Pediatric Pearls Perfectly Repolished: Part 1 Molecular Pathways: Towards a Better Understanding of Genetic Disorders Ilona J. Frieden, MD
In this presentation, Dr Frieden discusses molecular pathways and how the science can be applied into clinical practice in order to optimize the outcomes for patients with dermatologic diseases.
The concept of Molecular Pathways
Dr Frieden’s concept of molecular pathways is described here. Signaling pathways are essential in regulation and growth development. These pathways are the key to understanding of the phenotypic overlap of many genetic disorders because even diseases with distinct genetic causes can show overlap if they involve a molecular pathway because the defect can be present either upstream or downstream of another condition and thus show similar features. Understanding these pathways can also help to bring us closer to more rational therapies because if we find things that inhibit overactivity of an element of a pathway, it may work not just for one disease but for several.
RAS/MAP Kinase Pathway
The RAS/MAP kinase pathway is essential to our central understanding of melanoma genetics, for example melanomas with mutations in NRAS and BRAF. This pathway also plays a major role in NF1 and other genetic syndromes.
Collectively germ-line genetic diseases in this pathway can be referred to as “Rasopathies”. They include Noonan syndrome, cardiofaciocutaneous syndrome, NF1, and Legius syndrome. All share in common features of developmental delay and most also have café-au-lait macules as a common feature.
Geneticists call this group (CFC, Noonan, NF-1, and Costello) of overlapping disorders RASopathies.
Another Important Pathway: PI3K
PI3K stands for phophatidylinositol-3-kinase, and the pathway in which PI3K is involved is sometimes called the PI3K/AKT/mTOR pathway. This pathway is critical to cell growth and survival. It is intimately involved in normal vascular development and angiogenesis. The mammalian target of Rapamycin (mTOR) integrates signals from the pathway to coordinate cell growth and proliferation both in the fetus and continues to work later in post-natal life as well.
PTEN is the most important negative regulator of the cell-survival signaling pathway initiated by P13K. There is also crosstalk between P13K pathways and other tumorigenic signaling pathways, such as those that involve Ras, p53, TOR (target of rapamycin) or DJ1, can contribute to this deregulation.
Genetics of Proteus Syndrome
Based on a paper published by Lindhurst et al in 2011, we now know that the cause of Proteus Syndrome is due to mutations in the oncogene AKT1 that is found right in the center of the P13K pathway. The researchers in this study conducted exome sequencing of DNA from biopsy samples obtained from patients with the Proteus syndrome—158 samples from 29 patients. 26 out of the 29 had a somatic activating mutation in the oncogene AKT1. Tissues and cell lines harbored admixtures of mutant alleles that ranged from 1% to approximately 50%. Two of the 38 peripheral-blood DNA samples were positive for the mutation compared with affected tissue (75 of 97, P<0.001) and unaffected samples that were positive (13 of 41, P = 0.004). This was a very important breakthrough as it determined that AKT1 was the cause of Proteus syndrome.
PI3K Syndromes: Overgrowth is a Common Motif
- Cowden and Bannayan syndrome (PTEN)
- Proteus (ALK)
- Tuberous Sclerosis
- Capillary Malformation-AVM and Parkes Weber
- Familial venous malformations
Diseases Probably in the Pathway (but not proven)
- Macrocephaly-Capillary Malformation
- CLOVE syndrome
- Diffuse capillary malformation with overgrowth
- Probably others…
