A 54-year-old man was found to have asymptomatic, bilateral renal tumors by ultrasonography and computed tomography (CT) (Fig. a, b). CT scan also showed left pneumothorax (Fig. c). No apparent cutaneous lesions were found by careful inspection and palpation of the skin. The patient had a history of spontaneous pneumothorax at the age of 30. His son also had a history of spontaneous pneumothorax at the age of 17. Open bilateral and partial nephrectomies were performed. Histopathologic examination revealed that the tumor in the left kidney was chromophobe RCC, nuclear grade G2 (partial G1), and 1.7 cm × 1.5 cm × 1.5 cm in size (Fig. d); the tumor in the right kidney was clear-cell RCC, nuclear grade G2, and 5.0 cm × 4.7 cm × 4.5 cm in size (Fig. e).\nGenomic DNA was extracted from blood samples collected from the patient and his son. Mutation examination revealed that the proband and his son carried a deletion of two bases (AG) at nucleotides c.946-947 in exon 9 (c.946-947delAG) of the FLCN gene (Fig. f), which caused a frameshift mutation starting at the 316th amino acid (p.316fs388x). No RCC was detected by abdominal CT scan on the son.
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 [].