A 56-year-old non-smoking Chinese woman visited our hospital; she has cough, expectoration, and throat discomfort for the past 45 days. The patient had no fever, chest congestion, or chest pain. Upon physical examination, multiple white dome-shaped papules were found on her cheek, palpebra, fossa axillaris, and back (Fig. ). Her medical history showed a tendency to illness. The patient first developed pneumothorax at the age of 36, with multiple bilateral pulmonary cysts and subsequently underwent a tube thoracostomy. After 12 years, the pneumothorax recurred. At 50 years of age, the patient had a third pneumothorax; her right lung was compressed by 40%. Finally, the patient consented to surgical intervention for therapeutic purposes. During surgery, thin-walled bullae with sizes from 0.1 cm to 3.0 cm in diameter were observed on the right lung pleura. The bulla over 10 cm in diameter was found in the right horizontal fissure, and a 2.5 cm -diameter intrapulmonary bulla containing liquid was found in the lateral segment of the right middle lobe. Partial pleura adhesions were released by an electrosurgical generator. The 10 cm bulla was completely removed through wedge-shaped excision. The other bubblae on the pleura were clamped, closed and removal. The incisions were sutured, and the thoracic wall was rubbed and congested for pleurodesis. Histopathological examination showed that the inner surfaces of the cysts were lined with epithelial cells positive for CK7 and TTF-1; the cysts occasionally contained internal septa consisting of alveolar walls (Fig. ).\nThe patient is a non-smoker, who easily became ill even when she was young. Furthermore, she had a family history of spontaneous pneumothorax. The mother and maternal aunt of the patient had histories of pulmonary bullae and pneumothoraxes; her mother died of renal cancer at the age of 71, with pulmonary bubblae and recurrent pneumothorax. Her 31-year-old daughter and 69-year-old male cousin were classified as BHD-unaffected because they did not show manifestations of BHD upon physical examinations. Her maternal aunt died in her 80s without tumor diseases, but with several recurrent pneumothoraxes. A chest computed tomography (CT) scan taken at our hospital showed multiple cystic lesions throughout the lungs, mainly in the basilar regions (Fig. ). A 2.8 cm × 2.3 cm solid lesion was present in the posterior basal segement of the lower right lobe (Fig. ), which was subsequently proven to be a PIT by ultrasound guided percutaneous lung biopsy.\nBiopsy revealed massive infiltrations of inflammatory cells, including plasma cells and lymphocytes admixed with fibroblasts and myofibroblasts (Fig. ). Immunohistochemical studies showed positive reactions for CD3, CD20, and Ki-67, whereas no staining was observed with antibodies against CEA, IgG4, IgG, and ALK. These findings were reported as fibrous changes at the same location in the CT performed previously (Fig. , ). Ultrasound examination showed that the patient did not develop a renal carcinoma, but multiple thyroid nodules had emerged.\nGiven that the patient had multiple skin papules, cystic lesions, pneumothorax, and a family history of pneumothorax and renal tumor, we suspected a congenital disease, particularly BHD. Therefore, we performed blood DNA analysis, and four mutations were identified (Table ). A mutation of T to C (c.2297 T > C) in exon 14 leads to the change from Phe to Ser (p.Phe766Ser). To our knowledge, this mutation has never been reported before (Fig. ). Besides the mutation in exon 14, we also detected a mutation in exon 1 (c.-299C > T) with a mutation rate of 0.42. Another mutation in intron 8 (c.871 + 36G > A), with a mutation rate of 0.17, causes the codon 303 mutation (p.G ly303Arg) in FLCN 2 transcription. The third mutation in intron 9 (c.1062 + 6C > T) has mutation rate of 0.66. However, these three mutations were previously reported to have a minimal correlation to the onset of BHD [].
A 32-year-old female presented with an incidentally found pneumothorax during a workup for a vocal cord mass, after having experienced the symptom of voice change for several months. A chest X-ray and high-resolution chest tomography (HRCT) scan showed a left-side pneumothorax with a small amount of pleural effusion. In addition, several variably-sized thin-walled air cysts were found, mostly located on the basal or medial side of the bilateral lungs (). However, she had neither a history of smoking nor of pneumothorax. She had no history of underlying disease, such as an immunologic or collagen vascular disorder. Of note, her maternal relatives had a family history of pneumothorax. Because the multiple cysts in the bilateral lungs could increase the risk of recurrence, surgical repair was planned.\nVideo-assisted thoracoscopic surgery (VATS) was done for the single-stage resection of bilateral multiple cystic lesions. A double-lumen endotracheal tube was placed for bilateral sequential one-lung ventilation under general anaesthesia. The patient was placed in the lateral decubitus position, and 2-ports VATS exploration was performed using a 30° thoracoscope (Karl Storz endoscope; Karl Storz, Tuttlingen, Germany) for multiple wedge resections using endostaplers. Both bulla plication and ligation were also performed to remove multiple discrete small lesions, and sequential VATS for the contralateral side was conducted. There were multiple large cysts, especially at the base of the lower lobes, and some cysts were assessed as being at the stage of impending rupture (). After a air-leak test using saline solution, 20-Fr chest tubes were placed in the bilateral pleural space through the scope ports. Mechanical pleurodesis was not performed. The examination of the gross specimen revealed multiple, variably-sized subpleural cysts on both lungs, and the largest one measured up to 6.5×4.6 cm.\nThe HRCT and operative findings were uncommon; it is rare for young females to present with numerous thin-walled cysts in the bilateral lungs, especially in the lower lung fields. Furthermore, her grandmother had a history of pneumothorax at a relatively young age. After obtaining an informed consent for a genetic analysis with the suspicion of Birt-Hogg-Dubé syndrome (BHDS), genomic DNA was isolated from peripheral blood leukocytes using the QIAmp DNA Mini Kit (Qiagen, Hamburg, Germany). Polymerase chain reaction (PCR) was carried out using gene-specific primers for all coding exons and splice junctions of FLCN as previously described []. PCR amplicons were bidirectionally sequenced using a BigDye Terminator version 3.1 cycle sequencing kit (Applied Biosystems, Foster City, CA, USA) on an ABI PRISM 3100 Genetic Analyzer (Applied Biosystems). The chromatograms were analyzed using Sequencher ver. 5.0 (Gene Codes, Ann Arbor, MI, USA) and all mutations were described according to the Human Genome Variation Society nomenclature []. The RefSeq ID NM_144997.5 was used for alignment. Direct sequencing of the PCR products revealed a heterozygous, novel nonsense mutation, c.1135A>T; p.Arg379* in exon 10 of FLCN. This mutation has not been previously reported and is absent from locus-specific databases [,] as well as public databases (HGMD; ExAC; 1000 Genomes; dbSNP; and the ethnically specific Korean Reference Genome database, KRGDB). A subsequent familial genetic study was performed in both parents and an older brother of the proband, revealing an identical heterozygous mutation in the proband’s mother ().\nThe bilateral chest tubes were removed on postoperative day 1, and the patient was discharged on postoperative day 2 with complete resolution of the pneumothorax. The vocal cord mass was excised a month later, and was confirmed as a glomus tumor, measuring 2.0×1.2 cm. The patient has been followed for 12 months after the operation, and neither recurrence of pneumothorax nor other symptoms have been noted.