Phelan Mcdermid Syndrome: Symptoms, Types, Causes and Treatment

Phelan McDermid Syndrome (PMS), also known as 22q13 deletion syndrome, is a rare neurodevelopmental disorder that has captured increasing scientific attention in recent years. Its wide-ranging symptoms, complex genetic origins, and evolving treatment landscape make it a condition of high interest for clinicians, researchers, and families alike. This comprehensive guide unpacks everything you need to know about PMS: how it presents, its different types, underlying causes, and the latest in treatment approaches.

Symptoms of Phelan McDermid Syndrome

PMS is known for its considerable clinical variability. While some symptoms are nearly universal, others may vary in severity or be influenced by specific genetic changes. Understanding these symptoms is key to early recognition and effective support.

Symptom	Frequency/Severity	Notable Features	Source(s)
Intellectual Disability	Very common, variable	Ranges from mild to severe	1 2 3 8 9
Speech Impairment	Common (often severe)	Delayed/absent speech, poor expressive language	1 3 8 9
Autism Spectrum Disorder (ASD)	Frequent (up to 80%)	Social deficits, repetitive behaviors	1 2 3 8 9
Hypotonia	Common	Low muscle tone, especially in infancy	1 2 3 8
Motor Delay	Frequent	Delayed walking, poor coordination	1 3 8
Regression	Notable risk in adolescence/adulthood	Loss of skills, psychiatric symptoms	2 4 5 7
Behavioral Issues	Variable	Hyperactivity, impulsiveness, repetitive behaviors	2 8 9
Seizures	Present in subset	May develop at any age	1 3 9
Medical Features	Variable	Renal, spine, GI, dysmorphic features	3 7 8 9

Table 1: Key Symptoms

Intellectual and Developmental Disabilities

Most individuals with PMS experience global developmental delay and intellectual disability. The severity can range from mild to profound, but moderate to severe impairment is most common. Early milestones like sitting, walking, and talking are typically delayed, and some children may never develop fluent speech 1 3 8 9.

Speech and Language Impairment

Speech deficits are a hallmark of PMS. While some children may develop single words or short phrases, many have minimal or absent expressive language. Speech impairment is generally more severe in those with larger chromosomal deletions 1 3 8.

Autism Spectrum Disorder and Behavioral Features

Around 70–80% of individuals with PMS show features of ASD, including difficulties with social interaction, repetitive behaviors, and restricted interests. Additional behavioral issues can include hyperactivity, impulsivity, and episodes of nonstop crying 1 2 3 8 9.

Hypotonia and Motor Skills

Almost all children with PMS have hypotonia (low muscle tone), especially in infancy, contributing to delayed motor milestones such as sitting and walking. Poor coordination and gait abnormalities may persist into adulthood 1 3 8.

Regression and Psychiatric Symptoms

A significant subset of individuals, often during adolescence or adulthood, may experience regression — losing previously acquired skills, especially in speech and daily functioning. This can be accompanied by psychiatric symptoms like bipolar disorder, depression, catatonia, or psychosis, sometimes triggered by stress, infection, or hormonal changes 2 4 7.

Medical and Physical Features

Other medical issues can include seizures, renal abnormalities, spine deformities, gastrointestinal problems, and mild facial dysmorphisms. Some patients also have increased pain tolerance and feeding difficulties 3 7 8 9.

Types of Phelan McDermid Syndrome

While PMS is unified by its association with disruptions in the SHANK3 gene region, the genetic changes underlying the syndrome are diverse. Understanding these types helps explain the variability in symptoms and guides clinical management.

PMS Type	Genetic Basis	Clinical Differences	Source(s)
22q13.3 Deletion	Deletion of chromosome 22q13.3 (includes SHANK3 and possibly other genes)	More severe speech and motor deficits; higher rate of medical features	1 3 6 7 8 9
SHANK3 Point Mutation/Sequence Variant	Pathogenic variant in SHANK3 only	Intellectual disability, ASD common; speech/motor impairment may be less severe than in large deletions	1 7 8 9
Large Deletions	>1 Mb, often involving multiple genes	More severe, additional features (renal, spine, etc.)	3 6 7 8
Small Deletions	<1 Mb, may involve only SHANK3	ASD more likely, speech impairment less severe	3 6 7
Mosaicism/Ring Chromosome/Translocation	Structural variations in chromosome 22	Variable features; may complicate diagnosis	9

Table 2: Main Types of PMS

22q13.3 Deletion Syndrome

This is the most common form of PMS, caused by deletion of the distal region of chromosome 22 (22q13.3), which almost always includes the SHANK3 gene but may also encompass many neighboring genes. The size of the deletion can vary widely — from a few kilobases to several megabases. Larger deletions are associated with more severe symptoms and a broader range of medical problems 1 3 7 8 9.

SHANK3 Point Mutations and Sequence Variants

Some individuals have PMS due to a change (mutation) within the SHANK3 gene itself, without broader chromosomal loss. These so-called “monogenic” cases often present with intellectual disability, speech problems, and ASD, but may have milder medical involvement compared to those with larger deletions 1 7 8 9.

Deletion Size and Subtypes

• Large deletions (>1 Mb): Typically result in more severe intellectual and speech disabilities, and a higher likelihood of additional medical issues such as renal or spine abnormalities 3 6 7 8.
• Small deletions (<1 Mb) or SHANK3-only deletions: More likely to present with ASD, but may retain some speech skills and have fewer medical complications 3 6 7.

Other Structural Variations

Less commonly, PMS can be caused by chromosomal rearrangements such as ring chromosome 22, unbalanced translocations, or mosaicisms (where not all cells have the deletion). These variations can result in a spectrum of symptoms and may complicate genetic diagnosis 9.

Epigenetic and Mitochondrial Subtypes

Emerging research suggests that differences in DNA methylation patterns (epi-signatures) and mitochondrial function may define additional subgroups within PMS, potentially explaining some of the variability in symptoms and responses to treatment 5 6.

Causes of Phelan McDermid Syndrome

The root cause of PMS is genetic, but the underlying mechanisms are multifaceted and continue to be unraveled by researchers.

Cause	Description	Impact on Symptoms	Source(s)
SHANK3 Haploinsufficiency	Loss/disruption of one copy of SHANK3	Core neurological/behavioral symptoms	1 3 7 8 10
22q13.3 Deletion	Deletion extends beyond SHANK3 to neighboring genes	Broader, more severe symptoms	3 6 7 8 9
De Novo vs. Inherited	Most cases are new mutations; rare familial cases	Inherited cases may show compensation	1 3 9
Additional CNVs	Other chromosomal changes (e.g., 16p11.2, 15q11q13)	Modulate severity, may add features	3 9
Mitochondrial Dysfunction	Abnormal energy production due to gene loss	May explain fatigue, regression, ASD features	5
Epigenetic Epi-signatures	DNA methylation pattern alterations	May define distinct clinical subtypes	6

Table 3: Causes and Modifiers of PMS

The Role of SHANK3

The SHANK3 gene encodes a scaffolding protein critical for synaptic function in the brain. Loss of one copy (haploinsufficiency) disrupts neural connectivity, underpinning many of the neurodevelopmental and behavioral symptoms seen in PMS 1 3 7 8 10.

Chromosome 22q13.3 Deletions

Most PMS cases arise from deletions affecting the distal part of chromosome 22. The size and gene content of these deletions influence the severity and breadth of symptoms. Larger deletions that include genes beyond SHANK3 lead to more complex and severe phenotypes, including additional medical issues 3 6 7 8 9.

Inheritance Patterns

The vast majority of PMS cases are caused by de novo (new) genetic changes, meaning they are not inherited from a parent. However, rare familial cases have been reported, with evidence that in some instances, unaffected parents can pass on the mutation, possibly due to compensatory mechanisms 1 3 9.

Genetic Modifiers and Additional Variants

The presence of other copy number variants (CNVs) in different parts of the genome can modulate the severity of PMS, especially when they involve regions associated with ASD or developmental delay 3 9.

Mitochondrial Dysfunction

Recent research has highlighted the role of mitochondrial genes within the deleted region of 22q13.3. Abnormal mitochondrial function may contribute to fatigue, developmental regression, and a subset of ASD-like symptoms, offering new avenues for research and treatment 5.

Epigenetic Mechanisms

Some PMS patients exhibit a unique DNA methylation “epi-signature,” which correlates with specific genetic subtypes and clinical features, suggesting that epigenetic changes may further influence the syndrome’s presentation 6.

Treatment of Phelan McDermid Syndrome

There is currently no cure for PMS, but supportive therapies and emerging targeted treatments are making a meaningful difference for many individuals and families.

Treatment	Approach/Intervention	Evidence/Outcome	Source(s)
Supportive Therapies	Speech, occupational, behavioral, physical therapy	Core management, improve skills	10
Educational Support	Special education, individualized plans	Essential for cognitive/academic development	10
Pharmacological	Medications for seizures, sleep, psychiatric symptoms	Symptom relief, individualized	2 4 10
IGF-1 Therapy	Insulin-like growth factor-1	Improves social/repetitive behaviors, hyperactivity	11 12 13
rhGH Therapy	Recombinant human growth hormone	Elevates IGF-1, improves social withdrawal, sensory symptoms	13
Oxytocin Trials	Intranasal oxytocin	No significant benefit in trials	14
Mitochondrial Targeting	Supplements, metabolic support	Experimental, based on symptom patterns	5

Table 4: Treatments and Interventions

Supportive and Symptomatic Therapies

Speech and Language Therapy: Crucial for maximizing communication skills, even for nonverbal individuals. Augmentative and alternative communication (AAC) devices are often recommended.

Occupational and Physical Therapy: Address hypotonia, poor coordination, and motor delays, supporting independence in daily activities.

Behavioral Therapy: Applied behavior analysis (ABA) and other interventions can help manage ASD symptoms, repetitive behaviors, and impulsivity 10.

Educational and Social Supports

Customized educational plans and special education services are vital. Early intervention and individualized education programs (IEPs) help optimize learning and social participation 10.

Medical and Psychiatric Management

• Seizure Control: Antiepileptic drugs when needed.
• Behavioral/Psychiatric Treatments: Medications may be used for mood disorders, aggression, hyperactivity, or sleep disturbances, tailored to the individual 2 4 10.

Targeted and Experimental Therapies

Insulin-Like Growth Factor-1 (IGF-1)

Two small placebo-controlled trials have shown that IGF-1 can improve social withdrawal, repetitive behaviors, and sensory reactivity in children with PMS, with good safety profiles 11 12. More research is needed to confirm and extend these findings.

Recombinant Human Growth Hormone (rhGH)

A pilot study found that rhGH safely increased IGF-1 levels and led to improvements in social and sensory symptoms, suggesting it may be a feasible alternative to direct IGF-1 administration 13.

Oxytocin

Despite promising animal studies, a clinical trial of intranasal oxytocin in children with PMS did not find significant improvement in core ASD symptoms. The treatment was safe but not effective in this context 14.

Mitochondrial and Metabolic Therapies

Given the role of mitochondrial dysfunction in some PMS cases, metabolic supplements and mitochondrial support strategies are being explored, though these are still experimental 5.

Multidisciplinary Care and Future Directions

Optimal management of PMS requires a team approach, involving geneticists, neurologists, psychiatrists, therapists, educators, and families. Ongoing research into the genetics, biology, and treatment of PMS continues to offer hope for more targeted and effective therapies in the future 10.

Conclusion

Phelan McDermid Syndrome is a complex genetic disorder with diverse and often challenging symptoms. Advances in genetic research and targeted therapies are helping to improve understanding, diagnosis, and management. Key points include:

• Symptoms are wide-ranging but include intellectual disability, speech impairment, ASD, hypotonia, behavioral and psychiatric issues, and various medical problems.
• Types are defined by the nature and size of the genetic change (deletion vs. point mutation), influencing severity and features.
• Causes center on loss or disruption of SHANK3 and neighboring genes, with additional genetic and epigenetic modifiers playing a role.
• Treatment is primarily supportive, but emerging therapies like IGF-1 show promise for improving core symptoms.

As research continues, families and clinicians can look forward to even more personalized approaches and, hopefully, better long-term outcomes for those living with PMS.