Phelan-McDermid syndrome due to 22q13.3 deletion

Phelan-McDermid syndrome (PMS) due to 22q13.3 deletion is a rare neurodevelopmental disorder caused by the loss of genetic material from the terminal region of the long arm of chromosome 22. This deletion typically involves the SHANK3 gene, which plays a critical role in synaptic function and is considered the primary gene responsible for the neurological features of the syndrome. The condition is also known as 22q13.3 deletion syndrome. Most cases arise de novo (as new mutations not inherited from parents), though in some instances a parent may carry a balanced chromosomal rearrangement that predisposes to the deletion. Phelan-McDermid syndrome primarily affects the nervous system, leading to global developmental delay, moderate to severe intellectual disability, absent or severely delayed speech, and neonatal hypotonia (low muscle tone). Many individuals exhibit features of autism spectrum disorder, including impaired social communication and repetitive behaviors. Additional common features include minor dysmorphic facial features (such as long eyelashes, prominent ears, bulbous nose, and pointed chin), large or fleshy hands, dysplastic toenails, and reduced perception of pain. Seizures occur in a significant proportion of patients and may develop at any age. Some individuals also experience renal abnormalities, gastrointestinal issues (including gastroesophageal reflux), and lymphedema. Growth is typically normal, though some patients may show accelerated growth. There is currently no cure for Phelan-McDermid syndrome. Management is supportive and multidisciplinary, involving speech therapy, occupational therapy, physical therapy, behavioral interventions, and seizure management when needed. Research into targeted therapies, including insulin-like growth factor 1 (IGF-1) and other agents that modulate synaptic function, is ongoing but remains investigational. Early intervention programs are strongly recommended to optimize developmental outcomes.

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