BHD syndrome and Cowden’s disease

Cowden’s disease is an autosomal dominant syndrome characterised by the development of multiple mucocutaneous lesions, benign tumours and enhanced cancer predisposition. Phenotypically this sounds very familiar to the triad of symptoms that characterise BHD: fibrofolliculoma development, renal cancer and the development of pulmonary cysts which lead to pneumothorax.

Cowden’s disease is caused by loss of function of the PTEN tumour suppressor gene. This gene encodes a lipid phosphatase, PTEN, which inhibits the PI3K-AKT signaling pathway. Loss of this function is accompanied by constitutive activation of the PI3K-AKT signaling pathway which leads to uncontrolled cellular proliferation.

Hasumi et al, (2009) showed that kidney tumours from a BHD heterozygous mouse model had increased levels of total AKT  as well as increased AKT phosphorylation, indicating that both PTEN and FLCN could be upstream modulators of AKT, which lends itself to the phenotypic similarities resulting from inactivation of these genes.

So what can be learned from this similarity? There is currently no cure for Cowden’s disease, but several clinical trials are investigating the efficacy of mTOR inhibitors (e.g. Sirolimus) in humans, since AKT inhibitors have undesirable side effects. The use of mTOR inhibitors as a potential therapy for BHD syndrome is not novel since FLCN has been implicated in the mTOR signalling pathway for a good few years now, nevertheless it will be interesting to see how these clinical trials pan out since the clinicians researching Cowden’s disease have a bit of a head start over their counterparts in the BHD field.

3 thoughts on “BHD syndrome and Cowden’s disease

  1. I have CS and I have been on Sirolimus for 20 months. The effects are amazingly positive. Both my son and daughter also have CS and are both taking the medication.

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