Birt–Hogg–Dubé (BHD) syndrome was first described in 1977¹ by three Canadian doctors – Birt, Hogg and Dubé – and has since been determined to be an autosomal, dominantly inherited, monogenic condition, characterised by the development of benign skin tumours (fibrofolliculomas) on the face and upper torso, pulmonary cysts and collapsed lung (pneumothorax), and predisposition to kidney cancers with clear cell, chromophobic or oncocytic features¹.

Clinical manifestations of BHD syndrome:

Benign skin tumours

Benign skin tumours usually develop in patients with BHD after the age of 20 years², as multiple whitish papules. These develop primarily on the face, but can also appear on the neck, ears and the upper torso². They are benign hair follicle tumours known clinically as fibrofolliculomas. Previously, fibrofolliculomas and trichodiscomas were considered hallmarks of BHD syndrome but recent studies suggest that they may not be distinct histological entities, and that a morphological spectrum of these benign skin tumours may exist, upon which both these two lie³.

Pulmonary cysts and spontaneous pneumothorax

The presence of pulmonary cysts in BHD syndrome was first described in 1999⁴ and additional cases of pulmonary cysts and spontaneous pneumothorax have since been reported^{5, 6, 7, 8, 9, 10, 11, 12, 13}.

Lung anatomy and histology generally appears normal in patients with BHD, and despite the presence of multiple pulmonary cysts, lung function is usually unaffected⁶. A 50-fold increase in the risk of pneumothorax for BHD-affected individuals has been identified⁵, which is believed to be related to the presence of pulmonary cysts⁶. Pneumothorax has been reported in BHD syndrome patients as young as seven and sixteen years¹⁴. Following a single episode of spontaneous pneumothorax, recurrent events are more common⁶.

Smoking is an important risk factor for spontaneous primary pneumothorax; however, the role of smoking as a risk factor in BHD has been not been clarified^{6, 15}.

Renal Cell Carcinoma (Kidney Cancer)

Individuals with BHD syndrome are predisposed to develop bilateral multifocal tumours of the kidneys which has implications for clinical management, since regular surveillance of the kidneys is required to monitor tumour growth and size, and surgery is required to excise these tumours once they are larger than 3cm^{1,  4, 5}. Chromophobe renal cancer and a mixed pattern of chromophobe and oncocytic renal tumours are typical for patients with BHD. However, other histological subtypes can occur, including clear-cell and papillary carcinoma, and several mixed patterns¹⁶. Relatively few patients with BHD and metastatic renal cancer have been reported¹⁷ and prospective studies are required to clarify the exact mechanisms of renal carcinogenesis in BHD syndrome¹⁸.

Renal cancer is the most life-threatening complication associated with BHD Syndrome and various studies have reported the incidence of renal cancer in individuals with BHD syndrome, with the mean age of RCC incidence described as 50.4 years¹⁶ and the earliest reported age at diagnosis of renal cancer in a patient with BHD syndrome being twenty years old¹⁹. Further difficulties in establishing the risk of renal cancer in BHD patients include the possible under diagnosis of BHD Syndrome, variations (interfamilial or otherwise) in cancer risk due to different types of mutations and differences in genetic background.

Genetics

The gene Folliculin, was identified as being mutated in BHD Syndrome in 2002²⁰ and encodes for the Folliculin protein. The function of Folliculin is currently under significant scrutiny, but an involvement in the mTOR signalling network has been firmly established^{21, 22}, suggesting a role for FLCN in nutrient/energy-sensing mediated through the mTOR signalling pathway.

To find out more, continue on to specific areas of www.BHDSyndrome.org, using the links above.

References

1. Birt AR, Hogg GR and Dubé WJ, Hereditary multiple fibrofolliculomas with trichodiscomas and acrochordons, Arch. Dermatol. 1977; 113, 1674–1677.

2. 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. Birt-Hogg-Dubé syndrome: diagnosis and management. Lancet Oncol. 2009 Dec; 10(12):1199-206.

3. 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.

4.  Toro JR, Glenn G, Duray P, et al. Birt-Hogg-Dubé  syndrome: a novel marker of kidney neoplasia. Arch Dermatol 1999;135(10):1195-202.

5. Zbar B, Alvord WG, Glenn G, et al. Risk of renal and colonic neoplasms and spontaneous pneumothorax in the Birt-Hogg-Dubé  syndrome. Cancer Epidemiol Biomarkers Prev  2002;11(4):393-400.

6. Toro JR, Pautler SE, Stewart L, 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: 1044–53.

7.  Johannesma PC, Lammers JW, van Moorselaar RJ, Starink TM, Postmus PE, Menko FH. Spontaneous pneumothorax as the first manifestation of a hereditary condition with an increased renal cancer risk. Ned Tijdschr Geneeskd. 2009; 153. pii: A581.

8. Koga S, Furuya M, Takahashi Y, Tanaka R, Yamaguchi A, Yasufuku K, Hiroshima K, Kurihara M, Yoshino I, Aoki I, Nakatani Y. Lung cysts in Birt-Hogg-Dubé syndrome: histopathological characteristics and aberrant sequence repeats. Pathol Int. 2009; 59(10):720-8.

9. Kluger N, Giraud S, Coupier I, Avril MF, Dereure O, Guillot B, Richard S, Bessis D.  Birt-Hogg-Dubé syndrome: clinical and genetic studies of 10 French families. Br J Dermatol. 2009.

10. Ishii H, Oka H, Amemiya Y, Iwata A, Otani S, Kishi K, Shirai R, Tokimatsu I, Kawahara K, Kadota J. A Japanese family with multiple lung cysts and recurrent pneumothorax: a possibility of Birt-Hogg-Dubé syndrome. Intern Med. 2009; 48(16):1413-7.

11. So SY. Spontaneous pneumothorax due to Birt-Hogg-Dubé  syndrome in a Chinese family. Respirology. 2009 Jul;14(5):775-6.

12.  Sundaram S, Tasker AD, Morrell NW. Familial spontaneous pneumothorax and lung cysts due to a Folliculin exon 10 mutation. Eur Respir J. 2009 Jun;33(6):1510-1512.

13.  Diamond JM, Kotloff RM. Recurrent spontaneous pneumothorax as the presenting sign of the Birt-Hogg-Dubé syndrome. Ann Intern Med. 2009 Feb 17; 150(4):289-90.

14. Bessis D, Giraud S, Richard S. A novel familial germline mutation in the initiator codon of the BHD gene in a patient with Birt-Hogg-Dubé syndrome. Br J Dermatol 2006; 155: 1067–69.

15.  Ayo DS, Aughenbaugh GL, Yi ES, et al. Cystic lung disease in Birt-Hogg-Dubé  syndrome. Chest 2007; 132: 679–84.

16. Pavlovich CP, Walther MM, Eyler RA, et al. Renal tumours in the Birt-Hogg-Dubé  syndrome. Am J Surg Pathol 2002; 26: 1542–52.

17. Kluijt I, de Jong D, Teertstra HJ, et al. Early onset of renal cancer in a family with Birt-Hogg-Dubé  syndrome. Clin. Genet 2009; 75: 537–43.

18. Toro JR, Wei M-H, Glenn GM, et al. BHD mutations, clinial 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: 321–31.

19. Khoo, SK, Giraud  S, Kahnoski K, Chen J, Motorna O, Nickolov R, Binet O, Lambert D, Friedel J, Levy R, Ferlicot S, Wolkenstein P, Hammel P, Bergerheim U, Hedblad MA, Bradley M, Teh BT, Nordenskjold M, Richard S. Clinical and genetic studies of Birt-Hogg-Dubé  syndrome. J. Med. Genet. 2002; 39: 906-912.

20. Nickerson, 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-Dube syndrome. Cancer Cell 2: 2002157-164.

21. Baba M et al. Folliculin encoded by the BHD gene interacts with a binding protein, FNIP1, and AMPK, and is involved in AMPK and mTOR signalling. Proc. Natl. Acad. Sci. USA 2006; 103, pp. 15552–15557.

22. Hasumi H, et al. Identification and characterization of a novel folliculin-interacting protein FNIP2, Gene 2008; 415: 60–67.