BHD syndrome is a rare autosomal dominant genetic disease, which is often misdiagnosed as pulmonary bullae. In this study, we included 26 patients with BHD and observed their chest CT and clinical features. The cysts of BHD patients were mainly of round and irregular shape, characterized by subpleural distribution. About 54% of BHD patients developed pneumothorax, and the occurrence of pneumothorax was related to the long-axis diameter, short-axis diameter and volume of the largest cysts (P < 0.05).
The mutation of the folliculin (FLCN) gene is closely related to the occurrence of BHD syndrome. BHD syndrome is named after the Canadian doctors Birt, Hogg, and Dubé who reported a family with fibrofolliculomas, trichodiscomas, and acrochordons in 1977. Benign tumors of the skin, various types of renal tumors, and multiple lung cysts are the characteristic manifestations of BHD syndrome. Skin damage mainly manifests as fibrofolliculomas, which may be accompanied by trichodiscomas and acrochordons. Mixed oncocytoma or chromophobe cell tumor is a typical renal manifestation [3]. Epidemiological data have shown that the incidence of tumors in the skin and lungs is higher than that of renal tumors [4]. Skin lesions and FLCN gene mutations are classified as the main diagnostic criteria of BHD syndrome [5]. There are ethnic differences in the clinical manifestations of BHD syndrome. Previous studies have shown that > 80% of BHD syndrome cases in Europe and the United States have specific skin lesions, while the incidence of skin lesions and renal tumors in Asians is low [6,7,8]. There were no typical skin and kidney lesions in the cases included in our study.
A majority of patients with BHD syndrome have pulmonary cysts [2, 9,10,11]. In our study, lung cysts were found in all the 23 (100%) patients’ chest CT images. The cysts in the lungs of all patients were bilateral and multiple, with different sizes. The larger cysts were often irregular, while the smaller cysts were mostly round or oval. Some of the larger cysts near the mediastinal spine showed plastic changes along the mediastinum and spine, which may have been caused by high pressure in the capsule, with limited growth space. In the current study, 76.3% of the cysts were distributed under the pleura of both lungs, and 93.6% of the cysts with a long-axis diameter > 20 mm were distributed under the pleura, especially near the mediastinum (48.4%). Furuya and Koga et al. [12, 13]studied the unruptured pulmonary cysts associated with BHD syndrome and found that the cyst wall expanded toward the visceral pleura and was partially embedded in parenchyma, interlobular septum, and bronchovascular bundles. Additionally, enlarged cysts were segmented by the alveolar wall and deeply embedded in the interlobular septum. These complex structures were usually accompanied by varying degrees of chronic inflammatory cell infiltration, suggesting possible inflammation-induced development of cysts. Cystic alveoli and fusion of the epithelium of the cyst to the mesenchyme are indicators for BHD-associated lung lesions [14]. BHD syndrome-associated cysts are originally located close to the interlobular septum or subpleura [14], which could explain why 76.3% of the cysts on chest CT images in our study were under the pleura of both lungs. Our study showed that in addition to subpleural cysts of the mediastinum and chest wall, multiple cysts were also observed in the bilateral interlobar pleura. This finding is consistent with the above-mentioned pathological results. Despite the existence of multiple cysts in the lungs, the patients’ pulmonary function remains unaffected [15]. In our study, a BHD patient with normal pulmonary function had experienced pneumothorax for four times and received surgical treatment.
Lung-associated symptoms are usually the first to appear in patients with BHD syndrome. Pneumothorax may be the first and only symptom that causes most patients with BHD syndrome to visit the hospital. Though classified as minor criteria for the diagnosis of BHD syndrome, pulmonary CT findings are the main indication for BHD syndrome that can prompt patients to undergo further examinations to determine the diagnosis. Many studies have shown that the prevalence of spontaneous pneumothorax in patients with BHD syndrome reaches > 60% [6, 8, 16, 17]. Additionally, the risk of pneumothorax in patients with BHD syndrome is 50 times that of family members without BHD syndrome [4]. In our study, 54% of the patients with BHD syndrome developed pneumothorax, of whom 43% had it twice or more times. We deemed that the high incidence of pneumothorax in patients with BHD syndrome, especially recurrent pneumothorax, was related to their lung cysts. Therefore, we carefully examined the patients’ chest CT images and classified them according to the distribution and size of the lesions. We found that the long-axis diameter, short-axis diameter, and volume of the largest cyst were correlated with the occurrence of pneumothorax, especially the short-axis diameter and volume of the largest cyst. This finding may be related to the shape and tension of the capsule, because the short-axis diameter can better reflect tension of the cyst. For capsules of the same volume, the larger the short-axis diameter is, the closer the cyst is to the spheroid and the greater the tension is. As the tension increases, the risk of bursa rupture is higher under the same condition.
In our study, the cysts with long-axis diameter ≤ 10 mm were the most common in both lungs. However, we thought that cysts with long-axis diameter ≥ 20 mm, especially the subpleural ones, were more characteristic, which could help to diagnose BHD. Toro et al.[2] found that the exon position of a BHD mutation was related to the number of lung cysts, as well as the size and volume of the largest cyst. This finding indicates that an FLCN mutation may play an important role in the occurrence of pneumothorax. Pathologically abnormal epithelial/mesenchymal interactions may weaken the extracellular matrix of the visceral pleura, leading to pneumothorax [14].
The occurrence of pneumothorax in patients with BHD syndrome is not only related to the patient’s lung lesions, but also related to the external environment and various inducements. Johannesma et al. [9] found that flying or diving-associated air pressure changes may increase the risk of pneumothorax for patients with BHD syndrome, and the risk of pneumothorax is higher during flight. It is suggested that BHD patients with presence of any clinical symptoms (such as shortness of breath or chest pain) during flight or shortly after air travel should receive a chest X-ray or CT examination to exclude pneumothorax. In our study, one patient developed pneumothorax after returning from a trip to Yunnan plateau region by plane and another patient developed pneumothorax after dumbbell lifting. We speculate that the occurrence of pneumothorax in these patients was related to the change in atmospheric pressure and thoracic pressure. For patients with recurrent pneumothorax, pleural closure/covering technology [18] or the combined intervention with mechanical and chemical pleurodesis [19] can effectively treat pneumothorax and reduce recurrence.
In our study, 4 patients developed lung tumors (including small cell lung cancer, adenocarcinoma, and alveolar cell tumor). There is limited information currently available about the incidence of lung cancer in patients with BHD syndrome. Notably, lung adenocarcinoma has been reported in heterozygous FLCN knockout mice [20]. Whether FLCN gene mutations increase the risk of tumorigenesis in BHD patients requires further investigation.
Chest CT findings of BHD syndrome are characterized by bilateral, multiple, irregular shaped cysts of various sizes with subpleural predominance. Our quantitative analysis of the number, size, and distribution of lung cysts showed that there was a correlation between lung cysts and the occurrence of pneumothorax. Clinicians (especially emergency department physicians and surgeons) need to obtain more information about the disease history and family history when treating patients with pneumothorax. For patients with suspected BHD syndrome, a chest CT examination should be used rather than X-ray for more comprehensive assessment of lung lesions, and gene testing and a visit to the dermatology clinic are recommended. Following early detection of this syndrome, the patients and their families should be followed up, given personalized advice on diving and other related exercises, and pay close attention to pneumothorax and renal tumors that may affect prognosis and quality of life.
There are some limitations of our study. First, our study was a small sample retrospective study, which may lead to potential bias, uncertainty and generality in our statistical results. Second, some patients had a history of pneumothorax, which may affect the characteristic morphology, distribution, and number of pulmonary cysts. Therefore, we will enroll more patients in prospective design studies in the future to better observe the characteristics of pulmonary cysts and explore their relationship with pneumothorax in patients with BHD.