What is Phelan-McDermid Syndrome?

What is Phelan-McDermid Syndrome?

Phelan-McDermid Syndrome(PMS) is a rare genetic condition caused by a deletion or other structural change of the terminal end of chromosome 22 in the 22q13 region or a disease-causing mutation of the SHANK3 gene. PMS is sometimes called 22q13 Deletion Syndrome.

As is the case with many rare conditions, families may come across several different descriptions of this syndrome based on varying genetic descriptions and varying symptoms. As the research progresses, the science advances, the descriptions will continue to change; the Foundation will continue to monitor and participate in the full characterization of Phelan-McDermid Syndrome over time and will evolve as the syndrome is further described by the scientific community.

Therefore, any family with a genetic report showing a pathogenic mutation of SHANK3 or deletion on the 22q13 region of chromosome 22 is encouraged to join the Phelan-McDermid Syndrome Foundation membership.

Phelan-McDermid Syndrome is a rare genetic condition caused by a deletion or variation of the terminal end of chromosome 22 in the 22q13 region or a disease-causing mutation of the SHANK3 gene.

Introduction to Phelan-McDermid Syndrome

Phelan-McDermid Syndrome (PMS), is also known as 22q13 Deletion Syndrome. It is a genetic condition that is caused by a mutation of the SHANK3 gene or a deletion (a missing piece) of genetic material that causes many different but related symptoms. The genetic changes that cause PMS vary from person to person and can occur randomly (de novo) or be inherited from a parent who carries a related genetic change.

Because the genetic changes vary, the symptoms of PMS vary too, and can cause a wide range of medical, intellectual, and behavioral challenges. The most common characteristics found in those with PMS are intellectual disability of varying degrees, delayed or absent speech, symptoms of autism spectrum disorder, low muscle tone, motor delays, and epilepsy. There is currently no cure or treatment specifically for PMS, but we know how to manage many of the symptoms and researchers are working hard to improve our knowledge of PMS and to find drugs and therapies that can help people affected by PMS.

What causes Phelan-McDermid Syndrome?

PMS is caused by changes to the genetic material near the end of the long arm of chromosome 22. The changes occur at a specific location, or address, 22q13, on the chromosome.

Most people with PMS are missing a segment of that chromosome, called a deletion, which is generally a new event in that person (de novo), and was not inherited from a parent. These deletions usually happened by chance; nothing they or their parents did could have caused or prevented the deletion. The gene SHANK3 is located within the 22q13 segment of the chromosome, and is thought to be the most important gene in causing PMS. Some people with PMS don’t have a deletion, but instead have a misspelling in the  SHANK3 gene, called a mutation. Mutations are also typically new events and not inherited from a parent.

Genes like SHANK3 instruct the body how it should form and function. When genetic material is altered, whether it is a deletion or a mutation, it can cause the gene not to work properly. The body then gets a different set of instructions, and so the body functions differently. These differences make up the disease symptoms.

About 20% of people with PMS have a deletion, or even a duplication, that is caused by a chromosomal translocation. A translocation happens when one or more “arms” of different chromosomes break off and switch places. Additionally, other people with PMS have what is called a ring chromosome, or ring 22, so called because the very distal ends of chromosome 22 break off and the ‘new ends’ of the chromosome stick to each other to create a circular chromosome.

What are the symptoms?

People who have PMS often show symptoms in very early childhood, sometimes at birth and within the first six months of life. They often have hypotonia (low or weak muscle tone) and developmental delay (not achieving developmental milestones such as rolling over, sitting up, walking, or talking on time). Less frequently, some children present with heart defects (such as a hole in the heart) or kidney defects, although these are usually not life-threatening. These are often the first noticeable symptoms and are what prompt families to start down the diagnostic journey.

As children grow, different symptoms develop. People with PMS typically have moderate to severe developmental and intellectual impairment, most do not develop functional language, and about 75% have been diagnosed with an Autism Spectrum Disorder. Behavioral issues may stem from autism (e.g., repetitive behaviors), from poor communications skills, or from an unknown origin. Sleep disorders are commonly reported, as are difficulties with toilet training, and problems with eating. About 40% of people develop seizures. Although seizures don’t appear to be a common symptom of PMS, those that occur can range from mild to severe.

Many parents report that their child does not seem to feel pain as most people do, but instead has a very high tolerance for pain. High pain tolerance in conjunction with communication issues can make it difficult for parents to know when their child has pain due to constipation, reflux, or other conditions that need to be treated. People with PMS also seem to sweat less than others, and are at risk of overheating. It’s very important that caregivers monitor carefully for injuries and overheating.

In spite of these medical and developmental issues, infants with PMS tend to be easily amused, and adults often have a sweet disposition.

You doctor may also talk to you about facial and body characteristics that are common in people with PMS, but don’t cause any medical problems. Common facial characteristics include dolichocephaly (a head shape that is longer than usual, from front to back), flat midface, wide brow, wide nasal bridge, deep-set eyes, full cheeks, puffy eyelids, long eyelashes, and bulbous nose. Large fleshy hands, dysplastic toenails, sacral dimple, and large, differently formed ears are frequently observed.

Thus far relatively few cases of PMS have been identified. Most people that have been identified are children because testing is usually done early in life and testing to detect submicroscopic deletions did not become commonly available until about 1998. As a result, most of our information about PMS is about children, and less is about the experiences of adults with PMS. We are working hard to engage our adult community members and promote the availability of testing to adults.

Are all cases of PMS the same?

Deletion sizes, SHANK3 gene mutations and the features of Phelan-McDermid Syndrome are all highly variable. Studies suggest that people with larger deletions are more likely than those with smaller deletions to have characteristic body features, feeding problems in infancy, differences in their reflexes and greater delays in meeting developmental milestones.

Is there treatment?

People who have PMS are treated based on the symptoms they experience. There are no medications, drugs or therapies specifically for PMS. Due to multiple medical and educational issues, a management team consisting of several medical and developmental/educational specialists may be needed to address the areas of concern. Ongoing conditions may include intellectual disability and speech delay, seizures, sleep disturbance, hypotonia, poor feeding, chronic constipation, gastroesophageal reflux, renal problems, decreased perspiration and heat intolerance, and lymphedema.  PMSF has created a PMS Clinical Care infographic to help families discuss their child’s needs with doctors.

How rare is Phelan-McDermid?

We’re not sure and we don’t have a reliable estimate. There are people who have not been diagnosed using the most sophisticated chromosomal testing, or have not joined our organization and so we can’t count them.

It is estimated that 1% of people with autism have Phelan-McDermid Syndrome.  That means that between 1/8,000-15,000 (including 22q13.3 deletions and SHANK3 gene variants) have PMS. However, this may be an underestimate since not all patients with PMS will present with autism.

As of January 2017, PMSF’s membership includes over 1400 individuals who have been diagnosed with PMS.  We know our syndrome is under-diagnosed, and this number does not reflect all of the diagnosed cases, but PMSF does have the largest PMS membership in the world. Please consider joining our membership to be counted. Any person with a genetic change in the 22q13 region is welcome to join.

How are cases of PMS diagnosed?

The diagnosis of PMS should be considered in individuals with intellectual disability with or without autism and/or atypical physical features. Since lack of speech development is a common feature in PMS, this diagnosis should also be considered in any child with severe speech delay. PMS should also be considered in the differential diagnosis for individuals with a history of neonatal hyptonial of unknown cause.

A type of genetic test called chromosomal microarray is the most common method for diagnosing Phelan-McDermid Syndrome. The main types of microarray technology includes aCGH (array comparative genomic hybridization), and SNP array (single nucleotide polymorphism). Both of these tests will find loss or gain of chromosome material including very small changes. This means they can detect loss or gains that result from simple deletions or duplications, unbalanced translocation, ring chromosomes, and any structural change that results in a loss/gain of material. However, these tests cannot ‘see’ the structure of the chromosome so they cannot tell if a translocation or ring chromosome is present.

Fluorescence in situ hybridization (FISH) or chromosome analysis ( karyotype) may detect larger deletions and they study the structure of the chromosome. Either FISH or a karyotype is necessary to identify unbalanced translocations or ring chromosome. FISH or karyotype is also used to study parents of individuals with unbalanced translocations to determine if either parent carries a balanced form of the translocation that is seen in their child.

DNA sequencing tests may detect mutations in the SHANK3 gene. Sequencing tests look for spelling errors by proofreading the letters than make up the gene.

For a more detailed description of genetic tests, please read the Diagnosis page.

The Phelan-McDermid Syndrome International Registry (PMSIR) has the largest database of diagnosed cases of PMS in the world. We encourage you to read about the PMSIR and consider enrolling in the registry. Any person with a genetic change in the 22q13 region is welcome to participate.

Resources

For more information on PMS, we recommend the following websites:

Genetics Home Reference

This website is run by the National Institutes of Health (NIH)’s US National Library of Medicine. This is a good overview that is written in an understandable way.

+  https://ghr.nlm.nih.gov/condition/22q133-deletion-syndrome

GeneReviews

This website is produced by the National Center for Biotechnology Information (NCBI), a branch of the NIH. This is a much longer, more detailed description of PMS. It is a resource doctors and genetic counselors use; therefore, it uses more technical terms and can be more difficult to understand. It is also out of date, but still provides some good information.

+  http://www.ncbi.nlm.nih.gov/books/NBK1198/

PMSF | Phelan-McDermid Syndrome Foundation