Clinical and genetic studies of Birt-Hogg-Dube syndrome

Abstract

Birt-Hogg-Dubé syndrome (BHD) is an autosomal dominant cancer syndrome characterised by benign skin tumours, renal tumours, and spontaneous pneumothorax. The gene has been mapped to chromosome 17p11.2 and recently identified, expressing a novel protein called folliculin. We report the clinical and genetic studies of four sporadic BHD cases and four families with a total of 23 affected subjects. Haplotype analysis of these families using BHD linked markers showed they did not share the same affected alleles, excluding common ancestry. Mutation analysis of the BHD gene identified two germline mutations on exon 11 (c.1733insC and c.1733delC) in three of four families as well as two of four sporadic cases. A novel somatic mutation, c.1732delTCinsAC, was detected in a BHD related chromophobe renal carcinoma. Our results confirmed the (C) 8 tract in exon 11 as a mutational hot spot in BHD and should always be considered for future genetic testing. Our observation also indicated that the second hit (of Knudson's two hit theory) in some BHD related tumours is in the form of somatic mutation rather than LOH. In a large French family in which eight affected subjects carry the c.1733delC mutation, a phenocopy who has multiple episodes of spontaneous pneumothorax was identified. A total of five mutation carriers (aged between 37 to 66) did not have any evidence of BHD features, suggesting either reduced penetrance or late age of onset of the disease. In addition, six out of eight affected subjects who have positive germline mutation have confirmed neoplastic colonic polyps, indicating that colorectal neoplasia is an associated feature of BHD in some families. Our studies have observed several interesting genetic features in BHD: (1) the poly (C) tract in exon 11 as a mutational hot spot; (2) the existence of phenocopy; (3) reduced penetrance or late age of onset of disease; (4) association with colorectal neoplasia in some families; and (5) somatic mutation instead of LOH as the second hit in BHD tumours.

Mutations in BHD and TP53 genes, but not in HNF1β gene, in a large series of sporadic chromophobe renal cell carcinoma

“…The study of hereditary kidney cancer syndromes has led to the identification of kidney cancer-related genes that are also involved in sporadic RCC. Recently, germline BHD mutations were found in patients with Birt -Hogg -Dubé (BHD) syndrome (Nickerson et al, 2002), and a diverse spectrum of renal tumours have been described with somatic inactivation of BHD reported in BHD-related renal tumours (Khoo et al, 2002;Schmidt et al, 2005;Vocke et al, 2005). BHD promoter methylation has been reported in a subset of sporadic clear cell and chromophobe RCC, but somatic mutation of BHD in sporadic cases is rare (da Silva et al, 2003;Khoo et al, 2003).…”

A new locus-specific database (LSDB) for mutations in the folliculin (FLCN) gene

“…The database lists previously published point mutations, deletions, duplications and splice site mutations in the FLCN gene (Bessis et al, 2006;Cho et al, 2008;Frohlich et al, 2008;Gad et al, 2007,Graham et al, 2005Gunji et al, 2007;Imada et al, 2009;Kawasaki et al, 2005;Khoo et al, 2002;Kim et al, 2008;Lamberti et al, 2005;Leter et al, 2008;Murakami et al, 2007;Nickerson et al, 2002;Painter et al, 2005;Palmirotta et al, 2008;Ren et al, 2008;Schmidt et al, 2005;Toro et al, 2008;van Steensel et al, 2007;Woodward et al, 2008). In addition 10 previously unpublished novel mutations/variants are included.…”

“…In a series of 124 BHD patients, 27% developed renal tumours at a mean age of 50.4 years . The earliest age of diagnosis of renal cancer reported in BHD was 20 years (Khoo et al, 2002). A range of histological types are seen and include oncocytoma, chromophobe/oncocytic hybrid, clear cell and papillary (Vocke et al, 2005).…”

Lack of mutation of the folliculin gene in sporadic chromophobe renal cell carcinoma and renal oncocytoma

“…16 The germline mutation of the folliculin gene is associated with the development of chromophobe and mixed oncocytic-chromophobe RCCs. 6,7 Somatic inactivation of the VHL gene has been found in ϳ60 -70% of the sporadic conventional RCCs as well. 17 Despite the high frequency of allelic duplication at chromosome 7q (85%), however, only 5-8% of the sporadic papillary RCCs display an activating mutation of the MET gene and no mutation of the FH gene was detected in sporadic RCCs.…”

“…4,5 Germline mutation of the folliculin gene (in most cases a C insertion or deletion in the hypermutable (C) 8 tract at nt 1733-1740 in exon 11) has been found recently in affected family members. 6,7 A systematic histopathological survey indicated that most patients with BHD syndrome develop a particular type of renal cell tumor, the overwhelming majority of which corresponds to chromophobe RCCs (34%) or so called "hybrid" neoplasms (50%) resembling a mixture of chromophobe RCC and RO. 8 Previous CGH and microsatellite studies indicated that chromosome 17 is lost in ϳ80% of sporadic chromophobe RCC.…”