• Birt-Hogg-Dubé syndrome
• colorectal cancer
• microsatellite instability

Birt-Hogg-Dubé (BHD) syndrome, an inherited autosomal genodermatosis characterised by benign tumours of the hair follicle, is associated with renal neoplasia, lung cysts, and spontaneous pneumothorax.¹ The novel causative gene, identified by linkage analysis in BHD families, is localised on chromosome 17p11.2.² Protein truncating germinal mutations within a hypermutable (C)₈ tract occur in patients with BHD syndrome and lead to an increased risk of kidney cancer.³

Microsatellite repeats are widely distributed throughout the genome. Owing to a defect in the DNA mismatch repair gene, a subset of tumours accumulates frequent deletion and insertion mutations in these repetitive DNA sequences.^4–6 Most microsatellite instability (MSI) has so far been described in non-coding DNA within introns of intergenic regions in the genome. However, in some cancer related genes and mismatch repair genes, MSI has been identified in protein coding regions. The first target sequence identified within a coding region was a poly (A)₁₀ nucleotide tract of the TGFBR2 gene.⁷ The other mutational targets of MSI have been found in repetitive sequences of IGF2R⁸ and BAX⁹ genes involved in the regulation of cell growth and in the promotion of apoptosis, respectively. Furthermore, frameshift mutations in repeat sequences of the DNA mismatch repair genes MSH3 and MSH6 have been reported.¹⁰ In tumours with MSI, the mechanism of tumorigenesis is believed to involve frameshift mutations of microsatellite repeats within the coding regions of genes, the inactivation of which is considered to contribute to tumorigenesis.

Early reports suggested that BHD syndrome was associated with a predisposition to colon neoplasms,^11–13 but Zbar et al¹⁴ reported that colon cancer and colon polyps are not related to BHD syndrome. Recently, Khoo et al¹⁵ reported that colorectal neoplasia is an associated feature of BHD in some families. …