Heterogeneity of Epileptic Phenotypes in KBG Syndrome: A Series of Four Cases and Literature Review

Background To investigate the clinical features, electroencephalography (EEG) findings, genetic basis, and therapeutic response of epilepsy in KBG syndrome patients and to explore its phenotypic spectrum. Methods A retrospective analysis was performed on four children with KBG syndrome presenting with epilepsy who were admitted to Hebei Children's Hospital between January 2023 and December 2025. Clinical data were collected, and a systematic database search identified 108 reported KBG syndrome patients with epileptic phenotypes. Results Among our 4 cases (3 males, 1 female), the median epilepsy onset age was 4 years. Focal and myoclonic seizures were predominant, and 1 patient presented with multiple seizure types. In accordance with the 2022 ILAE criteria, 1 patient presented with epilepsy with myoclonic-atonic seizures (EMAS), whereas another patient presented with a phenotype analogous to childhood occipital visual epilepsy (COVE). All patients exhibited abnormal electroencephalogram (EEG) findings, predominantly epileptiform discharges, whereas 2 patients presented nonspecific changes on cranial imaging. Pathogenic ANKRD11 mutations were detected in all the children, encompassing 2 transpositions, 1 nonsense, and 1 missense, with 3 de novo and 1 maternally inherited mutations. Two patients with focal epilepsy achieved seizure control with lacosamide, and 1 was diagnosed with refractory epilepsy. For the 108 literature cases, the male-to-female ratio was 1.7:1, and the median age at epilepsy onset was 3 years and 10 months. Bilateral tonic‒clonic seizures (n = 47) and focal seizures (n = 31) were most common, and 36.3% had multiple types. Seventeen patients met the criteria for epileptic syndrome, predominantly EMAS, which was the most common type. This is the first report of the association between COVE and KBG syndrome. The overall response to antiseizure medications (ASMs) was favorable, with the incidence of refractory epilepsy being 27.8%. Conclusion Epilepsy in KBG syndrome has significant phenotypic heterogeneity and a high incidence in childhood. EMAS is the most commonly associated epileptic syndrome, and COVE is a novel phenotypic association. This disease has a high rate of EEG abnormalities, while brain structural lesions are nonspecific. Lacosamide may be an effective drug for treating focal seizures. Given the limited sample sizes, the exact efficacy requires further verification in large-sample studies.