Published ahead of print on February 22, 2007, doi:10.1164/rccm.200610-1483OC
© 2007 American Thoracic Society doi: 10.1164/rccm.200610-1483OC
Lung Cysts, Spontaneous Pneumothorax, and Genetic Associations in 89 Families with Birt-Hogg-Dubé Syndrome1 Genetic Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland; 2 Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland; 3 Basic Research Program, SAIC–Frederick, Inc., NCI–Frederick, Frederick, Maryland; and 4 Molecular Imaging Program, 5 Biostatistics and Data Management Section, and 6 Surgery Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland Correspondence and requests for reprints should be addressed to Jorge R. Toro, M.D., Genetic Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, 6120 Executive Boulevard, Executive Plaza South, Room 7012, Rockville, MD 20892-7231. E-mail: torojo{at}exchange.nih.gov
Rationale: Birt-Hogg-Dubé syndrome (BHDS) is an autosomal, dominantly inherited genodermatosis that predisposes to fibrofolliculomas, kidney neoplasms, lung cysts, and spontaneous pneumothorax. Objectives: We evaluated 198 patients from 89 families with BHDS to characterize the risk factors for pneumothorax and genotype–pulmonary associations. Methods: Helical computed tomography scans of the chest were used to screen for pulmonary abnormalities. BHD mutation data were used for genotype–pulmonary associations. We examined the relationship of pneumothorax with categorical parameters (sex, smoking history, and lung cysts) and continuous parameters (number of cysts, lung cyst volume, and largest cyst diameter and volume). Logistic regression analyses were used to identify the risk factors associated with pneumothorax. Measurements and Main Results: Twenty-four percent (48/198) of patients with BHDS had a history of pneumothorax. The presence of lung cysts was significantly associated with pneumothorax (p = 0.006). Total lung cyst volume, largest cyst diameter and volume, and every parameter related to the number of lung cysts were significantly associated (p < 0.0001) with pneumothorax. A logistic regression analysis showed that only the total number of cysts in the right parenchymal lower lobe and the total number of cysts located on the pleural surface in the right middle lobe were needed to classify a patient as to whether or not he or she was likely to have a pneumothorax. Exon location of the BHD mutation was associated with the numbers of cysts (p = 0.0002). Conclusions: This study indicates that patients with BHDS have a significant association between lung cysts and spontaneous pneumothorax.
Key Words: Birt-Hogg-Dubé • syndrome • familial spontaneous pneumothorax • lung cysts • fibrofolliculomas • renal neoplasms
Birt-Hogg-Dubé syndrome (BHDS; OMIM [Online Mendelian Inheritance in Man] no. 135150) is the autosomal, dominantly inherited genodermatosis that predisposes to the development of fibrofolliculomas, kidney cancer, lung pneumatocysts, and spontaneous pneumothorax (1, 2). In our first article, we identified three kindreds in whom renal neoplasms and fibrofolliculomas cosegregated (2). In that report, we also identified two individuals with pulmonary cysts and one individual who had a history of spontaneous pneumothorax. These preliminary observations and isolated reports in the literature suggested that pulmonary manifestations were a major feature of BHDS (2, 3). In our studies of the first reported large kindred with BHDS (1), we mapped the BHD locus to chromosome 17p11.2 (4). Subsequently, we identified germline mutations in a novel gene, BHD (also known as FLCN), in BHDS kindreds (5). Most mutations in BHD are frameshift or nonsense mutations that are predicted to truncate the BHD protein folliculin (5, 6). The biologic significance of the discovery of the BHD gene is supported by the recent identification of germline mutations in BHD homologs responsible for naturally occurring inherited kidney cancer syndromes in animals (7, 8). Recently, a novel folliculin-interacting protein, FNIP1, was identified that binds to 5'-AMP activated protein kinase, a negative regulator of mammalian target of rapamycin (mTOR), suggesting that folliculin and its interacting partner may be involved in energy and/or nutrient sensing through the AMPK and mTOR signaling pathways (9). BHD mRNA is expressed in stromal cells and type I pneumocytes of the lung, suggesting that folliculin plays an important role in lung tissues (10). We have also reported that patients with BHDS are associated with the development of spontaneous pneumothorax (11). Recently, families with isolated familial spontaneous pneumothorax (SP) and germline BHD mutations have been described (12, 13).
SP is a rare disorder. A history of smoking, height, male sex, and family history are known risk factors for sporadic SP (14). Most cases of SP are sporadic but familial cases have been reported (15–18). Familial SP is genetically heterogeneous and various patterns of inheritance have been reported, including autosomal dominant (16, 18), X-linked recessive (15) and autosomal recessive patterns (17). However, most cases of familial SP are inherited in an autosomal dominant pattern with incomplete penetrance (19, 20). Familial SP may be a complication of various inherited disorders, such as
Patient Recruitment and Evaluation We recruited families and individuals to screen for BHDS by mailing four cycles of letters over a 3-year period seeking referrals from the 11,000 members of the American Academy of Dermatology for patients with cutaneous signs of BHDS. Patients were evaluated in consecutive order in a protocol approved by the National Cancer Institute's Institutional Review Board. All members of families screened for BHDS who participated in this study gave written, informed consent.
Families with BHDS were evaluated at the Clinical Center of the National Institutes of Health. Medical histories (fibrofolliculomas, spontaneous pneumothorax, and renal tumors) were obtained and physical examinations were performed. A detailed dermatologic examination was conducted and skin biopsies were obtained of selected lesions suspicious for fibrofolliculoma. The presence of fibrofolliculomas was designated as the sole criterion for the diagnosis of BHDS because fibrofolliculomas are rare and specific for BHDS (2). We defined a family as affected with BHDS when it contained one or more members with BHDS cutaneous lesions and a minimum of one lesion histologically confirmed as a fibrofolliculoma. Helical computed tomography (CT) scans of the chest were used to screen for pulmonary abnormalities in our patient population. The chest was scanned before and after intravenous administration of 120 cm3 of Ioxilan 300 (Cook Imaging Corp., Bloomington, IN). High-resolution 1-mm sections were obtained through the chest at 10-mm intervals. Pulmonary cysts were diagnosed on the basis of CT scans, and the numbers, location, and size of cysts were recorded. Pneumothorax was documented by history and a review of medical records. We defined recurrence of a pneumothorax as one occurring on the ipsilateral side more than 7 days after the most recent prior pneumothorax has resolved. The genomic sequence analysis of the BHD gene was performed as previously reported (5). The first reported BHDS family (1), in whom a BHD germline mutation was not identified (6), although haplotype analysis showed linkage to chromosome 17p11.2 (4), was included in the present study.
Statistical Analysis Analyses of dichotomized parameters and their relationship to presence or absence of a pneumothorax were done using a chi-square test. Associations between categorical parameters and presence or absence of a pneumothorax were done using an exact Cochran-Armitage test (28), as were associations between the number of pneumothoraces and dichotomous parameters. Associations between the number of pneumothoraces and ordered categorical parameters were performed using an exact Jonckheere-Terpstra test (29). Continuously measured parameters were compared between subjects with and without a pneumothorax using the Wilcoxon rank sum test. The Jonckheere-Terpstra test was used to assess the statistical significance of the trend in continuously measured parameters across increasing numbers of pneumothoraces. A Kruskal-Wallis test was used to determine whether continuously measured parameters differed according to mutation exon location, and to determine the association between exon location of the mutation and the number of pneumothoraces. Mehta and Patel's version of Fisher's exact test was used to evaluate the significance of the association between continuous parameters and the presence of one or more pneumothoraces (30). Logistic regression analysis was used to identify whether a combination of factors could be jointly associated with either the presence or absence of a pneumothorax or with increasing numbers of pneumothoraces. Many of the variables related to the numbers of cysts were derived from one another (e.g., the number of lung cysts on the right lung is the sum of the cysts on the right lower and upper lobes). Therefore, the variables included in the model only consisted of parameters that were not directly calculated from one another. In the final regression modeling for classification of "pneumothorax or not," all possible classifications were examined, and a threshold for classification was selected that simultaneously provided high sensitivity and specificity. The Kaplan-Meier method was used to describe the association between age and the probability of development of a first spontaneous pneumothorax (31). All p values are two-sided and were not adjusted for multiple comparisons.
General Clinical and Pulmonary Characteristics Patients' clinical characteristics and the frequencies are listed in Table 1. Our cohort included 101 men and 97 women with a median age of 49 years. The age range was 22 to 77 years, with only eight patients younger than 30 years. Eighty-nine percent (177/198) of patients with BHDS had lung cysts on CT scans of the chest. Approximately 24% (48/198) of patients and 35% (31/89) of BHDS families screened for lung cysts had a history of spontaneous pneumothorax. In our cohort of patients affected with BHDS, we found a relatively equal distribution of pneumothorax for men and women. Of the men affected with BHDS, 20% (20/101) had a history of a pneumothorax and, of the women with BHDS, 29% (28/97) had a history of a pneumothorax. All patients with a history of pneumothorax had multiple lung cysts identified by chest CT imaging (Figure 1). The earliest reported age of initial pneumothorax was 22 years, the median age of occurrence was 38 years (range, 22–71 yr), and the median age of the last pneumothorax was 42 years (range, 22–75 yr). Seventy-five percent (36/48) of patients had a second pneumothorax, the average number of pneumothoraces per patient was two, and four patients experienced five separate pneumothoraces. Differences in recurrence among patients may reflect efficacy of treatment used.
Ninety-three percent of patients with a diagnosis of BHDS had fibrofolliculomas with a distinctive clinical presentation characterized by multiple white or skin-colored papules distributed over the face, neck, and upper trunk. However, 14 patients in our cohort had fewer than 10 skin lesions suspicious for fibrofolliculoma, but all 14 patients had at least one biopsy-confirmed lesion. Forty-five patients with BHDS had kidney tumors. Of these, 27% (14/45) had a history of pneumothorax and 93% (42/45) had lung cysts. Table 2 shows the pneumothorax history and treatment of the 48 patients affected by spontaneous pneumothorax. Of these patients, 58% (28/48) were women and 41% (20/48) were men. Sixty-seven percent (32/48) of patients were nonsmokers. There were 101 episodes of pneumothoraces and no patient had simultaneous bilateral pneumothoraces. The right lung had the highest frequency of pneumothorax. Approximately 48% (23/48) of patients had a pneumothorax in the right lung only, 29% (14/48) had a pneumothorax in the left lung only, and 23% (11/48) of patients had a pneumothorax in both the right and the left lungs at different times.
Twenty-three percent of pneumothoraces were managed with observation alone. These patients were in stable condition and only minimally compromised by the pneumothorax. Of the pneumothoraces managed by observation alone, only 39% (9/23) completely resolved, and the remaining 61% (14/23) recurred, requiring medical treatment. Of the 101 pneumothoraces, 77% required medical intervention and were treated by various methods. Thirty-five percent (35/101) were treated with tube thoracostomy (chest tube) only. Six pneumothoraces were managed with a combination of tube thoracostomy and chemical pleurodesis (quinacrine, tetracycline, silver nitrate, or talc). Approximately 14% (15/101) of pneumothoraces were treated by open thoracotomy and a second treatment, including mechanical pleurodesis (abrasion to produce adhesion between parietal and visceral pleura) in 10% (10/101), chemical pleurodesis in 2% (2/101), and lung resection in 3% (3/101). Approximately 13% (13/101) of pneumothoraces were treated with combined tube thoracostomy, thoracotomy, and a third treatment, including mechanical pleurodesis in 7% (7/101), lung resection in 6% (6/101), and chemical pleurodesis in 2% (2/101), respectively. In addition, seven pneumothoraces were treated with a combination of tube and open thoracostomies, lung resection, and mechanical pleurodesis. Another pneumothorax was treated with both a combination of tube and open thoracostomy, lung resection, and chemical pleurodesis. Three patients with BHDS treated at the NIH underwent video-assisted thoracoscopic surgery. Pneumothoraces were not related to a particular calendar period. After serum  1-antitrypsin levels in 50 patients were within normal limits, we no longer performed the test. Capillary O2 saturation showed no significant abnormality in the measurements performed during routine screening for BHDS.
Risk Factor Analysis
In a second analysis, we investigated the association of continuous parameters (the total number of cysts per lung lobe, total number of intraparenchymal cysts, total number of subpleural cysts, number of lung lobes with cysts, smoking history, age when scanned, and lung cyst total volume) with pneumothorax. The results of tests for significance from the univariate analysis of continuous parameters are summarized in Table 4. We found that every parameter related to the number of lung cysts was significantly associated with history of pneumothorax. No association was found between age at scan or smoking history and presence or frequency of pneumothoraces. In addition, total lung cyst volume and largest cyst diameter and volume were significantly associated (p < 0.0001) with history of pneumothorax (Table 5). In addition, we found an association between the number of pneumothoraces and the total cyst volume (p < 0.0001) (Table 5). There was an increase in median total cyst volume (0.8, 5.1, 8.5, and 10.3 cm3) with increasing number of pneumothoraces (0, 1, 2, +3, respectively). Similarly, we found that the largest cyst diameter and volume were significantly associated with the number of pneumothoraces (Table 5).
The relationship between history of pneumothorax and different parameters related to lung volume and cysts was investigated using a logistic regression model. The logistic regression model determined that only the total number of cysts in the right parenchymal lower lobe (p = 0.050) and the total number of cysts in the right pleura-based middle lobe (p = 0.002) were needed to classify a patient as to whether he or she was likely to have a pneumothorax or not. These same parameters were also associated with increasing numbers of pneumothoraces. We used the Kaplan-Meier method to describe the association between age and the first spontaneous pneumothorax among all patients in the BHDS cohort (Figure 2). No pneumothoraces were diagnosed before age 22 years in this cohort, with the oldest patient experiencing her first pneumothorax at 71 years. By age 30 years, the probability of having the first pneumothorax is 6% (95% confidence interval [CI], 3–10%), 14% (95% CI, 10–20%) by 40 years, and 75% (95% CI, 19–32%) by age 50. Of the 48 patients who had a pneumothorax, 88% (42/48) of them had his or her first pneumothorax before age 50, 10% (5/48) had one between the ages of 51 and 60 years, whereas only 1 patient had a pneumothorax that occurred after age 60, at 71 years.
BHD Mutation Detection BHD mutations were present in 81% (154/190) of patients and 85% (68/80) of BHDS families tested. The cytosine mononucleotide tract in exon 11 of BHD was most frequently mutated, accounting for 48% (70/154) of patients and 47% (32/68) of BHDS families who had a mutation detected. Thirteen patients from one large BHDS kindred that previously showed linkage to chromosome 17p11.2 by haplotype (4) had no sequence variation in the BHD gene (6). Nine families were not screened for BHD mutations by direct sequencing. Patients with a history of pneumothorax share a similar BHDS mutation spectrum with all the patients with BHDS in this study, but with some exceptions. BHD mutations were present in 87% (41/47) of individuals and 90% (27/30) of BHDS families with a history of pneumothorax tested. Similar to previous studies, the "hot spot" mutation, c.1733ins/delC, in exon 11 was the most frequent site of mutation, accounting for 38% (18/47) of individuals with a history of a pneumothorax and 44% (18/41) of all the mutations detected. We were unable to detect a sequence variation in BHD by direct sequence in six individuals, but four of these individuals were part of a family that showed linkage to chromosome 17p11.2 by haplotype analysis (4). In addition, one individual was not screened for BHD mutations.
Analyses of Genotype–Phenotype Correlation
This is the largest and most comprehensive study to date of individuals and families affected with BHDS relating the pulmonary risk factors, CT screening, and genotype–pulmonary associations. In this study, for the first time, we showed that lung cysts and every parameter related to the number of lung cysts were significantly associated with spontaneous pneumothorax. Univariate analysis revealed that total lung cyst volume, largest cyst diameter, and largest cyst volume were statistically associated with pneumothorax in patients with BHDS. In addition, logistic regression analysis showed that only the total number of cysts in the right parenchymal lower lobe and in the right pleura-based middle lobe were needed to classify a patient as to whether he or she was likely to have a pneumothorax. The role of lung cysts in the mechanism leading to a spontaneous pneumothorax in BHDS has not been established. One explanation is that lung cysts may be a precursor lesion; a second possibility is that rupture of subpleural blebs on the visceral pleura may lead to a spontaneous pneumothorax. Furthermore, the pathophysiology of lung cysts in BHDS is unknown. Although inactivation of the BHD wild-type allele by loss of heterozygosity (LOH) or somatic mutation may explain the BHDS-associated kidney tumors (32), it is possible that haploinsufficiency alone may be responsible for the development of lung cysts. Age of onset of the first reported pneumothorax is also important. Approximately 90% of patients with BHDS had their first pneumothorax by age 50, suggesting that pneumothorax tends to occur during adulthood in patients with BHDS. Screening of 198 patients with BHDS at the NIH Clinical Center using high-resolution plus standard CT of the chest revealed that most (89%) patients with BHDS have multiple pulmonary cysts. Twenty-four percent of patients with BHDS had a history of one or more pneumothoraces, all of whom had multiple lung cysts identified by chest CT imaging. This study revealed a relatively equal distribution of pneumothorax among men and women. In contrast, previous studies have identified male sex as a risk factor for primary spontaneous pneumothorax (33). In this study, 67% of patients with BHDS who had a history of pneumothorax were nonsmokers, and 61% of those without a pneumothorax were also nonsmokers, supporting the view that smoking is not a risk factor for pneumothorax in our cohort of patients with BHDS. However, in lung studies of other populations, smoking has been shown to be a risk factor for pneumothorax (34). It is important to recognize that smoking can lead to emphysematous cystic and bullous changes in the lung in the general population. However, the location and characteristics of the cystic lesions are usually different from BHDS. The effects of smoking in exacerbating or worsening the pulmonary lung disease (lung cyst and spontaneous pneumothorax) in the setting of BHDS is unknown. In this study, we also found that severity of cutaneous involvement or kidney tumors was not a risk factor for pneumothorax. Sporadic spontaneous pneumothorax is associated with apical subpleural lung blebs, whereas individuals with BHDS all have extraapical blebs or cysts (12, 13, 35). The cysts are lined by a smooth wall, with most found in the basilar subpleural region of the lung (12). In this study, the BHD mutation detection rate and spectrum of mutation among patients with BHDS were very similar to our previous reports (5, 6). Similarly, the hot-spot mutation (c.1733ins/delC) in exon 11 was the most common mutation in this study. In this report, the hot-spot mutation was present in 48% of BHDS families, whereas this mutation in exon 11 was reported in 53% of BHDS families previously (6). One major difference from our previous report is that all patients with BHDS included in this study were only evaluated at the NIH Clinical Center and patients seen on field trips were excluded. This criterion was needed for a systematic chest screening evaluation of lung cysts of all patients. Recently, Painter and colleagues (13) reported on a large Finnish family with primary spontaneous pneumothorax in 8 members and 14 family members who had lung bullae (cysts) on high-resolution CT examination. Direct sequencing of genomic DNA from affected individuals revealed a 4-bp deletion in the first exon of the BHD gene. This mutation was not present among our patients with BHDS. Similarly, Graham and coworkers reported two different nonsense mutations (E315X and R477X) in two different families with primary spontaneous pneumothorax (12). These nonsense BHD mutations were not identified in our cohort of patients. Painter and colleagues and Graham and coworkers reported that these families lack dermatologic findings. However, dermatologic examinations were not conducted in both studies. On the other hand, we recognized that BHDS can occur in the absence of skin lesions, although it is uncommon. In this study, we also investigated potential genotype–pulmonary relationships in our patients with BHDS. In general, we found no associations between BHD mutation status, or mutation types, and lung cysts parameters and pneumothorax. However, an analysis showed that individuals with BHD mutations in exon 9 were associated with more lung cysts than individuals with mutations in other exons. In addition, we found that the size and volume of the largest lung cyst differed significantly by exon, and that these were greater in individuals with BHD mutation in exons 9 and 12 than in those with mutations in other exons. These findings suggest that there may be an association between mutation location and lung cyst number and size. It is of interest that recently we also reported that 40% (7/17) of patients with BHDS with putative splice-site mutations in intron 9 (predicted to cause exon 9 skipping) developed renal tumors (6). This is a significantly higher frequency of renal tumors than the overall frequency in all mutation carriers. These two independent observations suggest that exon 9 may have functional importance. These findings need to be confirmed in a future study with a larger number of patients with BHDS. We also found variability of expression of lung cysts and spontaneous pneumothorax both between and within families. These findings suggest that the existence of other genetic and/or environmental factors may also influence the pulmonary phenotype. In addition, the number of lung cysts and pneumothoraces was not a good predictor for kidney cancer status.
The differential diagnosis for a patient with a history of familial spontaneous pneumothorax and diffuse pulmonary cystic changes includes TSC (25), Treatment of spontaneous pneumothorax in our patients with BHDS varied from simple observation to open thoracotomy with pleurodesis and lung resection. Seven primary treatment approaches were reported as being used over the study period, including the following: observation alone, tube thoracostomy alone, tube thoracostomy with chemical pleurodesis, thoracotomy with mechanical pleurodesis, and thoracotomy with lung resection. Because different physicians at different hospitals treated patients with a variety of treatment modalities, we cannot exclude that these variables are confounding the risk for recurrence of pneumothorax. The treatment of pneumothorax in patients with BHDS is similar to the approach taken for any patient with spontaneous pneumothorax. It ranges from observation with repeated radiographic examinations in asymptomatic patients to urgent intervention to evacuate air from the intrapleural space and to prevent recurrence. The mode of therapy is dictated by the clinical presentation of the patient, the chronicity of the condition, and the underlying lung conditions that induced the development of pneumothorax. Placement of a tube thoracostomy enables evacuation of pleural air, and reexpansion of the compressed portion of the lung, and provides a means for chemical pleurodesis. For patients with discreet lung bullae or blebs, or those with recurrent pneumothoraces, treatment may include surgical intervention (thoracotomy or video-assisted thoracoscopy) in combination with mechanical pleurodesis and resection of lung bullae when present. Prospective treatment trials are needed to investigate the best treatment of BHDS-associated pneumothoraces. The clinical presentation of spontaneous pneumothorax in patients with BHDS is variable. Furthermore, a spontaneous pneumothorax may not be detected on a plain chest X-ray; therefore, it may be overlooked. We advised our patients to inform medical examiners that they have a condition that predisposes them to spontaneous pneumothorax. Although in BHDS it is unknown how to prevent pneumothoraces, certain measures can decrease the risk of developing one. Patients should be cautioned about the increased risk of pneumothorax with scuba diving and air travel due to ambient pressure effects, especially if they have chest symptoms such as pain, discomfort, and/or shortness of breath. We have not observed fatalities or chronic debilitation associated with BHDS lung cysts or pneumothoraces. In conclusion, this study describes the unique pulmonary features, genetic characteristics, and risk factors for pneumothorax in 198 patients with BHDS. It is important to recognize that, based on the temporality limitations of the study, we cannot clearly determine the true relationship between the number of lung cysts and the risk for spontaneous pneumothorax because, in most cases, the pneumothorax was documented and confirmed before the initiation of study. However, our study has shown a significant association between the lung cysts (number and location) and pneumothorax. Our study contributes to the understanding of the genetic basis of hereditary spontaneous pneumothorax. A prospective study following a cohort of patients should be conducted to validate our present findings. Recognition of the pulmonary features associated with BHDS will improve the diagnosis and treatment of patients with BHDS. Furthermore, recognition of the diagnosis of BHDS will also provide awareness to patients and health care providers of the need for screening and surveillance for renal neoplasms. Future molecular studies may be able to demonstrate if the BHD gene is involved in the etiology of sporadic spontaneous pneumothorax and/or emphysema.
The authors thank the families of patients with BHDS for their participation in our study and the members of the American Academy of Dermatology for their help in the recruitment of families. They also thank Cia Manolatos, Robin Eyler, Kathleen Hurley, James Peterson, and Lindsay Middelton for their many contributions to this project.
Supported in part by Intramural Research Program of the National Cancer Institute, National Institutes of Health. This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract no. NO1-CO-12400. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. government. Originally Published in Press as DOI: 10.1164/rccm.200610-1483OC on February 22, 2007 Conflict of Interest Statement: J.R.T. is an inventor on a patent application that has been filed for the BHD gene. S.E.P. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. L.S. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. G.M.G. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. M.W. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. O.T. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. M.-H.W. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. L.S.S. is an inventor on a patent application that has been filed for the BHD gene. L.D. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. B.Z. is an inventor on a patent application that has been filed for the BHD gene. P.C. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. S.M.S. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. D.M.N. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. W.M.L. is an inventor on a patent application that has been filed for the BHD gene. Received in original form October 16, 2006; accepted in final form February 21, 2007
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ABSTRACT
AT A GLANCE COMMENTARY
ab2, where a is one-half the length of the longest semi-axis and b is one-half the length of the shorter semi-axis. The sum of the individual cyst volumes was used to calculate the total cystic space volume in each lung. 
