A 31-yr-old woman visited the Department of Dermatology for evaluation of long-standing mildly pruritic facial papules that she had had for 10 yr (). Previously she had been treated with CO2 laser and Aldara ointment with the impression of verruca or syringoma but with little effect. Physical examination revealed several firm, flesh-colored, dome-shaped, papular lesions ranging from 2 to 5 mm in diameter, distributed on the face and neck area. The patient had a history of pneumothorax; otherwise, her medical history was not notable. Skin biopsies of the facial papules were performed. One sample showed concentric layers of cellular fibrous tissue around hair follicles with an aritifactual cleft separating the fibroma from adjacent connective tissue (). Also in another sample, a raised papule composed of connective tissue surrounded by a lateral collarette was seen (). Staining with alcian blue and elastin stain revealed an unencapsulated loosely woven admixture of collagen and thin elastic fibers with mucin. Periodic acid-schiff (PAS) staining showed multiple thin and thick walled blood vessels with PAS-positive basement membrane within the substane of the tumor. The biopsy findings were consistent with perifollicular fibroma and trichodiscoma, respectively.\nComputed tomographic scan of the chest, abdomen, and pelvis showed multiple cysts on both lower lung zone, with sizes ranging from 1.4-2.4 cm and a small amount of pneumothorax noted on the left anterior basal hemithorax. The scan did not show any abnormalities in the kidney or colon. There was no family history of renal tumors, colon carcinoma, or other benign or malignant neoplasm. However, the patient reported that her two aunts died of 'lung disease' (diagnosis unknown) and one of her older sisters was remembered to have had multiple tumorous lesions. Both of her older sisters passed away at an early age but she did not know the cause of death.\nMolecular analysis of the BHD gene was performed after informed consent from the patient. Genomic DNA was extracted from peripheral blood leukocytes, and subjected to mutation analysis. All the coding regions of the BHD gene (exons 4-14) were amplified using polymerase chain reaction (PCR) with oligonucleotide primers we designed (). The amplified PCR products were sequenced using the ABI 3100 Genetic Analyzer (Applied Biosystems/Hitachi, Foster City, CA, U.S.A.). Sequencing analysis revealed a novel deletion mutation (p.F519LfsX17 [c.1557delT]) in the BHD gene exon 14 of the patient (). This mutation results in producing the truncated protein folliculin, which is caused by frameshift of amino acid sequence in the BHD gene product. Also, this deletion mutation has not yet been found in the normal populations, indicating that this mutation is the real cause of the syndrome in this case.
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.