Phelan-McDermid syndrome (PMS) is a rare genetic condition caused by a missing or disrupted section of chromosome 22. It primarily affects brain development, leading to low muscle tone in infancy, significant speech delays, intellectual disability, and often autism-like behaviors. The condition is also known as 22q13.3 deletion syndrome, named for the specific region of the chromosome involved.
The Genetic Cause
PMS centers on a gene called SHANK3, located near the tip of the long arm of chromosome 22. SHANK3 produces a protein that acts as scaffolding inside brain cells, helping to stabilize the connections (synapses) where neurons communicate with each other. When one copy of SHANK3 is deleted or disrupted, there isn’t enough of this protein to maintain healthy synaptic connections, and brain development is affected from early on.
The genetic change can take several forms. Most commonly, a chunk of chromosome 22 is simply missing. These deletions vary enormously in size, from less than 50 kilobases (a tiny segment containing just SHANK3) to more than 9 megabases (a large stretch encompassing many genes). In other cases, a smaller point mutation within the SHANK3 gene itself is enough to cause the syndrome. Rarely, a chromosomal rearrangement disrupts SHANK3 without deleting it outright. The size of the deletion matters: larger deletions tend to affect more genes beyond SHANK3 and can contribute to additional medical problems.
Most cases occur spontaneously rather than being inherited from a parent, though inherited forms do exist. Not every person diagnosed with PMS has a detectable SHANK3 disruption, but the vast majority do.
Core Features and Early Signs
The hallmark signs of PMS typically appear in infancy or early childhood. Low muscle tone (hypotonia) is often the first thing parents and pediatricians notice. Babies with PMS may feel “floppy” and have difficulty with feeding, rolling over, or sitting up on a typical timeline. Global developmental delay follows: milestones like crawling, walking, and especially talking come significantly late or, in some cases, don’t develop at all.
Speech is one of the most severely affected areas. Many children with PMS have absent or very limited spoken language, even into adulthood. Some develop a few words or short phrases, while others rely entirely on alternative communication methods like picture boards or speech-generating devices. The degree of intellectual disability ranges from moderate to severe, though it varies from person to person.
Other features described in the medical literature include seizures, visual and hearing impairments, crossed eyes (strabismus), cyclic vomiting, and early puberty. Growth is often normal or even advanced for age, which can be an unusual contrast to the developmental delays.
Autism and Behavioral Traits
PMS has a strong overlap with autism spectrum disorder. Published estimates of how many people with PMS also meet criteria for autism range widely, from near zero to over 90 percent depending on how the assessment is done. One study that used parent-reported clinical diagnoses found that about 53 percent of its 40-person sample had an autism diagnosis. In practice, many children with PMS show behaviors that look very much like autism: repetitive movements, difficulty with social interaction, and restricted interests.
The sensory profile in PMS is distinctive. Research published in Brain Sciences found that most individuals with PMS scored unusually high in both sensory seeking and sensory avoiding, a combination that might seem contradictory but is common in this population. About 43 percent of patients in that study were rated as “more” or “much more than” typical peers in both categories. This means a child might crave deep pressure or strong movement input while simultaneously becoming overwhelmed by certain sounds or textures. Understanding this dual pattern can help caregivers and therapists tailor sensory strategies rather than assuming a child is purely a “seeker” or purely an “avoider.”
High pain tolerance is another frequently reported behavioral trait, which carries practical safety implications since injuries or infections may go unnoticed.
How PMS Is Diagnosed
PMS is confirmed through genetic testing, not clinical observation alone. The most common first-line test is chromosomal microarray analysis (CMA), which can detect the deletions on chromosome 22 that cause most cases. If a microarray comes back normal but suspicion remains, whole exome sequencing (WES) can identify smaller mutations within the SHANK3 gene that microarray would miss. Traditional karyotyping (the older method of examining chromosomes under a microscope) can catch large deletions and chromosomal rearrangements but will miss smaller ones. Combining all three methods gives the highest diagnostic yield.
Many families go through a long diagnostic journey. A child may initially receive a general diagnosis of “developmental delay” or “autism” before genetic testing reveals PMS as the underlying cause. Because PMS is rare and not always on a clinician’s radar, years can pass between the first concerns and a confirmed diagnosis.
Day-to-Day Management
There is no cure for PMS, and management follows the same general framework used for other developmental disorders: early, consistent, multidisciplinary therapy. Speech therapy is a priority given the severity of language delays. Many speech therapists working with PMS focus on augmentative and alternative communication early rather than waiting to see if spoken language emerges on its own. Occupational therapy addresses fine motor skills, self-care tasks like dressing and eating, and sensory processing challenges. Physical therapy targets gross motor development and helps manage the effects of low muscle tone on posture, balance, and coordination.
Because seizures, kidney abnormalities, and vision or hearing problems can accompany the syndrome, children with PMS typically benefit from a coordinated care team that includes neurology, nephrology, and ophthalmology alongside their developmental specialists. Updated consensus guidelines published in the American Journal of Medical Genetics emphasize that treatment is largely symptom-based, since PMS-specific protocols are still limited.
Experimental Treatments Under Study
One of the more promising research avenues involves a growth factor called IGF-1, which plays a role in brain cell growth and the formation of synaptic connections. Preclinical studies showed that IGF-1 could reverse some synaptic deficits in mouse and human neuronal models of PMS, and a clinical trial in children with PMS showed improvement in social withdrawal and restricted behaviors.
Because IGF-1 itself is expensive, difficult to manufacture, and carries a risk of low blood sugar, researchers at Mount Sinai conducted a small proof-of-concept trial using growth hormone instead, which stimulates the body to produce its own IGF-1 naturally. Six children with PMS received daily growth hormone injections for 12 weeks. Their IGF-1 levels rose by at least two standard deviations, and the treatment was well tolerated with no serious side effects. Clinicians observed improvements in social withdrawal, hyperactivity, and sensory symptoms. The results are preliminary, given the tiny sample size and lack of a placebo group, but they point toward a treatment approach that could be tested in larger trials.
Living With PMS Long Term
PMS is a lifelong condition. Most individuals require significant support throughout adulthood, including help with daily living tasks, ongoing therapy, and structured environments. The degree of independence varies considerably and tends to correlate with the severity of intellectual disability and the size of the chromosomal deletion.
Specific data on life expectancy in PMS is limited. The syndrome itself is not typically life-threatening, but associated medical issues like seizures and organ abnormalities require monitoring over a lifetime. As children with PMS grow into adults, the focus of care gradually shifts from developmental milestones toward maintaining skills, managing behavioral changes that can emerge around puberty or in early adulthood, and planning for long-term housing and support.
Families navigating a PMS diagnosis often connect through organizations like the Phelan-McDermid Syndrome Foundation, which maintains a patient registry and facilitates connections between affected families worldwide. These networks can be a practical resource for finding experienced clinicians, sharing strategies that work in daily life, and staying informed about research developments.