Sleep disturbances in Phelan-McDermid syndrome: Clinical and metabolic profiling of 56 individuals.

Phelan-McDermid Syndrome (PMS) is caused by deletions at chromosome 22q13.3 or pathogenic/likely pathogenic SHANK3 variants. The clinical presentation is extremely variable and includes global developmental delay/intellectual disability (ID), seizures, neonatal hypotonia, and sleep disturbances, among others. This study investigated the prevalence of sleep disturbances, and the genetic and metabolic features associated with them, in a cohort of 56 individuals with PMS. Sleep data were collected via standardized observer/caregiver questionnaires, while genetic data from array-CGH and sequencing of 9 candidate genes within the 22q13.3 region, and metabolic profiling utilized the Biolog Phenotype Mammalian MicroArray plates. Sleep disturbances were present in 64.3% of individuals with PMS, with the most common problem being waking during the night (39%). Sleep disturbances were more prevalent in individuals with a SHANK3 pathogenic variant (89%) compared to subjects with 22q13.3 deletions of any size (59.6%). Distinct metabolic profiles for individuals with PMS with and without sleep disturbances were also identified. These data are helpful information for recognizing and managing sleep disturbances in individuals with PMS, outlining the main candidate gene for this neurological manifestation, and highlighting potential biomarkers for early identification of at-risk subjects and molecular targets for novel treatment approaches.

Lymphedema is associated with CELSR1 in Phelan-McDermid syndrome.

Lymphedema is a troubling condition present in many disorders including the rare genetic disorder known as Phelan-McDermid syndrome (PMS). The neurobehavioral features of PMS, also known as 22q13.3 deletion syndrome, have been investigated, but little research exists on lymphedema in PMS. In this investigation, clinical and genetic data from 404 people with PMS were reviewed from the PMS-International Registry revealing a prevalence of 5% with lymphedema. Lymphedema was reported in 1 out of 47 people (2.1%) with PMS due to a SHANK3 variant and 19 out of 357 people (5.3%) with PMS due to 22q13.3 deletions. Lymphedema was more common among those in their teens or adulthood (p = 0.0011) and those with deletions >4 Mb. People with lymphedema had significantly larger deletions (mean 5.375 Mb) than those without lymphedema (mean 3.464 Mb, p = 0.00496). Association analysis identified a deletion of the CELSR1 gene to be the biggest risk factor (OR = 12.9 95% CI [2.9-56.2]). Detailed assessment of 5 subjects identified all had deletions of CELSR1, developed symptoms of lymphedema starting at age 8 or older, and typically responded well to standard therapy. In conclusion, this is the largest assessment of lymphedema in PMS to date and our results suggest that individuals with deletions >4 Mb or those with CELSR1 deletions should be assessed for lymphedema.

Genetic and metabolic profiling of individuals with Phelan-McDermid syndrome presenting with seizures.

Phelan-McDermid syndrome (PMS) (OMIM*606232) is a rare genetic disorder characterized by intellectual disability, autistic features, speech delay, minor dysmorphia, and seizures. This study was conducted to investigate the prevalence of seizures and the association with genetic and metabolic features since there has been little research related to seizures in PMS. For 57 individuals, seizure data was collected from caregiver interviews, genetic data from existing cytogenetic records and Sanger sequencing for nine 22q13 genes, and metabolic profiling from the Phenotype Mammalian MicroArray (PM-M) developed by Biolog. Results showed that 46% of individuals had seizures with the most common type being absence and grand-mal seizures. Seizures were most prevalent in individuals with pathogenic SHANK3 mutations (70%), those with deletion sizes >4 Mb (16%), and those with deletion sizes <4 Mb (71%) suggesting involvement of genes in addition to SHANK3. Additionally, a 3 Mb genomic region on 22q13.31 containing the gene TBC1D22A, was found to be significantly associated with seizure prevalence. A distinct metabolic profile was identified for individuals with PMS with seizures and suggested among other features a disrupted utilization of main energy sources using Biolog plates. The results of this study will be helpful for clinicians and families in anticipating seizures in these children and for researchers to identify candidate genes for the seizure phenotype.

Clinical, cytogenetic, and molecular characterization of six patients with ring chromosomes 22, including one with concomitant 22q11.2 deletion.

We report here on six patients with a ring chromosome 22 and the range of cytogenetic and phenotypic features presented by them. Genomic analysis was carried out using classical and molecular cytogenetics, MLPA (Multiplex Ligation-dependent Probe Amplification) and genome-wide SNP-array analysis. The ring was found in all patients, but Patient 6 displayed constitutional mosaicism with a normal cell line. Five patients had deletions in the ring chromosome 22, and in four of them the breakpoints--unique for each patient--could be identified by genome-wide SNP-array analysis. One patient presented with a 22q11.2 deletion concomitant with the deletion caused by the ring formation. Common phenotypic features included autism, speech delay and seizures, as previously reported for individuals with r(22) and/or 22q13.3 deletions. Investigation of the genes within the deletions revealed multiple genes related to development of the central nervous system, psychomotor delay, severe language impairment, hypotonia, and autistic symptoms. There was no clear correlation between the severity of clinical features and the size of the deleted segment. This study underscores the variability in ring structure and clinical presentation of the r(22) and adds information to the limited literature on this rare disorder.

A patient with the classic features of Phelan-McDermid syndrome and a high immunoglobulin E level caused by a cryptic interstitial 0.72-Mb deletion in the 22q13.2 region.

Phelan-McDermid syndrome, also known as the 22q13 deletion syndrome, is a chromosomal microdeletion syndrome characterized by neonatal hypotonia, normal growth, profound developmental delay, absent or delayed speech, and minor dysmorphic features. Almost all of the 22q13 deletions published so far have been described as terminal. It is believed that the SHANK3 gene is the major candidate gene for the neurologic features of the syndrome. Here we describe a patient with a 0.72-Mb interstitial 22q13.2 deletion, intellectual disability, autistic behavior, epilepsy, mild dysmorphic features, and no deletion in the SHANK3 gene. The patient also has urticarial rash and an elevated level of immunoglobulin E, the latter has previously been described only once in a patient with monosomy 22q13.2-qter and SHANK3 gene deletion. To our knowledge, this is one of the smallest interstitial deletion in this region which has been published up to now. Although the patient has the classic phenotype of the 22q13 terminal deletion syndrome, the etiology for the neurologic and immunological features must be due to genes located more proximal to SHANK3 and this is also supported by other previously published cases of interstitial 22q13.2 deletions. The deleted area in our patient is gene-rich (26 genes), containing several known genes with different functions. Two of them-NFAM1 and TNFRSF13C are involved in immune system functioning. We suggest the haploinsufficiency of these genes might be related to hyper IgE syndrome in our patient.

Clinical, developmental and serotonemia phenotyping of a sample of 70 Italian patients with Phelan-McDermid Syndrome.

BACKGROUND: Phelan-McDermid syndrome (PMS) is caused by monoallelic loss or inactivation at the SHANK3 gene, located in human chr 22q13.33, and is often associated with Autism Spectrum Disorder (ASD). OBJECTIVES: To assess the clinical and developmental phenotype in a novel sample of PMS patients, including for the first time auxometric trajectories and serotonin blood levels. METHODS: 70 Italian PMS patients were clinically characterized by parental report, direct medical observation, and a thorough medical and psychodiagnostic protocol. Serotonin levels were measured in platelet-rich plasma by HPLC. RESULTS: Our sample includes 59 (84.3%) cases with chr. 22q13 terminal deletion, 5 (7.1%) disruptive SHANK3 mutations, and 6 (8.6%) ring chromosome 22. Intellectual disability was present in 69 (98.6%) cases, motor coordination disorder in 65 (92.9%), ASD in 20 (28.6%), and lifetime bipolar disorder in 12 (17.1%). Prenatal and postnatal complications were frequent (22.9%-48.6%). Expressive and receptive language were absent in 49 (70.0%) and 19 (27.1%) cases, respectively. Decreased pain sensitivity was reported in 56 (80.0%), hyperactivity in 49 (80.3%), abnormal sleep in 45 (64.3%), congenital dysmorphisms in 35 (58.3%), chronic stool abnormalities and especially constipation in 29 (41.4%). Parents reported noticing behavioral abnormalities during early childhood immediately after an infective episode in 34 (48.6%) patients. Brain MRI anomalies were observed in 53 (79.1%), EEG abnormalities in 16 (23.5%), kidney and upper urinary tract malformations in 18 (28.1%). Two novel phenotypes emerged: (a) a subgroup of 12/44 (27.3%) PMS patients displays smaller head size at enrollment (mean age 11.8 yrs) compared to their first year of neonatal life, documenting a deceleration of head growth (p < 0.001); (b) serotonin blood levels are significantly lower in 21 PMS patients compared to their 21 unaffected siblings (P < 0.05), and to 432 idiopathic ASD cases (p < 0.001). CONCLUSIONS: We replicate and extend the description of many phenotypic characteristics present in PMS, and report two novel features: (1) growth trajectories are variable and head growth appears to slow down during childhood in some PMS patients; (2) serotonin blood levels are decreased in PMS, and not increased as frequently occurs in ASD. Further investigations of these novel features are under way.

Brain Gene Co-Expression Network Analysis Identifies 22q13 Region Genes Associated with Autism, Intellectual Disability, Seizures, Language Impairment, and Hypotonia.

Phelan-McDermid syndrome (PMS) is a rare genetic neurodevelopmental disorder caused by 22q13 region deletions or SHANK3 gene variants. Deletions vary in size and can affect other genes in addition to SHANK3. PMS is characterized by autism spectrum disorder (ASD), intellectual disability (ID), developmental delays, seizures, speech delay, hypotonia, and minor dysmorphic features. It is challenging to determine individual gene contributions due to variability in deletion sizes and clinical features. We implemented a genomic data mining approach for identifying and prioritizing the candidate genes in the 22q13 region for five phenotypes: ASD, ID, seizures, language impairment, and hypotonia. Weighted gene co-expression networks were constructed using the BrainSpan transcriptome dataset of a human brain. Bioinformatic analyses of the co-expression modules allowed us to select specific candidate genes, including EP300, TCF20, RBX1, XPNPEP3, PMM1, SCO2, BRD1, and SHANK3, for the common neurological phenotypes of PMS. The findings help understand the disease mechanisms and may provide novel therapeutic targets for the precise treatment of PMS.

Consensus recommendations on communication, language and speech in Phelan-McDermid syndrome.

Phelan-McDermid syndrome is a genetic condition primarily caused by a deletion on the 22q13.3 region or a likely pathogenic/pathogenic variant of SHANK3. The main features comprise global developmental delay, marked impairment or absence of speech, and other clinical characteristics to a variable degree, such as hypotonia or psychiatric comorbidities. A set of clinical guidelines for health professionals covering relevant aspects of clinical management have been written by the European PMS Consortium, and consensus has been reached regarding final recommendations. In this work, attention is given to communication, language and speech impairments in PMS, and the findings from available literature are presented. Findings from the literature review reveal marked speech impairment in up to 88% of deletions and 70% of SHANK3 variants. Absence of speech is frequent and affects 50%-80% of the individuals with PMS. Communicative skills in the expressive domain other than spoken language remain understudied, but some studies offer data on non-verbal language or the use of alternative/augmentative communication support. Loss of language and other developmental skills is reported in around 40% of individuals, with variable course. Deletion size and possibly other clinical variables (e.g., conductive hearing problems, neurological issues, intellectual disability, etc.) are related to communicative and linguistic abilities. Recommendations include regular medical check-ups of hearing and the assessment of other factors influencing communication, thorough evaluation of preverbal and verbal communicative skills, early intervention, and support via alternative/augmentative communication systems.

Head Size in Phelan-McDermid Syndrome: A Literature Review and Pooled Analysis of 198 Patients Identifies Candidate Genes on 22q13.

Phelan-McDermid syndrome (PMS) is a multisystem disorder that is associated with deletions of the 22q13 genomic region or pathogenic variants in the SHANK3 gene. Notable features include developmental issues, absent or delayed speech, neonatal hypotonia, seizures, autism or autistic traits, gastrointestinal problems, renal abnormalities, dolichocephaly, and both macro- and microcephaly. Assessment of the genetic factors that are responsible for abnormal head size in PMS has been hampered by small sample sizes as well as a lack of attention to these features. Therefore, this study was conducted to investigate the relationship between head size and genes on chromosome 22q13. A review of the literature was conducted to identify published cases of 22q13 deletions with information on head size to conduct a pooled association analysis. Across 56 studies, we identified 198 cases of PMS with defined deletion sizes and head size information. A total of 33 subjects (17%) had macrocephaly, 26 (13%) had microcephaly, and 139 (70%) were normocephalic. Individuals with macrocephaly had significantly larger genomic deletions than those with microcephaly or normocephaly (p < 0.0001). A genomic region on 22q13.31 was found to be significantly associated with macrocephaly with CELSR1, GRAMD4, and TBCD122 suggested as candidate genes. Investigation of these genes will aid the understanding of head and brain development.

Definition and clinical variability of SHANK3-related Phelan-McDermid syndrome.

Phelan-McDermid syndrome (PMS) is an infrequently described syndrome that presents with a disturbed development, neurological and psychiatric characteristics, and sometimes other comorbidities. As part of the development of European medical guidelines we studied the definition, phenotype, genotype-phenotype characteristics, and natural history of the syndrome. The number of confirmed diagnoses of PMS in different European countries was also assessed and it could be concluded that PMS is underdiagnosed. The incidence of PMS in European countries is estimated to be at least 1 in 30,000. Next generation sequencing, including analysis of copy number variations, as first tier in diagnostics of individuals with intellectual disability will likely yield a larger number of individuals with PMS than presently known. A definition of PMS by its phenotype is at the present not possible, and therefore PMS-SHANK3 related is defined by the presence of SHANK3 haploinsufficiency, either by a deletion involving region 22q13.2-33 or a pathogenic/likely pathogenic variant in SHANK3. In summarizing the phenotype, we subdivided it into that of individuals with a 22q13 deletion and that of those with a pathogenic/likely pathogenic SHANK3 variant. The phenotype of individuals with PMS is variable, depending in part on the deletion size or whether only a variant of SHANK3 is present. The core phenotype in the domains development, neurology, and senses are similar in those with deletions and SHANK3 variants, but individuals with a SHANK3 variant more often are reported to have behavioural disorders and less often urogenital malformations and lymphedema. The behavioural disorders may, however, be a less outstanding feature in individuals with deletions accompanied by more severe intellectual disability. Data available on the natural history are limited. Results of clinical trials using IGF-1, intranasal insulin, and oxytocin are available, other trials are in progress. The present guidelines for PMS aim at offering tools to caregivers and families to provide optimal care to individuals with PMS.

A patient presenting a 22q13 deletion associated with an apparently balanced translocation t(16;22): An illustrative case in the investigation of patients with low ARSA activity.

A 10-year-old speechless, mentally deficient male, with low arylsulfatase A (ARSA) activity, and presumably, methachromatic leukodystrophy, underwent genetic evaluation. As the clinical picture was not compatible with this diagnosisan ARSA gene and chromosome analysis were performed, showing the presence of a pseudodeficiency ARSA allele and a de novo apparently balanced t(16;22)(p11.2;q13) translocation. A deletion on the long arm of chromosome 22 encompassing the ARSA gene, as shown by FISH and array-CGH, indicated a 22q13 deletion syndrome. This case illustrates the importance of detailed cytogenetic investigation in patients presenting low arylsulfatase A activity and atypical/unspecific clinical features.

Phelan-McDermid syndrome: a classification system after 30 years of experience.

Phelan-McDermid syndrome (PMS) was initially called the 22q13 deletion syndrome based on its etiology as a deletion of the distal long arm of chromosome 22. These included terminal and interstitial deletions, as well as other structural rearrangements. Later, pathogenetic variants and deletions of the SHANK3 gene were found to result in a phenotype consistent with PMS. The association between SHANK3 and PMS led investigators to consider disruption/deletion of SHANK3 to be a prerequisite for diagnosing PMS. This narrow definition of PMS based on the involvement of SHANK3 has the adverse effect of causing patients with interstitial deletions of chromosome 22 to "lose" their diagnosis. It also results in underreporting of individuals with interstitial deletions of 22q13 that preserve SHANK3. To reduce the confusion for families, clinicians, researchers, and pharma, a simple classification for PMS has been devised. PMS and will be further classified as PMS-SHANK3 related or PMS-SHANK3 unrelated. PMS can still be used as a general term, but this classification system is inclusive. It allows researchers, regulatory agencies, and other stakeholders to define SHANK3 alterations or interstitial deletions not affecting the SHANK3 coding region.

Phelan-McDermid Syndrome in Pediatric Patients With Novel Mutations: Genetic and Phenotypic Analyses.

Background: PhelanrMcDermid syndrome (PMS) is an uncommon autosomal dominant inherited developmental disorder. The main characteristics are hypotonia, intellectual disability, autism spectrum disorder, autism-like behaviors and tiny facial deformities. Most cases are caused by the deletion of the 22q13 genomic region, including the deletion of SHANK3. Methods: Genetic and phenotype evaluations of ten Chinese pediatric patients were performed. The clinical phenotypes and genetic testing results were collected statistically. We analyzed the deletion of the 22q13 genomic region and small mutations in SHANK3 (GRCh37/hg19) and performed parental genotype verification to determine whether it was related to the parents or was a novel mutation. Results: The age of the patients diagnosed with PMS ranged from 0 to 12 years old. Nine of the pediatric patients experienced Intellectual Disability, language motion development delay and hypotonia as prominent clinical features. One subject had autism, two subjects had abnormal electroencephalogram discharge and one subject was aborted after fetal diagnosis. Three patients had a SHANK3 mutation or deletion. All but the aborted fetuses had intellectual disability. Among the ten patients, a deletion in the 22q13 region occurred in seven patients, with the smallest being 60.6 kb and the largest being >5.5 Mb. Three patients had heterozygous mutations in the SHANK3 gene. Conclusion: All ten patients had novel mutations, and three of these were missense or frameshift mutations. For the first time reported, it is predicted that the amino acid termination code may appear before protein synthesis. The novel mutations we discovered provide a reference for clinical research and the diagnosis of PMS.

Sleep and Phelan-McDermid Syndrome: Lessons from the International Registry and the scientific literature.

BACKGROUND: Sleep is essential to maintaining a healthy life. Sleep disturbances among individuals with neurodevelopmental disorders are not well studied, affecting their early detection and treatment. Sleep disturbances in individuals with Phelan-McDermid Syndrome (PMS) are among the primary concerns reported by parents. However, little research has been aimed at addressing their concern. METHODS: The purpose of this investigation was to identify and quantify specific sleep disturbances in people with PMS by analyzing data collected by the PMS Foundation International Registry. RESULTS: The registry shows that 284 out of 384 (73.4%) individuals with confirmed chromosome 22q13 deletions or SHANK3 pathogenic variants have a sleep disturbance. The prevalence of sleep disturbances increases with age with 56% reporting a sleep disturbance in the 0-3 year age group and 90% reporting these disturbances in those over age 18 years old. The primary sleep disturbances were circadian rhythm sleep disorders that included 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 were similarly frequent among individuals with SHANK3 pathogenic variants (84.8%) and those with deletions (71.9%), supporting the role of haploinsufficiency of SHANK3 in sleep. CONCLUSION: Sleep disturbances are a common feature of PMS and should be considered in clinical evaluation and management because of the effect they have on the quality of life of the patients and their families.

Understanding Behavior in Phelan-McDermid Syndrome.

Background: Phelan-McDermid syndrome (PMS) or 22q13.3 deletion syndrome is a rare genetic disorder characterized by developmental delay, hypotonia and severely delayed speech. Behavioral difficulties are often reported in PMS, although knowledge of behavioral profiles and the interpretation of reported behavior remains limited. Understanding the meaning of behavior requires considering the context as well as other domains of functioning, for example the individual's level of cognitive, social and emotional development. Combining structured direct in-person neurodevelopmental assessments with contextual assessments to enable meaningful interpretations of reported behavior on functional dimensions across multiple units of analysis, as proposed by the RDoc framework, is essential. Methods: In this article we present a structured multidisciplinary method of assessment through direct in-person neurodevelopmental assessments and assessment of contextual factors. Our study sample includes data of 33 children with an average age of 6.2 years (range 1.1 to 15.7) with PMS, obtained through individual in-person assessments in combination with parent informed questionnaires. We assessed developmental age using the Bayley-III, adaptive behavior was assessed with the Vineland screener, social-emotional development with the ESSEON-R and behavior by using the CBCL. Results: Our results show a great deal of variability in phenotypic presentation with regard to behavior, symptom expression and symptom severity in individuals with PMS. The data on behavior is interpreted in the context of the individual's level of cognitive, adaptive development and the (genetic) context. Behavioral data showed high levels of withdrawn behavior and attention problems. More than half of the children showed borderline or clinical symptoms related to Autism Spectrum Disorder (ASD). Conclusions: The interpretation of the meaning of certain behavior in PMS is often based on questionnaires and descriptions without taking the specific context of development into account. Combining questionnaires with direct in-person assessments measuring different domains of functioning should be considered a more accurate method to interpret the meaning of findings in order to understand behavior in rare genetic disorders associated with developmental delay such as PMS. Direct in-person assessment provides valuable and specific information relevant to understanding individual behavior and inform treatment as well as increase knowledge of the neurodevelopmental phenotype in individuals with PMS. More specific application of the proposed frameworks on behavior in PMS is desirable in making useful interpretations.

Molecular cytogenetic and phenotypic characterization of Phelan McDermid and 22q13 duplication syndrome: a case report.

BACKGROUND: Phelan-McDermid syndrome (PHMDS) is a rare genetic disorder mostly caused by haploinsufficincy of SHANK3 gene, and characterized by neonatal hypotonia, developmental delay, minor dysmorphic features, seizures and behavior problems. Literature of this syndrome is scanty and confusing, and represents a challenge for pediatricians, in terms of finding the correct diagnoses. CASE PRESENTATION: In a postnatal case with hypotonia and dysmorphic features a de novo ring chromosome r(22) leading to in parallel microdeletion and micro duplication in 22q13 was diagnosed by banding cytogenetics, and further characterized in detail by molecular cytogenetic and chromosomal microarray. CONCLUSION: Here a rare PHMDS case caused by a r(22) is presented. Less than 10 comparable cases are reported in the literature. The present case highlights the importance of conducting genetic counseling and appropriate genetic tests for newborns with mild dysmorphic features.

Variability in Phelan-McDermid Syndrome in a Cohort of 210 Individuals.

Phelan-McDermid syndrome (PMS, OMIM# 606232) results from either different rearrangements at the distal region of the long arm of chromosome 22 (22q13.3) or pathogenic sequence variants in the SHANK3 gene. SHANK3 codes for a structural protein that plays a central role in the formation of the postsynaptic terminals and the maintenance of synaptic structures. Clinically, patients with PMS often present with global developmental delay, absent or severely delayed speech, neonatal hypotonia, minor dysmorphic features, and autism spectrum disorders (ASD), among other findings. Here, we describe a cohort of 210 patients with genetically confirmed PMS. We observed multiple variant types, including a significant number of small deletions (<0.5 Mb, 64/189) and SHANK3 sequence variants (21 cases). We also detected multiple types of rearrangements among microdeletion cases, including a significant number with post-zygotic mosaicism (9.0%, 17/189), ring chromosome 22 (10.6%, 20/189), unbalanced translocations (de novo or inherited, 6.4%), and additional rearrangements at 22q13 (6.3%, 12/189) as well as other copy number variations in other chromosomes, unrelated to 22q deletions (14.8%, 28/189). We compared the clinical and genetic characteristics among patients with different sizes of deletions and with SHANK3 variants. Our findings suggest that SHANK3 plays an important role in this syndrome but is probably not uniquely responsible for all the spectrum features in PMS. We emphasize that only an adequate combination of different molecular and cytogenetic approaches allows an accurate genetic diagnosis in PMS patients. Thus, a diagnostic algorithm is proposed.

Phenotypic Variability in Phelan-McDermid Syndrome and Its Putative Link to Environmental Factors.

Phelan-McDermid syndrome (PMS) is a multi-systemic disorder characterized by both genetic and phenotypic variability. Genetic abnormalities causing PMS span from pathogenic variants of the SHANK3 gene to chromosomal rearrangements affecting the 22q13 region and leading to the loss of up to over nine megabases. The clinical presentation of individuals with PMS includes intellectual disability, neonatal hypotonia, delayed or absent speech, developmental delay, and minor dysmorphic facial features. Several other features may present with differences in age of onset and/or severity: seizures, autism, regression, sleep disorders, gastrointestinal problems, renal disorders, dysplastic toenails, and disrupted thermoregulation. Among the causes of this phenotypic variability, the size of the 22q13 deletion has effects that may be influenced by environmental factors interacting with haploinsufficiency or hemizygous variants of certain genes. Another mechanism linking environmental factors and phenotypic variability in PMS involves the loss of one copy of genes like BRD1 or CYP2D6, located at 22q13 and involved in the regulation of genomic methylation or pharmacokinetics, which are also influenced by external agents, such as diet and drugs. Overall, several non-mutually exclusive genetic and epigenetic mechanisms interact with environmental factors and may contribute to the clinical variability observed in individuals with PMS. Characterization of such factors will help to better manage this disorder.

Phelan-McDermid and general anesthesia with different hypnotics.

Phelan-McDermid syndrome (PMS) is a rare neurodevelopmental disease, caused by an autosomal dominant mutation due to the terminal deletion of 22q13, leading to a defect in the SHANK3 protein. We present the clinical case of a 12-year-old patient with this syndrome, who underwent three interventions that required general anesthesia. In none of them did she present intraoperative or postoperative complications.

Characterisation of the clinical phenotype in Phelan-McDermid syndrome.

BACKGROUND: Phelan-McDermid syndrome (PMS) is a rare genetic disorder compromising the 22q13 terminal region and affecting SHANK3, a gene crucial to the neurobehavioural phenotype and strongly linked to autism (ASD) and intellectual disability (ID). The condition is characterised by global developmental delay, ID, speech impairments, hypotonia and autistic behaviours, although its presentation and symptom severity vary widely. In this study, we provide a thorough description of the behavioural profile in PMS and explore differences related to deletion size and language ability. METHODS: We used standard clinical assessment instruments to measure altered behaviour, adaptive skills and autistic symptomatology in sixty participants with PMS (30 females, median age 8.5 years, SD=7.1). We recorded background information and other clinical manifestations and explored associations with deletion size. We performed descriptive and inferential analyses for group comparison. RESULTS: We found delayed gross and fine motor development, delayed and impaired language (~70% of participants non or minimally verbal), ID of different degrees and adaptive functioning ranging from severe to borderline impairment. Approximately 40% of participants experienced developmental regression, and half of those regained skills. Autistic symptoms were frequent and variable in severity, with a median ADOS-2 CSS score of 6 for every domain. Sensory processing anomalies, hyperactivity, attentional problems and medical comorbidities were commonplace. The degree of language and motor development appeared to be associated with deletion size. CONCLUSIONS: This study adds to previous research on the clinical descriptions of PMS and supports results suggesting wide variability of symptom severity and its association with deletion size. It makes the case for suitable psychotherapeutic and pharmacological approaches, for longitudinal studies to strengthen our understanding of possible clinical courses and for more precise genomic analysis.