Phelan-McDermid syndrome

Phelan-McDermid syndrome is a neurodevelopmental condition that primarily affects the brain, muscles, and several other body systems. It is most often caused by a small missing piece of chromosome 22 at region 22q13 or by a pathogenic variant in the SHANK3 gene, which encodes a protein critical for communication between brain cells. Signs usually become apparent in infancy or early childhood when developmental milestones such as speech and motor skills are delayed. Precise population figures are not yet available, but the condition is considered uncommon and is likely under-diagnosed because milder presentations can be overlooked. Both males and females can be affected, and the severity and specific symptoms vary widely from one individual to another.

The earliest features often noticed by parents and clinicians are marked neonatal or early-infancy hypotonia (poor muscle tone) and delayed developmental milestones. Speech and language are especially affected: many children say few or no words, and expressive language remains limited throughout life. Global developmental delay is universal, yet the degree of intellectual disability ranges from mild to severe. Neurological and behavioral aspects dominate the clinical picture. Many individuals show autistic characteristics, atypical social interaction, or sensory-seeking behaviors. Seizures occur in a sizeable minority, and impaired pain sensation, bruxism, and sleep disturbance are also reported. Because the SHANK3 protein functions at synapses in the brain, these neurological features reflect disrupted neuronal signaling. Several physical findings help clinicians recognize the syndrome. Tall stature and accelerated growth are common. Characteristic facial traits can include long eyelashes, thick eyebrows, epicanthal folds, full cheeks, and palpebral puffiness, though these are often subtle. Limb findings such as fifth-finger clinodactyly or 2-3 toe syndactyly may be present. Generalized or persistent hypotonia contributes to delayed sitting, standing, and walking. Multi-system involvement means complications can arise outside the nervous system. Kidney anomalies, gastroesophageal reflux, feeding difficulties, and diminished sweating (hypohidrosis) are each reported in about one-third to two-thirds of affected individuals. Not all individuals experience all features, and severity varies considerably across the lifespan.

Phelan-McDermid syndrome results from either a deletion that removes the tip of chromosome 22 at band q13 or a disease-causing variant in the SHANK3 gene located in the same region. SHANK3 encodes a scaffolding protein that helps organize receptors and signaling molecules at synapses, so its loss disrupts neuronal communication and leads to the developmental and behavioral features described above. The condition follows an autosomal dominant inheritance pattern, meaning that a change in only one copy of SHANK3 or the loss of one chromosome segment is sufficient to cause symptoms. Most cases occur sporadically as new (de novo) genetic changes, so parents are typically unaffected. When an individual with the syndrome has children, each child faces up to a 50 percent chance of inheriting the altered chromosome segment or SHANK3 variant. Even within a family, the condition can show variable expressivity, so the type and severity of symptoms may differ among relatives. Because recurrence risks and family planning options are complex, families are strongly encouraged to meet with a genetic counselor.

Currently, management focuses on supportive care and symptom management, tailored to each person’s needs. Early intervention with physical, occupational, and speech therapy is foundational and can maximize developmental potential. Because many individuals have behavioral and cognitive challenges, applied behavior analysis, social skills training, and educational supports are central to care. Long-term management requires a multidisciplinary team that may include neurologists, developmental pediatricians, gastroenterologists, nephrologists, and rehabilitation specialists. Regular surveillance is an essential part of care, helping to detect complications such as seizures, kidney abnormalities, or severe reflux before they become serious. Nutritional monitoring addresses feeding difficulties, while orthopedic and physical therapy assessments track motor progress and manage hypotonia. No therapies are specifically approved for Phelan-McDermid syndrome, but several investigational treatments are being studied in clinical trials. Families should discuss emerging options with their healthcare providers to understand eligibility, potential benefits, and risks. Genetic counseling is recommended for affected individuals and at-risk relatives to review inheritance, recurrence risk, and family planning choices.

Phelan-McDermid syndrome is a lifelong condition. Many individuals continue to make developmental gains, especially when therapies and educational supports start early, but most will need assistance with daily living skills as adults. Seizure control, feeding problems, and behavioral challenges can affect quality of life, yet proactive medical management often mitigates these issues. Severity and symptoms vary widely between individuals, so long-term outcomes are individualized rather than predictable. Outcomes described in medical literature continue to evolve as standards of care improve. Families often find it helpful to connect with expert centers, patient advocacy groups, and registries that facilitate research and provide practical support.

Several clinical trials are currently investigating new treatments aimed at improving cognitive and behavioral symptoms or targeting the underlying biology of SHANK3 deficiency. Research directions include molecules that modulate synaptic signaling, growth factor pathways, and gene-based strategies. Individuals interested in clinical trials can search ClinicalTrials.gov or consult their care team about eligibility.