Hereditary leioyomatosis and renal cell cancer (HLRCC) is a hereditary syndrome that predisposes individuals to renal cancer and is accompanied by a cutaneous manifestation, much like BHD Syndrome.
HLRCC is caused by mutations in the fumarate hydratase (FH) gene. The skin lesions originate from smooth muscle that surrounds hair follicles, the ones that give you ‘goosebumps’ and the kidney tumour pathology is very specific since there is a high prevalence of papillary type tumours as opposed to the oncocytomas or chromophobe cancers found in BHD. So whilst superficially the two syndromes do share similar phenotypes there appear to be no specific overlap. Also at first glance the biochemistry behind the syndromes don’t seem interlinked.
However, several studies have indicated that biallelic loss of fumarate hydratase results in aberrant signalling, mediated through HIF dependent pathways, suggesting that mechanisms of pseudo-hypoxia may play a role in tumourigenesis in a similar fashion to VHL disease, effectively linking the three diseases. Clearly since the ‘hypoxia’ aspect of tumourigenesis keeps cropping up it would be prudent to at least keep it in mind when thinking about the functions of folliculin.