An Overview of Phelan-McDermid Syndrome

Phelan-McDermid syndrome (PMS) or 22q13 is a rare genetic disorder caused by microdeletion that occurs on the terminal end of the 22nd chromosome. It can also occur as a result from changes to the SHANK3 gene that causes related symptoms. Because of the rare documented occurrences of Phelan-McDermid syndrome, you may see a variety of personal and professional findings in online forums.

Because many of the symptoms associated with Phelan-McDermid syndrome are nonspecific, there are likely more cases present than currently are identified. In cases where this genetic disorder has not been identified, the child may have a diagnosis such as autism and global developmental delay.

Symptoms related to Phelan-McDermid syndrome typically can be identified within the first six months after birth; occasionally the symptoms can be identified at birth. The most common symptoms first identified include:

• Hypotonia—low muscle tone
• Developmental delay—delayed attainment of developmental milestones

As your child develops, you may see the development of other common symptoms including:

• Delayed or absent development of speech
• Moderate to severe developmental and intellectual impairment
• Heart or kidney defects—not common and usually not life-threatening
• Autistic-like behaviors
• Chewing on non-edible objects
• Grinding teeth
• Decreased sense of pain

It is also fairly common (greater than 25% of reported cases) to see abnormal facial or other physical characteristics associated with Phelan-McDermid syndrome. While you may not notice any abnormal features, you may also find multiple features from this list:

• Bulbous nose—nose is ball-shaped at the tip of the nose
• Dolicocephaly—face disproportionately longer than wide in comparison to other children
• Ear shape abnormalities
• Full eyebrows
• Full or puffy eyelids and/or cheeks
• Long eyelashes
• Pointed chin
• Wide nasal bridge
• Dysplastic toenails—may be brittle, slow-growing, small, or cracked
• Large hands

Seizures can be an alarming symptom that is not as prevalent as some of the other symptoms; occurring in more than 25% of the cases. Severity of the seizures will also vary from person-to-person.

Despite the variety of symptoms and autistic behaviors, people with Phelan-McDermid often have a sweet disposition and can be easily amused. People will often comment how happy people with this disorder can be. It is estimated that about 1% of children with autism may have Phelan-McDermid syndrome, however this may in actuality be higher due to under-reporting or under-diagnosing.

Phelan-McDermid syndrome is a genetic disorder caused by a process known as microdeletion or other genetic mutations. Deletions are segments of a chromosome that is missing, while microdeletions are missing sections of chromosomes on the DNA that are too small to be seen by light microscopy. Special testing is needed to be able to identify these changes to the chromosome. In genetic disorders that involve microdeletion, the segments that are missing or mutated may vary slightly but have the same region that is considered the critical segment involved that results in the genetic disorder.

In Phelan-McDermid the chromosome segment labeled 22q13.3 has been deleted along with the SHANK3 gene. The SHANK3 gene is the critical segment for neurological symptoms related to the disorder.

It is important for you to know that these deletions or mutations occur naturally and are not related to any genetics or behaviors of the parents. You may hear a physician or geneticist refer to this as a de novo mutation; which means it is a new event that was not passed down from the parents. Phelan-McDermid syndrome is found equally in both males and females.

You may also hear your physician refer to this as a terminal mutation. Do not be alarmed by this terminology. In this case, terminal describes the location on the chromosome. Phelan-McDermid syndrome mutations or deletions occur at the terminal location, also referred to as the end of the chromosome.

Related to the non-specific nature of Phelan-McDermid syndrome, this genetic disorder is likely not identified in all cases. In fact, Phelan-McDermid syndrome can look very similar to these other disorders:

• Angelman syndrome
• Rett syndrome
• Velocardiofacial/DiGeorge syndrome
• Williams syndrome
• Trichorhinophalangeal syndrome
• Spastic paraplegia
• Cerebral palsy

Without genetic testing to confirm many of these disorders, it may be actually be misdiagnosed. Generally, Phelan-McDermid syndrome will not be diagnosed prenatally. Testing usually is initiated as a result of trying to identify the cause of hypotonia or global developmental delay.

Genetic testing may be performed by a variety of methods. The most common testing method is chromosomal microarray analysis (CMA). This test should be recommended for children with autism, as well as children that have a high clinical suspicion of Phelan-McDermid syndrome or other genetic disorders. CMA testing to tell whether or not there are deletions or mutations to chromosomes, however it is unable to show what type of mutation occurred leading to the deletion. Mutation types include:

• Deletion—chromosome was incidentally missed during replication
• Unbalanced translocation—piece of chromosome breaks off and attaches somewhere else. When there is not a loss or gain, this is referred to as a balanced translocation, whereas when there is a loss or gain of genetic material it is referred to as unbalanced translocation.
• Ring chromosome—ends of chromosomes fuse together forming a ring.

If CMA testing is positive for Phelan-McDermid syndrome, additional testing will likely be requested. Chromosome analysis allows karyotyping, which enables a geneticist to visualize the structure of the chromosomes and determine whether or not the cause is related to a deletion, unbalanced translocation, or ring chromosome.

Your physician will want to have this additional testing as ring chromosome mutations may carry additional risks and this is referred to as ring chromosome 22. Symptoms are relatively the same, however there is a greater risk for seizures, the child may have webbing between the second and third toes, have an unstable gait (walk), growth delays, and hyperactive disorders. There is also a higher risk for the development of neurofibromatosis type 2.

When CMA or chromosome analysis does not provide enough information or gives inconsistent results, the last form of testing is whole exome sequencing (WES). DNA is made up of nucleic acids: adenine, cytosine, guanine, and thymine. Instruments used for WES read the DNA by using the first letter of each nucleic acid: A, C, G, T. It can then review or read how the strings of nucleic acids compare looking for mutations. Because we are all different, there are expected variations. In WES analysis, the geneticist will be looking for known disorder-causing (pathogenic) variations. In particular, WES can be used to identify mutations to SHANK3. If pathogenic SHANK3 mutations are discovered, the parents will likely be requested to also undergo WES testing to determine if it is an inherited disorder or a de novo cause.

No treatment or medication exists to cure Phelan-McDermid syndrome. However, you can engage your medical care team in treating symptoms as part of a comprehensive treatment plan of care. Early intervention is always best, particularly in your child's early development years.

If your child is having seizures, you will want to include a neurologist to your care team. A neurologist will determine the optimal medication regimen for the specific type of seizures your child is experiencing. An electroencephalogram (EEG) will be a test that is used to help determine the type of seizure your child is having. If a formal EEG in the clinic does not provide enough information, home EEGs can be performed over a period of about three days.

Prior to school age, treatment to help achieve milestones can be treated by working with physical therapists, occupational therapists or speech-language pathologists. When your child reaches the age to attend school, you will want to establish an individualized learning plan (IEP) with the school your child attends.

For communication issues, a speech-language pathologist will be integral in your team to optimize speech and find alternative methods of communication. Electronic devices, picture systems, and sign language are some common methods used.

As hypotonia is one of the most common symptoms related to Phelan-McDermid syndrome, working with physical therapy and occupational therapy are critical in your child's early years. They will work on any mobility needs, which are considered gross motor skills. Occupational therapy will specifically focus on fine motor skills needed to eat, groom, dress themselves, or other more formal skills such as writing.

As behavior disorders are autistic-like, autism spectrum disorder therapies are often found to be helpful in treating any behavior disorders. Applied behavior analysis (ABA) is a popular method to target behavior management.

While Phelan-McDermid syndrome presents many different physical and mental difficulties, children and adults with this genetic disorder are generally very happy. The demands on parents can be great, so realize that it is common to feel very frustrated from time to time. Utilizing respite care or other methods to ensure you get personal time is very important. These children are likely to be "the twinkle in your eye" and will be loved by your family and those around you. However, their needs can be very demanding. Take care of yourself so that you can be there for your child.