Phelan-McDermid Syndrome

Overview

Phelan-McDermid Syndrome (PMS) is a rare genetic disorder that results from a deletion or mutation affecting the terminal end of chromosome 22, specifically the 22q13.3 region, which includes the SHANK3 gene. This syndrome is also sometimes referred to as 22q13 deletion syndrome. PMS primarily affects the nervous system and is characterized by global developmental delay, intellectual disability, delayed or absent speech, low muscle tone (hypotonia), and features associated with autism spectrum disorder. Some individuals may also exhibit seizures, sleep disturbances, and minor facial differences. The severity of symptoms varies depending on the size of the deletion and whether additional genetic material is affected.

Causes

Phelan-McDermid Syndrome is most commonly caused by a deletion on the long arm (q arm) of chromosome 22 at position 22q13.3. In many cases, this deletion occurs de novo (spontaneously), meaning it is not inherited from either parent. However, in a minority of cases, the deletion can be inherited from a parent with a balanced chromosomal rearrangement.

The key gene involved in PMS is SHANK3, which plays a crucial role in the formation and function of synapses (the connections between nerve cells in the brain). Mutations or deletions of SHANK3 disrupt normal synaptic signaling, leading to many of the neurological and developmental features observed in PMS.

Symptoms

The clinical presentation of Phelan-McDermid Syndrome is highly variable but often includes a combination of the following features:

Developmental and Neurological Features:

• Global developmental delay: Delayed achievement of motor and cognitive milestones

• Intellectual disability: Ranging from moderate to severe

• Speech delay or absence: Many individuals are non-verbal or have limited verbal ability

• Hypotonia: Poor muscle tone, particularly noticeable in infancy

• Autism spectrum disorder traits: Poor eye contact, repetitive behaviors, sensory sensitivities

• Seizures: May occur in some individuals, often beginning in childhood or adolescence

• Motor coordination issues: Including gait abnormalities and fine motor skill challenges

Behavioral and Emotional Features:

• Social withdrawal or limited social interaction

• Periods of hyperactivity or aggression

• Self-injurious behaviors in some individuals

Other Physical and Medical Features:

• Minor facial features: Such as full cheeks, prominent eyelashes, or a broad nasal bridge

• Large, fleshy hands or feet

• Feeding difficulties: Particularly in infancy

• Sleep disturbances: Including difficulty falling or staying asleep

• Immune system irregularities: Increased susceptibility to infections in some cases

Diagnosis

Phelan-McDermid Syndrome is diagnosed through genetic testing. Because the physical features are often subtle and overlap with other neurodevelopmental disorders, genetic confirmation is essential.

Diagnostic Methods Include:

• Chromosomal microarray (CMA): Detects deletions in the 22q13.3 region

• Whole exome sequencing or targeted gene panel: Identifies mutations in the SHANK3 gene

• Fluorescence in situ hybridization (FISH): Can also detect deletions of chromosome 22q13

• Karyotyping: Useful for identifying large chromosomal rearrangements or inherited translocations

Early diagnosis is important for initiating interventions and providing appropriate developmental support.

Treatment

There is currently no cure for Phelan-McDermid Syndrome. Treatment is supportive and focused on managing symptoms and maximizing developmental potential through early intervention. A multidisciplinary approach is essential, involving specialists in neurology, developmental pediatrics, speech and language therapy, occupational therapy, and behavioral therapy.

Key Treatment Strategies Include:

Developmental and Educational Support:

• Early intervention programs targeting motor, speech, and cognitive development

• Individualized education plans (IEPs) tailored to the child’s needs

• Speech therapy, often including augmentative and alternative communication (AAC) systems

Behavioral and Emotional Support:

• Applied behavior analysis (ABA) or other structured behavioral therapies

• Sensory integration therapy for sensory sensitivities

• Psychiatric care when behavioral challenges are severe

Medical Management:

• Antiepileptic drugs (AEDs) for seizure control if seizures are present

• Sleep aids for chronic sleep disturbances

• Nutritional support for feeding difficulties or gastrointestinal issues

Regular monitoring for developmental progress and emerging medical issues is critical. Genetic counseling is recommended for families, especially if the deletion is inherited.

Prognosis

The prognosis for individuals with Phelan-McDermid Syndrome varies depending on the size of the genetic deletion and the severity of associated symptoms. Many individuals require lifelong care and support, especially for communication, daily living skills, and behavior management.

Some children make significant developmental progress with early and intensive intervention, particularly in motor and communication skills. Others may have more severe intellectual and functional limitations.

While PMS is a lifelong condition, many individuals enjoy a good quality of life with the right support system, therapies, and education. Research into targeted therapies, especially those addressing SHANK3 function, is ongoing and offers hope for future treatment options.