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Birt–Hogg–Dubé Syndrome: A Review of Dermatological Manifestations and Other Symptoms

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Abstract

Birt–Hogg–Dubé syndrome (BHD) is an autosomal dominant genodermatosis with malignant potential characterized by cutaneous and extracutaneous stigmata. Aberrations in the folliculin (FLCN) gene, which is located on chromosome 17, have been discovered in individuals with this condition. Over 150 unique mutations have been identified in BHD. The skin lesions associated with this condition include fibrofolliculomas, trichodiscomas, perifollicular fibromas, and acrochordons. Extracutaneous features of the syndrome typically include the lung (spontaneous pneumothorax and cysts) and the kidney (neoplasms). The only malignancies associated with BHD are renal cancers; however, other tumors have been observed in individuals with BHD. In this article, the skin lesions associated with this condition are reviewed, lung and renal manifestations associated with this syndrome are presented, and malignancies occurring in these patients are summarized.

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References

  1. Birt AR, Hogg GR, Dubé WJ. Hereditary multiple fibrofolliculomas with trichodiscomas and acrochordons. Arch Dermatol. 1977;113(12):1674–7.

    Article  CAS  PubMed  Google Scholar 

  2. Schaffer JV, Gohara MA, McNiff JM, Aasi SZ, Dvoretzky I. Multiple facial angiofibromas: a cutaneous manifestation of Birt–Hogg–Dubé syndrome. J Am Acad Dermatol. 2005;53(2 Suppl):S108–11.

    Article  PubMed  Google Scholar 

  3. Nickerson ML, Warren MB, Toro JR, Matrosova V, Glenn G, Turner ML, et al. Mutations in a novel gene lead to kidney tumors, lung wall defects, and benign tumors of the hair follicle in patients with the Birt–Hogg–Dubé syndrome. Cancer Cell. 2002;2(2):157–64.

    Article  CAS  PubMed  Google Scholar 

  4. Menko FH, van Steensel MA, Giraud S, Friis-Hansen L, Richard S, Ungari S, et al. Birt–Hogg–Dubé syndrome: diagnosis and management. Lancet Oncol. 2009;10(12):1199–206.

    Article  CAS  PubMed  Google Scholar 

  5. Gupta N, Sunwoo BY, Kotloff RM. Birt–Hogg–Dubé syndrome. Clin Chest Med. 2016;37(3):475–86.

    Article  PubMed  Google Scholar 

  6. Burnier M, Rejsek P. Fibromas sores-cutaneus peripilaries multiples die. Corr Bull Soc Fr Dermatol Syphiligr. 1925;32:46–9.

    Google Scholar 

  7. Burnier M, Rejsek P. Appendix: the original description of perifollicular fibromas (Birt–Hogg–Dubé syndrome). National Center for Biotechnology Information (US); 2009. https://www.ncbi.nlm.nih.gov/books/NBK45327/. Accessed 14 Nov 2016.

  8. Toro JR, Glenn G, Duray P, Darling T, Weirich G, Zbar B, et al. Birt–Hogg–Dubé syndrome: a novel marker of kidney neoplasia. Arch Dermatol. 1999;135(10):1195–202.

    Article  CAS  PubMed  Google Scholar 

  9. Hornstein OP, Knickenberg M. Perifollicular fibromatosis cutis with polyps of the colon—a cutaneo-intestinal syndrome sui generis. Arch Dermatol Res. 1975;253(2):161–75.

    Article  CAS  PubMed  Google Scholar 

  10. Hornstein OP. Generalized dermal perifollicular fibromas with polyps of the colon. Hum Genet. 1976;33(2):193–7.

    Article  CAS  PubMed  Google Scholar 

  11. Happle R. Hornstein–Birt–Hogg–Dubé syndrome: a renaming and reconsideration. Am J Med Genet A. 2012;158A(6):1247–51.

    Article  PubMed  Google Scholar 

  12. Schulz T, Hartschuh W. Birt–Hogg–Dubé-syndrome and Hornstein–Knickenberg-syndrome are the same. Different sectioning technique as the cause of different histology. J Cutan Pathol. 1999;26(1):55–61.

    Article  CAS  PubMed  Google Scholar 

  13. Skolnik K, Tsai WH, Dornan K, Perrier R, Burrowes PW, Davidson WJ. Birt–Hogg–Dubé syndrome: a large single family cohort. Respir Res. 2016;17:22.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  14. Schmidt LS, Linehan WM. Molecular genetics and clinical features of Birt–Hogg–Dubé-syndrome. Nat Rev Urol. 2015;12(10):558.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Nikolaidou C, Moscarella E, Longo C, Rosato S, Cavazza A, Piana S. Multiple angiomatous nodules: a novel skin tumor in Birt–Hogg–Dubé syndrome. J Cutan Pathol. 2016;43(12):1197–202.

    Article  CAS  PubMed  Google Scholar 

  16. Toro JR. Birt–Hogg–Dubé syndrome. In: Pagon RA, Adam MP, Ardinger HH, Wallace SE, Amemiya A, Bean LJ, et al., editors. GeneReviews®. Seattle: University of Washington, Seattle; 2006. http://www.ncbi.nlm.nih.gov/books/NBK1522/. Accessed 21 Dec 2016.

  17. Furuya M, Yao M, Tanaka R, Nagashima Y, Kuroda N, Hasumi H, et al. Genetic, epidemiologic and clinicopathologic studies of Japanese Asian patients with Birt–Hogg–Dubé syndrome. Clin Genet. 2016;90(5):403–12.

    Article  CAS  PubMed  Google Scholar 

  18. Toro JR, Wei M-H, Glenn GM, Weinreich M, Toure O, Vocke C, et al. BHD mutations, clinical and molecular genetic investigations of Birt–Hogg–Dubé syndrome: a new series of 50 families and a review of published reports. J Med Genet. 2008;45(6):321–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Aivaz O, Berkman S, Middelton L, Linehan WM, DiGiovanna JJ, Cowen EW. Comedonal and cystic fibrofolliculomas in Birt–Hogg–Dube syndrome. JAMA Dermatol. 2015;151(7):770–4.

    Article  PubMed  Google Scholar 

  20. Gumaste P, Ortiz AE, Patel A, Baron J, Harris R, Barr R. Generalized basaloid follicular hamartoma syndrome: a case report and review of the literature. Am J Dermatopathol. 2015;37(3):e37–40.

    Article  PubMed  Google Scholar 

  21. Kazakov DV. Brooke–Spiegler syndrome and phenotypic variants: an update. Head Neck Pathol. 2016;10(2):125–30.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Potenziani S, Applebaum D, Krishnan B, Gutiérrez C, Diwan AH. Multiple clear cell acanthomas and a sebaceous lymphadenoma presenting in a patient with Cowden syndrome—a case report. J Cutan Pathol. 2017;44(1):79–82.

    Article  PubMed  Google Scholar 

  23. Vashi N, Hunt R, Fischer M, Meehan S, Pomeranz MK. Angiofibromas in multiple endocrine neoplasia type 1. Dermatol Online J. 2012;18(12):20.

    PubMed  Google Scholar 

  24. Saggini A, Brandi ML. Skin lesions in hereditary endocrine tumor syndromes. Endocr Pract. 2011;17(Suppl 3):47–57.

    Article  PubMed  Google Scholar 

  25. Starink TM, Houweling AC, van Doorn MBA, Leter EM, Jaspars EH, van Moorselaar RJA, et al. Familial multiple discoid fibromas: a look-alike of Birt–Hogg–Dubé syndrome not linked to the FLCN locus. J Am Acad Dermatol. 2012;66(2):259.e1-9.

  26. Mintsoulis D, Beecker J. Muir-Torre syndrome. CMAJ. 2016;188(5):E95.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Cohen PR. Segmental neurofibromatosis and cancer: report of triple malignancy in a woman with mosaic neurofibromatosis 1 and review of neoplasms in segmental neurofibromatosis. Dermatol Online J. 2016;22(7):8.

    Google Scholar 

  28. MalaCards. Rombo syndrome. http://www.malacards.org/card/rombo_syndrome. Accessed 30 Dec 2016.

  29. Northrup H, Krueger DA, International Tuberous Sclerosis Complex Consensus Group. Tuberous sclerosis complex diagnostic criteria update: recommendations of the 2012 International Tuberous Sclerosis Complex Consensus Conference. Pediatr Neurol. 2013;49(4):243–54.

    Article  PubMed  PubMed Central  Google Scholar 

  30. De la Torre C, Ocampo C, Doval IG, Losada A, Cruces MJ. Acrochordons are not a component of the Birt–Hogg–Dubé syndrome: does this syndrome exist? Case reports and review of the literature. Am J Dermatopathol. 1999;21(4):369–74.

    Article  PubMed  Google Scholar 

  31. Vincent A, Farley M, Chan E, James WD. Birt–Hogg–Dubé syndrome: a review of the literature and the differential diagnosis of firm facial papules. J Am Acad Dermatol. 2003;49(4):698–705.

    Article  PubMed  Google Scholar 

  32. Steffen C, Ackerman AB. Fibrofolliculoma, trichodiscoma and Birt–Hogg–Dubé syndrome. Neoplasms Sebaceous Differ. Philadelphia: Lea & Febiger; 1994. pp. 205–37.

  33. Toro JR, Pautler SE, Stewart L, Glenn GM, Weinreich M, Toure O, et al. Lung cysts, spontaneous pneumothorax, and genetic associations in 89 families with Birt–Hogg–Dubé syndrome. Am J Respir Crit Care Med. 2007;175(10):1044–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Murakami Y, Wataya-Kaneda M, Tanaka M, Takahashi A, Tsujimura A, Inoue K, et al. Two Japanese cases of Birt–Hogg–Dubé syndrome with pulmonary cysts, fibrofolliculomas, and renal cell carcinomas. Case Rep Dermatol. 2014;6(1):20–8.

    Article  PubMed  PubMed Central  Google Scholar 

  35. Balus L, Crovato F, Breathnach AS. Familial multiple trichodiscomas. J Am Acad Dermatol. 1986;15(4):603–7.

    Article  CAS  PubMed  Google Scholar 

  36. Nam J-H, Min JH, Lee G-Y, Kim W-S. A case of perifollicular fibroma. Ann Dermatol. 2011;23(2):236.

    Article  PubMed  PubMed Central  Google Scholar 

  37. Palmirotta R, Savonarola A, Ludovici G, Donati P, Cavaliere F, Marchis MLD, et al. Association between Birt Hogg Dubé syndrome and cancer predisposition. Anticancer Res. 2010;30(3):751–7.

    CAS  PubMed  Google Scholar 

  38. Gillott M, Flemming B, Ravenel JG. Imaging of cystic lung disease. Semin Roentgenol. 2015;50(1):23–30.

    Article  PubMed  Google Scholar 

  39. Kumasaka T, Hayashi T, Mitani K, Kataoka H, Kikkawa M, Tobino K, et al. Characterization of pulmonary cysts in Birt–Hogg–Dubé syndrome: histopathological and morphometric analysis of 229 pulmonary cysts from 50 unrelated patients. Histopathology. 2014;65(1):100–10.

    Article  PubMed  PubMed Central  Google Scholar 

  40. Ayo DS, Aughenbaugh GL, Yi ES, Hand JL, Ryu JH. Cystic lung disease in Birt–Hogg–Dube syndrome. Chest. 2007;132(2):679–84.

    Article  PubMed  Google Scholar 

  41. Furuya M, Tanaka R, Koga S, Yatabe Y, Gotoda H, Takagi S, et al. Pulmonary cysts of Birt–Hogg–Dubé syndrome: a clinicopathologic and immunohistochemical study of 9 families. Am J Surg Pathol. 2012;36(4):589–600.

    Article  PubMed  Google Scholar 

  42. Tomassetti S, Carloni A, Chilosi M, Maffè A, Ungari S, Sverzellati N, et al. Pulmonary features of Birt–Hogg–Dubé syndrome: cystic lesions and pulmonary histiocytoma. Respir Med. 2011;105(5):768–74.

    Article  CAS  PubMed  Google Scholar 

  43. Hoshika Y, Takahashi F, Togo S, Hashimoto M, Nara T, Kobayashi T, et al. Haploinsufficiency of the folliculin gene leads to impaired functions of lung fibroblasts in patients with Birt–Hogg–Dubé syndrome. Physiol Rep. 2016;4(21):e13025.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  44. Furuya M, Tanaka R, Okudela K, Nakamura S, Yoshioka H, Tsuzuki T, et al. Pulmonary neoplasms in patients with Birt–Hogg–Dubé syndrome: histopathological features and genetic and somatic events. PLoS One. 2016;11(3):e0151476.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  45. Gupta N, Kopras EJ, Henske EP, James LE, El-Chemaly S, Veeraraghavan S, et al. Spontaneous pneumothoraces in patients with Birt–Hogg–Dubé syndrome. Ann Am Thorac Soc. 2017;14(5):706–13.

    Article  PubMed  Google Scholar 

  46. Minnis P, Riddell P, Keane MP. A rare cause of cystic lung disease—Birt–Hogg–Dubé syndrome. Respir Med Case Rep. 2016;18:90–2.

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Kunogi M, Kurihara M, Ikegami TS, Kobayashi T, Shindo N, Kumasaka T, et al. Clinical and genetic spectrum of Birt–Hogg–Dube syndrome patients in whom pneumothorax and/or multiple lung cysts are the presenting feature. J Med Genet. 2010;47(4):281–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Burkett A, Coffey N, Tomiak E, Voduc N. Recurrent spontaneous pneumothoraces and bullous emphysema. A novel mutation causing Birt–Hogg–Dube syndrome. Respir Med Case Rep. 2016;19:106–8.

    PubMed  PubMed Central  Google Scholar 

  49. Zbar B, Alvord WG, Glenn G, Turner M, Pavlovich CP, Schmidt L, et al. Risk of renal and colonic neoplasms and spontaneous pneumothorax in the Birt–Hogg–Dubé syndrome. Cancer Epidemiol Biomark Prev. 2002;11(4):393–400.

    Google Scholar 

  50. Houweling AC, Gijezen LM, Jonker MA, van Doorn MBA, Oldenburg RA, van Spaendonck-Zwarts KY, et al. Renal cancer and pneumothorax risk in Birt–Hogg–Dubé syndrome; an analysis of 115 FLCN mutation carriers from 35 BHD families. Br J Cancer. 2011;105(12):1912–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Pavlovich CP, Walther MM, Eyler RA, Hewitt SM, Zbar B, Linehan WM, et al. Renal tumors in the Birt–Hogg–Dubé syndrome. Am J Surg Pathol. 2002;26(12):1542–52.

    Article  PubMed  Google Scholar 

  52. Pavlovich CP, Grubb RL, Hurley K, Glenn GM, Toro J, Schmidt LS, et al. Evaluation and management of renal tumors in the Birt–Hogg–Dubé syndrome. J Urol. 2005;173(5):1482–6.

    Article  PubMed  Google Scholar 

  53. Benusiglio PR, Giraud S, Deveaux S, Méjean A, Correas J-M, Joly D, et al. French National Cancer Institute Inherited Predisposition to Kidney Cancer Network. Renal cell tumour characteristics in patients with the Birt–Hogg–Dubé cancer susceptibility syndrome: a retrospective, multicentre study. Orphanet J Rare Dis. 2014;9:163.

    Article  PubMed  PubMed Central  Google Scholar 

  54. Schmidt LS, Nickerson ML, Warren MB, Glenn GM, Toro JR, Merino MJ, et al. Germline BHD-mutation spectrum and phenotype analysis of a large cohort of families with Birt–Hogg–Dubé syndrome. Am J Hum Genet. 2005;76(6):1023–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Raymond VM, Long JM, Everett JN, Caoili EM, Gruber SB, Stoffel EM, et al. An oncocytic adrenal tumour in a patient with Birt–Hogg–Dubé syndrome. Clin Endocrinol (Oxf). 2014;80(6):925–7.

    Article  Google Scholar 

  56. Leter EM, Koopmans AK, Gille JJP, van Os TAM, Vittoz GG, David EFL, et al. Birt–Hogg–Dubé syndrome: clinical and genetic studies of 20 families. J Invest Dermatol. 2008;128(1):45–9.

    Article  CAS  PubMed  Google Scholar 

  57. DiCicco B, Johnson W, Allred J, Soldano AC, Ramsdell WM. 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. JAAD Case Rep. 2016;2(3):196–8.

    Article  PubMed  PubMed Central  Google Scholar 

  58. Chung JY, Ramos-Caro FA, Beers B, Ford MJ, Flowers F. Multiple lipomas, angiolipomas, and parathyroid adenomas in a patient with Birt–Hogg–Dube syndrome. Int J Dermatol. 1996;35(5):365–7.

    Article  CAS  PubMed  Google Scholar 

  59. Jaster A, Wachsmann J. Serendipitous discovery of peritoneal mesothelioma. Proc Bayl Univ Med Cent. 2016;29(2):185–7.

    Article  PubMed  PubMed Central  Google Scholar 

  60. Kasi PM, Dearmond DT. Birt–Hogg–Dubé syndrome: answering questions raised by a case report published in 1962. Case Rep Oncol. 2011;4(2):363–6.

    Article  PubMed  PubMed Central  Google Scholar 

  61. Imada K, Dainichi T, Yokomizo A, Tsunoda T, Song YH, Nagasaki A, et al. Birt–Hogg–Dubé syndrome with clear-cell and oncocytic renal tumour and trichoblastoma associated with a novel FLCN mutation. Br J Dermatol. 2009;160(6):1350–3.

    Article  CAS  PubMed  Google Scholar 

  62. Martínez-Pérez A, Santos-Alarcón S, Armañanzas-Villena E, Soriano-Camacho P. Birt–Hogg–Dubé syndrome and colon polyps. Rev Gastroenterol Mex. 2016;81(1):53–4.

    PubMed  Google Scholar 

  63. Dodds T, Delprado W, Meagher A, Tucker K, Earls P. Colorectal carcinoma with an oncocytic component occurring in a patient with Birt–Hogg–Dubé syndrome. Pathology. 2016;48(3):283–4.

    Article  PubMed  Google Scholar 

  64. Spring P, Fellmann F, Giraud S, Clayton H, Hohl D. Syndrome of Birt–Hogg–Dubé, a histopathological pitfall with similarities to tuberous sclerosis: a report of three cases. Am J Dermatopathol. 2013;35(2):241–5.

    Article  PubMed  Google Scholar 

  65. Kluger N, Giraud S, Coupier I, Avril M-F, Dereure O, Guillot B, et al. Birt–Hogg–Dubé syndrome: clinical and genetic studies of 10 French families. Br J Dermatol. 2010;162(3):527–37.

    Article  CAS  PubMed  Google Scholar 

  66. Ishii H, Oka H, Amemiya Y, Iwata A, Otani S, Kishi K, et al. A Japanese family with multiple lung cysts and recurrent pneumothorax: a possibility of Birt–Hogg–Dubé syndrome. Intern Med Tokyo Jpn. 2009;48(16):1413–7.

    Article  Google Scholar 

  67. Khoo SK, Giraud S, Kahnoski K, Chen J, Motorna O, Nickolov R, et al. Clinical and genetic studies of Birt–Hogg–Dubé syndrome. J Med Genet. 2002;39(12):906–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Liu V, Kwan T, Page EH. Parotid oncocytoma in the Birt–Hogg–Dubé syndrome. J Am Acad Dermatol. 2000;43(6):1120–2.

    Article  CAS  PubMed  Google Scholar 

  69. Whitworth J, Stausbøl-Grøn B, Skytte A-B. Genetically diagnosed Birt–Hogg–Dubé syndrome and familial cerebral cavernous malformations in the same individual: a case report. Fam Cancer. 2017;16:139–42.

    Article  PubMed  Google Scholar 

  70. Benusiglio PR, Gad S, Massard C, Carton E, Longchampt E, Faudot T, et al. Case report: expanding the tumour spectrum associated with the Birt–Hogg–Dubé cancer susceptibility syndrome. F1000Res. 2014;3:159.

  71. Pérez García L, Antón Miguel MÁ, Fuentes Gómez CR. Medullary thyroid carcinoma in a patient with Birt–Hogg–Dube syndrome. Med Clin (Barc). 2017;148(11):528–9.

    Article  Google Scholar 

  72. Dong L, Gao M, Hao W-J, Zheng X-Q, Li Y-G, Li X-L, et al. Case report of Birt–Hogg–Dubé syndrome: germline mutations of FLCN detected in patients with renal cancer and thyroid cancer. Medicine (Baltimore). 2016;95(22):e3695.

    Article  CAS  Google Scholar 

  73. Lindor NM, Kasperbauer J, Lewis JE, Pittelkow M. Birt–Hogg–Dube syndrome presenting as multiple oncocytic parotid tumors. Hered Cancer Clin Pract. 2012;10(1):13.

    Article  PubMed  PubMed Central  Google Scholar 

  74. Graham RB, Nolasco M, Peterlin B, Garcia CK. Nonsense mutations in folliculin presenting as isolated familial spontaneous pneumothorax in adults. Am J Respir Crit Care Med. 2005;172(1):39–44.

    Article  PubMed  Google Scholar 

  75. Frantzen B, Rose C, Schulz T, Bröcker EB, Hamm H. Hornstein–Knickenberg and Birt–Hogg–Dube syndrome. Report of a case with spontaneous pneumothorax and aplasia of the left internal carotid artery [in German]. Hautarzt. 2001;52(11):1016–20.

    Article  CAS  PubMed  Google Scholar 

  76. Mikesell KV, Kulaylat AN, Donaldson KJ, Saunders BD, Crist HS. A rare soft tissue tumor masquerading as a parathyroid adenoma in a patient with Birt–Hogg–Dubé syndrome and multiple cervical endocrinopathies. Case Rep Pathol. 2014;2014:753694.

    PubMed  PubMed Central  Google Scholar 

  77. Fontcuberta IC, Salomão DR, Quiram PA, Pulido JS. Choroidal melanoma and lid fibrofoliculomas in Birt–Hogg–Dubé syndrome. Ophthalmic Genet. 2011;32(3):143–6.

    Article  PubMed  Google Scholar 

  78. Renfree KJ, Lawless KL. Multiple neurilemmomas in Birt–Hogg–Dubé syndrome: case report. J Hand Surg. 2012;37(4):792–4.

    Article  Google Scholar 

  79. De Keyzer L, De Leenheer EMR, Claes K, Janssens S. A vestibular schwannoma in a patient with Birt–Hogg–Dube syndrome. Genet Couns. 2014;25(2):203–8.

    PubMed  Google Scholar 

  80. Nishida C, Yatera K, Yamasaki K, Torii R, Kawanami Y, Kawanami T, et al. Possible familial case of Birt–Hogg–Dubé syndrome complicated with lung cancer: a possible link between these two disease entities. Respir Med. 2015;109(7):923–5.

    Article  PubMed  Google Scholar 

  81. Gunji-Niitsu Y, Kumasaka T, Kitamura S, Hoshika Y, Hayashi T, Tokuda H, et al. Benign clear cell “sugar” tumor of the lung in a patient with Birt–Hogg–Dubé syndrome: a case report. BMC Med Genet. 2016;17(1):85.

    Article  PubMed  PubMed Central  Google Scholar 

  82. Dow E, Winship I. Renal angiomyolipoma in Birt–Hogg–Dube syndrome: a case study supporting overlap with tuberous sclerosis complex. Am J Med Genet A. 2016;170(12):3323–6.

    Article  CAS  PubMed  Google Scholar 

  83. Claessens T, Weppler SA, van Geel M, Creytens D, Vreeburg M, Wouters B, et al. Neuroendocrine carcinoma in a patient with Birt–Hogg–Dubé syndrome. Nat Rev Urol. 2010;7(10):583–7.

    Article  PubMed  Google Scholar 

  84. Furuya M, Hong S-B, Tanaka R, Kuroda N, Nagashima Y, Nagahama K, et al. Distinctive expression patterns of glycoprotein non-metastatic B and folliculin in renal tumors in patients with Birt–Hogg–Dubé syndrome. Cancer Sci. 2015;106(3):315–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Maffé A, Toschi B, Circo G, Giachino D, Giglio S, Rizzo A, et al. Constitutional FLCN mutations in patients with suspected Birt–Hogg–Dubé syndrome ascertained for non-cutaneous manifestations. Clin Genet. 2011;79(4):345–54.

    Article  PubMed  CAS  Google Scholar 

  86. Cohen PR, Kurzrock R. Miscellaneous genodermatoses: Beckwith–Wiedemann syndrome, Birt–Hogg–Dube syndrome, familial atypical multiple mole melanoma syndrome, hereditary tylosis, incontinentia pigmenti, and supernumerary nipples. Dermatol Clin. 1995;13(1):211–29.

    CAS  PubMed  Google Scholar 

  87. Park G, Kim HR, Na CH, Choi KC, Shin BS. Genetic study in a case of Birt–Hogg–Dubé syndrome. Ann Dermatol. 2011;23(Suppl 2):S188–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Vernooij M, Claessens T, Luijten M, van Steensel MAM, Coull BJ. Birt–Hogg–Dubé syndrome and the skin. Fam Cancer. 2013;12(3):381–5.

    Article  PubMed  Google Scholar 

  89. Kahle B, Hellwig S, Schulz T. Multiple mantleomas in Birt–Hogg–Dubé syndrome: successful therapy with CO2 laser (in German). Hautarzt. 2001;52(1):43–6.

    Article  CAS  PubMed  Google Scholar 

  90. Fujita WH, Barr RJ, Headley JL. Multiple fibrofolliculomas with trichodiscomas and acrochordons. Arch Dermatol. 1981;117(1):32–5.

    Article  CAS  PubMed  Google Scholar 

  91. Pinkus H, Coskey R, Burgess GH. Trichodiscoma. A benign tumor related to haarscheibe (hair disk). J Invest Dermatol. 1974;63(2):212–8.

    Article  CAS  PubMed  Google Scholar 

  92. Starink TM, Kisch LS, Meijer CJ. Familial multiple trichodiscomas. A clinicopathologic study. Arch Dermatol. 1985;121(7):888–91.

    Article  CAS  PubMed  Google Scholar 

  93. Collins GL, Somach S, Morgan MB. Histomorphologic and immunophenotypic analysis of fibrofolliculomas and trichodiscomas in Birt–Hogg–Dube syndrome and sporadic disease. J Cutan Pathol. 2002;29(9):529–33.

    Article  PubMed  Google Scholar 

  94. Reese E, Sluzevich J, Kluijt I, Teertstra HJ, De Jong D, Horenblas S, et al. Birt–Hogg–Dubé syndrome. In: Riegert-Johnson DL, Boardman LA, Hefferon T, Roberts M, editors. Cancer syndromes. Bethesda: National Center for Biotechnology Information (US); 2009. http://www.ncbi.nlm.nih.gov/books/NBK45326/. Accessed 12 Dec 2016.

  95. Balus L, Fazio M, Sacerdoti G, Morrone A, Marmo W. Fibrofolliculoma, trichodiscoma and acrochordon. The Birt–Hogg–Dubé syndrome [in French]. Ann Dermatol Venereol. 1983;110(8):601–9.

    CAS  PubMed  Google Scholar 

  96. Kacerovska D, Michal M, Kazakov DV. Trichodiscoma with lipomatous metaplasia and pleomorphic stromal cells. J Cutan Pathol. 2010;37(10):1110–1.

    Article  PubMed  Google Scholar 

  97. Starink TM, Brownstein MH. Fibrofolliculoma: solitary and multiple types. J Am Acad Dermatol. 1987;17(3):493–6.

    Article  CAS  PubMed  Google Scholar 

  98. Junkins-Hopkins JM, Cooper PH. Multiple perifollicular fibromas: report of a case and analysis of the literature. J Cutan Pathol. 1994;21(5):467–71.

    Article  CAS  PubMed  Google Scholar 

  99. Misago N, Kimura T, Narisawa Y. Fibrofolliculoma/trichodiscoma and fibrous papule (perifollicular fibroma/angiofibroma): a revaluation of the histopathological and immunohistochemical features. J Cutan Pathol. 2009;36(9):943–51.

    Article  PubMed  Google Scholar 

  100. Godbolt AM, Robertson IM, Weedon D. Birt–Hogg–Dubé syndrome. Aust J Dermatol. 2003;44(1):52–6.

    Article  Google Scholar 

  101. Welsch MJ, Krunic A, Medenica MM. Birt–Hogg–Dubé syndrome. Int J Dermatol. 2005;44(8):668–73.

    Article  PubMed  Google Scholar 

  102. Vocke CD, Yang Y, Pavlovich CP, Schmidt LS, Nickerson ML, Torres-Cabala CA, et al. High frequency of somatic frameshift BHD gene mutations in Birt–Hogg–Dubé-associated renal tumors. J Natl Cancer Inst. 2005;97(12):931–5.

    Article  CAS  PubMed  Google Scholar 

  103. van Steensel MAM, Verstraeten VLRM, Frank J, Kelleners-Smeets NWJ, Poblete-Gutiérrez P, Marcus-Soekarman D, et al. Novel mutations in the BHD gene and absence of loss of heterozygosity in fibrofolliculomas of Birt–Hogg–Dubé patients. J Invest Dermatol. 2007;127(3):588–93.

    Article  PubMed  CAS  Google Scholar 

  104. Warren MB, Torres-Cabala CA, Turner ML, Merino MJ, Matrosova VY, Nickerson ML, et al. Expression of Birt–Hogg–Dubé gene mRNA in normal and neoplastic human tissues. Mod Pathol. 2004;17(8):998–1011.

    Article  CAS  PubMed  Google Scholar 

  105. Luijten MNH, Basten SG, Claessens T, Vernooij M, Scott CL, Janssen R, et al. Birt–Hogg–Dube syndrome is a novel ciliopathy. Hum Mol Genet. 2013;22(21):4383–97.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Zhong M, Zhao X, Li J, Yuan W, Yan G, Tong M, et al. Tumor suppressor folliculin regulates mTORC1 through primary cilia. J Biol Chem. 2016;291(22):11689–97.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Baba M, Hong S-B, Sharma N, Warren MB, Nickerson ML, Iwamatsu A, et al. Folliculin encoded by the BHD gene interacts with a binding protein, FNIP1, and AMPK, and is involved in AMPK and mTOR signaling. Proc Natl Acad Sci USA. 2006;103(42):15552–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Hasumi H, Baba M, Hong S-B, Hasumi Y, Huang Y, Yao M, et al. Identification and characterization of a novel folliculin-interacting protein FNIP2. Gene. 2008;415(1–2):60–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Yan M, Gingras M-C, Dunlop EA, Nouët Y, Dupuy F, Jalali Z, et al. The tumor suppressor folliculin regulates AMPK-dependent metabolic transformation. J Clin Invest. 2014;124(6):2640–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. van Slegtenhorst M, Khabibullin D, Hartman TR, Nicolas E, Kruger WD, Henske EP. The Birt-Hogg-Dube and tuberous sclerosis complex homologs have opposing roles in amino acid homeostasis in Schizosaccharomyces pombe. J Biol Chem. 2007;282(34):24583–90.

    Article  PubMed  CAS  Google Scholar 

  111. Hartman TR, Nicolas E, Klein-Szanto A, Al-Saleem T, Cash TP, Simon MC, et al. The role of the Birt–Hogg–Dubé protein in mTOR activation and renal tumorigenesis. Oncogene. 2009;28(13):1594–604.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Hasumi Y, Baba M, Ajima R, Hasumi H, Valera VA, Klein ME, et al. Homozygous loss of BHD causes early embryonic lethality and kidney tumor development with activation of mTORC1 and mTORC2. Proc Natl Acad Sci USA. 2009;106(44):18722–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Baba M, Furihata M, Hong S-B, Tessarollo L, Haines DC, Southon E, et al. Kidney-targeted Birt-Hogg-Dube gene inactivation in a mouse model: Erk1/2 and Akt-mTOR activation, cell hyperproliferation, and polycystic kidneys. J Natl Cancer Inst. 2008;100(2):140–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Togashi Y, Kobayashi T, Momose S, Ueda M, Okimoto K, Hino O. Transgenic rescue from embryonic lethality and renal carcinogenesis in the Nihon rat model by introduction of a wild-type Bhd gene. Oncogene. 2005;25(20):2885–9.

    Article  CAS  Google Scholar 

  115. Hong S-B, Oh H, Valera VA, Stull J, Ngo D-T, Baba M, et al. Tumor suppressor FLCN inhibits tumorigenesis of a FLCN-null renal cancer cell line and regulates expression of key molecules in TGF-beta signaling. Mol Cancer. 2010;9:160.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  116. Nahorski MS, Lim DHK, Martin L, Gille JJP, McKay K, Rehal PK, et al. Investigation of the Birt–Hogg–Dube tumour suppressor gene (FLCN) in familial and sporadic colorectal cancer. J Med Genet. 2010;47(6):385–90.

    Article  CAS  PubMed  Google Scholar 

  117. Johannesma PC, van den Borne BEEM, Gille JJP, Nagelkerke AF, van Waesberghe JTM, Paul MA, et al. Spontaneous pneumothorax as indicator for Birt–Hogg–Dubé syndrome in paediatric patients. BMC Pediatr. 2014;14:171.

    Article  PubMed  PubMed Central  Google Scholar 

  118. Raoof S, Bondalapati P, Vydyula R, Ryu JH, Gupta N, Raoof S, et al. Cystic lung diseases: algorithmic approach. Chest. 2016;150(4):945–65.

    Article  PubMed  Google Scholar 

  119. Gupta N, Vassallo R, Wikenheiser-Brokamp KA, McCormack FX. Diffuse cystic lung disease. Part I. Am J Respir Crit Care Med. 2015;191(12):1354–66.

    Article  PubMed  PubMed Central  Google Scholar 

  120. Gupta N, Vassallo R, Wikenheiser-Brokamp KA, McCormack FX. Diffuse cystic lung disease. Part II. Am J Respir Crit Care Med. 2015;192(1):17–29.

    Article  PubMed  PubMed Central  Google Scholar 

  121. Gupta N, Langenderfer D, McCormack FX, Schauer DP, Eckman MH. Chest computed tomographic image screening for cystic lung diseases in patients with spontaneous pneumothorax is cost-effective. Ann Am Thorac Soc. 2017;14(1):17–25.

    Article  PubMed  PubMed Central  Google Scholar 

  122. Stamatakis L, Metwalli AR, Middelton LA, Marston LW. Diagnosis and management of BHD-associated kidney cancer. Fam Cancer. 2013;12(3):397–402.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Tobino K, Seyama K. Birt–Hogg–Dubé syndrome with renal angiomyolipoma. Intern Med Tokyo Jpn. 2012;51(10):1279–80.

    Article  Google Scholar 

  124. Schmidt LS, Linehan WM. Clinical features, genetics and potential therapeutic approaches for Birt–Hogg–Dubé syndrome. Expert Opin Orphan Drug. 2015;3(1):15–29.

    Article  CAS  Google Scholar 

  125. Pritchard SE, Mahmoudizad R, Parekh PK. Successful treatment of facial papules with electrodessication in a patient with Birt–Hogg–Dubé syndrome. Dermatol Online J. 2014;20(7):13.

    Google Scholar 

  126. Farrant PBJ, Emerson R. Letter: hyfrecation and curettage as a treatment for fibrofolliculomas in Birt–Hogg–Dube syndrome. Dermatol Surg. 2007;33(10):1287–8.

    CAS  PubMed  Google Scholar 

  127. Jacob CI, Dover JS. Birt–Hogg–Dube syndrome: treatment of cutaneous manifestations with laser skin resurfacing. Arch Dermatol. 2001;137(1):98–9.

    CAS  PubMed  Google Scholar 

  128. Gambichler T, Wolter M, Altmeyer P, Hoffman K. Treatment of Birt–Hogg–Dubé syndrome with erbium:YAG laser. J Am Acad Dermatol. 2000;43(5 Pt 1):856–8.

    Article  CAS  PubMed  Google Scholar 

  129. Gijezen LMC, Vernooij M, Martens H, Oduber CEU, Henquet CJM, Starink TM, et al. Topical rapamycin as a treatment for fibrofolliculomas in Birt–Hogg–Dubé syndrome: a double-blind placebo-controlled randomized split-face trial. PLoS One. 2014;9(6):e99071.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  130. Okada A, Hirono T, Watanabe T, Hasegawa G, Tanaka R, Furuya M. Partial pleural covering for intractable pneumothorax in patients with Birt–Hogg–Dubé Syndrome. Clin Respir J. 2017;11(2):224–9.

    Article  CAS  PubMed  Google Scholar 

  131. Hasumi H, Baba M, Hasumi Y, Furuya M, Yao M. Birt–Hogg–Dubé syndrome: clinical and molecular aspects of recently identified kidney cancer syndrome. Int J Urol. 2016;23(3):204–10.

    Article  CAS  PubMed  Google Scholar 

  132. Nakamura M, Yao M, Sano F, Sakata R, Tatenuma T, Makiyama K, et al. A case of metastatic renal cell carcinoma associated with Birt–Hogg–Dubé syndrome treated with molecular-targeting agents [in Japanese]. Hinyokika Kiyo. 2013;59(8):503–6.

    PubMed  Google Scholar 

  133. Rossing M, Albrechtsen A, Skytte A-B, Jensen UB, Ousager LB, Gerdes A-M, et al. Genetic screening of the FLCN gene identify six novel variants and a Danish founder mutation. J Hum Genet. 2017;62(2):151–7.

    Article  CAS  PubMed  Google Scholar 

  134. Middelton LA. Birt–Hogg–Dubé: beyond the clinical manifestations. Fam Cancer. 2013;12(1):97–9.

    Article  PubMed  PubMed Central  Google Scholar 

  135. Johannesma PC, van de Beek I, van der Wel JWT, Paul MA, Houweling AC, Jonker MA, et al. Risk of spontaneous pneumothorax due to air travel and diving in patients with Birt–Hogg–Dubé syndrome. Springerplus. 2016;5(1):1506.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Tobino K, Hirai T, Johkoh T, Kurihara M, Fujimoto K, Tomiyama N, et al. Differentiation between Birt–Hogg–Dubé syndrome and lymphangioleiomyomatosis: quantitative analysis of pulmonary cysts on computed tomography of the chest in 66 females. Eur J Radiol. 2012;81(6):1340–6.

    Article  PubMed  Google Scholar 

  137. Ebana H, Otsuji M, Mizobuchi T, Kurihara M, Takahashi K, Seyama K. Pleural covering application for recurrent pneumothorax in a patient with Birt–Hogg–Dubé syndrome. Ann Thorac Cardiovasc Surg. 2016;22(3):189–92.

    Article  PubMed  Google Scholar 

  138. Tellechea O, Cardoso JC, Reis JP, Ramos L, Gameiro AR, Coutinho I, et al. Benign follicular tumors. An Br Dermatol. 2015;90(6):780–98.

    Article  Google Scholar 

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Authors and Affiliations

  1. Department of Dermatology, University of California San Diego, 8899 University Center Lane, Suite 350, San Diego, CA, 92122, USA

    Yun Tong, Jeremy A. Schneider, Tissa R. Hata & Philip R. Cohen

  2. Scripps Health, La Jolla, CA, USA

    Alvin B. Coda

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Tong, Y., Schneider, J.A., Coda, A.B. et al. Birt–Hogg–Dubé Syndrome: A Review of Dermatological Manifestations and Other Symptoms. Am J Clin Dermatol 19, 87–101 (2018). https://doi.org/10.1007/s40257-017-0307-8

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