When BHD was first described in 1977 it was based on the presence of characteristic skin lumps (Birt et al., 1977). In addition BHD is now known to be associated with increased risk of renal cancer, the development of lung cysts and an associated increased risk in pneumothorax. In 2002, the association of BHD with mutations in the folliculin (FLCN) gene provided the definitive mechanism for BHD diagnosis (Nickerson et al., 2002). As such all patients suspected of having BHD should undergo genetic testing to confirm this diagnosis.
Pneumothorax in BHD patients is associated with the development of pulmonary cysts. Numerous research and clinical groups have confirmed high prevalence (up to 90%) of lung cysts in BHD patients (Toro et al., 2008, Agarwal et al., 2011). Whilst the development of lung cysts or blebs is not limited to BHD patients – pulmonary blebs are also associated with other pulmonary disease and smoking – the distribution and formation of the cysts seen in BHD is quite distinct. In BHD patients it is typical to find multiple, thin-walled, elliptical or lentiform, well-defined but with no internal structure, air-filled cysts. These cysts are also predominantly found in the medial or basal sections of the lung and are often subpleural (Tobino et al., 2009, Johannesma et al., 2014d). Toro et al., (2007) reported that BHD patients with a family history of spontaneous pneumothorax and more pulmonary cysts were significantly more likely to develop pneumothoraces.
BHD is underdiagnosed due to a lack of awareness in the medical profession of such a rare disease in combination with its variable presentation and onset. Only a small percentage of BHD diagnoses are suspected based on the presentation of pulmonary pathologies alone. However over the last few years there have been increasing numbers of such case studies where individuals have presented with spontaneous pneumothorax and genetic testing was used to confirm a BHD diagnosis (Predina et al., 2011, Auerbach et al., 2014, Kilincer et al., 2014, Johannesma et al., 2013, Johannesma et al., 2014c, Johannesma et al., 2014f, Ardilouze et al., 2015).
It has been estimated that BHD patients have a 50-times higher risk of developing pneumothorax than non-BHD individuals (Zbar et al., 2002). Two large cohort studies also looked at the incidence of BHD in cases of primary spontaneous pneumothorax (PSP) and found that approximately 5-10% of PSP patients carried FLCN mutations (Ren et al., 2008, Johannesma et al., 2014f). PSP incidence is 1.2-6/100,000 for women and 7.4-18/100,000 for men, annually (Luh, 2010)) and the global population is 7×109. This suggests that the total number of PSP annually is 300,000-800,000, with 15,000-80,000 of those patients carrying FLCN mutations. These suggested figures are vastly more than the current number of diagnosed BHD patients, which might be a result of unintentional cohort sampling bias or due to the difficultly of establishing accurate statistics when dealing with such a small sample population as BHD patients. The true number of un- or mis-diagnosed BHD patients is difficult to estimate however it is clear that many BHD patients are being misdiagnosed as PSP patients. This will continue to be the case unless there is more awareness of BHD as a potential cause of spontaneous pneumothorax. The variation in BHD presentation makes it is highly important, especially with younger patients, to obtain a detailed family history with regards to BHD pathologies as these can contain additional differential diagnostic information.
New diagnosis guidelines suggested by Gupta et al., (2013) would allow diagnosis of BHD to be based on the presence of “characteristic BHD-cysts” on a high resolution CT scan in combination with fibrofolliculomas, BHD-related renal cancer, a first or second degree relative with confirmed BHD, or a positive genetic test. Whilst the numerous individual case and cohort studies suggest that the presence of characteristic lung cysts is indicative of BHD, it is only via genetic testing that the diagnosis can be confirmed. Identifying these patients, and any other affected family members, as early as possible is important as it will impact on future monitoring and treatment. Therefore it is of great importance that awareness of BHD and its pulmonary presentation is increased in pulmonologists and associated professions.
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