NORD gratefully acknowledges Katy Phelan, PhD, FACMG, Florida Cancer Specialist & Research Institute, Fort Myers, Florida, Phelan-McDermid Foundation (Founder), Phelan-McDermid Scientific Advisory Board (Member); Luigi Boccuto, MD, Clemson University, School of Nursing, College of Behavioral, Social and Health Sciences, Clemson University, Phelan-McDermid Scientific Advisory Board (Member); and Kate Still, PhD, Phelan-McDermid Syndrome Foundation Scientific Director, 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 (pathogenic) variant of the SHANK3 gene.
The genetic change that causes PMS can occur sporadically (de novo) or be inherited from a parent (20%) who carries a related genetic change. Because the genetic change varies in terms of the size of the deleted segment of chromosome 22 or the specific pathogenic variant of SHANK3, the signs and symptoms of PMS are variable as well and can cause a wide range of medical, intellectual and behavioral challenges. Although the range and severity of symptoms may vary, PMS is generally characterized by neonatal hypotonia (low muscle tone in the newborn), intellectual disability of varying degrees, absent to severely delayed speech, moderate to profound developmental delay, and minor dysmorphic features. Other common characteristics are behavioral issues including autism spectrum disorder or autistic-like traits, decreased perception of pain, motor delays, sleep disorders and seizures. Individuals with PMS may also present with gastrointestinal, renal and cardiac problems. There is currently no cure or treatment specifically for PMS, but many of the symptoms are managed by therapies and/or medications and researchers are working diligently to improve the understanding and knowledge of PMS and to find drugs and therapies that can improve the lives of people affected by PMS.
Current research indicates that the inability of the single functioning copy of the SHANK3 gene to produce sufficient SHANK3 protein for normal functioning (haploinsufficiency) may be responsible for most of the neurologic symptoms (developmental and speech delay, hypotonia, seizures) associated with PMS.
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 is often accompanied by feeding difficulties, weak cry and poor head control. Children also experience a significant delay in reaching early developmental milestones, such as rolling over, sitting, crawling and walking; this delay is likely associated with low muscle tone. These are often the first noticeable symptoms that prompt families to start their diagnostic journey.
As children grow, additional symptoms develop. People with PMS typically have moderate to severe developmental and intellectual impairment, absent or severely delayed speech and about 75% have been diagnosed with an autism spectrum disorder or autistic traits. “Autistic-like” behavior includes tactile defensiveness, anxiety in social situations, avoidance of eye contact and self-stimulatory behavior. Individuals also exhibit obsessive chewing of non-food items. 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 and other medical conditions that require treatment, or physical injuries. 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 shield the individual from direct sunlight, avoid dehydration, use sunblock or sunscreen and wear protective clothing.
The facial features associated with PMS include long head shape (dolichocephaly), 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 underdeveloped (dysplastic) toenails during infancy and early childhood and relatively large, fleshy hands.
Up to 40% of individuals with PMS have kidney abnormalities, including multi-cystic kidneys, one non-functioning (under-developed or dysplastic) kidney, collection of fluid in the kidney (hydronephrosis) and backward flow of urine into the ureter and eventually the kidney (vesicoureteral reflux). All individuals diagnosed with PMS should have a renal ultrasound performed to check for kidney defects since many of these defects can be asymptomatic but may pose serious health risks that require intervention.
Gastrointestinal issues have been reported in several individuals with PMS, including gastroesophageal reflux (30% of cases), cyclic vomiting (25%), liver dysfunction and/or steatosis, constipation and diarrhea. Management of patients with gastrointestinal issues such as vomiting or diarrhea should prioritize the prevention of dehydration.
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 (MRI) and computed tomography (CT scan) are indicated if an arachnoid cyst is suspected based on symptoms of increased intracranial pressure.
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. Lymphedema can be treated by elevation, exercise, compression bandages and sequential pneumatic compression to move the fluid from the affected limb.
Neuropsychiatric illnesses including bipolar disorder, anxiety, depression, catatonia, psychosis, temporary loss of skills or long-term regression of skillsets occur in a subset of individuals with PMS. The exact percentage of people with PMS that experience these issues is not yet known. These problems often arise at the onset of puberty or early adulthood. Medical treatment guidelines devised by PMS medical experts continue to be refined in this area.
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 chromosomal variant in the egg or in the sperm cell 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 cell) than the chromosome 22 inherited from the mother (in the egg cell).
Because the deletion of chromosome 22 typically occurs on the distal portion of the long arm of the chromosome that is away from the centromere, 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. A translocation is an unusual arrangement of chromosomes, where pieces of genetic material from chromosomes may be switched, added or lost to other chromosomes. Translocations may be balanced (switched without loss of function of genes) or unbalanced (switched in a way that causes loss or addition of genes) and may be inherited or may occur as a new event (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, or karyotyping, and fluorescence in situ hybridization (FISH) can be used to determine whether a parent has a balanced translocation and is at risk of passing an unbalanced translocation to his or her offspring. Chromosomal microarray (CMA) detects the presence or absence of genetic material; therefore, it would not be effective in detecting a balanced chromosome translocation because there is no loss or gain of material. (See Diagnosis)
Unbalanced translocations may also occur de novo, or as a new event, 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. An unbalanced translocation can be inferred by CMA when there is a deletion of chromosome 22 and a gain of a distal segment from a second chromosome. Unbalanced translocations can also be detected by karyotyping if the involved segments are visible at the resolution of the microscope.
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, forming a circular structure, or ring. About 14-33% of individuals with PMS carry a ring 22, although this is likely to be an underestimate because not all individuals with ring 22 report their diagnosis as PMS and not everyone who has been diagnosed with PMS by chromosomal microarray (CMA) has a follow-up chromosome studies to determine if a ring chromosome is present (see “Diagnosis”). 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. However, due to the instability of the ring chromosome during cell division (mitosis), one of the daughter cells may receive only one copy of chromosome 22, a condition called monosomy 22. Individuals with ring 22 are at risk of developing neurofibromatosis type 2 (NF2), a condition associated with non-cancerous tumors of the nervous system. This risk arises from a “two-hit” sequence. The first hit is the loss of the ring 22 in cells in the nervous system. If one of these cells undergoes a second hit – a pathogenic variant in the NF2 gene – neurofibromatosis type 2 can result. Parents, caregivers, and healthcare professionals must be aware of this risk. It is imperative chromosome analysis (karyotyping) is performed in follow-up whenever a deletion of 22q13 is diagnosed by CMA. CMA can detect the deletion of 22q but cannot rule out the presence of a ring 22. The risk of NF2 is not related to a pathogenic variant of the NF2 gene or deletion of the NF2 locus. It results from the presence of a ring chromosome 22 and parents must be aware of this risk so their child can be monitored appropriately. (See Chromosome 22 Ring https://rarediseases.org/rare-diseases/chromosome-22-ring/)
Deletion of 22q13 was initially described in the medical literature in 1985. Since that time, increased understanding through scientific research, advances in genetic testing and advocacy have led to approximately 3,000 members in the Phelan-McDermid Syndrome Foundation as of 2022. 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. Prior to the advent of CMA testing, over 30% of individuals with this deletion required two or more chromosome studies before the deletion was detected. It is likely that there are many older individuals who had “normal” chromosome studies at an earlier age but who actually carry this subtle chromosome abnormality or pathogenic variant of SHANK3. Unless these individuals are studied by CMA testing or NGS, their diagnosis will remain a mystery.
The diagnosis of PMS is based on genetic testing for the identification of a deletion or disruption of the chromosome region 22q13. The first tier of genetic testing for individuals with intellectual disability or developmental delay includes chromosomal microarray analysis (CMA) and next generation sequencing (NGS).
Chromosomal microarray analysis (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. Deletions within the 22q13 region, which commonly impact the SHANK3 gene, are consistent with a diagnosis of PMS.
If a deletion of 22q13 is detected through microarray, additional steps should be undertaken to determine if the individual has a ring configuration of chromosome 22, in which the ends of the chromosome stick together at deletion breakpoints. A chromosome analysis will show the structure of the chromosomes (karyotype) and should be performed to determine if the individual has ring 22. Ring 22 carries an added risk of neurofibromatosis type 2 (NF2), a disorder linked with the development of noncancerous tumors in the nervous system.
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 to visualize the chromosome are warranted. Unbalanced translocations may arise from parental balanced rearrangements. Although 80% of PMS cases occur spontaneously at birth (de novo), inheritance of a parental genetic alteration can occur in about 20% of those affected. Parents who carry a balanced rearrangement, although healthy, have an increased risk of having another affected child and should undergo metaphase FISH and/or karyotype testing.
Next-Generation sequencing (NGS): If chromosomal microarray analysis (CMA) has been done but a pathogenic deletion is not identified, the next step is NGS. NGS detects genetic spelling errors, called variants, in a genetic sequence by essentially “reading” the genome. NGS can include sequencing of protein-coding genes, sequencing of the whole genome or targeted sequencing of specific genes. Some variants detected with sequencing are benign (do not cause disease). Some variants have uncertain effects (variants of unknown significance). Other variants are known to cause disease (pathogenic variants).
Pathogenic variants of the SHANK3 gene are associated with PMS. If a likely pathogenic variant of SHANK3 is detected, the parents should also undergo NGS 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 variants in SHANK3 are de novo in most people with PMS (they are present in the child and absent in the parents). Data on the medical consequence of SHANK3 variants continue to accrue with time, especially as NGS is more widely used. It is recommended practice for genetic experts to regularly check the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar//) and other variant databases for updates connecting variants to pathogenicity.
In terms of prenatal testing, there are no characteristic structural abnormalities that would lead to the diagnosis of deletion 22q13 by an ultrasound exam before birth.
Nonetheless, some renal abnormalities have been detected in fetuses that were found after birth to have PMS. In some children, the diagnosis of PMS can be determined before birth 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. CMA, FISH or karyotype 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 (CMA). 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.
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.
No known treatments have been successful at targeting the underlying cause of Phelan-McDermid syndrome. Instead, treatments are based on symptom management and monitoring organ function. Some frequently used treatment approaches in PMS include but are not limited to: occupational therapy, physical therapy, behavioral therapy (especially if autism spectrum disorder is indicated), anticonvulsants and benzodiazepines for those with seizures and myoclonus, anti-psychotics/electroconvulsive therapy/alpha agonists/stimulants for psychiatric and attention disorders, melatonin and other treatments for sleep disturbances and fluids and anti-nausea medications for gastrointestinal distress. Individuals with PMS may have some or a subset of the symptoms for which these treatments are indicated, and treatment is highly specialized.
Research towards finding effective therapies for PMS has increased significantly over the past decade. This has resulted from contributions from academic scientists, physicians, rare disease and neurodevelopmental disease consortiums, patient advocacy groups such as the Phelan-McDermid Syndrome Foundation, interest from pharmaceutical companies and promotion of research from the patient community.
In 2015, a long-term natural history study was launched to characterize the course of PMS. The natural history study is conducted at five U.S. medical sites and has resulted in numerous publications. The study has also identified useful assessments which can serve as outcome measures for clinical trials.
Many of the clinical trials in PMS have been initiated in recent years. Investigational therapies currently listed on clinicaltrials.gov include insulin-like growth factor-1 (IGF-1), recombinant human growth hormone, AMO-01, intranasal oxytocin, Q10 ubiquinol, lithium and NNZ-2591. Some of these trials are in development, some have concluded and others are proceeding to the next phase. Certain trials have resulted in improvement in measures for some symptoms of people with PMS, while others have been unsuccessful. The most current details on clinical trial results and recruitment are also on this website.
The Phelan-McDermid Syndrome Foundation (PMSF) has maintained an international genetic registry – now called the PMS DataHub (https://pmsf.org/datahub), to increase available medical information on PMS genetics, symptoms and medications to accelerate research. The registry also facilitates recruitment for research studies.
The nonprofit organization CureSHANK (www.cureshank.org) was launched in 2020 and is dedicated to increasing SHANK3 research and therapeutic interventions.
For more information for the PMS community concerning research, family support or advocacy, physicians and parents may contact:
Executive Director, Phelan-McDermid Syndrome Foundation
P.O. Box 1153
8 Sorrento Drive
Osprey, FL 34229
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 web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Toll-free: (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, in the main, contact: www.centerwatch.com
For more information about clinical trials conducted in Europe, contact: https://www.clinicaltrialsregister.eu/
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