Phelan-McDermid syndrome (PMS) is a rare genetic condition caused by the loss or disruption of the SHANK3 gene on chromosome 22, resulting in a wide range of developmental, neurological, and physical challenges. Most people with PMS have significant speech and language impairment, intellectual disability, and low muscle tone from early life, though the severity varies enormously from one person to the next. The syndrome was originally known as 22q13 deletion syndrome, named for the chromosomal region involved, and was later renamed to reflect the clinicians who helped characterize it.
What Causes Phelan-McDermid Syndrome
PMS results from changes affecting the tip of the long arm of chromosome 22, specifically the region that contains the SHANK3 gene. The loss of SHANK3 can happen in several ways: a straightforward deletion of the chromosome’s end, a translocation (where chromosome segments swap places), the formation of a ring chromosome, or other less common structural rearrangements.1PubMed Central. Deletion 22q13.3 syndrome Some individuals have a point mutation or small intragenic deletion that knocks out SHANK3 without affecting surrounding genes at all. The condition was first recognized through visible chromosomal deletions, but as genetic testing improved, researchers discovered that even tiny disruptions limited to the SHANK3 gene itself could produce the characteristic features.2PubMed Central. Phelan-McDermid syndrome: a classification system after 30 years of experience
A formal diagnosis is established when genetic testing identifies one of three things: a deletion at 22q13.3 that involves at least part of SHANK3 (these can range from under 50 kilobases to over 9 megabases), a disease-causing variant within SHANK3, or a chromosomal rearrangement that breaks the gene apart.3PubMed. Phelan-McDermid Syndrome-SHANK3 Related Most cases arise as new (de novo) mutations rather than being inherited from a parent, which means a family with no history of the condition can still have an affected child.
Why SHANK3 Matters So Much
SHANK3 produces a large protein that sits at the postsynaptic side of excitatory synapses, essentially acting as scaffolding that holds together the molecular machinery neurons use to communicate with each other.4PubMed Central. Importance of Shank3 protein in regulating metabotropic glutamate receptor 5 (mGluR5) expression and signaling at synapses When a person has only one working copy of the gene instead of two, synapses do not form or function properly. Mouse models in which SHANK3 has been knocked out show structural and functional synaptic defects, strongly supporting the idea that most of the neurological features of PMS trace back to this single gene’s loss.5PubMed Central. The 22q13.3 Deletion Syndrome (Phelan-McDermid Syndrome) That said, SHANK3 alone does not explain the full picture. People with larger deletions that sweep up neighboring genes tend to have a broader and often more severe set of symptoms, suggesting those extra genes contribute to the variability seen across individuals.
How Deletion Size Shapes the Picture
One of the more striking findings in PMS research is how much the size of the deletion matters. Loss of SHANK3 alone is sufficient to cause many of the core neurobehavioral features, including intellectual disability, speech impairment, and autism-like behaviors.6PubMed Central. Genotype-phenotype correlation in Phelan-McDermid syndrome: A comprehensive review of chromosome 22q13 deleted genes But when the deletion extends further along the chromosome, additional problems begin to stack up. In a study examining the relationship between deletion size and clinical features, larger deletions were significantly associated with worse neonatal muscle tone, greater delays in crawling and walking, more severe developmental impairment, male genital anomalies, abnormal toenails, large fleshy hands, and several other physical findings.7Journal of Medical Genetics. Association between deletion size and important phenotypes expands the genomic region of interest in Phelan–McDermid syndrome (22q13 deletion syndrome)
Data from a large international registry confirmed and extended these patterns, showing that increased deletion size was also linked to renal malformations, congenital heart defects, lymphedema, more frequent brain imaging abnormalities, and recurring infections.8PubMed Central. Phenome-wide profiling identifies genotype-phenotype associations in Phelan-McDermid syndrome using family-sourced data from an international registry This is why two people who both “have PMS” can look very different from each other: one may have a small deletion affecting only SHANK3 and present primarily with speech delay and mild intellectual disability, while another with a multi-megabase deletion may face seizures, heart problems, kidney issues, and more profound cognitive impairment.
Speech and Communication
Difficulty with speech is one of the most consistent and most burdensome features of the syndrome. Up to about 88% of individuals with deletions and around 70% of those with SHANK3 point mutations have marked speech impairment, and between half and 80% of people with PMS never develop functional speech at all.9PubMed. Consensus recommendations on communication, language and speech in Phelan-McDermid syndrome For families, the inability to communicate needs is frequently cited as the single most debilitating aspect of the condition.10PubMed Central. Caregiver perspectives on patient-focused drug development for Phelan-McDermid syndrome
Expert consensus recommendations call for regular hearing checks (because even mild hearing loss can worsen an already fragile communication system), early and thorough evaluation of both preverbal and verbal skills, early intervention, and the introduction of augmentative and alternative communication (AAC) systems such as picture exchange boards or speech-generating devices.11PubMed. Consensus recommendations on communication, language and speech in Phelan-McDermid syndrome The emphasis on AAC is worth underlining: waiting for spoken language to develop before offering communication tools can mean years of unnecessary frustration for the child and family.
The Autism Connection
A large proportion of people with PMS meet diagnostic criteria for autism spectrum disorder (ASD), and PMS is in fact one of the more commonly identified single-gene causes of autism. But the overlap is not straightforward. Research comparing the autism profile of PMS to that of idiopathic autism (autism without a known genetic cause) has found some meaningful differences. Most individuals with PMS show persistent deficits in social communication, one of the two core autism domains. However, only about half meet criteria in the other domain, restricted and repetitive behaviors, and general developmental delay appears to be a significant driver of the ASD diagnosis itself.12PubMed Central. Autism spectrum disorder in Phelan-McDermid syndrome: initial characterization and genotype-phenotype correlations
A prospective study comparing PMS to fragile X syndrome, Down syndrome, and idiopathic ASD found that the overall profile of autism-like features in PMS as a group differed from typical autism across social, communication, and repetitive behavior domains. Yet those individuals with PMS who did cross the clinical threshold for an autism diagnosis looked very similar to people with idiopathic ASD.13PubMed Central. Prospective study of autism phenomenology and the behavioural phenotype of Phelan-McDermid syndrome: comparison to fragile X syndrome, Down syndrome and idiopathic autism spectrum disorder In practical terms, this means that ASD-focused interventions (applied behavior analysis, social skills training, structured teaching) are often relevant for people with PMS, but clinicians should be careful not to attribute every behavioral difficulty to autism when some may stem from intellectual disability, sensory overload, or pain that the person cannot communicate.
Seizures and Epilepsy
Epilepsy is a common and sometimes underrecognized complication. In one prospective study using overnight video-EEG monitoring, about 44% of participants had a confirmed history of epilepsy with multiple seizure types, and nearly all of them (15 out of 16) had abnormal EEG recordings regardless of seizure history. About three-quarters showed epileptiform activity on their EEGs, though only a minority had definitive discharges during a standard routine recording. Extended overnight monitoring picked up more frequent or more definitive abnormalities in roughly 69% of participants, suggesting that routine daytime EEGs alone may miss the full extent of epileptiform brain activity in this population.14PubMed. Prospective longitudinal overnight video-EEG evaluation in Phelan-McDermid Syndrome
Generalized slowing with poor background organization was also frequently noted on EEGs, pointing to broadly disrupted brain electrical activity beyond just seizures.15PubMed. Prospective longitudinal overnight video-EEG evaluation in Phelan-McDermid Syndrome For families, the takeaway is that seizures in PMS can be subtle, varied in type, and easy to miss without careful monitoring. When a person with PMS has unexplained behavioral changes, staring spells, or sudden regressions, seizure activity should be on the differential.
Sleep Problems
Disturbed sleep is one of those features that can quietly erode quality of life for the whole household. In a study of 384 individuals drawn from an international registry, about 73% had at least one sleep disturbance. The most frequently reported problems were frequent nighttime awakenings (53%), difficulty going back to sleep after waking (about 50%), and difficulty falling asleep (47%). Sleep troubles increased steadily with age: just over half of children under three had reported disturbances, compared to 90% of adults aged 18 and older.16PubMed Central. Sleep and Phelan–McDermid Syndrome: Lessons from the International Registry and the scientific literature Sleep disturbances were similarly common whether the person had a SHANK3 point variant or a deletion, reinforcing the role of SHANK3 itself in sleep regulation.17PubMed Central. Sleep and Phelan–McDermid Syndrome: Lessons from the International Registry and the scientific literature
Despite the high prevalence, formal sleep evaluations remain rare. One study found that 90% of individuals with PMS showed evidence of marked sleep disturbance on a standardized questionnaire, yet only 22% had ever undergone a formal sleep assessment.18SLEEP. Sleep Disturbances in Individuals With Phelan-McDermid Syndrome: Correlation With Caregivers’ Sleep Quality and Daytime Functioning That same study found a direct statistical relationship between the child’s sleep disturbance and increased sleep problems and daytime sleepiness in caregivers, making this a family-wide health concern. Consensus recommendations now list comorbid mental health conditions, physical discomfort, and medications as possible triggers for sleep disruption and emphasize that sleep should be actively assessed and managed rather than simply accepted as part of the syndrome.19PubMed. Consensus recommendations on sleeping problems in Phelan-McDermid syndrome
Sensory Processing
Atypical responses to sensory input are common and can drive a lot of the day-to-day behavioral challenges families navigate. A cross-sectional study found that an atypical sensory profile was present in close to 75% of individuals with PMS. Particular areas of difficulty included heightened tactile sensitivity, under-responsiveness to certain stimuli (paired with sensation-seeking behaviors), difficulty filtering auditory input, and low energy or weak responses to sensory information.20PubMed Central. Sensory processing and adaptive behavior in Phelan-McDermid syndrome: a cross-sectional study In practice, this can look like a child who mouths objects constantly, seems indifferent to pain, melts down in noisy environments, or has unusual reactions to textures. These are not purely behavioral quirks; they reflect differences in how the nervous system processes incoming information, and occupational therapy with a sensory integration focus can help.
The high pain tolerance that many caregivers report is worth special attention. When a person cannot speak and also does not show typical pain responses, medical problems like ear infections, dental issues, gastrointestinal pain, or fractures can go unnoticed longer than they should.21PubMed Central. Caregiver perspectives on patient-focused drug development for Phelan-McDermid syndrome
Brain Imaging Findings
When brain MRIs are performed on individuals with PMS, abnormalities are frequently found, though they vary in type and severity. Commonly reported findings include thinning or underdevelopment of the corpus callosum (the band of nerve fibers connecting the brain’s two hemispheres), delayed myelination, white matter abnormalities, dilated ventricles, and arachnoid cysts.22PubMed. The Neurological Manifestations of Phelan-McDermid Syndrome Studies of adults with PMS have also highlighted cerebellar vermis hypoplasia, which may contribute to motor coordination difficulties and possibly to some emotional and cognitive patterns.23PubMed. Neuropsychological phenotype and psychopathology in seven adult patients with Phelan-McDermid syndrome: implications for treatment strategy Not every person with PMS has visible brain abnormalities on imaging, and the findings do not always predict functional severity, but baseline neuroimaging is generally recommended as part of a comprehensive evaluation.
Medical Concerns Beyond the Brain
PMS is not exclusively a neurological condition. Practice guidelines emphasize the need to assess and monitor for problems across multiple organ systems, including the kidneys, heart, gastrointestinal tract, and endocrine system. Recurring infections, dental problems, vision difficulties, and lymphedema also require attention.24PubMed Central. Phelan-McDermid syndrome: a review of the literature and practice parameters for medical assessment and monitoring Gastrointestinal issues, including constipation and gastroesophageal reflux, are particularly common and are another source of discomfort that a nonverbal individual may struggle to signal. Comprehensive medical monitoring from an early age, ideally coordinated through a team familiar with PMS, helps catch these issues before they become crises.
Regression in Adolescence and Adulthood
One of the most alarming aspects of PMS for families is the growing recognition that some individuals experience significant loss of skills and new neuropsychiatric symptoms during adolescence or early adulthood. A systematic review identified 56 cases showing signs of behavioral and neurologic decompensation, with a mean age of onset around 20 years. The clinical presentations included features resembling bipolar disorder, catatonia, psychosis, and broader loss of previously acquired abilities.25PubMed Central. Neuropsychiatric decompensation in adolescents and adults with Phelan-McDermid syndrome: a systematic review of the literature
Regression can affect communication, self-care, social engagement, and motor function. Caregivers consistently name worsening disease progression and loss of communication as among their top concerns and highest priorities for future treatment.26PubMed Central. Caregiver perspectives on patient-focused drug development for Phelan-McDermid syndrome The mechanisms behind this regression are not yet well understood, and no study has definitively identified what triggers it. The phenomenon does mean, though, that long-term follow-up and psychiatric monitoring are important even for individuals who seem relatively stable in childhood. Sudden personality changes, new agitation, loss of interest in activities, or withdrawal should prompt a thorough medical and psychiatric workup rather than being dismissed as “just part of the syndrome.”
Emerging Treatment Approaches
There is no cure for PMS, and no drug has been specifically approved for it. Current management revolves around symptom-targeted therapies: speech therapy, physical therapy, occupational therapy, behavioral interventions, and standard medications for epilepsy, sleep, or psychiatric symptoms as they arise. But several experimental approaches have shown early promise in clinical trials.
Insulin-like growth factor-1 (IGF-1) has been the most studied pharmacological candidate. A pilot controlled trial in children with PMS found that the IGF-1 treatment phase was associated with significant improvement in social impairment and restrictive behaviors compared to placebo, with no serious adverse events.27PubMed Central. A pilot controlled trial of insulin-like growth factor-1 in children with Phelan-McDermid syndrome A follow-up clinical trial did not reach significance on its primary social withdrawal outcome, but did find significant improvements in sensory reactivity, repetitive behaviors, and hyperactivity, and pooled analyses across both studies supported those gains.28PubMed Central. Clinical trial of insulin-like growth factor-1 in Phelan-McDermid syndrome These are still small trials, and IGF-1 is far from an established treatment, but the results have been encouraging enough to sustain ongoing research interest.
For the subset of individuals who experience catatonia and regression, case reports have documented that lithium therapy reversed clinical regression, stabilized behavioral symptoms, and allowed patients to recover their pre-regression level of functioning, without significant side effects.29PubMed Central. Lithium as a rescue therapy for regression and catatonia features in two SHANK3 patients with autism spectrum disorder: case reports Case reports are the weakest form of clinical evidence, but given how devastating catatonia and regression can be, lithium is a treatment option that clinicians increasingly keep in mind for these specific presentations.
Animal Models and the Road to Better Therapies
Much of what researchers understand about SHANK3’s role in the brain comes from animal models. Mouse models with Shank3 mutations have been the workhorse of the field, reproducing synaptic deficits and some behavioral features of PMS. However, the gap between a mouse brain and a human brain is substantial, especially for a condition defined by social behavior, communication, and complex cognition. To bridge that gap, researchers have used gene editing to create a primate model by disrupting SHANK3 in cynomolgus monkeys. The resulting animals showed impaired social interaction, repetitive behaviors, and reduced brain network activity on imaging, recapitulating core features of autism spectrum disorder in a species whose brain architecture is much closer to our own.30PubMed Central. CRISPR/Cas9-mediated disruption of SHANK3 in monkey leads to drug-treatable autism-like symptoms These primate models are expensive and ethically complex, but they may prove critical for testing therapies before they reach human trials, particularly gene therapies or other interventions that need to be evaluated in a brain with human-like connectivity.
What Caregivers Say Matters Most
In a structured meeting designed to capture caregiver perspectives for drug development, certain themes recurred across families regardless of their child’s age or severity. The inability to communicate effectively, developmental delay and intellectual disability, and difficulty with self-care tasks like bathing, dressing, and toileting were consistently rated as the most common and most burdensome features. Communication loss in particular was flagged not only as a current challenge but as a source of intense worry about the future, especially when regression had already occurred or seemed possible. Caregivers also repeatedly raised physical health concerns including increased pain tolerance, seizures, low muscle tone, and motor planning difficulties as priorities for treatment development.31PubMed Central. Caregiver perspectives on patient-focused drug development for Phelan-McDermid syndrome These perspectives are increasingly being used to shape clinical trial endpoints, ensuring that the outcomes researchers measure actually align with what families experience as meaningful improvement. A drug that slightly shifts a score on a behavior checklist but does not change a family’s daily reality is, from the caregiver perspective, not much of a drug at all.