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Birt-Hogg-Dubé Syndrome (PDQ®): Genetics - Health Professional Information [NCI]

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Introduction

Birt-Hogg-Dubé syndrome (BHD) is an autosomal dominantly inherited hamartomatous disorder caused by germline pathogenic variants in the FLCNgene.[1,2] First described by Birt in 1977, BHD is characterized by cutaneous hamartomas known as fibrofolliculomas /trichodiscomas.[3] Clinical characteristics of BHD also include pulmonary cysts, spontaneous pneumothoraxes, and various histological types of renal tumors.[4]Acrochordons can be found in individuals with BHD, but they are also commonly found in the general population and are therefore, not diagnostic.[5,6,7]

Disease severity can vary significantly. Skin lesions typically appear during the third or fourth decades of life and increase in size and number with age. Lung cysts are usually bilateral and multifocal. Most individuals with lung cysts are asymptomatic but have a high risk of developing spontaneous pneumothoraxes.

Approximately 15% to 30% of individuals with BHD develop renal tumors, which are typically bilateral, multifocal, and slow growing.[8,9,10] Tumors are diagnosed at a median age of 46 to 50 years. In BHD, hybrid oncocytic renal tumors (these tumors have features of both oncocytomas and chromophobe histological cell types) (50%), chromophobe renal cell cancers (34%), and oncocytomas (9%) are diagnosed most often. Clear cell and papillary tumors have been described, but they make up less than 10% of all BHD-associated renal tumors.[8] Some families present with renal tumors and/or autosomal dominant spontaneous pneumothoraxes without cutaneous manifestations.[9,11,12]

Natural History

The clinical characteristics of BHD include fibrofolliculomas/trichodiscomas (types of cutaneous hamartomas), pulmonary cysts/histories of pneumothoraxes, and various histological types of renal tumors. BHD is characterized by phenotypic heterogeneity, and disease severity can vary significantly among family members and between families. To date, there is no evidence of increased risk of skin cancer or malignant transformation of these hamartomatous lesions.

In 2001, a family-based study showed that patients with the clinical diagnosis of BHD were seven times more likely than clinically unaffected family members to develop renal tumors.[13] Patients with clinical diagnoses of BHD were also 50 times more likely than clinically unaffected family members to develop spontaneous pneumothoraxes. This study confirmed that renal tumors and spontaneous pneumothoraxes are both major manifestations of BHD. While BHD-associated renal tumors can be aggressive, they are generally indolent. Most appropriately managed patients will require no more than one partial nephrectomy on each kidney during their lifetimes.[14] Metastatic disease, although described, is rare.[14]

References:

  1. 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 45 (6): 321-31, 2008.
  2. 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 2 (2): 157-64, 2002.
  3. Birt AR, Hogg GR, Dubé WJ: Hereditary multiple fibrofolliculomas with trichodiscomas and acrochordons. Arch Dermatol 113 (12): 1674-7, 1977.
  4. Schmidt LS, Linehan WM: Molecular genetics and clinical features of Birt-Hogg-Dubé syndrome. Nat Rev Urol 12 (10): 558-69, 2015.
  5. Boza JC, Trindade EN, Peruzzo J, et al.: Skin manifestations of obesity: a comparative study. J Eur Acad Dermatol Venereol 26 (10): 1220-3, 2012.
  6. Sanfilippo AM, Barrio V, Kulp-Shorten C, et al.: Common pediatric and adolescent skin conditions. J Pediatr Adolesc Gynecol 16 (5): 269-83, 2003.
  7. Yosipovitch G, DeVore A, Dawn A: Obesity and the skin: skin physiology and skin manifestations of obesity. J Am Acad Dermatol 56 (6): 901-16; quiz 917-20, 2007.
  8. Pavlovich CP, Walther MM, Eyler RA, et al.: Renal tumors in the Birt-Hogg-Dubé syndrome. Am J Surg Pathol 26 (12): 1542-52, 2002.
  9. 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 9: 163, 2014.
  10. Shuch B, Vourganti S, Ricketts CJ, et al.: Defining early-onset kidney cancer: implications for germline and somatic mutation testing and clinical management. J Clin Oncol 32 (5): 431-7, 2014.
  11. Graham RB, Nolasco M, Peterlin B, et al.: Nonsense mutations in folliculin presenting as isolated familial spontaneous pneumothorax in adults. Am J Respir Crit Care Med 172 (1): 39-44, 2005.
  12. Painter JN, Tapanainen H, Somer M, et al.: A 4-bp deletion in the Birt-Hogg-Dubé gene (FLCN) causes dominantly inherited spontaneous pneumothorax. Am J Hum Genet 76 (3): 522-7, 2005.
  13. 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 11 (4): 393-400, 2002.
  14. Stamatakis L, Metwalli AR, Middelton LA, et al.: Diagnosis and management of BHD-associated kidney cancer. Fam Cancer 12 (3): 397-402, 2013.
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