The major symptom of TSC is the development of benign tumours within vital organs. With respect to the kidneys and the lung it is not the development of carcinoma that causes clinical morbidity but the risk that benign growths become so numerous and/or large that they obliterate the organ and seriously compromise their functions.
BHD is not a cystic disease and tumours are only likely to develop in the kidneys. Lung pneumothoraces are a common symptom in BHD (although not everyone will get them) and are caused by the development of air filled sacs or ’blebs’ on the surface of the lungs, which then spontaneously burst resulting in a collapsed lung. Could it be that development of a cystic phenotype occurs similarly in both syndromes (albeit tissue specific )but that initiation of tumourigenesis occurs through a different mechanism?
We know through genetic studies that the development of cancer starting from normal epithelial cells through to cysts and adenomas ending up with a highly vascularised malignant tumour requires the accumulation of genetic mutations: inactivation mutations in tumour suppressor genes or activation of oncogenes is normally considered and ‘early step’, this is usually followed by genetic instability promoting the accumulation of mutations resulting in aberrant functioning of crucial signalling pathways and angiogenesis within the tumour microenvironment .
Essentially, the message here is that whilst a mutation in a specific gene may initiate the entire process, it does not drive subsequent mutational events. Could it be that BHD starts off similarly to TSC in that tissue specific cysts develop in the kidneys and lung surface but then at a specific point, the two processes diverge? We know that TSC is caused by constitutive mTOR activation and that folliculin is implicated in mTOR signalling. Is aberrant mTOR signalling an initiator of the cystic phenotype? If so, what drives tumourigenesis in BHD?