Abstract
Blue Rubber Bleb Nevus Syndrome (BRBNS) is a rare vascular disorder characterized by multiple venous malformations affecting the skin, gastrointestinal tract, and other visceral organs. While globally reported cases are limited, the condition poses significant diagnostic and therapeutic challenges due to its variable presentation and potential for severe complications such as gastrointestinal bleeding. In South Korea, where medical research on rare disorders is evolving, BRBNS remains under-documented, with sparse case studies and limited epidemiological data. This article investigates the clinical manifestations, diagnostic approaches, and treatment strategies for BRBNS in South Korea through a situational analysis of available cases and a comprehensive literature review. The study highlights cultural and healthcare system factors influencing the management of BRBNS, alongside global comparisons. Recommendations for improved diagnosis, multidisciplinary care, and research initiatives are provided to address the unique challenges faced in South Korea. This work aims to contribute to the limited body of knowledge on BRBNS in the region and foster greater awareness among healthcare professionals.
Introduction
Blue Rubber Bleb Nevus Syndrome (BRBNS), also known as Bean Syndrome, is an exceedingly rare congenital disorder marked by the presence of multifocal venous malformations. These malformations typically manifest as bluish, rubbery nodules on the skin and can involve visceral organs, most commonly the gastrointestinal (GI) tract, leading to complications such as chronic anemia due to recurrent bleeding. First described by Gascoyen in 1860, and later named by William Bean in 1958, BRBNS has been documented in fewer than 300 cases worldwide. The etiology remains largely unknown, though recent genetic studies suggest somatic mutations in the TEK (TIE2) gene as a potential cause in some patients.
In South Korea, a country with a well-developed healthcare system and a growing focus on rare disease research, BRBNS remains an understudied condition. Despite the nation’s advancements in medical technology and infrastructure, the rarity of BRBNS poses significant challenges in terms of awareness, diagnosis, and management. Cultural perceptions of visible vascular anomalies and systemic barriers in accessing specialized care further complicate the situation. This article seeks to explore the current state of BRBNS in South Korea by analyzing documented cases, reviewing global literature, and discussing the unique challenges and opportunities for addressing this condition within the local context. The objectives are to synthesize existing knowledge, identify gaps, and propose actionable recommendations for healthcare providers and policymakers.
Situational Analysis
In South Korea, the prevalence of BRBNS is not well-documented due to the absence of a centralized registry for rare vascular disorders. The country’s healthcare system, while advanced, prioritizes common and high-incidence diseases, often leaving rare conditions like BRBNS on the periphery of medical research and clinical focus. However, a few case reports provide insight into the local experience of BRBNS. For instance, a notable case published in the Korean Journal of Internal Medicine in 2008 described a 14-year-old female patient presenting with dizziness and multiple hemangiomas on the skin and GI tract. The patient was diagnosed with BRBNS and treated with methylprednisolone, demonstrating a conservative approach to management.
The South Korean healthcare system operates under a universal health insurance framework, ensuring broad access to medical services. Yet, for rare diseases, patients often face delays in diagnosis due to a lack of specialized centers and limited familiarity among general practitioners with conditions like BRBNS. Moreover, cultural factors, such as stigma associated with visible skin lesions, may deter patients from seeking timely care, particularly in rural areas where access to dermatological or gastroenterological expertise is limited. The National Health Insurance Service (NHIS) does provide coverage for rare disease treatments, but the reimbursement process for novel or experimental therapies (e.g., sirolimus for vascular malformations) is often slow and inconsistent, posing additional barriers.
Epidemiologically, there is no clear data on the incidence or prevalence of BRBNS in South Korea, reflecting a broader global challenge of underreporting. The majority of available information stems from individual case reports rather than population-based studies. This scarcity of data underscores the need for systematic documentation and collaborative research efforts. Furthermore, environmental or genetic factors specific to the South Korean population that might influence the expression of BRBNS have not been explored, highlighting an area ripe for investigation.
Literature Review
Globally, BRBNS is characterized by its sporadic nature, with most cases lacking a clear familial pattern, though autosomal dominant inheritance linked to chromosome 9p has been reported in some families. The hallmark of BRBNS is the presence of cutaneous venous malformations, often described as soft, compressible, and tender nodules ranging from a few millimeters to several centimeters in diameter. These lesions can appear anywhere on the body, from the scalp to the soles of the feet. Visceral involvement, particularly in the GI tract, is common and frequently leads to chronic bleeding, iron-deficiency anemia, and, in severe cases, life-threatening hemorrhage.
Diagnostic criteria for BRBNS are primarily clinical, relying on the presence of characteristic cutaneous lesions alongside evidence of visceral involvement, often confirmed through endoscopy or imaging modalities such as magnetic resonance imaging (MRI) and computed tomography (CT). Differential diagnoses include other vascular malformation syndromes such as Klippel-Trenaunay syndrome and hereditary hemorrhagic telangiectasia, necessitating a thorough clinical evaluation. Recent genetic research has identified somatic double (cis) mutations in the TEK gene, which encodes the TIE2 receptor involved in endothelial cell signaling, as a key driver in BRBNS pathogenesis. These mutations lead to ligand-independent hyperactivation of the TIE2 receptor, promoting abnormal vascular development.
In terms of management, there is no standardized protocol for BRBNS due to its rarity and heterogeneous presentation. Treatment is largely symptomatic and depends on the extent and location of malformations. For cutaneous lesions without functional impairment, observation is often sufficient. However, GI bleeding necessitates interventions such as endoscopic sclerotherapy, band ligation, or surgical resection in severe cases. Pharmacological approaches, including corticosteroids and, more recently, mTOR inhibitors like sirolimus, have shown promise in reducing lesion size and bleeding frequency. Sirolimus, in particular, targets the PI3K/AKT/mTOR pathway downstream of TIE2 signaling, offering a novel therapeutic avenue.
In the South Korean context, the literature is sparse but aligns with global patterns in terms of clinical presentation and management challenges. The aforementioned 2008 case report highlighted the use of corticosteroids as a primary treatment, reflecting a conservative strategy that may not address underlying vascular pathology. No studies have explicitly explored genetic mutations in South Korean patients with BRBNS, representing a critical gap in the local literature. Moreover, cultural factors influencing patient care-seeking behavior and psychological impacts of visible lesions remain underexplored in both global and local contexts.
Discussion
The investigation of BRBNS in South Korea reveals a complex interplay of clinical, systemic, and cultural challenges. Clinically, the rarity of the condition means that many healthcare providers may encounter only a handful of cases in their careers, leading to potential misdiagnosis or delayed diagnosis. For instance, cutaneous lesions may be mistaken for benign nevi or other dermatological conditions, while GI bleeding might be attributed to more common causes such as peptic ulcers without thorough investigation for vascular malformations. This diagnostic delay can exacerbate patient outcomes, particularly when bleeding leads to severe anemia or other complications.
From a systemic perspective, South Korea’s healthcare infrastructure, while robust, is not fully equipped to address the needs of patients with rare disorders like BRBNS. The concentration of specialized medical centers in urban areas such as Seoul creates disparities in access for rural populations. Additionally, the lack of a national registry for rare vascular disorders hinders epidemiological understanding and the ability to track patient outcomes over time. The NHIS coverage, while comprehensive, often lags in approving cutting-edge treatments such as sirolimus, which have shown efficacy in global studies but are not yet widely available or reimbursed in South Korea.
Culturally, South Korea places significant emphasis on physical appearance, which can amplify the psychosocial burden of visible cutaneous lesions associated with BRBNS. Patients, particularly adolescents, may experience stigma or social isolation, potentially deterring them from seeking medical help. This cultural dimension is critical yet understudied, and healthcare providers must be trained to address not only the physical but also the emotional and social aspects of the condition.
Comparing South Korea to other regions, such as Europe or the United States, reveals both similarities and differences. A recent European multicenter cohort study highlighted the importance of multidisciplinary care teams in managing BRBNS, an approach that South Korea could adopt to improve outcomes. In the United States, genetic testing for TEK mutations is becoming more accessible, offering insights into personalized treatment strategies—a development that South Korea has yet to fully embrace due to cost and availability constraints. These comparisons underscore the need for South Korea to integrate global best practices while addressing local barriers.
Potential areas of improvement include increasing awareness among primary care physicians through targeted education programs and establishing referral pathways to specialized centers for suspected cases of BRBNS. Furthermore, the role of genetic testing in confirming diagnosis and guiding therapy cannot be overstated, especially given the recent identification of TEK mutations as a molecular hallmark of the condition. South Korea, with its strong biotechnology sector, is well-positioned to lead regional research into the genetic underpinnings of BRBNS, potentially identifying population-specific variants or modifiers.
Recommendations
Based on the analysis and discussion, several recommendations emerge for addressing the challenges of BRBNS in South Korea:
- Establish a National Registry for Rare Vascular Disorders: A centralized database would facilitate the collection of epidemiological data, track patient outcomes, and support research initiatives. Collaboration between the Korea Disease Control and Prevention Agency (KDCA) and academic institutions could drive this effort.
- Enhance Physician Training and Awareness: Medical education curricula should include modules on rare vascular disorders, emphasizing early recognition of BRBNS symptoms. Continuing medical education (CME) programs can target practicing physicians, particularly in rural areas.
- Promote Multidisciplinary Care Models: Establishing dedicated centers for vascular anomalies, staffed by dermatologists, gastroenterologists, hematologists, and geneticists, would improve diagnostic accuracy and treatment planning. These centers could serve as regional hubs, reducing disparities in access.
- Expand Access to Genetic Testing: Government and private sector partnerships should aim to subsidize genetic testing for TEK mutations in suspected BRBNS cases, integrating results into personalized treatment plans.
- Accelerate Approval of Novel Therapies: The NHIS should streamline reimbursement processes for emerging treatments such as sirolimus, ensuring that South Korean patients benefit from global advancements in BRBNS management.
- Address Psychosocial Impacts: Healthcare providers should be trained to offer psychological support to patients with visible lesions, potentially integrating counseling services into routine care. Public awareness campaigns can also reduce stigma associated with vascular anomalies.
- Foster Research Initiatives: Funding should be allocated for studies exploring the genetic, environmental, and cultural factors influencing BRBNS in South Korea. Collaborative international projects can provide comparative data and enhance global understanding of the condition.
Conclusion
Blue Rubber Bleb Nevus Syndrome represents a rare but significant vascular challenge in South Korea, where limited awareness, systemic barriers, and cultural factors complicate diagnosis and management. This article has provided a comprehensive overview of the condition within the local context, drawing on available case reports, global literature, and situational analysis. The clinical complexity of BRBNS, coupled with its potential for severe complications, underscores the urgency of addressing gaps in knowledge and care delivery. By implementing the outlined recommendations—ranging from establishing a national registry to promoting multidisciplinary care and genetic research—South Korea can improve outcomes for patients with BRBNS and contribute to the global understanding of this rare disorder. Future studies should prioritize longitudinal data collection and population-specific investigations to uncover unique aspects of BRBNS presentation and progression in the region. Through concerted efforts, South Korea has the potential to become a leader in the management of rare vascular disorders, ensuring that even the rarest conditions receive the attention and resources they deserve.
References
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- Cho, W. Y., et al. (2008). A case of blue rubber bleb nevus syndrome. Korean Journal of Internal Medicine, 23(4), 208-212. doi:10.3904/kjim.2008.23.4.208
- Fishman, S. J., & Mulliken, J. B. (1993). Hemangiomas and vascular malformations of infancy and childhood. Pediatric Clinics of North America, 40(6), 1177-1200. doi:10.1016/S0031-3955(16)38649-9
- Soblet, J., et al. (2017). Blue Rubber Bleb Nevus (BRBN) Syndrome Is Caused by Somatic TEK (TIE2) Mutations. Journal of Investigative Dermatology, 137(1), 207-216. doi:10.1016/j.jid.2016.07.034
- Wong, C. H., et al. (2024). Blue rubber bleb nevus syndrome: A European multicenter cohort study. Digestive and Liver Disease. doi:10.1016/j.dld.2024.09.012