Date of Award

2026

Abstract

Fibrous Dysplasia (FD) is a rare disease where healthy bone is replaced by lesions of fragile, porous tissue. FD lesions may affect a single bone or occur throughout the entire skeleton and can grow rapidly. A diagnosis of McCune-Albright syndrome (MAS) is made when FD is accompanied by endocrinopathies and skin hyperpigmentation. FD/MAS can cause debilitating complications, including disabilities, deformities, fractures, and chronic pain. Pain is one of the most common symptoms of FD/MAS and can have a profound impact on patients’ quality of life. However, FD/MAS pain is complex and varies substantially between patients. This complexity and a lack of research has resulted in limited understanding about what causes and influences pain in FD/MAS patients. Interestingly, pain severity does not correlate with the number, size, or activity of lesions, suggesting that factors beyond the physical presence of FD drives pain. Other structural characteristics (e.g., location, density, and appearance on imaging) that may influence pain remain unexplored. The potential contribution of circulating plasma proteins to FD-associated pain remains insufficiently understood. Additionally, the psychosocial influences on pain perception in patients with FD/MAS have not been fully characterized, and the extent to which addressing these factors may mitigate pain has not been evaluated. Without understanding its causes, clinicians cannot effectively treat FD/MAS pain. Conventional pain medications, such as opioids or anti-inflammatory drugs (e.g., ibuprofen), provide little to no relief for patients. This reflects the critical gap in understanding the mechanisms underlying FD/MAS pain, which creates a significant barrier to effective treatment. My dissertation research seeks to address these challenges by using a biopsychosocial approach to assess, understand, and manage pain in FD/MAS. FD lesions vary in structure and appearance, making it challenging to predict disease progression or pain patterns. While pain severity does not correlate with the size or number of lesions, other potentially relevant features such as lesion location, bone density, and growth patterns have not been investigated. Chapter 1 describes the use of three advanced imaging techniques (CT, MRI, and PET) to identify structural characteristics that may correlate with pain symptoms. In the spring of 2024, CT, MRI, and PET images of 35 FD lesions in 15 patients were analyzed. These patients completed validated questionnaires about their pain and kept a diary for eight weeks describing the severity, frequency, location, and duration of their pain. Advanced statistical methods were applied to categorize lesions into three subtypes based on structural characteristics revealed by imaging. These subtypes were then correlated with patients’ reported pain symptoms, including impact on daily life. The analyses revealed that lesions in certain bones, particularly the temples and skull base, were strongly associated with severe, frequent, and disruptive pain. These findings, published in two journal articles, represent the first study to integrate CT, MRI, and PET data for such detailed lesion analysis. This work establishes the foundation for personalized, imaging-guided pain management strategies. While imaging highlights structural contributors to FD/MAS pain, the role of biochemical messengers, such as proteins, remains a mystery. Proteomics is an emerging field of study that allows for the identification and quantification of proteins. A total of 57 proteins were quantified in plasma samples from 20 patients with FD/MAS. Seven inflammatory proteins significantly correlated with pain, depression, or stress levels. Notably, four proteins were consistently elevated in patients with severe, frequent pain and emotional distress, suggesting these proteins may exacerbate pain symptoms. This study, published in 2025, offers original insights into the biochemical mechanisms of FD/MAS pain, which could inform the development of targeted pharmaceutical interventions. While the structural and biochemical contributors to FD/MAS pain are not fully understood, the urgent need for effective treatment options is evident. Although ongoing research aims to identify potential targets for future drug development, this process is lengthy and hindered by the limited funding allocated to rare disease research. Given the debilitating nature of pain, patients require more immediate solutions. Intensive, interdisciplinary pain treatment programs (IIPT) integrate physical therapy, occupational therapy, and psychotherapy to address chronic pain. This treatment model addresses not only the biological aspects of pain, but also the psychological and social factors that influence pain perception, which are often underappreciated in chronic pain management. Five FD/MAS patients went through a three-week IIPT program conducted at the Young Adult Pain Rehabilitation Center at Boston Children’s Hospital in 2025. Pain severity significantly decreased after treatment – patients reported an average decrease of 3 points on the 1-10 pain scale. Importantly, these results were sustained three months later, with an average pain severity 3.2 points lower than pre-treatment ratings. Psychological outcomes improved across all domains, and anxiety and depression symptoms decreased. Health outcomes improved, and patients reported less disability after treatment. This approach represents an entirely new direction in FD/MAS treatment, one that prioritizes holistic well-being and long-term resilience against the burden of chronic pain. The findings from this study serve as an initial proof of concept that could ultimately shift how FD/MAS pain and pain in other rare conditions is treated in the future. FD/MAS profoundly impacts patients’ lives, and current pain management strategies are inadequate due to a lack of understanding of the disease’s underlying mechanisms. The imaging analysis establishes connections between structural characteristics and pain, which could allow for personalized treatments based on lesion subtype and location. The proteomic analysis has uncovered proteins associated with pain and emotional distress, potentially guiding the development of targeted therapies to reduce pain at the source. Finally, the intensive, interdisciplinary pain treatment approach addresses biopsychosocial factors of pain to promote holistic care. Together, these findings could lead to transformative improvements in how FD/MAS pain is understood and treated, improving the quality of life for patients with this complex and understudied disease.

Document Type

Dissertation

First Advisor

Jessica Bolker

Second Advisor

Jaymin Upadhyay

Third Advisor

W. Kelley Thomas

Department or Program

Biological Sciences

Degree Name

Doctor of Philosophy

Download

Share

COinS