Fibrofolliculomas, pulmonary cysts, pneumothorax and renal cell carcinoma are the only manifestations associated with BHD syndrome. 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
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 thirteen of twenty 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.
Melanoma
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). Other reported benign and malignant tumours are listed by Menko et al. (2009), but, so far, a direct relationship between BHD syndrome and these tumours has not been shown.
