For decades, children born with vascular malformations—tangled, malformed networks of blood vessels that can distort limbs, faces, and internal organs—have been sorted into diagnostic boxes largely by what clinicians can see. A new multicenter Italian study, published in the World Journal of Pediatrics, argues that this phenotype-first approach is failing a substantial group of patients: those whose vascular malformations come with regional overgrowth but who do not carry mutations in PIK3CA, the gene that defines the best-known overgrowth spectrum. By combining deep sequencing of affected tissue with systematic clinical characterization across five tertiary centers, the researchers have produced one of the most detailed portraits to date of this underrecognized population, and their findings challenge how these disorders are classified, diagnosed, and treated.
The study enrolled 41 children and adolescents—20 males and 21 females—each of whom presented with a vascular malformation, clinically appreciable overgrowth of a body region beyond the vascular lesion itself, and a confirmed pathogenic or likely pathogenic variant in genes of the PI3K/AKT/mTOR pathway or related vascular signaling pathways, with PIK3CA deliberately excluded. The mean age at first clinical assessment was 9.0 years, while the mean age at molecular diagnosis was 12.1 years, a gap that underscores how long these conditions can evade a definitive label. Participants were recruited from the Regina Margherita Children’s Hospital in Turin, the Fondazione Policlinico Universitario Agostino Gemelli and the Bambino Gesù Children’s Hospital in Rome, the Santa Maria della Misericordia Hospital in Udine, and the San Bortolo Hospital in Vicenza, with genetic analysis performed in Bari.
The molecular results reveal a landscape far more diverse than the PIK3CA-centric literature might suggest. Variants in TEK, a gene encoding the TIE2 receptor tyrosine kinase that governs venous endothelial cell survival, were the most common, found in 24.4 percent of patients. GNAQ and GNA11, two closely related G-protein genes recurrently implicated in capillary malformations and Sturge-Weber syndrome, each accounted for 21.9 percent. PTEN variants, which define the PTEN hamartoma tumor syndrome spectrum, were present in 14.6 percent, RASA1 in 12.2 percent, and single patients carried variants in AKT3 and EPHB4. Critically, 65.9 percent of the identified variants were somatic—acquired after fertilization and present only in a mosaic fraction of cells—while 34.1 percent were germline, inherited or present in every cell of the body.
Detecting these variants demanded sequencing strategies far beyond conventional diagnostic testing. The team used next-generation sequencing with a targeted 17-gene panel at a read depth exceeding 2,000 reads per base, a level of coverage that allows detection of mosaic variants present at allele fractions as low as roughly 5 percent or below. Samples were drawn from peripheral blood in 12 patients, buccal swabs in 2, and—most importantly—biopsies of affected tissue in 27. This tissue-first strategy proved decisive: somatic variants identified in lesions were absent from blood DNA in every case, confirming that blood-based testing alone would have missed nearly two-thirds of the molecular diagnoses. Conversely, in several patients whose segmental, apparently sporadic presentations strongly suggested mosaicism, germline variants were ultimately identified, a discordance the authors emphasize as a warning against inferring mutational origin from clinical pattern alone.
The phenotypic data are equally revealing. Soft tissue or muscular overgrowth was documented in 60.9 percent of patients, skeletal anomalies in 46.3 percent, and macrocrania in 19.5 percent, the latter concentrated among children with PTEN variants. Adipose overgrowth appeared in a smaller subset, and internal organ involvement in just three individuals, including one child with a germline TEK variant whose colon harbored extensive vascular malformations and two patients with GNA11 or AKT3 variants who exhibited hemimegalencephaly, a dysplastic overgrowth of one cerebral hemisphere. Perhaps most strikingly, a minority of patients displayed segmental undergrowth rather than overgrowth: in one TEK patient, serpiginous vascular overgrowth coexisted with limb hypoplasia and muscle atrophy, and a GNA11 patient with cutis marmorata telangiectatica congenita showed mild hypoplasia of the affected limb. The authors interpret these cases as evidence that disturbed vascular hemodynamics—venous hypertension, microvascular shunting, chronic hypoperfusion—can impair normal tissue development, meaning the same underlying biology can push growth in opposite directions depending on timing, location, and severity.
Genotype-phenotype correlations, however, proved frustratingly loose. A syndromic diagnosis could be assigned on clinical grounds alone in 63.4 percent of patients, but the same clinical entities mapped onto multiple genes and vice versa. GNAQ and GNA11 variants surfaced in patients labeled with Klippel-Trenaunay syndrome, diffuse capillary malformation with overgrowth, Sturge-Weber syndrome, phakomatosis pigmentokeratotica, and in several cases that fit no defined syndrome at all. TEK variants spanned Klippel-Trenaunay syndrome, blue rubber bleb nevus syndrome, and unclassifiable presentations, while RASA1 variants appeared in Parkes-Weber syndrome and beyond. Even within a single gene, severity varied enormously. The authors argue that this overlap renders phenotype-based classification unreliable and advocate a shift toward molecularly driven frameworks, in which the gene and pathway—rather than the eponym—anchor the diagnosis.
The study also probes what overgrowth actually means. Regional enlargement in these patients may reflect true mesenchymal proliferation, but it can equally represent apparent enlargement driven by venous ectasia, increased regional perfusion, or secondary deformation of neighboring structures. Macrocrania in PTEN-related disease, for instance, likely reflects hamartomatous dysplasia rather than vascular-mediated expansion, and hemimegalencephaly in GNA11 and AKT3 patients represents cortical dysplasia rather than classical somatic overgrowth. These distinctions matter clinically, because they influence how imaging findings are interpreted, how cohorts are compared across studies, and ultimately how therapeutic decisions are made. The authors acknowledge that their inclusive definition—accepting both true and apparent overgrowth—broadens the cohort but also blurs a boundary that current imaging techniques cannot reliably draw.
The clinical burden documented in the cohort was substantial and, notably, not strictly proportional to lesion size. Nearly 44 percent of patients reported functional limitations ranging from fatigue and impaired high-demand physical activity to gait abnormalities, pain episodes, and visual deficits. Four patients experienced significant hemostatic or thrombotic complications, including one GNA11 patient who suffered cerebral ischemia with subsequent epilepsy and hemiparesis, and several TEK patients with recurrent intralesional thrombosis and phlebolithiasis. Psychosocial impact was formally recorded in only one patient, but the authors suspect this dramatically underestimates the true toll of disfiguring lesions, which families often underreport to clinicians. The findings argue for multidisciplinary assessment that encompasses functional and psychological dimensions alongside anatomical characterization, and for structured transition pathways as patients move into adult care.
Treatment data carry perhaps the most consequential message. Surgery was frequently non-curative, with relapse of overgrowth in nearly every treated region. Sirolimus, an mTOR inhibitor often used off-label in vascular anomalies, showed limited or absent benefit and was discontinued in all four patients who received it, in one case because of severe recurrent infections. Yet alpelisib, a selective PI3K inhibitor developed for PIK3CA-driven disease, produced clinical and volumetric improvement in a subset of TEK-variant patients despite the absence of any PIK3CA mutation. This unexpected efficacy supports the concept of convergent downstream pathway activation: distinct upstream genetic lesions—whether in TEK, GNAQ, or PIK3CA—may funnel into shared PI3K/AKT/mTOR signaling, creating a biological rationale for pathway-targeted therapies that extends beyond the classical PROS population. One TEK patient also responded favorably to propranolol, though the authors caution that this single observation remains anecdotal, since propranolol’s established use is confined to infantile hemangiomas.
The study’s limitations are acknowledged candidly: its retrospective design, the selection bias inherent in requiring an identifiable pathogenic variant, and the absence of standardized quality-of-life measures that likely understated disease burden. Even so, the implications are clear. For children with vascular malformations and overgrowth who test negative for PIK3CA, the diagnostic journey should not end; broad gene panels, deep sequencing of affected tissue whenever feasible, and systematic parental testing offer the best route to a molecular diagnosis. And as targeted therapies mature, the gene a child carries—not the name of a syndrome—may determine whether an effective drug exists. This cohort of 41 patients makes a compelling case that the era of molecularly driven classification for vascular overgrowth disorders has arrived, and that the patients it will benefit most are precisely those the old system left unclassified.
Subject of Research: Genetic and clinical characterization of non-PIK3CA vascular malformations with overgrowth in children
Article Title: Clinical and molecular characterization of non-PIK3CA-related vascular malformations with overgrowth in a pediatric cohort
Article References: Reynolds, G., Luca, M., Coppo, P., La Selva, R., Leoni, C., Bellani, I., Ragusa, S., Massuras, S., Perrelli, S., Martino, S., Buonuomo, P. S., Rondot, F., Spinelli, A. M., Morando, C., Piglionica, M., Resta, N., & Mussa, A. (2026). Clinical and molecular characterization of non-PIK3CA-related vascular malformations with overgrowth in a pediatric cohort. World Journal of Pediatrics. https://doi.org/10.1007/s12519-026-01098-3
Image Credits: AI Generated
DOI: 10.1007/s12519-026-01098-3
Keywords: vascular malformations, overgrowth, PIK3CA, TEK, GNAQ, GNA11, PTEN, RASA1, somatic mosaicism, next-generation sequencing, alpelisib, sirolimus
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Juliet Wilcox. (September 30, 2026). Beyond PIK3CA: Genetic Study Redraws the Map of Childhood Vascular Malformations with Overgrowth. Scienmag. https://scienmag.com/beyond-pik3ca-genetic-study-redraws-the-map-of-childhood-vascular-malformations-with-overgrowth/
Juliet Wilcox. “Beyond PIK3CA: Genetic Study Redraws the Map of Childhood Vascular Malformations with Overgrowth.” Scienmag, 30 September 2026, https://scienmag.com/beyond-pik3ca-genetic-study-redraws-the-map-of-childhood-vascular-malformations-with-overgrowth/. Accessed 30 September 2026.
Juliet Wilcox. “Beyond PIK3CA: Genetic Study Redraws the Map of Childhood Vascular Malformations with Overgrowth.” Scienmag. September 30, 2026. https://scienmag.com/beyond-pik3ca-genetic-study-redraws-the-map-of-childhood-vascular-malformations-with-overgrowth/
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Tags: alpelisibalternative genetic pathways in vascular anomalieschildhood overgrowth syndromesclinical characterization of vascular overgrowthdeep sequencing in vascular disordersdiagnostic challenges in vascular malformationsgenetic basis of vascular malformationsGNA11GNAQmulticenter pediatric vascular researchnext-generation sequencingovergrowthpediatric vascular malformation classificationpersonalized treatment approaches for vascular overgrowthPI3K/AKT/mTOR pathway mutationsPIK3CAPIK3CA-negative vascular anomaliesPTENRASA1sirolimussomatic mosaicismTEKvascular malformations
