A 43-year-old man presented with a 15-year history of intermittent pruritic, multiple, skin-colored papules on the face and neck. The lesions developed on the face at first, and then slowly progressed to the neck, covering a 15-year period. Physical examination revealed multiple firm, skin-colored, 2~4 mm sized, papular lesions distributed on the face and neck area (). Except for the cutaneous findings, the patient was otherwise well and had no past history of kidney disease, pneumothorax, or other tumors. The result of the routine laboratory studies and chest x-ray were either normal or negative. His father died after suffering from colon cancer and his younger brother was ill with a pneumothorax. He also stated that his daughters had similar symptoms to his skin lesions.\nA biopsy of one of the facial papules was performed, and the lesion was reminiscent of a fibrofolliculoma by concentric fibrous tissue around follicular epithelium with thin and anastomosing bands separating from adjacent fibrovascular proliferation (). Meanwhile, another section of the same sample showed a relatively well-defined fibrovascular lesion with vascular proliferation and hair follicle at the margin of the lesion, suggesting trichodiscoma (). We studied the molecular genetic status of the FLCN gene after informed consent from the patient. We performed direct amplification of all exons (exon 1-14) of FLCN using previously reported primer sets and PCR conditions. Direct amplification of FLCN from EDTA-treated whole blood was performed using AnyDirectMaxTM Taq REDMix (BioQuest, Seoul, Korea). After gel purification of direct amplicon using a Gel Purification Kit (Solgent, Daejeon, Korea), direct sequencing was performed by ABI 3730XL Sequencer (Applied Biosystems, Foster, CA, USA). Sequencing analysis revealed a heterozygotic c.1285dupC mutation (accession No. NM_144997) in the FLCN gene exon 11 (). This mutation was the same as the previously described 1733insC mutation. This mutation results in producing the truncated protein folliculin, which is caused by a frameshift of the amino acid sequence in the FLCN gene product (). Based on this, we were able to diagnose this patient as BHDS, with support from his clinical and histological findings, family history, and gene mutation revealed by sequencing analysis at genomic DNA level.
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.