In 2011, a study by Tobino et al. discussed the differences between BHD syndrome and the cystic lung disease lymphangioleiomyomatosis (LAM), as described here. The importance of these differences has been underlined by a recent case report in which a BHD patient was initially diagnosed and treated for LAM (Pimenta et al., 2012). Interestingly, this report indicates that matrix metalloproteinases (MMPs) may also be involved in the development of BHD lung cysts, as they are in LAM.
In this report, a 44-year old female presented with difficulty breathing after exertion and a spontaneous pneumothorax. CT scans showed bilateral cystic lesions, a biopsy and pleurodesis was performed, and the patient was diagnosed with LAM. Matrix degradation by MMPs is thought to play a role in cyst development in LAM (McCormack, 2008), and inhibition of MMPs with doxycycline has been used as a treatment for this condition (Moses et al., 2006). After 6 months of doxycycline therapy, Pimenta et al. noted an improvement in the patient’s lung function, as well as a decrease in the serum and urinary levels of MMP-9.
However, upon follow-up the authors found papules on the patient’s neck and upper thorax, as well as a family history of cystic lung disease and pneumothorax. Histological analysis of the lung biopsy showed an absence of markers for LAM, as well as cyst walls formed by collapsed alveoli or thickened pleural tissue, as has been observed in BHD lung samples by Furuya et al. (2012). Consequently, a diagnosis of BHD syndrome was established.
Notably, pulmonary symptoms worsened following an interruption of the doxycycline treatment due to gastric intolerance. As doxycycline was producing a clinical effect, the distribution of MMP-9 in the lung biopsy was assessed by immunohistochemistry. Using this technique, a large number of MMP-9-positive cells, which were mostly macrophages and neutrophils, were observed in the cyst wall when compared to normal adjacent lung tissue.
It is important to note that the authors did not report the results of a genetic test, which is the only way to conclusively confirm the presence of a FLCN mutation and a diagnosis of BHD syndrome. However, the potential role of FLCN in maintaining lung matrix integrity has been discussed in previous BHD studies (Kalhan et al., 2007; Fröhlich et al., 2008). Furthermore, MMPs are known to be involved in cell migration and angiogenesis (Jackson 2002; Elkington & Friedland, 2006), which are also linked to FLCN (as seen in our recently updated signalling diagram). Therefore, this study highlights an association between MMP activity and BHD syndrome, which could be used as a potential therapeutic target.
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