World journal of pediatrics : WJP · 2026
Clinical and molecular characterization of non-PIK3CA-related vascular malformations with overgrowth in a pediatric cohort.
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Reynolds Giuseppe, Luca Maria, Coppo Paola, La Selva Roberta, Leoni Chiara, Bellani Iacopo, Ragusa Simona, Massuras Stefania, Perrelli Sonia, Martino Stefania, Buonuomo Paola Sabrina, Rondot Federico, Spinelli Alessandro Mauro, Morando Carla, Piglionica Marilidia, Resta Nicoletta, Mussa Alessandro
Аннотация
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.
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.