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.
- Elkington PT, & Friedland JS (2006). Matrix metalloproteinases in destructive pulmonary pathology. Thorax, 61 (3), 259-66 PMID: 16227332
- Fröhlich BA, Zeitz C, Mátyás G, Alkadhi H, Tuor C, Berger W, & Russi EW (2008). Novel mutations in the folliculin gene associated with spontaneous pneumothorax.The European respiratory journal : official journal of the European Society for Clinical Respiratory Physiology, 32 (5), 1316-20 PMID: 18579543
- Furuya M, Tanaka R, Koga S, Yatabe Y, Gotoda H, Takagi S, Hsu YH, Fujii T, Okada A, Kuroda N, Moritani S, Mizuno H, Nagashima Y, Nagahama K, Hiroshima K, Yoshino I, Nomura F, Aoki I, & Nakatani Y (2012). Pulmonary cysts of Birt-Hogg-Dubé syndrome: a clinicopathologic and immunohistochemical study of 9 families. The American journal of surgical pathology, 36 (4), 589-600 PMID:22441547
- Jackson C (2002). Matrix metalloproteinases and angiogenesis. Current opinion in nephrology and hypertension, 11 (3), 295-9 PMID: 11981259
- Kalhan R, Yeldandi AV, & Jain M (2007). A 48-year-old woman with skin lesions, renal masses, and spontaneous pneumothorax. Chest, 131 (2), 624-7 PMID:17296671
- McCormack FX (2008). Lymphangioleiomyomatosis: a clinical update. Chest, 133(2), 507-16 PMID: 18252917
- Moses MA, Harper J, & Folkman J (2006). Doxycycline treatment for lymphangioleiomyomatosis with urinary monitoring for MMPs. The New England journal of medicine, 354 (24), 2621-2 PMID: 16775248
- Pimenta SP, Baldi BG, Nascimento EC, Mauad T, Kairalla RA, & Carvalho CR (2012). Birt-Hogg-Dubé syndrome: metalloproteinase activity and response to doxycycline. Clinics (Sao Paulo, Brazil), 67 (12), 1501-4 PMID: 23295609
- Tobino K, Hirai T, Johkoh T, Kurihara M, Fujimoto K, Tomiyama N, Mishima M, Takahashi K, & Seyama K (2012). Differentiation between Birt-Hogg-Dubé syndrome and lymphangioleiomyomatosis: quantitative analysis of pulmonary cysts on computed tomography of the chest in 66 females. European journal of radiology, 81 (6), 1340-6 PMID: 21550193
www.bhdsyndrome.org – the primary online resource for anyone interested in BHD Syndrome.