cancer compared to the unaffected population. Estimates of the incidence among people with the disease range from 14 to 34%. Rarely, it is associated with clear cell renal cell carcinoma and papillary renal cell carcinoma. If it develops in someone with BHD, renal cell carcinoma occurs later in life and has a poor prognosis. Though the types of tumors typically associated with BHD are considered less aggressive, cases of advanced or metastatic kidney cancer have been observed in people with the syndrome. Both benign and cancerous tumors can reduce kidney function over time as they grow larger. Lungs Along with fibrofolliculomas and kidney tumors, affected individuals frequently develop cysts (blebs or bullae) in the subpleural lung base or intraparenchymal space that may rupture and cause an abnormal collection of air in the chest cavity (pneumothorax), which could result in the collapse of a lung. The cysts do not cause other symptoms and lung function is usually normal. More than 83% of people with BHD have cysts, but the syndrome does not cause conditions like progressive chronic obstructive pulmonary disease or generalized respiratory failure, though it does cause emphysema. Spontaneous, sometimes recurrent, pneumothorax occurs far more often and at a younger age with BHD than in the unaffected population. Around 24% of people with the disease have at least one spontaneous pneumothorax, 30 times the occurrence in unaffected people. Though pneumothorax caused by BHD often occurs in middle age, at a median age of 38, 17% of affected people have a spontaneous pneumothorax before turning 40. Pneumothoraces have been seen in people as young as 7 and 16 years of age. Some families have a form of BHD that only affects the lungs. Other organs Thyroid nodules have been associated with the Birt–Hogg–Dubé phenotype, present in 65% of individuals and 90% of families with the syndrome. However, a connection between BHD and thyroid cancer has not been substantiated. Other conditions have been reported to be associated, but may not be caused by the mutation in FLCN or may not be related at all. These include multinodular goiter, medullary thyroid carcinoma, parotid oncocytoma, colonic polyposis, connective tissue nevus, lipomas, angiolipomas, parathyroid adenomas, flecked chorioretinopathy, neurothekeoma, meningiomas, angiofibromas of the face, trichoblastomas, cutaneous focal mucinosis, cutaneous leiomyoma, breast cancer, tonsillar cancer, colorectal cancer, sarcoma of the leg, lung cancer, melanoma, dermatofibrosarcoma protuberans, basal cell carcinoma, cutaneous leiomyosarcoma, and squamous cell carcinoma. Pathophysiology Genetics