A recent paper by Tobino et al. (2011) investigated the differentiation between two cystic lung diseases: BHD syndrome and lymphangioleiomyomatosis (LAM). LAM is a rare lung disease, mainly affecting women, in which multiple cysts develop in the lungs, often leading to pneumothorax. As with BHD syndrome, cysts and tumours can also occur in the kidneys. LAM is caused by mutations in the TSC1 or TSC2 genes, and it occurs in approximately 30% of women with tuberous sclerosis complex (TSC), but its onset can also be sporadic.
In this study of 14 BHD patients and 52 LAM patients, Tobino et al. found similarities in the occurrence of pneumothoraces between the diseases; including the frequency, age of first pneumothorax, number of pneumothoraces per year and treatment. Differences between the diseases occurred in the family history; unlike BHD, none of the LAM patients had a family history of pneumothorax. The characterisation of the cysts also differed: LAM patients had more cysts than BHD patients, and these were rounder and smaller, with a homogenous distribution throughout the lung. In contrast, lung cysts associated with BHD syndrome were predominantly found in the lower zones of the lungs.
Additionally, this was the first study to assess pulmonary function in BHD patients. Unlike LAM, which has a rapid decline of lung function, pulmonary function was found be to almost normal in BHD patients. Often, BHD patients are unaware they have lung cysts, with symptoms only arising when a pneumothorax occurs.
The outcome of this study found four variables that can be used to differentiate between BHD and LAM during a diagnosis: the family history of pneumothorax, the zonal predominance of the cysts, the diffusing capacity (associated with lung function) and the size of the cysts. Using these variables, diagnosis was shown to occur with 93.9 % accuracy.
The authors also discuss the mechanism of cyst formation in the two diseases. It has been reported that a protease imbalance involving matrix metalloproteinases may play a role in cyst formation in LAM (McCormack, 2008). In BHD syndrome, abnormal growth of the lungs (Graham et al., 2005) and inflammation of the lungs (Painter et al., 2005) have both been reported as contributing to cyst formation. However, neither mechanism explains the lower zone predominance of BHD lung cysts or the normal lung function that is observed. It may be that mechanical forces are involved in BHD lung cyst formation, explaining the lower zone predominance, or that the extracellular matrix, which may have distinct properties throughout the lung, is affected or weakened only in this area. Although this study has described the characterisation of BHD lung cysts in more detail, it is clear that further research is required to fully understand the biology behind cyst formation in BHD syndrome.
- Tobino K, Hirai T, Johkoh T, Kurihara M, Fujimoto K, Tomiyama N, Mishima M, Takahashi K, Seyama K. Differentiation between Birt-Hogg-Dubé syndrome and lymphangioleiomyomatosis: Quantitative analysis of pulmonary cysts on computed tomography of the chest in 66 females. Eur J Radiol. 2011 May 5. [Epub ahead of print]
- Graham RB, Nolasco M, Peterlin B, Garcia CK. Nonsense mutations in folliculin presenting as isolated familial spontaneous pneumothorax in adults. Am J Respir Crit Care Med. 2005 Jul 1;172(1):39-44.
- Painter JN, Tapanainen H, Somer M, Tukiainen P, Aittomäki K. A 4-bp deletion in the Birt-Hogg-Dubé gene (FLCN) causes dominantly inherited spontaneous pneumothorax. Am J Hum Genet. 2005 Mar;76(3):522-7.
- McCormack FX. Lymphangioleiomyomatosis: a clinical update. Chest. 2008 Feb;133(2):507-16.
www.bhdsyndrome.org – the primary online resource for anyone interested in BHD Syndrome.