Striking progress has been achieved with respect to the diagnosis and management of rare diseases in China in recent decades. Although more than 220 cases with BHDS has been reported up to December 2020 in China(7), these cases were distributed mostly in the Beijing and Jiangsu Province due to advanced medical resources and great economic levels associated with these regions(7, 19). To our knowledge, current study describes the largest cohort of patients with BHDS in the Chinese population. The number of patients and families diagnosed in our hospital has increased year by year, especially after the initiation of our Rare Lung Disease Clinic.
Multiple pulmonary cysts detected on chest CT are the most common manifestation and has been described in 85-99% of cases in various study cohorts(7, 8, 10). The number, shape, size, and distribution of pulmonary cystic lesions are helpful to distinguish BHDS from other cystic lung diseases(20, 21). On chest CT, BHDS is characterized by multiple, irregular-shaped cysts of varying sizes with medial and basal predominance in distribution(20, 22, 23). These features were observed in most of the patients in our study. The detection of lung cysts led to the diagnosis of BHDS in one-fifth of our cases with a relatively shorter delay to eventual diagnosis (4.7 years) compared to those with other presentation modes.
The presence of multiple pulmonary cysts is associated with spontaneous pneumothorax which is 50-times more likely to occur in BHD-affected individuals compared to those not affected as found by Zbar and colleagues(24). In 2008, Ren et al first demonstrated that FLCN mutation contributes to not only familial primary spontaneous pneumothorax but also patients with apparently sporadic (nonfamilial) primary spontaneous pneumothorax(6). Recent studies showed 64% of familial spontaneous pneumothorax was BHDS in China and 6/7 in Italy(19). Thus, 42% of our patients were suspected due to pneumothorax history. Less than 60% of patients had experienced at least one episode of spontaneous pneumothorax and had family history of pneumothorax in our study, which are lower than previous data in China (71% and 85%, respectively)(7). These differences might reflect the earlier recognition of BHDS prior to onset of pneumothoraces.
In our cohort, BHDS-related pneumothorax was associated with a higher recurrence rate after conservative therapy compared to surgical intervention. Similar finding was observed for a thoracic surgery cohort reported from Beijing and a patient survey study in America (8, 19). The high recurrence rate after conservative management may be due to the multiplicity of pulmonary cysts in patients with BHD syndrome, which predispose to recurrent pneumothoraces. Surgical pleurodesis (mechanical abrasion) was recommended in the American Thoracic Society/Japanese Respiratory Society Clinical Practice Guideline to manage pneumothorax in another diffuse cystic lung disease, LAM(25). Thus, early surgical management should be considered for patients presenting with BHDS-related pneumothorax.
Skin lesions in patients with BHDS usually appear after the age of 20 years, as multiple, dome-shaped, whitish papules on the face, neck, and sometimes trunk(26). Skin lesions are a common feature observed in Caucasian patients with BHDS, in whom it is found in over 90% (26). However, the patients in China seem to have a lower prevalence of skin lesions (18%) (7). These finding was also reported in other East Asian countries(10, 27). However, our study shows that skin lesions were present in nearly 70% of patients and suggests this feature may have been overlooked previously. This explanation is supported by the observation that the prevalence of skin manifestations in patients with BHDS reported from Peking Union Medical College hospital (PUMCH) increased from 11% in 2017 to 47.2% in 2019 and 54.5% in 2020(11, 17, 20). Furthermore, Iwabuchi et al detected skin lesions in 26/31 (83.9%) Japanese patients with BHDS using dermoscopy and skin biopsy confirmed fibrofolliculoma and/or trichodiscoma histologically in 73.9%(28). Skin biopsy in the context of an experienced multidisciplinary team is helpful to recognize skin findings suspicious for BHDS. Thus, recent evidence suggests that the skin involvement in BHDS may not be significantly lower in Chinese patients compared to Caucasians.
Renal cancer is the most serious complication of BHDS, are often bilateral and multifocal, with the oncocytoma and chromophobe variant being the most common types of malignancy(29). The risk of developing renal tumors is seven-fold higher in patients with BHDS, compared to the general population(24). The low prevalence of renal involvement in our cohort may be due to selection bias since nearly all patients in our study were recruited from respiratory department. Another reason might be lack of long-term follow-up for most patients. However, further studies on potential racial differences int the prevalence of renal cancer may be warranted.
The most frequent mutations associated with BHDS in our study were c.1285del/dup on exon 11, similar to the results in previous studies(30, 31). Toro et al. reported that 48% mutations were identified in exon 11, as a mutation ‘hotspot’ for BHDS(31). The most frequent mutation in Chinese BHDS patients was the single deletion, duplication of cytosine in codon 1285 of exon 11 as reported from PUMCH (11). Mutation c.1015C>T accounted for about 1/6 of patients in this study and three novel mutations of c.1381_1382insA in exon 12, c.761T༞C in exon 7, c.1283_1284insA in exon 11 were encountered. Mutation was not detected in a forty-three-year-old female who manifested fibrofolliculomas by skin biopsy. Toro et al. reported that patients with mutation in exon 9 or 12 have a higher risk of pneumothorax compared to those patients carrying mutation in other exons(31). A recent study from Germany reported that the mutation c.250-2A > G was associated with twice as high risk of pneumothorax compared with the mutation c.1285dup (30). However, the correlation between genotype and phenotype was not found in our study. This issue needs to be explored further with larger number of patients.
It was reported that 399 patients with BHDS were identified in Netherlands within the total population of about 17.1 million (32). Anhui Province, located in Eastern of China with 61-million citizens, would be estimated to have over 1400 estimated patients with BHDS. There has been no previous data regarding the actual prevalence of BHDS in China. Although our study cohort in Anhui Province comprises the largest number of cases of BHDS described from China, it only accounts for 3.6% of estimated total number of cases in our Province. This highlights the underrecognition of rare diseases in developing regions of the world. Establishment of a Rare Lung Disease Clinic supported multidisciplinary team at our medical center led to improved recognition and diagnosis of BHDS over a 2.5-year period. Similar model of care may allow better care of patients with rare diseases in other developing parts of the world.
There were several limitations to our study. Firstly, the number of cases is modest in this cohort. However, considering the rarity of disease we have collected a relatively large cohort in a single center. Secondly, due to the retrospective nature of this study, the family history/screening and annual follow-up evaluations were not always available. Thirdly, skin biopsies were only performed on 9 patients as many individuals refused to undergo this procedure. However, all the skin lesions were examined by a same multidisciplinary team focused on diffuse cystic lung diseases. A long-term, muti-center prospective study is needed to allow better understanding of this rare disease that will improve management.