To the best of our knowledge, this study comprises the largest number of families of BHDS in the Chinese population. We found most BHDS families were reported from Beijing and Jiangsu Province, and over 80% of them were reported in only the past five years. In comparison to USA and Japanese BHDS cohorts, the dominant manifestations of Chinese patients were pulmonary cysts associated with recurrent pneumothorax, while skin lesions and renal tumors were less prevalent. Delayed diagnosis and suboptimal medical management presented common challenges for Chinese patients with BHDS.
BHDS is a rare inherited autosomal dominant disorder caused by germline mutations in the tumor suppressor gene FLCN that predisposes affected individuals to develop benign skin tumors (fibrofolliculomas), renal neoplasms, and pulmonary cysts with a risk of spontaneous pneumothorax. Since a research team from Nanjing University firstly explored the FLCN gene mutations on patients with spontaneous pneumothorax history in 2008, there has been more than 20 families with BHDS in China up to 2017 according to the BHD foundation statistics. Our study included 221 cases from 120 families that were reported between January 2008 and December 2020 in China. More than 80% of families were described in the past five years, half of them in the past two years. The increasing number of BHDS in China likely reflects the increasing awareness and recognition rather than increasing incidence of disorder. In recent decades, a fascinating progress has been achieved with respect to the diagnosis and management of rare diseases in China. A registry study on rare respiratory diseases including another diffuse cystic lung disease, LAM, has been ongoing nation-wide since 2016. Therefore, BHDS is also being increasingly diagnosed by clinicians in China. Nonetheless, over two-thirds of BHDS families were managed in Beijing. This huge imbalance of diagnosis and management on patients with rare diseases between Beijing and the rest of China suggests urgent need for improvements in the recognition of rare diseases nation-wide.
As in prior reports, respiratory system was the most frequently affected in Chinese patients with BHDS with 92.4% of our cohort manifesting lung cysts (Table 3). A study of 312 Japanese BHDS patients reported that almost all patients had lung cysts7. Similarly, a study of Korean BHDS patients reported all cases had lung cysts29. On the contrary, it was reported that the prevalence of lung cysts of BHDS in USA was 85%, which was lower compared to the Japanese cohort7,30. This might indicate that Asian patients were more prone to pulmonary cysts than Caucasian patients. However, most of cases with BHDS in our study was diagnosed by respiratory physicians which may have introduced a bias. The widespread use of high-resolution computed tomography in recent decades has provided better detection of cystic lung diseases. As a result, cystic lung diseases such as BHDS have been better recognized and distinguished from emphysema.
Due to the high prevalence of lung cysts in adult patients with BHDS, spontaneous pneumothorax has been found to be a common presentation3. In our study, 71% of confirmed patients had at least one episode of pneumothorax and nearly 85% of them had a family history of pneumothorax. This was consistent with the features of patients with BHDS reported from other Asian countries26. A recent survey of 104 American patients with BHDS reported a similar rate of spontaneous pneumothorax during their lifetime30. BHDS-related pneumothorax seems to have a higher recurrence rate after conservative therapy (observation, chest drainage and chemical pleurodesis) compared to surgical management. Liu et al reported only 9% of patients had recurrence of pneumothorax after surgical treatment (pulmonary bullectomy and/or pleurodesis) while 52% of recurrence rate was observed after conservative treatment24. Gupta et al reported pleurodesis (chemical or surgical) to reduce the ipsilateral recurrence rate by half (33% versus 63%)30. Another diffuse cystic lung disease LAM is also associated with high recurrence rate of pneumothorax. In 2017, American Thoracic Society/Japanese Respiratory Society Guideline suggested that patients with LAM be offered ipsilateral pleurodesis after their initial pneumothorax rather than waiting for a recurrent pneumothorax before intervening with a pleural symphysis procedure31.
Renal cell cancer has been found to be the main manifestation associated with the poor prognosis of BHDS. Zbar et al found a 7-fold increase in the risk of renal tumors for BHD-affected family members when adjusted for age32. Subsequent study revealed that the prevalence of renal tumors in patients with BHD was 34% with a mean age at diagnosis of approximately 50 years33. Chromophobe renal carcinoma was the most common histological type of renal cancer, followed by hybrid oncocytic/chromophobe tumor3,7. Similar findings were reported in a recent largest study including 312 Japanese cases from 120 different families7. Renal carcinoma was detected in 8 (3.6%) patients in this study while that in Japan was 34.8% and 25% in Korea, respectively7,29. The differences between these countries might attribute to less awareness and evaluation for renal manifestations of BHDS among Chinese physicians or ethnic differences; further studies are needed on this issue. In addition, lack of follow-up evaluations might have contributed to the low prevalence of renal cancer in the Chinese cohort. Thus, a long-term prospective observation study is needed to explore the true incidence of renal tumors among BHDS-affected families in the Chinese population.
Skin lesions were a common feature of BHDS in Caucasians, in whom it is found in about 80%~90%3,34. Characteristic lesions fibrofolliculomas and trichodiscomas are important clues in recognizing BHDS, but the patients in Asian countries seem to have lower prevalence of skin lesions3,7,29. Previous study demonstrated skin lesions developed in less than 30% in Chinese patients26, similar to the current study. Only 6 patients were histologically diagnosed to have fibrofolliculomas. However, this probably represents an underestimation due to limited diagnostic capacity of this rare disease, especially among general pulmonologists. The incidence of skin lesions among patients with BHDS reported from Peking Union Medical College Hospital, a national referral center for rare respiratory diseases, significantly increased from 11% (3/27) in 2017 to 47.2% (17/36) in 20199,21. The awareness of characteristic skin manifestations was likely an important factor in the increased diagnosis rate over the interval. Similarly, dermatologist Chikako Iwabuchi and colleagues reported the increasing diagnosis rates of skin lesions in 31 Japanese individuals35. Skin lesions were recognized in over 80% of BHDS patients, including almost 75% of them histologically confirmed by skin biopsies35. Therefore, skin lesions appear to be more prevalent than previously reported in east Asian population, which would be warrant further assessment in clinical practice through cooperation with an experienced multidisciplinary team.
The FLCN mutations in exon 11 were found to be the most frequently detected among Caucasian population, mainly c.1285dup/del and c.1300G > C36. Our study also showed that the most frequent mutation in Chinese BHD patients was the single deletion, duplication of cytosine in codon 1285 of exon 11. The correlation between genotype and phenotype has been explored in the past decades. There was rather high incidence of pneumothorax associate with FLCN hotspot mutation c.1285dup (60% risk) in this cohort. However, a cohort from Germany reported less than 50% of 197 patients with BHDS had pneumothorax. Significantly increased pneumothorax risks were observed for mutations c.1300G > C (59%) and c.250-2A > G (77%) compared with FLCN hotspot mutation c.1285dup (37% risk)36. We are not able to explain the discrepant rates of pneumothorax associated with the mutation c.1285dup in Chinese patients compared to the Germany cohort. It would need further research on large-scale population to explore the correlation between these mutation and phenotype.
To date, there is no effective treatment for BHDS, but the benefits of an early diagnosis include appropriate screening for renal tumors among BHDS individuals, patient education and family counseling. An average delay from first symptom to diagnosis was up to 13 years in 104 patients reported from USA30. The misdiagnosis was quite common. Previous results have demonstrated lower prevalence of skin lesions and renal tumors among of BHDS patients in China9,26. Thus, the presenting manifestation of pneumothorax associated with characteristic lung cysts are important clues to achieve an early diagnosis. A study in Japan established a scoring system that has a high degree of sensitivity and specificity for distinguishing suspected BHDS from primary spontaneous pneumothorax37. Several radiological studies also found appropriate evaluation of chest CT images to be helpful in differentiating BHDS from other diffuse cystic lung diseases38–42. Therefore, the most common presentation pneumothorax in setting of characteristic cystic lung lesions or a family history of pneumothorax should suggest the need for FLCN gene testing to make timely diagnosis.
There were several limitations of this study. Firstly, this was a retrospective study, and majority of reported cases were from tertiary referral centers in Beijing. Secondly, some cases lacked data regarding the FLCN gene mutations as well as aspects of management and follow-up. However, this study collected all the consecutively cases reported in the Chinese population in recent decades and fully described the real-life diagnosis and managements of BHDS which should be valuable for better understanding this rare disease in the coming years.