PIK3CA vascular overgrowth syndromes: an update

Abstract

Purpose of review Over the past decade many previously poorly understood vascular malformation disorders have been linked to somatic activating mutations in PIK3CA, which regulates cell survival and growth via activation of the mTOR1-AKT pathway. The goal of this article is to describe and provide an update on the clinical features, complications, and management strategies for the PIK3CA-related overgrowth spectrum (PROS). Recent findings PROS encompasses a heterogenous group of disorders with complications related to the tissues harboring the mutation. Vascular malformation syndromes, such as Klippel–Trenaunay syndrome and Congenital Lipomatous Overgrowth Vascular malformations Epidermal nevi and Skeletal abnormalities, have an increased risk of thromboembolic complications, which is accentuated postprocedurally. Asymmetric overgrowth, particularly of limbs, results in a high rate of orthopedic complications. Hypoglycemia screening in the neonatal period and ongoing monitoring for growth failure is recommended in megalencephaly capillary malformation due to its association with multiple endocrinopathies. Recently, sirolimus, an mTOR1 inhibitor, has shown promise in vascular anomalies and now PROS. PIK3CA direct inhibitor, Alpelisib (BYL719), was recently trialed with significant clinical benefit. Summary As the pathogenesis of these conditions is better elucidated and targeted treatments are developed, recognizing the clinical features, comorbidities, and evolving therapeutic landscape across the PROS spectrum becomes more crucial for optimization of care.

True radial artery aneurysm in a patient with somatic mosaicism for a mutation in platelet-derived growth factor receptor β gene

“… 18 KTS has been linked to somatic mutations in PIK3CA , which encodes a kinase (PI3K) implicated in complex signaling pathways influencing cell growth and division, cell migration, and cell survival. 19 The key to the present patient's diagnosis was the results of the analysis of the cerebral artery aneurysm and abnormal cutaneous tissue. 1 PDGFRB acts upstream of PIK3CA, which might explain the similarity in the present patient's phenotype to that of KTS.…”

Genotypes and phenotypes heterogeneity in PIK3CA-related overgrowth spectrum and overlapping conditions: 150 novel patients and systematic review of 1007 patients with PIK3CA pathogenetic variants

“…Over the past decade, molecular classification of PROS has paved the way to several novel targeted treatment options derived from oncology57 including direct PIK3CA inhibitors,58 59 such as the alpha-specific Alpelisib (BYL719) recently used in a compassionate access scheme in PROS 26 60 61. Also drugs reducing oversignalling through the PI3K pathway have been successfully employed in PROS or related/overlapping conditions, such as miransertib (ARQ092), an oral, allosteric pan-AKT inhibitor62–66 or rapamycin, the first identified mTOR inhibitor 24 67–73…”

Lymphatic Anomalies in Children: Update on Imaging Diagnosis, Genetics, and Treatment

“…The term encompasses a wide variety of clinical phenotypes, which have been recently found to be associated with activating mutations in PIK3CA. The group includes Klippel-Trenaunay syndrome, CLOVES, PTEN-associated hamartoma syndrome, and macrocephaly-capillary malformation (M-CM) syndrome [25,58]. Closely related, but distinct, is Proteus syndrome which is due to mutations in AKT1 [59,60].…”