- Author: Krista K Buckley, DO; Chief Editor: Dirk M Elston, MD more...
In 1977, Birt, Hogg, and Dubé reported small papular skin lesions distributed over the scalp, forehead, face, and neck in 15 of 70 members in a kindred study. Histologic examination of the lesions revealed fibrofolliculomas, trichodiscomas, and acrochordons. The presence of this triad has been termed Birt-Hogg-Dubé syndrome (BHDS).[1, 2, 3, 4, 5, 6, 7] However, evidence suggests that these 3 lesions may actually represent only 1 lesion, the fibrofolliculoma, cut in various planes of section.[3, 8]
Multiple or bilateral renal carcinomas, commonly chromophobe renal carcinoma and renal oncocytomas, and rarely, clear cell renal carcinomas have been reported in association with this syndrome.[9, 10, 11, 12, 13, 14, 15] The overall lifetime risk of renal cancer in patients with Birt-Hogg-Dubé syndrome was noted to be 16% by Houweling et al.
Pulmonary cysts and spontaneous pneumothoraces have also been increasingly reported manifestations of Birt-Hogg-Dubé syndrome.[17, 18, 19, 20, 21, 22, 23, 24] In one study, Toro et al reported 89% of patients with Birt-Hogg-Dubé syndrome had pulmonary cysts on CT scans. Further, the study demonstrated 24% of Birt-Hogg-Dubé syndrome patients and 34% of Birt-Hogg-Dubé syndrome family members screened for lung cysts had a history of spontaneous pneumothorax. Additionally, the overall risk of having a pneumothorax in patients with Birt-Hogg-Dubé syndrome was noted to be 29%.
Other, less commonly associated features include a large connective-tissue nevus, parathyroid adenomas, flecked chorioretinopathy, bullous emphysema, lipomas, angiolipomas, parotid oncocytomas, multiple oral mucosal papules, neural tissue tumors (including neurilemomas), multiple facial angiofibromas, and desmoplastic melanoma.[25, 26, 27, 28, 29, 30, 31, 32] Colonic polyps and colonic adenocarcinoma had previously been described with Birt-Hogg-Dubé syndrome; however, a large cohort study by Zbar et al failed to demonstrate such findings. Additionally, medullary thyroid cancer was reported in 9 members of the original family described by Birt, Hogg, and Dubé, but it has not been reported in subsequent cases. A case of neuroendocrine cancer of prostate or bladder origin has also been reported.
In summary, Birt-Hogg-Dubé syndrome is an autosomal dominant disorder clinically manifested by fibrofolliculomas, renal cell carcinoma, lung cysts, and spontaneous pneumothorax.
Several authors have theorized that an ectodermal-mesodermal interaction stimulates hair development and growth of adjacent dermal structures. The cause of mesodermal proliferation is unknown, but autosomal dominant inheritance has been identified in patients with Birt-Hogg-Dubé syndrome (BHDS). Schmidt et al demonstrated that Birt-Hogg-Dubé syndrome maps to band 17p11.2.[18, 34] Further, Nickerson et al used recombination mapping to delineate the susceptibility focus to 700 kB on band 17p11.2. They also demonstrated a Birt-Hogg-Dubé syndrome tumor-suppressor protein, folliculin. Expression of the Birt-Hogg-Dubé syndrome protein has been widespread in a variety of tissues, including the kidneys, lungs, and skin.
The exact origin of the folliculin mutation remains under investigation. Several possible mechanisms exist. In recent studies, renal and pulmonary tumors in Birt-Hogg-Dubé syndrome appear to follow the two-hit tumorigenesis theory relating to the interaction of folliculin with the FLCN-interacting protein 1 (FNIP1) and FLCN-interacting protein 2 (FNIP2).[29, 30, 37] FNIP1 then interacts with 5'-AMP (activated protein kinase), which interacts with mammalian target of rapamycin (mTOR) that is involved in cellular energy, cytokinesis, cell motility, cellular adhesion, and nutrient sensing.[38, 39, 40] The formation of pulmonary cysts may be related to the dysregulation of mTOR signaling, which facilitates S6-mediated protein synthesis and HIF-1-alpha–mediated angiogenesis.
Gaur et al suggest FLCN acts as a tumor suppressor by negatively regulating rRNA synthesis. Another study by Nahorski et al demonstrated tumor suppression by the interaction of p0071 (plakophilin-4, a potential novel folliculin-interacting protein) and the regulation of RhoA. Additionally, knockdown of slingshot 2 (SSH2) serine phosphatase was demonstrated to induce caspase 3/7 activation that can trigger apoptosis in human carcinoma cells with a FLCN mutation. Possik et al demonstrated FLCN is an AMPK-binding partner and considered to act as a negative regulator of AMPK, therefore serving as a tumor suppressor.[45, 46]
Pradella et al suggest that FLCN may not always follow a classic two-hit model of tumorigenesis and may alternatively be a noncanonical tumor suppressor gene. This was demonstrated by the somatic PTEN deletion in parotid tumors in addition to the germline loss of FLCN, thereby following a model of compound heterozygosity, instead of the classic two-hit mutation.
Benhammou et al and Nahorski et al noted other changes, besides germline mutations, in FLCN causing folliculin mutation. FLCN protein instability or deletion of a FLCN exon caused reduced protein production, thus supporting the theory of haploinsufficiency and contributing to disease pathogenesis.[48, 49]
While the poly C tract in exon 11 of the folliculin gene is the mutational hotspot, multiple other germline mutations have been detected.[50, 51, 47, 30, 52, 53] The folliculin mutation detection rate was 88% by direct bidirectional DNA sequencing in the National Cancer Institute Birt-Hogg-Dubé syndrome cohort. Folliculin mutation databases have been established by Wei and colleagues at the National Cancer Institute and by the European BHDS Consortium.[54, 55, 56]
Birt-Hogg-Dubé syndrome is uncommon in the United States. Several families have been reported since Birt, Hogg, and Dubé described the original kindred in 1977.
No racial predilection is reported in Birt-Hogg-Dubé syndrome. Perifollicular fibromas may represent a part of the spectrum of lesions in Birt-Hogg-Dubé syndrome and are reported only in white and light-skinned persons.
No sexual predilection is reported in Birt-Hogg-Dubé syndrome. Reports of patients with perifollicular fibromas have demonstrated no predilection for either sex.
Cutaneous lesions usually develop in the third and fourth decades of life and persist indefinitely. Dermatologic manifestations typically have an earlier onset than associated renal cell cancer.
Birt AR, Hogg GR, Dube WJ. Hereditary multiple fibrofolliculomas with trichodiscomas and acrochordons. Arch Dermatol. 1977 Dec. 113(12):1674-7. [Medline].
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 Aug. 21(4):369-74. [Medline].
Fujita WH, Barr RJ, Headley JL. Multiple fibrofolliculomas with trichodiscomas and acrochordons. Arch Dermatol. 1981 Jan. 117(1):32-5. [Medline].
Haimowitz JE, Halpern AC, Heymann WR. Multiple, hereditary dome-shaped papules and acrochordons. Birt-Hogg-Dubé syndrome. Arch Dermatol. 1997 Sep. 133(9):1163, 1166. [Medline].
Starink TM, Kisch LS, Meijer CJ. Familial multiple trichodiscomas. A clinicopathologic study. Arch Dermatol. 1985 Jul. 121(7):888-91. [Medline].
Ubogy-Rainey Z, James WD, Lupton GP, Rodman OG. Fibrofolliculomas, trichodiscomas, and acrochordons: the Birt-Hogg-Dubé syndrome. J Am Acad Dermatol. 1987 Feb. 16(2 Pt 2):452-7. [Medline].
Welsch MJ, Krunic A, Medenica MM. Birt-Hogg-Dubé Syndrome. Int J Dermatol. 2005 Aug. 44(8):668-73. [Medline].
Junkins-Hopkins JM, Cooper PH. Multiple perifollicular fibromas: report of a case and analysis of the literature. J Cutan Pathol. 1994 Oct. 21(5):467-71. [Medline].
Adley BP, Smith ND, Navar XJ. Birt-Hogg-Dube syndrome: clinicpathologic findings and genetic alterations. Arch Pathol Lab Med. 2006. December 130 (12):1865-1870.
Roth JS, Rabinowitz AD, Benson M, Grossman ME. Bilateral renal cell carcinoma in the Birt-Hogg-Dubé syndrome. J Am Acad Dermatol. 1993 Dec. 29(6):1055-6. [Medline].
Schmidt LS, Warren MB, Nickerson ML, et al. Birt-Hogg-Dubé syndrome, a genodermatosis associated with spontaneous pneumothorax and kidney neoplasia, maps to chromosome 17p11.2. Am J Hum Genet. 2001 Oct. 69(4):876-82. [Medline]. [Full Text].
Toro JR, Glenn G, Duray P, et al. Birt-Hogg-Dubé syndrome: a novel marker of kidney neoplasia. Arch Dermatol. 1999 Oct. 135(10):1195-202. [Medline].
Tobino K, Seyama K. Birt-Hogg-Dubé syndrome with renal angiomyolipoma. Intern Med. 2012. 51(10):1279-80.
Mallipeddi R, Pichert G, Whittaker S. Birt-Hogg-Dubé syndrome with a renal angiomyolipoma: further evidence of a relationship between Birt Hogg-Dubé syndrome and tuberous sclerosis complex. Byrne Australas J Dermatol. 2012 May. 53(2):151-4.
Lin Z, Gong K, Pang B, Zeng C, Zhang D. Birt-Hogg-Dubé syndrome with clear cell renal cell carcinoma in a Chinese family. Intern Med. 2014. 53 (24):2825-8. [Medline].
Houweling AC, Gijezen LM, Jonker MA, 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 Dec 6. 105(12):1912-9. [Medline]. [Full Text].
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 Jul 1. 172(1):39-44. [Medline].
Schmidt LS. Birt-Hogg-Dube syndrome, a genodermatosis that increases risk for renal carcinoma. Curr Mol Med. 2004 Dec. 4(8):877-85. [Medline].
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 May 15. 175(10):1044-53. [Medline]. [Full Text].
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 Apr. 11(4):393-400. [Medline].
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 Apr. 35(2):241-5. [Medline].
Auerbach A, Roberts DH, Gangadharan SP, Kent MS. Birt-Hogg-Dubé syndrome in a patient presenting with familial spontaneous pneumothorax. Ann Thorac Surg. 2014 Jul. 98 (1):325-7. [Medline].
Johannesma PC, van den Borne BE, Gille JJ, Nagelkerke AF, van Waesberghe JT, Paul MA, et al. Spontaneous pneumothorax as indicator for Birt-Hogg-Dubé syndrome in paediatric patients. BMC Pediatr. 2014 Jul 3. 14:171. [Medline].
Liu V, Kwan T, Page EH. Parotid oncocytoma in the Birt-Hogg-Dubé syndrome. J Am Acad Dermatol. 2000 Dec. 43(6):1120-2. [Medline].
Nadershahi NA, Wescott WB, Egbert B. Birt-Hogg-Dubé syndrome: a review and presentation of the first case with oral lesions. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 1997 Apr. 83(4):496-500. [Medline].
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 Aug. 53(2 Suppl 1):S108-11. [Medline].
Vincent A, Farley M, Chan E, James WD. Birt-Hogg-Dubé syndrome: two patients with neural tissue tumors. J Am Acad Dermatol. 2003 Oct. 49(4):717-9. [Medline].
Cocciolone RA, Crotty KA, Andrews L, Haass NK, Moloney FJ. Multiple desmoplastic melanomas in Birt-Hogg-Dubé syndrome and a proposed signaling link between folliculin, the mTOR pathway, and melanoma susceptibility. Arch Dermatol. 2010 Nov. 146(11):1316-8. [Medline].
Mota-Burgos A, Acosta EH, Márquez FV, Mendiola M, Herrera-Ceballos E. Birt-Hogg-Dubé syndrome in a patient with melanoma and a novel mutation in the FCLN gene. Int J Dermatol. 2013 Mar. 52(3):323-6.
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. [Medline].
Renfree KJ, Lawless KL. Multiple neurilemmomas in Birt-Hogg-Dubé syndrome: case report. J Hand Surg Am. 2012 Apr. 37(4):792-4. [Medline].
Claessens T, Weppler SA, van Geel M, et al. Neuroendocrine carcinoma in a patient with Birt-Hogg-Dubé syndrome. Nat Rev Urol. 2010 Oct. 7(10):583-7. [Medline].
Schmidt LS, Nickerson ML, Warren MB, 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 Jun. 76(6):1023-33. [Medline]. [Full Text].
Nickerson ML, Warren MB, Toro JR, 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 Aug. 2(2):157-64. [Medline].
Khoo SK, Kahnoski K, Sugimura J, et al. Inactivation of BHD in sporadic renal tumors. Cancer Res. 2003 Aug 1. 63(15):4583-7. [Medline].
Hasumi H, Baba M, Hasumi Y, Lang M, Huang Y, Oh HF, et al. Folliculin-interacting proteins Fnip1 and Fnip2 play critical roles in kidney tumor suppression in cooperation with Flcn. Proc Natl Acad Sci U S A. 2015 Mar 31. 112 (13):E1624-31. [Medline].
Baba M, Hong SB, Sharma N, 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 U S A. 2006 Oct 17. 103(42):15552-7. [Medline]. [Full Text].
Tee AR, Pause A. Birt-Hogg-Dubé: tumour suppressor function and signalling dynamics central to folliculin. Fam Cancer. 2012 Oct 25.
Medvetz DA, Khabibullin D, Hariharan V, Ongusaha PP, Goncharova EA, Schlechter T, et al. Folliculin, the product of the Birt-Hogg-Dube tumor suppressor gene, interacts with the adherens junction protein p0071 to regulate cell-cell adhesion. PLoS One. 2012. 7(11):
Nishii T, Tanabe M, Tanaka R, Matsuzawa T, Okudela K, Nozawa A. Unique mutation, accelerated mTOR signaling and angiogenesis in the pulmonary cysts of Birt-Hogg-Dubé syndrome. Pathol Int. 2013 Jan. 63(1):45-55. [Medline].
Gaur K, Li J, Wang D, Dutta P, Yan SJ, Tsurumi A. The Birt-Hogg-Dubé tumor suppressor Folliculin negatively regulates ribosomal RNA synthesis. Hum Mol Genet. 2013 Jan 15. 22(2):284-99. [Medline].
Nahorski MS, Seabra L, Straatman-Iwanowska A, Wingenfeld A, Reiman A, Lu X. Folliculin interacts with p0071 (plakophilin-4) and deficiency is associated with disordered RhoA signalling, epithelial polarization and cytokinesis. Hum Mol Genet. 2012 Dec 15. 21(24):5268-79. [Medline].
Lu X, Boora U, Seabra L, Rabai EM, Fenton J, Reiman A. Knockdown of Slingshot 2 (SSH2) serine phosphatase induces Caspase3 activation in human carcinoma cell lines with the loss of the Birt-Hogg-Dubé tumour suppressor gene (FLCN). Oncogene. 2013 Feb 18. [Medline].
Possik E, Jalali Z, Nouët Y, Yan M, Gingras MC, Schmeisser K, et al. Folliculin regulates ampk-dependent autophagy and metabolic stress survival. PLoS Genet. 2014 Apr. 10 (4):e1004273. [Medline].
Yan M, Gingras MC, Dunlop EA, Nouët Y, Dupuy F, Jalali Z, et al. The tumor suppressor folliculin regulates AMPK-dependent metabolic transformation. J Clin Invest. 2014 Jun. 124 (6):2640-50. [Medline].
Pradella LM, Lang M, Kurelac I, Mariani E, Guerra F, Zuntini R, et al. Where Birt-Hogg-Dubé meets Cowden syndrome: mirrored genetic defects in two cases of syndromic oncocytic tumours. Eur J Hum Genet. 2013 Oct. 21 (10):1169-72. [Medline]. [Full Text].
Nahorski MS, Reiman A, Lim DH, Nookala RK, Seabra L, Lu X, et al. Birt Hogg-Dubé syndrome-associated FLCN mutations disrupt protein stability. Hum Mutat. 2011 Aug. 32 (8):921-9. [Medline].
Benhammou JN, Vocke CD, Santani A, Schmidt LS, Baba M, Seyama K, et al. Identification of intragenic deletions and duplication in the FLCN gene in Birt-Hogg-Dubé syndrome. Genes Chromosomes Cancer. 2011 Jun. 50 (6):466-77. [Medline].
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 Nov. 155(5):1067-9. [Medline].
Leter EM, Koopmans AK, Gille JJ, et al. Birt-Hogg-Dubé syndrome: clinical and genetic studies of 20 families. J Invest Dermatol. 2008 Jan. 128(1):45-9. [Medline].
Kim J, Yoo JH, Kang DY, Cho NJ, Lee KA. Novel in-frame deletion mutation in FLCN gene in a Korean family with recurrent primary spontaneous pneumothorax. Gene. 2012 May 15. 499(2):339-42. [Medline].
Nagashima Y, Furuya M, Gotohda H, Takagi S, Hes O, Michal M. FLCN gene-mutated renal cell neoplasms: mother and daughter cases with a novel germline mutation. Int J Urol. 2012 May. 19(5):468-70. [Medline].
Toro JR, Wei MH, Glenn GM, 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 Jun. 45(6):321-31. [Medline]. [Full Text].
Wei MH, Blake PW, Shevchenko J, Toro JR. The folliculin mutation database: an online database of mutations associated with Birt-Hogg-Dubé syndrome. Hum Mutat. 2009 Sep. 30(9):E880-90. [Medline].
Lim DH, Rehal PK, Nahorski MS, et al. A new locus-specific database (LSDB) for mutations in the folliculin (FLCN) gene. Hum Mutat. 2010 Jan. 31(1):E1043-51. [Medline].
Aivaz O, Berkman S, Middelton L, Linehan WM, DiGiovanna JJ, Cowen EW. Comedonal and Cystic Fibrofolliculomas in Birt-Hogg-Dube Syndrome. JAMA Dermatol. 2015 Jul. 151 (7):770-4. [Medline].
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 May. 35(5):365-7. [Medline].
Shvartsbeyn M, Mason AR, Bosenberg MW, Ko CJ. Perifollicular fibroma in Birt-Hogg-Dubé syndrome: an association revisited. J Cutan Pathol. 2012 Jul. 39(7):675-9. [Medline].
Kamada T, Yoshikawa Y, Shirase T, Furuya M, Yutaka Y. Perifollicular fibromas associated with Birt-Hogg-Dubé syndrome. J Dermatol. 2015 Sep 21. [Medline].
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 Aug. 53 (2 Suppl 1):S108-11. [Medline].
Menko FH, van Steensel MA, Giraud S, et al. Birt-Hogg-Dubé syndrome: diagnosis and management. Lancet Oncol. 2009 Dec. 10(12):1199-206. [Medline].
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 Jan. 26(1):55-61. [Medline].
Gupta P, Eshaghi N, Kamba TT, Ghole V, Garcia-Morales F. Radiological findings in Birt-Hogg-Dubé syndrome: a rare differential for pulmonary cysts and renal tumors. Clin Imaging. 2007 Jan-Feb. 31(1):40-3. [Medline].
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 Oct. 29(9):529-33. [Medline].
Heenan PJ. Tumors of the fibrous tissue involving the skin. Elder D, Elenitsas R, Jaworsky C, Johnson B Jr, eds. Lever's Histopathology of the Skin. 8th ed. Lippincott Wilkins & Williams; 1997. 872-4.
Pinkus H, Coskey R, Burgess GH. Trichodiscoma. A benign tumor related to haarscheibe (hair disk). J Invest Dermatol. 1974 Aug. 63(2):212-8. [Medline].
Lopez-Garcia DR, Teague D, Landis ET, Sangueza OP. Morphological diversity of trichodiscomas and fibrofolliculomas. Am J Dermatopathol. 2014 Sep. 36 (9):734-40. [Medline].
Gijezen LM, Vernooij M, Martens H, Oduber CE, Henquet CJ, 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. [Medline].
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 Jul 15. 20 (7):[Medline].
Gambichler T, Wolter M, Altmeyer P, Hoffman K. Treatment of Birt-Hogg-Dubé syndrome with erbium:YAG laser. J Am Acad Dermatol. 2000 Nov. 43(5 Pt 1):856-8. [Medline].
Jacob CI, Dover JS. Birt-Hogg-Dube syndrome: treatment of cutaneous manifestations with laser skin resurfacing. Arch Dermatol. 2001 Jan. 137(1):98-9. [Medline].
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 Oct. 49(4):698-705. [Medline].
Ayo DS, Aughenbaugh GL, Yi ES, Hand JL, Ryu JH. Cystic lung disease in Birt-Hogg-Dube syndrome. Chest. 2007 Aug. 132(2):679-84. [Medline].