Updated consensus guidelines on the management of Phelan–McDermid syndrome

Phelan–McDermid syndrome (PMS) is a genetic condition caused by SHANK3 haploinsufficiency and characterized by a wide range of neurodevelopmental and systemic manifestations. The first practice parameters for assessment and monitoring in individuals with PMS were published in 2014; recently, knowledge about PMS has grown significantly based on data from longitudinal phenotyping studies and large‐scale genotype–phenotype investigations. The objective of these updated clinical management guidelines was to: (1) reflect the latest in knowledge in PMS and (2) provide guidance for clinicians, researchers, and the general community. A taskforce was established with clinical experts in PMS and representatives from the parent community. Experts joined subgroups based on their areas of specialty, including genetics, neurology, neurodevelopment, gastroenterology, primary care, physiatry, nephrology, endocrinology, cardiology, gynecology, and dentistry. Taskforce members convened regularly between 2021 and 2022 and produced specialty‐specific guidelines based on iterative feedback and discussion. Taskforce leaders then established consensus within their respective specialty group and harmonized the guidelines. The knowledge gained over the past decade allows for improved guidelines to assess and monitor individuals with PMS. Since there is limited evidence specific to PMS, intervention mostly follows general guidelines for treating individuals with developmental disorders. Significant evidence has been amassed to guide the management of comorbid neuropsychiatric conditions in PMS, albeit mainly from caregiver report and the experience of clinical experts. These updated consensus guidelines on the management of PMS represent an advance for the field and will improve care in the community. Several areas for future research are also highlighted and will contribute to subsequent updates with more refined and specific recommendations as new knowledge accumulates.

knowledge gained over the past decade allows for improved guidelines to assess and monitor individuals with PMS. Since there is limited evidence specific to PMS, intervention mostly follows general guidelines for treating individuals with developmental disorders. Significant evidence has been amassed to guide the management of comorbid neuropsychiatric conditions in PMS, albeit mainly from caregiver report and the experience of clinical experts. These updated consensus guidelines on the management of PMS represent an advance for the field and will improve care in the community. Several areas for future research are also highlighted and will contribute to subsequent updates with more refined and specific recommendations as new knowledge accumulates.
Current guidelines for evaluating and monitoring PMS have existed since 2014 and established recommendations pertinent to multiple medical specialties. The main basis for these recommendations was 13 published case series describing close to 600 affected individuals (Kolevzon, Angarita, et al., 2014).
More recently, knowledge surrounding PMS has grown significantly, and there is now data from randomized controlled trials (Fastman et al., 2021;Kolevzon et al., 2022;Zwanenburg, Bocca, et al., 2016), large-scale genotypephenotype investigations Nevado et al., 2022;Sarasua et al., 2014), and neurobehavioral phenotyping studies (Gergoudis et al., 2020;Srivastava et al., 2021). The Developmental Synaptopathies Consortium (DSC) is a research collaboration of medical centers throughout the United States focused on three rare genetic causes of ASD and ID including PMS that launched in 2014.
One of its projects is a multisite, prospective, longitudinal, observational cohort study evaluating the genotype, phenotype, and natural history of PMS (ClinicalTrial.gov identifier NCT02461420).
This additional knowledge has necessitated an update to clinical management guidelines for PMS. To accomplish this goal, we established a taskforce of PMS clinical experts and representatives from the parent community. Our primary objective was to generate updated recommendations for the clinical management of PMS which (1) reflect the latest in knowledge about the disorder and (2) provide guidance for clinicians, researchers, and the general community.
As part of this taskforce, experts joined one or more of the following subgroups based on their areas of specialty: genetics, neurology, neurodevelopment (including psychiatry, psychology, speech and language pathology), gastroenterology, primary care, physiatry, nephrology, endocrinology, cardiology, gynecology, and dentistry. The task force members represented more than 20 different academic institutions from the United States, Europe, and South America; encompassed diverse ethnic backgrounds; and included males/ females. Importantly, a parent/caregiver from the PMS community also joined each sub-group to ensure adequate representation from the family perspective.
Members of each subgroup convened regularly between 2021 and 2022 and produced specialty-specific guidelines based on iterative feedback and discussion. The taskforce leaders then established consensus within their respective specialty group and harmonized the guidelines. Summaries of recommendations for each specialty are presented in Tables 1-12. Definitions for some genetic terms used in this article are listed in Table 13.
Regarding nomenclature, a recent proposal has suggested that individuals with PMS in the setting of SHANK3 haploinsufficiency receive the label of "PMS-SHANK3 related," in contrast to individuals with interstitial deletions of Chromosome 22 without involvement of SHANK3, or "PMS-SHANK3 unrelated" . The guidelines presented here are based on data about individuals who have deletions that include SHANK3 or SHANK3 sequence variants because in general, published literature and research efforts to date have defined PMS based on SHANK3 haploinsufficiency (OMIM no. 606232). We have therefore focused our efforts on consolidating the evidence from the vast amount of studies which indicate that SHANK3 is the critical gene in PMS (Bonaglia et al., 2001(Bonaglia et al., , 2006(Bonaglia et al., , 2011Durand et al., 2007) and that de novo sequence variants in SHANK3 have been identified in cohorts ascertained for ASD and ID (Boccuto et al., 2013;De Rubeis et al., 2014;Durand et al., 2007;Fu et al., 2022;Gauthier et al., 2009;Gong et al., 2012;Hamdan et al., 2011;Leblond et al., 2014;Lelieveld et al., 2016;Moessner et al., 2007;O'Roak et al., 2014;Satterstrom et al., 2020;Yuen et al., 2017).

| Genotype-phenotype relationships
Haploinsufficiency of SHANK3 causes ID, ASD, hypotonia, motor impairment, epilepsy, increased pain tolerance, and GI problems in PMS (De Rubeis et al., 2018). Some features observed in PMS due to 22q13.3 deletions may be unrelated to monoallelic loss of SHANK3.
Genotype-phenotype studies have elucidated several relationships in PMS. A large genotype-phenotype analysis of 170 individuals with PMS stratified variants into three categories: Class I deletions (deletions which include SHANK3 only or SHANK3 with ARSA and/or ACR and RABL2B, with loss of a single copy of the latter three genes not expected to contribute to the phenotype); Class II deletions (all other deletions); and SHANK3 sequence variants. Those with Class I deletions or sequence variants had milder language, cognitive, and motor deficits-but more frequent skill regressions-versus those with Class II deletions. In addition, the former group had a greater risk for psychiatric diagnoses, such as bipolar disorder, depression, and schizophrenia . Alternatively, a smaller study in a cohort of 22 individuals with PMS showed significant methylation differences compared with controls in those with deletions of at least 1 Mb, but not in the group with smaller deletions (Schenkel et al., 2021).
There is a correlation between larger deletion size and increased neurodevelopmental severity in PMS (Nevado et al., 2022;Sarasua et al., 2014;Soorya et al., 2013), further indicating that genes proximal to SHANK3 contribute to phenotypic severity in individuals with larger deletions. TCF20, a gene in the deleted interval in some patients, is implicated in an autosomal dominant neurodevelopmental disorder, characterized by variable dysmorphic features, ID, ASD, hypotonia, movement disorders, sleep disturbances, seizures, and structural brain abnormalities (Torti et al., 2019). TCF20 is located 8.7 Mb from the 22q telomere, thus contributing to the phenotype in only the largest 22q13 terminal deletions.

Diagnostic testing
Genetic evaluation for PMS should include evaluation for both 22q13 deletions and SHANK3 sequence variants. Deletions may be detected by CMA and many NGS-based methods. Some deletions may be smaller than the limit of detection for specific CMA or NGS assays. Depending on the specific test used to detect a deletion, additional testing may be indicated to characterize its extent.
SHANK3 sequence variants (including single nucleotide variants and small insertions and deletions) are typically assessed by NGS-based methods such as gene panels, exome sequencing, and genome sequencing. Rarely, a balanced rearrangement can disrupt SHANK3.
Balanced rearrangements affecting SHANK3 may be detectable by karyotype or some NGS-based methods. We recommend genetic counseling prior to genetic testing and concurrently with return of results. Following the diagnosis of PMS, referral to a clinical geneticist or other specialists familiar with the interdisciplinary management of the condition is recommended.
Identification of a deletion. The finding of a deletion of 22q13 can indicate the presence of an unbalanced chromosomal rearrangement such as a translocation or inversion. For example, a terminal deletion in conjunction with duplication of the terminal segment of another chromosome is consistent with an unbalanced reciprocal chromosome translocation. All patients with a terminal deletion should undergo testing by karyotype and fluorescence in situ hybridization (FISH) to assess for an unbalanced rearrangement. Following the identification of an unbalanced rearrangement in an individual with PMS, we recommend parental studies to assess its origin using FISH studies and/or karyotyping depending on the rearrangement identified in the patient.
The detection of a 22q13 terminal deletion may also indicate the presence of a ring chromosome 22, a circular structure formed when the distal long arm and the distal short arm of the chromosome truncate and join. Therefore, an additional rationale for karyotyping following the detection of a terminal deletion is to assess for the presence of a ring chromosome. Individuals with ring chromosome 22 are at increased risk of developing neurofibromatosis type 2 (NF2) due to mosaic aneuploidy of chromosome 22 followed by a somatic second hit in the NF2 gene (located at 22q12.2) that results in biallelic loss of function. We recommend that individuals with ring chromosome 22 undergo monitoring for complications of NF2 (provided in Sections 2.2 and 2.5).
Because patients with presymptomatic or early-stage MLD may be candidates for hematopoietic stem cell transplantation, some authors suggest MLD screening with urine sulfatides at the time of diagnosis of PMS associated with a deletion including ARSA (Mingbunjerdsuk et al., 2021).
Identification of a SHANK3 sequence variant. The majority of pathogenic SHANK3 sequence variants occur de novo. For individuals with a variant of uncertain significance (VUS; as defined in Richards et al., 2015), we recommend parental testing to determine inheritance status. The finding of a SHANK3 VUS inherited from a healthy, neurotypical parent argues against the pathogenicity of the variant. For individuals with pathogenic or likely pathogenic SHANK3 variants, we recommend parental testing to evaluate for the (rare) possibility of mosaicism or a mildly affected parent. While the likelihood of detecting mosaicism is low, if present, the risk of recurrence may increase up to 50%.

Recurrence risk counseling
We recommend genetic counseling for families in which PMS has been diagnosed. In this context, parental testing should be offered following the identification of a deletion including SHANK3 or a pathogenic SHANK3 variant. The recommended approach to parental testing and a summary of possible outcomes is shown in Figure 1. For interested families who are at increased risk of having future affected offspring, genetic counseling should include discussion of the option of prenatal testing and preimplantation genetic diagnosis.
Terminal deletions. For parents of individuals with terminal 22q13 deletions in isolation or in the context of a chromosomal rearrangement, we recommend karyotype and FISH testing to assess de novo status and the possibility of a predisposing rearrangement. Normal parental studies predict a low recurrence risk (empirically <1%, due to the possibility of gonadal mosaicism). In the rare case that a parent harbors a deletion, the recurrence risk in his/her offspring is predicted 50%. When parents carry a chromosomal rearrangement such as an T A B L E 1 Recommendations pertaining to genetic considerations in Phelan-McDermid syndrome (PMS). There are reports of four families with multiple affected siblings with SHANK3 variants, consistent with gonadal mosaicism in one of the parents (Durand et al., 2007;Gauthier et al., 2010;Nemirovsky et al., 2015;Nevado et al., 2022). Detection of a pathogenic SHANK3 variant in a mildly affected parent is possible due to variable expressivity (Tabet et al., 2017a). In this situation, the recurrence risk is 50%.

Cause of PMS Recommendations
Detection of a somatic mosaic pathogenic variant in a parent would confer a case-specific increased recurrence risk (Kankuri-Tammilehto et al., 2021).

Risk to children of affected individuals
To date, there are no reports in the literature of individuals with PMS having children. For an individual with PMS due to a 22q13 deletion or pathogenic SHANK3 variant, the estimated risk of having an affected child with each pregnancy is 50%, consistent with autosomal dominant inheritance.

Risk to children of siblings of affected individuals
In most cases, the risk of an unaffected sibling of an individual with PMS having a child with PMS is low and similar to the general population risk. In families with parents who are balanced chromosome rearrangement carriers, we recommend offering karyotype and FISH to siblings who are family planning.

| Neuroimaging abnormalities
There is a spectrum of brain magnetic resonance imaging (MRI) abnormalities associated with PMS. These findings are largely nonspecific, including white matter changes (specifically T2 hyperintensities of the deep white matter), ventriculomegaly, arachnoid cysts, and cerebral/ cerebellar atrophy (Holder & Quach, 2016;Srivastava et al., 2019).
Most of these findings are nonactionable, except for hydrocephalus, which is a rare occurrence in PMS but may require ventricular shunting.
Neuroimaging may show additional abnormalities under specific circumstances. In the case of ring chromosome 22, MRI may show F I G U R E 1 Recommendations for parental testing in Phelan-McDermid syndrome. We recommend parental testing following the identification of a 22q13 deletion including SHANK3 or a pathogenic SHANK3 sequence variant (orange). The estimated risk of familial recurrence (light blue) depends on the nature of the pathogenic variant (purple) in the proband and the results of parental testing (green). Karyotype and FISH can be used for parental evaluation of most deletions (see note below). Targeted sequencing may be used for parental evaluation of pathogenic SHANK3 variants. FISH, fluorescence in situ hybridization. **When a deletion in a patient is smaller than can be detected by FISH, chromosomal microarray, or next generation sequencing-based methods can potentially be used for parental testing with the understanding that balanced rearrangements may not be detected.
NF2-specific findings, such as intracranial acoustic neuromas/ vestibular schwannomas (Lyons-Warren et al., 2017;Ziats et al., 2020) as well as intraspinal meningiomas and ependymomas (Kresbach et al., 2021). In the rare co-occurrence of PMS and MLD, brain MRI may show changes consistent with the leukodystrophy, such as bilateral, symmetric, confluent periventricular white matter changes, as well as cortical and subcortical atrophy (Ahn et al., 2020).
In MLC, brain MRI may show subcortical cysts and edema in the subcortical white matter (Bosch & Estévez, 2020).
The need for a baseline brain MRI after initial diagnosis of PMS depends on the cause of the syndrome. For an individual with PMS due to ring chromosome 22, we recommend brain and spine MRI T A B L E 2 Recommendations pertaining to neurological considerations in Phelan-McDermid syndrome.

Cause of PMS Domain Recommendations
Any cause of PMS Neuroimaging abnormalities Work-up should include a lumbar puncture with standard cell count, protein level, and glucose level. Consider evaluation for autoimmune antibodies, including anti-NMDA receptor, anti-AMPA receptor, and anti-voltage gated potassium channel antibodies from both cerebrospinal fluid (CSF) and blood For those patients with positive autoantibodies from either CSF or serum, consider immune modulators, including intravenous methylprednisolone and intravenous immunoglobulin In cases associated with sudden onset of new neurologic symptoms (seizures, regression) where the work-up fails to identify any laboratory abnormalities, consider empirical use of immunomodulatory therapies, targeting presumed seronegative autoimmune encephalitis

Ring chromosome 22
Screening/ surveillance Obtain brain and spine MRI (with gadolinium) upon initial diagnosis Repeat brain MRI (with gadolinium) as part of surveillance schedule every 1-2 years after age 10 years until at least age 40 years Repeat spine MRI (with gadolinium) based on clinical symptoms Perform neurological examination upon initial diagnosis and then annually Note: Recommendations pertaining to ring Chromosome 22 are in addition to those pertaining to any cause of PMS.
(with gadolinium), given the increased risk of NF2-related acoustic neuromas/vestibular schwannomas and spinal tumors. Without ring chromosome 22, reasons to consider baseline brain MRI (with gadolinium, unless there is an institutional policy in place about use of contrast agents) include focal neurological findings on exam; focal seizures or focal abnormalities on electroencephalogram (EEG); concerns for increased intracranial pressure; regression (motor regression or dramatic language regression); macrocephaly; microcephaly; and clinician judgment. In the absence of these factors, clinicians may consider brain MRI (without gadolinium) if there is a desire to establish a neuroimaging baseline in case neurological status changes in the future.
We recommend repeating brain MRI based on the following considerations: sudden change in seizure frequency and/or characteristics (especially new emergence of focal seizures); changes in neurological examination (including pyramidal or extrapyramidal findings); regression: clinician judgment. Repeating brain MRI as part of a surveillance schedule is not necessary in PMS, except in the presence of ring chromosome 22. For individuals with ring chromosome 22, we recommend repeating brain MRI with gadolinium every 1-2 years starting at age 10 years until at least age 40 years, in accordance with NF2-specific guidelines (Evans, 1993); it is not necessary to repeat spine MRI unless there are concerning symptoms.

| Epilepsy and EEG abnormalities
In individuals with PMS, epilepsy occurs with a varying prevalence ranging from 17% to 41%, and approximately half have a history of a single lifetime seizure (Holder & Quach, 2016;Jeffries et al., 2005;Khan et al., 2018;Soorya et al., 2013;Wilson et al., 2003). The onset of the first-lifetime seizure is likewise highly variable. Reported seizure semiologies include atypical absence, tonic, tonic-clonic, and myoclonic seizures. Electrographic seizures and status epilepticus are infrequently noted in PMS. Seizure burden and frequency are highly variable. The incidence and prevalence of intractable epilepsy in PMS are not well established (Holder & Quach, 2016;Khan et al., 2018). A small percentage of affected individuals can develop Lennox-Gastaut syndrome (Holder & Quach, 2016;Srikanth et al., 2021), an epilepsy syndrome characterized by multiple seizure types, refractory epilepsy, and characteristic EEG findings including slow spike-and-wave bursts.
Among individuals with PMS who do not have epilepsy, epileptiform activity may still occur. EEG abnormalities include generalized slowing, multifocal slowing, focal spike and sharp waves, and generalized bursts of spike and slow-wave activity (Holder & Quach, 2016;Khan et al., 2018). Routine EEGs detect about 50% of the interictal epileptiform abnormalities seen in prolonged overnight EEG recordings containing portions of sleep (Khan et al., 2018; (Bey et al., 2020). In PMS, the area of neuropsychiatric presentations sensitive to immune modulation requires further study.
There is no data yet definitely stating whether individuals with PMS are at an increased risk for autoimmune encephalitis.
We recommend an evaluation for autoimmune encephalitis in individuals with PMS who experience (1) abrupt regression, (2)  Recommendations (Table 3).  (Brignell et al., 2021;Levy et al., 2022;Nevado et al., 2022;Sarasua et al., 2011Sarasua et al., , 2014. In PMS, the language gap compared with the normative population widens with age. Receptive language skills may slightly exceed expressive language skills in people with PMS (though both are often at or below the 12-month level; Soorya et al., 2013;Zwanenburg, Ruiter, et al., 2016), with the caveat that overestimation of receptive language levels is possible in individuals with severe developmental disabilities (Brignell et al., 2021). Some individuals with PMS use scripted phrases with good syntax and grammar that sound socially appropriate which can lead to assumptions of more intact receptive language.
Therapeutic interventions in PMS should prioritize efficient and functional communication. We suggest directly testing receptive language skills rather than presuming abilities based upon expressive language skills or parent/caregiver reports on standardized measures (Brignell et al., 2021 (Phelan et al., 2001;Wilson et al., 2003;Zwanenburg, Ruiter, et al., 2016), though there can be considerable heterogeneity.

| Challenging behavior and neuropsychiatric symptoms
Repetitive behavior and restricted interests (e.g., repetitive play, stereotyped language, and inflexibility with routines) are present in people with PMS, although generally less common than in people with ASD. Self-injurious behaviors in PMS include head-banging, skinpicking, and biting. Sensory reactivity symptoms are common and most frequently characterized by hyposensitivity across sensory domains (Droogmans et al., 2020;Serrada-Tejeda et al., 2022;Tavassoli et al., 2021;Mieses et al., 2016). An increased pain threshold is prevalent in PMS and can be associated with reduced response to potentially dangerous injuries (De Rubeis et al., 2018).
Symptoms associated with attention-deficit/hyperactivity disorder (ADHD), including impulsivity, are common in PMS, although it Define a bedtime routine, including a series of activities that represent a predictable and consistent "path to sleep" (e.g., put on pajamas, brush teeth, play a quiet game, get into bed, read a story with caregiver, turn off the light, and go to sleep) Other options include clonidine, trazodone, doxepin, mirtazapine, quetiapine, gabapentin, benzodiazepines, zolpidem, amitriptyline, and antihistamines For adolescents and young adults, turn off, unplug, or remove smartphone and other electronic devices present in the bedroom Make the bedroom a pleasant location associated with sleep and not with other exciting, stressful, or demanding activities Reduce ambient light and noise to the extent possible may be difficult to make the diagnosis in the context of severeprofound ID.
The exact prevalence of ADHD in PMS is not clear, but one study showed that 16/32 (50%) cases had hyperactivity (Soorya et al., 2013). Aggression may occur as a behavioral outcome of underlying discomfort or anxiety or as an incipient manic switch in bipolar disorder.
Individuals with PMS may exhibit anxiety manifesting as disruptive or repetitive behaviors when stressed by performance-related demands, novel situations, or transitions. However, anxiety may be difficult to assess due to cognitive and language deficits.
There are increasing reports of PMS-associated mood changes, like irritability, depression, and mood cycling (Egger et al., 2016;Kohlenberg et al., 2020;Kolevzon et al., 2019;Verhoeven et al., 2020). Bipolar disorder appears to be more common among The onset of neuropsychiatric difficulties may begin with dramatic worsening of anxiety and compulsive behaviors, and/or episodes of mania and depression. A small number of patients, mostly male, present with severe impulsive aggression, sometimes in the context of catatonia. In young women, onset of mania may be coincident with menstrual cycles . In the context of mania, new sleep difficulties can include complete insomnia lasting days, and mood episodes may be accompanied by the emergence of disorganized behavior and apparent psychosis.

| Regression
If regression occurs in PMS, affected areas include cognitive functioning, daily living skills, communication skills, and other adaptive skills . Regression may also affect academics (reading, writing) and technology utilization (e.g., tablets; Kohlenberg et al., 2020).
The pathophysiology of regression in PMS is not yet known.
Anecdotal and published accounts indicate regression in PMS may affect speech and/or language skills (Brignell et al., 2021;Kohlenberg et al., 2020). Characteristics of speech and language regression range from a notable reduction to complete absence of intelligibility and word production. Language regression in individuals with PMS typically happens around age 3 years but may also occur later (Reierson et al., 2017). In PMS, regression in language often occurs earlier than regression in other domains, such as motor functioning and self-help skills.
Loss of ADLs can occur in regression in PMS. In one study focusing on developmental regression, 53% of the sample (ages 4-48 years old) reported a regression and loss of self-help skills, often during the school-aged period (ages 6-12 years). The average age of regression was 6 years, and most of the skills lost during the regression were not regained (Reierson et al., 2017). In another study examining regression associated with neuropsychiatric changes, psychiatric decompensation had a median age of onset of 20 years, with 55% of individuals reporting loss of skills, including those related to ADLs such as toileting . Most of the time, ADLs are never fully recovered, although individuals can regain some of their skills .
Loss of skills can occur in the years after the onset of psychiatric illness in teens and young adults Kolevzon et al., 2019). In about half of those with regression, lost skills return when the underlying neuropsychiatric illness is controlled, particularly if significant rehabilitation services are available .

Recommendations.
At present, there are no clear methods to prevent or treat regression but vigilant monitoring and aggressive intervention for potential triggers are necessary. EEG should be considered to rule out seizures, and brain imaging may identify structural abnormalities that could provide clues about the cause of the regression. Regression may also be the first indication of a second genetic disorder, including MLD, where brain MRI might be informative. If skills are lost, re-training is warranted, and the specific intervention will depend on the domain/s affected.
In some cases, worsening GI symptoms may be associated with developmental regression or neuropsychiatric decompensation. In one cohort of patients with severe psychiatric disorders and regression, 32/38 (84%) had chronic constipation, compared with 15% of patients in the PMS International Registry . In the context of regression, families may describe toileting as a "lost" skill, but this aspect of regression requires additional study (Reierson et al., 2017).
Many individuals with PMS have a decreased response to painful stimuli, impairing the ability to fully delineate pain sources, including ones that are GI-related. Thus, when symptoms like sleep disturbance, behavioral changes, slow growth, or feeding problems are unexplained, we recommend a thorough GI evaluation.
Supportive strategies that are effective in individuals without PMS may also be helpful in PMS. Examples include sufficient soluble fiber intake, regular physical activity, and pelvic floor PT, although none of these therapies have been formally studied in PMS. Anecdotal data from families and clinicians favor the use of behavioral strategies like ABA therapy to improve toilet training and limit stool holding.
In the setting of GER, constipation, encopresis, functional vomiting disorders, and other GI disorders, we recommend early consideration of gastroenterology referral. Affected individuals may have GI manifestations of their symptoms that are atypical compared with those of patients usually referred to gastroenterology specialists. A referral to a neurogastroenterologist/motility specialist or gastroenterologist who specializes in children with neurodevelopmental/neuromuscular disorders may be helpful, especially when standard therapies have not been effective, although these experts may not always be available.

| Rumination syndrome
Rumination syndrome, a effortless regurgitation of ingested food, anecdotally occurs more frequently in PMS compared with the general population.
Nonspecific strategies to improve rumination, such as introduction of nonpalatable substances via a gastrostomy tube, have been successful in limited cases (Severio et al., 2015). Behavioral approaches to rumination syndrome are more challenging in PMS, given their requirement of certain cognitive abilities. Rumination syndrome is often difficult to diagnose, and many individuals with PMS have other foregut disorders such as GER, gastroparesis, and small bowel dysmotility.
Further diagnostic testing, such as antroduodenal manometry, may be helpful in more complex cases.

| Liver disease
Autoimmune hepatitis (AIH) is a rare complication of PMS, with only two reported cases (Bartsch et al., 2010;Tufano et al., 2009)

. A query of the Phelan-McDermid Syndrome Data Network (PMS-DN) in 2021
found that 0/389 cases answered "yes" to having "Autoimmune Liver Failure" (unpublished data). The prevalence of AIH is about 1/10,000 in the general population (Francque et al., 2012). Given the rarity of PMS, even two instances of AIH may represent increased risk. However, given the rarity of these diagnoses, routine monitoring of transaminases is not likely to be helpful.
Liver dysfunction in PMS can sometimes be due to nonalcoholic fatty liver disease, which is characterized by hepatic steatosis not secondary to known causes like alcohol consumption, medication use, or genetic liver disease. There is report of a 20-year-old male with a 22q13.33 deletion including SHANK3, ID, epilepsy, and digestive problems who developed transaminitis, with liver ultrasound showing findings consistent with moderate steatosis (Boccuto et al., 2018).
In individuals with PMS and elevated transaminase levels, consider AIH and nonalcoholic fatty liver disease as possible causes. Other diagnostic possibilities include drug-induced liver injury, given the high degree of polypharmacy in patients with neurodevelopmental disorders.

GI manifestations of NF2
Individuals with ring chromosome 22 can rarely develop GI manifestations of NF2, such as GI nerve sheath tumors (Lasota et al., 2003

| Nutritional deficiencies
PMS can predispose affected individuals to certain nutritional deficiencies. Some may develop zinc deficiency, possibly related to the association of SHANK3 with zinc uptake proteins in the CNS and GI tract (Pfaender et al., 2017). Feeding via gastrojejunostomy tube may raise the risk of copper and B 12 deficiency, due to bypass of the stomach. This effect may be exacerbated by zinc supplementation, so those with zinc deficiency should also receive additional copper supplementation (Duncan et al., 2015). Copper deficiency itself can cause neutropenia.
Individuals with PMS and functional gastric bypass (gastrectomy, gastrojejunostomy, or jejunostomy) should undergo periodic laboratory monitoring for copper deficiency, B 12 deficiency, and neutropenia. In addition to nutritional supplementation, behavioral strategies (e.g., ABA) are also recommended for treating pica.

Recommendations (Table 6).
For these medical concerns, we recommend standard management.
To evaluate for refractive errors and strabismus, we recommend ophthalmology evaluation at the time of diagnosis and then yearly (which is also recommended for individuals with ring chromosome 22). To screen for hearing loss, we recommended audiology evaluation at the time of diagnosis and annually in the case of ring chromosome 22. We recommend avoiding extreme temperatures, providing adequate hydration, and using equipment such as fans and cold packs in hot environments. Thermoregulatory differences, which predispose to skin redness, can sometimes mask cellulitis. Having high clinical suspicion for cellulitis and starting timely treatment is important. We T A B L E 6 Recommendations pertaining to primary care considerations in Phelan-McDermid syndrome. and difficulty walking more than 1 mi (1.6 km), and leg length discrepancies (unpublished data). The mechanisms underlying this motor dysfunction are unclear, but joint hypermobility may suggest connective tissue pathology as one possible contributing factor (Geuze, 2005;Johnston et al., 2002); another contributing factor may be the fact that SHANK3 plays a role in the maturation of neuromuscular junctions and striated muscle (Lutz et al., 2020;Raab et al., 2010).

Cause of PMS Domain Recommendations
Recommendations (Table 7).
Surveillance to identify physical impairments. We recommend annual evaluations with a physiatrist, if feasible. When there is no available physiatrist, other specialists such as developmental pediatricians or orthopedists may be able to play this role, in consultation with a remotely available pediatric physiatrist. Examination should include assessment of (1) range of motion and alignment, (2) spinal asymmetry and pelvic obliquity, and (3) leg length discrepancy. If there is a concerning clinical finding, imaging (plain radiographs in most cases) can verify the finding and assess its severity. We recommend monitoring gait efficiency (e.g., speed, cadence, symmetry, and step/stride length) and stability; assessing reach and grasp; and assessing for lymphedema in both upper and lower limbs.

Screening/ surveillance
Consider evaluation by physiatry at the time of diagnosis and annually, if feasible Annual assessment should evaluate range of motion and alignment; spinal asymmetry and pelvic obliquity; and leg length discrepancy Physiatry can monitor gait efficiency (e.g., speed, cadence, symmetry, step/stride length) and stability; assess reach and grasp; and assess for lymphedema in upper and lower limbs

Helpful equipment
Depending on the motor impairment in the individual, consider orthoses for the upper and/or lower extremities to improve function In individuals with significant swelling due to lymphedema, consider compression garments, massage, and sequential pumps Consider mobility equipment (e.g., adaptive strollers) if needed as soon as the person is beginning to outgrow a standard infant/toddler stroller

Therapeutic interventions
Physical therapy (PT) should focus on gross motor activities which promote strength and improve reaction time Other modalities which improve gross motor skills include aquatherapy, hippotherapy, and use of adaptive tricycles Occupational therapy (OT) should focus on fine motor activities which improve strength, wrist and hand alignment, and reaction time In a school setting, PT and OT should address musculoskeletal impairments and physical disabilities that impact education and performance it may be difficult to obtain accurate molds for custom-molded orthoses due to cognitive, behavioral, and/or sensory issues interfering with the acquisition of the mold.
We recommend mobility equipment (e.g., adaptive strollers) if needed to facilitate long-distance mobility as soon as the person is beginning to outgrow a standard infant/toddler stroller. This type of equipment eases the burden on parents/caregivers. In individuals with significant swelling due to lymphedema, consider compression garments, massage, and sequential pumps. Choosing an appropriate therapy must account for issues of tolerance to tactile stimuli. Serial measurement of limb volume (circumferential tape measure, perometry, or bioimpedance) can help track effectiveness of the chosen therapy for lymphedema.
In a school setting, PT and OT should address musculoskeletal impairments and physical disabilities that impact education and performance. Establishing and addressing these goals in the school setting is required by the Individuals with Disabilities Education Act (IDEA) in the United States.

| Spectrum of renal and genitourinary issues
The most common nonstructural genitourinary abnormality is delayed or persistent incontinence, common in PMS (Hussong et al., 2020;Witmer et al., 2019). Individuals with large chromosomal deletions may be more likely to have urinary or bowel incontinence compared with those with small chromosomal deletions (Witmer et al., 2019).
The degree to which incontinence in PMS might be a nonspecific feature common among individuals with neurodevelopmental disorders (von Gontard, 2013;von Gontard et al., 2015) is unclear, although general therapeutic and practical approaches will be similar.
Structural renal abnormalities and genitourinary problems are relatively common in PMS, with rates reported as high as 38% (Soorya et al., 2013). However, few studies have systematically examined the prevalence of these problems, and none have used prospective methods. On a comprehensive review of medical records from 32 patients in one study, renal abnormalities included vesicoureteral reflux (13%), hydronephrosis (13%), renal agenesis (6%), dysplastic kidney (3%), and horseshoe kidneys and pyelectasis (3%) (Soorya et al., 2013). Another study documented renal problems in 39 of 148 cases (26%), including vesicoureteral reflux (14%), frequent urinary tract infections (8%), polycystic kidney (5%), duplicated kidney (1%), and dilated renal pelvis (5%); some of the renal problems remained unspecified because in 19% of the cases, the kidney problem was unclassified ("other") whether alone or in combination with a different (specified) kidney problem (Sarasua et al., 2014). A third study on ring chromosome 22 specifically reported that 17% of the cohort had renal abnormalities in the context of genitourinary abnormalities, including neonatal urinary infection and malformed clitoris, vesicoureteral reflux, unilateral multicystic kidney, and "partial renal failure" of unknown cause (Jeffries et al., 2005). There is at least one report of an affected child with a unilateral multicystic kidney and Wilms' tumor in the contralateral, unaffected kidney, as detected with prenatal ultrasound (Kirkpatrick & El-Khechen, 2011).
Anecdotal evidence from PMS parent groups, albeit outside published literature, suggests that other abnormalities may occur. There are reports of hypospadias, persistent urinary leakage beyond incontinent voiding, kidney stones, urinary retention, and neurogenic bladder with need for intermittent urinary catheterization.
Recommendations (Table 8). If there are urinary symptoms beyond periodic incontinence that develop over time-such as "dribbling," signs of urinary retention, or difficulty voiding-perform repeat renal and bladder sonography and refer to nephrology or urology Family and primary care team should have communication in advance with the specialist prior to the appointment, given that the genitourinary system is a physically and emotionally sensitive area deletions involving only SHANK3 are not likely to have a clinically relevant renal or bladder abnormality at birth. Thus, in the future, it may be possible to revise this recommendation for that specific subgroup of patients with PMS if active screening programs support that observation.
Regardless of genetic findings and despite a normal baseline renal and bladder ultrasound, it is possible that renal/urological pathology could exist or emerge at a later time. For example, renal and bladder sonography may be normal in the setting of vesicoureteral reflux; therefore, urinary tract infection at a young age or recurrent urinary tract infections (UTIs) should prompt consideration of this diagnosis.
Urinary symptoms beyond periodic incontinence that develop over time-such as "dribbling," signs of urinary retention, or difficulty voiding-should prompt repeat renal and bladder sonography and referral to nephrology or urology.
If any of the diagnostic screening tests are abnormal, then we recommend referral to a pediatric nephrologist and/or urologist for monitoring or treatment. Blood tests (e.g., urea, creatinine, and electrolytes) may be indicated for those individuals with identified renal anomalies or bladder/voiding dysfunction, as these conditions may lead to reduced renal function. Attention to the ability of the individual to empty the bladder and void spontaneously is important, as is attention to constipation, which is commonly associated with voiding dysfunction. Specific review of urinary continence, hygiene, and presence/absence of UTIs between visits is advised.
The genitourinary system is a physically and emotionally sensitive area, and its assessment adds to the existing stress of a medical visit.
Therefore, we recommend communication in advance by the family and primary care team to the specialist. Ideally, this approach will help organize information, guide any evaluations that can occur before the visit, and enable the best possible experience during the visit itself.
An accurate assessment of growth parameters and growth trajectory is essential. We recommend obtaining and recording gestational age, birth weight, birth length, and birth head circumference. For longitudinal assessments of length and height, appropriate measuring devices (such as a stadiometer) should be used. We recommend monitoring height, weight, and body mass index using standard growth curves (such as those from the US Centers for Disease Control). If there are concerns about growth (short or tall stature), then referral to an endocrinologist is indicated.

| Hypothyroidism
Hypothyroidism occurs in 3%-6% of individuals with PMS (Sarasua et al., 2014;Soorya et al., 2013), but more studies are needed to clarify if this risk is increased compared with that of the general population. There are no reports of children younger than 5 years of age with PMS and hypothyroidism, suggesting that congenital hypothyroidism may not be common. There is a report of one individual with PMS and hyperthyroidism (Sarasua et al., 2014).
It is important to monitor and record appearance of pubertal signs (acne, body odor, axillary and pubic hair, breast development in girls, and testicular volume in boys) and age at menarche. Recording these data will allow the correlation of pubertal events with linear growth data.  (Jeffries et al., 2005).
In a prospectively ascertained sample of 32 patients with PMS, only one patient had a cardiovascular abnormality (aortic regurgitation; valve morphology not described; Soorya et al., 2013). Recent case reports have reported the following: a 4-month-old girl with PMS secondary to a 22q13.3 deletion who underwent surgical ligation of a patent ductus arteriosus at 3 weeks of age (Kim et al., 2016); a 32-year-old man with PMS who presented with postictal atrial fibrillation (Sanchez-Larsen et al., 2017), a very infrequent cardiac arrhythmia associated with seizures; and a 33-month-old girl with PMS who had one episode of supraventricular tachycardia, progressive dilation of the ascending aorta (Zscore + 4.6) and main pulmonary artery (Z-score + 3), and an aortic root dimension at the upper limit of normal (Deibert et al., 2019).
As part of the initial evaluation in all patients with PMS, we recom-  (Sarasua et al., 2014), and there are no reports of delayed puberty.
There is anecdotal evidence that puberty may be associated with worsening of neuropsychiatric symptoms, especially in girls . Menstruation can present significant challenges for a person with physical disability and ID (Greenwood & Wilkinson, 2013). Adolescents/adults with PMS may suffer from premenstrual syndrome and dysmenorrhea at similar rates as the general population. As with adolescents/adults with other developmental disabilities, individuals with PMS may have medical causes of menstrual irregularities, including thyroid disease, elevated prolactin levels due to antipsychotic use, and polycystic ovary syndrome in the setting of epilepsy and/or use of certain antiseizure medications. Behavioral and hygiene issues that accompany menstrual periods can cause significant challenges for individuals with ID.
Reducing the risk of developing oral disease is an integral part of comprehensive oral healthcare for individuals with PMS. The AAPD publishes best practices and clinical guidelines related to the management of dental patients with special healthcare needs. These recommendations outline important components of dental care such as establishment of a dental home, patient assessment, appointment scheduling, T A B L E 1 1 Recommendations pertaining to gynecological considerations in Phelan-McDermid syndrome. We recommend establishing a dental home, with the first visit to a dentist by 1 year of age and no later than 6 months after the first tooth erupts. This visit will help the dentist discuss how to keep the child's teeth as healthy as possible and what to expect in individuals T A B L E 1 3 Definitions of commonly used genetics terms.

Term Definition
Aneuploidy A condition in which the total number of chromosomes in a cell is not the typical number (e.g., 45 chromosomes instead of 46 in a human cell)

Autosomal
Pertaining to chromosomes 1-22 and not to the X or Y chromosome Autosomal dominant An autosomal mode of inheritance of a genetic condition in which only one copy of a gene must be abnormal for a condition to manifest Autosomal recessive An autosomal mode of inheritance of a genetic condition in which both copies of a gene must be abnormal for a condition to manifest

Balanced chromosomal rearrangement
Chromosomal rearrangement (see definition) in which the total amount of DNA is the same (i.e., there is no net gain or loss of genetic material)

Chromosomal inversion
Chromosomal rearrangement in which a portion of one chromosome inverts (rotates 180 degrees) Chromosomal microarray A test that uses binding of probes (DNA fragments arranged on a chip) to detect deletions or duplications of chromosomal material at a higher resolution than that of fluorescence in situ hybridization or karyotype Fluorescence in situ hybridization A test that uses fluorescent probes to bind to chromosomes to assess for the presence, absence, and position of specific DNA regions Genome sequencing A type of next-generation sequencing (see definition) involving sequencing the coding and noncoding portions of all genes and the regions between genes (i.e., genome) Gonadal mosaicism (also known as germline mosaicism) A state in which a variant is present in either sperm or egg cells, but not in other tissue types Haploinsufficiency A state in which loss of function of one copy of a gene or genetic region is sufficient to cause symptoms of a genetic disorder Interstitial deletion A chromosomal deletion within the interior of a chromosome Karyotype A test that using a microscope to visualize the size, shape, and number of chromosomes in an individual Mosaic aneuploidy Aneuploidy (see definition) which affects some cells, but not every cell, in the body Next-generation sequencing Term used for sequencing of DNA that involves sequencing many DNA targets in parallel, in contrast to traditional (Sanger) sequencing which involves sequencing one DNA target at a time Ring chromosome A circular structure formed when the distal long arm and the distal short arm of a chromosome truncate and join Sequence variant A change in the DNA sequence within a gene, involving one or several nucleotides, manifesting as substitutions of one nucleotide for another; deletion of one or more nucleotides; duplication of one or more nucleotides; insertion of one or more nucleotides; or deletion of one or more nucleotides and replacement by new nucleotides

Somatic variant A variant that is present in some cells, but not all cells, in the body
Terminal deletion A chromosomal deletion including the end of a chromosome

Unbalanced chromosomal rearrangement
Chromosomal rearrangement in which there is a net gain or loss of total chromosomal material Variable expressivity Variability in the severity/range of symptoms of those who have a genetic disorder Variant of uncertain significance A classification of the pathogenicity of a variant in which there is uncertainty about whether the variant is causative of the condition with PMS. It is important to establish preventive strategies for daily oral hygiene at home that accommodate the abilities of both the patient and the caregiver. We recommend daily use of fluoridated toothpaste. We recommend providing oral health education and anticipatory guidance pertaining to dietary/medication considerations (such as medications with high sugar content) and oral habits (such as bruxism). We recommend scheduling routine dental visits every 6 months or sooner depending on the child's risk for developing cavities or gum disease. We recommend obtaining dental radiographs when clinically appropriate for the child. We recommend providing treatment strategies for dental care, including behavior guidance as well as options for treatment in a hospital setting able to provide procedural sedation or general anesthesia.

| CONCLUSIONS
In this report, we have provided updated consensus guidelines for the management of PMS, spanning the domains of genetics, neurology, neurodevelopment, gastroenterology, primary care, physiatry, nephrology, endocrinology, cardiology, gynecology, and dentistry. From a GI perspective, functional GI disorders are common and may be related to enteric nervous system and pelvic floor dysfunction from SHANK3 disruption. Earlier referral and more aggressive therapy may be necessary in PMS.
From a primary care standpoint, individuals with PMS are at increased risk for a variety of primary care concerns and require increased vigilance and screening for vision issues, hearing issues, thermoregulation challenges, infections, and skin issues. Families should assess the capacity and availability of practices in advance, as not every practice is equipped for patients with special needs. If feasible, a "medical home" model is ideal, wherein "complex care" physicians, care coordinators, social workers, and home-based care may be available.
From a physiatry standpoint, individuals with PMS manifest impairments in musculoskeletal and lymphatic function which can impact mobility and self-care. Function can be improved and optimized by early involvement of a physical rehabilitation team using therapy, orthoses, and rehabilitation devices. Ideally, the rehabilitation team should include a physiatrist, occupational therapist, and physical therapist, in addition to existing providers like speech and language pathologists. Where a physiatrist is unavailable, a neurodevelopmental pediatrician or pediatric orthopedist could fill the physiatrist's role, ideally in consultation with a physiatrist.
From a nephrology perspective, individuals with PMS can be affected with structural and functional renal/bladder abnormalities warranting baseline screening with renal and bladder sonography.
Depending on the abnormalities identified, further evaluation with a nephrologist and/or urologist may be needed. Regarding dentistry needs, individuals with PMS can be at higher risk for dental problems due to underlying medical issues, similar to other neurodevelopmental disorders. Management of dental needs should be in accordance with best practices and guidelines published by the AAPD.
These updated consensus guidelines represent an advance for the field and will improve care for affected individuals and their families in the community. Nevertheless, significant gaps in knowledge remain and may be addressed by ongoing studies using deep phenotyping and carefully tracking the natural history of the syndrome.
The guidelines developed here are relevant to individuals who have involvement of SHANK3 and thus do not necessarily apply to those without SHANK3 haploinsufficiency; more efforts are needed to better understand the phenotypic impact of other genes in the 22q13 region.
Biomarker studies using EEG and other technology may be especially helpful for understanding the clinical heterogeneity. Several converging and ongoing areas of research are dedicated to clinical trial readiness as more potential treatments become worthy of testing in randomized, controlled, multicentered trials. In addition, as knowledge about genotype-phenotype relationships deepens, future guidelines will provide more practical information about course of illness and enhance genetic counseling efforts. With additional research, subsequent updates to these guidelines will provide more refined and specific recommendations for the PMS community.

AUTHOR CONTRIBUTIONS
Alexander Kolevzon conceptualized and designed the study; cochaired the taskforce to update the guidelines; and drafted and edited a significant portion of the article. Siddharth Srivastava co-chaired the taskforce to update the guidelines; drafted and edited a significant portion of the article. The remaining authors contributed to intellectual content contained in the guidelines and drafted or edited a significant portion of the article.