Phelan-McDermid Syndrome (PMS) is a rare neurodevelopmental disorder caused by SHANK3 haploinsufficiency on chromosome 22q13.3. It is characterized by global developmental delay, autism spectrum features, hypotonia, and variably dysmorphic traits. SHANK3 encodes a synaptic scaffolding protein essential for glutamatergic transmission and cortical connectivity; its disruption leads to widespread neurodevelopmental impairment. Advances in genetic testing have improved recognition of PMS and its overlap with epilepsy syndromes such as Lennox–Gastaut, underscoring the importance of early genetic evaluation in refractory epilepsy.

A 19-year-old male with a history of Lennox–Gastaut syndrome, autism spectrum disorder, and cerebral palsy presented with increased seizure frequency and emesis due to small bowel obstruction, requiring surgical intervention. Seizures began at age nine, consisting of brief tonic episodes with bilateral arm flexion and upward gaze, occurring in clusters lasting 3–5 seconds. Examination revealed microcephaly, gingival hypertrophy, nystagmus, spastic quadriparesis, low axial tone, and dyskinetic movements. EEG showed diffuse slowing with rare right central and left temporal discharges, and one generalized seizure. Brain MRI demonstrated mild diffuse atrophy with stable ventricular prominence.