Histology
BHD patients often develop pulmonary cysts and have an increased risk for pneumothorax. Lung anatomy and histology generally appears normal in individuals with BHD, and despite the presence of multiple pulmonary cysts, lung function is usually unaffected (Toro et al., 2007). Tobino et al. (2009) have characterised BHD lung cysts and found them to have characteristics distinct from those which develop in other cystic lung diseases. Of the 12 BHD patients analysed by Tobino et al. (2009), the number of cysts were found to vary from 29-407, and the size varied from a few millimetres to more than 2 cm. The cysts were generally irregularly-shaped and most commonly found in the lower medial zone of the lungs. This evaluation of cysts by thin-section chest CT images can assist in differentiating BHD from other cystic lung diseases (Tobino et al., 2009). A second evaluation of BHD lung cysts confirmed the presence of multiple cysts, mainly in the lower lungs, that varied in size and shape (Agarwal et al., 2011). Koga et al. (2009) have hypothesised that these cysts represent an aberrant cystic alveolar formation.
Prevalence
The presence of pulmonary cysts in BHD syndrome was first described by Toro et al. (1999) in a study of 152 individuals from 49 families with familial renal neoplastic syndromes. Three of the thirteen patients who had BHD syndrome exhibited pulmonary cysts, and one of these three patients developed pneumothorax (Toro et al., 1999). Additional cases of pulmonary cysts and spontaneous pneumothorax have since been reported in the literature (Zbar et al., 2002; Toro et al., 2007; Johannesma et al., 2009; Koga et al., 2009; Kluger et al., 2010, Ishii et al., 2009; So, 2009; Sundaram et al., 2009; Diamond and Kotloff, 2009; Kunogi et al., 2010; Hayashi et al., 2010; Predina et al., 2011; Bae et al., 2011).
Pulmonary cysts are the most common BHD manifestation, seen in up to 90 % of patients (Predina et al., 2011). Zbar et al. (2002) identified an increase in the risk of pneumothorax for BHD-affected individuals, which was hypothesised to be related to the presence of pulmonary cysts. Toro et al. (2007) found BHD patients with pulmonary cysts had a 24 % risk for spontaneous pneumothorax, and that following a single episode of spontaneous pneumothorax, recurrent events were more common. It is believed that lung problems may be the earliest symptoms of BHD syndrome, as pneumothoraces have been reported in BHD patients as young as seven and sixteen years of age (Bessis et al., 2006; Gunji et al., 2007).
Gunji et al. (2007) screened for FLCN mutations in eight unrelated Japanese patients with multiple pulmonary cysts and recurrent pneumothorax (mean age of first pneumothorax was 30.4 years), but without skin or renal lesions, and identified mutations in five of the eight. All five patients had a family history of spontaneous pneumothorax. The authors suggested that isolated pulmonary cysts and pneumothorax may be a milder form of BHD syndrome and that patients should be monitored for renal or skin lesions. Another study by Hayashi et al. (2010) also identified BHD patients with lung cysts and recurrent pneumothorax but with no skin manifestations or renal tumours. The authors suggest that BHD syndrome should be considered for patients with multiple lung cysts, even when no other symptoms are present.
FLCN association
A genome wide scan in a large Finnish family with a dominantly inherited predisposition to primary spontaneous pneumothorax (PSP) discovered that the PSP locus mapped to chromosome 17p11, where the FLCN gene is located (Painter et al., 2005). Screening of FLCN revealed a 4-bp deletion in the first coding exon, resulting in a frameshift of the reading frame and subsequent truncation of the protein. All carriers of the deletion presented with bullous lung lesions. Unlike previously identified mutations in FLCN, the exon 4 deletion seemed to be associated only with PSP, which showed 100% penetrance. This family had no evidence of other BHD manifestations, suggesting a genotype-phenotype correlation. These results suggest that FLCN may have a significant role in normal pulmonary physiology since its inactivation in this study results in an exclusive PSP phenotype. There is no evidence of other genotype-phenotype correlations regarding lung manifestations or other BHD symptoms (Kunogi et al., 2010).
