Clinical and genetic spectrum of Birt–Hogg–Dubé syndrome patients in whom pneumothorax and/or multiple lung cysts are the presenting feature

Department of Respiratory Medicine, Juntendo University School of Medicine, Tokyo, Japan.
Journal of Medical Genetics (Impact Factor: 6.34). 04/2010; 47(4):281-7. DOI: 10.1136/jmg.2009.070565
Source: PubMed


Birt-Hogg-Dubé syndrome (BHDS) is an inherited autosomal genodermatosis characterised by fibrofolliculomas of the skin, renal tumours and multiple lung cysts. Genetic studies have disclosed that the clinical picture as well as responsible germline FLCN mutations are diverse.
BHDS may be caused by a germline deletion which cannot be detected by a conventional genetic approach. Real-time quantitative polymerase chain reaction (qPCR) may be able to identify such a mutation and thus provide us with a more accurate clinical picture of BHDS.
This study analysed 36 patients with multiple lung cysts of undetermined causes. Denaturing high performance liquid chromatography (DHPLC) was applied for mutation screening. If no abnormality was detected by DHPLC, the amount of each FLCN exon in genome was quantified by qPCR.
An FLCN germline mutation was found in 23 (63.9%) of the 36 patients by DHPLC and direct sequencing (13 unique small nucleotide alterations which included 11 novel mutations). A large genomic deletion was identified in two of the remaining 13 patients by qPCR (one patient with exon 14 deletion and one patient with a deletion encompassing exons 9 to 14). Mutations including genomic deletions were most frequently identified in the 3'-end of the FLCN gene including exons 12 and 13 (13/25=52.0%). The BHDS patients whose multiple cysts prompted the diagnosis in this study showed a very low incidence of skin and renal involvement.
BHDS is due to large deletions as well as small nucleotide alterations. Racial differences may occur between Japanese and patients of European decent in terms of FLCN mutations and clinical manifestations.

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Available from: Shin-Ichiro Iwakami, Oct 06, 2015
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    • "First, denaturing high-performance liquid chromatography (DHPLC) method was applied. As no abnormality was detected by DHPLC, the copy number of each exon of the FLCN gene in the genome was quantified using real-time quantitative polymerase chain reaction (qPCR) methods [3] [9] to detect a large genomic deletion in the FLCN gene. "
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    ABSTRACT: This study was performed in 24 members of a family with spontaneous pneumothorax to test clinical suspicion of Birt-Hogg-Dubé syndrome (BHDS). Computed tomography scan was performed for confirmation of pneumothorax, while genetic tests were done using real-time quantitative polymerase chain reaction. Genetic studies showed a deletion of exon 1 in the FLCN gene in the index case as well as nine other individuals, including two with clinical phenotypes of pneumothorax and seven who are symptom-free to date. Proper imaging and taking accurate family history could be the keys to test clinical suspicion in some syndromes, including BHDS.
    Clinical imaging 01/2013; 37(1):111-5. DOI:10.1016/j.clinimag.2012.03.003 · 0.81 Impact Factor
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    • "The functions of folliculin have partly been clarified and might include a role in the mammalian target of rapamycin pathway (Hasumi et al, 2009). Although many BHD kindreds exhibit all three components of the syndrome, ‘pneumothorax-only' and ‘renal-cancer-only' families have also been described (Graham et al, 2005; Painter et al, 2005; Woodward et al, 2008; Kunogi et al, 2010). Among 69 patients with early-onset or familial clear cell renal cancer without further characteristics of BHD, germline FLCN mutations were found in 4% of cases (Woodward et al, 2008). "
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    ABSTRACT: Birt-Hogg-Dubé (BHD) syndrome is an autosomal dominant condition caused by germline FLCN mutations, and characterised by fibrofolliculomas, pneumothorax and renal cancer. The renal cancer risk, cancer phenotype and pneumothorax risk of BHD have not yet been fully clarified. The main focus of this study was to assess the risk of renal cancer, the histological subtypes of renal tumours and the pneumothorax risk in BHD. In this study we present the clinical data of 115 FLCN mutation carriers from 35 BHD families. Among 14 FLCN mutation carriers who developed renal cancer 7 were <50 years at onset and/or had multifocal/bilateral tumours. Five symptomatic patients developed metastatic disease. Two early-stage cases were diagnosed by surveillance. The majority of tumours showed characteristics of both eosinophilic variants of clear cell and chromophobe carcinoma. The estimated penetrance for renal cancer and pneumothorax was 16% (95% minimal confidence interval: 6-26%) and 29% (95% minimal confidence interval: 9-49%) at 70 years of age, respectively. The most frequent diagnosis in families without identified FLCN mutations was familial multiple discoid fibromas. We confirmed a high yield of FLCN mutations in clinically defined BHD families, we found a substantially increased lifetime risk of renal cancer of 16% for FLCN mutation carriers. The tumours were metastatic in 5 out of 14 patients and tumour histology was not specific for BHD. We found a pneumothorax risk of 29%. We discuss the implications of our findings for diagnosis and management of BHD.
    British Journal of Cancer 12/2011; 105(12):1912-9. DOI:10.1038/bjc.2011.463 · 4.84 Impact Factor
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    • "Among these, an apparent difference in mutations were found, which include insertion, deletion, inactivating frameshift and nonsense mutations1,4. Because no genotype-phenotype correlation has been found to date and clinical expression is widely variable, BHDS is most likely under-diagnosed2,5. "
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    ABSTRACT: Simple benign tumors can present as part of a syndrome with substantial mortality. Fibrofolliculomas are benign skin tumors most often associated with the Birt-Hogg-Dubé syndrome (BHDS). The most life-threatening complication of this syndrome is renal cancer and other major features include multiple lung cysts and spontaneous pneumothorax. We present the case of a 54 year-old man with multiple flesh-colored papules on his face confirmed histologically as fibrofolliculomas. He had a history of recurrent pneumothorax and chest computed tomography showed multiple lung cysts. To confirm the diagnosis of BHDS, we conducted gene analysis that revealed a single nucleotide duplication in the folliculin (FLCN) gene (Exon 11, C.1285dupC). BHDS confirmed by the FLCN gene mutation is rarely reported in Korea. Appropriate investigation is recommended whenever a patient with benign skin tumors is encountered.
    Annals of Dermatology 10/2011; 23(Suppl 2):S193-6. DOI:10.5021/ad.2011.23.S2.S193 · 1.39 Impact Factor
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