*From the Division of Pulmonary and Critical Care Medicine (Drs. Kalhan and Jain) and the Department of Pathology (Dr. Yeldandi), Northwestern University Feinberg School of Medicine, Chicago, IL.
Correspondence to: Ravi Kalhan, MD, Division of Pulmonary/Critical Care, 240 E Huron, McGaw M-300, Chicago, IL 60611; e-mail: firstname.lastname@example.org
A 48-year-old woman with a distant smoking history presented to the emergency department with progressive breathlessness and cough. Initially, her dyspnea occurred while she lay on her right side, but it progressed over 1 week until she was unable to speak full sentences. In the emergency department, a chest CT scan revealed a large right-sided pneumothorax, which resolved with a small-bore chest tube. The patient gradually returned to normal activities and presented to the pulmonary clinic for further evaluation.
Her medical history included the removal of several “moles” from her trunk and face. She denied liver disease, sinus symptoms, and prior attempts at pregnancy. Her mother had experienced three spontaneous pneumothoraces. The patient had quit smoking 20 years ago after smoking 5 pack-years. She denied risk factors for HIV infection, including illicit drug use.
Height, weight, and vital signs were normal. She had a few scattered papules on her face and trunk. Her chest expanded symmetrically, the diameter was normal. On auscultation she had normal air entry, no wheezing, and a normal inspiratory/expiratory ratio. The findings of the remainder of her physical examination were normal.
The results of the CBC count, serum chemistry, and hepatic and thyroid panels were all normal. Antinuclear antibody and an α1-antitrypsin levels were normal. A high-resolution CT scan of the chest demonstrated several small cystic lung lesions (Fig 1
). Of note, multiple renal masses were seen on abdominal images of the chest CT scan. Subsequently, a dedicated triphasic renal and pelvic CT scan was ordered (Fig 2
). Two weeks later, the patient had a recurrent right-sided pneumothorax which prompted pleurodesis and a thoracoscopic lung biopsy (Fig 3
The Birt-Hogg-Dube (BHD) syndrome, a rare genetic disorder affecting the lungs, skin, and kidneys, may be complicated by secondary spontaneous pneumothoraces. More common causes of spontaneous pneumothorax are detailed in Table 1
. The BHD syndrome was first reported in 1977 in a study of one family in which 15 of 70 members had multiple papules, 2 to 4 mm in diameter, over the face, neck, and trunk that were inherited in an autosomal-dominant fashion. Histopathologically, these lesions were fibrofolliculomas. Investigators later provided the link between BHD syndrome renal neoplasms, lung cysts, and/or spontaneous pneumothorax. While BHD is well recognized in the dermatology and urology communities, only sporadic reports are available in the pulmonary literature.
The genetic locus for BHD syndrome was identified on chromosome 17 in the folliculin gene, and the syndrome results from frameshift mutations resulting in a loss-of-function truncated protein. The function of folliculin is not known with certainty, but it seems to have roles in tumor suppression and epithelial-mesenchymal cell interactions. Folliculin is expressed in most normal adult tissues, including skin, lung, and kidney, and demonstrates sequence conservation across species including the mouse, Drosophila, and Caenorhabditis elegans, suggesting an important developmental function.
Patients with BHD syndrome are at significantly increased risk for renal carcinomas and pneumothoraces. In a cross-sectional analysis of 98 patients with BHD syndrome (13 BHD haplotype carriers who did not have skin manifestations of disease and 112 unaffected family members), renal cancer was 6.9 times more likely to develop, and pneumothorax was 50 times more likely to develop in BHD syndrome patients than in their control family members. Twenty-one percent of the patients with BHD syndrome had spontaneous pneumothorax as did four of the BHD haplotype carriers (31%). Pulmonary cysts were detected in 81 patients (83%) with skin manifestations of BHD syndrome and in 11 unaffected members of BHD syndrome families (10%). All of the patients with pneumothorax had concomitant lung cysts. The cysts were predominantly, but not exclusively, subpleural, smooth, and well circumscribed, and their images were not enhanced with the use of contrast medium. It is not known whether smoking modifies the risk for the development of spontaneous pneumothorax in BHD syndrome patients.
While the precise pathogenesis of lung cyst formation and pneumothorax in BHD syndrome patients is not known, we speculate that risk is conferred by loss-of-function mutations in folliculin that subsequently alter the extracellular matrix in the lung parenchyma. Because folliculin is strongly expressed in lung fibroblasts and macrophages, folliculin mutations may alter cytokines and proteases that are important in extracellular matrix expression. The high rate of spontaneous pneumothorax (31%) among haplotype carriers who did not have skin manifestations of BHD syndrome suggests that folliculin may play a more important role in maintaining matrix integrity in the lung than in other organs.
A percutaneous needle biopsy of a right renal mass documented clear cell carcinoma. Bilateral partial nephrectomies were performed and demonstrated renal cell carcinoma with chromophobe features. A skin biopsy of the patient’s left ear revealed a fibrofolliculoma. On genotypic analysis, the patient was discovered to have a mutation in the splice donor sequence of exon 7 of the BHD gene. The patient’s bilateral partial nephrectomies have been deemed curative for her renal malignancy, although detailed monitoring will be essential in the future. Her siblings have been evaluated for fibrofolliculomas, and counseled about signs and symptoms of pneumothorax. The pulmonary cysts are being managed expectantly.
The triad of the BHD syndrome, skin fibrofolliculomas, lung cysts, and renal tumors, should be included in the differential diagnosis of a secondary spontaneous pneumothorax.
Spontaneous pneumothorax should prompt detailed questioning regarding a family history of pneumothorax, head and neck skin lesions, and renal malignancies, as well as a detailed skin examination for fibrofolliculomas.
Early diagnosis of BHD syndrome is essential to appropriately screen for and treat the malignant renal tumors that are associated with BHD syndrome.
The authors have reported to the ACCP that no significant conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.
PCP = Pneumocystis carinii pneumonia.
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