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      Koenen's tumor and facial angiofibromas in a case of Birt-Hogg-Dubé syndrome: A cutaneous contribution to growing evidence of a relationship with tuberous sclerosis complex

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          Abstract

          Birt-Hogg-Dubé syndrome (BHD) is an uncommon autosomal dominant genodermatosis characterized by fibrofolliculomas and trichodiscomas on the face and neck with acrochordons in flexural areas. These skin signs serve as markers for internal disease, most importantly spontaneous pneumothoraces and renal cancers. BHD is caused by a mutation in a tumor suppressor gene. This gene encodes the protein folliculin (FLCN), important for normal functioning of the mammalian target of rapamycin (mTOR) signaling pathway. 1 Case report A 33-year-old man presented with multiple 1- to 3-mm firm, flesh-colored papules on the face (Fig 1, A); numerous, scattered 2- 3-mm white papules on the trunk; and a discrete, well-demarcated 6-mm periungual papule on the fourth digit of the right hand (Fig 1, B). The patient reported no history of trauma to the digit. Histology from one facial papule found an angiofibroma. Similar histology was noted from the periungual lesion (Fig 1, C). Analysis of 2 truncal papules showed fibrofolliculomas. A complete cutaneous examination found no shagreen patches, hypopigmented macules, or obvious tooth enamel pitting. The patient also reported an extensive family history of facial papules in a pattern consistent with autosomal dominant inheritance. Two spontaneous pneumothoraces were reported in a paternal uncle and a single pneumothorax in that uncle's son (Fig 2). Gene sequence analysis of FLCN found a previously unreported deletion in the gene responsible for BHD in both our patient and his cousin. Subsequent genetic analysis of the proband found no mutations indicative of tuberous sclerosis complex (TS). No family history of renal tumors was reported. Discussion This case and family history demonstrate the hereditary nature of BHD and its significant association with internal disease processes. Unique to this case is the presence of a Koenen's tumor (periungual angiofibroma). A PubMed search of the English-language literature failed to reveal a similar association. Koenen's tumors are typically associated with TS. Whereas the typical facial papules of BHD consist of fibrofolliculomas and trichodiscomas, facial angiofibromas indistinguishable from those in TS have also been reported.2, 3 Likewise, there is a report of fibrofolliculomas typical of BHD in a patient with confirmed TS. 4 Accordingly, significant cutaneous clinical overlap exists between BHD and TS. Internal manifestations overlap as well. Both BHD and TS are associated with pulmonary cysts, renal cysts, and renal cancers. Recent case reports describe 2 BHD patients with seizures and a patient with a renal angiomyolipoma, both presentations typically associated with TS.3, 5 The similarities between BHD and TS extend beyond clinical presentation. FLCN and the TS proteins, hamartin and tuberin, appear to have different yet important roles in the mTOR pathway. 1 BHD results in inhibition of the mTOR pathway. In contradistinction, TS results in mTOR activation. This finding suggests a new paradigm in which both inappropriately high and inappropriately low levels of mTOR activity can result in tumorigenesis. 6 Multiple histologically different renal tumor types are associated with BHD. This finding suggests a 2-hit mechanism in which a second individual mutation, on the wild-type FLCN allele, is necessary for tumor promotion. 7 In contrast, cutaneous fibrofolliculomas 8 and lung cysts 9 show retention of the wild-type allele, suggesting that other genetic mechanisms, such as haplodeficiency, play a role as well. This case adds to the constellation of cutaneous manifestations of BHD and illustrates the overlap between BHD and TS. If overlapping features of BHD and TS are present, genetic testing is important to establish the correct diagnosis. Once the diagnosis is established, genetic counseling should be provided to the patient and family members.

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          Birt-Hogg-Dubé syndrome: diagnosis and management.

          Birt-Hogg-Dubé syndrome (BHD) is an autosomal dominant condition characterised clinically by skin fibrofolliculomas, pulmonary cysts, spontaneous pneumothorax, and renal cancer. The condition is caused by germline mutations in the FLCN gene, which encodes folliculin; the function of this protein is largely unknown, although FLCN has been linked to the mTOR pathway. The availability of DNA-based diagnosis has allowed insight into the great variation in expression of FLCN, both within and between families. Patients can present with skin signs and also with pneumothorax or renal cancer. Preventive measures are aimed mainly at early diagnosis and treatment of renal cancer. This Review gives an overview of current diagnosis and management of BHD.
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            The role of the Birt-Hogg-Dubé protein in mTOR activation and renal tumorigenesis.

            Birt-Hogg-Dubé (BHD) syndrome is a tumor-suppressor gene disorder characterized by skin tumors, cystic lung disease and renal cell carcinoma. Very little is known about the molecular pathogenesis of BHD. Clinical similarities between BHD and tuberous sclerosis complex (TSC) suggest that the BHD and TSC proteins may function within a common pathway. The TSC proteins inhibit the activity of the mammalian target of rapamycin complex 1 (TORC1), and in Schizosaccharomyces pombe, Bhd and Tsc1/Tsc2 have opposing roles in the regulation of amino-acid homeostasis. We report here that in mammalian cells, downregulation of BHD reduces the phosphorylation of ribosomal protein S6, an indicator of TORC1 activity. To determine whether folliculin, the product of the BHD gene, regulates mammalian target of rapamycin activity in vivo, we generated a mouse with targeted inactivation of the Bhd gene. The mice developed spontaneous oncocytic cysts and tumors composed of cells that resemble the renal cell carcinomas in BHD patients. The cysts and tumors had low levels of phospho-S6. Taken together, these data indicate that folliculin regulates the activity of TORC1, and suggest a new paradigm in which both inappropriately high and inappropriately low levels of TORC1 activity can be associated with renal tumorigenesis.
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              Clinical and genetic studies of Birt-Hogg-Dubé syndrome.

              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.
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                Author and article information

                Contributors
                Journal
                JAAD Case Rep
                JAAD Case Rep
                JAAD Case Reports
                Elsevier
                2352-5126
                25 May 2016
                May 2016
                25 May 2016
                : 2
                : 3
                : 196-198
                Affiliations
                [a ]University of Texas Medical School at Houston, Houston, Texas
                [b ]Stanford University, Stanford, California
                [c ]Dell School of Medicine at the University of Texas at Austin, Austin, Texas
                [d ]Clinical Pathology Associations at the University of Texas at Austin, Austin, Texas
                [e ]Private practice, Austin, Texas
                Author notes
                []Correspondence to: William M. Ramsdell, MD, 102 Westlake Dr #100, Austin, TX 78746.102 Westlake Dr #100AustinTX78746 wmr@ 123456centexderm.com
                Article
                S2352-5126(16)30016-9
                10.1016/j.jdcr.2016.03.014
                4885148
                27274535
                3851106d-dcf5-4d5f-9108-447ee732a65e
                © 2016 by the American Academy of Dermatology, Inc. Published by Elsevier, Inc.

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                Categories
                Case Report

                birt-hogg-dubé,folliculin,genodermatoses,koenen's tumor,mammalian target of rapamycin,periungual angiofibroma,tuberous sclerosis,bhd, birt-hogg-dubé syndrome,flcn, folliculin,mtor, mammalian target of rapamycin,ts, tuberous sclerosis complex

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