Although 90% of BHD patients develop lung cysts, there is very little information about the natural history of BHD lung cysts. In order to determine how lung cysts change over time, Johannesma et al. (2014a) compared the results of two CT scans taken at separate intervals, from six BHD patients, five of whom had suffered recurrent pneumothoraces. The time interval between scans ranged from 9 days to 44 months.
One patient developed one new lung cyst in 44 months, and the mean increase in cyst size was 0.4 mm, suggesting that BHD lung cysts do not increase in number or size particularly rapidly. Additionally, if BHD were a progressive degenerative disease, there would be a trend for older patients to develop more pneumothoraces, which has not been reported. Thus, it seems that BHD is not a degenerative disease, with respect to the lung symptoms.
This does raise the question as to when BHD lung cysts develop; there have been five reported cases of children with BHD having pneumothoraces, and FLCN has been shown to be important for alveolar development in mice. Thus, it is possible that lung cysts form during infanthood, childhood or adolescence as lungs are developing, and then remain largely stable during adulthood.
In a separate study, Johannesma et al. (2014b) found that pneumothorax was strongly correlated with the number of lung cysts, but not with their distribution, size or shape. Thus, it seems that the presence of lung cysts somehow causes pneumothoraces.
Johannesma et al. hypothesise that the heterozygous loss of FLCN in the epithelial cells lining cysts means they are more brittle due to increased cell-cell adhesion as reported by Medvetz et al. This causes cysts, and possibly the overlaying visceral pleura, to burst under the mechanical stresses of respiration, allowing air to build up in the pleural space and causing a pneumothorax.
This is similar to the hypothesis suggested by Kumasaka et al. who suggested that reduced cell-cell adhesion, as reported by Nahorski et al, made cyst walls weaker and more likely to burst under mechanical stress, also leading to a build up of air in the pleural space and potentially causing a pneumothorax.
Since the Nahorski and Medvetz studies were published in 2012, FLCN’s function has been shown to be highly cell-specific, which may account for the opposing results of the two studies. However, mouse studies have shown that deletion of FLCN in typeII alveolar lung cells leads to reduced E-cadherin localization at cell membranes, suggesting that lung cysts may indeed have weaker cell-cell contacts.
In either case, it seems that increased numbers of cysts rupturing and causing air to build in the pleural space is a likely mechanism that causes pneumothoraces to develop in BHD patients. Johannesma et al. therefore suggest that eliminating the pleural space by combined pleurectomy and chemical pleurodesis will reduce the recurrence of pneumothoraces in BHD patients. They do however caution that this treatment approach should first be tested in a phase II multicenter clinical trial before becoming the standard of care.
- Johannesma PC, Houweling AC, van Waesberghe JH, van Moorselaar RJ, Starink TM, Menko FH, & Postmus PE (2014). The pathogenesis of pneumothorax in Birt-Hogg-Dubé syndrome: A hypothesis. Respirology (Carlton, Vic.), 19 (8), 1248-50 PMID: 25302759
- Johannesma PC,, van Waesberghe JH,, Reinhard R,, Gille J,, van Moorselaar J,, Houweling A,, Starink T,, Menko FH,, & Postmus PE (2014b). Birt-Hogg-Dube Syndrome Patients With And Without Pneumothorax: Findings On Chest CT. American Journal of Respiratory and Critical Care Medicine, 189. [Abstract]
- Kumasaka T, Hayashi T, Mitani K, Kataoka H, Kikkawa M, Tobino K, Kobayashi E, Gunji Y, Kunogi M, Kurihara M, & Seyama K (2014). Characterization of pulmonary cysts in Birt-Hogg-Dubé syndrome: histopathological and morphometric analysis of 229 pulmonary cysts from 50 unrelated patients. Histopathology, 65 (1), 100-10 PMID: 24393238
- Medvetz DA, Khabibullin D, Hariharan V, Ongusaha PP, Goncharova EA, Schlechter T, Darling TN, Hofmann I, Krymskaya VP, Liao JK, Huang H, & Henske EP (2012). Folliculin, the product of the Birt-Hogg-Dube tumor suppressor gene, interacts with the adherens junction protein p0071 to regulate cell-cell adhesion. PloS one, 7 (11) PMID: 23139756
- Nahorski MS, Seabra L, Straatman-Iwanowska A, Wingenfeld A, Reiman A, Lu X, Klomp JA, Teh BT, Hatzfeld M, Gissen P, & Maher ER (2012). Folliculin interacts with p0071 (plakophilin-4) and deficiency is associated with disordered RhoA signalling, epithelial polarization and cytokinesis. Human molecular genetics, 21 (24), 5268-79 PMID: 22965878