifting osteotomy was performed with fi lling of the intra-ossal space with cement. Furthermore, a blade osteosynthesis was performed of a large cystic lesion of the femur. She then developed a spontaneous fracture of the right lower leg which was treated conservatively. A disfi guring cyst of the maxilla was surgically removed.
Because of bone pain, high bone turnover and increased fracture risk she was treated with intravenous bisphosphonates. Nonetheless, throughout her life she suff ered from multiple fractures and severe bone pain.
Figure 1. MRI image of the gluteal muscle and skeletal scintigraphy.
The MRI image shows multiple myxomas in the gluteal muscle. The skeletal scintigraphy shows multiple sites of increased activity in the craniofacial bones, both humeral, radial, femoral, tibial and fi bula bones, as well as in multiple ribs, feet and toes.
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Chapter 1
but are often asymptomatic, resulting in a heterogeneous clinical presentation of MZB patients. A recently published European collaboration on patients with MZB has characterized this rare patient population [13]. Patients with MZB are frequently only consulted by an orthopedic surgeon and screening for extraskeletal features related to the GNAS mutation, such as a variety of endocrinopathies, was up until recently not standard of care. It is however currently unknown whether this would be advisable.
Depending on the timing of the GNAS mutation during embryogenesis, a wide spectrum of skeletal and extraskeletal abnormalities can occur in tissues derived from germ cells of ectodermal, endodermal and mesodermal origin, including pre-malignant and malignant tumors. In addition to hyperactive endocrinopathies, the GNAS mutation may also be associated with other extraskeletal manifestations such as in Mazabraud’s syndrome, testicular or ovarian abnormalities and/or pre-malignant pancreatic lesions in the form of intraductal papillary mucosa neoplasms (IPMN’s) [14-16]. Malignant transformation of skeletal FD lesions as well as other, GNAS related, (pre-)malignant tumors have been previously described in FD/MAS, although mostly as case reports [17].
QUALITY OF LIFE IN PATIENTS WITH FD/MAS
In a recent study from the LUMC Center for Bone Quality, it was shown that patients with fibrous dysplasia (FD), particularly those patients with bone pain, reported significant impairment in quality of life (QoL), and that disease severity, as reflected by higher skeletal burden scores (SBS) and elevated serum bone turnover markers, was associated with more severe impairment in QoL [18]. The two major determinants that influence QoL are illness perceptions and coping strategies, according to the Common-Sense Model of self- regulation [19]. The CSM provides a framework for describing the way by which patients manage the perceived threat of their illness using coping behavior. The model consists of three stages, of which the first is the illness perceptions stage. Illness perceptions are the thoughts and emotions that a patient has concerning his or her disease and its treatment.
It has been previously demonstrated that illness perceptions of patients with FD/MAS differed significantly from patients with acute or chronic pain due to other medical conditions [20].
Coping strategies are the second stage of the CSM. These are based on illness perceptions, and concern the skills a person has to handle situations or life events. The way individuals handle the burden of a chronic illness is influenced by their coping strategies, which are not set at birth but develop during early childhood. Coping skills include emotional, behavioral, and cognitive responses.
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The impact of craniofacial involvement in FD/MAS on QoL has not been previously assessed, nor has there been any literature on the differences in illness perceptions and QoL between patients with isolated CFD or CFD in the context of FD/MAS. Recognizing unhelpful illness perceptions in these patients and subsequently altering these may prove to be a valuable strategy in improving quality of life in patients with craniofacial FD/MAS.
In chapters 7 and 8 we will discuss our data on illness perceptions, coping and QoL of patients with FD/MAS.
TREATMENT OF FD/MAS
FD/MAS is an incurable disease for which there is no approved pharmacological treatment.
The symptom which has proved to be the most challenging to manage is pain. Complete, impending or microfractures may cause pain at the FD lesion site, but deformities causing abnormal mechanical forces or mineralization defects are also known to contribute to the etiology of pain in FD/MAS.
Bone affected by FD is under-mineralized which makes it less rigid [21]. This results in more dynamic bone tissue which, especially in weight-bearing bones such as the femur, is under constant pressure during daily activity [22]. This causes the periosteum, the membrane that covers the outer surface of all bones, to ‘slide’ over the bone potentially causing pain that is not related to (micro-)fractures of the bone but solely caused by the pathophysiology of FD.
As seen in patients with bone metastases [23-25], it has been suggested that pain in FD/MAS may not only be correlated to disease burden or bone remodeling, but that neuropathic involvement may also play a role [26, 27]. Nerve involvement and/or the formation of neuromas in close proximity of FD lesions may induce or exacerbate pain [24].
Surgery has traditionally been the main therapeutic approach to the management of FD/
MAS [28, 29]. Surgical treatment of FD/MAS focusses on treating the symptoms of fibrous dysplasia, such as deformities and pathological fractures. These are most prevalent in the femur as this is often the site of predilection for an FD lesion and the weight-bearing forces these lesions are submitted to increase the risk of complications. Although a number of different surgical options, such as different types of plates, intramedullary devices or other forms of bone grafts have been proposed for the treatment of FD, there is to date no guideline on the most optimal surgical intervention to use in the management of these patients to achieve best treatment outcomes.
General introduction | 21
Chapter 1
Evidence on the presence of increased bone resorption in FD lesions has led to the use of antiresorptive agents in FD/MAS. These aim at decreasing the local increase in bone turnover and thereby potentially decreasing or preventing expansion of lesions, controlling symptoms and decreasing the risk for deformities and fractures. Nitrogen- containing bisphosphonates, which inhibit the mevalonate pathway by preventing post- translational prenylation of GTP-binding proteins and thereby resulting in osteoclast apoptosis, are the most commonly used antiresorptive drugs in the management om FD/
MAS [30]. Bisphosphonates have been the most frequently prescribed antiresorptive drug, albeit off label, followed more recently by the anti-RANK ligand antibody denosumab [31].
Before any antiresorptive agent is considered, however, FGF-23 mediated hypophosphatemia should be identified and treated with active vitamin D metabolites, as this can lead to increased pain, deformity and increased fracture risk [32-36]. Other than vitamin D, phosphate levels should be adequate prior to initiating antiresorptive therapy, particularly in children in whom sufficient phosphate levels are essential for normal growth and the maintenance of bone quality.
A second important step to be taken before initiating treatment with antiresorptive agents is the identification and treatment of endocrinopathies, especially in the more severe forms of FD/MAS. This is especially the case for growth hormone excess, in which the stimulatory effects of excess of growth hormone on bone turnover may compete or negate the inhibitory effects of antiresorptive treatment, calling for higher doses of bisphosphonates. Thyroid abnormalities are also relatively common in FD/MAS patients, in patients with MAS prevalence is even estimated to be as high as 54% [37]. These include sonographic changes in thyroid gland structure, and/or T3 thyrotoxicosis due to a shifted T3/T4 ratio [37]. Thyroidal dysregulation is known to potentially increase disease burden in FD/MAS and should therefore be identified and treated as required [38, 39].
In patients who do not respond to bisphosphonate therapy, Denosumab (anti-RANK-L) seems to be a useful alternative, especially in patients with severe skeletal burden [40].
Early reports on the use of this agent are promising. Before Denosumab can be advocated to be used in a wider range of patients, however, issues such as the rebound effect observed after discontinuing treatment should be further investigated [31, 41].
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OUTLINE AND AIMS OF THIS THESIS
This thesis is structured in 2 parts. The first part describes the characterization of FD/
MAS with a focus on extraskeletal manifestations and craniofacial FD. The second part addresses QoL in patients with FD/MAS.
I aimed to specifically address the following questions in this thesis:
1. Do patients with MZB have a more severely affected phenotype? In other words, is it necessary to perform a more extended survey of these patients? In chapter 3 we study the presence of benign tumors (myxomas) in patients with FD/MAS and the Mazabraud’s syndrome. We combine patients with MZB of three cohorts from international tertiary referral centers and assess the prevalence of extraskeletal manifestations of the GNAS mutation in this patient population.
2. Are patients with FD/MAS more prone to malignancies? In chapter 4 the concurrence of malignancies in Dutch patients with FD/MAS is discussed.
3. How should patients with FD/MAS be characterized? Chapter 5 describes the clinical outcome of the current cohort of patients with craniofacial localizations of FD seen in Leiden since 1978 up until 2018. Chapter 6 describes the protocol of the prospective observational study in FD/MAS (the PROFID study). This study was initiated in the LUMC in January 2018 and is currently running within two other academic centers in The Netherlands.
4. How is QoL affected in patients with FD/MAS? In chapter 7, illness perceptions and QoL in patients with FD localized in the craniofacial area are discussed and correlations between illness perceptions and QoL within the CFD patient population are explored. Further on in this section of the thesis, coping strategies of patients with FD/MAS in general are discussed. Chapter 8 presents the results of our study using the Utrecht Coping List, a questionnaire used to asses coping strategies of patients with a disease/disorder.
To conclude this thesis, general conclusions (chapter 9) and summary (chapter 10) will provide the current insights in the disorder and a summary of all things discussed in this thesis.
General introduction | 23
Chapter 1
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