Somatic activating PIK3CA mutations have been identified in peripheral nerve from patients with lipomatosis of nerve with type I macrodactyly, which is now classified as a PIK3CA-related overgrowth spectrum disorder.
As well, a number of overlapping overgrowth disorders attributable to mosaic PIK3CA variants have now been characterized, leading to the designation of PIK3CA-related overgrowth spectrum (PROS).
PIK3CA-related overgrowth spectrum (PROS) encompasses a range of debilitating conditions defined by asymmetric overgrowth caused by mosaic activating PIK3CA variants.
PIK3CA-related overgrowth spectrum (PROS) is a group of rare genetic disorders with asymmetric overgrowth caused by somatic mosaic mutations in PI3K-AKT-mTOR pathway that encompass a heterogeneous group of rare disorder that are associated with the appearance of overgrowth.
PIK3CA-related overgrowth spectrum (PROS) is a group of rare genetic disorders with asymmetric overgrowth caused by somatic mosaic mutations in PI3K-AKT-mTOR pathway that encompass a heterogeneous group of rare disorder that are associated with the appearance of overgrowth.
Here, we summarize current knowledge of PROS, evaluate challenges and strategies for disease modeling, and consider the implications of PROS as a paradigm for understanding activating PIK3CA mutations in human development and cancer.
This report expands the clinical and molecular spectrum of PROS, emphasizes that different molecular methods can be complimentary in the diagnosis of these disorders, and highlights the risk of coagulopathy in a subset of patients with PIK3CA-related overgrowth.
We demonstrated the following: (a) that PROS cells are dependent on AKT; (b) the advantage of inhibiting the pathway immediately downstream of PI3K to circumventing problems depending on multiple classes a PI3K kinases; and (c) that PROS patients benefit from inhibition of AKT rather than mTOR.
Recently, mosaic or segmental overgrowth, a clinical condition caused by heterozygous somatic activating mutations in PIK3CA, was established as PIK3CA-related overgrowth spectrum (PROS).
In this context, a new entity comprising different syndromes with phenotypic mutations in PIK3CA has been proposed, designated PIK3CA-related overgrowth spectrum (PROS), with the aim of facilitating clinical management and establishing appropriate genetic study criteria.
Post-zygotic activating mutations in PIK3CA and other genes encoding members of PI3K-AKT-mTOR pathway have been found in various overgrowth syndromes that have been grouped together as PIK3CA-related overgrowth spectrum (PROS).
Our findings expand upon the recently proposed "PIK3CA-related overgrowth spectrum" associated with PIKC3A mutations and PI3K hyperactivation, adding constitutional PIK3CA mutations as an underlying cause of megalencephaly and macrosomia in newborns.
It is not known if the specific PIK3CA mutation, the mosaic distribution, or the clinical presentation affect the Wilms tumor or nephroblastomatosis risk in individuals with PROS.
Of note, PI3K pharmacological blockade resulted in a significant reduction of the proliferation rate in culture, suggesting that inhibition of PI3K might prove beneficial in future therapies for PROS patients.
The umbrella term of "PIK3CA-Related Overgrowth Spectrum (PROS)" was agreed upon to encompass both the known and emerging clinical entities associated with somatic PIK3CA mutations including, macrodactyly, FAO, HHML, CLOVES, and related megalencephaly conditions.