Fibrofolliculomas, pulmonary cysts, pneumothorax and renal cell carcinoma are the only confirmed manifestations associated with BHD syndrome. At present there is no evidence of a genotype-phenotype correlation with respect to the lung, skin, or kidney manifestations of BHD (Schmidt et al., 2005; Toro et al., 2008). Studies have indicated that other manifestations may also be linked to BHD, but these have yet to be confirmed. These manifestations are discussed below.
Colorectal polyps and colorectal cancer
Early studies suggested an association between BHD syndrome and colorectal neoplasia (Hornstein, 1976; Birt et al., 1977; Schachtschabel et al., 1996; Schulz and Hartschuh, 1999). However, this has been subject to some debate, and a subsequent study by Zbar et al. (2002) found no association between BHD and colonic polyps or colorectal cancer (CRC) in a study involving a large cohort of 111 BHD syndrome patients.
Nevertheless, Khoo et al. (2002) reported a high incidence of colorectal polyps and CRC in BHD patients with confirmed FLCN germline mutations, suggesting that some BHD families are at increased risk of colorectal neoplasia, and indicating that FLCN may be involved in colorectal tumourigenesis. Another study, by Nahorski et al. (2010), found that 10 BHD patients out of the 149 assessed had CRC or colorectal polyps. This was linked to the c.1285dupC exon 11 mutation, suggesting patients with this particular mutation are more at risk of developing CRC. Interestingly, the BHD patients identified by Khoo et al. (2002) who had colonic polyps also had an exon 11 mutation (c.1285delC), suggesting a possible genotype-phenotype correlation.
Thyroid nodules and cancer
In a five year clinical study of 22 patients from ten unrelated French families with BHD syndrome, Kluger et al. (2010) attempted to define the characteristics of pulmonary, thyroid, renal and colorectal manifestations associated with BHD syndrome more clearly. Notably, thyroid nodules and/or cysts were identified by ultrasound in 13 of 20 cases (65%). No thyroid carcinomas or colorectal carcinomas were detected in any patient. The high prevalence of thyroid nodules in this study is interesting, but crucially the lack of a control group does not enable the authors to assess the significance of these results. No genotype-phenotype correlation was observed in this study. Benhammou et al. (2011) also identified thyroid pathology in 4 out of 11 patients studied, 3 of whom had hypothyroidism and one with a benign thyroid nodule.
One case report describes a BHD patient with thyroid cancer (Benusiglio et al., 2014). Loss of heterozygosity of FLCN was observed in the tumour, but other genetic lesions or causes of thyroid cancer were not investigated, meaning a causal link between this patient’s BHD and their thyroid cancer cannot be conclusively proven. A second case study describes a BHD patient who had thyroid cancer, but as the thyroid tumour predated the patient’s BHD diagnosis, the authors did not attribute this tumour to the patient’s BHD syndrome or investigate a link between the two (Yamada et al., 2014).
Somatic mutation of FLCN, TSC2 and TP53 were found in a sporadic case of anaplastic thyroid cancer that was successfully treated with everolimus for 18 months, at which point the tumour developed a mutation in the mTOR gene and became resistant to treatment (Wagle et al., 2014). This suggests that somatic FLCN mutation – together with other mutations that activate mTOR signalling – can cause additional types of cancer to renal cell carcinoma, and make tumours sensitive to treatment with mTOR inhibitors.
At least eight cases of parotid tumours have been reported in patients with a FLCN mutation (Liu et al., 2000; Schmidt et al., 2005; Palmirotta et al., 2008; Maffé et al., 2011; Lindor et al., 2012; Pradella et al., 2013) and it is of note that the parotid tumours analysed by Lindor et al. (2012) and Pradella et al. (2013) were oncocytic, a characteristic commonly seen in BHD kidney tumours.
However, there is currently not sufficient statistical evidence to conclusively associate parotid tumours with BHD syndrome.
BHD syndrome has also been associated with melanoma in several reported cases (Toro et al., 1999; Khoo et al., 2002; Menko et al., 2009; Sempau et al., 2010; Cocciolone et al., 2010; Houweling et al., 2011; Mota-Burgos et al., 2013). Additionally, adrenal carcinoma may also be a low risk manifestation of BHD, with up to five cases having been reported in the literature (Raymond et al., 2014).
There have been three reported cases of rhabdomyoma formation in patients with BHD; one patient developed the a cardiac rhabdomyomas (Bondavalli et al., 2015), a second reported a previous laryngeal rhabdomyoma (Toro et al., 2008) and the third was found to have a rhabdomyoma in the parathyroid gland (Mikesell et al., 2014).
Other reported benign and malignant tumours are listed by Menko et al. (2009) and Houweling et al. (2011), but, so far, a direct relationship between BHD syndrome and these tumours has not been shown.
A recent report from Kapoor et al., (2015) hypothesises a link between BHD and intracranial vascular pathologies (aneurysms and hematomas). Although there is no firm link the authors suggest an association with BHD based on aberrant HIF-1α and MMP9 activity.