Birt-Hogg-Dubé syndrome: metalloproteinase activity and response to doxycycline

Birt-Hogg-Dubé syndrome (BHDS) is a rare, inherited autosomal-dominant genodermatosis caused by mutations in the folliculin gene (FLCN), which is located within the chromosomal band 17p11.2 (1). Patients with BHDS are prone to fibrofolliculomas, trichodiscomas, and acrochordons on the face, neck, and upper trunk; renal tumors; pulmonary cysts; and spontaneous pneumothorax (2-4). The pathogenesis of lung cyst formation and pneumothorax remains unclear, but studies have shown that folliculin is strongly expressed in lung fibroblasts and macrophages. Folliculin mutations may alter cytokines and proteases, which are important in maintaining extracellular matrix (ECM) integrity, leading to an inflammatory response and matrix degradation with subsequent remodeling (5,6). The pulmonary architecture depends on interactions between collagen and elastin fibers in the ECM, which maintain alveoli wall integrity (7). The overexpression of metalloproteinases (MMPs), regardless of whether they are associated with the suppression of tissue inhibitors of metalloproteinases (TIMPs), leads to matrix breakdown, tissue destruction and cystic lesions (7,8). Because there is currently no treatment for BHDS, we decided to describe our experience treating one BHDS patient with doxycycline, which is an MMP inhibitor (9) that has been previously used to treat cystic lung disease (10).