PIK3CA Mutation in PROS

PIK3CA mutations are at the root of PROS (PIK3CA-Related Overgrowth Spectrum)

PROS disorders are understood to share a single cause: somatic mutations of the PIK3CA gene.1

 
The PIK3CA gene codes for the alpha isoform of PI3K, which is known to be involved in cell development and growth.1-3
When mutated, the PIK3CA gene can drive unchecked cellular growth and proliferation.1-3
In the case of PROS, the mutation occurs during embryonic development, resulting in a mosaic overgrowth pattern (ie, patches of affected and unaffected areas).1
 

Mechanism of Disease video

Discover how PIK3CA mutations are at the root of PROS.

PIK3CA-related overgrowth spectrum (PROS) is an umbrella term that includes rare, phenotypically varied, but overlapping features driven by somatic, gain-of-function mutations in the PIK3CA gene and presents with variable expression. Diagnostic features of PROS may include the presence of somatic PIK3CA mutation, congenital or early childhood onset, and abnormal tissue growth in a sporadic or mosaic pattern. Somatic gain-of-function mutations in the PIK3CA gene, which encodes the catalytic alpha subunit of phosphatidylinositol 3-kinase (PI3K), can result in hyperactivation of the PI3K pathway. This can lead to increased cellular proliferation and abnormal growth of affected tissue. PROS is driven by postzygotic somatic activating mutations in PIK3CA that arise in a mosaic pattern. The stage of embryonic development in which the mutations are acquired determines the mosaicism. PROS-related abnormal growth can range from pleiotropic, severe and/or extensive to tissue specific and localized. Diagnosis of PROS is often based on clinical features, imaging, and/or genetic testing for PIK3CA mutation. However, absence of identification of PIK3CA mutation does not preclude PROS, as low-level mosaicism is observed in many patients. Common features of PROS include congenital or early childhood onset and segmental growth, but clinical presentation of PROS disorders is highly variable. For example, megalencephaly-capillary malformation (M-CM) is a PROS disorder. Macrodactyly is also a PROS disorder. Despite differences in the range of tissues affected and phenotypic severity, both overgrowth disorders are part of the spectrum of PROS because they are caused by PIK3CA mutations. Complications from PROS depend on the site and extent of overgrowth. These complications may include psychological impact, chronic pain, superficial infections, hemorrhages and embolisms, neurologic complications, functional impairments, and cardiac and renal abnormalities. Complications may be debilitating and may lead to early mortality. Management of patients with PROS is tailored to patient-specific manifestations and often involves referral to appropriate specialists and a coordinated, multidisciplinary care team.

 
References:
  1. Keppler-Noreuil KM, Rios JJ, Parker VER, et al. PIK3CA-related overgrowth spectrum (PROS): diagnostic and testing eligibility criteria, differential diagnosis, and evaluation. Am J Med Genet A. 2015;167A(2):287-295.
  2. Keppler-Noreuil KM, Sapp JC, Lindhurst MJ, et al. Clinical delineation and natural history of the PIK3CA-related overgrowth spectrum. Am J Med Genet A. 2014;164A(7):1713-1733.
  3. Lindhurst MJ, Parker VER, Payne F, et al. Mosaic overgrowth with fibroadipose hyperplasia is caused by somatic activating mutations in PIK3CA. Nat Genet. 2012;44(8):928-933.