Abstract
Abstract
Introduction
Vascular malformations (VMs) associated with overgrowth represent a heterogeneous group of congenital disorders driven by somatic or germline variants in genes regulating vascular morphogenesis and cellular proliferation. While
PIK3CA
-related overgrowth spectrum (PROS) is relatively well characterized, non-
PIK3CA
VMs with overgrowth remain poorly defined, with limited genotype-phenotype correlations and no standardized therapeutic strategies. This study aimed to characterize the clinical and molecular features of this underrecognized group in a pediatric cohort.
Methods
We conducted a multicentric retrospective study across five Italian tertiary centers. Patients were included if they presented with a vascular malformation, clinically appreciable regional overgrowth beyond the vascular lesion itself, and a confirmed pathogenic or likely pathogenic variant in genes of the PI3K/AKT/mTOR or related signalling pathways, excluding
PIK3CA
. Genetic testing was performed via next-generation sequencing (NGS) using a 17-gene targeted panel (read depth >2000 ×) on peripheral blood, buccal swab, or affected-tissue biopsies. Clinical data were systematically collected across six predefined domains including phenotype, imaging, hemostatic parameters, and therapeutic management.
Results
A total of 41 patients were enrolled, including 20 males and 21 females. The mean age at diagnosis was 12.1 ± 1.4 years. Variants were identified in
TEK
(24.4%),
GNAQ
(21.9%),
GNA11
(21.9%),
PTEN
(14.6%),
RASA1
(12.2%),
AKT3
(2.4%) and
EPHB4
(2.4%). Somatic variants accounted for 65.9% of cases. Phenotypic features included skeletal anomalies (46.3%), soft tissue overgrowth (60.9%), macrocrania (19.5%), and segmental undergrowth in a subset. A syndromic diagnosis was established in 63.4% of patients; however, marked phenotypic overlap across genes was observed. Functional limitations affected 43.9% of patients. Alpelisib yielded clinical improvement in selected TEK-variant patients, whereas sirolimus showed limited efficacy.
Conclusions
Non-
PIK3CA
VMs with overgrowth constitute a clinically and molecularly heterogeneous spectrum with substantial phenotypic overlap across genotypes, rendering phenotype-based classification unreliable. Somatic mosaicism, variable allele frequency, and tissue-specific expression underlie this heterogeneity. Our findings advocate for broad NGS panels with tissue-based analysis, systematic parental testing, and molecularly driven classification. The observed response to alpelisib in
TEK
-related disease supports the concept of convergent downstream pathway activation as a rationale for targeted therapies beyond PROS.