Mosaic overgrowth with fibroadipose hyperplasia
Mosaic overgrowth with fibroadipose hyperplasia is a rare genetic disease which causes unrestrained and sometimes massive fatty 'overgrowth' affecting only some body regions. The disease is mainly caused by the mutations in genes that regulate growth pathways such that abnormal growth of parts of body takes place. The mutations, related to this disease, cause either growth factors to be hyperactive or tumour-suppressor proteins to lose their function. An example of mutation related to mosaic overgrowth is mutation in PTEN gene. If PTEN gene encoding for the PTEN undergoes mutation, the person with mutated PTEN gene would no longer be able to synthesize normal functional PTEN which prevents uncontrolled cellular division (loss-of-function mutation), and hence unlimited cellular division would take place in the part of his body, resulting in segmental overgrowth.
This fact that the mutation of PTEN gene is related to mosaic overgrowth is revealed by the exome sequencing of DNA from affected cell and unaffected cell from a diseased individual.
The data from the exome sequencing showed that the affected cell had PTEN gene mutation while the unaffected cell had no mutation in PTEN gene. Furthermore, the data also showed that the mutation in PIK3CA gene (gain-of-function mutation) is found only in DNA of the affected cell (see Fig 1.3). PIK3CA gene encodes for the synthesis phosphatidylinositol 3-kinase (PIK3CA) which is family of lipid kinase and phosphorylates proteins to transduce growth signalling pathway. Normal functional PIK3CA activates AKT1, AKT2 and AKT3. ATK1 is associated with growth, AKT2 is associated with metabolic actions of insulin and AKT3 is associated with brain and heart.
The defective PIK3CA synthesized by the mutated PIK3CA gene is often hyperactive and thus it over-stimulates the activation of AKT1, AKT2 and AKT3, resulting in overgrowth of part of the body as well as sever hypoglycaemia.
Apart from the mutation in PIK3CA, the mutation within the gene coding for AKT1 is observed. Once AKT1 gene is mutated, there is great chance of having cells divide indefinitely despite of the presence intact normal functional PIK3CA. This is because hyperactive AKT1 may no longer require PIK3CA to become activated. In other words, it may remain activated all the time, resulting in constant growth stimulation and overgrowth of that part of the body.
Surprisingly, most individuals with mosaic overgrowth with fibroadipose hyperplasia have been found to have these various mutations affecting normal growth pathway. Furthermore, several observations show that the mutations related to this disease can actually initiate cancer.
So far, the treatment for mosaic overgrowth was primarily cutting off the oversized part of the body to make it look normal. However, thanks to the research that has revealed the genetic factors causing the disease, it is now possible to approach the disease in different angles and suggest alternative treatment that can specifically target the defective cells. Although it might be as hard as finding complete treatment for cancer, there is still chance as long as scientists keep up with their research.
Miguel H. Bronchud, MaryAnn Foote, Giuseppe Giaccone, Olufunmilayo I. Olopade, Paul Workman, (2008) Principles of Molecular Oncology, HUMANA PRESS, New Jersey, USA, p58-59.
Gavin J. Gordon, (2008), Bioinformatics in Cancer and Cancer Therapy, HUMANA PRESS, New Jersey, USA, p183-186.
Marjorie J Lindhurst, Victoria E R Parker, Felicity Payne, etc, ‘Mosaic overgrowth with fibroapidose hyperplasia is caused by somatic activating mutations in PIK3CA.’ <http://www.nature.com/ng/journal/v44/n8/full/ng.2332.html>