Clinical characteristics.

Phelan-McDermid syndrome-SHANK3 related (PMS-SHANK3 related) is characterized by neonatal hypotonia, absent to severely delayed speech, developmental delay, and minor dysmorphic facial features. Most affected individuals have moderate-to-profound intellectual disability. Other features include relatively large fleshy hands, dysplastic toenails, and decreased perspiration that results in a tendency to overheat. Normal stature and normal head size distinguish PMS-SHANK3 related from other autosomal chromosome disorders. Neurobehavioral characteristics include mouthing or chewing non-food items, decreased perception of pain, and autism spectrum disorder or autistic-like affect and behavior. Some individuals experience regression / loss of skills, epilepsy, ataxic/abnormal gait, and sleep disturbance (difficulty falling asleep and staying asleep, hypersomnia, and parasomnias). Less commonly, affected individuals may have strabismus, vision problems (hyperopia or myopia), cardiac anomalies, renal anomalies, and lymphedema. Those who have PMS-SHANK3 related due to a ring chromosome 22 also have a high risk of developing features of NF2-related schwannomatosis (NF2).

Diagnosis/testing.

The diagnosis of PMS-SHANK3 related is established in a proband with suggestive findings and either (1) a <50-kb to >9-Mb heterozygous deletion at chromosome 22q13.3 with involvement of at least part of SHANK3; (2) a heterozygous pathogenic variant in SHANK3; OR (3) a chromosomal rearrangement with breakpoints disrupting SHANK3 identified by molecular genetic testing.

Management.

Treatment of manifestations: Standard treatment for developmental delay / intellectual disability, epilepsy, hearing loss, recurrent ear infections, refractive error, strabismus, gastroesophageal reflux disease, autoimmune hepatitis / liver failure, renal anomalies, vesicoureteral reflux, hypothyroidism, pubertal abnormalities, bruxism, malocclusion, and cardiac issues. Those who experience poor feeding may benefit from feeding therapy or, if the feeding issues are persistent, placement of a gastrostomy tube. Immunomodulation therapy (such as intravenous immunoglobulins) may be considered in those with autoimmune encephalitis. Sleep hygiene, healthy habits, light therapy, and potential medical management may be considered to treat sleep disturbance. More complex vision issues, such as optic nerve hypoplasia or cortical visual impairment, may require input from an ophthalmic subspecialist. Use of pressure stockings and elevation of the foot of the bed may be helpful for those who have lymphedema; depending on the stage of the symptom, compression therapy, weight reduction, and stimulation mobility may also be indicated. In those who have a ring chromosome 22, see the GeneReview on NF2-related schwannomatosis for further information about treatment of manifestations.

Surveillance: At each visit, measurement of growth parameters; evaluation of nutritional status and safety of oral intake; monitor for signs/symptoms of GERD; monitor for new manifestations, such as seizures, changes in tone, and developmental regression; monitor developmental progress and educational needs; evaluate for neurobehavioral issues, such as anxiety, ADHD, autism, aggression, and self-injury; monitor for signs/symptoms of sleep apnea and sleep disturbance. Annually, perform audiology evaluation and ophthalmology evaluation. At each visit in childhood and adolescence, monitor for signs and progression of puberty. At regular intervals, perform dental evaluation for evidence of tooth decay, malocclusion, and crowding. In those with poor growth or as clinically indicated, assess thyroid function. In those with a ring chromosome 22, perform annual neurologic examination by a provider with experience with NF2; brain MRI annually beginning at age 10-12 years until fourth decade of life; annual audiology evaluation, including BAER, to assess for the earliest symptoms of vestibular schwannomas; annual ophthalmology evaluation.

Agents/circumstances to avoid: Exposure to high temperatures and extended periods in the sun due to reduced perspiration and tendency to overheat easily; exposure to excessive heat or cold, sharp objects, or clothes/shoes that may be too tight and cause skin lesions due to decreased perception of pain; radiotherapy for NF2-associated tumors in those with a ring chromosome 22.

Genetic counseling.

PMS-SHANK3 related is an autosomal dominant disorder most often caused by a de novo genetic alteration. Recurrence risk in family members depends on the genetic mechanism underlying PMS-SHANK3 in the proband and the genetic status of the parents of the proband.

22q13.3 deletion: Most probands have a de novo deletion; some probands have the deletion as the result of an unbalanced structural rearrangement that includes 22q13 (about half of these individuals have a parent who is a carrier of a balanced translocation) or a ring chromosome 22 (karyotype screening of the proband for a ring chromosome 22 must be done if a terminal 22q13.3 deletion is detected by CMA). Rarely, a proband inherited the genetic alteration from a heterozygous or mosaic parent. If a parent has (1) a non-mosaic 22q13.3 deletion, the risk to each sib of inheriting the deletion is 50%; (2) a mosaic 22q13.3 deletion, the risk to each sib is increased but impossible to quantify because the level of mosaicism in gonadal tissue is unknown; (3) a chromosomal rearrangement, the risk to sibs is increased and depends on the specific chromosomal rearrangement and the possibility of other variables.

Intragenic SHANK3 pathogenic variant: Most probands have a de novo pathogenic variant; rarely, a proband inherited the pathogenic variant from a heterozygous or mosaic parent. If a parent of the proband is affected and/or known to have an intragenic SHANK3 pathogenic variant, the risk to the sibs is 50%.

Once a 22q13.3 deletion involving SHANK3 or a SHANK3 intragenic pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible. Prenatal test results cannot reliably predict the phenotype.

Suggestive Findings

PMS-SHANK3 related should be considered in probands with the following clinical findings:

Clinical findings

• Moderate-to-profound developmental delay (DD) or intellectual disability (ID) with absent to severely delayed speech

AND

• Any of the following features presenting in infancy or childhood:
  • Minor dysmorphic facial features (see Clinical Description) with relatively large, fleshy hands and dysplastic toenails
  • Generalized hypotonia
  • Decreased perspiration and/or tendency to overheat
  • Normal stature and head circumference for age and sex
  • Neurobehavioral/psychiatric manifestations including mouthing or chewing non-food items, decreased perception of pain, and autism spectrum disorder or autistic-like features
  • Regression / loss of skills
  • Epilepsy
  • Sleep disturbances, including difficulty falling asleep and staying asleep, hypersomnia, and parasomnias

Family history. Because PMS-SHANK3 related is typically caused by a de novo pathogenic variant, most probands represent a simplex case (i.e., a single occurrence in a family). Rarely, the family history may be consistent with autosomal dominant inheritance (e.g., affected males and females in multiple generations).

Establishing the Diagnosis

The diagnosis of PMS-SHANK3 related is established in a proband with suggestive findings and one of the following identified on molecular genetic testing (see Table 1):

• A <50-kb to >9-Mb heterozygous deletion at chromosome 22q13.3 with involvement of at least part of SHANK3
• A heterozygous pathogenic (or likely pathogenic) variant in SHANK3
• A chromosomal rearrangement with breakpoints disrupting SHANK3

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this GeneReview is understood to include likely pathogenic variants. (2) Identification of a heterozygous SHANK3 variant of uncertain significance does not establish or rule out the diagnosis.

Molecular genetic testing approaches can include a combination of gene-targeted testing (chromosomal microarray, single gene testing, multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing).

Clinical Description

More than 600 individuals have been identified with pathogenic genetic alterations involving SHANK3 [Soorya et al 2013, Tabet et al 2017, De Rubeis et al 2018, Samogy-Costa et al 2019, Levy et al 2022, Nevado et al 2022, Schön et al 2023]. Some features of the condition appear to be due to heterozygous loss of SHANK3 alone, while other features may be seen primarily in those who have larger deletions of 22q13.3 that include SHANK3 and adjacent genes (see Genotype-Phenotype Correlations). The following description summarizes the phenotypic features associated with both molecular mechanisms. Clinical features associated with deletions of 22q13.3 that do NOT include SHANK3 are not included here (see Genetically Related Disorders).

Developmental delay (DD) and intellectual disability (ID). Most individuals with PMS-SHANK3 related experience delays in all developmental areas. Although the severity of the delay tends to vary with deletion size [Sarasua et al 2011, Zwanenburg et al 2016], individuals with the same size deletion may be vastly different in their degree of disability [Dhar et al 2010].

For motor skills, the average age of achievement is as follows:

• Rolling over: eight months
• Crawling: approximately 16 months
• Walking: approximately three years
  • Poor muscle tone, lack of balance, and decreased upper body strength contribute to the delay in walking.
  • Gait is typically broad based and unsteady.
  • Individuals may walk on their toes to achieve balance.

Speech delay. In general, individuals with smaller deletions or with SHANK3 pathogenic variants not involving adjacent genes have better speech and language development and better receptive language skills compared to expressive language skills [Tabet et al 2017, Manning et al 2021]. Infants typically babble at the appropriate age, and children may acquire a limited vocabulary; however, by approximately age four years many children have lost the ability to speak. Although speech remains impaired throughout life, individuals can learn to communicate with the aid of intensive speech therapy and communication training.

• In a study of 21 individuals with PMS-SHANK3 related with deletions varying between 41 kb and 8.3 Mb, 45% were nonverbal [Brignell et al 2021].
• Nevado et al [2022] reported absence of speech for 80%-100% of individuals with terminal 22q13 deletions spanning 5-6 Mb or more.
• Receptive communication skills are more advanced than expressive language skills, as evidenced by the ability of affected children to follow simple commands, demonstrate humor, and express emotions.

Overall development

• Developmental assessment using the Developmental Profile II (DPII) and the Scales of Independent Behavior-Revised – Full Scale (SIB-R) demonstrated that while all participants had moderate-to-profound intellectual disability, compared to most children with this level of impairment, those with PMS-SHANK3 related had less frequent and less severe problematic behaviors [Wilson et al 2003].
• Developmental delay with a maximum developmental age equivalent of three to 4.5 years and more pronounced delays in older individuals than in younger children as measured by the Bayley-II-NL scale of infant development (a trend referred to as "growing into deficit") was reported by one group [Zwanenburg et al 2016].
• Toilet training is difficult to achieve and requires extreme vigilance by parents and caregivers. Children may stay dry at night but become wet or soiled during the day because they are unable to communicate their needs.

Regression / loss of skills. The regression in PMS-SHANK3 related is distinct from the regression seen in autism spectrum disorder and Rett syndrome in that it occurs later in life and has a stronger impact on motor and self-help skills [Reierson et al 2017]. Loss of speech is most frequently reported, but loss of social interactions, purposeful hand movements, self-help skills, and walking have also been described. In a study of 42 individuals aged four to 48 years using the Autism Diagnostic Interview, Revised (ADI-R), parents reported regression in 43% of affected individuals with onset around age six years. About 40% of individuals recovered skills; time to recovery ranged from one month to 10 years [Reierson et al 2017]. More specifically, parents reported regression and loss of:

• Language in 33% at a mean age of three years;
• Motor skills in 50% at a mean age of four years;
• Self-help skills in 50% at a mean age of four years;
• Social engagement/responsiveness in 33% at a mean age of five years;
• Purposeful hand movement in 28% at a mean age of seven years;
• Constructive/imaginative play in 22% at a mean age of seven years.

No apparent cause for the regression has been found in a majority of individuals, although infection, changes in hormone status, and stressful life events may be possible triggers [Kohlenberg et al 2020] (see Decreased perception of pain below). Comorbidities or secondary diagnoses may also contribute to regression in affected individuals.

• Autoimmune dysfunction has been proposed as a trigger for regression, with Bey et al [2020] reporting a positive response to immune modulation therapy utilizing intravenous immunoglobulin infusions in four females suspected to have autoimmune encephalitis.
• Additionally, an affected female in her mid-twenties presented with regression and dystonic spastic hemiparesis; she was subsequently diagnosed with concomitant multiple sclerosis that responded to steroid treatment [Jesse et al 2021].

Neurobehavioral/psychiatric manifestations. Individuals with PMS-SHANK3 related are at increased risk of developing severe neuropsychiatric illnesses in adolescence or early adulthood, although many of the reports describing psychiatric manifestations are based on parental observation; therefore, direct in-person assessment to determine a more accurate understanding of behavior in PMS has been recommended [Kohlenberg et al 2020, Landlust et al 2022]. Between one half and three quarters of affected individuals meet clinical diagnostic criteria for autism spectrum disorder. Others may exhibit one or more autistic features but do not meet the strict diagnostic criteria for autism spectrum disorder. Specific findings may include poor eye contact, stereotypic movements, persistent deficits in social communication (see Speech delay above), self-stimulation, and restricted, repetitive patterns of behavior, interests, or activities [Soorya et al 2013, Oberman et al 2015]. Other abnormal behaviors may include:

• Habitual chewing or mouthing
• Tooth grinding
• Agitation in unfamiliar, noisy, or crowded surroundings
• Aggressive behavior, including biting, hair pulling, or pinching, which is seen in approximately 25% of affected individuals
  • The behavior is typically displayed when individuals are frustrated and may indicate that they are in pain but cannot express themselves appropriately.
  • The behavior is not self-injurious but is often directed at the parent or caregiver.
• Catatonia, which may present after neurologic regression, psychosis, and loss of skills [Kolevzon et al 2019]. Catatonia occurs more frequently in females than in males.
• Schizophrenia and/or bipolar disorder [Levy et al 2022]
  • Bipolar disorder is reported more commonly in individuals with small deletions and SHANK3 sequence variants (16%) than in individuals with larger deletions (3%).
  • Prevalence of schizophrenia or schizoaffective disorder has been estimated at around 5%.

Decreased perception of pain. As a result of decreased perception of pain and lack of expressive communication skills, affected individuals may suffer cuts, scrapes, or even broken bones without indicating that they are in pain. They may suffer ear infections, gastroesophageal reflux, increased intracranial pressure, or other painful medical conditions without indicating discomfort. Caregivers should have a high index of suspicion for a possibly painful organic process when affected individuals display new-onset behavioral issues or aggressive behaviors.

Hypotonia. Newborns with PMS-SHANK3 related have generalized hypotonia that may be associated with weak cry, poor head control, and feeding difficulties leading to slow growth [Frank 2021]. Neonatal hypotonia in individuals with PMS-SHANK3 related may evolve differently with age. In some individuals hypotonia persists throughout adulthood, in others it resolves, and in others it may be replaced by dystonia or, more rarely, hypertonia.

Epilepsy. The lifetime prevalence of seizures is >60% with a wide range in age of onset [de Coo et al 2023]. Other studies have reported an incidence of seizures between 25% and 50%, many of which are febrile and do not require treatment. Both EEG findings and seizure type are highly variable, including grand mal, focal, and absence seizures, and do not correlate with the onset of regression.

Neuroimaging. MRI studies reveal a variety of abnormalities, including delayed myelination, agenesis of the corpus callosum, ventriculomegaly, white matter atrophy and other white matter abnormalities, generous extracerebral space, large cisterna magna, and arachnoid cyst [Soorya et al 2013, Tabet et al 2017, Xu et al 2020].

• Volumetric MRI in 11 affected children demonstrated decreased volumes of the striatum and left pallidum and reduced volume of the cerebellar vermis, which was associated with increased repetitive behavior severity [Srivastava et al 2019].
• Volumetric investigations have also shown global atrophy of the white matter correlated with structural connectivity losses suggestive of accelerated central nervous system aging [Jesse et al 2023].
• In individuals with a ring chromosome 22, MRI studies may show NF2-related schwannomatosis (NF2)-related changes, including acoustic neuromas, vestibular schwannomas, meningiomas, and/or ependymomas [Srivastava et al 2023] (see Ring chromosome 22 below).

Sleep disturbances. Up to 90% of individuals with PMS-SHANK3 related were reported by caregivers to have a sleep disturbance, although only 22% had a formal sleep evaluation [Bro et al 2017]. Sleep problems are a major disruptor of family health and functioning, negatively impacting the well-being of caregivers, with more than 40% of caregivers averaging six or fewer hours of sleep per night [Bro et al 2017, San José Cáceres et al 2023].

• The prevalence of sleep disturbances increases with age, with a rate of 53% in toddlers to 90% in adults [Moffitt et al 2022].
• The primary sleep disturbances include difficulty falling asleep, frequent nighttime awakenings, difficulty returning to sleep after a nighttime awakening event, and hypersomnia and parasomnias, including enuresis, night terrors, sleepwalking, and sleep apnea.
• Sleep disturbances are more prevalent in individuals with a SHANK3 pathogenic variant compared to individuals with 22q13.3 deletions that include SHANK3 and adjacent genes [Soorya et al 2013, De Rubeis et al 2018, Nevado et al 2022, Landlust et al 2023, Moffitt et al 2023].
• Distinct metabolic profiles indicated a minor disruption of the major metabolic pathways involved in energy production in those with sleep disturbances [Moffitt et al 2023].

Eyes/vision. The most common ocular abnormality is strabismus, which is seen in fewer than one quarter of affected individuals [Srivastava et al 2023]. Ptosis has been reported in anywhere from 3% to 57% of affected individuals but is not severe enough to obstruct vision. Most affected individuals have normal vision, although hyperopia and myopia have been reported. The following features have been observed in some affected individuals:

• Cortical visual impairment, characterized by extensive use of peripheral vision. Blindness and optic nerve hypoplasia have been associated with cortical visual impairment [Phelan et al 2010].
• Difficulty in processing cluttered images
• Problems with depth perception
• A tendency to look away from objects before reaching for them

Hearing. True hearing loss is reported in about 9% of affected individuals [Samogy-Costa et al 2019, Xu et al 2020, Schön et al 2023], although delayed response to verbal cues, difficulty discerning spoken words from background noise, and frequent ear infections may contribute to the perception that hearing is impaired. The risk of hearing loss is increased in individuals with ring chromosome 22 due to association with NF2 (see Ring chromosome 22 below).

Renal. Urinary tract infections and urinary incontinence are frequent, although incontinence may be no more common in PMS-SHANK3 related than in other neurodevelopmental disorders [Srivastava et al 2023]. The frequency of renal abnormalities ranges from 10%-40% in individuals with deletions greater than 1 Mb but is not reported in individuals with SHANK3 pathogenic sequence variants or small deletions involving only SHANK3 [De Rubeis et al 2018, Nevado et al 2022, McCoy et al 2024]. Renal anomalies include:

• Cystic kidneys
• Renal agenesis or dysplastic kidneys
• Hydronephrosis or pyelectasis
• Vesicoureteral reflux
• Horseshoe kidney

Gastrointestinal. Gastroesophageal reflux is seen in approximately 24% of affected individuals [Schön et al 2023], whereas constipation and diarrhea are reported in about 28% [Soorya et al 2013, Tabet et al 2017, De Rubeis et al 2018, Samogy-Costa et al 2019].

• Precautions must be taken to avoid dehydration and nutritional deficits, including zinc deficiency.
• Regression and severe psychiatric disorders may accompany worsening gastrointestinal issues [Srivastava et al 2023].
• Two individuals with PMS-SHANK3 related developed autoimmune hepatitis, both requiring liver transplantation for fulminant hepatic failure [Tufano et al 2009, Bartsch et al 2010].
• Two affected males with abnormal liver function developed hepatic steatosis [Boccuto et al 2018].

Growth. Intrauterine growth in PMS-SHANK3 related is appropriate for gestational age; the mean gestational age is 38.2 weeks. In most affected individuals, postnatal growth is normal. Overall, 16% of individuals have macrocephaly and 15% have microcephaly [Schön et al 2023]. About 10% are below the 3rd centile in length/height, while 20% are above the 95th centile [Schön et al 2023].

• Weight is not increased, giving some of the children a tall, thin appearance.
• Whereas children may have increased height for age, adults tend to fall within the normal range for height.
• Most adults are also within the normal range for weight, although inactivity and overeating (possibly a manifestation of compulsive mouthing) result in increased weight gain in approximately 10% of affected individuals.

Endocrinologic

• Hypothyroidism occurs in 3%-6% of affected individuals [Soorya et al 2013, Sarasua et al 2014a]. Symptoms include lethargy, loss of interest, weight gain, and decline in skills and typically manifest in teens or young adults (see Management).
• Precocious puberty has been reported in 13% of affected individuals, occurring more frequently in females than in males [Sarasua et al 2014a, Samogy-Costa et al 2019]. Neuropsychiatric symptoms may worsen during puberty, especially in females [Kolevzon et al 2019].

Dental. Malocclusion is the most frequently encountered dental problem. Poor muscle tone, incessant chewing, tooth grinding, and tongue thrusting may contribute to malocclusion. Malocclusion may be accompanied by drooling and difficulty swallowing and may contribute to difficulties in verbalization.

Lymphedema and recurrent cellulitis have been observed in approximately 10% of individuals, typically becoming problematic during the teen and adult years.

• The majority of cases are found in individuals with 22q13 deletions, occurring in only about 1% of individuals with intragenic SHANK3 pathogenetic variants [Srivastava et al 2023].
• Progressive lymphedema leading to pleural effusions has been reported in a female with PMS-SHANK3 related resulting from a ring chromosome r(22)(p11.2q12.3) [McGaughran et al 2010].
• CELSR1 has been proposed as the major candidate gene for lymphedema [Smith et al 2023].

Dysmorphic features / craniofacial. Among the most common and striking craniofacial features are long eyelashes, pointed chin, broad nose, wide nasal bridge, bulbous nose, malocclusion, and periorbital fullness. Other physical findings include large, fleshy hands and abnormal ears.

• The characteristics may change over time, particularly if the individual is on anticonvulsants that tend to coarsen the features.
• Adults have a more prominent, square jaw and less bulbous-appearing nose.
• Other less common features include dolichocephaly, strabismus, and abnormal toenails that may be dysplastic, thin, and flaky in the neonate and toddler but may harden and become ingrown as the individual ages.
• Fingernails are usually normal but occasionally may be thin and dysplastic.

Cardiac. Various congenital heart defects have been reported, including aortic regurgitation, patent ductus arteriosus, total anomalous venous return, atrial septal defect, and tricuspid valve regurgitation; estimates of the incidence of congenital heart defects range from 3% to 25% [Phelan & McDermid 2012, Soorya et al 2013, Kolevzon et al 2014a, Schön et al 2023].

Malignancy. An atypical teratoid/rhabdoid tumor (ATRT) has been reported in at least four affected individuals, three of whom had a ring chromosome 22, whereas the other had a 7.2-Mb deletion of 22q13 [Korones et al 1999, Sathyamoorthi et al 2009, Cho et al 2014, Byers et al 2017]. At present, there are no consensus cancer screening recommendations for ATRT in PMS-SHANK3 related (see also Ring chromosome 22 below).

Adulthood. Longitudinal data are insufficient to determine life expectancy. However, life-threatening or life-limiting cardiac, pulmonary, or other organ system defects are not common. The paucity of older adults with PMS-SHANK3 related reflects the difficulty in establishing the diagnosis prior to the advent of high-resolution chromosome analysis, FISH, and CMA.

In older individuals, behavioral problems tend to subside, developmental abilities improve, and some features such as large or fleshy hands, full or puffy eyelids, hypotonia, lax ligaments, and hyperextensible joints are reported as less frequent [Sarasua et al 2014a]. Late-onset seizures, unexplained weight loss, and loss of motor skills may occur in older individuals, adversely affecting quality of life and life expectancy. In general, individuals with intellectual impairment tend to have a short life span compared to the general population due to lack of exercise, poor diet, decreased access to health care, poor hygiene, etc.

Ring chromosome 22. Individuals with PMS-SHANK3 related as a result of a ring chromosome 22 have a specific risk of developing NF2-related schwannomatosis (NF2). Ziats et al [2020] reported a 16% prevalence of NF2 among 44 individuals with PMS-SHANK3 related and a ring chromosome 22.

NF2 (pathogenic variants in which cause NF2) is at 22q12.2 adjacent to the PMS-SHANK3 related deletion region. The risk for NF2 is due to the instability of ring chromosomes during mitosis and follows a two-hit model. The first hit is the loss of the ring chromosome 22 during mitosis, making a cell hemizygous for chromosome 22. The second hit is a somatic mutation of the remaining NF2 allele [Zirn et al 2012].

Children with a ring chromosome 22 should be monitored for NF2 in the same manner as if they had an affected parent. This includes baseline and annual ocular, dermal, and neurologic examinations between ages two and ten years with annual audiology screening and brain MRI every two years after age ten years [Lyons-Warren et al 2017].

Mosaic 22q13.3 deletion. Mosaic 22q13.3 deletion has been reported on occasion. The level of mosaicism for 22q13.3 deletion varies among affected individuals. Note: Because most testing is performed on blood samples, because the level of mosaicism in blood can change over time, and because the level of mosaicism in the blood is not representative of the level of mosaicism in the brain and other tissues, the level of mosaicism that is sufficient for expression of the major features of PMS-SHANK3 related is unknown.

Mosaicism is particularly common in 22q13 deletion associated with ring chromosomes because of the instability of the ring structure during cell division. Low-level mosaicism for monosomy 22 or dicentric ring chromosome 22 should be interpreted with caution, as either abnormality might represent an in vitro artifact. Despite this, one adult with characteristic features of PMS-SHANK3 related showed ring chromosome 22 in only 8% of blood cells [K Phelan, unpublished data].

Genotype-Phenotype Correlations

Pathogenic variants of SHANK3 without involvement of other adjacent genes

• Common features of individuals who have pathogenic variants involving solely SHANK3 include hypotonia, intellectual disability, autism spectrum disorder, epilepsy, high pain tolerance, sleep disturbances, abnormal brain MRI, gastroesophageal reflux, and certain dysmorphic features [Soorya et al 2013, De Rubeis et al 2018, Samogy-Costa et al 2019, Xu et al 2020, Levy et al 2022, Nevado et al 2022].
• When compared to individuals with larger deletions involving adjacent genes, those with solely SHANK3 pathogenic variants or small 22q13.33 deletions (including only SHANK3 plus ARSA and/or ACR and RABL2B) often have fewer delayed developmental milestones and higher cognitive ability [Levy et al 2022] and lack a distinctive facial appearance [Nevado et al 2022].

Larger deletions of 22q13.3 that include SHANK3 and adjacent genes

• In general, there is a statistically significant correlation between larger deletion sizes and a more significant degree of developmental delay and hypotonia [Wilson et al 2003].
• Larger deletions are also associated with an increased likelihood of dysmorphic features and medical comorbidities. Individuals with larger deletions are more likely to have renal/urinary tract anomalies and lymphedema compared to those with smaller deletions or pathogenic variants involving SHANK3 alone [Srivastava et al 2023].
• Sarasua et al [2014a] and Sarasua et al [2014b] confirmed the trend correlating larger deletions with more severe clinical presentations and smaller deletions with autism spectrum disorder, and also identified specific loci and candidate genes within the 22q13.2-q13.32 region associated with certain features of PMS-SHANK3 related: severity of speech/language delay, neonatal hypotonia, delayed age at walking, hair-pulling behaviors, male genital anomalies, dysplastic toenails, large/fleshy hands, macrocephaly, short and tall stature, facial asymmetry, and atypical reflexes.
• Although there is a tendency for larger deletions to be correlated with more severe intellectual and physical phenotypes than smaller deletions, the correlation is not 100%; individuals with the same size deletion may vary significantly in their presentation [Dhar et al 2010].

Penetrance

Although it was previously thought that features of PMS-SHANK3 related were apparent in all individuals with non-mosaic 22q13.3 deletions that include SHANK3, evidence suggests that small deletions involving SHANK3 may be associated with reduced penetrance and variable expressivity [Tabet et al 2017]. Pathogenic variants in SHANK3 have been associated with apparently non-syndromic autism and schizophrenia. In addition, classic manifestations have been seen in individuals with as low as 8% mosaicism for the 22q13.3 deletion in peripheral blood [K Phelan, unpublished data].

Nomenclature

Previously referred to as 22q13.3 deletion syndrome to reflect the chromosomal basis of this deletion, the condition was subsequently referred to as Phelan-McDermid syndrome (PMS).

Although the majority of individuals with PMS have a genetic alternation that involves SHANK3, disruption of SHANK3 is not identified in all affected individuals. To reflect this, a dyadic classification system was proposed in which the designation "PMS-SHANK3 related" refers to individuals with PMS and a genetic alteration involving SHANK3 and the designation "PMS-SHANK3 unrelated" refers to individuals with PMS who do not have a genetic alteration involving SHANK3 [Phelan et al 2022].

Prevalence

The prevalence of PMS-SHANK3 related is unknown. More than 1,500 individuals are registered with the Phelan-McDermid Syndrome Foundation (Venice, Florida, 2017), although some registered individuals may have PMS-SHANK3 unrelated (see Nomenclature). This does not represent the total number of affected individuals, as not all families worldwide register with the foundation.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with PMS-SHANK3 related, the evaluations summarized in Table 4 (if not performed as part of the evaluation that led to diagnosis) are recommended.

It is not intuitive that individuals with a deletion of chromosome 22q13 might be at risk for NF2-related schwannomatosis, but those with a ring chromosome 22 are at significant risk.

Treatment of Manifestations

There is no cure for PMS-SHANK3 related. Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see Table 6). For those individuals with PMS-SHANK3 related who have a ring chromosome 22, see NF2-related schwannomatosis for further management guidelines.

Surveillance

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Table 7 are recommended.

Agents/Circumstances to Avoid

Exposure to high temperatures and extended periods in the sun should be avoided because individuals with PMS-SHANK3 related have reduced perspiration and tend to overheat easily.

Considering that individuals with PMS-SHANK3 related may present with decreased perception of pain, close surveillance is recommended to prevent exposure to dangers including sources of excessive heat or cold, sharp objects, or clothes/shoes that may be too tight and cause skin lesions.

In affected individuals with a ring chromosome 22, radiotherapy for NF2-associated tumors should be avoided in children when malignancy risks are likely to be substantially higher [Evans et al 2006].

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Lithium. Lithium has been used to treat behavioral issues in three affected individuals. Serret et al [2015] reported two adolescents with PMS-SHANK3 related and autism spectrum disorder (ASD) resulting from pathogenic variants in SHANK3. The individuals presented with catatonia, regression, and behavioral issues after stressful events. Lithium reversed the regression and improved the behavioral issues, and the individuals returned to their pre-catatonia level of functioning. Egger et al [2017] described an adult with a SHANK3 pathogenic variant who had an atypical bipolar mood disorder that was stabilized by lithium treatment.

Insulin-like growth factor-1 / growth hormone

• Insulin-like growth factor 1 (IGF-1) was investigated in a placebo-controlled, double-blind crossover study involving nine children with PMS-SHANK3 related [Kolevzon et al 2014b]. Results indicated a significant improvement in social impairment and restrictive behavior during the IGF-1 phase compared to the placebo phase. Following these preliminary findings, a clinical trial (NCT01525901) showed that IGF-1 improves sensory reactivity symptoms, repetitive behaviors, and hyperactivity in children with PMS-SHANK3 related [Kolevzon et al 2022]. Nonetheless, the trial was conducted on a very small cohort (ten children with PMS- SHANK3 related, aged 5-9 years), and larger studies are required to confirm the validity of IGF-1 therapy.
• Several studies have investigated the effects of growth hormone (GH), which induces the expression of IGF-1, activates similar target pathways, and is significantly less expensive. Preliminary results revealed improvement in social withdrawal, hyperactivity, and sensory symptoms and led to a clinical trial (NCT04003207) but need to be validated on larger cohorts [Xie et al 2021, Li et al 2022, Sethuram et al 2022,].

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for information on clinical studies for a wide range of diseases and conditions.

Mode of Inheritance

Phelan-McDermid syndrome-SHANK3 related (PMS-SHANK3 related) is an autosomal dominant disorder most often caused by a de novo genetic alteration (i.e., a deletion at chromosome 22q13.3 involving at least part of SHANK3, a pathogenic variant in SHANK3, or, rarely, a chromosomal rearrangement with breakpoints disrupting SHANK3).

Recurrence risk in family members depends on the genetic mechanism underlying PMS-SHANK3 related in the proband and the genetic status of the parents of the proband.

22q13.3 Deletion – Risk to Family Members

Parents of a proband

• Most probands with PMS-SHANK3 related caused by a terminal or interstitial deletion of 22q13.3 have a de novo deletion.
• Some probands with a 22q13 deletion have the deletion as the result of:
  • An unbalanced structural rearrangement that includes 22q13 (e.g., a reciprocal translocation, insertional translocation, or inversion). About half of these individuals have a parent who is a carrier of a balanced translocation [Koza et al 2023].
  • Ring chromosome 22.
    Note: Karyotype screening of the proband for a ring chromosome 22 must be done if a terminal 22q13.3 deletion is detected by chromosomal microarray analysis (CMA). Individuals with PMS-SHANK3 related as a result of a ring chromosome 22 have a specific risk of developing NF2-related schwannomatosis (see Clinical Description, Ring chromosome 22).
• Rarely, a proband with a 22q13.3 deletion inherited a genetic alteration from a heterozygous or mosaic parent.
  • Mild expression of PMS-SHANK3 related was described in the heterozygous mother of a child with a maternally inherited deletion [Wilson et al 2008].
  • Maternal mosaicism has been described in several families:
    • Recurrence in two affected brothers of a 3.5-Mb deletion of maternal origin (testing of parental peripheral blood did not detect a balanced chromosomal rearrangement or low-level mosaicism, leading to the suspicion of maternal germline mosaicism) [Tabolacci et al 2005].
    • An asymptomatic mosaic mother with a 22q13 deletion resulting from a structural chromosomal anomaly transmitted the deletion to two affected children (the derivative chromosome 22 was observed in 6% of maternal peripheral blood cells) [K Phelan, unpublished data].
    • An asymptomatic mother with mosaicism for a ring chromosome 22 (in fewer than 2% of peripheral blood cells) transmitted the ring chromosome 22 to her affected child [K Phelan, unpublished data].
• Evaluation of the parents by genomic testing that will detect the 22q13.3 deletion identified in the proband is recommended. In addition, karyotype of the parents is recommended to determine if a parent has a predisposing chromosomal anomaly.
• If the 22q13 deletion identified in the proband is not identified in either parent, a chromosome anomaly is not detected in either parent, and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
  • The proband has a de novo deletion.
  • The proband inherited a deletion from a parent with germline (or somatic and germline) mosaicism [Koza et al 2023].* Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a genetic alteration that is present in the germ (gonadal) cells only.
    * Although the probability of parental mosaicism for 22q13.3 deletion is low, it is important that parental mosaicism be considered when parental studies are performed (see Clinical Description, Mosaic 22q13.3 deletion).
• The family history of some individuals diagnosed with PMS-SHANK3 related may appear to be negative because of failure to recognize the disorder in family members or the absence of diagnostic testing in nonviable conceptuses. Therefore, an apparently negative family history cannot be confirmed without genomic testing and karyotype analysis of the parents of the proband.

Sibs of a proband. The risk to sibs of a proband with a 22q13.3 deletion depends on the genetic status of the parents:

• If a parent has a non-mosaic 22q13.3 deletion, the risk to each sib of inheriting the deletion is 50% [Koza et al 2023]. If a parent has a mosaic 22q13.3 deletion, the risk to each sib of inheriting the deletion is increased but impossible to quantify because the level of mosaicism in gonadal tissue is unknown.
• If a parent has a balanced chromosomal rearrangement, a ring chromosome 22, or other complex chromosomal rearrangement, the risk to sibs is increased and depends on the specific chromosomal rearrangement and the possibility of other variables.
• It is not possible to reliably predict the phenotype in a sib who inherits a familial genetic alteration (see Genotype-Phenotype Correlations).
• If the proband represents a simplex case (i.e., the only affected family member) and neither parent has a detected 22q13.3 deletion or a chromosomal rearrangement, the recurrence risk to sibs of PMS-SHANK3 related is <2% because of the possibility of parental germline mosaicism [Koza et al 2023].

Offspring of a proband. Offspring of an individual with a non-mosaic 22q13.3 deletion have a 50% chance of inheriting the deletion [Terrone et al 2017].

Other family members. The risk to other family members depends on the genetic status of the proband's parents: if a parent has a balanced chromosomal rearrangement or deletion, the parent's family members may be at risk and should be offered karyotype analysis.

Intragenic SHANK3 Pathogenic Variant – Risk to Family Members

Parents of a proband

• Most probands with PMS-SHANK3 related caused by an intragenic SHANK3 pathogenic variant have a de novo pathogenic variant.
• Rarely, a proband with an intragenic SHANK3 pathogenic variant inherited the pathogenic variant from a heterozygous or mosaic parent.
  • Transmission of an intragenic SHANK3 deletion from a heterozygous mother without intellectual disability or autism spectrum disorder to five affected daughters was reported in one family [Tabet et al 2017]. (Of note, the absence of intellectual disability and autism spectrum disorder in the heterozygous mother suggests that small deletions involving SHANK3 may be associated with reduced penetrance and variable expressivity.)
  • The frequency of parental mosaicism for a SHANK3 pathogenic variant was 3.7% in one study [Koza et al 2023].
• Molecular genetic testing is recommended for the parents of the proband to assess their genetic status and inform recurrence risk counseling.
• If the SHANK3 pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
  • The proband has a de novo pathogenic variant.
  • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.
• The family history of some individuals diagnosed with PMS-SHANK3 related may appear to be negative because of failure to recognize the disorder in family members or reduced penetrance. Therefore, an apparently negative family history cannot be confirmed unless molecular genetic testing has demonstrated that neither parent is heterozygous for the pathogenic variant identified in the proband.

Sibs of a proband. The risk to the sibs of the proband depends on the genetic status of the proband's parents:

• If a parent of the proband is affected and/or known to have an intragenic SHANK3 pathogenic variant, the risk to the sibs is 50%; intrafamilial clinical variability has been reported [Tabet et al 2017].
• If the SHANK3 pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be <2% because of the possibility of parental germline mosaicism [Koza et al 2023].
• If the parents have not been tested for the SHANK3 pathogenic variant but are clinically unaffected, the risk to the sibs appears to be low. However, the sibs of a proband with clinically unaffected parents are still at increased risk for inheriting the SHANK3 pathogenic variant because of the possibility of parental germline mosaicism and the possibility of reduced penetrance and/or variable expressivity in a heterozygous parent [Tabet et al 2017].

Offspring of a proband. Individuals with a SHANK3 pathogenic variant have a 50% chance of transmitting the pathogenic variant to each child.

Related Genetic Counseling Issues

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are at risk of having a child with PMS-SHANK3 related. Note: If a parent is known to have a balanced chromosome rearrangement, genetic counseling should also address reproductive risks associated with balanced chromosome rearrangements.

Prenatal Testing and Preimplantation Genetic Testing

Once a 22q13.3 deletion involving SHANK3 or a SHANK3 intragenic pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Prenatal testing to detect the genetic alteration identified in the proband may be offered in the following instances:

• The parents do not have a SHANK3 pathogenic variant, 22q13.3 deletion, or balanced chromosomal rearrangement but have had an affected child. In this instance, the recurrence risk associated with the possibility of parental germline mosaicism or other predisposing genetic mechanisms is <2%.
• A parent has a balanced chromosomal rearrangement that resulted in a previous child with a 22q13.3 deletion. Note: Most unbalanced chromosomal rearrangements can be detected by CMA. Conventional cytogenetic analysis can be considered to exclude rare chromosomal rearrangements (such as translocations) that involve SHANK3. In all families, genetic counseling is necessary to determine the priorities of the parents.

Note: Prenatal test results cannot reliably predict the phenotype.

Differences in perspective regarding the use of prenatal testing may exist among medical professionals and within families. While most centers would consider the use of prenatal testing to be a personal decision, a discussion of these issues may be helpful.

Molecular Pathogenesis

The size of the 22q13.3 deletion in Phelan-McDermid syndrome-SHANK3 related (PMS-SHANK3 related) ranges from <50 kb to >9 Mb. The majority of terminal deletions of 22q13.3 (69%-74%) occur on the paternal chromosome 22 [Luciani et al 2003, Wilson et al 2003]. The gene included in the critical region is SHANK3, near the q terminus on chromosome 22. SHANK3 (previously known as PROSAP2) is completely or partially deleted in virtually all cases; rarely, it is disrupted by an apparently balanced translocation [Bonaglia et al 2001].

The product of the main mRNA isoform of SHANK3 is composed of 1,730 amino acids and belongs to a family of Shank proteins that interact with receptors of the postsynaptic membrane. These multidomain proteins are important scaffolding molecules in the postsynaptic density (PSD) and function to receive and integrate synaptic signals and transduce them into postsynaptic cells. In addition to their role in the assembly of the PSD during synaptogenesis, the Shank proteins may play a role in synaptic plasticity and in the regulation of dendritic spine morphology [Boeckers et al 2002]. Loss-of-function pathogenic variants or chromosome rearrangements encompassing or disrupting SHANK3 cause haploinsufficiency of the gene, leading to destabilization of the PSD due to lack of Shank3. In addition, pathogenic missense variants supposedly affecting the interaction of Shank3 with other PSD proteins result in a destabilizing effect. Molecular characterization of terminal deletions in three unrelated individuals with PMS-SHANK3 related identified the same 15-base pair repeat unit in the D22S167 sequence variant between exons 8 and 9 as a recurrent breakpoint [Wong et al 1997, Anderlid et al 2002, Bonaglia et al 2006].

In addition to deletion/disruption of SHANK3, deletion/disruption of other nearby genes as a cause of Phelan-McDermid syndrome seems possible. MAPK8IP2 is approximately 70 kb proximal to SHANK3 and is deleted in the majority of individuals with Phelan-McDermid syndrome [Giza et al 2010]. Experiments in mice demonstrate that Mapk8ip2 is highly expressed in the brain and is an essential component of the postsynaptic density. Mice lacking Mapk8ip2 demonstrate cognitive deficits reminiscent of those in individuals with deletion of 22q13.

Mechanism of disease causation. Loss of function

Acknowledgments

The authors gratefully acknowledge the members of the Phelan-McDermid Syndrome Foundation for their participation in research and for their generous sharing of information.

Revision History

• 6 June 2024 (ma) Comprehensive update posted live
• 7 June 2018 (ha) Comprehensive update posted live
• 25 August 2011 (me) Comprehensive update posted live
• 25 October 2007 (me) Comprehensive update posted live
• 11 May 2005 (me) Review posted live
• 22 November 2004 (kp) Original submission

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