NORD gratefully acknowledges Katy Phelan, PhD, Director of Cytogenetics, Florida Cancer Specialists, Fort Myers, Florida, and the Phelan-McDermid Syndrome Foundation, for assistance in the preparation of this report.
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. Although the range and severity of symptoms may vary, PMS is generally thought to be characterized by neonatal hypotonia (low muscle tone in the newborn), normal growth, absent to severely delayed speech, moderate to profound developmental delay, and minor dysmorphic features.
The genetic changes that cause PMS vary from person to person and can occur randomly (de novo) or be inherited from a parent (20%) 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 diligently to improve our knowledge of PMS and to find drugs and therapies that can help people affected by PMS.
Current research indicates that the inability of the single functioning copy of SHANK3 to produce sufficient Shank3 protein for normal functioning (haploinsufficiency) may be responsible for most of the neurologic symptoms (developmental delay and absent speech) associated with this disorder.
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, additional symptoms develop. People with PMS typically have moderate to severe developmental and intellectual impairment, most do not acquire 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 swallowing and eating. About 40% of people develop seizures which 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 low perception of pain. Low perception of pain 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 perspire less than others, and are at risk of overheating. It is very important that caregivers monitor carefully for injuries and overheating. Precautions must be taken to protect the individual from direct sunlight, use sunscreen, and keep the individual hydrated.
Despite these medical and developmental issues, infants with PMS tend to be easily amused, and adults often have a sweet disposition.
Most infants with PMS exhibit normal growth before birth (intrauterine growth) with normal growth after birth (postnatally). The first physical sign associated with PMS is neonatal hypotonia (low muscle tone) which may be accompanied by feeding difficulties, weak cry, and poor head control. Children also experience significant delay in reaching early developmental milestones, such as rolling over, crawling and walking, associated with low muscle tone.
The facial features associated with PMS include long head shape (dolicocephaly), large/prominent ears, full brow, deep set eyes, long eyelashes, full or puffy eyelids, droopy eyelids (ptosis), flat midface, full or puffy cheeks, wide nasal bridge, bulbous nose, and pointed chin. Other features include relatively large hands and underdeveloped (dysplastic) toenails. Behavior is described as “autistic-like” with tactile defensiveness, anxiety in social situations, avoidance of eye contact, and self-stimulatory behavior. Other behavioral traits include decreased perception of pain and obsessive chewing of non-food items.
About 25% of individuals with PMS have kidney abnormalities, including multi-cystic kidneys, one non-functioning (under-developed or dysplastic) kidney, kidney stones, and backward flow of urine into the kidney (ureteral reflux). All children diagnosed with PMS should have a renal ultrasound performed to check for kidney defects.
Over 15% of individuals with PMS have arachnoid cysts (fluid filled sacs on the surface of the brain) compared to about 1% of the general population. While small arachnoid cysts may remain without symptoms (asymptomatic), larger cysts may cause increased intracranial pressure resulting in irritability, incessant crying bouts, severe headaches, cyclic vomiting, and seizures. Brain imaging with magnetic resonance imaging and computed tomography are indicated if an arachnoid cyst is suspected based on symptoms of increased intracranial pressure.
Although significant information is not available on older individuals with PMS, current data suggest that lymphedema (accumulation of fluid in the arms and legs) and cellulitis (inflammation of subcutaneous tissue due to infection) may develop during the teenage and early adult years.
PMS is caused by the deletion or disruption of the segment of the long arm (q) of chromosome 22 that is identified as 22q13. Chromosomes are found in the nucleus of all body cells. They carry the genetic information for the growth and development of each individual. Pairs of human chromosomes include the autosomes, numbered from 1 to 22, and the sex chromosomes, X and Y. Females have two X chromosomes while males have one X and one Y chromosome. Each chromosome has a short arm designated as “p” and a long arm identified by the letter “q.” Chromosomes are further subdivided into numbered bands. Therefore, “chromosome 22q13” refers to band 13 on the long arm (q) of chromosome 22.
Most cases of PMS are due to a spontaneous (de novo) break in the long arm of chromosome 22 that occurs for unknown reasons (sporadic). The segment of chromosome 22 beyond (distal to) the break is lost (deleted). In such cases, called simple deletions, the disorder is not inherited from the parents. That is, the parents have normal chromosomes but the break in chromosome 22 has occurred as a “new mutation” in the egg or in the sperm that contributes to the formation of the embryo. As in many other distal deletion syndromes, the deletion of 22q13 is more likely to occur on the chromosome 22 that is inherited from the father (in the sperm) than the chromosome 22 inherited from the mother (in the egg).
Because the deletion of chromosome 22 typically occurs on the distal portion of the long arm of the chromosome that is away from the center (distal), it is often referred to as a “terminal” deletion. In this sense, “terminal” refers to the end of the chromosome. It is important that families and healthcare providers understand that in this context “terminal” refers to the distal portion of the chromosome and does not imply that the PMS is a “terminal” or lethal (life-threatening) condition.
About 20% of deletions of 22q13 are due to unbalanced translocations. Translocations may be balanced or unbalanced, and may be inherited or may occur as a new mutation (de novo). Translocations typically occur when breaks occur on two different chromosomes and the segments distal to the breakpoints trade places. For example, consider a translocation between the short arm (p) of chromosome 2 and the long arm (q) of chromosome 22. One break occurs in 2p and a second break occurs in 22q. The segment distal to the breakpoint on 2p trades places with the segment distal to the breakpoint on 22q. Such a translocation is called “balanced” because the correct amount of genetic material is present although its position has been altered. Balanced translocations are usually harmless to the carrier. However, a parent with a balanced rearrangement is at risk of transmitting an unbalanced translocation to a child. Chromosomal (cytogenetic) testing can determine whether or not a parent has a balanced translocation and is at risk of passing an unbalanced translocation to his or her offspring.
Unbalanced translocations may also occur de novo, or as a new mutation, when both parents have normal chromosomes. Even though neither parent carries a balanced translocation, a segment of chromosome 22 may switch places with a segment from another chromosome (example: chromosome 2) during the formation of the germ cell (egg or sperm). If the mature egg or sperm carries the translocated chromosome 22 but a normal copy of chromosome 2, an unbalanced translocation results. The embryo will be missing a piece of chromosome 22 but will have an extra copy of a segment of chromosome 2. The loss of 22q13 leads to PMS. The extra piece of chromosome 2 may also be associated with unusual features. Although chromosome 2 was used in this example, a translocation can occur between chromosome 22 and any of the other autosomes (chromosomes 1 to 22), or the sex chromosomes (X and Y). About half of the unbalanced translocations in PMS are inherited while the other half occur de novo.
Ring 22 is another structural chromosome change that can result in PMS. Chromosome 22 breaks at both ends (i.e., the ends of the long arm [22q] and the short arm [22p]) and the distal segments are lost (deleted). The “new” chromosomal ends then join together, forming a ring. The formation of the ring is usually accompanied by a similar loss of genetic material as seen in cases of 22q13 deletion, and the symptoms observed to date appear to be consistent between the two conditions.
PMS was initially described in the medical literature in 1985. Since that time, additional cases have been reported in the literature, with more than 1500 members in the Phelan-McDermid Syndrome Foundation membership. Males and females are equally likely to be affected. Based on limited statistical analysis, the occurrence rate has been estimated to fall in the range of 2.5-10 per million births, although this is likely to be a gross underestimate. Due to the subtle appearance of the deletion of chromosome 22 and the relatively mild physical features of affected individuals, diagnosis of PMS is often difficult. Over 30% of individuals with this deletion have required two or more chromosome studies before the deletion is detected. It is likely that there are many individuals who had “normal” chromosome studies at an earlier age but who actually carry this subtle chromosome abnormality.
The diagnosis of PMS is based on the demonstration of a deletion or disruption of the chromosome region 22q13. A simple deletion of 22q13 is often difficult to detect by high resolution chromosome studies. The deletion may be “submicroscopic” or beyond the level of resolution at the microscope. Likewise, unbalanced translocations may be “cryptic” or hidden because 22q13 has been replaced by a chromosomal segment that is similar in size and staining pattern. In contrast to the other chromosome changes, ring chromosomes are often easily detected by chromosome analysis.
Chromosomal microarray analysis (CMA): Individuals with autism or developmental delay should be referred for a CMA. The test involves providing a small amount of blood. Deletions of 22q13 are reliably detected by CMA because this test detects copy number variations (CNVs), including chromosomal deletions and duplications, across the entire genome.
If a deletion of 22q13 is detected through microarray, additional steps should be undertaken because there can be special health concerns for individuals with a ring chromosome, in which the ends of the chromosome stick together at deletion breakpoints. A chromosome analysis will show a picture of the chromosomes (karyotype) and should be performed to determine if the individual has Ring 22.
If the CMA shows a terminal deletion of chromosome 22q and a terminal duplication in another chromosome, the individual may have an unbalanced translocation, and fluorescence in situ hybridization (FISH) and/or karyotype studies are warranted.
PMS-related deletions arise from parental balanced rearrangements in about 20% of those affected. Parents who carry a balanced rearrangement, although healthy, have an increased risk of having another affected child.
Parents should undergo metaphase FISH and/or karyotype testing to determine if the child’s deletion is de novo (spontaneous) or if it resulted from a parental chromosomal rearrangement, such as a balanced translocation or inversion, or if one of the parents themselves has the same deletion.
Whole exome sequencing (WES): If chromosomal microarray analysis (CMA) has been done, but a pathogenic deletion is not identified, the next step is WES. WES detects genetic spelling errors, called variants, in genetic sequence. Some variants are benign (do not cause disease). Some variants have uncertain effects (variants of unknown significance). Other variants are known to cause disease (pathogenic mutations).
Pathogenic mutations of the SHANK3 gene are associated with PMS. If a likely pathogenic variant of SHANK3 is detected, the parents should also undergo WES to determine if one of the parents carries the same variant. If the variant is present in a healthy parent, it is unlikely to be pathogenic. Indeed, pathogenic mutations in SHANK3 are de novo in the vast majority of people with PMS (they are present in the child and absent in the parents).
There are no characteristic structural abnormalities that would lead to the diagnosis of deletion 22q13 by prenatal ultrasound. Nonetheless, some renal abnormalities have been detected in fetuses that were found after birth (postnatally) to have PMS. In some children, the diagnosis of PMS can be determined before birth (prenatally) by specialized tests such as amniocentesis, and/or chorionic villus sampling (CVS). During amniocentesis, a sample of fluid that surrounds the developing fetus is removed and studied. During chorionic villus sampling, a tissue sample is removed from a portion of the placenta. Chromosome, FISH, or microarray studies performed on this fluid or tissue sample may indicate a partial monosomy, or deletion, of chromosome 22q.
PMS can also be diagnosed and/or confirmed postnatally by a thorough clinical evaluation, characteristic physical findings, and laboratory studies. The first tier of testing should include a chromosomal microarray. If additional testing is required to determine if a ring is present, chromosome analysis may be requested. If parental studies are needed, the ordering physician will determine which test will provide the best information for accurate genetic counseling.
Treatment
The treatment for PMS addresses the specific symptoms of each individual and typically requires the coordinated efforts of a team of specialists that may include several of the following. pediatricians, neurologists, nephrologists, gastroenterologists, immunologists, orthopedists, physical or occupational therapists, and speech/language pathologists. Cardiac abnormalities are not typical of PMS, but if present will require assessment and appropriate management. In some people, treatment may include surgical repair of certain malformations. The surgical procedures will depend on the severity of the anatomical abnormalities and their associated symptoms. Other treatment is symptomatic and supportive.
The Phelan-McDermid Syndrome Foundation’s (PMSF) goal is to find effective clinical therapies and, eventually, a cure. In 2010, the PMSF launched a strategic plan for science to accelerate PMS research.
The growth within both the PMSF and research communities has been astronomical in the past few years. PMSF has contributed to the growth through grants and fellowships, advocacy, engaging families in research initiatives, and establishing relationships with researchers and funders worldwide.
The goal of current research is to provide families and healthcare professionals with a better understanding of the natural history of this disorder. The information obtained through various research projects is shared with the parents through quarterly newsletters, personal communications, and through scientific presentations at biennial meetings of the PMSF. Information for professionals is published in scientific journals and shared though personal communications.
For information on potential participation in these studies or for more general information concerning research, family support or advocacy, physicians and parents may contact:
Ronni Blumenthal
Executive Director, Phelan-McDermid Syndrome Foundation
P.O. Box 1153
8 Sorrento Drive
Osprey, FL 34229
941-485-8000
[email protected]
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government website.
For information about clinical trials being conducted at the National Institutes of Health (NIH) in Bethesda, MD, contact the NIH Patient Recruitment Office:
Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]
Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/for-patients-and-families/information-resources/news-patient-recruitment/
For information about clinical trials sponsored by private sources, contact:
www.centerwatch.com
For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/
INTERNET
McKusick VA, ed. Online Mendelian Inheritance in Man (OMIM). The Johns Hopkins University. Chromosome 22q13.3 Deletion Syndrome. Entry Number;606232. Available at: https://www.omim.org/entry/606232?search=606232&highlight=606232. Last Edit Date 01/06/2017. Accessed September 25, 2017.
Monosomy 22q13. Orphanet. http://www.orpha.net/consor/cgi-bin/Disease_Search.php?lng=EN&data_id=10630&Disease_Disease_Search_diseaseGroup=Phelan-McDermid-syndrome&Disease_Disease_Search_diseaseType=Pat&Disease(s)/group%20of%20diseases=Monosomy-22q13&title=Monosomy-22q13&search=Disease_Search_Simple. Last update: May 2008. Accessed September 25, 2017.
Phelan K, Rogers RC. Phelan-McDermid Syndrome. 2005 May 11 [Updated 2011 Aug 25]. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2017. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1198/ Accessed September 25, 2017.
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