Birt-Hogg-Dubé Syndrome (BHD)

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Birt-Hogg-Dubé Syndrome (BHD)

Identity

Note Birt-Hogg-Dubé syndrome (BHDS) is characterized by renal oncocytic tumors, benign skin tumors (fibrofolliculomas and trichodiscomas), and spontaneous pneumothorax. The first description of an affected family was provided by Birt, Hogg, and Dubé in 1977.

Inheritance Autosomal Dominant with variable expressivity. Prevalence is estimated at about 1/200,000.

Clinics

Phenotype and clinics BHDS is a genodermatosis characterized by the triad of benign tumors of the hair follicle, spontaneous pneumothorax and kidney tumors. These manifestations do not have to be simultaneously present in the same individual in order to establish a diagnosis of BHDS, since the phenotype is variable and penetrance is not complete. Patients may also suffer from colonic polyps and colorectal cancer.Cutaneous tumors are fibrofolliculomas, trichodiscomas and/or acrochordons. Fibrofolliculomas and trichodiscomas tend to appear in the third or fourth decade of life as small white or skin-colored multiple papules on the face, neck and upper trunk. Acrochordon is a non specific designation for small and soft skin tags. Multiple angiofibromas, lipomas and collagenomas have also been reported. Affected individuals have a high chance of developing cysts in the lungs and spontaneous pneumothorax. Although almost all patients who have BHDS have lung blebs (90%), but only a fifth will have spontaneous pneumothorax. The strong association of spontaneous pneumothorax with BHDS suggests that the presence of spontaneous pneumothorax in a member of a BHDS family could be used as a criterion for the diagnosis of BHDS.

Neoplastic risk Approximately 27% of BHDS patients develop renal tumors of different histological type:
chromophobe (34%),
hybrid chromophobe/oncocytic (50%),
oncocytoma (5%), and
clear cell renal carcinoma (9%).
Hybrid tumors are most characteristic of this condition, and several lesions initially diagnosed as oncocytomas or chromofobe tumors have been defined as hybrid tumors upon reappraisal. Multiple histological types of kidney tumors can be found in the same BHDS family, in the same patient or even in the same kidney. Although colonic tumors have been observed in some families, it is not clear whether they represent a manifestation of BHDS.

Treatment
No specific medical treatment exists for the cutaneous lesions of BHDS. Surgical removal has provided definitive treatment of solitary perifollicular fibromas and electrodesiccation may be helpful in removal of multiple lesions, but these can recur.·
High-resolution CT scan is required in order to identify lung cysts ·
Individuals at risk or affected by BHDS should be radiographically screened for renal tumors at periodic intervals and they are best treated with nephron sparing surgical approaches·
Colonoscopy should be considered

Prognosis Prognosis depends on the number, type and age at diagnosis of kidney tumors. Hybrid and chromophobe tumors have malignant potential, while pure renal oncocytomas are benign. Mean age at diagnosis of kidney tumors is 50.7 years.

Genes involved and Proteins

Gene Name FLCN

Location 17p11.2

DNA/RNA
Description Total gene size: 24971 bp.

Protein
Note Folliculin

Description The protein contains a conserved SLS potential phosphorylation site, a glutamic acid-rich coiled-coil domain, an N-glycosylation site, and 3 myristoylation sites. Its function is yet unknown

Mutations
Note Cytosine insertions or deletions in a mononucleotide repeat tract containing 8 cytosines within exon 11 are the most frequent constitutional mutations found, being detected in approximately 50% of BHDS families. These mutations result in an abnormally small, non functional folliculin protein. Other mutations located elsewhere in the coding sequence are heterogeneous. Overall, point mutations in the FLCN gene are found in approximately 80% of BHDS cases.

External links

Association Hogg Dube Family Alliance http://www.birthoggdube.org/

Bibliography

Hereditary multiple fibrofolliculomas with trichodiscomas and acrochordons.

Birt AR, Hogg GR, Dubˆ© WJ

Archives of dermatology. 1977 ; 113 (12) : 1674-1677.

PMID 596896

Multiple fibrofolliculomas (Birt-Hogg-Dubˆ©) associated with a large connective tissue nevus.

Weintraub R, Pinkus H

Journal of cutaneous pathology. 1977 ; 4 (6) : 289-299.

PMID 753849

Multiple fibrofolliculomas with trichodiscomas and acrochordons.

Fujita WH, Barr RJ, Headley JL

Archives of dermatology. 1981 ; 117 (1) : 32-35.

PMID 7458379

Familial multiple trichodiscomas. A clinicopathologic study.

Starink TM, Kisch LS, Meijer CJ

Archives of dermatology. 1985 ; 121 (7) : 888-891.

PMID 4015134

Fibrofolliculomas, trichodiscomas, and acrochordons: the Birt-Hogg-Dubˆ© syndrome.

Ubogy-Rainey Z, James WD, Lupton GP, Rodman OG

Journal of the American Academy of Dermatology. 1987 ; 16 (2 Pt 2) : 452-457.

PMID 3819093

Fibrofolliculomas, tricodiscomas and acrochordons (Birt-Hogg-Dubˆ©) associated with intestinal polyposis.

Rongioletti F, Hazini R, Gianotti G, Rebora A

Clinical and experimental dermatology. 1989 ; 14 (1) : 72-74.

PMID 2805394

Familial multiple desmoplastic trichoepitheliomas.

Shapiro PE, Kopf AW

Archives of dermatology. 1991 ; 127 (1) : 83-87.

PMID 1986711

Bilateral renal cell carcinoma in the Birt-Hogg-Dubˆ© syndrome.

Roth JS, Rabinowitz AD, Benson M, Grossman ME

Journal of the American Academy of Dermatology. 1993 ; 29 (6) : 1055-1056.

PMID 8245249

Multiple lipomas, angiolipomas, and parathyroid adenomas in a patient with Birt-Hogg-Dube syndrome.

Chung JY, Ramos-Caro FA, Beers B, Ford MJ, Flowers F

International journal of dermatology. 1996 ; 35 (5) : 365-367.

PMID 8734663

The Heidelberg classification of renal cell tumours.

Kovacs G, Akhtar M, Beckwith BJ, Bugert P, Cooper CS, Delahunt B, Eble JN, Fleming S, Ljungberg B, Medeiros LJ, Moch H, Reuter VE, Ritz E, Roos G, Schmidt D, Srigley JR, Stˆrkel S, van den Berg E, Zbar B

The Journal of pathology. 1997 ; 183 (2) : 131-133.

PMID 9390023

[Multiple trichodiscomas associated with colonic polyposis]

Le Guyadec T, Dufau JP, Poulain JF, Vaylet F, Grossin M, Lanternier G

Annales de dermatologie et de venereologie. 1998 ; 125 (10) : 717-719.

PMID 9835964

Familial renal oncocytoma: clinicopathological study of 5 families.

Weirich G, Glenn G, Junker K, Merino M, Stˆrkel S, Lubensky I, Choyke P, Pack S, Amin M, Walther MM, Linehan WM, Zbar B

The Journal of urology. 1998 ; 160 (2) : 335-340.

PMID 9679872

Parotid oncocytoma in the Birt-Hogg-Dubˆ© syndrome.

Liu V, Kwan T, Page EH

Journal of the American Academy of Dermatology. 2000 ; 43 (6) : 1120-1122.

PMID 11100034

Birt-Hogg-Dubˆ© syndrome: mapping of a novel hereditary neoplasia gene to chromosome 17p12-q11.2.

Khoo SK, Bradley M, Wong FK, Hedblad MA, Nordenskjˆld M, Teh BT

Oncogene. 2001 ; 20 (37) : 5239-5242.

PMID 11526515

Birt-Hogg-Dubˆ© syndrome, a genodermatosis associated with spontaneous pneumothorax and kidney neoplasia, maps to chromosome 17p11.2.

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

American journal of human genetics. 2001 ; 69 (4) : 876-882.

PMID 11533913

Clinical and genetic studies of Birt-Hogg-Dubˆ© syndrome.

Khoo SK, Giraud S, Kahnoski K, Chen J, Motorna O, Nickolov R, Binet O, Lambert D, Friedel J, Lˆ©vy R, Ferlicot S, Wolkenstein P, Hammel P, Bergerheim U, Hedblad MA, Bradley M, Teh BT, Nordenskjˆld M, Richard S

Journal of medical genetics. 2002 ; 39 (12) : 906-912.

PMID 12471204

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-Dubˆ© syndrome.

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

Cancer cell. 2002 ; 2 (2) : 157-164.

PMID 12204536

Renal tumors in the Birt-Hogg-Dubˆ© syndrome.

Pavlovich CP, Walther MM, Eyler RA, Hewitt SM, Zbar B, Linehan WM, Merino MJ

The American journal of surgical pathology. 2002 ; 26 (12) : 1542-1552.

PMID 12459621

Risk of renal and colonic neoplasms and spontaneous pneumothorax in the Birt-Hogg-Dubˆ© syndrome.

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

Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology. 2002 ; 11 (4) : 393-400.

PMID 11927500

Expression of Birt-Hogg-Dubˆ© gene mRNA in normal and neoplastic human tissues.

Warren MB, Torres-Cabala CA, Turner ML, Merino MJ, Matrosova VY, Nickerson ML, Ma W, Linehan WM, Zbar B, Schmidt LS

Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc. 2004 ; 17 (8) : 998-1011.

PMID 15143337

Evaluation and management of renal tumors in the Birt-Hogg-Dubˆ© syndrome.

Pavlovich CP, Grubb RL 3rd, Hurley K, Glenn GM, Toro J, Schmidt LS, Torres-Cabala C, Merino MJ, Zbar B, Choyke P, Walther MM, Linehan WM

The Journal of urology. 2005 ; 173 (5) : 1482-1486.

PMID 15821464

Germline BHD-mutation spectrum and phenotype analysis of a large cohort of families with Birt-Hogg-Dubˆ© syndrome.

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

American journal of human genetics. 2005 ; 76 (6) : 1023-1033.

PMID 15852235

REVIEW articles automatic search in PubMed

Last year publications automatic search in PubMed

Contributor(s)

Written 02-2006 Benedetta Toschi, Maurizio Genuardi

Department of Clinical Pathophysiology, University of Florence, Viale Gaetano Pieraccini 6, 50139 Firenze, Italy

Citation

This paper should be referenced as such :
Toschi B, Genuardi M . Birt-Hogg-Dubé Syndrome (BHD). Atlas Genet Cytogenet Oncol Haematol. February 2006 .
URL : http://AtlasGeneticsOncology.org/Genes/BirtHoggDubeID10091.html

© Atlas of Genetics and Cytogenetics in Oncology and Haematology
indexed on : Wed Sep 24 21:07:55 2008

Home Genes Leukemias Solid Tumours Cancer-Prone Deep Insight Case Reports Journals Portal Teaching

For comments and suggestions or contributions, please contact us

j.l.huret@chu-poitiers.fr.

Note	Birt-Hogg-Dubé syndrome (BHDS) is characterized by renal oncocytic tumors, benign skin tumors (fibrofolliculomas and trichodiscomas), and spontaneous pneumothorax. The first description of an affected family was provided by Birt, Hogg, and Dubé in 1977.
Inheritance	Autosomal Dominant with variable expressivity. Prevalence is estimated at about 1/200,000.

Phenotype and clinics	BHDS is a genodermatosis characterized by the triad of benign tumors of the hair follicle, spontaneous pneumothorax and kidney tumors. These manifestations do not have to be simultaneously present in the same individual in order to establish a diagnosis of BHDS, since the phenotype is variable and penetrance is not complete. Patients may also suffer from colonic polyps and colorectal cancer.Cutaneous tumors are fibrofolliculomas, trichodiscomas and/or acrochordons. Fibrofolliculomas and trichodiscomas tend to appear in the third or fourth decade of life as small white or skin-colored multiple papules on the face, neck and upper trunk. Acrochordon is a non specific designation for small and soft skin tags. Multiple angiofibromas, lipomas and collagenomas have also been reported. Affected individuals have a high chance of developing cysts in the lungs and spontaneous pneumothorax. Although almost all patients who have BHDS have lung blebs (90%), but only a fifth will have spontaneous pneumothorax. The strong association of spontaneous pneumothorax with BHDS suggests that the presence of spontaneous pneumothorax in a member of a BHDS family could be used as a criterion for the diagnosis of BHDS.
Neoplastic risk	Approximately 27% of BHDS patients develop renal tumors of different histological type: chromophobe (34%), hybrid chromophobe/oncocytic (50%), oncocytoma (5%), and clear cell renal carcinoma (9%). Hybrid tumors are most characteristic of this condition, and several lesions initially diagnosed as oncocytomas or chromofobe tumors have been defined as hybrid tumors upon reappraisal. Multiple histological types of kidney tumors can be found in the same BHDS family, in the same patient or even in the same kidney. Although colonic tumors have been observed in some families, it is not clear whether they represent a manifestation of BHDS.
Treatment	No specific medical treatment exists for the cutaneous lesions of BHDS. Surgical removal has provided definitive treatment of solitary perifollicular fibromas and electrodesiccation may be helpful in removal of multiple lesions, but these can recur.· High-resolution CT scan is required in order to identify lung cysts · Individuals at risk or affected by BHDS should be radiographically screened for renal tumors at periodic intervals and they are best treated with nephron sparing surgical approaches· Colonoscopy should be considered
Prognosis	Prognosis depends on the number, type and age at diagnosis of kidney tumors. Hybrid and chromophobe tumors have malignant potential, while pure renal oncocytomas are benign. Mean age at diagnosis of kidney tumors is 50.7 years.

Protein
Note	Folliculin
Description	The protein contains a conserved SLS potential phosphorylation site, a glutamic acid-rich coiled-coil domain, an N-glycosylation site, and 3 myristoylation sites. Its function is yet unknown

REVIEW articles	automatic search in PubMed
Last year publications	automatic search in PubMed

Written	02-2006	Benedetta Toschi, Maurizio Genuardi
		Department of Clinical Pathophysiology, University of Florence, Viale Gaetano Pieraccini 6, 50139 Firenze, Italy