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Year : 2013  |  Volume : 59  |  Issue : 4  |  Page : 324-325

Primary spontaneous pneumothorax and the Birt-Hogg-Dubé syndrome

Department of Internal and Pulmonary Medicine, Sher-I-Kashmir Institute of Medical Sciences, Srinagar, India

Date of Web Publication17-Dec-2013

Correspondence Address:
P A Koul
Department of Internal and Pulmonary Medicine, Sher-I-Kashmir Institute of Medical Sciences, Srinagar
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Source of Support: None, Conflict of Interest: None

PMID: 24430303

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How to cite this article:
Koul P A. Primary spontaneous pneumothorax and the Birt-Hogg-Dubé syndrome. J Postgrad Med 2013;59:324-5

How to cite this URL:
Koul P A. Primary spontaneous pneumothorax and the Birt-Hogg-Dubé syndrome. J Postgrad Med [serial online] 2013 [cited 2023 Sep 24];59:324-5. Available from:

Primary spontaneous pneumothorax is a global problem with a reported incidence of 18-28/100,000 per year for men and 1.2-6/100,000 per year for women. [1] About 11% of spontaneous pneumothorax patients have a positive family history, and the various heritable causes include Marfan syndrome,  Ehlers-Danlos syndrome More Details, α1-antitrypsin deficiency, lymphangioleiomyomatosis, Langerhan's cell hisiocytosis, cystic light chain disease, and cystic fibrosis. [2] Birt-Hogg-Dubé syndrome (BHDS) is a genodermatosis that, in addition to the dermatological manifestations, is characterized by predisposition to lung cysts and renal neoplasms. [3],[4] The cutaneous manifestations include fibrofolicullomas, trichodiscomas, and achrodons, [3],[4] whereas the renal neoplasms include renal oncocytoma, chromophobe renal cell carcinoma, oncocytic hybrid tumor, and clear cell renal cell carcinoma. While renal cell carcinoma is the most common and feared neoplasm reported in association with BHDS, non-renal tumors have been reported as well.

Even as the primary focus of care in BHDS is the management of renal tumors, pulmonary manifestations are among the most common manifestations. Cystic lung disease is seen in up to 90% of patients with BHDS, whereas spontaneous pneumothorax occurs in about 38%, [5] with a family history of pneumothorax in about 35%. [6] The syndrome typically exhibits clinical heterogeneity and the patients do not always have the three characteristic phenotypes (that of skin, kidney, and lung involvement). Lung disease (both cysts as well as pneumothoraces) may exist without the cutaneous manifestations, [7] and may be the earliest involvement. On radiological imaging, the cysts generally are elliptical or lentiform in shape with basilar and peripheral predominance and have a perivascular and periseptal localization. [6] As against cysts in other pulmonary conditions, cysts in BHDS are located in the middle and lower lobes toward the mediastinum and have an intimate association with interlobular septa and/or visceral pleura. These characteristic computed tomographic (CT) imaging features help clinicians differentiate the cysts from other cystic lung diseases. [8] Histopathologically, these cysts lack subpleural fibroelastic scars and changes of smoking, whereas cysts associated with pneumothorax in other pulmonary conditions show changes of respiratory bronchiolitis and fibroelastic scars. [9] Recently, it has been demonstrated that in BHDS, the cyst wall expands toward visceral pleura and gets incorporated partially into the interlobular septum, parenchyma, and/or bronchovascular bundle. [10] The cysts are lined on the inside by alveolar cells which may at times be attenuated and on occasion interspersed with cuboidal cells resembling type II pneumocytes. [10] The structural architecture of the cysts, however, gets distorted in pneumothorax-associated cysts. [10]

BHDS is caused by heterozygous mutations in the folliculin (FLCN) gene that is located on the short arm of chromosome 17 (17p 11.2). Folliculin is a 579-amino acid protein that is expressed in skin, skin appendages, stromal cells, the distal nephron, and pneumocytes. [5] It has 14 exons, and even as its exact molecular functions are unknown, it is believed to be a conserved tumor suppressor gene. [11] More than 100 germline mutations have been reported in the FLCN gene. They are seen in around 88% of cases of BHDS and include splice, deletions, insertions, nonsense, deletion/insertion, and missense mutations. [5] Geographic variation has been noted in these mutations. Whereas a cytosine duplication or deletion in the C8 tract of exon 11 is known to be a hotspot in Western patients, c.1347_1353dupCCACCCT in exon 12 and c.1533_1536delGATG in exon 13 are the hotspots in Asian kindreds. [12],[13]

Specific germline mutations or mutation types have not been associated with distinct phenotypic expression in BHDS due to the sheer lack of numbers to record such associations. [5] In this issue of the journal, a Taiwanese kindred with mutation c.1579_1580insA in exon 14 has been presented and the authors conclude that this mutation is associated with predominant lung involvement in BHDS without any renal involvement. Sequence analysis of select exons has shown that 53% of the families with BHDS had deletion or duplication of a C-nucleotide in the polycytosine tract in exon 11, which is a mutational hotspot, [5] with c.1733insC or c.1733delC being the most common BHDS mutation reported to date. [14],[15],[16],[17],[18],[19],[20],[21],[22] In a recent review of about 89 families, the most common 5' BHDS mutation was reported to have occurred at nucleotide 454 (c. 458delG) in exon 4 affecting the initiator codon of FLCN, [22] whereas the most common 3' mutation was reported to have occurred at nucleotide 2034 (c.2034 C>T) in exon 14. [5] The c.1579_1580insA reported by the authors in exon 14 is unique in being the only insertion mutation reported in this exon, although recently, an FLCN exon 14 deletion mutation has been reported from Spain and Japan. [13],[23] Predominant pulmonary manifestations were also reported in a Finnish kindred in whom a 4-bp deletion in exon 4 (c.235_238delTCGG) was detected with 100% penetrance. [24] Furuya and Nakatani also reported a 4-bp deletion in exon 13 (c.1533 1536delGATG) causing pulmonary cysts with 100% penetrance. [10] The size and volume of the lung cysts were demonstrated recently to be greater in individuals with FLCN mutation in exons 9 and 12 than in those with mutations in other exons, suggesting that there may be an association between the cyst size, number, and the underlying mutation. [25] While mutations in exon 14 have been rare, a novel deletion mutation (p.F519LfsX17 [c.1557delT]) in the BHDS gene exon 14 of the patient was reported recently from a Korean patient. [26] Pertinently, a 7-bp duplication in exon 12 (c.1347_1353dupCCACCCT) [12],[13] and mutations of a splice acceptor site in intron 5 [13],[19] have been reported only in Asian kindreds and not in American and European pedigrees.

All the mutations reported in FLCN gene result in truncation in the protein leading to its dysfunction. Recent evidence, however, suggests that FLCN also localizes to cilia, centrosomes, and the mitotic spindle, and alteration of FLCN levels can cause changes to the onset of ciliogenesis, without abrogating it. [27] FLCN mutants with BHDS may retain partial functionality and the clinical features in such patients may be due to abnormal levels rather than a complete loss of FLCN function. [27]

Establishing the links between the germline mutation and the phenotype may be possible in future by combining clinical and FLCN mutation data on clinically well-described BHDS patients and families from different centers. That should help our understanding of the BHDS and the peculiar organ involvement seen in certain kindreds. Currently, however, the data are too scant to imprint the association without conjecture.

 :: References Top

1.Melton LJ 3 rd , Hepper NG, Offord KP. Incidence of spontaneous pneumothorax in Olmsted County, Minnesota: 1950 to 1974. Am Rev Respir Dis 1979;120:1379-82.  Back to cited text no. 1
2.Toro JR, Pautler SE, Stewart L, Glenn GM, Weinreich M, Toure O, et al. Lung cysts, spontaneous pneumothorax, and genetic associations in 89 families with Birt-Hogg-Dubé syndrome. Am J Respir Crit Care Med 2007;175:1044-53.  Back to cited text no. 2
3.Birt AR, Hogg GR, Dubé WJ. Hereditary multiple fibrofolliculomas with trichodiscomas and acrochordons. Arch Dermatol 1977;113:1674-7.   Back to cited text no. 3
4.Toro JR, Glenn G, Duray P, Darling T, Weirich G, Zbar B, et al. Birt-Hogg-Dubé syndrome: A novel marker of kidney neoplasia. Arch Dermatol 1999;135:1195-202.  Back to cited text no. 4
5.Toro JR, Wei MH, Glenn GM, Weinreich M, Toure O, Vocke C, 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 2008;45:321-31.  Back to cited text no. 5
6.Gupta N, Seyama K, McCormack FX. Pulmonary manifestations of Birt-Hogg-Dubé syndrome. Fam Cancer 2013;12:387-96.  Back to cited text no. 6
7.Graham RB, Nolasco M, Peterlin B, Garcia CK. Nonsense mutations in folliculin presenting as isolated familial spontaneous pneumothorax in adults. Am J Respir Crit Care Med 2005;172:39-44.  Back to cited text no. 7
8.Tobino K, Hirai T, Johkoh T, Kurihara M, Fujimoto K, Tomiyama N, et al. Differentiation between Birt-Hogg-Dubé syndrome and lymphangioleiomyomatosis: Quantitative analysis of pulmonary cysts on computed tomography of the chest in 66 females. Eur J Radiol 2012;81:1340-6.  Back to cited text no. 8
9.Fabre A, Borie R, Debray MP, Crestani B, Danel C. Distinguishing histological and radiological features between pulmonary cystic lung disease in Birt-Hogg-Dubé Syndrome and tobacco-related spontaneous pneumothorax. Histopathology 'Accepted article' doi: 10.1111/his.12318   Back to cited text no. 9
10.Furuya M, Nakatani Y. Birt-Hogg-Dube syndrome: Clinicopathological features of the lung. J Clin Pathol 2013;66:178-86.  Back to cited text no. 10
11.Liu W, Chen Z, Ma Y, Wu X, Jin Y, Hou S. Genetic characterization of the Drosophila birt-hogg-dubé syndrome gene. PLoS One 2013;8:e65869.  Back to cited text no. 11
12.Furuya M, Tanaka R, Koga S, Yatabe Y, Gotoda H, Takagi S, et al. Pulmonary cysts of Birt-Hogg-Dubé syndrome: A clinicopathologic and immunohistochemical study of 9 families. Am J Surg Pathol 2012;36:589-600.  Back to cited text no. 12
13.Kunogi M, Kurihara M, Ikegami TS, Kobayashi T, Shindo N, Kumasaka T, 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 2010;47:281-7.  Back to cited text no. 13
14.Schmidt LS, Nickerson ML, Warren MB, Glenn GM, Toro JR, Merino MJ, et al. Germline BHD-mutation spectrum and phenotype analysis of a large cohort of families with Birt-Hogg-Dubé syndrome. Am J Hum Genet 2005;76:1023-33.  Back to cited text no. 14
15.Nickerson ML, Warren MB, Toro JR, Matrosova V, Glenn G, Turner ML, 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 2002;2:157-64.   Back to cited text no. 15
16.Khoo SK, Giraud S, Kahnoski K, Chen J, Motorna O, Nickolov R, et al. Clinical and genetic studies of Birt-Hogg-Dubé syndrome. J Med Genet 2002;39:906-12.  Back to cited text no. 16
17.van Steensel MA, Verstraeten VL, Frank J, Kelleners-Smeets NW, Poblete-Gutiérrez P, Marcus-Soekarman D, et al. Novel mutations in the BHD gene and absence of loss of heterozygosity in fibrofolliculomas of Birt-Hogg-Dubé patients. J Invest Dermatol 2007;127:588-93.  Back to cited text no. 17
18.Leter EM, Koopmans AK, Gille JJ, van Os TA, Vittoz GG, David EF, et al. Birt-Hogg-Dubé syndrome: Clinical and genetic studies of 20 families. J Invest Dermatol 2008;128:45-9.  Back to cited text no. 18
19.Gunji Y, Akiyoshi T, Sato T, Kurihara M, Tominaga S, Takahashi K, et al. Mutations of the Birt Hogg Dube gene in patients with multiple lung cysts and recurrent pneumothorax. J Med Genet 2007;44:588-93.  Back to cited text no. 19
20.Kawasaki H, Sawamura D, Nakazawa H, Hattori N, Goto M, Sato-Matsumura KC, et al. Detection of 1733insC mutations in an Asian family with Birt-Hogg-Dubé syndrome. Br J Dermatol 2005;152:142-5.  Back to cited text no. 20
21.Lamberti C, Schweiger N, Hartschuh W, Schulz T, Becker-Wegerich P, Küster W, et al. Birt-Hogg-Dubé syndrome: Germline mutation in the (C)8 mononucleotide tract of the BHD gene in a German patient. Acta Derm Venereol 2005;85:172-3.  Back to cited text no. 21
22.Bessis D, Giraud S, Richard S. A novel familial germline mutation in the initiator codon of the BHD gene in a patient with Birt-Hogg-Dubé syndrome. Br J Dermatol 2006;155:1067-9.  Back to cited text no. 22
23.Sempau L, Ruiz I, González-Morán A, Susanna X, Hansen TV. New mutation in the Birt Hogg Dube gene. Actas Dermosifiliogr 2010;101:637-40.  Back to cited text no. 23
24.Painter JN, Tapanainen H, Somer M, Tukiainen P, Aittomäki K. A 4-bp deletion in the Birt-Hogg-Dubé gene (FLCN) causes dominantly inherited spontaneous pneumothorax. Am J Hum Genet 2005;76:522-7.  Back to cited text no. 24
25.Kim EH, Jeong SY, Kim HJ, Kim YC. A case of Birt-Hogg-Dubé syndrome. J Korean Med Sci 2008;23:332-5.  Back to cited text no. 25
26.Luijten MN, Basten SG, Claessens T, Vernooij M, Scott CL, Janssen R, et al. Birt-Hogg-Dube syndrome is a novel ciliopathy. Hum Mol Genet 2013;22:4383-97.   Back to cited text no. 26
27.Toro JR, Pautler SE, Stewart L, Glenn GM, Weinreich M, Toure O, et al. Lung cysts, spontaneous pneumothorax, and genetic associations in 89 families with Birt-Hogg-Dubé syndrome. Am J Respir Crit Care Med 2007;175:1044-53.  Back to cited text no. 27


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