- Edward W Cowen, MD, MHSc
Edward W Cowen, MD, MHSc
- Director, American Board of Dermatology
- Newton, MA, USA;
- Fellow, American Academy of Dermatology
- Schaumburg, IL, USA;
- Senior Clinician and Head, Dermatology Consultation Service
- Center for Cancer Research, National Cancer Institute,
- National Institutes of Health
- Bethesda, MD, USA
Birt-Hogg-Dubé syndrome (BHD, MIM #135150) is an autosomal dominant condition first described in 1977, characterized by benign skin hamartomas, most commonly located on the head and neck; pulmonary cysts and spontaneous pneumothorax; and an increased risk of renal cancer. BHD syndrome is caused by germline mutations in the folliculin gene (FLCN), which encodes the protein folliculin, a putative tumor suppressor gene whose function is still under investigation.
This topic review will discuss the pathogenesis, clinical features, diagnosis, and management of BHD syndrome. Renal tumors and other inherited renal cancer syndromes are discussed separately. (See "Clinical manifestations, evaluation, and staging of renal cell carcinoma" and "Hereditary kidney cancer syndromes".)
The incidence of BHD syndrome is unknown. Approximately 200 families have been identified worldwide . The overall penetrance of folliculin (FLCN) mutations in affected families is high; however, the presence of cutaneous, pulmonary, and renal manifestations varies significantly, even within families. Although the penetrance of renal cancer is relatively low, patients with BHD syndrome have a sevenfold increased risk of kidney tumors compared with the general population .
In a review of 89 patients with BHD syndrome from 51 families from the National Institutes of Health (NIH), cutaneous lesions were found in 90 percent of patients, pulmonary cysts in 84 percent, and history of pneumothorax in 38 percent . Renal tumors were found in 30 patients from 25 families, indicating that most families with renal tumors had only one member affected, even after screening for renal tumors all carriers of FLCN mutations with abdominal computed tomography (CT) or magnetic resonance imaging (MRI) of the kidneys.
BHD syndrome is caused by germline mutations in the folliculin (FLCN) gene, located on chromosome 17p11.2. These mutations are small insertion/deletions, splice-site, and nonsense mutations, which lead in most cases to premature truncation and loss of function of the folliculin protein . To date, 149 unique FLCN germline mutations spanning all 14 exons have been identified in BHD families and catalogued in the Leiden Open Variation Database.
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- Nahorski MS, Lim DH, Martin L, et al. Investigation of the Birt-Hogg-Dube tumour suppressor gene (FLCN) in familial and sporadic colorectal cancer. J Med Genet 2010; 47:385.
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- Chung JY, Ramos-Caro FA, Beers B, et al. Multiple lipomas, angiolipomas, and parathyroid adenomas in a patient with Birt-Hogg-Dube syndrome. Int J Dermatol 1996; 35:365.
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- Wheeler CE Jr, Carroll MA, Groben PA, et al. Autosomal dominantly inherited generalized basaloid follicular hamartoma syndrome: report of a new disease in a North Carolina family. J Am Acad Dermatol 2000; 43:189.
- Starink TM, Houweling AC, van Doorn MB, et al. Familial multiple discoid fibromas: a look-alike of Birt-Hogg-Dubé syndrome not linked to the FLCN locus. J Am Acad Dermatol 2012; 66:259.e1.
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- Furuya M, Hong SB, Tanaka R, et al. Distinctive expression patterns of glycoprotein non-metastatic B and folliculin in renal tumors in patients with Birt-Hogg-Dubé syndrome. Cancer Sci 2015; 106:315.
- Klomp JA, Petillo D, Niemi NM, et al. Birt-Hogg-Dubé renal tumors are genetically distinct from other renal neoplasias and are associated with up-regulation of mitochondrial gene expression. BMC Med Genomics 2010; 3:59.
- Hes O, Petersson F, Kuroda N, et al. Renal hybrid oncocytic/chromophobe tumors - a review. Histol Histopathol 2013; 28:1257.
- Farrant PB, Emerson R. Letter: hyfrecation and curettage as a treatment for fibrofolliculomas in Birt-Hogg-Dube syndrome. Dermatol Surg 2007; 33:1287.
- Gambichler T, Wolter M, Altmeyer P, Hoffman K. Treatment of Birt-Hogg-Dubé syndrome with erbium:YAG laser. J Am Acad Dermatol 2000; 43:856.
- Kahle B, Hellwig S, Schulz T. [Multiple mantleomas in Birt-Hogg-Dubé syndrome: successful therapy with CO2 laser]. Hautarzt 2001; 52:43.
- 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; 20.
- Gijezen LM, Vernooij M, Martens H, 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:e99071.
- Stamatakis L, Metwalli AR, Middelton LA, Marston Linehan W. Diagnosis and management of BHD-associated kidney cancer. Fam Cancer 2013; 12:397.
- Jamis-Dow CA, Choyke PL, Jennings SB, et al. Small (< or = 3-cm) renal masses: detection with CT versus US and pathologic correlation. Radiology 1996; 198:785.
- Benusiglio PR, Giraud S, Deveaux S, et al. Renal cell tumour characteristics in patients with the Birt-Hogg-Dubé cancer susceptibility syndrome: a retrospective, multicentre study. Orphanet J Rare Dis 2014; 9:163.
- 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; 105:1912.
- CLINICAL MANIFESTATIONS
- Cutaneous lesions
- Pulmonary manifestations
- - Radiologic findings
- Kidney tumors
- Other neoplasms
- Clinical suspicion
- Skin biopsy
- Imaging studies
- Genetic testing
- Diagnostic criteria
- DIFFERENTIAL DIAGNOSIS
- Skin lesions
- Lung cysts and recurrent pneumothorax
- Renal tumors
- Skin lesions
- Renal tumors
- Genetic counseling
- SUMMARY AND RECOMMENDATIONS