Phelan-McDermid Syndrome

Phelan-McDermid Syndrome results from deletion of chromosome 22q13 (the smallest deletion is 100 kb involving only SHANK3, while larger deletions involve multiple adjacent genes). The SHANK3 gene encodes a scaffold protein crucial for dendritic spine formation and stabilization, synaptic transmission, and neurodevelopment. SHANK3 is highly expressed in the brain and is critical for proper synaptic function and plasticity. Loss of SHANK3 leads to abnormal dendritic spine development, impaired glutamatergic synaptic transmission, and disrupted neural circuit development. Clinical features of Phelan-McDermid Syndrome include significant intellectual disability (usually moderate to severe), autism spectrum features (present in 50-80% of individuals), and severe speech and language delay. Hypotonia is common in infancy, improving somewhat with development but often resulting in motor delays and coordination problems. Seizures occur in 25-40% of individuals and may be difficult to manage. Behavioral challenges including autism features, anxiety, self-injurious behaviors, and attention problems are common. Some individuals have distinctive facial features and other minor dysmorphisms. Growth may be affected with some children showing failure to thrive or short stature. Cardiac defects and renal anomalies occur in some cases.