Background: Phosphatidylinositol-3-kinase (PI3K) is a critical mediator of insulin action, and influences cellular growth, survival and metabolism. Recently, somatic gain-of-function mutations in the p110α catalytic subunit of PI3K (PIK3CA) have been found in a spectrum of overgrowth disorders, outlining the possibility of treatment with inhibitors of the PI3KAKTmTOR pathway.
Methods/Results: A 37-year-old female, presented with life-long, massive, progressive overgrowth of her legs in association with a lean, normal sized upper body. There was no history of malignancy, nor was their evidence for metabolic disturbance on biochemical profiling. Magnetic resonance imaging and histologic analysis demonstrated overgrowth of fibroadipose tissue in her legs, with fatty infiltration of muscles. We performed whole exome sequencing on DNA extracted from her legs and arms, and identified a heterozygous mis-sense mutation p.PIK3CA. His1047Leu, exclusively in the legs. Using mass spectrometry we found elevated basal PIP3 levels in leg derived dermal fibroblasts, and concomitant hyperactivation of key growth signals, AKT and p70S6K, and this was reversed by chronic exposure to the mTOR inhibitor everolimus.
Sirolimus therapy was initiated in the patient on clinical grounds due to continued growth and compromised mobility. Treatment was well tolerated, and at 1 year a 12% reduction in fat mass from the legs was recorded by dual-energy X-ray absorptiometry scanning.
Discussion: A mosaic activating PIK3CA mutation has caused a phenotype of progressive overgrowth of mainly adipose tissue in the legs of this patient. Metabolic disturbance was not prominent, and we speculate that this is because the liver is unaffected. Proof-of-concept studies in dermal fibroblasts suggest mTOR inhibitors could be an effective treatment strategy, and our index patient has made encouraging progress on sirolimus. These findings will, however, need to be substantiated by a future randomised controlled trial, and p110α inhibitors, currently in phase development, remain an attractive prospect for the future.