No abstract

be fully clarified. The increased cytoplasmic concentrations of fumarate or succinate substrates, due to low or absent FH/SDH activity, inhibit the degradation of HIF. Persistence of HIF induces activation of sustained hypoxic response signals, which are considered to be involved in hypervascularization or neoplastic growth (Pollard, 2005). However, some major questions still remain unanswered. Why, for example, do mutations in FH, SDH or VHL genes, that are components of the same pathway of hypoxia detection, cause different tumors? Moreover, as a unique mutation should lead to a unique phenotype, could the specific duplication of exon 7, which we detected in this family, be in some way related to cerebral cavernomas? To our knowledge this is the first time that cerebral angiomatous lesions are described in MCUL patients. We believe that this finding adds new insight into the genetic background of this syndrome, suggesting that a reassessment of the overall clinical spectrum of MCUL might be required.