Primary Spontaneous Pneumothorax and Renal Cell Carcinoma

More than 15% of all kidney tumors are related to germline mutations (1). Part
of this is caused by the autosomal dominant mutation in the folliculin (FLCN)
gene on chromosome 17p11.2 (OMIM # 135150). This mutation is responsible for a
number of phenomena that are all, or in part, present in the carriers of the
mutation and are associated with the names of 3 Canadian researchers, resulting
in Birt-Hogg-Dubé syndrome (BHD). Although this was later corrected in
Hornstein-Birt-Hogg-Dubé (2), the most commonly used indication is still BHD.
This hereditary syndrome is characterized by fibrofolliculomas in the face and
upper part of the thorax, usually numerous lung cysts that occur both
subpleural and in the lung parenchyma, and a high frequency of renal cell
cancer (RCC). Characteristic of the thin-walled lung cysts is the often varying
size from a few millimeters to several centimeters in diameter and the presence
in all lung lobes (3). Pathological examination of resection material shows
that the cysts are usually not connected to the bronchial tree (4). The genetic
defect is responsible for the strongly limited possibility of the covering
epithelium of the cysts to stretch (5), so that the thin-walled cysts can
easily rupture and a pneumothorax can develop. This is particularly evident in
situations with external pressure changes (6). Research has shown that 5-10% of
SP patients have a mutation in the FLCN gen 7,8
Standard diagnostics for PSP is chest X-ray, CT is only performed on indication
(9). SP has a relapse frequency of about 50%, with relapse, pleurodesis is
performed. In SP by BHD, the risk of recurrence is about 75% (10). Research
into factors that give a high risk of recurrence is cost-effective as far as
the prevention of recurrence is concerned (11). Nevertheless, this is not (yet)
part of the existing guidelines. The characteristic lung cysts of BHD are only
clearly visible on CT and are so specific that the diagnosis can often be made
with CT chest (12). After this, confirmation by determining the mutation is
indicated.
Approximately 35% (13) of the BHD carriers develop one or more kidney tumors
(RCC), chromophobic or oncocytic type. Determining carrier status offers
opportunities for identification of family members who, in the presence of the
mutation, are also at risk for developing RCC. For the detection of new BHD
carriers there is no standard research, patients are found by symptoms, and
through them family members with this mutation. A potentially effective
alternative way of detecting a large proportion of the BHD patients may be the
standard examination of SP patients with CT and NGS (14). This is still
supported by the high frequency of pneumothorax as the first symptom of BHD
syndrome, up to 65% of the BHD population (15).
The VUMC database shows that in a cohort of 115 carriers (16) with 5 years of
follow-up, 2 new RCCs were found, the frequency being 0.3 / 100 man-years, and
moreover, per discovered carrier 3.6 family members found with the same
mutation (17).

By performing a low-dose CT of the thorax in patients with primary spontaneous
pneumothorax (PSP) the typical pulmonary abnormalities are detected related to
the mutation in the folliculine gene. In this way the Birt-Hogg-Dube syndrome
can be diagnosed and the prevalence of the syndrome in patients with
pneumothorax can be determined. Also other abnormalities as probable cause for
the pneumothorax could be found.

After treatment for primary spontaneous pneumothorax at first policlinic check
a low-dose CT of the chest will be performed and a blood sample by which
pulmonary abnormalities in the lung parenchyma and an eventual present mutation
of the folliculin gene can be detected.

There will be a minimal burden for the patient when participating in this
study. After treatment for the pneumothorax a tube of blood and a low-dose CT
is performed in an outpatient setting at first outpatient regular check. The
patient included in the study will have to spend one extra visit to the
hospital to have the CT scan and blood sample being performed. We estimate that
the visit to the hospital for the CT scan and blood sampling will take about
1.5 hour. There will be a minimal risk for the patient in perspective of the
irradiation exposure by performing a low-dose CT scan of the thorax. In fact,
the current guidelines do not recommend CT chest with a primary spontaneous
pneumothorax, usually no CT scan is performed with a pneumothorax. However, the
risk of the radiation load is very small for the patient.