Abstract
Erdheim-Chester Disease (ECD) is a rare, multi-systemic non-Langerhans cell histiocytosis characterized by the infiltration of lipid-laden histiocytes into various tissues and organs. While ECD has been documented globally, its presentation and management in small, isolated populations such as the Faroe Islands present unique challenges and opportunities for research. This article explores the epidemiology, etiology, and clinical manifestations of ECD, with a specific focus on the situational context of the Faroe Islands. It examines the genetic, environmental, and potential autoimmune factors contributing to ECD, alongside the diagnostic and therapeutic hurdles faced in a geographically isolated region with limited healthcare resources. Through a comprehensive literature review and situational analysis, this paper highlights the need for tailored approaches to ECD management in such settings, offering recommendations for improved diagnosis, treatment, and international collaboration. The discussion also touches on emerging insights into the disease’s etiology, including possible autoimmune links, while critically assessing speculative connections to vaccination. The article concludes with a call for increased research and policy focus to address rare diseases in unique sociocultural and geographic contexts like the Faroe Islands.
Introduction
Erdheim-Chester Disease (ECD) is an exceptionally rare histiocytic disorder first described in 1930 by Jakob Erdheim and William Chester. Characterized by the abnormal proliferation of non-Langerhans cell histiocytes and their infiltration into multiple organ systems, ECD often manifests with skeletal involvement, particularly in the long bones, alongside systemic symptoms such as cardiovascular, pulmonary, and neurological impairments. The disease predominantly affects adults in their fifth to seventh decades of life, with no significant gender predisposition reported (Cives et al., 2013). Despite advances in understanding ECD, particularly with the identification of BRAFV600E mutations in over 50% of cases, its etiology remains incompletely understood, and treatment strategies are largely experimental or targeted toward symptom management (Diamond et al., 2014).
The Faroe Islands, a self-governing archipelago within the Kingdom of Denmark, located in the North Atlantic, provide a unique context for studying rare diseases like ECD. With a population of approximately 54,000 and a healthcare system constrained by geographic isolation and limited specialist access, the diagnosis and management of rare conditions pose significant challenges. Additionally, the Faroese population’s genetic homogeneity, shaped by historical isolation and founder effects, offers a valuable opportunity to explore genetic contributions to rare diseases (Als et al., 2008). This article seeks to unravel the complexities of ECD with a particular focus on the Faroe Islands, addressing the intersection of genetic predisposition, environmental factors, and healthcare delivery challenges. It also critically examines the speculative links between ECD, autoimmunity, and external factors such as vaccines, while providing evidence-based recommendations for addressing these challenges in isolated settings.
Situational Analysis
The Faroe Islands’ unique demographic and geographic characteristics significantly influence the management of rare diseases like ECD. The population’s small size and genetic homogeneity, a result of limited historical immigration and intermarriage, have made the region a focal point for genetic research, notably in conditions such as multiple sclerosis and Parkinson’s disease (Binzer et al., 2015). However, specific data on ECD prevalence in the Faroe Islands are scarce, reflecting both the disease’s rarity and the under-reporting of cases in small populations. The absence of local tertiary care centers equipped to diagnose and treat complex histiocytic disorders further compounds these challenges. Patients suspected of having ECD often require referral to specialized facilities in Denmark or other European countries, which introduces delays in diagnosis and treatment, alongside financial and logistical burdens.
Healthcare in the Faroe Islands is managed through a publicly funded system, with primary care provided locally and specialized care often outsourced. The National Hospital in Tórshavn serves as the primary healthcare hub, but it lacks the diagnostic tools—such as advanced imaging modalities (e.g., PET-CT scans) and genetic testing facilities—necessary for confirming ECD. Moreover, the rarity of ECD means that local clinicians may lack familiarity with its clinical presentation, leading to misdiagnosis or delayed recognition. For instance, bone pain, a hallmark of ECD, may be initially attributed to more common conditions like osteoarthritis or osteoporosis, delaying the identification of characteristic radiologic findings such as symmetric osteosclerosis of the long bones (Cives et al., 2013).
Beyond diagnostic challenges, the cultural and social context of the Faroe Islands influences patient outcomes. The tight-knit community structure can both support and hinder disease management. While social networks provide emotional and practical support, stigma surrounding chronic or poorly understood illnesses may discourage individuals from seeking timely medical care. Additionally, the harsh climate and limited transportation infrastructure exacerbate access issues, particularly for elderly patients or those with mobility impairments—a common demographic for ECD (Diamond et al., 2014).
Literature Review
ECD is classified as a non-Langerhans cell histiocytosis, distinguishing it from more common histiocytic disorders like Langerhans cell histiocytosis (LCH). Histologically, ECD is characterized by the infiltration of CD68-positive, CD1a-negative foamy histiocytes into affected tissues, often accompanied by fibrosis and chronic inflammation (Cives et al., 2013). The disease’s clinical spectrum is broad, ranging from asymptomatic skeletal involvement to life-threatening multi-organ dysfunction. Common manifestations include bone pain (present in approximately 50-70% of cases), retroperitoneal fibrosis, diabetes insipidus due to pituitary infiltration, and cardiac involvement, which is a leading cause of mortality (Goyal et al., 2020).
Recent genetic studies have provided critical insights into ECD’s pathogenesis. Over 50% of ECD patients harbor the BRAFV600E mutation, a gain-of-function alteration in the MAPK/ERK signaling pathway that drives histiocyte proliferation (Diamond et al., 2014). Additional mutations in genes such as NRAS, KRAS, and PIK3CA have been identified in smaller subsets of patients, suggesting a clonal, neoplastic origin for the disease (Haroche et al., 2015). These findings have revolutionized ECD treatment, with BRAF inhibitors like vemurafenib demonstrating significant efficacy in improving symptoms and survival in mutation-positive patients (Goyal et al., 2020).
Despite these advances, the etiology of ECD remains elusive. Environmental triggers, immune dysregulation, and genetic predisposition are hypothesized to contribute to disease onset, though no definitive causal factors have been established. The potential autoimmune component of ECD has garnered attention, as chronic inflammation and immune activation are hallmarks of the disease. Some studies suggest that ECD may represent an overlap between inflammatory and neoplastic processes, with histiocytes acting as both effectors of tissue damage and targets of immune dysregulation (Cohen-Aubart et al., 2019). This hypothesis is supported by reports of ECD coexisting with autoimmune conditions such as systemic lupus erythematosus and rheumatoid arthritis, as well as the observation that inflammatory markers like C-reactive protein are often elevated in ECD patients (Cohen-Aubart et al., 2019).
Speculation regarding external triggers, including vaccines, has emerged in the broader context of autoimmune and inflammatory disorders. While no direct evidence links ECD to vaccination, the temporal association between vaccine administration and the onset of immune-mediated conditions in some case reports has fueled debate. For instance, studies examining the pediatric population during the COVID-19 pandemic found no significant increase in autoimmune disease incidence following SARS-CoV-2 vaccination, though ECD was not specifically addressed (Shavit et al., 2025). In the absence of robust data, any connection between ECD and vaccines remains speculative and requires rigorous investigation, particularly given the disease’s rarity and the complexity of establishing causality in small cohorts.
In the context of isolated populations like the Faroe Islands, literature on rare diseases often emphasizes the role of genetic founder effects and environmental exposures. The Faroese population’s high prevalence of certain genetic disorders underscores the potential for unique genetic contributions to ECD, though no specific studies have investigated this link. Furthermore, environmental factors such as dietary patterns (e.g., high consumption of marine pollutants like mercury) and infectious disease exposure, which are prevalent in the region, may modulate immune responses and contribute to inflammatory conditions, potentially including ECD (Weihe et al., 2008). However, these associations remain hypothetical and warrant targeted research.
Discussion
The management of ECD in the Faroe Islands exemplifies the broader challenges of addressing rare diseases in small, isolated populations. The interplay of genetic, environmental, and systemic factors creates a complex landscape for diagnosis and treatment. Genetic homogeneity may increase the likelihood of identifying novel mutations or founder effects in ECD, yet the lack of local expertise and diagnostic infrastructure hinders such discoveries. The reliance on international referrals introduces further disparities, as not all patients can afford or access overseas care. This situation mirrors challenges observed in other remote regions, where rare disease patients often experience diagnostic odysseys and fragmented care (Zurynski et al., 2017).
The potential autoimmune nature of ECD adds another layer of complexity. If ECD indeed involves immune dysregulation, therapies targeting inflammation—such as corticosteroids or interleukin inhibitors—may offer benefits, as seen in preliminary studies (Cohen-Aubart et al., 2019). However, distinguishing between inflammatory and neoplastic drivers is critical, particularly in BRAF-mutation-negative patients who may not respond to targeted therapies. In the Faroe Islands, where access to genetic testing is limited, such distinctions are difficult to make, potentially leading to suboptimal treatment plans. The speculative link between ECD and vaccines, while unsupported by current evidence, merits cautious consideration in future research. Given the high vaccination rates in the Faroe Islands, population-based studies could provide valuable data on whether immune stimulation via vaccines correlates with ECD onset, though such studies must account for the disease’s rarity and confounding factors.
Beyond etiology, the socioeconomic and cultural context of the Faroe Islands influences ECD outcomes. Community-based health initiatives could mitigate stigma and improve early detection, but they require investment in public health education tailored to rare diseases. Telemedicine also holds promise for connecting Faroese patients with international specialists, though barriers such as language differences and technology access must be addressed. These challenges are not unique to ECD but reflect systemic issues in rare disease care, particularly in regions with limited resources (Zurynski et al., 2017).
Finally, the global rarity of ECD necessitates international collaboration. While the Faroe Islands may contribute unique genetic and environmental data to ECD research, this potential remains untapped due to a lack of research infrastructure. Partnerships with Nordic or European rare disease networks could facilitate data sharing and clinical trials, ensuring that patients in isolated regions benefit from global advances. The integration of Faroese cases into international registries, such as those maintained by the Histiocyte Society, could further enhance understanding of ECD’s epidemiology and natural history (Goyal et al., 2020).
Recommendations
Addressing the challenges of ECD in the Faroe Islands requires a multi-faceted approach targeting healthcare delivery, research, and community engagement. The following recommendations aim to improve outcomes for ECD patients and contribute to global understanding of the disease:
- Enhance Diagnostic Capacity: Invest in training for local clinicians to recognize ECD and establish partnerships with Danish or European centers for access to advanced diagnostics (e.g., PET-CT, genetic testing). Telemedicine platforms can bridge gaps by facilitating remote consultations with histiocytosis experts.
- Develop Rare Disease Policies: Advocate for national policies in the Faroe Islands that prioritize funding for rare disease care, including travel subsidies for patients requiring overseas treatment and support for caregiver burdens.
- Promote Genetic Research: Leverage the genetic homogeneity of the Faroese population to investigate potential founder effects or novel mutations in ECD. Collaborations with genetic research institutes in Denmark or Iceland could accelerate these efforts.
- Investigate Autoimmune Hypotheses: Conduct longitudinal studies to explore the inflammatory and autoimmune components of ECD, including potential environmental triggers unique to the Faroe Islands, such as dietary exposures or infectious agents.
- Address Vaccine Speculation: While no evidence links ECD to vaccines, population-based studies in the Faroe Islands could assess any temporal associations between vaccination and immune-mediated conditions, ensuring robust methodology to avoid misinterpretation.
- Community Education and Support: Implement public health campaigns to reduce stigma around rare diseases and encourage early medical consultation. Support groups, even if virtual, can provide emotional and practical assistance to patients and families.
- International Collaboration: Integrate Faroese ECD cases into global registries and clinical trials to ensure representation of small populations in research, enhancing both local care and worldwide knowledge.
Conclusion
Erdheim-Chester Disease remains a complex and poorly understood condition, with significant challenges to diagnosis and management, particularly in isolated regions like the Faroe Islands. The interplay of genetic predisposition, potential autoimmune mechanisms, and environmental factors underscores the need for a nuanced approach to ECD research and care. While speculative links to external factors such as vaccines lack substantiation, they highlight the importance of rigorous, population-based studies to clarify disease triggers. In the Faroe Islands, geographic and systemic barriers exacerbate the difficulties faced by ECD patients, yet the region’s unique characteristics also offer untapped research opportunities. By enhancing local healthcare capacity, fostering international collaboration, and prioritizing rare disease policy, it is possible to improve outcomes for ECD patients in the Faroe Islands while contributing to global insights. Future research must focus on unraveling the multifaceted etiology of ECD, ensuring that even the smallest populations are not overlooked in the quest for understanding and treatment of rare diseases.
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