Phelan-McDermid Syndrome
/
Phelan-McDermid Syndrome
‹ Return to Disorder Directory

Disorder Directory Header 6 6

Authors: Katy Phelan, PhD, FACMG, Florida Cancer Specialist & Research Institute, Fort Myers, Florida 

Kate Still, PhD, Phelan-McDermid Syndrome Foundation Scientific Director

Reviewed: August 2022

SUMMARY

Phelan-McDermid syndrome (PMS) is a rare genetic disorder. It has two potential causes.

The first cause is the deletion of part of chromosome 22. Specifically, a section called the distal long arm is deleted. This section is also referred to as the 22q13 region.

The second cause is a pathogenic variant in a particular gene, called the SHANK3 gene. A pathogenic variant increases an individual’s chance of developing a disease.

People with PMS often show symptoms in early life. The earliest signs include:  

  • Low muscle tone  
  • Delay in achieving milestones such as:
    • Rolling over 
    • Sitting up 
    • Talking

In most cases of PMS, the SHANK3 gene is altered. Changes to the SHANK3 gene have been highly linked with autism spectrum disorder (ASD). Nearly 80% of people with PMS are diagnosed with ASD.

Based on extensive genetic studies, it is estimated that 1% of people with ASD have PMS. This means a case of PMS occurs in roughly 1 in 10,000 births (according to the World Health Organization – current as of 2022). Nearly every day, a new family joins the PMS Foundation.

Most PMS cases happen spontaneously. However, some cases are inherited. 

JUMP TO

Disorder Overview

DESCRIPTION

There is a wide range of symptoms in people with PMS. The severity of symptoms varies as well. People with PMS typically face challenges such as: 

  • Moderate to severe intellectual disability 
  • Poor communication or absent speech 
  • Complex medical issues  

People with larger deletions of chromosome 22 tend to have more complex medical problems. They are less likely to reach milestones.

People with more minor genetic changes in SHANK3 are more likely to reach milestones. However, they may regress later. This group may also be more likely to be affected by mental illness.

Teal and Gold Decorative Live Shopping Event Twitter Post 1

SIGNS AND SYMPTOMS

Common early signs and symptoms include: 

Hypotonia (low muscle tone)

Delay in reaching milestones

Such as:

  • Rolling over
  • Sitting
  • Walking

Intellectual disability

Delayed or absent speech

Autistic-like behaviors

Such as:

  • Difficulty making eye contact
  • Repetitive behaviors
  • Communication issues
  • Limited interests
  • Obsessive actions

Mild physical features

Such as:

  • Prominent forehead
  • Long eyelashes
  • Full cheeks
  • Flat midface
  • Large ears
  • Wide or rounded nose
  • Drooping or puffy eyelids
  • Thin, flaky toenails
  • Fleshy hands

These subtle physical features can easily be missed or perceived as normal. For example, long eyelashes can be overlooked. The combination of these features leads to a PMS diagnosis.

Additional medical symptoms may appear later. They may also only appear in a subset of people. These include:

Epilepsy and seizures

Epilepsy and seizures.

Gut symptoms

Such as:

  • Constipation
  • Reflux
  • Diarrhea
  • Repeated vomiting
  • Difficulty feeding or emptying the stomach

Abnormal response to pain (low or high)

Difficulties falling asleep or staying asleep

Swelling of a body part due to a build-up of lymph fluid (lymphedema)

Vision difficulties

Kidney abnormalities

Such as:

  • Collection of fluid
  • Backward flow of urine
  • One non-functioning kidney

Neuropsychiatric illnesses

Such as:

  • Bipolar disorder
  • Anxiety
  • Depression
  • Catatonia
  • Psychosis
  • Temporary or permanent loss of skills

CAUSES

Phelan-McDermid syndrome (PMS) has two causes. It can be caused by the deletion of a specific region of chromosome 22. This region is referred to as the distal long arm. It can also be caused by a pathogenic variant in the SHANK3 gene.  

Most cases of PMS happen spontaneously, prior to conception. They are not inherited from the parents.  

However, in some cases, a parent may have a “balanced translocation.” This means genetic material has been swapped between chromosomes. A balanced translocation does not typically affect the parent. This is because all genetic material is still present and functional in the parent who carries the balanced translocation.  

A parent with a balanced translocation may produce a child with an “unbalanced” translocation. In this case, genetic material is lost or altered. This can lead to PMS if there is loss of the distal segment of chromosome 22. 

Specific genetic tests can determine if either parent is at risk of having a child with genetic changes leading to PMS. Tests involve examining the chromosomes. 

30

LABORATORY INVESTIGATIONS

The diagnosis of PMS is based on finding a genetic alteration of the 22q13 region of the chromosome. Multiple tests that can be used to get a diagnosis or reveal added risks in PMS are described below.

Talk to your doctor about which testing option or options are best for your family. To learn more about testing options for PMS, visit the How PMS Is Diagnosed page on the Phelan-McDermid Syndrome Foundation‘s website.

Test options include: 

Chromosomal microarray analysis (CMA).

This test detects whether genetic material is missing or duplicated. A deletion of DNA in the 22q13 region indicates a diagnosis of PMS. CMA is often considered to be the first tier of testing in individuals with intellectual disability and/or ASD.

Cytogenetic testing.

“Cytogenetic” tests visualize chromosomes. They detect the number, structure, and rearrangements of chromosomes. This type of test is needed for people with 22q13 deletions for the following reasons: 

  • Karyotyping can detect Ring 22. Ring 22 occurs when there are deletions on each end of chromosome 22. The broken ends of the chromosome can fuse into a circle, or ring shape. Ring 22 carries a risk of tumors in the nervous system. It requires medical monitoring. 
  • Cytogenetics testing can detect the risk of PMS heritability. As mentioned above, a parent can have a “balanced translocation” in which genetic material is swapped between chromosomes. Because the correct amount of genetic material is present, the parent has no symptoms.  
    • However, a parent with a balanced translocation is at an increased risk of having a child with an “unbalanced” translocation in which some genetic material is lost and/or duplicated. This can result in a deletion of the 22q13 region.  
    • If a translocation in the child is suspected based on CMA results, both the child and the parent should have cytogenetic testing. This will show whether there is an increased risk of an unbalanced translocation in future pregnancies. 

Two types of cytogenetic tests are commonly used in Phelan-McDermid syndrome. Both tests can detect the two concerns listed above. These tests are: 

  • Conventional karyotyping. This test visualizes common features of chromosomes by staining them. Chromosomes can then be arranged by size and shape. The two copies of each chromosome are assessed to see if there are abnormalities. This testing can identify ring chromosomes. It can also identify most balanced and unbalanced translocations.  
  • Fluorescence in situ hybridization (FISH). FISH is a molecular cytogenetic test. It uses fluorescent probes (dyed pieces of DNA) to visualize specific DNA sequences. It highlights specific groups of genes or parts of specific chromosomes. This technique can identify smaller chromosomal rearrangements than conventional karyotyping. It is a targeted technique to study a particular segment of a chromosome. 

Whole exome sequencing (WES) and whole genome sequencing (WGS).

Sequencing tests can detect smaller errors in DNA. They can be needed if a deletion has not been detected but symptoms are consistent with:  

  • These tests can detect errors in only one or a few letters of the genetic code. They can be useful for detecting errors in the SHANK3 gene. The SHANK3 gene is in the 22q13 region. It is highly linked with autism and PMS symptoms.  
  • Sometimes a small change in SHANK3 does not impact the function of the gene. Other times, a change is detrimental. This causes SHANK3 to make no protein or an abnormal protein that does not function properly. In that case, the change is called “pathogenic.” 
  • If a variant in SHANK3 is detected in the child, the parents should be tested. Tests will detect whether they have the same variant as the child. If a parent has the variant, it is unlikely to be problematic. This is because it is not causing symptoms in the parent. Detrimental variants in SHANK3 are thought to occur spontaneously.  
  • WES and WGS can yield much of the same information. WES sequences the parts of the genome that code for proteins. This is known as the “exome.” Proteins make up many of the structures and functions within cells.  
  • WGS is more expansive. It captures the entire sequence of the genome. Some parts of the genome that don’t directly lead to proteins still impact regulation of processes within cells.

In some cases, PMS can be detected in a fetus before birth (prenatally). This is done using special tests that sample the fluid surrounding the fetus or part of the placenta.

Ring Chromosome 14 Syndrome 2

TREATMENT AND THERAPIES

No treatments have been shown to correct the cause of PMS. Treatment is aimed at managing symptoms and risks specific to each person.  

Symptoms can vary between people with PMS. This is due to different genetics and other factors. Some symptoms may occur only in some people with PMS. They may only occur during specific stages of life, or they may be cyclical.

Families often see a team of specialists, including the following: 

  • A neurologist 
  • A primary care physician 
  • A gastroenterologist 
  • An endocrinologist 
  • A psychiatrist 
  • A speech and language therapist 
  • Occupational and physical therapists  
  • A nephrologist and/or urologist 

Frequently, people with PMS undergo behavioral therapy. They may receive medication for:  

  • Seizures/epilepsy 
  • Psychiatric disorders 
  • Sleep disturbances 
  • GI symptoms 

Clinical trials to test new treatments for PMS have increased in recent years. See the clinical trials section below to find current trials.

Ring Chromosome 14 Syndrome 1

OUTLOOK

People with PMS can be active members of their home and school settings. They can foster friendships and interests.  

Typically, people with PMS need significant support from:  

  • Their family 
  • Their school system 
  • Their community 
  • Their adult service providers 

It is unlikely that a person with PMS will live independently. They will most likely need the aid of a companion or support individual. 

Resources 

Phelan-McDermid Syndrome Foundation

It is the mission of the Phelan-McDermid Syndrome Foundation (PMSF) to improve the quality of life of people affected by PMS worldwide by providing family support, accelerating research, and raising awareness. They provide a family resource library, a parent’s guide, networking capabilities through regional reps, and much more. 

 

Chromosome 22 Central

Chromosome 22 Central (C22C) is a global collection of parents and people affected by chromosome 22 disorders who can connect, advocate, and grow together. 

The website is a hub for people to find immediate connections with others through their various social media platforms, and to find basic information and links to other resources. Started in 1996 with just 17 families of children with what is now known as Emanuel syndrome, C22C has grown over the past 25 years into a community for anyone needing support or information about any of the disorders of chromosome 22, which includes Phelan-McDermid syndrome.  

Childhood Stroke 1

Child Neurology Foundation (CNF) solicits resources from the community to be included on this webpage through an application process. CNF reserves the right to remove entities at any time if information is deemed inappropriate or inconsistent with the mission, vision, and values of CNF. 

Research 

ClinicalTrials.gov for Phelan-McDermid Syndrome (birth to 17 years).

These are clinical trials that are recruiting or will be recruiting. Updates are made daily, so you are encouraged to check back frequently. 

ClinicalTrials.gov is a database of privately and publicly funded clinical studies conducted around the world. This is a resource provided by the U.S. National Library of Medicine (NLM), which is an institute within the National Institutes of Health (NIH). Listing a study does not mean it has been evaluated by the U.S. Federal Government. Please read the NLM disclaimer for details.    

Before participating in a study, you are encouraged to talk to your health care provider and learn about the risks and potential benefits.

Family Stories

The Phelan-McDermid Syndrome Foundation shares the amazing stories of families who have children diagnosed with Phelan-McDermid syndrome (PMS). These are candid stories of people affected by PMS and how they struggle, cope, love, hope and carry on.

The information in the CNF Child Neurology Disorder Directory is not intended to provide diagnosis, treatment, or medical advice and should not be considered a substitute for advice from a healthcare professional. Content provided is for informational purposes only.  CNF is not responsible for actions taken based on the information included on this webpage. Please consult with a physician or other healthcare professional regarding any medical or health related diagnosis or treatment options. 

References

National Institutes of Health. U.S. National Library of Medicine. 2022 [cited 2022 Mar 17]. Clinical trials in Phelan-McDermid syndrome [Internet]. Available from: https://clinicaltrials.gov/ct2/results?cond=Phelan-McDermid+syndrome&term=&cntry=&state=&city=&dist= 

De Rubeis S, Siper PM, Durkin A, Weissman J, Muratet F, Halpern D, Trelles MDP, Frank Y, Lozano R, Wang AT, Holder JL Jr, Betancur C, Buxbaum JD, Kolevzon A. Delineation of the genetic and clinical spectrum of Phelan-McDermid syndrome caused by SHANK3 point mutations. Mol Autism. 2018 Apr 27;9:31. https://doi.org/10.1186/s13229-018-0205-9PMID: 29719671; PMCID: PMC5921983. 

Durand CM, Betancur C, Boeckers TM, Bockmann J, Chaste P, Fauchereau F, Nygren G, Rastam M, Gillberg IC, Anckarsäter H, Sponheim E, Goubran-Botros H, Delorme R, Chabane N, Mouren-Simeoni MC, de Mas P, Bieth E, Rogé B, Héron D, Burglen L, Gillberg C, Leboyer M, Bourgeron T. Mutations in the gene encoding the synaptic scaffolding protein SHANK3 are associated with autism spectrum disorders. Nat Genet. 2007 Jan;39(1):25-7. https://doi.org/10.1038/ng1933. Epub 2006 Dec 17. PMID: 17173049; PMCID: PMC2082049. 

Keller R, Basta R, Salerno L, Elia M. Autism, epilepsy, and synaptopathies: a not rare association. Neurol Sci. 2017 Aug;38(8):1353-1361. https://doi.org/10.1007/s10072-017-2974-x. Epub 2017 Apr 28. PMID: 28455770. 

Kniffin, CL. Online Mendelian Inheritance in Man (OMIM). The Johns Hopkins University. 2020. Phelan-McDermid syndrome; PHMDS [Internet]. Available from: https://www.omim.org/entry/606232 

Kohlenberg TM, Trelles MP, McLarney B, Betancur C, Thurm A, Kolevzon A. Psychiatric illness and regression in individuals with Phelan-McDermid syndrome. J Neurodev Disord. 2020 Feb 12;12(1):7. https://doi.org/10.1186/s11689-020-9309-6. PMID: 32050889; PMCID: PMC7014655. 

Kolevzon A, Angarita B, Bush L, Wang AT, Frank Y, Yang A, Rapaport R, Saland J, Srivastava S, Farrell C, Edelmann LJ, Buxbaum JD. Phelan-McDermid syndrome: a review of the literature and practice parameters for medical assessment and monitoring. J Neurodev Disord. 2014;6(1):39. https://doi.org/10.1186/1866-1955-6-39. Epub 2014 Oct 8. PMID: 25784960; PMCID: PMC4362650. 

Leblond CS, Nava C, Polge A, Gauthier J, Huguet G, Lumbroso S, Giuliano F, Stordeur C, Depienne C, Mouzat K, Pinto D, Howe J, Lemière N, Durand CM, Guibert J, Ey E, Toro R, Peyre H, Mathieu A, Amsellem F, Rastam M, Gillberg IC, Rappold GA, Holt R, Monaco AP, Maestrini E, Galan P, Heron D, Jacquette A, Afenjar A, Rastetter A, Brice A, Devillard F, Assouline B, Laffargue F, Lespinasse J, Chiesa J, Rivier F, Bonneau D, Regnault B, Zelenika D, Delepine M, Lathrop M, Sanlaville D, Schluth-Bolard C, Edery P, Perrin L, Tabet AC, Schmeisser MJ, Boeckers TM, Coleman M, Sato D, Szatmari P, Scherer SW, Rouleau GA, Betancur C, Leboyer M, Gillberg C, Delorme R, Bourgeron T. Meta-analysis of SHANK Mutations in Autism Spectrum Disorders: a gradient of severity in cognitive impairments. PLoS Genet. 2014 Sep 4;10(9):e1004580. https://doi.org/10.1371/journal.pgen.1004580. PMID: 25188300; PMCID: PMC4154644. 

Levy T, Foss-Feig JH, Betancur C, Siper PM, Trelles-Thorne MDP, Halpern D, Frank Y, Lozano R, Layton C, Britvan B, Bernstein JA, Buxbaum JD, Berry-Kravis E, Powell CM, Srivastava S, Sahin M, Soorya L, Thurm A, Kolevzon A; Developmental Synaptopathies Consortium. Strong evidence for genotype-phenotype correlations in Phelan-McDermid syndrome: results from the developmental synaptopathies consortium. Hum Mol Genet. 2022 Feb 21;31(4):625-637. https://doi.org/10.1093/hmg/ddab280. PMID: 34559195; PMCID: PMC8863417. 

Phelan K, Boccuto L. National Organization for Rare Disorders. Chromosome 22 Ring [Internet]. 2021. Available from: https://rarediseases.org/rare-diseases/chromosome-22-ring/ 

Phelan K, Boccuto L, Powell CM, Boeckers TM, van Ravenswaaij-Arts C, Rogers RC, Sala C, Verpelli C, Thurm A, Bennett WE Jr, Winrow CJ, Garrison SR, Toro R, Bourgeron T. Phelan-McDermid syndrome: a classification system after 30 years of experience. Orphanet J Rare Dis. 2022 Jan 29;17(1):27. https://doi.org/10.1186/s13023-022-02180-5. PMID: 35093143; PMCID: PMC8800328. 

Phelan K, Rogers RC, Boccuto L. Phelan-McDermid Syndrome [Internet]. 2018. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews®. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1198/. 

Phelan K, McDermid HE. The 22q13.3 Deletion Syndrome (Phelan-McDermid Syndrome). Mol Syndromol. 2012 Apr;2(3-5):186-201. https://doi.org/10.1159/000334260. Epub 2011 Nov 22. PMID: 22670140; PMCID: PMC3366702. 

PMS Neuropsychiatric Consult Group. Pharmacological Treatment Guidelines [Internet]. 2020 [cited 2022 Mar 17]. Available from: https://pmsf.org/wp-content/uploads/2021/04/Combined-PMS-NCG-Pharmacological-Management-Consensus-1.pdf. 

Reierson G, Bernstein J, Froehlich-Santino W, Urban A, Purmann C, Berquist S, Jordan J, O’Hara R, Hallmayer J. Characterizing regression in Phelan McDermid Syndrome (22q13 deletion syndrome). J Psychiatr Res. 2017 Aug;91:139-144. https://doi.org/10.1016/j.jpsychires.2017.03.010. Epub 2017 Mar 16. PMID: 28346892; PMCID: PMC5469716. 

Sarasua SM, Dwivedi A, Boccuto L, Rollins JD, Chen CF, Rogers RC, Phelan K, DuPont BR, Collins JS. Association between deletion size and important phenotypes expands the genomic region of interest in Phelan-McDermid syndrome (22q13 deletion syndrome). J Med Genet. 2011 Nov;48(11):761-6. https://doi.org/10.1136/jmedgenet-2011-100225. Epub 2011 Oct 7. PMID: 21984749. 

Soorya L, Kolevzon A, Zweifach J, Lim T, Dobry Y, Schwartz L, Frank Y, Wang AT, Cai G, Parkhomenko E, Halpern D, Grodberg D, Angarita B, Willner JP, Yang A, Canitano R, Chaplin W, Betancur C, Buxbaum JD. Prospective investigation of autism and genotype-phenotype correlations in 22q13 deletion syndrome and SHANK3 deficiency. Mol Autism. 2013 Jun 11;4(1):18. https://doi.org/10.1186/2040-2392-4-18. PMID: 23758760; PMCID: PMC3707861. 

World Health Organization. Autism [Internet]. 2022. Available from: https://www.who.int/news-room/fact-sheets/detail/autism-spectrum-disorders 

Thank you to our 2022 Disorder Directory partner Jazz Pharmaceuticals. And to our 2021 partners Acadia, Aeglea, Amicus Therapeutics, bluebird bio, Eisai, Greenwich Biosciences (now Jazz Pharmaceuticals), Liva Nova, Origin, Ovid, PTC Therapeutics and UCB for their support of the Disorder Directory.

Start typing and press Enter to search

Shopping Cart
Skip to content