ABSTRACT
Solitary or multiple cutaneous leiomyomas are benign tumors derived from vascular, areolar, dartos, or pilar smooth muscle fibers (Holst et al., 2002), which can be part of a syndrome when associated with MCUL (Garman et al., 2003). Furthermore, 15–62% of MCUL patients may develop a papillary renal type II or renal duct cancer HLRCC configuring a more complex entity (MCUL/HLRCC, OMIM 150800) (Toro, 2003). This syndrome is due to heterozygous mutations in the FH gene (Kiuru et al., 2001; Tomlinson et al., 2002), which acts as a tumor-suppressor gene to protect cells from hypoxic stress (Pollard, 2005). Homozygous mutations cause a complete FHD syndrome (FHD; OMIM 606812), which is lethal in childhood (Bourgeron et al., 1994). FH enzymatic activity is absent in FHD, reduced by nearly 50% in MCUL/HLRCC, and very low or absent in tumors from MCUL patients (Tomlinson et al., 2002), suggesting loss of heterozygosity. Besides FH, a number of different Krebs cycle genes have also been found to be mutated in neoplasms, such as SDH in paraganglioma and pheochromocytoma (Baysal, 2000; Niemann and Muller, 2000); or in neo or hyper vascular conditions such as in VHL syndrome (Kim and Kaelin, 2004).
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