Familial Cancer

, Volume 12, Issue 3, pp 387–396 | Cite as

Pulmonary manifestations of Birt-Hogg-Dubé syndrome

  • Nishant GuptaEmail author
  • Kuniaki Seyama
  • Francis X. McCormack
Original Article


Birt-Hogg-Dubé syndrome (BHD) is a rare, autosomal dominant disorder characterized by the development of hair follicle tumors, renal tumors and pulmonary cysts. BHD is caused by heterozygous, predominantly truncating mutations in the folliculin (FLCN) gene located on chromosome 17, which encodes a highly conserved tumor suppressor protein. Although management of renal tumors of low malignant potential is the primary focus of longitudinal care, pulmonary manifestations including cyst formation and spontaneous pneumothorax are among the most common manifestations in BHD. Due to the lack of awareness, there is commonly a delay in the pulmonary diagnosis of BHD and patients are frequently mislabeled as having chronic obstructive lung disease, emphysema or common bullae/blebs. A family history of pneumothorax is present in 35 % of patients with BHD. Certain imaging characteristics of the cysts, including size, basilar and peripheral predominance, perivascular and periseptal localization, and elliptical or lentiform shape can suggest the diagnosis of BHD based on inspection of the chest CT scan alone. Recurrent pneumothoraces are common and early pleurodesis is recommended. A better understanding of role of FLCN in pulmonary cyst formation and long term studies to define the natural history of the pulmonary manifestations of BHD are needed.


Birt-Hogg-Dubé Pneumothorax Pulmonary cysts Folliculin 


Conflict of interest



  1. 1.
    Hornstein OP, Knickenberg M (1975) Perifollicular fibromatosis cutis with polyps of the colon—A cutaneo-intestinal syndrome sui generis. Arch Dermatol Res 253:161–175PubMedCrossRefGoogle Scholar
  2. 2.
    Hornstein OP (1976) Generalized dermal perifollicular fibromas with polyps of the colon. Hum Genet 33:193–197PubMedCrossRefGoogle Scholar
  3. 3.
    Hornstein OP, Knickenberg M, Mörl M (1976) Multiple dermal perifollicular fibromas with polyps of the colon—Report of a peculiar clinical syndrome. Acta Hepatogastroenterol (Stuttg) 23:53–58Google Scholar
  4. 4.
    Birt AR, Hogg GR, Dubé WJ (1977) Hereditary multiple fibrofolliculomas with trichodiscomas and acrochordons. Arch Dermatol 113:1674–1677PubMedCrossRefGoogle Scholar
  5. 5.
    Khoo SK, Bradley M, Wong FK, Hedblad MA, Nordenskjöld M, Teh BT (2001) Birt-Hogg-Dubé syndrome: mapping of a novel hereditary neoplasia gene to chromosome 17p12-q11.2. Oncogene 20:5239–5242PubMedCrossRefGoogle Scholar
  6. 6.
    Schmidt LS, Warren MB, Nickerson ML, Weirich G, Matrosova V, Toro JR, Turner ML, Duray P, Merino M, Hewitt S, Pavlovich CP, Glenn G, Greenberg CR, Linehan WM, Zbar B (2001) Birt-Hogg-Dubé syndrome, a genodermatosis associated with spontaneous pneumothorax and kidney neoplasia, maps to chromosome 17p11.2. Am J Hum Genet 69:876–882PubMedCrossRefGoogle Scholar
  7. 7.
    Nickerson ML, Warren MB, Toro JR, Matrosova V, Glenn G, Turner ML, Duray P, Merino M, Choyke P, Pavlovich CP, Sharma N, Walther M, Munroe D, Hill R, Maher E, Greenberg C, Lerman MI, Linehan WM, Zbar B, Schmidt LS (2002) 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 2:157–164PubMedCrossRefGoogle Scholar
  8. 8.
    Schmidt LS, Nickerson ML, Warren MB, Glenn GM, Toro JR, Merino MJ, Turner ML, Choyke PL, Sharma N, Peterson J, Morrison P, Maher ER, Walther MM, Zbar B, Linehan WM (2005) Germline BHD-mutation spectrum and phenotype analysis of a large cohort of families with Birt-Hogg-Dubé syndrome. Am J Hum Genet 76:1023–1033PubMedCrossRefGoogle Scholar
  9. 9.
    Toro JR, Wei MH, Glenn GM, Weinreich M, Toure O, Vocke C, Turner M, Choyke P, Merino MJ, Pinto PA, Steinberg SM, Schmidt LS, Linehan WM (2008) 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 45:321–331PubMedCrossRefGoogle Scholar
  10. 10.
    Kunogi M, Kurihara M, Ikegami TS, Kobayashi T, Shindo N, Kumasaka T, Gunji Y, Kikkawa M, Iwakami S, Hino O, Takahashi K, Seyama K (2010) 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 Apr 47:281–287Google Scholar
  11. 11.
    Lim DH, Rehal PK, Nahorski MS, Macdonald F, Claessens T, Van Geel M, Gijezen L, Gille JJ, Giraud S, Richard S, van Steensel M, Menko FH, Maher ER (2010) A new locus-specific database (LSDB) for mutations in the folliculin (FLCN) gene. Hum Mutat 1:E1043–E1051CrossRefGoogle Scholar
  12. 12.
    Baba M, Hong SB, Sharma N, Warren MB, Nickerson ML, Iwamatsu A, Esposito D, Gillette WK, Hopkins RF 3rd, Hartley JL, Furihata M, Oishi S, Zhen W, Burke TR Jr, Linehan WM, Schmidt LS, Zbar B (2006) 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 103:15552–15557PubMedCrossRefGoogle Scholar
  13. 13.
    Hasumi H, Baba M, Hong SB, Hasumi Y, Huang Y, Yao M, Valera VA, Linehan WM, Schmidt LS (2008) Identification and characterization of a novel folliculin-interacting protein FNIP2. Gene 415:60–67PubMedCrossRefGoogle Scholar
  14. 14.
    Takagi Y, Kobayashi T, Shiono M, Wang L, Piao X, Sun G, Zhang D, Abe M, Hagiwara Y, Takahashi K, Hino O (2008) Interaction of folliculin (Birt-Hogg-Dubé gene product) with a novel Fnip1-like (FnipL/Fnip2) protein. Oncogene 27:5339–5347PubMedCrossRefGoogle Scholar
  15. 15.
    Baba M, Furihata M, Hong SB, Tessarollo L, Haines DC, Southon E, Patel V, Igarashi P, Alvord WG, Leighty R, Yao M, Bernardo M, Ileva L, Choyke P, Warren MB, Zbar B, Linehan WM, Schmidt LS (2008) 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 100:140–154PubMedCrossRefGoogle Scholar
  16. 16.
    Chen J, Futami K, Petillo D, Peng J, Wang P, Knol J, Li Y, Khoo SK, Huang D, Qian CN, Zhao P, Dykema K, Zhang R, Cao B, Yang XJ, Furge K, Williams BO, Teh BT (2008) Deficiency of FLCN in mouse kidney led to development of polycystic kidneys and renal neoplasia. PLoS One 3:e3581PubMedCrossRefGoogle Scholar
  17. 17.
    van Slegtenhorst M, Khabibullin D, Hartman TR, Nicolas E, Kruger WD, Henske EP (2007) The Birt-Hogg-Dube and tuberous sclerosis complex homologs have opposing roles in amino acid homeostasis in Schizosaccharomyces pombe. J Biol Chem 282:24583–24590PubMedCrossRefGoogle Scholar
  18. 18.
    Hartman TR, Nicolas E, Klein-Szanto A, Al-Saleem T, Cash TP, Simon MC, Henske EP (2009) The role of the Birt-Hogg-Dubé protein in mTOR activation and renal tumorigenesis. Oncogene 28:1594–1604PubMedCrossRefGoogle Scholar
  19. 19.
    Hong SB, Oh H, Valera VA, Stull J, Ngo DT, Baba M, Merino MJ, Linehan WM, Schmidt LS (2010) 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 9:160PubMedCrossRefGoogle Scholar
  20. 20.
    Hong SB, Oh H, Valera VA, Baba M, Schmidt LS, Linehan WM (2010) Inactivation of the FLCN tumor suppressor gene induces TFE3 transcriptional activity by increasing its nuclear localization. PLoS One 5:e15793PubMedCrossRefGoogle Scholar
  21. 21.
    Klomp JA, Petillo D, Niemi NM, Dykema KJ, Chen J, Yang XJ, Sääf A, Zickert P, Aly M, Bergerheim U, Nordenskjöld M, Gad S, Giraud S, Denoux Y, Yonneau L, Méjean A, Vasiliu V, Richard S, MacKeigan JP, Teh BT, Furge KA (2010) Birt-Hogg-Dubé renal tumors are genetically distinct from other renal neoplasias and are associated with up-regulation of mitochondrial gene expression. BMC Med Genomics 3:59PubMedCrossRefGoogle Scholar
  22. 22.
    Hasumi H, Baba M, Hasumi Y, Huang Y, Oh H, Hughes RM, Klein ME, Takikita S, Nagashima K, Schmidt LS, Linehan WM (2012) Regulation of mitochondrial oxidative metabolism by tumor suppressor FLCN. J Natl Cancer Inst 104:1750–1764PubMedCrossRefGoogle Scholar
  23. 23.
    Nookala RK, Langemeyer L, Pacitto A, Ochoa-Montaño B, Donaldson JC, Blaszczyk BK, Chirgadze DY, Barr FA, Bazan JF, Blundell TL (2012) Crystal structure of folliculin reveals a hidDENN function in genetically inherited renal cancer. Open Biol 2:120071PubMedCrossRefGoogle Scholar
  24. 24.
    van Steensel MA, Verstraeten VL, Frank J, Kelleners-Smeets NW, Poblete-Gutiérrez P, Marcus-Soekarman D, Bladergroen RS, Steijlen PM, van Geel M (2007) Novel mutations in the BHD gene and absence of loss of heterozygosity in fibrofolliculomas of Birt-Hogg-Dubé patients. J Invest Dermatol 127:588–593PubMedCrossRefGoogle Scholar
  25. 25.
    Furuya M, Tanaka R, Koga S, Yatabe Y, Gotoda H, Takagi S, Hsu YH, Fujii T, Okada A, Kuroda N, Moritani S, Mizuno H, Nagashima Y, Nagahama K, Hiroshima K, Yoshino I, Nomura F, Aoki I, Nakatani Y (2012) Pulmonary cysts of Birt-Hogg-Dubé syndrome: a clinicopathologic and immunohistochemical study of 9 families. Am J Surg Pathol 36:589–600PubMedCrossRefGoogle Scholar
  26. 26.
    Painter JN, Tapanainen H, Somer M, Tukiainen P, Aittomäki K (2005) A 4-bp deletion in the Birt-Hogg-Dubé gene (FLCN) causes dominantly inherited spontaneous pneumothorax. Am J Hum Genet 76:522–527PubMedCrossRefGoogle Scholar
  27. 27.
    Gunji Y, Akiyoshi T, Sato T, Kurihara M, Tominaga S, Takahashi K, Seyama K (2007) Mutations of the Birt Hogg Dube gene in patients with multiple lung cysts and recurrent pneumothorax. J Med Genet 44:588–593PubMedCrossRefGoogle Scholar
  28. 28.
    Graham RB, Nolasco M, Peterlin B, Garcia CK (2005) Nonsense mutations in folliculin presenting as isolated familial spontaneous pneumothorax in adults. Am J Respir Crit Care Med 172:39–44PubMedCrossRefGoogle Scholar
  29. 29.
    Tomassetti S, Carloni A, Chilosi M, Maffè A, Ungari S, Sverzellati N, Gurioli C, Casoni G, Romagnoli M, Gurioli C, Ravaglia C, Poletti V (2011) Pulmonary features of Birt-Hogg-Dubé syndrome: cystic lesions and pulmonary histiocytoma. Respir Med 105:768–774PubMedCrossRefGoogle Scholar
  30. 30.
    Toro JR, Pautler SE, Stewart L, Glenn GM, Weinreich M, Toure O, Wei MH, Schmidt LS, Davis L, Zbar B, Choyke P, Steinberg SM, Nguyen DM, Linehan WM (2007) Lung cysts, spontaneous pneumothorax, and genetic associations in 89 families with Birt-Hogg-Dubé syndrome. Am J Respir Crit Care Med 175:1044–1053PubMedCrossRefGoogle Scholar
  31. 31.
    Tobino K, Gunji Y, Kurihara M, Kunogi M, Koike K, Tomiyama N, Johkoh T, Kodama Y, Iwakami S, Kikkawa M, Takahashi K, Seyama K (2011) Characteristics of pulmonary cysts in Birt-Hogg-Dubé syndrome: thin-section CT findings of the chest in 12 patients. Eur J Radiol Mar 77:403–409Google Scholar
  32. 32.
    Tobino K, Hirai T, Johkoh T, Kurihara M, Fujimoto K, Tomiyama N, Mishima M, Takahashi K, Seyama K (2012) 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 81:1340–1346PubMedCrossRefGoogle Scholar
  33. 33.
    Butnor KJ, Guinee DG Jr (2006) Pleuropulmonary pathology of Birt-Hogg-Dubé syndrome. Am J Surg Pathol 30:395–399PubMedCrossRefGoogle Scholar
  34. 34.
    Furuya M, Nakatani Y (2012) Birt-Hogg-Dube syndrome: clinicopathological features of the lung. J Clin Pathol Dec 8 (Epub ahead of print)Google Scholar
  35. 35.
    Koga S, Furuya M, Takahashi Y, Tanaka R, Yamaguchi A, Yasufuku K, Hiroshima K, Kurihara M, Yoshino I, Aoki I, Nakatani Y (2009) Lung cysts in Birt-Hogg-Dubé syndrome: histopathological characteristics and aberrant sequence repeats. Pathol Int 59:720–728PubMedCrossRefGoogle Scholar
  36. 36.
    Zbar B, Alvord WG, Glenn G, Turner M, Pavlovich CP, Schmidt L, Walther M, Choyke P, Weirich G, Hewitt SM, Duray P, Gabril F, Greenberg C, Merino MJ, Toro J, Linehan WM (2002) Risk of renal and colonic neoplasms and spontaneous pneumothorax in the Birt-Hogg-Dubé syndrome. Cancer Epidemiol Biomarkers Prev 11:393–400PubMedGoogle Scholar
  37. 37.
    Ayo DS, Aughenbaugh GL, Yi ES, Hand JL, Ryu JH (2007) Cystic lung disease in Birt-Hogg-Dube syndrome. Chest 132:679–684PubMedCrossRefGoogle Scholar
  38. 38.
    Menko FH, van Steensel MA, Giraud S, Friis-Hansen L, Richard S, Ungari S, Nordenskjöld M, Hansen TV, Solly J, Maher ER, European BHD Consortium (2009) Birt-Hogg-Dubé syndrome: diagnosis and management. Lancet Oncol 10:1199–1206PubMedCrossRefGoogle Scholar
  39. 39.
    Young LR, Vandyke R, Gulleman PM, Inoue Y, Brown KK, Schmidt LS, Linehan WM, Hajjar F, Kinder BW, Trapnell BC, Bissler JJ, Franz DN, McCormack FX (2010) Serum vascular endothelial growth factor-D prospectively distinguishes lymphangioleiomyomatosis from other diseases. Chest 138:674–681PubMedCrossRefGoogle Scholar
  40. 40.
    Seaman DM, Meyer CA, Gilman MD, McCormack FX (2011) Diffuse cystic lung disease at high-resolution CT. AJR Am J Roentgenol 196:1305–1311PubMedCrossRefGoogle Scholar
  41. 41.
    Chiu HT, Garcia CK (2006) Familial spontaneous pneumothorax. Curr Opin Pulm Med 12:268–272PubMedCrossRefGoogle Scholar
  42. 42.
    Hagaman JT, Schauer DP, McCormack FX, Kinder BW (2010) Screening for lymphangioleiomyomatosis by high-resolution computed tomography in young, nonsmoking women presenting with spontaneous pneumothorax is cost-effective. Am J Respir Crit Care Med 181:1376–1382PubMedCrossRefGoogle Scholar
  43. 43.
    Houweling AC, Gijezen LM, Jonker MA, van Doorn MB, Oldenburg RA, van Spaendonck-Zwarts KY, Leter EM, van Os TA, van Grieken NC, Jaspars EH, de Jong MM, Bongers EM, Johannesma PC, Postmus PE, van Moorselaar RJ, van Waesberghe JH, Starink TM, van Steensel MA, Gille JJ, Menko FH (2011) Renal cancer and pneumothorax risk in Birt-Hogg-Dubé syndrome; an analysis of 115 FLCN mutation carriers from 35 BHD families. Br J Cancer 105:1912–1919PubMedCrossRefGoogle Scholar
  44. 44.
    MacDuff A, Arnold A, Harvey J; BTS Pleural Disease Guideline Group (2010) Management of spontaneous pneumothorax: British Thoracic Society Pleural Disease Guideline 2010. Thorax 65 Suppl 2:ii pp 18–31Google Scholar
  45. 45.
    Almoosa KF, Ryu JH, Mendez J, Huggins JT, Young LR, Sullivan EJ, Maurer J, McCormack FX, Sahn SA (2006) Management of pneumothorax in lymphangioleiomyomatosis: effects on recurrence and lung transplantation complications. Chest 129:1274–1281PubMedCrossRefGoogle Scholar
  46. 46.
    Kurihara M, Kataoka H, Ishikawa A, Endo R (2010) Latest treatments for spontaneous pneumothorax. Gen Thorac Cardiovasc Surg 58:113–119PubMedCrossRefGoogle Scholar
  47. 47.
    British Thoracic Society Fitness to Dive Group, Subgroup of the British Thoracic Society Standards of Care Committee (2003) British Thoracic Society guidelines on respiratory aspects of fitness for diving. Thorax 58:3–13CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media Dordrecht 2013

Authors and Affiliations

  • Nishant Gupta
    • 1
    Email author
  • Kuniaki Seyama
    • 2
  • Francis X. McCormack
    • 1
  1. 1.Division of Pulmonary, Critical Care and Sleep Medicine, Department of Internal MedicineUniversity of CincinnatiCincinnatiUSA
  2. 2.Division of Respiratory MedicineJuntendo UniversityTokyoJapan

Personalised recommendations