Following the description of familial renal oncocytoma (Weirich et al. 1998), it was reported that some familial renal oncocytoma kindreds contained affected individuals with rare hamartomatous Tumours of the hair follicle known as fibrofolliculoma (Toro et al. 1999). Fibrofolliculomas are a characteristic feature of the dominantly inherited multisystem familial cancer syndrome Birt–Hogg–Dubé syndrome (Birt et al. 1977). Benign whitish-grey papular skin Tumours develop on the face and upper body in the third decade, and histological examination reveals fibrofolliculomas or trichodiscomas (Birt et al. 1977; Rongioletti et al. 1989). Additional features include lipomas and cystic lung lesions and pneumothorax. In some reports, colonic polyposis is described (the combination of skin fibrofolliculomas and colorectal polyps described by Hornstein and Knickenberg (1975) is now considered to be BHD syndrome), and an increased risk of colorectal cancer has been reported in some studies but not in others (Zbar et al. 2002; Nahorski et al. 2010).
The lifetime risk of renal cell carcinoma in BHD is about 30 % with a mean age of diagnosis of ~50 years (Menko et al. 2009). A variety of histopathological subtypes of RCC have been described in Birt–Hogg–Dubé syndrome; a hybrid oncocytoma/chromophobe is characteristic, but other types including chromophobe and clear cell (conventional) RCC may occur (Pavlovich et al. 2002; Menko et al. 2009). Germline BHD gene (FLCN) mutations may be detected in ~5 % of patients with features of non-syndromic inherited RCC and also in kindreds with familial pneumothorax (Woodward et al. 2008; Graham et al. 2005).
The suggested diagnostic criteria for BHD syndrome require the presence of one major (at least 5 fibrofolliculomas–trichodiscomas, at least one histologically confirmed, of adult onset or a pathogenic germline mutation) or two minor criteria (multiple lung cysts (bilateral basal lung cysts with no other apparent cause, with or without spontaneous primary pneumothorax) or renal cancer: early-onset (<50 years) and/or multifocal/bilateral renal cancer and/or renal cancer of mixed chromophobe/oncocytic histology) or a first- degree relative with BHD syndrome.
The BHD gene maps to 17p11.2 and encodes a 64-kDa protein (Nickerson et al. 2002). A frameshift mutation hotspot in a mononucleotide tract (C8) in exon 11 accounts for ~50 % of mutations and most mutations are protein truncating (see http://www.lovd.nl/flcn). Molecular genetic diagnostic testing diagnosis should consist of sequence analysis and analysis (e.g., MLPA) for exonic deletions and amplifications. Two naturally occurring animal models of Birt–Hogg–Dubé syndrome, in the German shepherd dog and rat, have been described (Jonasdottir et al. 2000; Okimoto et al. 2004).
The folliculin protein may negatively regulate AMPK and mTOR-related pathways, though the effects on mTOR may be context dependent and folliculin function has not yet been fully elucidated (Menko et al. 2009).
Surveillance for renal Tumours is recommended by annual MRI scan of the kidney starting at the age of 20 years. As in von Hippel–Lindau disease, renal Tumours <3 cm can be monitored and nephron-sparing surgery performed when they reach 3 cm. In view of the risk of pneumothorax, caution should
be exercised for circumstances which might precipitate pneumothorax, such as general anesthesia. Individuals with BHD syndrome who develop pneumothorax will have lung cysts (usually basal), and so a lung CT scan may predict a risk of pneumothorax. Fibrofolliculomas are benign and do not need treatment other than for cosmetic reasons. The role of colonoscopy in BHD syndrome is uncertain, but in families in which colorectal cancer has occurred, 3-yearly colonoscopy from age 45 years is indicated.