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

Abstract

BackgroundPostzygotic activating PIK3CA variants cause several phenotypes within the PIK3CA-related overgrowth spectrum (PROS). Variant strength, mosaicism level, specific tissue involvement and overlapping disorders are responsible for disease heterogeneity. We explored these factors in 150 novel patients and in an expanded cohort of 1007 PIK3CA-mutated patients, analysing our new data with previous literature to give a comprehensive picture.MethodsWe performed ultradeep targeted next-generation sequencing (NGS) on DNA from skin biopsy, buccal swab or blood using a panel including phosphatidylinositol 3-kinase/AKT/mammalian target of rapamycin pathway genes and GNAQ, GNA11, RASA1 and TEK. Additionally, 914 patients previously reported were systematically reviewed.Results93 of our 150 patients had PIK3CA pathogenetic variants. The merged PROS cohort showed that PIK3CA variants span thorough all gene domains, some were exclusively associated with specific PROS phenotypes: weakly activating variants were associated with central nervous system (CNS) involvement, and strongly activating variants with extra-CNS phenotypes. Among the 57 with a wild-type PIK3CA allele, 11 patients with overgrowth and vascular malformations overlapping PROS had variants in GNAQ, GNA11, RASA1 or TEK.ConclusionWe confirm that (1) molecular diagnostic yield increases when multiple tissues are tested and by enriching NGS panels with genes of overlapping ‘vascular’ phenotypes; (2) strongly activating PIK3CA variants are found in affected tissue, rarely in blood: conversely, weakly activating mutations more common in blood; (3) weakly activating variants correlate with CNS involvement, strong variants are more common in cases without; (4) patients with vascular malformations overlapping those of PROS can harbour variants in genes other than PIK3CA.

Brain Abnormalities in PIK3CA-Related Overgrowth Spectrum: Physician, Patient, and Caregiver Experiences

“…PROS is a broad term that describes a heterogeneous group of disorders characterized by overgrowth and other malformations arising as a result of somatic gain-of-function variants in the PIK3CA gene, which encodes the α isoform of the catalytic subunit of phosphatidylinositol-3-kinase (PI3Kα) [ 7 , 14 , 17 ]. These mutations lead to hyperactivation of the PI3K (phosphatidylinositol-3-kinase) signaling pathway [ 7 , 17 ] which in turn influences the activity of downstream effectors such as protein kinase B (AKT) and mammalian target of rapamycin (mTOR), leading to abnormalities in cell proliferation and growth of a wide range of cells and tissues [ 5 , 7 , 14 , 17 ] (Fig. 1 ).…”

Somatic non-cancerous overgrowth syndrome of obscure molecular etiology: what are the causes and options?

“…When the gene at cause is PIK3CA 1 itself, as is most frequently the case, the SOS is then referred to as PIK3CA-related overgrowth syndrome (PROS) but is still associated with diverse developmental phenotypes such as isolated digital hypertrophy, generalized fibroadipose overgrowth, and CLOVES syndrome 2 [ 2 – 5 ]. Some of these phenotypes are also seen in association with mutations in other proliferation/differentiation genes.…”

“…A molecular diagnosis should be obtained in all cases of SOSs to determine whether a pharmacological treatment could be indicated [ 1 – 6 ]. One such treatment consists of the oral PIK3CA inhibitor alpelisib 3 [ 7 ] that has shown efficacy in the treatment of PROS based on case reports, animal models, and ongoing clinical studies [ 1 – 5 ]. However, it has been offered thus far almost exclusively to patients in whom somatic DNA testing showed SOS to result from a gain-of-function mutation in the target enzyme.…”

“…One must nonetheless remember that the underlying somatic defect in SOS escapes identification in over 30% of patients [ 1 – 5 , 8 ], that PIK3CA is often the gene involved and that life-threatening complications can occur at any time. Unfortunately, the underlying molecular defect cannot be deduced with certainty from the clinical presentation alone given that there is much overlap in disease expression among the various types of SOSs.…”

“…The current case description is thus remarkable for illustrating the potential worth of treating SOS pharmacologically even when attempts to uncover the causative gene failed. PIK3CA could be seen as an initial target of choice in this setting because: (1) it is often the gene involved in SOS, (2) its inhibition is well-tolerated and effective in the treatment of PROS [ 1 – 5 ], and (3) SOSs can be associated with upstream regulators of PIKC3A (e.g., TEK, GNAQ, RAS) and improve under alpelisib even then (personal observations).…”