eMedicine Specialties > Dermatology > Benign Neoplasms

Birt-Hogg-Dube Syndrome

Author: Krista K Buckley, DO,, Dermatologist, Annapolis Dermatology Center
Coauthor(s): Jeffrey Meffert, MD, Assistant Clinical Professor of Dermatology, University of Texas Health Science Center-San Antonio
Contributor Information and Disclosures

Updated: May 22, 2009

Introduction

Background

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, particularly chromophobe renal carcinoma and renal oncocytomas, have been reported in association with this syndrome.9,10,11,12 Pulmonary cysts and spontaneous pneumothoraces have also been increasingly reported manifestations of Birt-Hogg-Dubé syndrome.13,14,15,16 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.15

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, and multiple facial angiofibromas.17,18,19,20 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.16 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.

Pathophysiology

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 17p11.2.14,21 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.22  Expression of the Birt-Hogg-Dubé syndrome protein has been widespread in a variety of tissues, including the kidneys, lungs, and skin.23

Baba et al identified the interaction of folliculin with the FLCN-interacting protein (FNIP1). FNIP1 interacts with 5'-AMP (activated protein kinase), which interacts with mammalian target of rapamycin (mTOR) and may be involved in cellular energy and nutrient sensing.24 In a mouse model, Baba et al have demonstrated homozygous loss of Birt-Hogg-Dubé syndrome protein results in uncontrolled cell proliferation and therefore may initiate tumorigenesis.25 While the poly C tract in exon 11 of the folliculin gene is the mutational hotspot, multiple other germline mutations have been detected.26,27

Frequency

United States

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.

Mortality/Morbidity

Mortality and morbidity associated with Birt-Hogg-Dubé syndrome may be related to associated internal manifestations, such as renal cell carcinoma, pulmonary cysts, and spontaneous pneumothoraces.28 Birt-Hogg-Dubé syndrome patients with a history of smoking appear to have more severe lung disease than those who do not smoke.29 Otherwise, the morbidity of cutaneous lesions is limited to cosmetic appearance.

Race

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.

Sex

No sexual predilection is reported in Birt-Hogg-Dubé syndrome. Reports of patients with perifollicular fibromas have demonstrated no predilection for either sex.

Age

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.

Clinical

History

Asymptomatic, small, papular skin lesions develop gradually over the scalp, face, neck, and upper trunk.

Physical

Multiple, small (2-4 mm), white–to–flesh-colored, smooth, dome-shaped papules are distributed predominately over the scalp, face, oral cavity, neck, and upper trunk. Acrochordons are small, soft, furrowed, 1- to 2-mm papules that may occur on the eyelids, neck, axilla, and upper half of the trunk. Oral mucosal polyps, collagenomas, angiolipomas, and deforming lipomas also have been reported in association with Birt-Hogg-Dubé syndrome.30

Causes

The cause is unknown, but Birt-Hogg-Dubé syndrome (BHDS) is inherited in an autosomal dominant pattern. Several reports suggest Birt-Hogg-Dubé syndrome may result from the inactivation of a tumor-suppressor gene, which results in the cutaneous hamartomas associated with internal neoplasia. The Birt-Hogg-Dubé syndrome gene locus has been localized to band 17p11.2.

More on Birt-Hogg-Dube Syndrome

Overview: Birt-Hogg-Dube Syndrome
Differential Diagnoses & Workup: Birt-Hogg-Dube Syndrome
Treatment & Medication: Birt-Hogg-Dube Syndrome
Follow-up: Birt-Hogg-Dube Syndrome
References
[ CLOSE WINDOW ]

References

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

  2. 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. Aug 1999;21(4):369-74. [Medline].

  3. Fujita WH, Barr RJ, Headley JL. Multiple fibrofolliculomas with trichodiscomas and acrochordons. Arch Dermatol. Jan 1981;117(1):32-5. [Medline].

  4. Haimowitz JE, Halpern AC, Heymann WR. Multiple, hereditary dome-shaped papules and acrochordons. Birt-Hogg-Dube syndrome. Arch Dermatol. Sep 1997;133(9):1163, 1166. [Medline].

  5. Starink TM, Kisch LS, Meijer CJ. Familial multiple trichodiscomas. A clinicopathologic study. Arch Dermatol. Jul 1985;121(7):888-91. [Medline].

  6. Ubogy-Rainey Z, James WD, Lupton GP, Rodman OG. Fibrofolliculomas, trichodiscomas, and acrochordons: the Birt-Hogg-Dube syndrome. J Am Acad Dermatol. Feb 1987;16(2 Pt 2):452-7. [Medline].

  7. Welsch MJ, Krunic A, Medenica MM. Birt-Hogg-Dube Syndrome. Int J Dermatol. Aug 2005;44(8):668-73. [Medline].

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

  9. 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.

  10. Roth JS, Rabinowitz AD, Benson M, Grossman ME. Bilateral renal cell carcinoma in the Birt-Hogg-Dubé syndrome. J Am Acad Dermatol. Dec 1993;29(6):1055-6. [Medline].

  11. Schmidt LS, Warren MB, Nickerson ML, et al. Birt-Hogg-Dube syndrome, a genodermatosis associated with spontaneous pneumothorax and kidney neoplasia, maps to chromosome 17p11.2. Am J Hum Genet. Oct 2001;69(4):876-82. [Medline].

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

  13. 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. Jul 1 2005;172(1):39-44. [Medline].

  14. Schmidt LS. Birt-Hogg-Dubé syndrome, a genodermatosis that increases risk for renal carcinoma. Curr Mol Med. Dec 2004;4(8):877-85. [Medline].

  15. 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. May 15 2007;175(10):1044-53. [Medline].

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

  17. Liu V, Kwan T, Page EH. Parotid oncocytoma in the Birt-Hogg-Dubé syndrome. J Am Acad Dermatol. Dec 2000;43(6):1120-2. [Medline].

  18. Nadershahi NA, Wescott WB, Egbert B. Birt-Hogg-Dube syndrome: a review and presentation of the first case with oral lesions. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. Apr 1997;83(4):496-500. [Medline].

  19. 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. Aug 2005;53(2 Suppl 1):S108-11. [Medline].

  20. Vincent A, Farley M, Chan E, James WD. Birt-Hogg-Dube syndrome: two patients with neural tissue tumors. J Am Acad Dermatol. Oct 2003;49(4):717-9. [Medline].

  21. 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. Jun 2005;76(6):1023-33. [Medline].

  22. 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. Aug 2002;2(2):157-64. [Medline].

  23. Khoo SK, Kahnoski K, Sugimura J, et al. Inactivation of BHD in sporadic renal tumors. Cancer Res. Aug 1 2003;63(15):4583-7. [Medline].

  24. 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. Oct 17 2006;103(42):15552-7. [Medline].

  25. Baba M, Furihata M, Hong SB, Tessarollo L, Haines DC, Southon E. 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. Jan 16 2008;100(2):140-54. [Medline].

  26. 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. Nov 2006;155(5):1067-9. [Medline].

  27. Leter EM, Koopmans AK, Gille JJ, et al. Birt-Hogg-Dubé syndrome: clinical and genetic studies of 20 families. J Invest Dermatol. Jan 2008;128(1):45-9. [Medline].

  28. 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. Oct 2003;49(4):698-705. [Medline].

  29. Ayo DS, Aughenbaugh GL, Yi ES, Hand JL, Ryu JH. Cystic lung disease in Birt-Hogg-Dube syndrome. Chest. Aug 2007;132(2):679-84. [Medline].

  30. 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. May 1996;35(5):365-7. [Medline].

  31. 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. Jan 1999;26(1):55-61. [Medline].

  32. 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. Jan-Feb 2007;31(1):40-3. [Medline].

  33. 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. Oct 2002;29(9):529-33. [Medline].

  34. Heenan PJ. Tumors of the fibrous tissue involving the skin. In: Elder D, Elenitsas R, Jaworsky C, Johnson B Jr, eds. Lever's Histopathology of the Skin. 8th ed. Lippincott Wilkins & Williams; 1997:872-4.

  35. Pinkus H, Coskey R, Burgess GH. Trichodiscoma. A benign tumor related to haarscheibe (hair disk). J Invest Dermatol. Aug 1974;63(2):212-8. [Medline].

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

  37. Jacob CI, Dover JS. Birt-Hogg-Dube syndrome: treatment of cutaneous manifestations with laser skin resurfacing. Arch Dermatol. Jan 2001;137(1):98-9. [Medline].

[ CLOSE WINDOW ]

Further Reading

[ CLOSE WINDOW ]

Keywords

Birt-Hogg-Dube syndrome, BHDS, BHD syndrome, fibrofolliculomas, trichodiscomas, acrochordons

[ CLOSE WINDOW ]

Contributor Information and Disclosures

Author

Krista K Buckley, DO,, Dermatologist, Annapolis Dermatology Center
Krista K Buckley, DO, is a member of the following medical societies: American Academy of Dermatology and Phi Beta Kappa
Disclosure: Nothing to disclose.

Coauthor(s)

Jeffrey Meffert, MD, Assistant Clinical Professor of Dermatology, University of Texas Health Science Center-San Antonio
Jeffrey Meffert, MD is a member of the following medical societies: American Academy of Dermatology, American Medical Association, Association of Military Dermatologists, and Texas Dermatological Society
Disclosure: Nothing to disclose.

Medical Editor

Franklin Flowers, MD, Chief, Division of Dermatology, Professor, Department of Medicine and Otolaryngology, University of Florida College of Medicine
Franklin Flowers, MD is a member of the following medical societies: American College of Mohs Micrographic Surgery and Cutaneous Oncology
Disclosure: Nothing to disclose.

Pharmacy Editor

Richard P Vinson, MD, Assistant Clinical Professor, Department of Dermatology, Texas Tech University School of Medicine; Consulting Staff, Mountain View Dermatology, PA
Richard P Vinson, MD is a member of the following medical societies: American Academy of Dermatology, Association of Military Dermatologists, Texas Dermatological Society, and Texas Medical Association
Disclosure: Nothing to disclose.

Managing Editor

Mary Farley, MD, Dermatologic Surgeon/Mohs Surgeon, Anne Arundel Surgery Center
Disclosure: Nothing to disclose.

CME Editor

Catherine Quirk, MD, Clinical Assistant Professor, Department of Dermatology, Brown University
Catherine Quirk, MD is a member of the following medical societies: Alpha Omega Alpha and American Academy of Dermatology
Disclosure: Nothing to disclose.

Chief Editor

Dirk M Elston, MD, Director, Department of Dermatology, Geisinger Medical Center
Dirk M Elston, MD is a member of the following medical societies: American Academy of Dermatology
Disclosure: Nothing to disclose.

RELATED EMEDICINE ARTICLES
 
 
HONcode

We subscribe to the
HONcode principles of the
Health On the Net Foundation

All material on this website is protected by copyright, Copyright© 1994- by Medscape.
This website also contains material copyrighted by 3rd parties.

DISCLAIMER: The content of this Website is not influenced by sponsors. The site is designed primarily for use by qualified physicians and other medical professionals. The information contained herein should NOT be used as a substitute for the advice of an appropriately qualified and licensed physician or other health care provider. The information provided here is for educational and informational purposes only. In no way should it be considered as offering medical advice. Please check with a physician if you suspect you are ill.