Familial Spontaneous Pneumothorax

Hsienchang Thomas Chiu; Christine Kim Garcia

Disclosures

Curr Opin Pulm Med. 2006;12(4):268-272. 

In This Article

Mutations in the Folliculin Gene Cause Familial Spontaneous Pneumothorax

Painter et al.[45**] studied one large Finnish family with dominant familial spontaneous pneumothorax. All individuals in this kindred were evaluated with high-resolution computed tomography (CT) scans of the chest. Fourteen individuals (including five who had a spontaneous pneumothorax) were found to have between 1 and > 30 pulmonary cysts, 1-6 cm in diameter, distributed throughout the lungs. Whole-genome linkage analysis revealed that all the family members with the pulmonary cysts inherited a common haplotype identical by descent on chromosome 17 and were heterozygous carriers of a 4 bp deletion in the fourth exon of the gene encoding folliculin (FLCN), the same gene associated with Birt-Hogg-Dubé syndrome. The mutation is predicted to cause a frameshift and premature termination of the folliculin protein. Of all the individuals who carried a mutation, there was 100% penetrance of the pulmonary cyst phenotype, but much lower penetrance (approx. 40%) of the pneumothorax phenotype.

In another study,[46**] families were collected solely on the basis of a familial spontaneous pneumothorax phenotype. A candidate gene approach revealed that the pneumothorax phenotype in two Caucasian families was linked to genetic markers that flanked the FLCN gene. Sequencing of genomic DNA from these individuals revealed two novel nonsense mutations that are predicted to prematurely truncate the folliculin protein. These two studies[45**,46**] used two different genetic approaches to study familial spontaneous pneumothorax, and both revealed novel mutations in the gene that previously had been associated with Birt-Hogg-Dubé syndrome.

Since the skin findings of Birt-Hogg-Dubé syndrome generally appear in the fourth decade and become progressively more noticeable with age, and since the renal cancer can be a late finding associated with this syndrome, a spontaneous pneumothorax may be the first presenting manifestation of Birt-Hogg-Dubé syndrome. Spontaneous pneumothorax may also be the only manifestation of Birt-Hogg-Dubé syndrome. Zbar et al.[23] found several individuals who were disease gene carriers with only the pneumothorax phenotype, who were 'skin negative'. Overall, individuals with Birt-Hogg-Dubé syndrome have a 50-fold higher risk of developing a spontaneous pneumothorax. Between 11.5% and 32% of patients develop this feature of the disease. In contrast, over 80% have pulmonary cysts, as detected by high-resolution CT scans of the chest.[23,26*]

The pulmonary cysts have been described as sharply marginated air-containing lesions with walls 2 mm thick or less and measuring ≥ 1 cm in diameter.[47*] The majority are located in basilar and subpleural locations, but small intraparenchymal cysts have also been described.[23] They are generally not confined to the apices of the lung, as is generally found in patients with sporadic spontaneous pneumothorax.[48] In some individuals pneumothorax occurs repeatedly and affects both lungs. At the time of surgical repair, blebs are generally seen on the pleural surface.[23,46**] Given the high recurrence rate of pneumothorax in many patients and the multitude of pulmonary cysts, surgical intervention with resection and pleurodesis would be an acceptable treatment option, even for a first-episode pneumothorax.

Resected lung tissue from non-smokers has revealed subpleural cysts and underlying emphysematous changes.[46**] At the present time, it is not known how mutations in folliculin give rise to the pulmonary cysts. The animal models of disease do not report a pulmonary phenotype. Folliculin is expressed in the macrophages within the alveolar space and in some cell types of the lung connective tissue, suggesting that it may have a role in the response to triggers such as tobacco smoke, or in tissue remodeling.[49]

So, how many cases of familial spontaneous pneumothorax can be explained by mutations in the folliculin gene? This remains to be seen. We have continued to collect families on the basis of the familial spontaneous pneumothorax phenotype and have found four additional mutations in this gene in patients of Caucasian, African American and Asian Ancestry (in preparation).

Families with familial spontaneous pneumothorax with a mutation in folliculin (FLCN) can be considered a forme fruste of Birt-Hogg-Dubé syndrome. These individuals and other members of their families should be evaluated for the dermatologic manifestations of the disease. Given the association of renal cancer with Birt-Hogg-Dubé syndrome, patients with familial spontaneous pneumothorax and FLCN mutations should be screened and followed for kidney masses. Surgery is recommended for patients when at least one tumor becomes greater than 3 cm in diameter, and surgery or close observation is recommended for smaller tumors.[50*] First-degree relatives should be counseled about their risk for developing the disease.

The molecular basis for familial spontaneous pneumothorax not explained by mutations in the folliculin gene is currently unknown. Collection and study of these families with this rare disorder may lead to the identification of additional genes which will provide insights into the molecular basis of this rare type of emphysema.

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