The current study is the first population-based research performed on the prevalence of BHD syndrome in Korea by using a nationwide claims database. Although the prevalence of BHD syndrome was extremely rare in South Korea (5.67 per 10 million), various comorbidities, including malignancy and repetitive pneumothorax, were found.
Given that the BHD syndrome is a rare inherited disorder , its incidence and prevalence remain unknown. Several previous reports focused on the prevalence of BHD syndrome in patients with spontaneous pneumothorax [13, 14] or family history [5, 15, 16]. Recently, Hu et al. conducted a literature review of a large BHD syndrome cohort (120 families with 221 cases) in China . However, they collected information using only published data; hence, the research was not representative of the nationwide data. In South Korea, Lee et al. reported only 12 patients (10 patients confirmed by FLCN gene test) who had BHD syndrome in a single largest tertiary hospital , suggesting the rarity of this condition. Our current data showed that BHD syndrome is ultrarare in South Korea, with a prevalence rate of only 5.67 per 10 million. As mentioned earlier, defining BHD syndrome cases using the ICD code alone seemed inadequate because it might omit other patients with BHD syndrome, leading to bias in evaluating epidemiologic data. In addition, patients with BHD syndrome who did not undergo the FLCN gene test were excluded in our analysis; this exclusion might have led to the underestimation of actual epidemiology. However, our data might serve as a reference for understanding this rare disease in South Korea.
Clinical manifestations of patients with BHD syndrome may also differ in terms of ethnicity [15, 18]. Kunogi et al. evaluated 30 Japanese patients with BHD syndrome and reported that while nearly all patients (96.7%) experienced pneumothorax, only 7 (23.3%) had skin lesion, and 2 (6.7%) had renal tumor . Hu et al. investigated 221 Chinese patients with BHD syndrome and showed prevalence of pneumothorax (71.0%), skin lesion (18.1%), and renal cancer (3.6%) . Thus, Asian patients might have a higher prevalence of pneumothorax and a lower incidence of cutaneous and renal manifestations than Western patients [4, 19–21]. Similarly, our current study found that pneumothorax occurred in over half of the patients (58.8%), but skin lesion (fibrofolliculoma, trichodiscoma, or accrocardon) and ureter and bladder cancer only accounted for 9 (34.6%) and 3 patients (11.5%), respectively. Recently, Liu et al. analyzed 51 Chinese patients with BHD syndrome and showed that Chinese patients had FLCN gene mutant loci that were different from those of Western patients . This observation might possibly explain the ethnic difference. Notably, our current study showed several comorbidities, especially malignant neoplasm, in patients with BHD syndrome. Various tumors other than renal cancer might also occur in these patients [5, 20, 22, 23]. However, the gold standard or guidelines on how to optimally screening and manage these patients are still unavailable. Hence, further studies are needed.
Patients with BHD syndrome are predisposed to pneumothorax [1, 7]. Zbar et al. reported that the odds ratio for spontaneous pneumothorax in patients with BHD syndrome was 32 when compared with that in the general population . In the current study, 65.4% of the patients experienced pneumothorax, comparable to other previous studies (approximately 24–76%) [4, 10, 19, 25]. In addition, the median age of pneumothorax development was 43 years, which is also comparable to other previous studies with a relatively large number of patients [12, 19, 21]. Repetitive pneumothorax might also occur [19, 25]. Toro et al. showed that 101 episodes of pneumothorax (1 to 5 times in each patient) occurred in 48 patients with BHD syndrome . In addition, Gupta et al. reported that the average number of pneumothorax was 3.6 in patients with BHD syndrome . Our study population showed a similar recurrence rate of pneumothorax (58.8%). Notably, the hospital stay was longer in the second episode than in the first episode, suggesting that treatment might be difficult in patients with repetitive pneumothorax. Moreover, pneumothorax within 3 months of BHD syndrome diagnosis occurred in 13 patients (50% of study population), consistent with the previous study of Gupta et al. , which showed that pneumothorax was the presenting manifestation of BHD in 65% of their patients.
This study has some limitations. Considering that it used a nationwide medical claims database, BHD syndrome without FLCN gene mutation is not included in our dataset, thereby possibly omitting approximately 10% of patients with BHD syndrome . Our study also did not include those with a family history of BHD syndrome and FLCN gene mutation, thereby reducing the representation of genetic features. Furthermore, if the clinician did not perform FLCN gene test for patients with suspected BHD syndrome, our criteria would underestimate the real prevalence. However, this study collected all FLCN gene tests performed in South Korea from 2016 to 2019, but only 26 patients were found. Moreover, we collected a maximum of 12.8-year follow-up data of patients suspected with BHD syndrome, including their clinical phenotypes combined with comorbidities and pneumothorax history, thereby showing the characteristics and clinical course of BHD syndrome.