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  IN THIS Article
 ::  Abstract
 :: Introduction
 :: Case Report
 :: Discussion
 :: Acknowledgments
 ::  References
 ::  Article Figures
 ::  Article Tables

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  Table of Contents     
Year : 2013  |  Volume : 59  |  Issue : 4  |  Page : 321-323

Isolated familial pneumothorax in a Taiwanese family with Birt-Hogg-Dubé syndrome

1 Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
2 Department of Surgery, National Taiwan University Hospital, Taipei, Taiwan

Date of Submission09-Aug-2013
Date of Decision10-Aug-2013
Date of Acceptance27-Aug-2013
Date of Web Publication17-Dec-2013

Correspondence Address:
H C Wang
Department of Internal Medicine, National Taiwan University Hospital, Taipei
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0022-3859.123169

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 :: Abstract 

Primary spontaneous pneumothorax usually occurs as a sporadic event, but may be clustered in certain families with an underlying inherited disorder. Birt-Hogg-Dubι (BHD) syndrome is a rare autosomal dominant disease accounting for familial pneumothorax. BHD syndrome, caused by mutation of the folliculin gene, is characterized by skin fibrofolliculoma, pulmonary cysts, pneumothorax, and renal cancer. We describe a BHD-affected Taiwanese family with clinical and genetic study. A rare mutation of the folliculin gene was detected in the patient and members with pulmonary cysts or pneumothorax, but no skin or renal lesions were found. This mutation was reported in a Taiwanese family and might indicate a pneumothorax-predominant phenotype. Isolated pneumothorax is an uncommon initial presentation of BHD syndrome. Family history should be carefully reviewed when managing a patient with pneumothorax.

Keywords: Inherited disease, pneumothorax, rare lung disease

How to cite this article:
Yang C Y, Wang H C, Chen J S, Yu C J. Isolated familial pneumothorax in a Taiwanese family with Birt-Hogg-Dubé syndrome. J Postgrad Med 2013;59:321-3

How to cite this URL:
Yang C Y, Wang H C, Chen J S, Yu C J. Isolated familial pneumothorax in a Taiwanese family with Birt-Hogg-Dubé syndrome. J Postgrad Med [serial online] 2013 [cited 2023 Oct 2];59:321-3. Available from:

 :: Introduction Top

Primary spontaneous pneumothorax (PSP) usually occurs from a sub-pleural bleb rupture in patients with unrecognized pulmonary disease. [1] Most cases of PSP are sporadic but may be clustered in certain families, implying an underlying inherited disorder, such as alpha-1 antitrypsin deficiency, Birt-Hogg-Dubé (BHD) syndrome,  Ehlers-Danlos syndrome More Details, Marfan syndrome, homocystinuria, or lymphangioleimyomatosis (LAM). BHD syndrome is a rare autosomal dominant disease characterized by skin fibrofolliculomas, pulmonary cysts with or without PSP, and renal cancer. [2] This syndrome is associated with mutation of folliculin (FLCN) gene, and certain FLCN mutations may have partial phenotypic expression and make diagnosis difficult. We investigated a Taiwanese family with a clustering of isolated PSP without notable skin or renal lesions. A rare frameshift mutation of FLCN gene was detected.

 :: Case Report Top

The index patient was a 48-year-old female who experienced chest tightness and dyspnea in July 2011. She denied any systemic disease or history of previous pneumothorax. Chest high-resolution computed tomography (HRCT) revealed bilateral pneumothorax and multiple cysts [Figure 1]. She underwent tube thoracotomy and bilateral bullectomywith pleurodesis by video-assisted thoracoscopic surgery and recovered a week later.
Figure 1: A chest computed tomography scan revealing left lower pulmonary cysts and bilateral pneumothorax

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A clustering of pneumothorax was observed in her family. Two of her siblings had a prior pneumothorax, both of whom underwent surgery. There was no known inherited or connective tissue diseases among the whole family. We performed a thorough clinical survey of 30 members across three generations of this family; including chest HRCTs in 7, serum alpha1-antitrypsin measurements in 9, mutation analyses of FLCN gene in 9, and questionnaire analyses regarding the presentation of BHD in all 30 members. The family pedigree is shown in [Figure 2], and their characteristics including genetic analysis are shown in [Table 1]. None of the family members had skin lesions or fibrofolliculomas. Two siblings (II.2 and II.5) in the second generation refused any further examinations. Another two siblings (II.4 and II.6) who previously had a pneumothorax refused HRCT. All the third-generation members (n=19) had only questionnaire analyses, and none had a pneumothorax.
Figure 2: Pedigree of a Taiwanese family with spontaneous pneumothorax. Generations and individuals indicated by Roman and Arabic numerals, respectively. Symbols: Arrow (index patient), circles (females), squares (males), open symbols (unaffected individuals), and filled symbols (affected individuals). *: Bullous lung disease shown on HRCT; §: Normal lung parenchyma on HRCT; †: Detected FLCN frameshift mutation; ‡: Wild-type FLCN gene

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Table 1: Characteristics of the family members with pneumothorax or confirmed genetic analysis

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The nine family members described in [Table 1] had no alpha-1 antitrypsin deficiencies. HRCT revealed bilateral lung cysts in five members (I.2, II.3, II.7, II.8, and II.9) that were compatible with an autosomal dominant inheritance pattern. Mutation analysis by direct sequencing of 11 coding exons of FLCN (exons 4-14) using peripheral blood mononuclear cell DNA identified a rare frameshift FLCN mutation with an adenine insertion in exon 14 (c. 1579_1580insA) [Figure 3] in seven of nine members examined (I.2, II.3, II.4, II.6, II.7, II.8, and II.9). All members harboring the FLCN mutation had bilateral pulmonary cysts per HRCT (I.2, II.3, II.7, II.8, and II.9) or clinically presented with a spontaneous pneumothorax (II.4, II.6, and II.7). Among seven members with FLCN gene mutations, six (II.3, II.4, II.6, II.7, II.8, and II.9) received renal echography, but no renal cancer was detected. This mutation may associate with a specific phenotype of BHD syndrome with predominant pneumothorax.
Figure 3: Direct sequencing of 11 coding exons of FLCN (exon 4-14) revealed the rare FLCN frameshift mutation: c. 1579_1580insA (top) on exon 14 and wild type (bottom)

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 :: Discussion Top

BHD syndrome was first reported in 1977 by Birt, Hogg, and Dubé in a family with specific skin fibrofolliculoma. [3] This syndrome is now documented as an autosomal inherited disorder caused by a mutation of the FLCN gene, [2] which is located on chromosome 17p11.2 and consists of 11 exons (exon 4-14). Currently, more than 100 germline FLCN mutations have been reported and registered in the online database ( European BHD consortium and USA). Different FLCN mutations may associate with specific phenotypes. As in our cases, isolated pneumothorax was reported in a large Finnish family with 24 BHD-affected members. A 4-bp deletion in exon 4 was detected with 100% penetrance. [4] Another study also reported two nonsense mutations in exon 9 and 12 in two American families with isolated pneumothorax. [5] In a large study of 198 patients with BHD syndrome and pulmonary cysts, patients with FLCN mutations in exon 9 and 12 were more prone to pneumothorax than those with FLCN mutations in other exons. [6] Additionally, patients with a specific cytosine deletion in exon 11 (c. 1285delC) may have a lower risk of renal cancer than that of patients with cytosine duplication in the same exon (c. 1285dupC). [7] The rare FLCN mutation in our cases was reported in another Taiwanese family in which three members had pneumothorax and one among the three had skin fibrofolliculoma. [8] Combining the two Taiwanese families, all BHD-affected patients (n=10) with FLCN gene mutations had pulmonary cysts or pneumothorax, and only one had fibrofollliculoma. This FLCN gene mutation, c. 1579-1580ins A in exon 14, may associate with a pneumothorax-predominant phenotype.

According to the registered database, the most frequently observed "hotspot" of FLCN mutation is a cytosine duplication (c. 1285dupC) or deletion (c. 1285delC) in exon 11. [2] However, FLCN mutation in this hotpot is less frequently seen in Asians while the majority of patients registered in the databases are Caucasians. A large analysis of 19 Asian families (18 Japanese, 1 Taiwanese mentioned earlier) with BHD revealed that a 7bp duplication in exon 12 (c. 1347_1353dupCCACCCT) and a 4bp deletion in exon 13 (c. 1533_1536delGATG) might be the hotspots. [9]

BHD-affected patients are prone to pneumothorax because of remarkable pulmonary cysts. Other cystic pulmonary disease should also be considered as differential diagnosis, such as LAM, Langerhans cell histiocytosis, and even rare, cystic lung light chain deposition disease. FLCN is a tumor suppressor gene, and mutation of FLCN causestruncation and dysfunction of the coding protein, FLCN, which may inducerenal carcinogenesis. FLCN protein is involved in the mammalian target of Rapamycin (mTOR) signaling pathway, but the exact mechanism in pulmonary cyst formation is poorly understood. One possible mechanism suggests that FLCN protein insufficiency in pulmonary cysts may activate mTOR pathway and up-regulate downstream molecules, such as vascular endothelial growth factor that may drive the cyst formation. [8] Other possible mechanisms include overexpression of matrix metalloproteinases (MMP), which may disrupt the integrity of extracellular matrix and cause cyst formation. Positive staining of MMP-9 in the wall of pulmonary cyst was reported in a BHD-affected patient with recurrent pneumothorax and rapid decline of pulmonary function. A favorable response was observed after treatment with doxycycline, a well-known anti-MMP agent. [10] BHD syndrome is frequently underdiagnosed, and family history should be carefully reviewed when managing a patient with pneumothorax. More data are needed to establish FLCN mutation database for Asian patients since the mutation and clinical presentation seem different from that of Caucasians.

 :: Acknowledgments Top

The authors would like to thank Dr. Su Yi-Ning, Department of Medical Genetics, National Taiwan University Hospital, for the help in genetic testing.

 :: References Top

1.Sahn SA, Heffner JE. Spontaneous pneumothorax. N Engl J Med 2000;342:868-74.  Back to cited text no. 1
2.Menko FH, van Steensel MA, Giraud S, Friis-Hansen L, Richard S, Ungari S, et al. Birt-Hogg-Dubésyndrome: Diagnosis and management. Lancet Oncol 2009;10:1199-206.  Back to cited text no. 2
3.Birt AR, Hogg GR, DubéWJ. Hereditary multiple fibrofolliculomas with trichodiscomas and acrochordons. Arch Dermatol 1977;113:1674-7.  Back to cited text no. 3
4.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. 4
5.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. 5
6.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-Dube syndrome. Am J Respir Crit Care Med 2007;175:1044-53.  Back to cited text no. 6
7.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-Dube syndrome. Am J Hum Genet 2005;76:1023-33.  Back to cited text no. 7
8.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. 8
9.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. 9
10.Pimenta SP, Baldi BG, Nascimento EC, Mauad T, Kairalla RA, Carvalho CR. Birt-Hogg-Dubé syndrome: Metalloproteinase activity and response to doxycycline. Clinics (Sao Paulo) 2012;67:1501-4.  Back to cited text no. 10


  [Figure 1], [Figure 2], [Figure 3]

  [Table 1]

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