Article

Clinical and genetic spectrum of Birt-Hogg-Dube 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: 5.64). 04/2010; 47(4):281-7. DOI: 10.1136/jmg.2009.070565
Source: PubMed

ABSTRACT 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.

0 Followers
 · 
215 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: To characterize pathologic features of pulmonary cysts and to elucidate the possible mechanism of cyst formation in lungs of patients with Birt-Hogg-Dubé syndrome (BHDS), a tumor suppressor gene syndrome, we used histologic and morphometric analyses. We evaluated 229 lung cysts from 50 patients with BHDS and 117 from 34 patients with primary spontaneous pneumothorax (PSP) for the number, size, location, and absence or presence of inflammation. These BHDS-cysts abutted interlobular septa (88.2%) and had intracystic septa (13.6%) or protruding venules (39.5%) without cell proliferation or inflammation. Frequencies of these histologic characteristics differed significantly from those of patients with PSP (P<0.05). Although the intrapulmonary BHDS-cysts were smaller than the subpleural BHDS-cysts (P<0.001), there was no difference in size between them when there was no inflammation. The number of cysts diminished logarithmically and the proportion of cysts with inflammation increased as their individual sizes enlarged (P<0.05). These results imply that the BHDS-cysts are likely to develop at the periacinar region, an anatomically weak site in a primary lobule, where alveoli attach to connective tissue septa. We hypothesize that the BHDS cysts possibly expand in size as the alveolar walls disappear at the alveolo-septal junction and grow even larger when several cysts fuse. This article is protected by copyright. All rights reserved.
    Histopathology 01/2014; 65(1). DOI:10.1111/his.12368 · 3.30 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Birt-Hogg-Dubé syndrome (BHD) is a rare autosomal dominant inherited disease caused by a germline mutation in the folliculin gene mapped in the region of chromosome 17p11.2. BHD predisposes the patient to cutaneous fibrofolliculomas (FFs), pulmonary cysts (PCs), and renal cell carcinoma (RC). Here, we present two cases of BHD in Japanese patients. One patient was a 37-year-old female, and the other a 35-year-old male. Each of the patients was affected by all three symptoms of BHD. Both patients had unremarkable FFs, asymptomatic PCs, and asymptomatic RC. The presence of RC was revealed by abdominal ultrasonic examination. We also summarized the data from 62 Asian cases of BHD from the available literature and found that their FFs were unremarkable. In addition, the proportion of BHD patients with FF is smaller for Asian patients than it is for Caucasian patients. We also found that it is rare for BHD patients in Asia to show all three symptoms of BHD. Careful inspection of the skin as well as skin biopsies are important for the early detection of BHD cases in Asia.
    Case Reports in Dermatology 01/2014; 6(1):20-8. DOI:10.1159/000358216
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The Birt-Hogg-Dubé syndrome is a rare cancer susceptibility syndrome characterised by renal tumours, lung cysts and pneumothoraces, and fibrofolliculomas. It is caused by dominantly inherited mutations in FLCN. Our objective was to report renal tumour characteristics in a large series of patients with the Birt-Hogg-Dubé syndrome. We studied French Birt-Hogg-Dubé patients with a history of renal tumour. We included 33 patients with 21 distinct germline FLCN mutations. Median age at diagnosis of first renal tumour was 46, and age varied from 20 to 83. Twenty cases had one renal tumour, the remainder had two or more tumours. Most cases (23/33, 70%) had oncocytoma or renal cell carcinoma of the chromophobe or hybrid chromophobe-oncocytoma type, three had clear cell carcinoma (9%), and the other seven had carcinoma of papillary, undifferentiated or undetermined histology. Four cases had metastatic disease, although none died of it. Age at renal tumour diagnosis was highly variable, highlighting the need for regular surveillance from young adulthood to old age. Most cases had tumour types classically associated with Birt-Hogg-Dubé, i.e. oncocytoma or renal cell carcinoma of the chromophobe or hybrid type. Nevertheless, 9% had clear cell renal cell carcinoma. Geneticists, urologists and oncologists should therefore be alert to the possibility of Birt-Hogg-Dubé in patients with renal cell carcinoma of clear cell histology, especially if there are associated manifestations. Finally, the behaviour of metastatic carcinoma seemed more indolent than in sporadic renal cancers.
    Orphanet Journal of Rare Diseases 12/2014; 9(1):163. DOI:10.1186/s13023-014-0163-z · 3.96 Impact Factor

Full-text (2 Sources)

Download
53 Downloads
Available from
Jun 2, 2014