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 25-year-old woman visited our hospital because of bilateral pneumothorax detected on a chest X-ray taken during a health screening (Figure ). She had neither chest-related symptoms nor a rash on her body or face. She was a non-smoker and had no history of major diseases. However, she had a family history of spontaneous pneumothorax that included her father, paternal uncle, and paternal aunt.\nA chest computed tomography (CT) scan taken at our hospital showed right-sided pneumothorax as well as almost healed left-sided pneumothorax (Figure ). It also showed multiple cystic lesions throughout both lungs.\nWe performed video-assisted thoracic surgery (VATS) on the patient's right lung. Repetition of pneumothorax was suspected because pleural adhesion and thick pleura were found in her thorax. Many bullas were found at the surface of the lung; therefore, resection and ablation of bullas were performed, followed by stapling of the staple lines and reinforcement of ablated sites using a polyglycolic acid (PGA) sheet and fibrin glue. The patient's post-operative course was uneventful.\nOne month after the operation, she visited our hospital again complaining of respiratory discomfort. Chest X-ray and CT scan showed left-sided pneumothorax. Therefore, we performed VATS on the left lung. Again, many minuscule bullas appeared throughout the whole lung, and pleural adhesion and thick pleura were observed as before in the right lung. The surgery was performed following the same methods used for the right lung. Again, the patient's post-operative course was uneventful, and the recurrence of pneumothorax was not observed in either lung at 6 months after the second operation.\nHistopathological examination showed that the inner surfaces of cysts were lined with epithelial cells, and the cysts occasionally contained internal septa consisting of alveolar walls (Figure ). There were no special pathological findings of lymphangioleiomyomatosis (LAM) or catamenial pneumothorax, including LAM cell clusters or formation of chocolate-like endometriotic cysts.\nBecause the patient was young and a non-smoker with prominent family history of pneumothorax and multiple cystic lesions were observed throughout her whole lung, we suspected congenital disease and particularly BHD, despite the absence of fibrofolliculomas. We presented this case to a special research team focusing on BHD, which was formed as a specialized disease treatment research program by the Japanese government. The patient was diagnosed as having BHD via a DNA analysis, which showed two deletions of bases in exon 12 of the BHD gene (Figure ). No renal tumors were observed by abdominal ultrasonography.