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While\n                      <jats:italic>PIK3CA<\/jats:italic>\n                      -related overgrowth spectrum (PROS) is relatively well characterized, non-\n                      <jats:italic>PIK3CA<\/jats:italic>\n                      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.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      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\n                      <jats:italic>PIK3CA<\/jats:italic>\n                      . Genetic testing was performed via next-generation sequencing (NGS) using a 17-gene targeted panel (read depth &gt;2000\u2009\u00d7) 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.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      A total of 41 patients were enrolled, including 20 males and 21 females. The mean age at diagnosis was 12.1 \u00b1 1.4\u00a0years. Variants were identified in\n                      <jats:italic>TEK<\/jats:italic>\n                      (24.4%),\n                      <jats:italic>GNAQ<\/jats:italic>\n                      (21.9%),\n                      <jats:italic>GNA11<\/jats:italic>\n                      (21.9%),\n                      <jats:italic>PTEN<\/jats:italic>\n                      (14.6%),\n                      <jats:italic>RASA1<\/jats:italic>\n                      (12.2%),\n                      <jats:italic>AKT3<\/jats:italic>\n                      (2.4%) and\n                      <jats:italic>EPHB4<\/jats:italic>\n                      (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.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      Non-\n                      <jats:italic>PIK3CA<\/jats:italic>\n                      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\n                      <jats:italic>TEK<\/jats:italic>\n                      -related disease supports the concept of convergent downstream pathway activation as a rationale for targeted therapies beyond PROS.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1007\/s12519-026-01098-3","type":"journal-article","created":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T11:33:49Z","timestamp":1790768029000},"page":"1024-1039","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Clinical and molecular characterization of non-PIK3CA-related vascular malformations with overgrowth in a pediatric cohort"],"prefix":"10.1007","volume":"22","author":[{"given":"Giuseppe","family":"Reynolds","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Luca","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paola","family":"Coppo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roberta","family":"La Selva","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chiara","family":"Leoni","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Iacopo","family":"Bellani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simona","family":"Ragusa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefania","family":"Massuras","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sonia","family":"Perrelli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefania","family":"Martino","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paola Sabrina","family":"Buonuomo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Federico","family":"Rondot","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessandro Mauro","family":"Spinelli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carla","family":"Morando","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marilidia","family":"Piglionica","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicoletta","family":"Resta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2795-6013","authenticated-orcid":false,"given":"Alessandro","family":"Mussa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,9,30]]},"reference":[{"key":"1098_CR1","doi-asserted-by":"publisher","first-page":"825","DOI":"10.1055\/a-0620-8925","volume":"190","author":"M Sadick","year":"2018","unstructured":"Sadick M, M\u00fcller-Wille R, Wildgruber M, Wohlgemuth W. 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Citt\u00e0 della Salute e della Scienza di Torino, A.O. Ordine Mauriziano di Torino, and A.S.L. Citt\u00e0 di Torino, with application number 256\/2022, protocol number 68301-17\/06\/2022. Informed consent was obtained from patients or their parents prior to their inclusion in the study and archived by the authors according to the local ethics committee's policy. The study was conducted in accordance with the ethical principles enshrined in the Helsinki Declaration.","order":2,"name":"Ethics","label":"Ethical approval","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"No AI was used in any part of the research or in the writing of the article.","order":3,"name":"Ethics","label":"AI usage statement","group":{"name":"EthicsHeading","label":"Declarations"}}]}}