Encyclopedia of Cancer (2016)
BHD syndrome; Fibrofolliculomas with trichodiscomas and acrochordons; Hornstein-Knickenberg syndrome
Birt-Hogg-Dubé syndrome is a rare, autosomal dominantly inherited genodermatosis characterized by multiple, benign cutaneous hair follicle tumors (fibrofolliculomas, characterized by multiple noncancerous tumors of the hair follicles particularly on the face, neck, and upper chest), trichodiscomas, acrochordons (skin tags), lung cysts, spontaneous pneumothorax (lung wall collapse), colon polyps and colon carcinoma, lipomas, angiolipomas, parathyroid adenomas, parotid oncocytomas, and an increased risk for developing kidney tumors such as oncocytomas, chromophobe, papillary carcinoma, and clear renal cell carcinoma (RCC).
BHD syndrome was originally described in 1977 by Birt, Hogg, and Dubé as a rare form of inherited autosomal dominant syndrome in large kindred, wherein 15 of 37 members were older than 25 years of age. Originally, it was characterized as a triad of multiple, skin hamartomatous lesions (fibrofolliculomas, trichodiscomas, and acrochordon). The fibrofolliculomas and trichodiscomas appear as multiple, small, dome-shaped, smooth, 2–4 mm, yellowish, or skin-colored papules, scattered over the forehead, face, neck, nose, chest, scalp, and upper trunk. The onset of skin lesions typically begins during the third or fourth decade of life. Skin lesions tend to increase in size and number with age. The acrochordons appear as small and soft skin tags (furrowed, 1–2 mm soft papules) composed of loose connective tissues. Histogenesis of skin lesions confirmed that trichodiscomas originated from the mesenchymal component of the pilar complex, acrochordons from epithelial components, and fibrofolliculomas from both epithelial and mesenchymal proliferation. Since its initial description, more than 60 families have been identified with BHD syndrome, and a number of other features of BHD have been recognized, including an increased incidence of fi renal carcinoma, most commonly chromophobe and hybrid oncocytic/chromophobe fi renal cell carcinomas (RCCs), lung cysts, pleural blebs, spontaneous pneumothorax, developing colonic adenomas and carcinoma, neurothekeomas, meningiomas, fiecked chorioretinopathy, parathyroid adenomas, multiple lipomas, intraoral papules, parotid oncocytoma, and other cutaneous tumors such as collagenomas, perivascular fibromas, angiofibromas, and fi melanomas.
Individuals with BHD syndrome were found to have sevenfold higher risk of developing kidney neoplasm, 50-fold higher risk of developing spontaneous pneumothorax, and 80-fold higher risk of developing pulmonary cysts over the general population. The first report of BHD syndrome with renal pathology when examined showed bilateral kidney tumors with a one clear RCC and one chromophobe RCC. Further, in a study of 13 patients with BHD syndrome, seven had renal neoplasms, including renal oncocytomas and papillary RCCs. BHD patients with renal neoplasia display multifocal, bilateral tumors of several histopathological variants including chromophobe RCC (34 %), oncocytic hybrid (50 %) with features of chromophobe RCC and renal oncocytoma, and less frequently clear cell RCC (9 %), renal oncocytoma (5 %), and papillary RCC (2 %). Oncocytoma and chromophobe RCC originate from the intercalated cells of renal collecting tubules and share overlapping histologic features. A study on 98 patients with BHD syndrome described the occurrence of both oncocytoma and chromophobe RCC with predominancy of chromophobe RCC in renal cancer, found in 7 of 14 histologically examined tumors. Chromophobe RCCs are slowly progressive, locally invasive, and average 7–9 cm in diameter but rarely metastasize. Mean age at diagnosis of kidney tumors is 50.7 years. Recent findings suggest that microscopic oncocytic lesions may be precursors of hybrid oncocytic tumors, chromophobe RCCs, and perhaps clear cell RCCs in patients with BHD syndrome. Strong associations between renal neoplasms and pulmonary cysts and spontaneous pneumothorax have been observed in BHD families. The lung cysts in BHD-affected individual are mostly bilateral and multifocal and have a high risk of developing spontaneous pneumothorax. Pneumothorax likely occurs in younger individuals with BHD syndrome. Male gender and older age have been associated with increased risk of renal tumors, whereas the risk of spontaneous pneumothorax is inversely associated with age. Based on these clinical manifestations, penetrance of BHD syndrome is considered to be very high. Thus, the BHD syndrome conferred an increased risk for the development of renal tumors, spontaneous pneumothorax, and lung cysts.
The following diagnostic features may be considered in a patient with BHD syndrome: the presence of
10–100 cream to fiesh-colored, smooth, firm skin papules on the face, neck, or upper torso, with at least one histologically confirmed fibrofolliculoma with or without family history of BHD or a single renal tumor or history of spontaneous pneumothorax; a patient with multiple and bilateral chromophobe, oncocytic, and/or oncocytic hybrid renal tumors; single oncocytic, chromophobe, or oncocytic-hybrid tumor and a family history of renal cancer with any of the above renal cell tumor types; and a family history of autosomal dominant primary spontaneous pneumothorax without a history of chronic obstructive pulmonary disease.
BHD gene mutations
The genetic defect responsible for BHD syndrome has been mapped to the pericentromeric region of chromosome 17p11.2 by linkage analysis, and the gene in this region has been cloned and is believed to be responsible for the BHD syndrome. This region is interesting because of the presence of low-copynumber repeat elements, unstable, and associated with a number of diseases. Several heterozygous germline mutations have been identified in a novel gene, BHD, in BHD families. The human BHD gene encodes a tumor suppressor protein, folliculin (FLCN), a cytoplasmic protein with an open reading frame of 579 amino acids, 64-kDa protein. Human FLCN consists of 14 exons. Folliculin contains a glutamic acid-rich, coiled-coil domain with no significant homology to any known human protein. Folliculin homologs have been identified in many species, including Drosophila, Caenorhabditis elegans, mouse, dog, and rat, implying a critical biological role for folliculin. Although the function of the BHD gene is unknown, germline mutations in FLCN, with somatic mutations and loss of heterozygosity in tumor tissue, suggest that loss of function of the folliculin protein is the basis of tumor formation in BHD syndrome. Recently, it has been shown that FLCN binds with FNIP1 (folliculin interacting protein 1) and may be involved in energy and/or nutrient sensing through AMPK and mTOR signaling pathways. Further, a recent study demonstrates that the Drosophila homolog of gene BHD regulates male germline stem cell maintenance and functions downstream of the JAK/STAT (Janus kinase/signal transducer and activator of transcription) and Dpp (decapentaplegic) signal transduction pathways. This study suggests that the BHD may regulate tumor formation through modulating stem cells in human. Recently, it has been demonstrated that folliculin (FLCN)-interacting proteins 1 and 2 (Fnip1 and Fnip2) play an important roles in kidney tumor suppression in cooperation with Flcn. Fnip1 and Fnip2 are essential for the tumor-suppressive function of Flcn. Their study also suggest that kidney tumorigenesis in human Birt-Hogg-Dubé syndrome may be triggered by loss of interactions among Flcn, Fnip1, and Fnip2. Their findings suggest crucial roles for Fnip1 and Fnip2 in kidney tumor suppression and may provide molecular targets for the development of novel therapeutics for kidney cancer.
The germline mutations identified in BHD families so far are frameshift or nonsense mutations, predicted to truncate folliculin, including insertions or deletions (44 %) of a hypermutable tract of eight cytosines (C8) in exon 11. Initially, the distinct germline mutations on exon 11 of the folliculin gene (c.1733insC and c.1733delC) in three of four families with BHD syndrome were identified. Later, mutations along the entire length of the coding region of the folliculin gene have been identified, including 16 insertions/deletions, 3 nonsense mutations, and 3 splice site mutations in 51 of 61 families with BHD syndrome. Interestingly, among patients with a mutation in the exon 11 hot spot, significantly fewer renal tumors were observed in patients with the C-deletion than those with the C-insertion mutation. Two unique features of renal tumors in patients with BHD syndrome are the variable expression of the phenotype among members of a given family who carry the same germline mutation and between families who carry the “hot spot” mutation in exon 11. Mutational hot spot is also reported to be a target
of mutation in fi microsatellite instability (MSI) sporadic colorectal cancer. Five of 32 (16 %) sporadic colorectal cancers with MSI were found to have insertion/deletion mutations in the poly(C)8 tract of the BHD exon 11. In addition, mutations truncating folliculin have been described in patients with 4-bp deletions in BHD exon 4, dominantly inherited lung cysts, and/or spontaneous pneumothorax without skin lesions or kidney tumors. Moreover, germline mutation in the rat and dog homologs of the BHD gene also resulted in inherited kidney tumors, suggesting that the BHD gene has a tumor suppressor function. Furthermore, recent evidence of somatic second “hit” mutations in renal tumors from BHD patients in which 53 % showed a second somatic mutation and 17 % showed loss of heterozygosity (LOH) of the wild-type allele strongly supports the Knudson “two-hit” tumor suppressor model for BHD, suggesting that BHD is a new fi tumor suppressor gene with roles in both human and animal carcinogenesis.
BHD mRNA is expressed in a wide variety of normal tissues including the differentiated epidermal layers of the skin and the outer and inner root sheath supporting structures of the hair follicle, lung, and kidney and also expressed in a variety of secretory cell types, including acinar cells of the parotid gland and pancreas, brain, lymphocytes, and ductal cells of the breast and prostate. Tissues with reduced expression of folliculin mRNA included the heart, muscle, and liver. Folliculin immunoreactivity also occurred in the nucleolus of normal cells and was associated with mitosis. In addition, folliculin mRNA was expressed strongly in fibrofolliculomas, but loss of folliculin expression was seen in oncocytoma (3.3 %), chromophobe RCC (60.7 %), papillary RCC (36.4 %), and clear cell RCC (21.1 %). Abnormal accumulation in the cytoplasm was also observed in oncocytoma (76.7 %), chromophobe RCC (3.6 %), and clear cell RCC (14.7 %). Thus, the protein may have important biological functions in a variety of tissues and organisms. Furthermore, the defective protein in BHD patients may affect the cell’s cytoskeleton, disrupting the extracellular matrix and affecting the regulation of cellular proliferation.
Screening and possible treatment for BHD
BHD syndrome is inherited in an autosomal dominant manner. A child having a parent with mutation on BHD has a 50 % chance of inheriting that mutation. No specific screening guidelines for BHD syndrome have been described. However, due to the risk of kidney cancer and other associated abnormalities, it has been suggested that individuals with BHD syndrome or a family history of BHD syndrome should have yearly ultrasounds of their kidneys from the age of 25 and abdominal computerized tomography (CT) scan or magnetic resonance imaging (MRI) every 2 years. Further, BHD syndrome can be identified by skin biopsies to confirm the fibrofolliculomas and X-rays to look for lung cysts and previous spontaneous pneumothorax. Individuals with BHD syndrome should avoid smoking because of increased risk of kidney cancer associated with smoking. No curative medical treatment is currently available for the cutaneous lesions associated with BHD syndrome. However, surgery and electrodesiccation have provided definitive treatment of solitary perifollicular fibromas and multiple lesions, respectively. Treatment of folliculoma/trichodiscoma shows substantial improvement after laser ablation but can be reverted. Renal tumors can be treated with nephron-sparing surgical approaches, depending on the size and location of the tumors. Individuals with spontaneous pneumothorax may avoid high ambient pressures, which can precipitate spontaneous pneumothorax. Consider colonoscopy for colonic polyps and colonic adenocarcinoma. Genetic testing for BHD syndrome is also available. Use of molecular genetic testing for early identification of at-risk family members before disease-causing mutations are manifested may improve diagnostic certainty and reduce costly screening procedures. Methods of using BHD encoding sequence also allow for a differential genetic diagnosis of spontaneous pneumothorax or collapsed lung.
Hasumi H, Baba M, Hasumi Y et al (2015) Folliculin-interacting proteins Fnip1 and Fnip2 play critical roles in kidney tumor suppression in cooperation with Flcn. Proc Natl Acad Sci USA 112:E1624E1631
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