"Tuberous sclerosis in Greece: A national cohort study on clinical features and rare manifestations"

Tuberous Sclerosis Complex (TSC) is a rare, multisystem genetic disorder with highly variable clinical manifestations. While international registries such as TOSCA have provided large-scale data, national-level studies remain limited. This study represents the first national cohort analysis of TSC patients in Greece, providing comprehensive insights into clinical characteristics, genotype-phenotype correlations, and previously underreported rare manifestations.

A descriptive analysis was conducted on 115 TSC patients diagnosed based on the latest criteria. Clinical, genetic, and treatment-related data were analysed, with a particular focus on neurological, renal, cardiac, dermatological, and pulmonary manifestations, as well as rare or atypical disease presentations.

The median age at diagnosis was 1.2 years (range: 0-43 years). Epilepsy was the most frequent initial symptom (70.4 %), with drug-resistant epilepsy (DRE) affecting 39.5 % of cases. Intellectual disability, autism spectrum disorder, and behavioral issues correlated significantly with early seizure onset and TSC2 variants. Common manifestations include cortical tubers (93.9 %), subependymal nodules (92.2 %), angiomyolipomas (48.7 %), and cardiac rhabdomyoma (33 %). Notably, we report several rare manifestations, including high-grade glioma in a pediatric patient, diffuse lipomatosis, pancreatic neuroendocrine tumours, rectal polyps, and erythema nodosum presented in a patient on everolimus therapy, further highlighting the systemic complexity and malignancy risks in TSC.

Our study provides novel epidemiological and clinical data on TSC in Greece, reinforcing genotype-phenotype correlations and expanding the spectrum of rare manifestations. These findings emphasise the need for lifelong surveillance, multidisciplinary management, and early detection strategies to mitigate long-term complications. This study also contributes to the broader understanding of TSC by documenting atypical presentations that may inform future clinical guidelines and patient care strategies.