Birt-Hogg-Dubé syndrome: mapping of a novel hereditary neoplasia gene to chromosome 17p12-q11.2

Khoo, Sok Kean; Bradley, Maria; Wong, Fung Ki; Hedblad, Mari‐Anne; Nordenskjöld, Magnus; Teh, Bin Tean

doi:10.1038/sj.onc.1204703

Cited by 183 publications

(102 citation statements)

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“…The human BHD gene was localized to chromosome 17p11.2 by linkage analysis 8,9 and identified by positional cloning. 10 Nearly all BHD gene mutations identified in the germ line of BHD patients are predicted to result in frameshifts, which produce a truncated protein.…”

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Expression of Birt–Hogg–Dubé gene mRNA in normal and neoplastic human tissues

et al. 2004

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Birt-Hogg-Dubé (BHD) syndrome is an inherited autosomal genodermatosis characterized by hamartomas of the hair follicle called fibrofolliculomas and an increased risk for developing spontaneous pneumothorax, lung cysts and renal neoplasia. BHD was localized to chromosome 17p11.2 by linkage analysis in BHD families, and germline insertion/deletion and nonsense mutations in a novel gene were identified which were predicted to prematurely truncate the BHD protein, folliculin. No homology to other human proteins was found although folliculin was conserved across species. As a first step toward understanding the function of BHD in the cell and how BHD mutations can lead to the BHD phenotype, we measured the expression of BHD mRNA in normal and neoplastic human tissues by fluorescent in situ hybridization. BHD mRNA was expressed in a variety of tissues, including the skin and its appendages, the distal nephron of the kidney, stromal cells and type 1 pneumocytes of the lung, acinar cells of the pancreas and parotid gland, and epithelial ducts of the breast and prostate. In the brain, BHD mRNA was expressed in neurons of the cerebrum, and Purkinje cells in the cerebellum. BHD mRNA was also expressed in macrophage and lymphocytes in the tonsils and spleen. Tissues with reduced expression of BHD mRNA included heart, muscle and liver. BHD mRNA was expressed strongly in the proliferating epithelial strands of fibrofolliculomas, the cutaneous lesions characteristic of BHD, but not in renal tumors from BHD patients. These results indicate a wide expression pattern for BHD mRNA in many tissues, including skin, lung and kidney, which are involved in the BHD phenotype, and support a tumor suppressor role for BHD in renal cancer. Birt-Hogg-Dube´(BHD) syndrome is a genodermatosis inherited as an autosomal dominant trait. The disorder, first recognized in 1977, 1 is characterized by the presence of multiple skin papules on the head and neck accompanied by acrochordons (skin tags) and trichodiscomas. Histologically, the cutaneous papules consist of thin, epithelial strands originating from a central hair follicle with prominent associated connective tissue. These skin lesions were named fibrofolliculomas and considered to be hamartomas of the hair follicle. Since the original description of the disorder by Drs Birt, Hogg and Dubé, BHD families with characteristic dermatologic lesions and other phenotypic features have been reported including renal neoplasia, 2 lung cysts, and/or spontaneous pneumothorax. 3,4 Patients with fibrofolliculomas have a 50-fold increased risk for developing spontaneous pneumothorax, and a seven-fold increased risk for renal carcinoma. 5 Patients affected with BHD syndrome are predisposed to develop several different histologic types of renal carcinoma including clear cell, papillary and chromophobe renal carcinomas, renal oncocytomas and a hybrid tumor containing elements of both chromophobe renal carcinoma and renal oncocytoma. 6,7 The oncocytic hybrid renal tumor is the most common renal neoplasm found i...

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Expression of Birt–Hogg–Dubé gene mRNA in normal and neoplastic human tissues

et al. 2004

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“…In 2001 evidence for linkage of BHD to chromosome 17p11 was demonstrated (Khoo et al, 2001;Schmidt et al, 2001). Germline mutations in the folliculin gene (FLCN) were first identified in BHD patients in 2002 (Nickerson et al, 2002).…”

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confidence: 99%

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

et al. 2010

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Birt-Hogg-Dubé syndrome (BHD) is an autosomal dominant condition characterised by the presence of facial fibrofolliculomas, pulmonary cysts which may be associated with spontaneous pneumothorax and renal tumours. Germline mutations in the gene Folliculin (FLCN) were first identified in BHD patients in 2002. In addition FLCN mutations have also been described in families with isolated primary spontaneous pneumothorax (PSP) and also familial clear cell renal carcinomas (FcRCC). We have established a locus-specific database based on the Leiden Open (source) Variation Database (LOVD) software. The version of the database contains 60 previously published mutations and 10 previously unpublished novel germline FLCN mutations. The mutations are comprised of deletions (44.3%), substitutions (35.7%), duplications (14.3%) and deletion/insertions (5.7%). The database is accessible online at http://www.lovd.nl/flcn

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“…1B). Papillary RCC with oncocytic change, clear cell RCC with focal papillary structures, RCC with a mixture of eosinophilic and focal clear cells with tubulopapillary architecture, sarcomatoid RCC and unclassified RCC have been described [17,29,31,36,37]. The association with renal angiomyolipoma has also been reported [38,39].…”

Section: Microscopic Findingsmentioning

confidence: 90%

Review of renal tumors associated with Birt-Hogg-Dubé syndrome with focus on clinical and pathobiological aspects

Furuya¹,

Nagashima²,

Gotohda³

et al. 2014

pjp

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Birt-Hogg-Dubé syndrome (BHDS) is an autosomal dominant inherited disorder characterized by clinical features of skin lesions, pulmonary lesions and renal tumor. The gene responsible for this syndrome is located on chromosome 17p11.2 and designated as FLCN. In this article, we review renal tumors associated with BHDS with a focus on clinical and pathobiological aspects. Renal tumors often occur multifocally or bilaterally in the imaging analyses or gross examination. Histological examination of renal tumors includes a variety of subtypes such as hybrid oncocytic tumor, chromophobe renal cell carcinoma (RCC), oncocytoma, clear cell RCC and papillary RCC. The histologic discordance in multiple tumors seems to be characteristic of this syndrome. Oncocytosis is observed histologically in about half of the cases. Several investigations have elucidated that folliculin may be involved in the mammalian target of rapamycin (mTOR) pathway recently. Renal tumors composed of clear cells may behave in an aggressive fashion. However, renal tumors including hybrid oncocytic tumor, chromophobe RCC and oncocytoma behave mostly in an indolent fashion.

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Birt-Hogg-Dubé syndrome: mapping of a novel hereditary neoplasia gene to chromosome 17p12-q11.2

Cited by 183 publications

References 20 publications

Expression of Birt–Hogg–Dubé gene mRNA in normal and neoplastic human tissues

Expression of Birt–Hogg–Dubé gene mRNA in normal and neoplastic human tissues

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

Review of renal tumors associated with Birt-Hogg-Dubé syndrome with focus on clinical and pathobiological aspects

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