Birt-Hogg-Dubé syndrome: diagnosis and management.

Birt-Hogg-Dubé syndrome (BHD) is an autosomal dominant condition characterised clinically by skin fibrofolliculomas, pulmonary cysts, spontaneous pneumothorax, and renal cancer. The condition is caused by germline mutations in the FLCN gene, which encodes folliculin; the function of this protein is largely unknown, although FLCN has been linked to the mTOR pathway. The availability of DNA-based diagnosis has allowed insight into the great variation in expression of FLCN, both within and between families. Patients can present with skin signs and also with pneumothorax or renal cancer. Preventive measures are aimed mainly at early diagnosis and treatment of renal cancer. This Review gives an overview of current diagnosis and management of BHD.

[1]  E. Silverman,et al.  Folliculin mutations are not associated with severe COPD , 2008, BMC Medical Genetics.

[2]  M. Benson,et al.  Bilateral renal cell carcinoma in the Birt-Hogg-Dubé syndrome. , 1993, Journal of the American Academy of Dermatology.

[3]  Kazuhisa Takahashi,et al.  Mutations of the Birt–Hogg–Dubé gene in patients with multiple lung cysts and recurrent pneumothorax , 2007, Journal of Medical Genetics.

[4]  O. Hino,et al.  Natural history of the Nihon (Bhd gene mutant) rat, a novel model for human Birt–Hogg–Dubé syndrome , 2006, Virchows Archiv.

[5]  J. H. Jansen,et al.  Second hits in the FLCN gene in a hereditary renal cancer syndrome in dogs , 2008, Mammalian Genome.

[6]  P. Crino,et al.  The tuberous sclerosis complex. , 2006, The New England journal of medicine.

[7]  E. Henske,et al.  The role of the Birt–Hogg–Dubé protein in mTOR activation and renal tumorigenesis , 2009, Oncogene.

[8]  N. Lindor,et al.  Cutaneous sinus tract of dental origin , 2001, International journal of dermatology.

[9]  P. Gupta,et al.  Radiological findings in Birt-Hogg-Dubé syndrome: a rare differential for pulmonary cysts and renal tumors. , 2007, Clinical imaging.

[10]  N. Craven,et al.  Multiple hereditary facial papules , 2005, Clinical and experimental dermatology.

[11]  B. Peterlin,et al.  Nonsense mutations in folliculin presenting as isolated familial spontaneous pneumothorax in adults. , 2005, American journal of respiratory and critical care medicine.

[12]  B. Zbar,et al.  Birt-Hogg-Dubé syndrome: a novel marker of kidney neoplasia. , 1999, Archives of dermatology.

[13]  O. Durrani,et al.  Chromophobe renal cell carcinoma in a patient with the Birt-Hogg-Dube syndrome. , 2002, The Journal of urology.

[14]  K. Aittomäki,et al.  A 4-bp deletion in the Birt-Hogg-Dubé gene (FLCN) causes dominantly inherited spontaneous pneumothorax. , 2005, American journal of human genetics.

[15]  Ximing J. Yang,et al.  Deficiency of FLCN in Mouse Kidney Led to Development of Polycystic Kidneys and Renal Neoplasia , 2008, PloS one.

[16]  T. Gambichler,et al.  Treatment of Birt-Hogg-Dubé syndrome with erbium:YAG laser. , 2000, Journal of the American Academy of Dermatology.

[17]  Peter L Choyke,et al.  Germline BHD-mutation spectrum and phenotype analysis of a large cohort of families with Birt-Hogg-Dubé syndrome. , 2005, American journal of human genetics.

[18]  N. Bissada,et al.  Multiple/bilateral renal tumors in patients with Birt–Hogg–Dubé syndrome , 2007, International Urology and Nephrology.

[19]  E. Bröcker,et al.  [Hornstein-Knickenberg and Birt-Hogg-Dube syndrome. Report of a case with spontaneous pneumothorax and aplasia of the left internal carotid artery]. , 2001, Der Hautarzt; Zeitschrift fur Dermatologie, Venerologie, und verwandte Gebiete.

[20]  J. McNiff,et al.  Multiple facial angiofibromas: a cutaneous manifestation of Birt-Hogg-Dubé syndrome. , 2005, Journal of the American Academy of Dermatology.

[21]  W. Hartschuh,et al.  Birt‐Hogg‐Dubé‐syndrome and Hornstein‐Knickenberg‐syndrome are the same. Different sectioning technique as the cause of different histology , 1999, Journal of cutaneous pathology.

[22]  J. Frank,et al.  Molecular pathways involved in hair follicle tumor formation: all about mammalian target of rapamycin? , 2009, Experimental dermatology.

[23]  T. Kobayashi,et al.  Transgenic rescue from embryonic lethality and renal carcinogenesis in the Nihon rat model by introduction of a wild-type Bhd gene , 2006, Oncogene.

[24]  W. J. Dubé,et al.  Hereditary multiple fibrofolliculomas with trichodiscomas and acrochordons. , 1977, Archives of dermatology.

[25]  P. Choyke,et al.  Hereditary renal cancers. , 2003, Radiology.

[26]  B. Dutta,et al.  Birt–Hogg–Dubé syndrome and multinodular goitre , 2002, The Australasian journal of dermatology.

[27]  J. Dover,et al.  Birt-Hogg-Dube syndrome: treatment of cutaneous manifestations with laser skin resurfacing. , 2001, Archives of dermatology.

[28]  H. Ris,et al.  Diagnosis of Birt-Hogg-Dube syndrome in a patient with spontaneous pneumothorax. , 2006, The Annals of thoracic surgery.

[29]  P. Choyke,et al.  Small (< or = 3-cm) renal masses: detection with CT versus US and pathologic correlation. , 1996, Radiology.

[30]  W. James,et al.  Birt-Hogg-Dubé syndrome: two patients with neural tissue tumors. , 2003, Journal of the American Academy of Dermatology.

[31]  M. Akiyama,et al.  Conradi–Hünermann–Happle syndrome with abnormal lamellar granule contents , 2009, The British journal of dermatology.

[32]  H. Shimizu,et al.  Birt–Hogg–Dubé syndrome with clear‐cell and oncocytic renal tumour and trichoblastoma associated with a novel FLCN mutation , 2009, The British journal of dermatology.

[33]  P. Walter,et al.  Flecked chorioretinopathy associated with Birt-Hogg-Dubé syndrome , 1997, Graefe's Archive for Clinical and Experimental Ophthalmology.

[34]  G. Haber,et al.  Minimally invasive nephron-sparing surgery , 2008, Current opinion in urology.

[35]  S. Richard,et al.  Clinical and genetic studies of Birt-Hogg-Dubé syndrome , 2002, Journal of medical genetics.

[36]  L. Schmidt,et al.  A germ-line insertion in the Birt–Hogg–Dubé (BHD) gene gives rise to the Nihon rat model of inherited renal cancer , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[37]  Kun-Liang Guan,et al.  Dysregulation of the TSC-mTOR pathway in human disease , 2004, Nature Genetics.

[38]  Kentaro Takahashi,et al.  [Von Hippel-Lindau disease]. , 2006, Nihon rinsho. Japanese journal of clinical medicine.

[39]  H. Hamm,et al.  Hornstein-Knickenberg-/Birt-Hogg-Dubé-Syndrom Fallbericht mit Spontanpneumothorax und Aplasie der linken A. carotis interna , 2001, Der Hautarzt.

[40]  N. Müller,et al.  Birt-Hogg-Dubé syndrome: a rare cause of pulmonary cysts. , 2005, AJR. American journal of roentgenology.

[41]  R. Kotloff,et al.  Recurrent spontaneous pneumothorax as the presenting sign of the Birt-Hogg-Dubé syndrome. , 2009, Annals of internal medicine.

[42]  Y. Narisawa,et al.  A BHD germline mutation identified in an Asian family with Birt-Hogg-Dubé syndrome. , 2008, Acta dermato-venereologica.

[43]  W. Linehan,et al.  Expression of Birt–Hogg–Dubé gene mRNA in normal and neoplastic human tissues , 2004, Modern Pathology.

[44]  J. Babar,et al.  Cysts, cavities, and honeycombing in multisystem disorders: differential diagnosis and findings on thin-section CT. , 2009, Clinical radiology.

[45]  M. Evert,et al.  An unusual case of Birt-Hogg-Dube syndrome with renal involvement. , 2008, Urology journal.

[46]  P. Farrant,et al.  Letter: hyfrecation and curettage as a treatment for fibrofolliculomas in Birt-Hogg-Dube syndrome. , 2007, Dermatologic surgery : official publication for American Society for Dermatologic Surgery [et al.].

[47]  P. Choyke,et al.  Risk of renal and colonic neoplasms and spontaneous pneumothorax in the Birt-Hogg-Dubé syndrome. , 2002, Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology.

[48]  S. Steinberg,et al.  Lung cysts, spontaneous pneumothorax, and genetic associations in 89 families with Birt-Hogg-Dubé syndrome. , 2007, American journal of respiratory and critical care medicine.

[49]  J. Dover,et al.  Birt-Hogg-Dube syndrome: treatment of cutaneous manifestations with laser skin resurfacing. , 2001, Archives of dermatology.

[50]  P. Silverman,et al.  Renal cell carcinoma: diagnosis, staging, and surveillance. , 2008, AJR. American journal of roentgenology.

[51]  A. Yeldandi,et al.  A 48-year-old woman with skin lesions, renal masses, and spontaneous pneumothorax. , 2007, Chest.

[52]  F. Guadagni,et al.  Birt-Hogg-Dubé (BHD) syndrome: report of two novel germline mutations in the folliculin (FLCN) gene. , 2008, European journal of dermatology : EJD.

[53]  P. Choyke,et al.  Kidney-targeted Birt-Hogg-Dube gene inactivation in a mouse model: Erk1/2 and Akt-mTOR activation, cell hyperproliferation, and polycystic kidneys. , 2008, Journal of the National Cancer Institute.

[54]  P. Bejarano.  Pleuropulmonary Pathology of Birt-Hogg-Dubé Syndrome , 2007 .

[55]  J. H. Jansen,et al.  Loss of heterozygosity at the FLCN locus in early renal cystic lesions in dogs with renal cystadenocarcinoma and nodular dermatofibrosis , 2009, Mammalian Genome.

[56]  S. Richard,et al.  Familial Non-VHL Clear Cell (Conventional) Renal Cell Carcinoma: Clinical Features, Segregation Analysis, and Mutation Analysis of FLCN , 2008, Clinical Cancer Research.

[57]  N. Morrell,et al.  Familial spontaneous pneumothorax and lung cysts due to a Folliculin exon 10 mutation , 2009, European Respiratory Journal.

[58]  D. Qiao,et al.  Mutation analysis of the FLCN gene in Chinese patients with sporadic and familial isolated primary spontaneous pneumothorax , 2008, Clinical genetics.

[59]  C. Meijer,et al.  Familial multiple trichodiscomas. A clinicopathologic study. , 1985, Archives of dermatology.

[60]  W. James,et al.  Birt-Hogg-Dubé syndrome: a review of the literature and the differential diagnosis of firm facial papules. , 2003, Journal of the American Academy of Dermatology.

[61]  B. Teh,et al.  Birt-Hogg-Dubé syndrome: mapping of a novel hereditary neoplasia gene to chromosome 17p12-q11.2 , 2001, Oncogene.

[62]  T. Schulz,et al.  Multiple Mantelome bei Birt-Hogg-Dubé-Syndrom Erfolgreiche Therapie mit dem CO2-Laser , 2001, Der Hautarzt.

[63]  S. Richard,et al.  A new locus‐specific database (LSDB) for mutations in the folliculin (FLCN) gene , 2010, Human mutation.

[64]  G. Aughenbaugh,et al.  Cystic lung disease in Birt-Hogg-Dube syndrome. , 2007, Chest.

[65]  W. Linehan,et al.  Renal Tumors in the Birt-Hogg-Dubé Syndrome , 2002, The American journal of surgical pathology.

[66]  Seung-Beom Hong,et al.  Identification and characterization of a novel folliculin-interacting protein FNIP2. , 2008, Gene.

[67]  F. Flowers,et al.  MULTIPLE LIPOMAS, ANGIOLIPOMAS, AND PARATHYROID ADENOMAS IN A PATIENT WITH BIRT‐HOGG‐DUBE SYNDROME , 1996, International journal of dermatology.

[68]  J. Hartley,et al.  Folliculin encoded by the BHD gene interacts with a binding protein, FNIP1, and AMPK, and is involved in AMPK and mTOR signaling , 2006, Proceedings of the National Academy of Sciences.

[69]  P L Choyke,et al.  Parenchymal sparing surgery in patients with hereditary renal cell carcinoma: 10-year experience. , 2001, The Journal of urology.

[70]  W. Linehan,et al.  Birt-Hogg-Dubé syndrome, a genodermatosis associated with spontaneous pneumothorax and kidney neoplasia, maps to chromosome 17p11.2. , 2001, American journal of human genetics.

[71]  S. Richard,et al.  A novel familial germline mutation in the initiator codon of the BHD gene in a patient with Birt–Hogg–Dubé syndrome , 2006, The British journal of dermatology.

[72]  D. Brenner,et al.  Cancer risks from diagnostic radiology. , 2008, The British journal of radiology.

[73]  P L Choyke,et al.  Renal cancer in families with hereditary renal cancer: prospective analysis of a tumor size threshold for renal parenchymal sparing surgery. , 1999, The Journal of urology.

[74]  H. Alkadhi,et al.  Novel mutations in the folliculin gene associated with spontaneous pneumothorax , 2008, European Respiratory Journal.

[75]  Peter Choyke,et al.  Evaluation and management of renal tumors in the Birt-Hogg-Dubé syndrome. , 2005, The Journal of urology.

[76]  T. Kwan,et al.  Parotid oncocytoma in the Birt-Hogg-Dubé syndrome. , 2000, Journal of the American Academy of Dermatology.

[77]  M. Gill,et al.  B-RAF and melanocytic neoplasia. , 2005, Journal of the American Academy of Dermatology.

[78]  W. Linehan,et al.  High frequency of somatic frameshift BHD gene mutations in Birt-Hogg-Dubé-associated renal tumors. , 2005, Journal of the National Cancer Institute.

[79]  M. Medenica,et al.  Birt–Hogg–Dubé Syndrome , 2005, International journal of dermatology.

[80]  W. B. Wescott,et al.  Birt-Hogg-Dubé syndrome: a review and presentation of the first case with oral lesions. , 1997, Oral surgery, oral medicine, oral pathology, oral radiology, and endodontics.

[81]  A. Sodickson,et al.  Recurrent CT, cumulative radiation exposure, and associated radiation-induced cancer risks from CT of adults. , 2009, Radiology.

[82]  E. Kirkness,et al.  A mutation in the canine BHD gene is associated with hereditary multifocal renal cystadenocarcinoma and nodular dermatofibrosis in the German Shepherd dog. , 2003, Human molecular genetics.

[83]  Maria Merino,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. , 2002, Cancer cell.

[84]  T. Kobayashi,et al.  Interaction of folliculin (Birt-Hogg-Dubé gene product) with a novel Fnip1-like (FnipL/Fnip2) protein , 2008, Oncogene.

[85]  D. de Jong,et al.  Early onset of renal cancer in a family with Birt–Hogg–Dubé syndrome , 2009, Clinical genetics.

[86]  M. Wei,et al.  The folliculin mutation database: An online database of mutations associated with Birt‐Hogg‐Dubé syndrome , 2009, Human mutation.

[87]  T. Sauerbruch,et al.  Birt-Hogg-Dubé syndrome: germline mutation in the (C)8 mononucleotide tract of the BHD gene in a German patient. , 2005, Acta dermato-venereologica.

[88]  S. Steinberg,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 , 2008, Journal of Medical Genetics.

[89]  P. Steijlen,et al.  Novel mutations in the BHD gene and absence of loss of heterozygosity in fibrofolliculomas of Birt-Hogg-Dubé patients. , 2007, The Journal of investigative dermatology.

[90]  T. Seki,et al.  Postoperative fibromatosis-type fibromas in the Bhd gene mutant (Nihon) rat. , 2008, Experimental and toxicologic pathology : official journal of the Gesellschaft fur Toxikologische Pathologie.

[91]  R. Barr,et al.  Multiple fibrofolliculomas with trichodiscomas and acrochordons. , 1981, Archives of dermatology.

[92]  E. Henske,et al.  The Birt-Hogg-Dube and Tuberous Sclerosis Complex Homologs Have Opposing Roles in Amino Acid Homeostasis in Schizosaccharomyces pombe* , 2007, Journal of Biological Chemistry.

[93]  O. Hornstein,et al.  Perifollicular fibromatosis cutis with polyps of the colon—a cutaneo-intestinal syndrome sui generis , 1975, Archives of Dermatological Research.