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. [PMC free article: PMC2564862] [PubMed: 18234728]
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. [PubMed: 12204536]
3. Birt AR, Hogg GR, Dubé WJ: Hereditary multiple fibrofolliculomas with trichodiscomas and acrochordons. Arch Dermatol 113 (12): 1674-7, 1977. [PubMed: 596896]
4. Schmidt LS, Linehan WM: Molecular genetics and clinical features of Birt-Hogg-Dubé syndrome. Nat Rev Urol 12 (10): 558-69, 2015. [PMC free article: PMC5119524] [PubMed: 26334087]
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. [PubMed: 21929550]
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. [PubMed: 14597015]
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. [PubMed: 17504714]
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. [PubMed: 12459621]
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. [PMC free article: PMC4219093] [PubMed: 25519458]
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. [PMC free article: PMC3912328] [PubMed: 24378414]
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. [PubMed: 15805188]
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. [PMC free article: PMC1196403] [PubMed: 15657874]
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. [PubMed: 11927500]
14. Stamatakis L, Metwalli AR, Middelton LA, et al.: Diagnosis and management of BHD-associated kidney cancer. Fam Cancer 12 (3): 397-402, 2013. [PMC free article: PMC4175415] [PubMed: 23703644]

FLCN Gene

FLCN, a novel tumor suppressor gene, comprises 14 exons located at chromosome 17p11.2.[1] In patients with Birt-Hogg-Dubé syndrome (BHD), FLCN pathogenic variants have been identified in all translated exons,[2-5] and pathogenic intronic variants have also been described.[6] FLCN encodes a 64-kDa phosphoprotein, folliculin (also known as the FLCN protein), which is highly conserved among species.

Prevalence

Fewer than 1,000 families with BHD have been described across all continents.[7,8] Studies have reported prevalence estimates between 1 in 200,000 and 1 in 500,000 for BHD. A study that analyzed data from a population-based biobank discovered that BHD's incidence may be 10 to 100 times higher than previously thought.[7] Eighty-nine percent of participants in this study did not have BHD diagnoses prior to genetic testing, which highlights the often subtle clinical manifestations associated with BHD.

Genotype-Phenotype Correlations

A correlation has not been established between specific FLCN variants and renal, pulmonary, and cutaneous manifestations that are associated with BHD. However, individuals with a deletion in the polycytosine tract of exon 11 may have a lower risk of developing BHD-associated renal cancers than individuals with other FLCN variants.[2] However, the sample size in this study was small, and this observation was not replicated in a subsequent study from the same institution.[3] On the basis of the three major clinical manifestations (fibrofolliculomas/trichodiscomas, lung cysts/pneumothoraxes, and renal tumors), penetrance of BHD is considered to be very high. Anticipation is not known to occur in BHD.

References

1. 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. [PubMed: 12204536]
2. 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 76 (6): 1023-33, 2005. [PMC free article: PMC1196440] [PubMed: 15852235]
3. 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. [PMC free article: PMC2564862] [PubMed: 18234728]
4. Maffé A, Toschi B, Circo G, et al.: Constitutional FLCN mutations in patients with suspected Birt-Hogg-Dubé syndrome ascertained for non-cutaneous manifestations. Clin Genet 79 (4): 345-54, 2011. [PubMed: 20618353]
5. Kunogi M, Kurihara M, Ikegami TS, et al.: Clinical and genetic spectrum of Birt-Hogg-Dube syndrome patients in whom pneumothorax and/or multiple lung cysts are the presenting feature. J Med Genet 47 (4): 281-7, 2010. [PMC free article: PMC2981024] [PubMed: 20413710]
6. Rossing M, Albrechtsen A, Skytte AB, et al.: Genetic screening of the FLCN gene identify six novel variants and a Danish founder mutation. J Hum Genet 62 (2): 151-157, 2017. [PubMed: 27734835]
7. Savatt JM, Shimelis H, Moreno-De-Luca A, et al.: Frequency of truncating FLCN variants and Birt-Hogg-Dubé-associated phenotypes in a health care system population. Genet Med 24 (9): 1857-1866, 2022. [PMC free article: PMC9703446] [PubMed: 35639097]
8. Muller ME, Daccord C, Taffé P, et al.: Prevalence of Birt-Hogg-Dubé Syndrome Determined Through Epidemiological Data on Spontaneous Pneumothorax and Bayes Theorem. Front Med (Lausanne) 8: 631168, 2021. [PMC free article: PMC8111214] [PubMed: 33987191]

References

1. Vocke CD, Yang Y, Pavlovich CP, et al.: High frequency of somatic frameshift BHD gene mutations in Birt-Hogg-Dubé-associated renal tumors. J Natl Cancer Inst 97 (12): 931-5, 2005. [PubMed: 15956655]
2. 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 103 (42): 15552-7, 2006. [PMC free article: PMC1592464] [PubMed: 17028174]
3. Hasumi H, Baba M, Hong SB, et al.: Identification and characterization of a novel folliculin-interacting protein FNIP2. Gene 415 (1-2): 60-7, 2008. [PMC free article: PMC2727720] [PubMed: 18403135]
4. Shaw RJ: LKB1 and AMP-activated protein kinase control of mTOR signalling and growth. Acta Physiol (Oxf) 196 (1): 65-80, 2009. [PMC free article: PMC2760308] [PubMed: 19245654]
5. Nahorski MS, Reiman A, Lim DH, et al.: Birt Hogg-Dubé syndrome-associated FLCN mutations disrupt protein stability. Hum Mutat 32 (8): 921-9, 2011. [PubMed: 21538689]
6. Baba M, Furihata M, Hong SB, et al.: 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 100 (2): 140-54, 2008. [PMC free article: PMC2704336] [PubMed: 18182616]
7. Hasumi Y, Baba M, Ajima R, et al.: Homozygous loss of BHD causes early embryonic lethality and kidney tumor development with activation of mTORC1 and mTORC2. Proc Natl Acad Sci U S A 106 (44): 18722-7, 2009. [PMC free article: PMC2765925] [PubMed: 19850877]
8. Yan M, Gingras MC, Dunlop EA, et al.: The tumor suppressor folliculin regulates AMPK-dependent metabolic transformation. J Clin Invest 124 (6): 2640-50, 2014. [PMC free article: PMC4038567] [PubMed: 24762438]

Cutaneous Lesions

Individuals with BHD usually present with multiple, small, skin-colored, dome-shaped papules distributed over the face, neck, and upper trunk. The characteristic dermatologic manifestation is a fibrofolliculoma or trichodiscoma (hamartoma of the hair follicle).[4] The age at diagnosis of cutaneous lesions ranges from 20 to 72 years (median age, 54 y). Only a small percentage of carriers of FLCN pathogenic variants lack cutaneous manifestations,[1,5,6] suggesting that this syndromic phenotype is highly penetrant in affected individuals. In two large BHD family studies, 73% and 84% of affected patients in whom skin lesions were biopsied were found to have fibrofolliculomas/trichodiscomas.[1,2]

Histologically, fibrofolliculomas/trichodiscomas are characterized by multiple anastomosing epithelial strands emanating from a central follicle. Mucin-rich or thick connective tissue stroma may encapsulate the epithelial component.[7] Some describe these as lesions that emanate from the sebaceous mantle of the hair follicle. The underlying molecular mechanism, which stems from FLCN loss and drives the development of fibrofolliculomas/trichodiscomas, is unclear, but one report suggests that increased WNT signaling may play a role.[7] Fibrofolliculomas and trichodiscomas are different stages of a single pathologic process.

Pulmonary Cysts and Spontaneous Pneumothorax

Computed tomography (CT) imaging results showed that lung cysts are present in 85% to 87% of patients with BHD.[1,2] These cysts are often bilateral and multifocal and are located predominantly within the lower lobes of the lung. Most BHD-related lung cysts are asymptomatic; however, individuals affected with BHD have an increased risk of developing spontaneous pneumothorax. Patients with a pathogenic variant in FLCN and a family history of spontaneous pneumothorax had a statistically significant increased risk of spontaneous pneumothorax compared with BHD patients without a family history of spontaneous pneumothorax (P = .011).[8]

In a study of 198 patients with BHD, spontaneous pneumothorax occurrences were comparable between men (20%) and women (29%). Initial pneumothoraxes occurred between the ages of 22 and 75 years.[8] However, patients had their first pneumothorax occurrences at a median age of 38 years, and these typically occurred before the fifth decade of life. Patients had a 6% chance of developing their first spontaneous pneumothoraxes by age 30 years (95% confidence interval [CI], 3%–10%). This probability increased to 75% by age 50 years (95% CI, 19%–32%).[8] A review of English PubMed literature analyzed data from 1,038 patients with BHD, and pneumothoraxes occurred in 50.9% of patients. Pneumothorax incidence seemed to differ between individuals of varying ancestries.[9]

The clinical presentation of spontaneous pneumothorax ranges from asymptomatic to dyspnea and chest pain. Clinical findings include tachypnea or decreased-to-absent breath sounds. Radiographic investigation may require a high-resolution chest CT to confirm the diagnosis because a chest x-ray may not be sensitive enough to detect a loculated pneumothorax. Up to 75% of patients with a history of spontaneous pneumothorax experience a second one. Differences in reported spontaneous pneumothorax recurrence may reflect the efficacy of different treatment modalities.

Histologic findings of pleuropulmonary lesions associated with BHD patients include thin-walled pleural and subpleural cysts and bullae, intraparenchymal air cysts, pleural blebs and changes consistent with spontaneous pneumothorax, and underlying emphysematous changes in lung tissue parenchyma adjacent to the bullae.[5]

Renal Tumors

Approximately 25% to 35% of individuals with BHD develop renal tumors,[1,4,10,11] which are multifocal in 65% of cases and often bilateral. The frequency of renal tumors among patients with BHD whose medical records were reviewed was 20%, and the frequency of renal tumors among BHD patients evaluated by CT scan was 29%. Most renal tumors associated with BHD are slow growing. Median age at diagnosis is 48 to 50 years (range, 31–71 y).[2,12-14] Men developed renal tumors more often than did women (27 males; 11 females). Renal tumors associated with BHD seem to occur at a younger age than do sporadic forms of renal cell cancer (RCC), in which the median age at diagnosis is 64 years.[15] Figure 1 depicts bilateral renal tumors in a patient with BHD.

Figure 1. Birt-Hogg-Dubé syndrome–associated renal tumors are commonly multifocal and bilateral. Arrows indicate the locations of the tumors.

The most common tumors are a hybrid of oncocytoma and chromophobe histologic cell types, so-called oncocytic hybrid tumors, chromophobe RCC, and renal oncocytoma. Only renal oncocytoma is considered a benign tumor.[12] Other histologic renal tumor subtypes, including clear cell renal cell cancer (ccRCC) and papillary renal carcinoma, are uncommon in patients with BHD.[11]

Among 70 BHD patients with renal tumors and an FLCN pathogenic variant seen at the National Institutes of Health and identified through a literature review, 5 (7%) reportedly died from metastatic RCC.[1] The tumor histology in these five patients included clear cell, tubulopapillary, and/or papillary features, which are known to have a more biologically aggressive natural history. Death related to BHD-related oncocytoma and chromophobe neoplasms is exceedingly uncommon. Similar to von Hippel-Lindau disease and hereditary papillary renal carcinoma, the renal parenchyma of BHD patients commonly shows microscopic renal tumors adjacent to RCCs. The presence of microscopic oncocytosis provides histologic evidence that patients with BHD have a lifetime risk of developing renal tumors. The high frequency of FLCN somatic "second hits" (70%) in BHD-associated renal tumors supports the hypothesis that FLCN functions as a tumor suppressor gene.[16] Acquired somatic FLCN mutations have been only rarely identified in sporadic ccRCC.[17,18]

Other Manifestations

Bilateral multifocal parotid oncocytomas [19] have been reported in eight patients with BHD.[1,2,19-21] The bilateral, multifocal presentation of these rare tumors, in combination with recent molecular investigations, has led to the speculation that parotid oncocytomas might be part of the BHD phenotypic spectrum.

It should be noted that germline FLCN variants were also found in patients without cutaneous findings but suspected of having BHD because of their specific renal and pulmonary manifestations.[21]

Lipomas, angiolipomas,[22] collagenomas,[4] cutaneous neurothekeomas, meningiomas,[23] multinodular goiters of thyroid,[24,25] ovarian cysts,[25] parathyroid adenomas,[22] pulmonary histiocytomas,[26] and chorioretinal lesions [25,27] have all been reported in patients with BHD. Whether these manifestations are truly associated with BHD remains to be determined.

Although initial epidemiologic observations linked BHD to an increased risk for colon polyps, subsequent epidemiologic studies did not confirm this association.[10,18,28] In a study from the Netherlands, individuals with BHD did not have increased colorectal cancer (CRC) prevalence when compared with their unaffected relatives, despite individuals with BHD participating in enhanced CRC screening.[29]

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. [PMC free article: PMC2564862] [PubMed: 18234728]
2. 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 76 (6): 1023-33, 2005. [PMC free article: PMC1196440] [PubMed: 15852235]
3. Schmidt LS, Linehan WM: Molecular genetics and clinical features of Birt-Hogg-Dubé syndrome. Nat Rev Urol 12 (10): 558-69, 2015. [PMC free article: PMC5119524] [PubMed: 26334087]
4. Toro JR, Glenn G, Duray P, et al.: Birt-Hogg-Dubé syndrome: a novel marker of kidney neoplasia. Arch Dermatol 135 (10): 1195-202, 1999. [PubMed: 10522666]
5. 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. [PubMed: 15805188]
6. 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. [PMC free article: PMC1196403] [PubMed: 15657874]
7. Vernooij M, Claessens T, Luijten M, et al.: Birt-Hogg-Dubé syndrome and the skin. Fam Cancer 12 (3): 381-5, 2013. [PubMed: 23307118]
8. 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 175 (10): 1044-53, 2007. [PMC free article: PMC1899269] [PubMed: 17322109]
9. Matsumoto K, Lim D, Pharoah PD, et al.: A systematic review assessing the existence of pneumothorax-only variants of FLCN. Implications for lifelong surveillance of renal tumours. Eur J Hum Genet 29 (11): 1595-1600, 2021. [PMC free article: PMC8560836] [PubMed: 34267338]
10. 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. [PubMed: 11927500]
11. 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. [PubMed: 12459621]
12. Pavlovich CP, Grubb RL, Hurley K, et al.: Evaluation and management of renal tumors in the Birt-Hogg-Dubé syndrome. J Urol 173 (5): 1482-6, 2005. [PubMed: 15821464]
13. 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. [PMC free article: PMC3912328] [PubMed: 24378414]
14. Sattler EC, Reithmair M, Steinlein OK: Kidney cancer characteristics and genotype-phenotype-correlations in Birt-Hogg-Dubé syndrome. PLoS One 13 (12): e0209504, 2018. [PMC free article: PMC6306193] [PubMed: 30586397]
15. Howlader N, Noone AM, Krapcho M, et al.: SEER Cancer Statistics Review (CSR) 1975-2017. Bethesda, Md: National Cancer Institute, 2020. Available online. Last accessed August 9, 2024.
16. Vocke CD, Yang Y, Pavlovich CP, et al.: High frequency of somatic frameshift BHD gene mutations in Birt-Hogg-Dubé-associated renal tumors. J Natl Cancer Inst 97 (12): 931-5, 2005. [PubMed: 15956655]
17. da Silva NF, Gentle D, Hesson LB, et al.: Analysis of the Birt-Hogg-Dubé (BHD) tumour suppressor gene in sporadic renal cell carcinoma and colorectal cancer. J Med Genet 40 (11): 820-4, 2003. [PMC free article: PMC1735328] [PubMed: 14627671]
18. Khoo SK, Kahnoski K, Sugimura J, et al.: Inactivation of BHD in sporadic renal tumors. Cancer Res 63 (15): 4583-7, 2003. [PubMed: 12907635]
19. Liu V, Kwan T, Page EH: Parotid oncocytoma in the Birt-Hogg-Dubé syndrome. J Am Acad Dermatol 43 (6): 1120-2, 2000. [PubMed: 11100034]
20. Vinit J, Friedel J, Bielefeld P, et al.: [Birt-Hogg-Dubé syndrome and multiple recurrent tumors]. Rev Med Interne 32 (3): e40-2, 2011. [PubMed: 20576330]
21. Maffé A, Toschi B, Circo G, et al.: Constitutional FLCN mutations in patients with suspected Birt-Hogg-Dubé syndrome ascertained for non-cutaneous manifestations. Clin Genet 79 (4): 345-54, 2011. [PubMed: 20618353]
22. 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 35 (5): 365-7, 1996. [PubMed: 8734663]
23. Vincent A, Farley M, Chan E, et al.: Birt-Hogg-Dubé syndrome: two patients with neural tissue tumors. J Am Acad Dermatol 49 (4): 717-9, 2003. [PubMed: 14512924]
24. Drummond C, Grigoris I, Dutta B: Birt-Hogg-Dubé syndrome and multinodular goitre. Australas J Dermatol 43 (4): 301-4, 2002. [PubMed: 12423440]
25. Welsch MJ, Krunic A, Medenica MM: Birt-Hogg-Dubé Syndrome. Int J Dermatol 44 (8): 668-73, 2005. [PubMed: 16101870]
26. Tomassetti S, Carloni A, Chilosi M, et al.: Pulmonary features of Birt-Hogg-Dubé syndrome: cystic lesions and pulmonary histiocytoma. Respir Med 105 (5): 768-74, 2011. [PubMed: 21356586]
27. Walter P, Kirchhof B, Korge B, et al.: Flecked chorioretinopathy associated with Birt-Hogg-Dubé syndrome. Graefes Arch Clin Exp Ophthalmol 235 (6): 359-61, 1997. [PubMed: 9202964]
28. 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 47 (6): 385-90, 2010. [PubMed: 20522427]
29. van de Beek I, Glykofridis IE, Wolthuis RMF, et al.: No evidence for increased prevalence of colorectal carcinoma in 399 Dutch patients with Birt-Hogg-Dubé syndrome. Br J Cancer 122 (4): 590-594, 2020. [PMC free article: PMC7028712] [PubMed: 31857718]

Risk Assessment for Birt-Hogg-Dubé Syndrome (BHD)

Surveillance

BHD patients display two main clinical presentations. Most commonly, individuals present with a documented family history of BHD. Other presentations include individuals without a BHD family history or one that is unknown. In the former clinical scenario, if the patient's biological relative has a genetic diagnosis with an identified FLCN pathogenic variant, the patient may choose to begin evaluation with genetic counseling and pathogenic variant testing.

Clinical surveillance for individuals at risk of BHD includes dermatologic, radiological, and histological examinations to identify characteristic cutaneous lesions, renal tumors, and lung cysts, with or without a history of spontaneous pneumothorax. Not all features are present in each at-risk individual, and some BHD family members may have no discernible phenotypic findings (i.e., they are clinically unaffected carriers of deleterious FLCN variants). This clinical scenario is being encountered with increasing frequency as the number of syndrome-associated genes for which pathogenic variant testing can be offered clinically expands. In most disorders, the natural history of genetically abnormal/clinically normal individuals has not yet been well characterized. These major features of BHD are described in the Clinical diagnosis section.

Decisions regarding the use of lifelong surveillance for hereditary RCC syndromes must consider both risks and benefits. Approximately 15% to 29% of individuals with BHD have renal tumors,[2,9] which are commonly bilateral and multifocal and include a number of specific histologies within an individual or family.[7] For at-risk individuals who will undergo periodic imaging for many years even when no tumor is present, a surveillance schedule that minimizes the lifetime dose of radiation is advised.

Contrast-enhanced computed tomography (CT) or magnetic resonance imaging (MRI) are both useful modalities for the detection of BHD-associated renal tumors.[7] Ultrasonography alone may not be sufficient for detecting renal tumors because some tumors are isoechoic with the renal parenchyma,[10] but they may help identify renal cysts. A series in the Netherlands failed to detect 9 of 18 renal tumors using ultrasonography alone. Thus, while ultrasonography may reliably detect larger lesions, it is not a reliable modality for detecting smaller lesions and is therefore not used routinely as a lone screening tool.[11] If a renal tumor is detected, the patient is referred to a urologic oncology surgeon for management, which may include continued monitoring or surgery, depending mainly on tumor size.[7] If no renal tumor is detected on initial imaging, experts recommend lifelong surveillance at least once every 36 months because of the risk of developing RCC.[10] Because MRI spares the patient from exposure to radiation, it is reasonable to assume that it may be the preferred mode of imaging over CT for lifelong surveillance.

Level of evidence: 5

Treatment

References

1. Schmidt LS, Warren MB, Nickerson ML, et al.: Birt-Hogg-Dubé syndrome, a genodermatosis associated with spontaneous pneumothorax and kidney neoplasia, maps to chromosome 17p11.2. Am J Hum Genet 69 (4): 876-82, 2001. [PMC free article: PMC1226073] [PubMed: 11533913]
2. 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 76 (6): 1023-33, 2005. [PMC free article: PMC1196440] [PubMed: 15852235]
3. 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. [PMC free article: PMC2564862] [PubMed: 18234728]
4. Benhammou JN, Vocke CD, Santani A, et al.: Identification of intragenic deletions and duplication in the FLCN gene in Birt-Hogg-Dubé syndrome. Genes Chromosomes Cancer 50 (6): 466-77, 2011. [PMC free article: PMC3075348] [PubMed: 21412933]
5. Toro JR, Glenn G, Duray P, et al.: Birt-Hogg-Dubé syndrome: a novel marker of kidney neoplasia. Arch Dermatol 135 (10): 1195-202, 1999. [PubMed: 10522666]
6. Menko FH, van Steensel MA, Giraud S, et al.: Birt-Hogg-Dubé syndrome: diagnosis and management. Lancet Oncol 10 (12): 1199-206, 2009. [PubMed: 19959076]
7. Pavlovich CP, Grubb RL, Hurley K, et al.: Evaluation and management of renal tumors in the Birt-Hogg-Dubé syndrome. J Urol 173 (5): 1482-6, 2005. [PubMed: 15821464]
8. Gupta N, Seyama K, McCormack FX: Pulmonary manifestations of Birt-Hogg-Dubé syndrome. Fam Cancer 12 (3): 387-96, 2013. [PMC free article: PMC4409425] [PubMed: 23715758]
9. 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. [PubMed: 11927500]
10. Stamatakis L, Metwalli AR, Middelton LA, et al.: Diagnosis and management of BHD-associated kidney cancer. Fam Cancer 12 (3): 397-402, 2013. [PMC free article: PMC4175415] [PubMed: 23703644]
11. Johannesma PC, van de Beek I, van der Wel TJWT, et al.: Renal imaging in 199 Dutch patients with Birt-Hogg-Dubé syndrome: Screening compliance and outcome. PLoS One 14 (3): e0212952, 2019. [PMC free article: PMC6405080] [PubMed: 30845233]
12. Jacob CI, Dover JS: Birt-Hogg-Dube syndrome: treatment of cutaneous manifestations with laser skin resurfacing. Arch Dermatol 137 (1): 98-9, 2001. [PubMed: 11176677]
13. Gambichler T, Wolter M, Altmeyer P, et al.: Treatment of Birt-Hogg-Dubé syndrome with erbium:YAG laser. J Am Acad Dermatol 43 (5 Pt 1): 856-8, 2000. [PubMed: 11050594]
14. Kahle B, Hellwig S, Schulz T: [Multiple mantleomas in Birt-Hogg-Dubé syndrome: successful therapy with CO2 laser] Hautarzt 52 (1): 43-6, 2001. [PubMed: 11220238]
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 175 (10): 1044-53, 2007. [PMC free article: PMC1899269] [PubMed: 17322109]

References

1. Johannesma PC, van de Beek I, van der Wel TJWT, et al.: Renal imaging in 199 Dutch patients with Birt-Hogg-Dubé syndrome: Screening compliance and outcome. PLoS One 14 (3): e0212952, 2019. [PMC free article: PMC6405080] [PubMed: 30845233]

Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the genetics of Birt-Hogg-Dubé syndrome. It is intended as a resource to inform and assist clinicians in the care of their patients. It does not provide formal guidelines or recommendations for making health care decisions.

Reviewers and Updates

This summary is reviewed regularly and updated as necessary by the PDQ Cancer Genetics Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).

Board members review recently published articles each month to determine whether an article should:

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Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.

The lead reviewers for Birt-Hogg-Dubé Syndrome are:

• Alexandra Perez Lebensohn, MS, CGC (National Cancer Institute)
• Brian Matthew Shuch, MD (UCLA Health)
• Ramaprasad Srinivasan, MD, PhD (National Cancer Institute)

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Levels of Evidence

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PDQ® Cancer Genetics Editorial Board. PDQ Birt-Hogg-Dubé Syndrome. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: https://www.cancer.gov/publications/pdq/information-summaries/genetics/bhd-syndrome-hp-pdq. Accessed <MM/DD/YYYY>. [PMID: 33724752]

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