Ring chromosome 14 syndrome is a rare genetic disorder characterized by the formation of a circular chromosome, resulting in a broad spectrum of clinical manifestations. Among the most significant are early-onset epilepsy, frequently refractory to conventional antiepileptic treatments, neurodevelopmental delay, intellectual disability, and distinctive facial dysmorphisms. Clinical management of these patients is complex due to the heterogeneity of symptoms and limited response to standard therapies.
Early recognition of the phenotype is essential to guide appropriate interventions and improve long-term outcomes. We present the case of a 5-year-old male, born at term without perinatal complications, diagnosed with congenital malformations including Tetralogy of Fallot and hypospadias. He underwent corrective cardiac surgery at 14 days of life, followed by surgical repair of hipospadias and inguinal hernia.
Developmental delays and characteristic facial features were noted early in life. At four months, he experienced his first prolonged seizure lasting approximately 40 minutes, complicated by a hemorrhagic stroke, requiring a five-month hospitalization for seizure management. Persistent, frequent, and refractory seizures prompted genetic testing, confirming ring chromosome 14 syndrome.
After discharge, the patient continued to experience weekly brief seizures, with EEG showing repetitive focal spikes in the right temporo-parieto-occipital region. At age three, a temporary remission of seizures occurred for approximately six months, followed by recurrence, with an average of three episodes per week. Current therapy includes phenobarbital, valproic acid, levetiracetam, and clobazam, along with rescue rectal diazepam for acute episodes. In May 2025, seizure control deteriorated following a prolonged flu-like illness, resistant to three different antimicrobial treatments, resulting in up to four seizures per day—the highest frequency recorded. Laboratory investigations revealed macrocytic anemia and thrombocytopenia, likely related to high-dose valproic acid therapy. Immunological assessment was requested due to recurrent respiratory infections, and referral for potential epilepsy surgery is in progress.

Ring chromosome 14 syndrome is typically associated with early-onset focal seizures, often progressing to secondary generalized seizures. Status epilepticus is reported in approximately half of cases, contributing to the complexity of management. Patients frequently demonstrate moderate-to-severe intellectual disability, language impairment, hypotonia, microcephaly, and typical facial dysmorphisms, including elongated face, downslanting palpebral fissures, flat nasal root with bulbous tip, thin upper lip, and low-set ears. Increased susceptibility to infections, particularly respiratory, may result from immunodeficiencies or craniofacial abnormalities impairing airway clearance. Coexisting congenital heart defects, such as Tetralogy of Fallot, may exacerbate neurological complications through chronic hypoxia or cyanotic episodes, further predisposing to seizures. In conclusion, ring chromosome 14 syndrome represents an extremely rare genetic condition with multifaceted clinical manifestations, including refractory epilepsy, congenital anomalies, and increased vulnerability to infections. Phenotypic variability emphasizes the need for early recognition, targeted genetic testing, and timely therapeutic interventions. Comprehensive clinical management, including optimized seizure control, careful monitoring of comorbidities, and multidisciplinary care, is essential to improve prognosis and enhance the quality of life in these patients.