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 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.