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Cystic Lung Disease in Birt-Hogg-Dubé Syndrome* FREE TO VIEW

Dereje S. Ayo, MD; Gregory L. Aughenbaugh, MD; Eunhee S. Yi, MD; Jennifer L. Hand, MD; Jay H. Ryu, MD, FCCP
Author and Funding Information

*From the Division of Pulmonary and Critical Care Medicine (Drs. Ayo and Ryu), Department of Radiology (Dr. Aughenbaugh), Division of Anatomic Pathology (Dr. Yi), and Department of Dermatology (Dr. Hand), Mayo Clinic, Rochester, MN.

Correspondence to: Jay H. Ryu, MD, FCCP, Division of Pulmonary and Critical Care Medicine, Desk East 18, Mayo Clinic, 200 First St SW, Rochester, MN 55905; e-mail: ryu.jay@mayo.edu



Chest. 2007;132(2):679-684. doi:10.1378/chest.07-0042
Text Size: A A A
Published online

Background: To describe the clinical, radiologic, and histopathologic aspects of cystic lung disease occurring in patients with Birt-Hogg-Dubé (BHD) syndrome, a rare, inheritable, multisystem disorder.

Methods: We retrospectively reviewed five patients with BHD syndrome evaluated at the Mayo Clinic Rochester from 1998 through 2005.

Results: Mean age (± SD) at the time of pulmonary evaluation was 56.4 ± 4.8 years; four patients were men. Three patients had not received a diagnosis of BHD syndrome at the time of initial CT of the chest. Three patients had a smoking history, and two were nonsmokers. Two patients had a history of recurrent pneumothoraces. Pulmonary function tests available in four patients revealed normal results in one patient and mild airflow obstruction or nonspecific pattern of abnormalities in three patients. CT of the chest revealed cystic lung disease in all five patients; cysts were round to oval in shape, ranged widely in size, and were randomly distributed throughout the lungs, except for a predilection to involve the lung bases more extensively. Three patients with a smoking history had more severe cystic changes compared to nonsmokers and included both patients with recurrent pneumothoraces. Surgical lung biopsy available in one patient revealed emphysema-like changes. Follow-up CT scans available in four patients revealed relative stability over a median interval of 20 months (range, 3 to 66 months).

Conclusion: We conclude that cystic lung disease in BHD syndrome varies widely in severity, mimics pulmonary lymphangioleiomyomatosis, and may be worsened by smoking.

Figures in this Article

Birt-Hogg-Dubé (BHD) syndrome is a rare, inheritable disorder (autosomal dominant) that was first described in 1977.1It is caused by germline mutations in the BHD (FLCN) gene that lies within the chromosomal band 17p11.2 and encodes for a tumor-suppressor protein, folliculin.2 Folliculin is highly expressed in a variety of tissues, including the skin, kidney, and lung (stromal cells and type I pneumocytes).3 BHD syndrome is characterized by the cutaneous triad of fibrofolliculomas (hamartoma of the hair follicle), trichodiscomas, and skin tags, along with a propensity for renal tumors.12 Characteristic skin lesions typically appear as firm, dome-shaped papules in adults during the third or fourth decades of life and occur predominantly on the face, scalp, neck, and upper chest (Fig 1 ).,1,45 Renal tumors associated with BHD syndrome have included oncocytic hybrid tumor, chromophobe renal cell carcinoma, clear cell carcinoma, and papillary renal cell carcinoma.6

In recent years, a relationship between BHD syndrome with pulmonary cysts and spontaneous pneumothorax has become recognized, but description of this lung disease has been limited.5,713 In this study, we sought additional details of cystic lung disease in BHD syndrome, including the clinical presentation, radiologic features, pulmonary function correlates, histopathology, and clinical course.

Study Population

A computer-aided search was conducted to identify all patients seen at the Mayo Clinic in Rochester, MN, during an 8-year period from January 1, 1998, to December 31, 2005, with a diagnosis of BHD syndrome or fibrofolliculoma. We identified seven patients with BHD syndrome, five of whom had CT of chest available for review and were included in this study. In all five patients, the diagnosis was confirmed clinically. Three patients chose to have genetic testing, and each patient was heterozygous for a FLCN mutation (Table 1 ). One of the excluded patients did not have any chest imaging, and the other patient had normal findings on chest radiography. The Mayo Foundation Institutional Review Board approved this study.

Clinical Data Collection

Data extracted from the medical records included demographics, clinical presentation, laboratory results, radiologic findings, and pulmonary function results. Presenting features were recorded from the first encounter at the Mayo Clinic that led to a diagnosis of cystic lung disease associated with BHD syndrome. Follow-up data were collected regarding subsequent clinical course, pulmonary function results, and imaging studies. Chest radiographs and CT scans of the chest were reviewed by a chest radiologist (G.L.A.). Four of five patients had both high-resolution and standard CT scans of the chest available; one patient had a standard CT only. Pulmonary function measurements included plethysmographically determined total lung capacity and residual volume, along with FVC, FEV1, ratio of FEV1 to FVC, and diffusing capacity for carbon monoxide. Spirometry and measurements of lung volumes and diffusing capacity were performed in our pulmonary function laboratory and were expressed as percentage of predicted normal values, using previously described techniques.14 Surgical lung biopsy slides were available in one patient and were reviewed by a pulmonary pathologist (J.E.Y.).

Patient Characteristics

None of the patients had a diagnosis of BHD syndrome at the time of the initial evaluation at our institution for skin lesions (three patients), renal mass (one patient), and recurrent pneumothorax (one patient). Mean age (± SD) at the time of pulmonary evaluation was 56.4 ± 4.8 years; four of five patients were men (Table 1). Three patients did not have BHD syndrome diagnosed at the time of the initial CT scan of the chest. Further examination after initial presentation revealed characteristic skin lesions in all five patients. Three patients had confirmed fibrofolliculomas, and two had trichodiscomas. One patient had the complete triad of trichodiscomas, trichofolliculomas, and skin tags. Mean age at the time of BHD syndrome diagnosis was 57.2 ± 5.4 years.

None of the patients were current smokers, but three had a smoking history. Two patients had respiratory symptoms, including exertional dyspnea (two patients) and chronic productive cough (one patient); three patients were asymptomatic. One of the symptomatic patients had a right pneumothorax on presentation; this patient had a previous personal history (12 episodes over 24 years) and a strong family history (father, uncle, sister, daughter, and nephew) of spontaneous pneumothoraces. One additional patient had a history of recurrent pneumothoraces (two episodes) for which surgical stapling and pleurodesis had been performed. Two patients with previous pneumothoraces were both ex-smokers.

Chest radiographs were available in all patients and revealed a right-sided, loculated hydropneumothorax in one patient; another patient had detectable cysts. No cysts were appreciable by chest radiography in the three remaining patients. CT scan of the chest revealed cystic lung disease in all five patients (Table 1); one patient had a right-sided pneumothorax (Fig 2 ). These cysts were round to oval in shape and ranged widely in size (a few millimeters to several centimeters). The cysts were randomly distributed in the cross-sectional dimension as well as in the cephalocaudal axis, with the exception of more extensive involvement in the lung bases for two patients (Fig 3 , top, A, and bottom, B). Two of three patients with a smoking history had evidence of emphysema by CT. Two nonsmokers had relatively mild lung involvement with small scattered cysts (3 to 16 mm in diameter), while those with a smoking history had more severe extensive disease with larger cysts (Table 1). The main indication for the initial CT of the chest included evaluation of BHD syndrome (two patients), assessment for possible metastatic disease from prior renal cancer (two patients), and recurrent pneumothorax (one patient). Follow-up CT scans available in four patients revealed minimal progression in only one patient over a median interval of 20 months (range, 3 to 66 months).

Pulmonary function results available in four patients revealed normal results in one patient (nonsmoker), mild airway obstruction in two patients, and nonspecific pattern of abnormalities (mildly reduced FEV1 with a normal FEV1/FVC ratio) in one patient. Three patients with abnormal pulmonary function results were previous smokers. Follow-up pulmonary function results were available in two patients and revealed no evidence of significant worsening over intervals of 42 months and 49 months, respectively.

A surgical lung biopsy specimen was available in one patient; wedge biopsies were performed from the right lower lobe of the lung at the time of surgical stapling and pleurodesis (Table 1). Histologic sections showed benign lung parenchyma with widespread emphysematous changes (Fig 4 , top, A). The visceral pleura and interlobular septa demonstrated patchy areas of fibrosis, mesothelial hyperplasia, and eosinophilic pleuritis, findings consistent with the patient’s clinical history of recurrent episodes of spontaneous pneumothorax. There was no apparent intraparenchymal air cyst or air-filled intrapleural bleb in the pleural surface. However, a focus of air accumulation was noted in the interlobular septa that displaced a vein to the opposite side (Fig 4, bottom, B). Incidentally, a 1-mm focus of low-grade atypical adenomatous hyperplasia was found in a random section.

Clinical follow-up was available in all five patients over a median duration of 36 months (range, 13 to 76 months) following the initial CT of the chest. No pneumothorax or other respiratory events occurred during this period. Two patients required partial nephrectomy for chromophobe carcinoma (58-year-old man) and clear renal cell cancer (50-year-old man), respectively. One of these patients had already undergone renal resections for chromophobe cell carcinoma and oncocytoma (58-year-old man).

In this study, cystic lung disease was seen by CT in all five middle-aged patients with BHD syndrome; two of these patients had recurrent pneumothoraces. All five patients had skin lesions characteristic of BHD syndrome; two patients had previously undergone resection of renal tumors (clear cell and chromophobe renal cancers, respectively) associated with BHD syndrome. Pulmonary function was only mildly impaired and may have been affected by smoking and pleural complications as well as the cystic lung disease. Cystic lung disease associated with BHD syndrome varied in severity and appeared to be more extensive in patients with a smoking history but remained relatively stable on follow-up CT scans over an interval ranging up to nearly 6 years.

In a case report, Chung and colleagues15 described a 60-year-old man who presented with numerous papules on the face, neck, and upper trunk that began to appear in his early 20s along with a history of recurrent pneumothoraces. No additional information was provided regarding this patient’s pulmonary disease. In 1999, Toro and colleagues7reported an association between cystic lung disease and BHD syndrome. Four of 28 patients (14%) with BHD syndrome and at-risk relatives had pulmonary cysts detected by chest radiography; one of these patients had a history of pneumothorax. In a study of 223 members of BHD syndrome families, Zbar and colleagues8 noted 26 subjects (11.7%) to have had spontaneous pneumothorax. CT scanning detected pulmonary cysts in 83% of affected member of BHD syndrome families. In this study, the odds ratio of pneumothorax in BHD syndrome-affected subjects, adjusted for age, was 50.3.

Mutations in the FLCN gene are responsible for BHD syndrome as well as the syndrome of dominantly inherited spontaneous pneumothorax.10,16 In the latter condition, nonsense mutations and a 4–base-pair deletion in exon 4 of FLCN gene have been identified.,10 Affected family members have cystic lung lesions that are scattered randomly throughout the lungs.10 The function of folliculin and how mutations of FLCN gene gives rise to pulmonary cysts and pneumothorax remain unknown, but association with cutaneous hamartomas and renal neoplasia suggests tumor suppressor function.,10

Pulmonary pathology in BHD syndrome was described in two patients by Butnor and Guinee.12 Histopathologic features were nonspecific and included intraparenchymal air-filled spaces surrounded by normal parenchyma or a thin fibrous wall. Lung tissue adjacent to the cysts appeared normal. Both of these patients were nonsmokers. Similar nonspecific findings were noted in our patient.

Cystic lung disease seen in BHD syndrome needs to be distinguished from other lung diseases characterized by multifocal or diffuse cystic changes, including lymphangioleiomyomatosis, pulmonary Langerhans cell histiocytosis, lymphocytic interstitial pneumonitis, and Pneumocystis pneumonia.1718 Lymphocytic interstitial pneumonia and Pneumocystis pneumonia both cause parenchymal changes aside from cysts such as ground-glass opacities, consolidation, nodules, and reticular opacities.1718 In addition, both of these disorders are usually symptomatic and are associated with specific clinical contexts. Pulmonary Langerhans cell histiocytosis encountered in adults is usually a smoking-related interstitial lung disease and is characterized by irregular cystic lesions and nodules predominantly affecting the upper and mid lung zones with relative sparing of the bases.1719 This pattern of distribution, irregular shape of the cysts, and architectural distortion seen in the intervening lung parenchyma are characteristics of pulmonary Langerhans cell histiocytosis, and distinguishable from cystic lung disease seen in BHD syndrome. Rarely, metastatic neoplasms, including adenocarcinomas and low-grade sarcomas, can present with cystic lung lesions.18,20

Pulmonary lymphangioleiomyomatosis may be more difficult to separate radiologically from cystic lesions of BHD syndrome since both disorders are characterized by scattered cystic lesions that are randomly distributed throughout the lungs with no appreciable changes in the intervening lung parenchyma.1718,21 Furthermore, both disorders can present with lung cysts and renal masses, although the fatty component of renal angiomyolipomas associated with pulmonary lymphangioleiomyomatosis can usually be distinguished radiologically from solid renal tumors of BHD syndrome. Pulmonary lymphangioleiomyomatosis almost exclusively affects women and typically presents in the third and fourth decades of life,21 earlier than patients with BHD syndrome described in this report. However, both of these disorders can be associated with recurrent spontaneous pneumothoraces, although a known family history of BHD syndrome would obviously be helpful in the differential diagnosis. Additional evaluation including biopsy of lung, skin lesions or renal tumor may help distinguish these two disorders. In some patients, BHD syndrome may be mistaken for tuberous sclerosis because the latter disorder is also associated with lung cysts (almost exclusively in women) and facial skin lesions.2122

BHD syndrome is associated with renal tumors of various histologic types, including clear cell, chromophobe, and papillary types of renal cell cancers, as well as oncocytomas.6,23 Thus, patients with BHD syndrome should be screened for renal tumors and carefully followed up at periodic intervals. Similarly, family members of patients with BHD syndrome should be screened for renal tumors and offered genetic counseling.

In conclusion, we find cystic lung disease in BHD syndrome to vary in severity in patients affected with this rare disorder. Although our data are limited by small number of patients, smoking appears to be associated with more severe lung disease compared to nonsmokers, a relationship not previously explored in BHD syndrome. Limited follow-up of our patients suggests a relatively slow rate of progression for this lung disease.

Abbreviation: BHD = Birt-Hogg-Dubé syndrome

The authors have no conflicts of interest to disclose.

Figure Jump LinkFigure 1. Photograph of fibrofolliculomas: multiple, firm, white papules on the jaw line and neck of a 50-year-old man.Grahic Jump Location
Table Graphic Jump Location
Table 1. Clinical and Radiologic Characteristics of Five Patients With BHD Syndrome
* 

Mild nonspecific pattern on pulmonary function testing consisted of mildly reduced FEV1 with a normal FEV1/FVC ratio.

Figure Jump LinkFigure 2. High-resolution CT of the chest of a 57-year-old woman, an ex-smoker, with undiagnosed BHD syndrome and recurrent right-sided pneumothoraces. There is a right pneumothorax with small cysts in both lungs. Pleural thickening on the right anteriorly is due to prior pleurodesis.Grahic Jump Location
Figure Jump LinkFigure 3. High-resolution CT of the chest of a 58-year-old man, an ex-smoker, with undiagnosed BHD and a history of recurrent right-sided pneumothoraces. Top, A: Focal low-attenuation areas without walls in the upper lungs consistent with emphysema. One probable cyst is seen in the right lung posterior to the trachea. Postoperative changes are shown in the right lung. Bottom, B: Numerous cysts in the lung bases including one dominant cyst measuring 8 × 5 cm in the left lung. Cystic walls are difficult to appreciate for some of these lesions.Grahic Jump Location
Figure Jump LinkFigure 4. Histopathology of cystic lung lesions obtained from a 57-year-old woman at the time of redo thoracotomy for mechanical pleurodesis and pleurectomy for management of recurrent pneumothoraces despite a previous pleurodesis elsewhere. Top, A: Severe emphysema involving the most alveolar parenchyma (hematoxylin-eosin, original × 20). Bottom, B: An interlobular septum is replaced by interstitial air, which results in the displacement and compression of the venous wall (left lower corner) on the side abutting the air-filled space (hematoxylin-eosin, original × 200).Grahic Jump Location
Birt, AR, Hogg, GR, Dubé, WJ (1977) Hereditary multiple fibrofolliculomas with trichodiscomas and acrochordons.Arch Dermatol113,1674-1777. [PubMed] [CrossRef]
 
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 Genet2005;76,1023-1033. [PubMed]
 
Warren, MB, Torres-Cabala, CA, Turner, ML, et al Expression of Birt-Hogg-Dube gene mRNA in normal and neoplastic human tissues.Mod Pathol2004;17,998-1011. [PubMed]
 
Ubogy-Rainey, Z, James, WD, Lupon, GP, et al Fibrofolliculomas, trichodiscomas, and acrochordons: the Birt-Hogg-Dubé syndrome.J Am Acad Dermatol1987;16,452-457. [PubMed]
 
Welsch, MJ, Krunic, A, Medenica, MM Birt-Hogg-Dubé syndrome.Int J Dermatol2005;44,668-673. [PubMed]
 
Pavlovich, CP, Grubb, RL, III, Hurley, K, et al Evaluation and management of renal tumors in the Birt-Hogg-Dubé syndrome.J Urol2005;173,1482-1486. [PubMed]
 
Toro, JR, Glenn, G, Duray, P, et al Birt-Hogg-Dube syndrome: a novel marker of kidney neoplasia.Arch Dermatol1999;135,1195-1202. [PubMed]
 
Zbar, B, Alvord, WG, Glenn, G, et al Risk of renal and colonic neoplasms and spontaneous pneumothorax in the Birt-Hogg-Dube syndrome.Cancer Epidemiol Biomarkers Prev2002;11,393-400. [PubMed]
 
Khoo, SK, Kahnoski, K, Sugimura, J, et al Inactivation of BHD in sporadic renal tumors.Cancer Res2003;63,4583-4587. [PubMed]
 
Painter, JN, Tapanainen, H, Somer, M, et al A 4-bp deletion in the Birt-Hogg-Dube gene (FLCN) causes dominantly inherited spontaneous pneumothorax.Am J Hum Genet2005;76,522-527. [PubMed]
 
Souza, CA, Finley, R, Müller, NL Birt-Hogg-Dubé syndrome: a rare cause of pulmonary cysts.AJR Am J Roentgenol2005;185,1237-1239. [PubMed]
 
Butnor, KJ, Guinee, DG, Jr Pleuropulmonary pathology of Birt-Hogg-Dubé syndrome.Am J Surg Pathol2006;30,395-399. [PubMed]
 
Pittet, O, Christodoulou, M, Staneczek, O, et al Diagnosis of Birt-Hogg-Dubé syndrome in a patient with spontaneous pneumothorax.Ann Thorac Surg2006;82,1123-1125. [PubMed]
 
Douglas, WW, Ryu, JH, Schroeder, DR Idiopathic pulmonary fibrosis: impact of oxygen and colchicine, prednisone, or no therapy on survival.Am J Respir Crit Care Med2000;161,1172-1178. [PubMed]
 
Chung, JY, Ramos-Caro, FA, Beers, B, et al Multiple lipomas, angiolipomas, and parathyroid adenomas in a patient with Birt-Hogg-Dubé syndrome.Int J Dermatol1996;35,365-367. [PubMed]
 
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 Med2005;172,39-44. [PubMed]
 
Koyama, M, Johkoh, T, Honda, O, et al Chronic cystic lung disease: diagnostic accuracy of high-resolution CT in 92 patients.AJR Am J Roentgenol2003;180,827-835. [PubMed]
 
Ryu, JH, Swensen, SJ Cystic and cavitary lung diseases: focal and diffuse.Mayo Clin Proc2003;78,744-752. [PubMed]
 
Vassallo, R, Ryu, JH Pulmonary Langerhans’ cell histiocytosis,Clin Chest Med2004;25,561-571. [PubMed]
 
Wallwork, J Metastatic endometrial stromal sarcoma masquerading as pulmonary lymphangioleiomyomatosis.J Clin Pathol1999;52,147-148. [PubMed]
 
Ryu, JH, Moss, J, Beck, GJ, et al The NHLBI Lymphangioleiomyomatosis Registry: characteristics of 230 patients at enrollment.Am J Respir Crit Care Med2006;173,105-111. [PubMed]
 
Franz, DN, Brody, A, Meyer, C, et al Mutational and radiographic analysis of pulmonary disease consistent with lymphangioleiomyomatosis and micronodular pneumocyte hyperplasia in women with tuberous sclerosis.Am J Respir Crit Care Med2001;164,661-668. [PubMed]
 
Adley, BP, Smith, ND, Nayar, R, et al Birt-Hogg-Dubé syndrome: clinicopathologic findings and genetic alterations.Arch Pathol Lab Med2006;130,1865-1870. [PubMed]
 

Figures

Figure Jump LinkFigure 1. Photograph of fibrofolliculomas: multiple, firm, white papules on the jaw line and neck of a 50-year-old man.Grahic Jump Location
Figure Jump LinkFigure 2. High-resolution CT of the chest of a 57-year-old woman, an ex-smoker, with undiagnosed BHD syndrome and recurrent right-sided pneumothoraces. There is a right pneumothorax with small cysts in both lungs. Pleural thickening on the right anteriorly is due to prior pleurodesis.Grahic Jump Location
Figure Jump LinkFigure 3. High-resolution CT of the chest of a 58-year-old man, an ex-smoker, with undiagnosed BHD and a history of recurrent right-sided pneumothoraces. Top, A: Focal low-attenuation areas without walls in the upper lungs consistent with emphysema. One probable cyst is seen in the right lung posterior to the trachea. Postoperative changes are shown in the right lung. Bottom, B: Numerous cysts in the lung bases including one dominant cyst measuring 8 × 5 cm in the left lung. Cystic walls are difficult to appreciate for some of these lesions.Grahic Jump Location
Figure Jump LinkFigure 4. Histopathology of cystic lung lesions obtained from a 57-year-old woman at the time of redo thoracotomy for mechanical pleurodesis and pleurectomy for management of recurrent pneumothoraces despite a previous pleurodesis elsewhere. Top, A: Severe emphysema involving the most alveolar parenchyma (hematoxylin-eosin, original × 20). Bottom, B: An interlobular septum is replaced by interstitial air, which results in the displacement and compression of the venous wall (left lower corner) on the side abutting the air-filled space (hematoxylin-eosin, original × 200).Grahic Jump Location

Tables

Table Graphic Jump Location
Table 1. Clinical and Radiologic Characteristics of Five Patients With BHD Syndrome
* 

Mild nonspecific pattern on pulmonary function testing consisted of mildly reduced FEV1 with a normal FEV1/FVC ratio.

References

Birt, AR, Hogg, GR, Dubé, WJ (1977) Hereditary multiple fibrofolliculomas with trichodiscomas and acrochordons.Arch Dermatol113,1674-1777. [PubMed] [CrossRef]
 
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 Genet2005;76,1023-1033. [PubMed]
 
Warren, MB, Torres-Cabala, CA, Turner, ML, et al Expression of Birt-Hogg-Dube gene mRNA in normal and neoplastic human tissues.Mod Pathol2004;17,998-1011. [PubMed]
 
Ubogy-Rainey, Z, James, WD, Lupon, GP, et al Fibrofolliculomas, trichodiscomas, and acrochordons: the Birt-Hogg-Dubé syndrome.J Am Acad Dermatol1987;16,452-457. [PubMed]
 
Welsch, MJ, Krunic, A, Medenica, MM Birt-Hogg-Dubé syndrome.Int J Dermatol2005;44,668-673. [PubMed]
 
Pavlovich, CP, Grubb, RL, III, Hurley, K, et al Evaluation and management of renal tumors in the Birt-Hogg-Dubé syndrome.J Urol2005;173,1482-1486. [PubMed]
 
Toro, JR, Glenn, G, Duray, P, et al Birt-Hogg-Dube syndrome: a novel marker of kidney neoplasia.Arch Dermatol1999;135,1195-1202. [PubMed]
 
Zbar, B, Alvord, WG, Glenn, G, et al Risk of renal and colonic neoplasms and spontaneous pneumothorax in the Birt-Hogg-Dube syndrome.Cancer Epidemiol Biomarkers Prev2002;11,393-400. [PubMed]
 
Khoo, SK, Kahnoski, K, Sugimura, J, et al Inactivation of BHD in sporadic renal tumors.Cancer Res2003;63,4583-4587. [PubMed]
 
Painter, JN, Tapanainen, H, Somer, M, et al A 4-bp deletion in the Birt-Hogg-Dube gene (FLCN) causes dominantly inherited spontaneous pneumothorax.Am J Hum Genet2005;76,522-527. [PubMed]
 
Souza, CA, Finley, R, Müller, NL Birt-Hogg-Dubé syndrome: a rare cause of pulmonary cysts.AJR Am J Roentgenol2005;185,1237-1239. [PubMed]
 
Butnor, KJ, Guinee, DG, Jr Pleuropulmonary pathology of Birt-Hogg-Dubé syndrome.Am J Surg Pathol2006;30,395-399. [PubMed]
 
Pittet, O, Christodoulou, M, Staneczek, O, et al Diagnosis of Birt-Hogg-Dubé syndrome in a patient with spontaneous pneumothorax.Ann Thorac Surg2006;82,1123-1125. [PubMed]
 
Douglas, WW, Ryu, JH, Schroeder, DR Idiopathic pulmonary fibrosis: impact of oxygen and colchicine, prednisone, or no therapy on survival.Am J Respir Crit Care Med2000;161,1172-1178. [PubMed]
 
Chung, JY, Ramos-Caro, FA, Beers, B, et al Multiple lipomas, angiolipomas, and parathyroid adenomas in a patient with Birt-Hogg-Dubé syndrome.Int J Dermatol1996;35,365-367. [PubMed]
 
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 Med2005;172,39-44. [PubMed]
 
Koyama, M, Johkoh, T, Honda, O, et al Chronic cystic lung disease: diagnostic accuracy of high-resolution CT in 92 patients.AJR Am J Roentgenol2003;180,827-835. [PubMed]
 
Ryu, JH, Swensen, SJ Cystic and cavitary lung diseases: focal and diffuse.Mayo Clin Proc2003;78,744-752. [PubMed]
 
Vassallo, R, Ryu, JH Pulmonary Langerhans’ cell histiocytosis,Clin Chest Med2004;25,561-571. [PubMed]
 
Wallwork, J Metastatic endometrial stromal sarcoma masquerading as pulmonary lymphangioleiomyomatosis.J Clin Pathol1999;52,147-148. [PubMed]
 
Ryu, JH, Moss, J, Beck, GJ, et al The NHLBI Lymphangioleiomyomatosis Registry: characteristics of 230 patients at enrollment.Am J Respir Crit Care Med2006;173,105-111. [PubMed]
 
Franz, DN, Brody, A, Meyer, C, et al Mutational and radiographic analysis of pulmonary disease consistent with lymphangioleiomyomatosis and micronodular pneumocyte hyperplasia in women with tuberous sclerosis.Am J Respir Crit Care Med2001;164,661-668. [PubMed]
 
Adley, BP, Smith, ND, Nayar, R, et al Birt-Hogg-Dubé syndrome: clinicopathologic findings and genetic alterations.Arch Pathol Lab Med2006;130,1865-1870. [PubMed]
 
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