Towards the end of 2014 two new case studies were published; the first a new multi-generational BHD case from China, and the second a thyroid tumour linked to mutations in TSC2 and FLCN.

Lin et al. (2014) report on a case study of a 67-year old woman presenting with skin lesions, multiple lung cysts and renal neoplasms characteristic of BHD. One of her two sons also exhibits similar skin and lung phenotypes but does not currently show renal neoplasms. Genetic analysis confirmed that both the mother and son have a heterozygous mutation in exon 10 of the FLCN gene predicted to result in protein truncation.

Wagle et al. (2014) report on a case study of a 57-year old metastatic anaplastic thyroid cancer patient who initially responded well to everolimus, an allosteric inhibitor of mTOR, however went on to develop a resistant tumour. Genomic analysis of the pre-treatment and resistant tumours identified a mutation in the TSC2 gene known to inactivate the protein. Additional mutations were seen in the TP53 and folliculin (FLCN) genes, the latter of which is associated with BHD. Both the TSC2 and FLCN mutations could be contributing to increased mTOR activity and subsequent tumour growth. The initial response to everolimus supports the belief that cancers with aberrant mTOR activation are uniquely sensitive to mTOR inhibitors. The subsequent resistant tumour developed after an additional mutation in the MTOR gene blocked everolimus binding to mTOR.

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