Birt-Hogg-Dubé Syndrome: A Large Single Family Cohort

Kate Skolnik; Willis H. Tsai; Kimberly Dornan; Renée Perrier; Paul W. Burrowes; Warren J. Davidson


Respiratory Research. 2016;17(22) 

In This Article


Cohort Demographic and Clinical Characteristics

Over seventy individuals from a single family were identified as biologic relatives of the proband and 68 of these consented to genetic testing. Of those tested, 36 were positive for the FLCN c.59delT. Twenty-eight individuals had CT scans of the chest and abdomen and 22 of these had a complete clinical assessment (Fig. 2).

Figure 2.

Patient Flow Chart. ^Chest imaging entailed a CT scan. *Abdominal imaging imaging was performed with MRI in 3 individuals (due to radiation or contrast concerns with CT). ** Referral to Medical Genetics refers to a formal appointment to review patient clinical history (genetic testing may have been performed in individuals due to family history with their consent in the absence of formal appointment Medical Genetics appointment with functional inquiry)

Baseline characteristics of the study population are summarized in Table 1. There were similar numbers of men and women. The average age at diagnosis was 42 years (range of 19–71 years). More than 50 % of subjects had an unknown smoking status or were current or former smokers. Seventeen percent of the group had asthma (as defined in Table 1). Thirty-six percent (8/22) had airflow obstruction; 6 were secondary to asthma and 2 due to unknown etiology. Of those who had diffusing capacity for carbon monoxide (DLCO) testing, the majority (11/19 or 58 %) were within normal limits. Seven subjects (37 %) had an elevated DLCO.

Manifestations of BHD Syndrome

Clinical sequelae of BHD syndrome are summarized in Table 2. All patients who underwent CT chest imaging had pulmonary cysts. The mean cyst size was 2.9 cm (SD 0.37) ranging from 0.7 to 9 cm in maximal diameter. The majority (83 %) had lower lung zone predominant cysts. There was no association between smoking and cyst size or number. Thirteen subjects (41 %) had at least one spontaneous pneumothorax. The mean age at first pneumothorax was 35.6 (SD 2.37) years. Seven subjects had multiple pneumothoraces; one individual had bilateral involvement at presentation. Among the remaining 6 people who experienced recurrent episodes, half of them had 4 pneumothoraces each. Of the 25 total pneumothoraces, there were a similar number of right and left sided occurrences (13 and 11, respectively; the location of one was unknown). Ten of the pneumothoraces were recurrent, 6 of which were on the contralateral side.

Of the total pneumothorax episodes, 21 (84 %) underwent an interventional procedure; chest tube insertion in 9 cases and thoracic surgery (as primary treatment) in 12. Of those undergoing surgical intervention, 8 were treated with bullectomy/pleurectomy, 2 underwent combination pleurectomy and wedge resection, 1 was managed with lobectomy alone, and in 1 case the surgical details were unclear. The number of pleurodesis procedures or the type (chemical or physical) could not be ascertained from the available data. The recurrence rate for pneumothoraces managed by chest tube alone was 16 % (1/6) and for those managed by surgical intervention was 9 % (1/11).

Dermatologic manifestations (primarily fibrofolliculomas) occurred in 53 % of the cohort. Twenty-six percent had kidney cysts and one individual was diagnosed with an unclassified renal cell carcinoma on routine screening, which was successfully removed. One individual had a pituitary tumor, a variant of spindle cell oncocytoma. No direct correlation between BHD syndrome and pituitary tumors has been documented.[6]

There were no clinical features or measures of pulmonary function associated with higher likelihood of pneumothorax (Table 3). In contrast, both cyst size (OR 3.23, 95 % CI 1.35–7.73) and extent of lower lung zone disease (OR 6.43, 95 % CI 1.41–29.2) were associated with pneumothorax. Specifically, those with pulmonary cysts with a maximum diameter less than 2.9 cm had a significantly lower risk of spontaneous pneumothorax (OR 0.06, 95 % CI 0.01–0.40). Individuals with more than 25 % lower lung zone cyst involvement were 5 times more likely to experience pneumothorax (OR 4.57, 95 % CI 0.88–23.7). Other imaging features, including cyst number, cyst distribution, and extent of upper lung zone disease were not associated with a higher likelihood of pneumothorax (Table 3).