Population-based prevalence of rare diseases in Jeju, Korea: a 2021 analysis using NHIS data

Article information

J Med Life Sci. 2025;22(2):69-80

Publication date (electronic) : 2025 May 28

doi : https://doi.org/10.22730/jmls.2025.22.2.69

Ki Soo Kang¹, Jung-Kook Song^,2

¹Department of Pediatrics, Jeju National University Hospital, Jeju National University College of Medicine, Jeju, Republic of Korea

²Department of Preventive Medicine, Jeju National University Hospital, Jeju National University College of Medicine, Jeju, Republic of Korea

Correspondence to Jung-Kook Song Department of Preventive Medicine, Jeju National University Hospital, Jeju National University College of Medicine, 15 Aran 13-gil, Jeju 63241, Republic of Korea Tel: 82-64-754-8115 Fax: 82-64-717-2966 E-mail: songj@jejunu.ac.kr

Received 2025 April 4; Revised 2025 April 21; Accepted 2025 April 23.

Abstract

INTRODUCTION

Rare diseases are defined by their extremely low prevalence and limited patient population, resulting in a scarcity of information and posing significant challenges to diagnosis and treatment. Most rare diseases have unknown etiologies and are difficult to cure, often requiring lifelong management and prolonged care. Consequently, they impose substantial psychosocial [1,2] and economic burdens [3,4] on affected individuals and their families, along with considerable societal costs. Globally, more than 7,000 rare diseases have been identified, affecting an estimated 300 million people [5]. However, due to a lack of specialists and infrastructure, even basic epidemiological data, such as accurate incidence and prevalence rates, remain insufficient for most rare diseases [6].

Definitions of rare diseases vary across countries. The European Union (EU) defines them as conditions affecting fewer than 50 individuals per 100,000 people, while the United States categorizes them as diseases affecting fewer than 200,000 individuals nationwide. In Japan, rare diseases are defined as diseases with unknown pathogenic mechanisms and no established treatments. Australia considers diseases rare if they affect fewer than 2,000 individuals, regardless of curability [7]. In Korea, rare diseases are defined as conditions affecting fewer than 20,000 individuals, or where the number of patients is unknown due to diagnostic difficulty. Additionally, ultra-rare diseases refer to those with specific diagnostic criteria and either fewer than 200 affected individuals or no designated Korean Standard Classification of Diseases (KCD) code. Newly identified chromosomal abnormalities are also included under rare diseases if they lack a specific KCD code and can be classified as diseases rather than symptoms [8].

The enactment of the Rare Disease Management Act in December 2015 established an official definition of rare diseases in Korea and led to the creation of a nationally managed list. This laid the foundation for statistical evaluation and policy development [6]. Within this framework, a registration and monitoring program was launched, resulting in the annual publication of the annual report on the rare disease patients in Korea. This report provides essential data on incidence (newly registered patients), mortality, and healthcare utilization [8]. However, systematic studies on the prevalence of rare diseases remain limited both domestically and internationally. One of the few resources available is the Orphanet database, coordinated by the French National Institute of Health and Medical Research (INSERM) and involving 40 European countries [9].

This study was prompted by the establishment of the Jeju Regional Center for Rare Diseases in February 2021 [10] and addressed the urgent need to investigate the epidemiological landscape of rare diseases in the region. The primary objective of this study was to generate foundational data on the prevalence of rare diseases in Jeju, thereby contributing to evidence-based policymaking.

METHODS

RESULTS

1. Number of patients with all rare diseases (cases) and claims

1) Comparison by sex and age in Jeju

Among the 4,669 patients with rare diseases, 2,083 (44.6%) were male and 2,586 (55.4%) were female. In adults aged 19 years and older, there were 1,753 males and 2,339 females, with a male-to-female ratio of 100:133, indicating a higher crude prevalence rate in females. In contrast, among children aged 18 years and younger, there were 330 males and 247 females, with a male-to-female ratio of 134:100 (equivalent to 100.0:74.8), showing a higher crude prevalence rate in males.

Regarding the total number of insurance claims (n=40,219), males filed 17,690 (44.0%) claims and females filed 22,529 (56.0%) claims. Among adults, males filed 13,214 claims and females filed 18,593 claims, resulting in a male-to-female ratio of 100.0:140.7. However, among children, males filed 4,476 claims and females filed 3,936 claims, with a male-to-female ratio of 114:100 (equivalent to 100.0:87.9), again indicating a higher rate among males (Table 1).

Table 1.

Number of patients with all rare diseases (cases) and claims by sex and age in Jeju (2021)

2) Comparison by eligibility type, age, and sex in Jeju

Among patients with all rare diseases, 284 (6.1%) were covered by medical aid, accounting for 2,402 claims (6.0% of all claims). Sex distribution among medical aid beneficiaries showed patterns similar to those observed in the overall population in both adult and pediatric groups. Specifically, Medical Aid recipients constituted 260/4,092 (6.4%) of adult patients and 24/577 (4.2%) of pediatric patients. Regarding claims, 2,195/31,807 (6.9%) of adult claims and 207/8,412 (2.5%) of pediatric claims were from medical aid beneficiaries, indicating that the proportion was higher among adults than among children (Table 2).

Table 2.

Number of patients with all rare diseases and claims by the National Health Insurance’s eligibility type, age, and sex in Jeju (2021)

2. Crude prevalence rate

1) Crude prevalence rate of all rare diseases by age and sex in Jeju

The overall crude prevalence rate of all rare diseases in Jeju was 696 cases per 100,000 people, with 619 per 100,000 among males and 774 per 100,000 among females. When categorized into 5-year age intervals, the age-specific crude prevalence rate ranged from a minimum of 458 per 100,000 in the 0-4 age group to a maximum of 1,441 per 100,000 in the 75-79 age group. Notably, individuals aged 65-89 years showed relatively higher crude prevalence rates than other age groups, ranging from 1,221 to 1,441 per 100,000 people (Table 3).

Table 3.

Crude prevalence rate of all rare diseases by age and sex in Jeju (2021)

2) Crude prevalence rate of hereditary and non-hereditary rare diseases by age and sex in Jeju

Among all rare diseases, the crude prevalence rate of hereditary diseases was 130 per 100,000 people, while that of non-hereditary diseases was 575 per 100,000 people, resulting in a ratio of 18:82 between hereditary and non-hereditary diseases. The proportion of hereditary diseases differed markedly between age groups: hereditary diseases accounted for 643/4,137 (15.5%) of adult patients compared to 226/593 (38.1%) of pediatric patients, which was more than twice the proportion observed in adults (Table 4). In this study, patients aged 18 years or younger were classified as pediatric patients and those aged 19 years or older were classified as adult patients. The number of patients and diseases was reported based on this classification. However, in Table 4, the population data from the national statistics, grouped in 5-year intervals, were used, resulting in the pediatric group being defined as up to 19 years of age, which caused a slight discrepancy.

Table 4.

Crude prevalence rate of hereditary and non-hereditary rare diseases except for ultra-rare diseases and other chromosomal abnormalities by age and sex in Jeju (2021)

3) Crude prevalence rate of top and bottom ranked rare diseases in Jeju

The crude prevalence rate of the top 30 most frequent rare diseases (except for ultra-rare diseases and other chromosomal abnormalities) in Jeju ranged from 51 to 4 cases per 100,000 people. Among these, 16 diseases had a crude prevalence rate of 10 or more per 100,000 people (Supplementary Table 1).

Notably, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) was previously classified as an ultra-rare disease (assigned the Special Case Exemption Code V900 under the rare disease benefit program) in 2020 but was reclassified as a rare disease in 2021. However, in the 2021 claim data used for analysis, two cases were recorded under the previous 2020 classification code. The crude prevalence rate of CADASIL was calculated as 14 per 100,000 people, based on 96 identified cases among 670,993 individuals.

The 10 most common rare diseases in Jeju were systemic lupus erythematosus with organ or system involvement (crude prevalence rate of 51), idiopathic dilated cardiomyopathy (crude prevalence rate of 45), non-obstructive hypertrophic cardiomyopathy (crude prevalence rate of 32), Sjögren's syndrome with myopathy (crude prevalence rate of 31), moyamoya disease (crude prevalence rate of 30), idiopathic pulmonary fibrosis (crude prevalence rate of 27), Behçet's disease (crude prevalence rate of 24), retinitis pigmentosa (crude prevalence rate of 15), CADASIL (crude prevalence rate of 14), and bicuspid aortic valve (crude prevalence rate of 13) (Supplementary Fig. 1).

Among the 248 rare diseases reported in 2021 among patients in the Jeju region, 56 were identified in only a single case. These diseases ranked 193 or below in the frequency distribution. The names of these single-occurrence diseases are presented in Supplementary Table 2.

4) Proportion of cases by system classification in Jeju

When classifying all rare diseases by system, based on the major categories of KCD, the most common categories were musculoskeletal system and connective tissue at 24.2%, followed by circulatory system at 18.5%, congenital malformations, deformations, and chromosomal abnormalities at 14.2%, and nervous system at 14.1%. Categories with a proportion of less than 5.0% included genitourinary system, skin and subcutaneous tissue, mental and behavioral disorders, eyes and ears, and respiratory system.

In the pediatric population, rare diseases were most prominently classified as congenital malformations, deformations, or chromosomal abnormalities, which account for 57% of all pediatric rare diseases. This notably high proportion distinguished the pediatric group from the adult group. The next most common categories were nervous system at 11% and musculoskeletal system and connective tissue at 10% (Fig. 1).

Figure 1.

Prevalence and proportion of cases by system classification in Jeju (2021) and comparison between children and adults.

3. Prevalent diseases in Jeju

1) All designated vs. observed rare diseases: the MOHW notification on July 1, 2021, and the NHIS data in 2021

As of July 1, 2021, 1,201 diseases were designated under the rare disease benefit program of the MOHW. Of these, 898 (74.8%) were classified as rare diseases (except for ultra-rare diseases and other chromosomal abnormalities), 249 (20.7%) as ultra-rare diseases, and 54 (4.5%) as other chromosomal abnormalities. In comparison, analysis of the 2021 NHIS claims data identified 640 rare diseases, including 470 (73.4%) rare diseases (except for ultra-rare diseases and other chromosomal abnormalities), 161 (25.2%) ultra-rare diseases, and nine (1.4%) chromosomal abnormalities (Table 5).

Table 5.

Numbers of all rare diseases in Jeju (2021)

2) All prevalent rare diseases in Jeju

Among Jeju residents, 279 rare diseases were identified based on data for patient claims. Of these, 249 (89.2%) were classified as rare diseases (except for ultra-rare diseases and other chromosomal abnormalities), 29 (10.4%) as ultra-rare diseases, and one (0.4%) as other chromosomal abnormalities.

Based on the NHIS claims data, the proportion of rare diseases with at least one patient identified among Jeju residents in 2021 was approximately 44% of all rare diseases recorded nationwide. When analyzed by classification, this proportion was 53% for rare diseases, 18% for ultra-rare dis eases, and 11% for other chromosomal abnormalities (Table 5).

3) Multiple rare disease diagnoses in Jeju

Among patients with rare diseases, excluding ultra-rare diseases and other chromosomal abnormalities (n=4,645), 382 (8.3%) patients had multiple rare disease diagnoses. The proportion was markedly higher among patients with ultra-rare diseases at 9 out of 36 (25.0%). However, the maximum number of diagnoses per patient was four among those with rare diseases (except for ultra-rare diseases and other chromosomal abnormalities) and three among those with ultra-rare diseases (Table 6).

Table 6.

Multiplicity of diagnosis and proportion of patients with multiple rare disease diagnoses in Jeju (2021)

DISCUSSION

This is the first population-based study to examine the prevalence of all rare diseases in Jeju using data from the customized database provided by the NHIS. We estimated the total number of patients diagnosed with rare diseases and identified 4,669 cases in 2021. Of these, 2,083 (44.6%) were male and 2,586 (55.4%) were female. In adults (≥19 years), females showed a higher crude prevalence rate (male-to-female ratio, 100:133), whereas in children (≤18 years), males were more prevalent (134:100). We estimated that the crude prevalence rate of all rare diseases in Jeju was 696 cases per 100,000 people, with 619 per 100,000 among males and 774 per 100,000 among females in 2021.

Although several studies in Korea have reported the prevalence of specific rare diseases [13-16], this is the first study to examine the overall prevalence of all rare diseases within a defined region. The lack of comparable studies makes it difficult to assess the relative significance of our findings. Nevertheless, this study offers meaningful empirical data that the Jeju Regional Center for Rare Diseases mandates to monitor and utilize.

This study did not include clinical diagnostic criteria or detailed disease characteristics, which may raise concerns regarding the potential misclassification of diagnoses. However, as this study used rare disease exemption codes designated through the national program, it is likely that diagnostic accuracy was relatively high, supporting the reliability of the results. Nevertheless, the study only included patients who were registered in the co-payment reduction program; therefore, it is possible that some cases were not captured, leading to an underestimation of the actual prevalence [8].

While the co-payment reduction program offers financial benefits that generally encourage accurate disease coding, there may still be instances in which rare diseases are under-coded. This could occur due to delays in receiving a confirmed diagnosis, administrative mistakes, or incomplete documentation in clinical records. Therefore, even with the use of exemption codes, the possibility of under-coding cannot be completely excluded.

Beyond the data-related limitations, this study highlights a critical aspect of patient vulnerability, namely the socioeconomic disadvantage of individuals living with rare diseases. In this study, the proportion of patients with rare diseases receiving medical aid was 6.0%, much higher than the proportion of recipients of National Basic Livelihood Security (30,634/670,992, 4.6%) in Jeju in the same year [17]. This proportion was 4.2% among children and 6.4% among adults, indicating a higher level of economic vulnerability in the adult population. These findings suggest that individuals with rare diseases may be more economically disadvantaged than the general population and that this vulnerability becomes more pronounced with age in Jeju.

Previous national statistics from 2019 to 2022 consistently reported that the proportion of male patients with newly diagnosed rare diseases was slightly higher than that of female patients [18-22]. In contrast, our analysis, which focused on prevalence, showed that the overall proportion of female patients was higher. Male patients were more common only among individuals aged 18 years or younger. This difference may reflect the cumulative nature of the prevalence data, which include all existing patients rather than just new cases, and may be influenced by differences in survival rates and other epidemiological factors. It may also be partly explained by the slightly higher number of male births in Korea compared with female births (105.0 in 2024) [23].

The discrepancy between the number of rare diseases listed in the MOHW notification and those identified in the NHIS data is mainly due to structural differences in classification and data recording systems. The number of officially announced diseases by the MOHW tends to increase annually (926 diseases in 2019 [17], 1,014 in 2020 [18,19], 1,086 in 2021 [20], and 1,123 in 2022 [21]) and includes conditions that are differentiated by assigning additional serial numbers to a single disease code [8]. However, the NHIS dataset does not include these serial numbers, resulting in multiple rare diseases sharing a single disease code. Moreover, ultra-rare diseases are grouped under the exemption code V900; however, some share one code among several conditions, whereas others are represented by multiple codes per disease. In certain cases, especially those classified under the syndrome classification guideline, the absence of a specific disease code makes identification impossible. These system-level characteristics explain the substantial discrepancy in the number of all rare diseases recognized by the two sources.

Interestingly, despite the difference in the total disease counts, the proportional distribution of rare diseases (except for ultra-rare diseases and other chromosomal abnormalities), ultra-rare diseases, and other chromosomal abnormalities was similar in both datasets, at approximately 75%, 25%, and less than 5%, respectively (Table 5). However, when comparing the rare diseases identifiable in the NHIS data with those observed in Jeju, differences were noted in the proportion of disease types. While the NHIS data showed a composition of approximately 73% of rare diseases, 25% of ultra-rare diseases, and 1% of other chromosomal abnormalities, the corresponding proportions in Jeju were 89%, 10%, and 0%, respectively. This suggests that the rarer the disease, the less likely it is to be represented in Jeju, likely due to the region’s small population, which accounts for only 1.3% of the national population. Therefore, the prevalence of extremely rare diseases in Jeju may be disproportionately lower than in larger regions on the mainland.

Among the identifiable rare diseases in the NHIS data, the proportion of diseases with at least one case in Jeju in 2021 was approximately 44%. Specifically, the proportions were 53% for rare diseases (excluding ultra-rare diseases and other chromosomal abnormalities), 18% for ultra-rare diseases, and 11% for other chromosomal abnormalities (Table 5). These findings suggest that the rarer the disease, the smaller its observed patient population, reflecting the challenges of detecting ultra-rare conditions in smaller regional populations.

Some patients were diagnosed with more than one rare disease, leading to the total number of prevalent cases by disease (Table 6) slightly exceeding the total number of individual patients with rare diseases (Tables 1, 2). This distinction is important when interpreting disease-specific prevalence, as it prevents an overestimation of the affected population.

This study had some inherent limitations. The analysis was based on the NHIS claims data [24], which are primarily collected for administrative and reimbursement purposes rather than research. Therefore, the potential for misclassification, diagnostic inaccuracies, and under-coding cannot be excluded, particularly for rare or underdiagnosed conditions. Despite these limitations, repeated prevalence surveys are a practical approach to monitor trends and guide policies for rare diseases, especially when conducted using population-level datasets [25]. Future studies should incorporate healthcare utilization and cost analysis to better inform evidence-based policies and resource allocation.

By utilizing the NHIS database and developing a systematic classification framework for the prevalence status, this study quantitatively analyzed the prevalence of rare diseases at the regional level. Based on this foundation, future research should include other regions and multicenter comparisons to validate and generalize the findings of this study. Furthermore, repeated prevalence studies within specific regions are necessary to monitor trends over time.

The findings of this study provide critical baseline data that can inform region-specific public health strategies for the management of rare diseases. Identifying local prevalence patterns by age, sex, and disease type allows policy-makers to prioritize resource allocation, enhance early diagnosis programs, and design tailored patient support services.

Compared to previous national reports (annual reports on patients with rare diseases) in Korea, which primarily focused on newly registered patients with rare diseases, this study analyzed the overall prevalence of rare diseases among all the registered patients, thereby offering a broader understanding of the regional burden of rare diseases. International efforts, such as Orphanet, have emphasized the necessity of region-specific surveillance of rare diseases, and our findings align with the growing need for localized epidemiological assessments to guide policy development.

In addition to the general limitations of the administrative data, the rare disease registration system (co-payment reduction program) presents structural limitations that may have resulted in an underestimation of the true prevalence reported in this study. Patients who have not received a diagnosis or who fail to complete mandatory re-registration every five years may be missed. Moreover, inaccuracies in disease coding within administrative datasets cannot be entirely ruled out.

This study is the first to report the overall crude prevalence rate of rare diseases in the Jeju region using a customized research database from the NHIS. The findings revealed the regional characteristics in prevalence by sex, age, and eligibility type. Due to Jeju’s small population size, the rarer the disease, the less likely it is to be observed. These findings provide important baseline data for regional surveillance of rare diseases and policy planning. Moreover, they underscore the importance of region-specific surveillance and can serve as a cornerstone for tailoring rare disease management strategies in geographically distinct populations, such as Jeju.

Supplementary Material

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