The condition arises from somatic mosaic, postzygotic activating variants in the phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) gene, leading to dysregulated phosphoinositide 3-kinase (PI3K)-protein kinase B (AKT)-mammalian target of rapamycin (mTOR) signaling and placing it within the PIK3CA-related overgrowth spectrum (PROS). Mutations in the PI3K-AKT-mTOR pathway can cause localized overgrowth of tissues such as vasculature, bone, soft tissue, and brain, with phenotypic expression depending on the developmental timing and cell lineage affected during embryogenesis [2]. This mechanism explains both the frequent unilateral presentation of features and the negative results on whole-exome sequencing of blood samples in most patients [2]. Furthermore, Klippel-Trenaunay syndrome must be distinguished from Parkes-Weber syndrome (previously termed ‘Klippel-Trenaunay-Weber’), which involves high-flow arteriovenous fistulas associated with RAS p21 protein activator 1 (RASA1) or EPH receptor B4 (EPHB4) mutations [2].

Intracranial involvement in Klippel-Trenaunay syndrome is uncommon but has been reported in association with arteriovenous malformations, cavernomas, aneurysms, hemimegalencephaly, cortical dysplasia, and polymicrogyria. These structural abnormalities may predispose patients to seizures, which are typically focal in onset. Prior case reports have documented associations between focal seizures and hemimegalencephaly [2]. However, to our knowledge, absence seizures have not previously been described in association with Klippel-Trenaunay syndrome.

We present a case of a 10-year-old girl with a history of Klippel-Trenaunay syndrome (Fig. 1A) and an unremarkable family history, who presented with multiple daily episodes beginning at approximately 6 years of age, characterized by staring and inattentive behavior lasting 10 to 15 seconds. Cutaneous and lymphatic stigmata were observed over the left lower limb, involving the lateral thigh, gluteal region, and extending to the leg. The lesions consisted of multiple irregularly bordered, violaceous to hyperpigmented macules and plaques of variable sizes, consistent with capillary-venous malformations. The involvement was strictly unilateral, confined to the left side, with no comparable lesions on the contralateral limb or trunk. Prolonged video-electroencephalogram (EEG) monitoring recorded multiple electroclinical absence seizures characterized by generalized, symmetric 3 Hz spike-and-slow-wave discharges, maximal over the frontal regions (Fig. 1B). No focal slowing, asymmetry, or focal interictal epileptiform discharges were detected in any epoch, and the interictal background activity was normal for age. Recordings were obtained using the standard 10 to 20 electrode placement system, with montage specifications indicated on the sample EEG tracing (Fig. 1B). Activation procedures, including photic stimulation and hyperventilation, did not elicit any additional abnormalities. Brain magnetic resonance imaging (MRI) revealed a large, remote right posterior cerebral artery (PCA) distribution infarction with marked volume loss and cystic encephalomalacia (Fig. 2A). The patient had no prior history of perinatal insult, transient ischemic attack, stroke-like event, or focal neurological deficit to account for this finding. Magnetic resonance angiography and venography were both unremarkable, showing no vascular malformation, venous anomaly, or large-vessel occlusion.

The patient was started on ethosuximide 250 mg twice daily, achieving complete seizure remission. Follow-up prolonged video-EEG showed a favorable treatment response, with only occasional diffuse spike-sharp wave discharges during sleep and no absence seizures. Her parents reported improved cognitive functioning and school performance during treatment. Whole-exome sequencing revealed no pathogenic variants. Informed consent was obtained from the patient for inclusion in this study.

To our knowledge, this is the first documented case of generalized absence seizures in a patient with Klippel-Trenaunay syndrome. To substantiate this claim, we conducted a comprehensive literature search across PubMed, Scopus, and Google Scholar using the keywords ‘Klippel-Trenaunay syndrome,’ ‘absence seizures,’ ‘childhood absence epilepsy,’ ‘epilepsy,’ ‘seizures,’ and ‘PIK3CA.’ The search spanned from database inception through July 2025 and was restricted to English-language human studies. Screening over 120 unique records identified reports describing focal seizures, hemimegalencephaly-associated epilepsy, and cortical malformations in Klippel-Trenaunay syndrome [2], but none documenting generalized absence seizures or 3-Hz spike-wave discharges.

Our patient demonstrated a remote right PCA-territory infarct with cystic encephalomalacia, likely reflecting a past vascular insult. Such a focal lesion could theoretically underlie an epileptogenic focus giving rise to focal-onset seizures. Although typical childhood absence epilepsy (CAE) is classified as generalized, rare cases have shown focal cortical onsets preceding generalized 3 Hz spike-wave discharges, a phenomenon termed secondary bilateral synchrony (SBS) [3]. Stereo-EEG and scalp EEG studies have identified focal leads—often in the frontal, parietal, or occipital cortex—that rapidly recruit the thalamocortical network to produce clinically typical absence events [4]. Kakisaka et al. [5] reported two pediatric cases in which focal epileptic activity within the temporal lobe generated generalized 3 Hz spike-and-wave complexes, characteristic of absence epilepsy. Both patients exhibited dialeptic seizures as the primary symptom; one had a left medial temporal mass, and the other had no MRI lesion. EEG and magnetoencephalography localized spikes to the left temporal region, and ictal Single Photon Emission Computed Tomography (SPECT) confirmed seizure onset there. In both cases, the generalized discharges appeared from onset and were temporally linked to the focal activity. Surgical removal of the lesion in one case resulted in complete seizure remission and disappearance of both focal and generalized EEG abnormalities [5].

Modern network models and invasive recordings suggest a two-step mechanism for this phenomenon: (1) a focal hyperexcitable cortical zone (e.g., infarct-related cortex) generates fast leading activity, and (2) this activity entrains the thalamic reticular nucleus and thalamocortical relay neurons, producing the hallmark bilateral, synchronous 3 to 4 Hz spike-wave complexes (Fig. 2B) [6]. Our patient’s PCA-territory lesion could therefore act as a focal driver for generalized-appearing absence seizures via SBS, particularly if the perilesional cortex or long-range association fibers are involved.

A second, non-mutually exclusive hypothesis is PIK3CA-mediated network hyperexcitability. Although CAE accounts for 2% to 8% of pediatric epilepsy cases [7], the somatic PIK3CA mosaicism underlying Klippel-Trenaunay syndrome provides a plausible mechanistic link. In mouse models, neural-specific Pik3ca mutations (e.g., H1047R, E545K) lead to brain overgrowth, cortical malformations, and epilepsy. Acute suppression of PI3K signaling reduces seizure activity even without reversing structural dysplasia, suggesting that PIK3CA-induced signaling itself is intrinsically epileptogenic [8]. In PROS subtypes such as megalencephaly-capillary malformation syndrome (MCAP), brain involvement and epilepsy are well documented, likely resulting from disruption of thalamocortical circuits central to absence seizure generation [9]. Although our patient did not exhibit overt malformations typical of MCAP, subclinical alterations in these circuits could contribute to CAE.

Whole-exome sequencing from peripheral blood was negative for PIK3CA variants in our patient. However, this finding does not exclude PIK3CA-related mosaicism, which may exist at low allele frequencies or be restricted to affected tissues, thereby evading detection in blood-based assays. Recent consensus statements and diagnostic guidelines emphasize that molecular confirmation should ideally be sought from affected tissues, such as skin, overgrown limbs, or vascular malformations, where the mutant clone is most concentrated. Techniques including targeted ultra-deep sequencing, droplet digital polymerase chain reaction, or amplicon-based next-generation sequencing provide substantially greater sensitivity [10].

Ethosuximide, a first-line treatment for absence seizures, was effective in this case. By blocking T-type Ca²⁺ channels in thalamocortical relay neurons, it prevents the excessive neuronal synchrony underlying generalized spike-wave discharges, thereby abolishing the patient’s seizures.

This case expands the clinical spectrum of Klippel-Trenaunay syndrome by presenting the first documented instance of generalized absence seizures and proposing several non-mutually exclusive mechanisms. Chronic cerebrovascular compromise due to abnormal venous drainage or prior infarction may disrupt thalamocortical circuits, creating a substrate for focal-onset generalized absence seizures. Concurrently, evidence from other PROS disorders, such as MCAP, and from experimental models suggests that somatic PIK3CA mosaicism can dysregulate the PI3K-AKT-mTOR pathway, altering thalamocortical excitability even in the absence of overt cortical malformations. Although a coincidental co-occurrence cannot be excluded given the background prevalence of CAE, the overlapping molecular and neurovascular mechanisms render a causal association biologically plausible.