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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., (© 2024. The Author(s).)

Background: Phelan-McDermid syndrome (PMS) is a genetic neurodevelopmental disorder caused by SHANK3 haploinsufficiency and is associated with an increased risk for seizures. Previous literature indicates that around one third of individuals with PMS also have epilepsy or seizures, with a wide range of types and ages of onset. Investigating the impact of seizures on intellectual and adaptive functioning for PMS is a primary concern for caregivers and is important to understanding the natural history of this syndrome., Methods: We report on results from 98 individuals enrolled in a prospective, longitudinal study. We detailed seizure frequency, type, and age of onset, and we analyzed seizure occurrence with best estimate IQ, adaptive functioning, clinical features, and genotype. We conducted multiple linear regression analyses to assess the relationship between the presence of seizures and the Vineland Adaptive Behavior Scale, Second Edition (VABS-II) Adaptive Behavior Composite score and the best estimate full-scale IQ. We also performed Chi-square tests to explore associations between seizure prevalence and genetic groupings. Finally, we performed Chi-square tests and t-tests to explore the relationship between seizures and demographic features, features that manifest in infancy, and medical features., Results: Seizures were present in 41% of the cohort, and age of onset was widely variable. The presence of seizures was associated with significantly lower adaptive and intellectual functioning. Genotype-phenotype analyses were discrepant, with no differences in seizure prevalence across genetic classes, but with more genes included in deletions of participants with 22q13 deletions and seizures compared to those with 22q13 deletions and no seizures. No clinical associations were found between the presence of seizures and sex, history of pre- or neonatal complications, early infancy, or medical features. In this cohort, generalized seizures were associated with developmental regression, which is a top concern for PMS caregivers., Conclusions: These results begin to eludicate correlates of seizures in individuals with PMS and highlight the importance of early seizure management. Importantly, presence of seizures was associated with adaptive and cognitive functioning. A larger cohort might be able to identify additional associations with medical features. Genetic findings suggest an increased capability to realize genotype-phenotype relationships when deletion size is taken into account., (© 2024. The Author(s).)

The rare genetic variants 16p11.2 duplication and 16p11.2 deletion have opposing effects on brain structure and function, yet are associated with broadly similar clinical phenotypes that include autism, intellectual impairment, psychiatric illness, and motor difficulties. In recent years, studies have identified subtle distinctions between the phenotypic effects of 16p11.2 duplication and 16p11.2 deletion with respect to patterns of autism, intellectual impairment, and psychiatric illness. However, although divergent phenotypic findings in some motor domains have been reported, no study has yet made a comprehensive comparison of motor difficulties between 16p11.2 deletion and 16p11.2 duplication carriers to elucidate points of convergence and divergence. We sought to make such a comparison in a group of 133 16p11.2 deletion carriers, 122 duplication carriers, and 388 familial controls, hypothesizing that motor impairment would overall be greater in deletion than duplication carriers. In a series of regression models, we found that 16p11.2 deletion status tended to predict greater impairment along indices of gross motor function, but less impairment along indices of fine motor function. These findings point to a potential pattern of performance difficulties that could be investigated in future studies. Elucidating motor differences between 16p11.2 duplication and 16p11.2 deletion carriers may help in understanding the complex effect of 16p11.2 copy number variation and other rare genetic causes of autism., (© 2024 International Society for Autism Research and Wiley Periodicals LLC.)

The authors describe a female in her late twenties, presenting with catatonia and diagnosed with epilepsy, autism spectrum disorder, mild intellectual disability, psychosis, dysthymia, anxiety and bipolar disorder, receiving weekly electroconvulsive therapy (ECT). After testing, findings indicated an interstitial deletion in the 22q13.33 region associated with Phelan-McDermid syndrome. In addition, the patient had low cerebral spinal fluid tetrahydrobiopterin (BH 4 ) levels, suggesting dysfunction in the pterin biosynthetic pathway. As a result, the patient started on sapropterin, a BH 4 replacement small molecule. After sapropterin treatment, catatonia improved, and the need for ECT decreased. There was an improvement in her cognitive ability, attention and independence. However, there has been no improvement in seizure frequency., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: 18q deletion syndrome is a rare genetic disorder characterized by various neurodevelopmental anomalies and medical issues. Although the occurrence of psychosis has been reported in a small number of cases, details regarding the nature of such symptoms and their response to treatment have not been described., Case Presentation: We describe a 31-year-old male with a history of speech delays, autistic features, a tethered spinal cord, bilateral vertical talus, subaortic stenosis and aortic regurgitation, recurrent otitis media, mild hearing loss, and hypospadias, who experienced a first episode of psychosis in his late 20s. His psychotic symptoms included auditory hallucinations, various delusions, and disorganization of thought. Although his presentation is atypical in certain ways (e.g., exhibiting highly fluctuant symptoms), he nonetheless meets criteria for schizophrenia. Given his overall clinical picture, chromosomal microarray analysis was completed, which revealed a 19.78 Mb deletion at 18q21.32 from nucleotide 58,226,713 to 78,015,180 (GRCh37). Despite exhibiting a somewhat idiosyncratic response to numerous antipsychotic medications, he eventually achieved partial remission of symptoms with improved insight on relatively low dose oral aripiprazole therapy., Conclusion: This is the first in-depth description of 18q deletion syndrome-associated schizophrenia. While our patient's atypical presentation and idiosyncratic response to treatment may be mediated by his comorbid diagnosis of autism, his unusual psychiatric phenotype may alternatively be directly related to his underlying genetic disorder. The description of additional cases in the future will hopefully help clarify matters further., (© 2024 S. Karger AG, Basel.)

Background: Phelan-McDermid syndrome is a genetic disorder caused by haploinsufficiency of the SHANK3 gene on chromosome 22q13.3 and is characterized by autism spectrum disorder, intellectual disability, speech and language abnormalities, hypotonia, and mild dysmorphic features. Early literature in Phelan-McDermid syndrome did not include gait abnormalities as part of the syndrome although recent prospective studies report that the prevalence of gait abnormalities ranges from 55% to 94%. We compared gait abnormalities in individuals with Phelan-McDermid syndrome, idiopathic autism spectrum disorder, and typically developing controls, and explored associations between gait abnormalities, autism spectrum disorder, and intellectual functioning. Method: The study cohort consists of 67 participants between the ages of 3 and 18 years, divided into 3 groups: Phelan-McDermid syndrome (n  =  46), idiopathic autism spectrum disorder (n  =  11), and typically developing controls (n  =  10). Gait was recorded using a video camera and scored across 26 gait features using a "Gait Clinical Observations scale" designed specifically for this study. Results: Gait abnormalities were significantly higher in the Phelan-McDermid syndrome group as compared to idiopathic autism spectrum disorder or typically developing controls. The number of gait abnormalities across groups was also significantly correlated with Intellectual Quotient/Developmental Quotient (IQ/DQ). In analysis of covariance including IQ/DQ, the effect of group was not significant, but the effect of IQ/DQ was significant. Conclusions: Overall differences in gait abnormalities were determined by the degree of intellectual disability, which was significantly higher in Phelan-McDermid syndrome., Competing Interests: Declaration of Conflicting InterestsThe authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: AK is on the Advisory Board for the Klingenstein Third Generation Foundation, Ovid Therapeutics, the David Lynch Foundation, ADNP Kids Research Foundation, and Ritrova Therapeutics and consults to Acadia, Alkermes, Jaguar Therapeutics, GW Pharmaceuticals, Neuren Pharmaceuticals, Clinilabs Drug Development Corporation, Scioto Biosciences, and Biogen.

Background: Patients with Trisomy 13(T13) and 18(T18) have many comorbidities that may require surgical intervention. However, surgical care and outcomes are not well described, making patient selection and family counseling difficult. Here the surgical history and outcomes of T13/ T18 patients are explored., Methods: A retrospective review of patients with T13 or T18 born between 1990 and 2020 and cared for at a tertiary children's hospital (Riley Hospital for Children, Indianapolis IN) was conducted, excluding those with insufficient records. Primary outcomes of interest were rates of mortality overall and after surgery. Factors that could predict mortality outcomes were also assessed., Results: One-hundred-seventeen patients were included, with 65% T18 and 35% T13. More than half of patients(65%) had four or more comorbidities. Most deaths occurred by three months at median 42.0 days. Variants of classic trisomies (mosaicism, translocation, partial duplication; p = 0.001), higher birth weight(p = 0.002), and higher gestational age(p = 0.01) were associated with lower overall mortality, while cardiac(p = 0.002) disease was associated with higher mortality. Over half(n = 64) underwent surgery at median age 65 days at time of first procedure. The most common surgical procedures were general surgical. Median survival times were longer in surgical rather than nonsurgical patients(p<0.001). Variant trisomy genetics(p = 0.002) was associated with lower mortality after surgery, while general surgical comorbidities(p = 0.02), particularly tracheoesophageal fistula/esophageal atresia(p = 0.02), were associated with increased mortality after surgery., Conclusions: Trisomy 13 and 18 patients have vast surgical needs. Variant trisomy was associated with lower mortality after surgery while general surgical comorbidities were associated with increased mortality after surgery. Those who survived to undergo surgery survived longer overall., Level of Evidence: III., Competing Interests: Declaration of Competing Interest ATC received financial support to attend the SAGES (Society of American Gastrointestinal and Endoscopic Surgeons) Annual Meeting including registration and travel expenses. BWG served as an independent consultant for MC3 Corp (Dexter, MI) for the design of training in the use of the Crescent RA ECMO cannula. All other authors have nothing to declare., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Early onset sleep problems and disorders are very common in individuals with Phelan-McDermid Syndrome (PMS) with rates of up to 90%. These sleep problems and disorders cannot be taken lightly. Not only do they have a major impact on the health, behaviour, functioning and learning opportunities of affected individuals, they can also have detrimental effects on the well-being and resilience of parents and caregivers, ultimately affecting the physical health, mental health and well-being of the whole social system. In this review we aim to understand the types and frequencies of sleeping problems in PMS as the basis for recommendations on their management and treatment and to provide general guidelines for clinicians and practitioners. We conducted an in-depth literature search, summarised findings, and participated in a series of consensus meetings with other consortium members - experts on PMS and stakeholders - to agree on guidelines and recommendations. In parallel, a world-wide survey was created and distributed amongst parents to include their perspective. Our literature search found only four articles specifically focused on sleeping problems in PMS, although some other articles mentioned prevalence and associated factors. Country-specific prevalence rates ranged between 24% and 46%, whereas our parental survey reported 59%. The main problems reported involved difficulty falling asleep and numerous night awakenings, with being restless in sleep, night-time incontinence, and tooth grinding also commonly reported. Only a small number of individuals had undergone a sleep study monitored by a specialist. Bedtime resistance normally decreases with age, but sleep-onset delay, sleep anxiety, parasomnias, problems falling and remaining asleep remain throughout lifespan, with total sleep time improving during adulthood. However, this improvement was also accompanied by a substantial increase in parasomnias. Ultimately, an increase in sleep disorders in children correlates with increased sleep disorders and daytime sleepiness in parents/caregivers. No study to date has focused on the underlying causes of sleeping problems in PMS, but comorbid mental health conditions, somatic causes, or (poly)pharmacy have been proposed as triggers for sleeping disturbances. Currently there is no PMS-specific treatment for sleeping problems, and current recommendations are mostly based on individuals with intellectual disability and/or neurodevelopmental conditions., (Copyright © 2023 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Deletions and duplications at the chromosomal region of 16p11.2 have a broad range of phenotypic effects including increased likelihood of intellectual disability, autism, attention deficit hyperactivity disorder (ADHD), epilepsy, and language and motor delays. However, whether and how sensory processing is affected has not yet been considered in detail. Parents/caregivers of 38 children with a 16p11.2 deletion and 31 children with a 16p11.2 duplication completed the Sensory Behavior Questionnaire (SBQ) and the Child Sensory Profile 2 (CSP-2) along with other standardized questionnaires assessing autistic traits (SRS-2), ADHD traits (Conners 3), anxiety (SCAS-P) and adaptive behavior (VABS-3). SBQ and CSP-2 responses found that sensory processing differences were clearly evident in both 16p11.2 deletion and 16p11.2 duplication, though there was significant variation in both cohorts. SBQ data indicated the frequency and impact of sensory behavior were more severe when compared to neurotypical children, with levels being similar to autistic children. CSP-2 data indicated over 70% of children displayed clear differences in sensory registration (missing sensory input). Seventy-one percent with 16p11.2 duplications were also unusually sensitive to sensory information and 57% with 16p11.2 duplications were unusually avoidant of sensory stimuli. This first detailed assessment of sensory processing, alongside other clinical features, in relatively large cohorts of children with a 16p11.2 deletion and 16p11.2 duplication demonstrates that sensory processing differences have a profound impact on their lives., (© 2022 The Authors. Autism Research published by International Society for Autism Research and Wiley Periodicals LLC.)

Background: Emanuel Syndrome (ES), a rare chromosomal disorder caused by a supernumerary chromosome 22 derivative (der(22)t(11;22)), was identified in a fetus with congenital diaphragmatic hernia (CDH) at our fetal center. We aimed to identify a precedent for clinical care and patient outcomes to guide family decision-making., Methods: This non-funded and non-registered study queried the entire CDH Registry (CDHR) including >10,000 patients since 1995 and conducted a systematic literature review for patients with concomitant ES and CDH., Results: Literature review captured 12 citations and identified 9 patients with CDH+ES from over 400 known ES cases. Given the rarity of the disease and to reduce bias, there were no exclusion criteria aside from non-English language. Of these 9, two underwent surgical CDH repair with neither surviving. The CDHR identified 6 patients with ES, all reported after 2013 and prenatally diagnosed. Median estimated gestational age was 39 weeks (range 37-40) and median birth weight was 2.72 kg (range 2.4-3.4 kg). 3 patients died within the first few postnatal days; surgical repair was not offered due to "anomalies" and "pulmonary hypertension" in two and one family chose comfort measures. The other 3 patients underwent surgical repair, and 2 were supported with ECMO. Two patients survived to discharge, incurring surgical comorbidities associated with severe CDH including gastrostomy dependence, tracheostomy, and CDH recurrence., Conclusions: ES patients with CDH have potential to tolerate repair and survive to discharge, however with significant additional morbidity combined with severe challenges inherent to ES. This represents the largest series of patients with CDH and ES to date., Level of Evidence: IV (Case series with no comparison group)., (Published by Elsevier Inc.)

The 8p inverted duplication deletion [inv dup del(8p)] is a complex structural rearrangement in chromosome 8. Patients with this chromosomal abnormality exhibit developmental delay, facial dysmorphism, central nervous abnormalities, hypotonia, orthopedic abnormalities, and congenital heart defects. However, cellular immune function in inv dup del(8p) syndrome has never been reported. We present the case of a 1-month-old boy with inv dup del(8p) syndrome who had severe respiratory syncytial (RS) virus bronchiolitis. Natural killer (NK) cells are recruited to airway epithelium in the early phase of RS viral infection. A cluster of defensin genes (DEFs), which are deleted in inv dup del(8p), are located in 8p23.1. Human defensins are involved in antiviral activity through the NK cell-mediated cytotoxic pathway and envelope disruption in the normal immune response. This patient showed lower NK cell activity and α-defensin level compared with healthy controls. These results suggest that decreased NK cell activity can result from DEF haploinsufficiency. In addition to a skeletal deformity with chromosomal abnormality, NK cell-mediated immune deficiency may account for the exacerbation of RS virus bronchiolitis.

Phelan-McDermid syndrome (PMS) is a genetic disorder caused by a mutation or deletion of the SHANK3 gene (chromosome 22q13.3), characterized by different sensory processing anomalies. The objective of this study is to expand and provide a detailed definition of the sensory profile of patients with PMS. The secondary objective was to examine the relationship between sensory patterns and adaptive behavior. A cross-sectional study was carried out among 51 Spanish patients with a confirmed genetic diagnosis of PMS. All the participants' parents completed the Short Sensory Profile-Spanish (SSP-S) and the Adaptive Behavior Assessment System II (ABAS-II). Correlational, multiple regression and hierarchical cluster analyses were performed. An atypical sensory profile was identified in almost 75% of PMS patients. Definite differences were found among scores; nonetheless, sub-threshold values were observed in tactile sensitivity, underresponsive/seeks sensation, auditory filtering, and low energy/weak sensory categories. Conceptual, social, and practical domains, as well as the General Adaptive Composite (GAC) of the ABAS-II showed extremely low scores (i.e., <70). Significant correlations were found (p<0.005) between SSP-S scores and the conceptual, social, practical, and GAC index of the ABAS-II, whereby higher SSP-S scores were associated with better skills and higher adaptive performance. The cluster analysis indicated that the group with the largest mutation size (7.23 Mb) showed the greatest sensory processing difficulties and very low adaptive skills., Conclusions: Patients with PMS show an atypical sensory profile, which correlates with limitations in general adaptive behaviors., What Is Known: • PMS sensory processing difficulties were associated with a pattern of underresponsive/seeks sensation, low energy/weak, and tactile hyporeactivity. • Sensory processing difficulties have been associated with limitations in the development of appropriate adaptive communication and interaction behaviors., What Is New: • Sensory definite differences associated with tactile hyperreactivity, as well as significant effects of underresponsiveness/seeks sensation and auditory filtering categories on the adaptive abilities were found in SHANK3 deletion patients. • Cluster analysis suggests that smaller mutation sizes were related to better sensory processing and higher adaptive skills, while patients with larger deletion sizes have greater adaptive difficulties and worse sensory processing skills., (© 2022. The Author(s).)

Background: Trisomy 13 (T13), trisomy 18 (T18), and trisomy 21 (T21) are the most common autosomal trisomies. One unifying feature of all trisomies is their association with major congenital malformations, which often require life-prolonging surgical procedures. Few studies, mostly among cardiac surgery patients, have examined the outcome of those who undergo surgical procedures. We examined the differences in postsurgical outcomes between the trisomy groups., Method: Using the National Surgical Quality Improvement Program dataset, we identified children (<18 years of age) with T13, T18, or T21 who underwent noncardiac surgery (2012-2018). We estimated the incidence of mortality and indicator of resource utilization (unplanned reoperation, unplanned tracheal reintubation, and extended length of hospital stay)., Results: Of the 349 158 inpatient surgical cases during the study period, we identified 4202 children with one of the autosomal trisomies of interest (T13: 152; T18: 335; and T21: 3715). The rates of postoperative mortality were substantially higher for T18 and T13 than T21 and nontrisomy children (T18 vs. T21: 11.1% vs. 1.6%, adjusted odds ratio: 5.01, 95%CI: 2.89,8.70, p < .01), (T13 vs. T21: 8.1% vs. 1.6%, adjusted odds ratio: 2.86, 95%CI: 1.25,6.54, p = .01). Children with T18 had the highest rates of extended length of stay (62.7%) and prolonged mechanical ventilation (32.5%). T18 and T13 neonates had the highest surgical mortality burden (T13: 26.5%, T18: 31.8%, and T21: 2.8%)., Conclusion: Approximately, one-third of T18 and T13 neonates, who had surgery, died, underscoring the lethality of these trisomies and the need for a comprehensive preoperative ethical discussion with families of these children., (© 2022 John Wiley & Sons Ltd.)

Background: Otodental syndrome and Treacher Collins syndrome are rare diseases that have similar clinical features, which can complicate the diagnostic process. These syndromes cause skeletal and dental abnormalities, the differential diagnosis can be based on clinical signs but only the genetic analysis can confirm it. The aim of this case report is to describe and compare clinical signs of these syndromes., Case Report: A 7-year-old patient came to our department: he presented abnormal tooth shapes and sizes, delayed teeth replacement and micrognathia. After extra- and intra-oral examination and radiographic exams, a clinical diagnosis of otodental syndrome was made, and a genetic testing was requested to confirm the diagnosis., Conclusion: Dental management of patients with otodental syndrome is challenging due to agenesis, teeth malformation, lack of space for permanent dentition. Proper treatment decision is crucial to obtain the best result for the patient.

Objective: Terminal 6q deletion is a rare genetic condition associated with a neurodevelopmental disorder characterized by intellectual disability and structural brain anomalies. Interestingly, a similar phenotype is observed in patients harboring pathogenic variants in the DLL1 gene. Our study aimed to further characterize the prenatal phenotype of this syndrome as well as to attempt to establish phenotype-genotype correlations., Method: We collected ultrasound findings from 22 fetuses diagnosed with a pure 6qter deletion. We reviewed the literature and compared our 22 cases with 14 fetuses previously reported as well as with patients with heterozygous DLL1 pathogenic variants., Results: Brain structural alterations were observed in all fetuses. The most common findings (>70%) were cerebellar hypoplasia, ventriculomegaly, and corpus callosum abnormalities. Gyration abnormalities were observed in 46% of cases. Occasional findings included cerebral heterotopia, aqueductal stenosis, vertebral malformations, dysmorphic features, and kidney abnormalities., Conclusion: This is the first series of fetuses diagnosed with pure terminal 6q deletion. Based on our findings, we emphasize the prenatal sonographic anomalies, which may suggest the syndrome. Furthermore, this study highlights the importance of chromosomal microarray analysis to search for submicroscopic deletions of the 6q27 region involving the DLL1 gene in fetuses with these malformations., (© 2021 John Wiley & Sons Ltd.)

Background: 18q- syndrome is a rare chromosomal disease caused by the deletion of the long arm of chromosome 18. Some cases with 18q- syndrome can be combined with growth hormone deficiency (GHD), but data on the efficacy of recombinant human growth hormone (rhGH) treatment in 18q- syndrome are limited., Methods: Here, we report one case of 18q- syndrome successfully treated with long-term rhGH supplement. Previously reported cases in the literature are also reviewed to investigate the karyotype-phenotype relationship and their therapeutic response to rhGH., Results: A 7.9-year-old girl was referred for evaluation for short stature. Physical exam revealed proportionally short stature with a height of 111.10 cm (-3.02 SD score (SDS)), low-set ears, a high-arched palate, a small jaw, webbed neck, widely spaced nipples, long and tapering fingers, and cubitus valgus. Thyroid function test indicated subclinical hypothyroidism. The peak value of growth hormone was 10.26 ng/ml in the levodopa provocation test. Insulin-like growth factor 1 (IGF-1) was 126 ng/ml (57-316 ng/ml). Other laboratory investigations, including complete blood cell count, liver and kidney function, gonadal function, serum adrenocorticotropin levels, and serum cortisol levels, were all within normal ranges. Karyotype analysis showed 46, XX, del (18) (q21). L-Thyroxine replacement and rhGH treatment were initiated and maintained in the following 7 years. At the age of 14.8, her height has reached 159.5 cm with a height SDS increase of 2.82 SDS (from -3.02 SDS to -0.20 SDS). No significant side effects were found during the treatment. The literature review indicated the average rhGH treatment duration of 16 patients was 5.9 ± 3.3 years, and the average height SDS significantly increased from -3.12 ± 0.94 SDS to -1.38 ± 1.29 SDS after the rhGH treatment (p < 0.0001)., Conclusion: The main clinical manifestations of 18q- syndrome include characteristic appearance, intellectual disability, and abnormal genital development. The literature review suggested a significant height benefit for short stature with 18q- syndrome from long-term rhGH treatment., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Liu, Chen, Yang, Chen, Wang, Duan, Zhu and Pan.)

Background: The current study used eye tracking to investigate attention and recognition memory in Phelan-McDermid syndrome (PMS), a rare genetic disorder characterized by intellectual disability, motor delays, and a high likelihood of comorbid autism spectrum disorder (ASD). Social deficits represent a core feature of ASD, including decreased propensity to orient to or show preference for social stimuli., Methods: We used a visual paired-comparison task with both social and non-social images, assessing looking behavior to a novel image versus a previously viewed familiar image to characterize social attention and recognition memory in PMS (n = 22), idiopathic ASD (iASD, n = 38), and typically developing (TD) controls (n = 26). The idiopathic ASD cohort was divided into subgroups with intellectual disabilities (ID; developmental quotient < 70) and without (developmental quotient > 70) and the PMS group into those with and without a co-morbid ASD diagnosis., Results: On measures of attention, the PMS group with a comorbid ASD diagnosis spent less time viewing the social images compared to non-social images; the rate of looking back and forth between images was lowest in the iASD with ID group. Furthermore, while all groups demonstrated intact recognition memory when novel non-social stimuli were initially presented (pre-switch), participants with PMS showed no preference during the post-switch memory presentation. In iASD, the group without ID, but not the group with ID, showed a novelty preference for social stimuli. Across indices, individuals with PMS and ASD performed more similarly to PMS without ASD and less similarly to the iASD group., Conclusion: These findings demonstrate further evidence of differences in attention and memory for social stimuli in ASD and provide contrasts between iASD and PMS., (© 2021. The Author(s).)

Background: Phelan McDermid syndrome (PMS) is a neurogenetic condition associated with a high prevalence of intellectual disability (ID) and autism spectrum disorder (ASD). This study provides a more comprehensive and quantitative profile of repetitive behaviors within the context of ID seen with the condition., Methods: Individuals age 3-21 years with a confirmed PMS diagnosis participated in a multicenter observational study evaluating the phenotype and natural history of the disorder. We evaluated data collected from this study pertaining to repetitive behaviors from the Repetitive Behavior Scales-Revised (RBS-R)., Results: There were n = 90 participants who were part of this analysis. Forty-seven percent (n = 42/90) were female, and the average age at baseline evaluation was 8.88 ± 4.72 years. The mean best estimate IQ of the cohort was 26.08 ± 17.67 (range = 3.4-88), with n = 8 with mild ID (or no ID), n = 20 with moderate ID, and n = 62 with severe-profound ID. The RBS-R total overall score was 16.46 ± 13.9 (compared to 33.14 ± 20.60 reported in previous studies of ASD) (Lam and Aman, 2007), and the total number of items endorsed was 10.40 ± 6.81 (range = 0-29). After statistical correction for multiple comparisons, IQ correlated with the RBS-R stereotypic behavior subscale score (r s = - 0.33, unadjusted p = 0.0014, adjusted p = 0.01) and RBS-R stereotypic behavior total number of endorsed items (r s = - 0.32, unadjusted p = 0.0019, adjusted p = 0.01). IQ did not correlate with any other RBS-R subscale scores., Conclusions: The RBS-R total overall score in a PMS cohort appears milder compared to individuals with ASD characterized in previous studies. Stereotypic behavior in PMS may reflect cognitive functioning., (© 2021. The Author(s).)

Background: Potocki -Lupski syndrome is an uncommon disorder caused by a micro-duplication in chromosome 17p11.2. Variable clinical manifestations bring troubles to the general and neuraxial anesthesia, including mental retardation, facial dysmorphisms, structural cardiovascular anomalies, scoliosis, and malignant hyperthermia. Until now, the anesthesia management for cesarean section in these patients has not been reported yet., Case Presentation: Here we present a 23-year-old Chinese parturient with Potocki -Lupski syndrome who underwent elective cesarean section under spinal anesthesia. She was transferred to our hospital in her 40th week of gestation. She had a history of IgA nephropathy for more than three years and was diagnosed with Potocki -Lupski syndrome (17p12p11.2 segment 3.1 Mb repeat) in the 29th week of pregnancy. Amniocentesis showed the fetus had no abnormal autosomes. Preoperative multidisciplinary consultation suggested that she should terminate the pregnancy as soon as possible. She was ASA II. Her BMI was 26.43 kg/m 2 . Her airway evaluation was normal. Her spine could bend well and her spinal interspace could be touched clearly. We did the single spinal anesthesia at L2-3 interspace and gave 0.5% bupivacaine 1.7 ml. The absolute anesthesia level reached T8. The Apgar score for the newborn infant was 10 for 1st minute, 5th minute, and 10th minute. The vital signs were steady without using any vasoactive drugs. The patient had a good prognosis, and was subsequently discharged from hospital., Conclusion: To date, the case may be the first reported spinal anesthesia for the parturient with Potocki -Lupski syndrome. Although its manifestations are variable, the spinal anesthesia is feasible under careful and comprehensive preoperative evaluation., (© 2021. The Author(s).)

Phelan-McDermid syndrome (PMS) is a genetic disorder, caused by haploinsufficiency of the SHANK3 gene on chromosome 22q13.3. PMS is characterized by neurobehavioral symptoms and signs including intellectual disability, speech and language impairment, autism spectrum disorder (ASD), hypotonia, and other motor abnormalities. In the brain, SHANK3 is expressed in neurons, especially in the synapse, and encodes a master scaffolding protein that forms a key framework in the postsynaptic density of glutamatergic synapses. Mutations in SHANK3 have also been identified in individuals with ASD, intellectual deficiency (ID), and schizophrenia. Shank3 deficient mice have defects in basal glutamatergic synaptic transmission in the hippocampus, and in synaptic transmission plasticity, including deficits in long-term potentiation, and show behavioral deficits compatible with the clinical manifestations of PMS. The PMS phenotype varies between affected individuals, but ID and speech and language impairment are present in all cases. ASD is present in a great majority of these individuals. Neurological examination demonstrates hypotonia and abnormalities of motor coordination, visual motor coordination, and gait in the majority of affected individuals. Sleep disturbances and increased pain tolerance are frequent parental complaints. Seizures and epilepsy are common, affecting more than 40% of individuals. Brain magnetic resonance imaging abnormalities include corpus callosum hypoplasia, delayed myelination and white matter abnormalities, dilated ventricles, and arachnoid cysts. Recent advanced imaging anatomic studies including diffusion tensor imaging, point to abnormal brain connectivity. The natural history of the syndrome is not yet fully known, but some individuals with PMS have a later onset of psychiatric illnesses including bipolar disease, accompanied by functional and neurological regression. Individuals with the syndrome are treated symptomatically. Advances in understanding the pathophysiology of this syndrome and the generation of animal models have raised opportunities for a biological cure for PMS. A pilot clinical trial with insulin-like growth factor-1 (IGF-1) showed positive effects on some behavioral core symptoms., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Chromosome 4q21 microdeletion leads to a human syndrome that exhibits restricted growth, facial dysmorphisms, mental retardation, and absent or delayed speech. One of the key genes in the affected region of the chromosome is PRKG2, which encodes cGMP-dependent protein kinase II (cGKII). Mice lacking cGKII exhibit restricted growth and deficits in learning and memory, as seen in the human syndrome. However, vocalization impairments in these mice have not been determined. The molecular pathway underlying vocalization impairment in humans is not fully understood. Here, we employed cGKII knockout (KO) mice as a model for the human microdeletion syndrome to test whether vocalizations are affected by loss of the PRKG2 gene. Mice emit ultrasonic vocalizations (USVs) to communicate in social situations, stress, and isolation. We thus recorded ultrasonic vocalizations as a model for human speech. We isolated postnatal day 5-7 pups from the nest to record and analyze USVs and found significant differences in vocalizations of KO mice relative to wild-type and heterozygous mutant mice. KO mice produced fewer calls that were shorter duration and higher frequency. Because neuronal activation in the arcuate nucleus in the hypothalamus is important for the production of animal USVs following isolation from the nest, we assessed neuronal activity in the arcuate nucleus of KO pups following isolation. We found significant reduction of neuronal activation in cGKII KO pups after isolation. Taken together, our studies indicate that cGKII is important for neuronal activation in the arcuate nucleus, which significantly contributes to the production of USVs in neonatal mice. We further suggest cGKII KO mice can be a valuable animal model to investigate pathophysiology of human microdeletion 4q21 syndrome., (Copyright © 2021 Elsevier B.V. All rights reserved.)

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., (© 2021. The Author(s).)

Background: This study aimed to identify best practices for treating 13q deletion syndrome (13q-) patients with retinoblastoma in the era of super-selective ophthalmic artery chemosurgery (OAC) and intravitreal injection therapy (IVIT)., Methods: Retrospective study of 21 eyes from 14 patients with retinoblastoma and 13q- who were treated at Memorial Sloan Kettering Cancer Center (MSKCC) between May 2006 and May 2020, with a mean follow up of 3.7 years. Ocular survival, patient survival, and treatment toxicities were assessed., Results: Nine of the 12 eyes that underwent OAC/IVIT at MSKCC have been progression free for at least 1 year since their last treatments. Fifteen out of 26 OAC cycles resulted in grade 3-4 hematologic toxicity. There was one death from sepsis in the setting of intravenous chemotherapy (IVC) for metastatic disease that occurred after OAC/IVIT therapy. The 2-year Kaplan-Meier ocular survival estimate for the whole cohort was 75% and for the eyes that received OAC or IVIT at MSKCC 83%. For OAC hematologic toxicities, one platelet transfusion and two filgrastim doses were administered, and one patient was hospitalized for neutropenic fevers., Conclusions: The majority of 13q- eyes treated with OAC/IVIT-based regimens can be cured, and there were no deaths related to complications from OAC or IVIT. 13q- Patients did have increased risk of systemic treatment complications, even from super-selective chemotherapies. Despite these toxicities, only one patient developed febrile neutropenia, one patient required a blood product transfusion, and two patients received filgrastim for both OAC and IVC complications. PRÉCIS: Children with 13q deletion syndrome with retinoblastoma managed with intra-arterial and intravitreal chemotherapy have excellent patient and ocular survival with acceptable toxicity., (© 2020 Wiley Periodicals LLC.)

Background: Phelan-McDermid Syndrome (PMS) is a rare condition caused by deletion or mutation of the SHANK3 gene. Individuals with PMS frequently present with intellectual disability, autism spectrum disorder, and other neurodevelopmental challenges. Electroencephalography (EEG) can provide a window into network-level function in PMS., Methods: Here, we analyze EEG data collected across multiple sites in individuals with PMS (n = 26) and typically developing individuals (n = 15). We quantify oscillatory power, alpha-gamma phase-amplitude coupling strength, and phase bias, a measure of the phase of cross frequency coupling thought to reflect the balance of feedforward (bottom-up) and feedback (top-down) activity., Results: We find individuals with PMS display increased alpha-gamma phase bias (U = 3.841, p < 0.0005), predominantly over posterior electrodes. Most individuals with PMS demonstrate positive overall phase bias while most typically developing individuals demonstrate negative overall phase bias. Among individuals with PMS, strength of alpha-gamma phase-amplitude coupling was associated with Sameness, Ritualistic, and Compulsive behaviors as measured by the Repetitive Behavior Scales-Revised (Beta = 0.545, p = 0.011)., Conclusions: Increased phase bias suggests potential circuit-level mechanisms underlying phenotype in PMS, offering opportunities for back-translation of findings into animal models and targeting in clinical trials.

The diagnosis of chromosomal mosaicism in the preimplantation and prenatal stage is fraught with uncertainty and multiple factors need to be considered in order to gauge the likely impact. The clinical effects of chromosomal mosaicism are directly linked to the type of the imbalance (size, gene content, and copy number), the timing of the initial event leading to mosaicism during embryogenesis/fetal development, the distribution of the abnormal cells throughout the various tissues within the body as well as the ratio of normal/abnormal cells within each of those tissues. Additional factors such as assay noise and culture artifacts also have an impact on the significance and management of mosaic cases. Genetic counseling is an important part of educating patients about the likelihood of having a liveborn with a chromosome abnormality and these risks differ according to the time of ascertainment and the tissue where the mosaic cells were initially discovered. Each situation needs to be assessed on a case-by-case basis and counseled accordingly. This review will discuss the clinical impact of finding mosaicism through: embryo biopsy, chorionic villus sampling, amniocentesis, and noninvasive prenatal testing using cell-free DNA., (© 2021 John Wiley & Sons Ltd.)

Purpose of Review: The purpose of this review is to summarize the literature on cognitive development, communication, behavioral or psychiatric aspects in Phelan-McDermid syndrome (PMS) and to discuss the clinical implications and recommendations of these summarized findings., Recent Findings: PMS is often associated with severe communication impairments, behavioral or psychiatric problems and regression. These challenges may adversely affect and impair the quality of life of the individual with PMS and his family., Summary: Individuals with PMS experience intellectual disability, communication and behavioral/psychiatric challenges, such as catatonia, bipolar disorder and regression across the lifespan. Providing appropriate guidance and support to them and their families demands a better understanding of these challenges., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Phelan-McDermid syndrome or 22q13.3 deletion syndrome is a rare neurodevelopmental disorder characterized by neonatal hypotonia, severe speech delay, moderate to profound intellectual disability, and minor dysmorphic features. Regression of developmental milestones is often recognized as characteristic of this syndrome. We report a 6-year-old patient with Phelan-McDermid syndrome who presented with rapid neurologic deterioration secondary to metachromatic leukodystrophy due to a mutation of the arylsulfatase A gene ( ARSA ) on the other allele of 22q13.3. Metachromatic leukodystrophy was diagnosed later after clinical deterioration. Currently, there are no guidelines for screening Phelan-McDermid syndrome patients for metachromatic leukodystrophy. We propose screening for urine sulfatides at the time of Phelan-McDermid syndrome diagnosis to identify patients with pre-symptomatic or early symptomatic metachromatic leukodystrophy as it is important to facilitate discussion of treatment options and prognosis and provide medical surveillance for associated complications.

Purpose: To describe a unique ocular presentation of Cat Eye Syndrome and review the ocular and systemic findings associated with the syndrome., Methods: Case report with multimodal imaging., Results: A newborn female presented with a unilateral Peters anomaly with contralateral microphthalmia with cyst. The patient's other systemic findings included a hypoplastic right heart, persistent ductus arteriosus, intrauterine growth retardation, bilateral anotia, preauricular ear pits and skin tags, micrognathia, hypoplastic female genitalia, and unilateral cranial nerve VII palsy. Chromosomal microarray testing showed tetrasomy of chromosome 22 in the q11.1-q11.21 region consistent with Cat Eye Syndrome. The patient ultimately underwent a successful optical iridectomy on one side and orbitotomy with excision of the cystic mass on the other., Conclusions: The co-occurrence of unilateral Peters anomaly with contralateral microphthalmia with cyst in Cat Eye Syndrome is rare and demonstrative of the syndrome's phenotypic variability. The medical and surgical management of these patients may require a multidisciplinary approach and must be tailored to the individual findings and overall systemic health of the patient.

Mutations in the FMS-like tyrosine kinase 3 (FLT3) gene in 13q12.2 are among the most common driver events in acute leukemia, leading to increased cell proliferation and survival through activation of the phosphatidylinositol 3-kinase/AKT-, RAS/MAPK-, and STAT5-signaling pathways. In this study, we examine the pathogenetic impact of somatic hemizygous 13q12.2 microdeletions in B-cell precursor (BCP) acute lymphoblastic leukemia (ALL) using 5 different patient cohorts (in total including 1418 cases). The 13q12.2 deletions occur immediately 5' of FLT3 and involve the PAN3 locus. By detailed analysis of the 13q12.2 segment, we show that the deletions lead to loss of a topologically associating domain border and an enhancer of FLT3. This results in increased cis interactions between the FLT3 promoter and another enhancer located distally to the deletion breakpoints, with subsequent allele-specific upregulation of FLT3 expression, expected to lead to ligand-independent activation of the receptor and downstream signaling. The 13q12.2 deletions are highly enriched in the high-hyperdiploid BCP ALL subtype (frequency 3.9% vs 0.5% in other BCP ALL) and in cases that subsequently relapsed. Taken together, our study describes a novel mechanism of FLT3 involvement in leukemogenesis by upregulation via chromatin remodeling and enhancer hijacking. These data further emphasize the role of FLT3 as a driver gene in BCP ALL., (© 2020 by The American Society of Hematology.)

Background: Corpus callosum agenesis (ACC) is one of the most frequent Central Nervous System (CNS) malformations. However, genetics underlying isolated forms is still poorly recognized. Here, we report on two female familial cases with partial ACC. The proband shows isolated partial ACC and a mild neurodevelopmental phenotype. A fetus from a previous interrupted pregnancy exhibited a complex phenotype including partial ACC and the occurrence of a de novo 17q12 microduplication, which was interpreted as probably disease-causing., Methods: A trio-based clinical exome sequencing (CES) was performed., Results: Clinical exome sequencing data analysis led to identifying a heterozygous nonsense variant (NM&#95;139058.3:c.922G>T; NP&#95;620689.1:p.Glu308Ter) in the aristaless related homeobox gene (ARX) in the proband, with a putative de novo occurrence, producing a hypothetical protein lacking two essential domains. Sanger analysis confirmed the wild-type status of both parents in different tissues, and disclosed the occurrence of the nonsense variant in the fetus of the interrupted pregnancy, suggesting a formerly unrecognized contribution of the ARX mutation to the fetus' phenotype and gonadal or gonadosomatic mosaicism in one of the parents., Conclusion: This study describes the phenotype associated with a heterozygous loss of function variant in ARX. Moreover, it highlights the importance of investigating both chromosomal and genetic contributions in cases of complex syndromic phenotypes involving CNS., (© 2020 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals LLC.)

Introduction: The infertile male individuals carrying the Y-autosome translocations are seldom reported in clinic. Herein, we described a severe oligozoospermic male with rare unbalanced Y;3 translocation transmitted through 3 generations., Patient Concerns: A 33-year-old Chinese male was referred for infertility consultation in our center after 10 years' primary infertility. He was diagnosed as severe oligozoospermia according to the semen analysis., Diagnosis: G-banding analysis initially described the karyotype as 46, XY, add (3) (p26) for the patient, and his wife's karyotype was 46, XX. The chromosomal microarray analysis identified 3.81Mb and 0.29Mb duplications in Yq11.223q11.23 and Yq12, separately. No deletions were detected in azoospermia factors (AZF)a, AZFb and AZFc. Fluorescence in situ hybridization analysis further confirmed the existence of sex-determining region Y gene and verified that Yq12 was translocated to the terminal short arm of chromosome 3(3p26)., Interventions: The couple chose intracytoplasmic sperm injection to get their offspring. The wife underwent amniocentesis for cytogenetic analysis but suffered termination of pregnancy due to premature rupture of membranes., Outcomes: The karyotype of the patient was finally described as 46, X, der(3)t(Y;3)(q11.22;p26). His father and the aborted fetus showed the same karyotypes as the patient., Conclusion: Our study not only enriched the karyotype-phenotype correlation of Y-autosome translocation, but also strengthened the critical roles of molecular genetic techniques in identifying the chromosomal breakpoints and regions involved.

Juvenile polyposis syndrome (JPS) is a rare autosomal dominant predisposition to hamartomatous polyps within the gastrointestinal tract, at high risk for malignant transformation. BMPR1A and SMAD4 loss-of-function variants account for 50% of the cases. More specifically, point mutations and structural abnormalities in BMPR1A lead to a highly penetrant yet variable phenotype of JPS. Intriguingly, in the developmental disorder caused by a recurrent 10q22.3q23.1 7 Mb deletion which includes BMPR1A, juvenile polyps have never been reported. We present the case of a young adult harboring this recurrent deletion, in a context of intellectual disability, ventricular septal defect and severe juvenile polyposis syndrome diagnosed at the age of 25 years, requiring a surgical preventive colectomy. She developed a gastric adenocarcinoma from which she died at the age of 32. We hypothesize that with the current available pangenomic CNV arrays, the diagnosis of 10q22.3q23.1 deletion is often made several years before the onset of the digestive phenotype, which could explain the absence of reports for juvenile polyps. This observation highlights the importance of an active digestive surveillance of patients with 10q22.3q23.1 deletion., (Copyright © 2019. Published by Elsevier Masson SAS.)

Objectives: Classically, Pierre Robin Sequence (PRS) is a triad of micrognathia, glossoptosis, and airway obstruction, although frequently associated with cleft palate. Current literature reports that Stickler syndrome is the most common syndrome associated with PRS, and 22q11 deletion syndrome (22q11 DS) as the second most common. This study identifies associations between PRS and genetic syndromes., Methods: A retrospective chart review was performed to identify patients diagnosed with PRS over a 10-year period from 4/1/2007 to 4/1/2017 at a tertiary children's hospital., Results: 4,052 consecutive charts were reviewed and 234 patients had a diagnosis of PRS confirmed with the triad of micrognathia, glossoptosis, and airway obstruction. Of note, all of these patients had cleft palate. Of the 234 patients with PRS, 65 patients had syndromic diagnoses (28%). One patient had 22q11 DS (0.43%), and 31 patients had Stickler syndrome (13.2%). Additionally, 3 patients had central hypoventilation syndrome, 3 patients had Duane syndrome, 2 patients had Cornelia de Lange syndrome, 2 patients had Emanuel syndrome, 2 patients had Gordon syndrome, 2 patients had Mobius syndrome, 2 patients had Nager syndrome. Multiple other syndromes were identified, but occurred in isolated cases., Conclusion: This study supports literature that PRS is most commonly associated with Stickler Syndrome but rarely associated with 22q11 DS given that only 1 patient had both PRS and 22q11 DS., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2020 Elsevier B.V. All rights reserved.)

The frequent occurrence of congenital heart defects (CHDs) in chromosome abnormality syndromes is well-known, and among aneuploidy syndromes, distinctive patterns have been delineated. We update the type and frequency of CHDs in the aneuploidy syndromes involving trisomy 13, 18, 21, and 22, and in several sex chromosome abnormalities (Turner syndrome, trisomy X, Klinefelter syndrome, 47,XYY, and 48,XXYY). We also discuss the impact of noninvasive prenatal screening (mainly, cell-free DNA analysis), critical CHD screening, and the growth of parental advocacy on their surgical management and natural history. We encourage clinicians to view the cardiac diagnosis as a "phenotype" which supplements the external dysmorphology examination. When detected prenatally, severe CHDs may influence decision-making, and postnatally, they are often the major determinants of survival. This review should be useful to geneticists, cardiologists, neonatologists, perinatal specialists, other pediatric specialists, and general pediatricians. As patients survive (and thrive) into adulthood, internists and related adult specialists will also need to be informed about their natural history and management., (© 2019 Wiley Periodicals, Inc.)

Purpose: Chromosomal microarray (CMA) is recommended in the diagnostic evaluation of cases with fetal structural anomalies when invasive testing is pursued. However, the utility of CMA for nonimmune hydrops fetalis (NIHF) specifically is not well known. Our objective was to describe the overall yield of CMA in the diagnostic evaluation of NIHF, comparing isolated cases to those with concurrent structural anomalies., Methods: This was a retrospective cohort study of all prenatally diagnosed NIHF cases evaluated at the University of California, San Francisco from 2008 to 2018. NIHF due to twin-twin transfusion syndrome was excluded., Results: There were 131 cases of prenatally diagnosed NIHF. In 43/44 cases with a CMA performed, results were categorized as normal or likely benign. One case was found on CMA to have a large pathogenic duplication of 21p11.2q22.3, which could have been detected by karyotype and was consistent with a diagnosis of Down syndrome. There was no incremental yield demonstrated for CMA over karyotype., Conclusions: Among a cohort of prenatally diagnosed NIHF cases, CMA did not identify any copy number variants beyond those detectable by karyotype, and the vast majority of CMAs were normal. These results suggest that CMA has low diagnostic utility for NIHF., (© 2020 John Wiley & Sons, Ltd.)

Purpose: We sought to determine whether the presence of a systemic SA with potential complicating factors affects waitlist and post-HT outcomes in pediatric patients., Methods: This is a single-center retrospective review of pediatric patients listed for HT between January 1, 2009, and July 1, 2018. Patients were selected based on the presence of any underlying syndromes, which included chromosomal anomalies, skeletal myopathies, connective tissue disorders, mitochondrial disease,and other systemic disorders. Waitlist and post-HT outcomes were compared to those without SA., Results: A total of 243 patients were listed for HT, of which 21 (9%) patients had associated SA. Of those, 16 (76%) survived to transplant, 3 (14%) died while on the waitlist, 1 (5%) improved and was removed from the waitlist, and 1 (5%) patient is currently listed. Waitlist survival was not different between those with/without an associated syndrome (P = 1.0). Among those who survived to HT, there was no difference in listing days (70 vs 90, P = .8), survival to hospital discharge [14 (93%) vs 150 (95%), P = .6], post-HT intubation days (2 vs 2 days, P = .6), or post-HT hospital length of stay (18 vs 18 days, P = .8). Overall survival during the study period post-HT was not different between groups (P = .8)., Conclusion: A SA was present in 9% of pediatric patients wait-listed for HT, but was not associated with an increased waitlist mortality or post-HT hospital morbidity or long-term survival. For several anomalies, HT is safe and feasible., (2019 Wiley Periodicals, Inc.)

A 6-year-old boy, known with Potocki-Lupski syndrome (17p11.2 duplication), mild intellectual disability and constipation, presented with episodes of abdominal pain. His defecation pattern was normal with polyethylene glycol. Physical examination showed a hypertympanic distended abdomen. Extreme dilatation and elongation of the colon was seen on abdominal x-ray, corresponding with aerophagia.

Potocki-Shaffer syndrome (PSS) is a rare contiguous gene deletion syndrome caused by heterozygous deletion of 11p11.2p12. Typical features described in patients with PSS include developmental delay, intellectual disability, multiple cartilaginous exostoses, biparietal foramina, craniofacial abnormalities, and genitourinary anomalies. While hypertension has been noted in three patients with PSS, it has not been described in most patients with this syndrome. This report details the evaluation and treatment of a teenager with PSS who presented on several occasions during childhood with elevated blood pressure measurements. The renin level was elevated, likely indicating a secondary cause for the HTN. The patient's BP responded to monotherapy with Angiotensin Converting Enzyme Inhibitor (ACEI)., (Copyright © 2019. Published by Elsevier Masson SAS.)

Aims: Phelan-McDermid syndrome (PMD) is a congenital syndrome caused by a deletion on chromosome 22q13.3. About 600 cases have been identified worldwide. PMD is characterized by neonatal hypotonia, moderate/severe intellectual impairment, impaired expressive language, and typical dysmorphic features. Psychological symptoms as hyperactivity, attention problems, restlessness, and stereotyped-repetitive behavior were reported. The aim of the study was to assess incontinence and associated psychological problems in PMD., Methods: Forty-one individuals with PMD were recruited through a German support group (48.8% male; mean age 13.4 years; range, 4-55 years). Parents or caregivers completed the developmental behavior checklist (DBC), as well as the parental questionnaire: enuresis/urinary incontinence, including six questions on adaptive toileting skills., Results: Rates of nocturnal enuresis (NE), daytime urinary incontinence, and fecal incontinence were 86%, 73%, and 79%. Rates were similar in all age groups (children, teens, adults). Constipation was present in 19%. Forty-two percent of the sample had a clinically relevant DBC score, with adults more affected than teens. Persons with NE had significantly higher "anxiety/depression" subscale scores. Toileting skills were more developed in adults than in children. Sixty-eight percent had further physical disabilities., Conclusions: Incontinence rates in PMD are high in all age groups. However, persons with PMD can improve their toilet skills. Therefore, the assessment and treatment of incontinence in persons with PMD is recommended. Constipation does not seem to be a major problem in PMD. Due to the high prevalence rates of somatic conditions, an assessment for organic and functional incontinence is recommended., (© 2019 Wiley Periodicals, Inc.)

A young man with neuropsychiatric problems has a small 22q13.33 duplication. We suggest this causes his condition. His disorder may represent a 22q13.33 behavioural phenotype. In childhood, he was diagnosed with mild intellectual disability. He was later diagnosed with Tourette syndrome, atypical autism spectrum disorder and bipolar disorder. Lithium seems effective in treating his affective symptoms. He has mild dysmorphic features, full lips and protruding ears. An array comparative genomic hybridisation showed a 300 kb duplication. The duplication harbours several genes, notably SH3 and multiple ankyrin repeat domain 3 (SHANK 3). The small size helps focus on a critical region for a 22q13.33 duplication syndrome. Mutations, deletions and duplications should be kept in mind as causes of neuropsychiatric disorders, especially in a patient with dysmorphic traits., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

We encountered an extremely rare case where a patient with cat eye syndrome (CES) who presented with symptoms of posterior semicircular canal dehiscence (PSCD). CES is a rare genetic disorder, resulting from duplication of chromosome 22. Patients may present with variable phenotypes, including characteristic of coloboma, heart defect, periauricular skin pit/tag, microtia, anal atresia and mildly retarded mental development in some cases. PSCD is also a disease of the inner ear, where patients present with third window signs and symptoms due to lack of bony coverage. PSCD is usually associated with a high riding jugular bulb and fibrous dysplasia. In this study, we report a new otologic finding in CES patient as an association of PSCD and high jugular pulp. We describe the work up and its findings and the management of this patient. SIMILAR CASES PUBLISHED:: None.

Background: Neurodevelopmental disorders such as 16p11.2 syndrome are frequently associated with motor impairments including locomotion. The lack of precise measures of gait, combined with the challenges inherent in studying children with neurodevelopmental disorders, hinders quantitative motor assessments. Gait and balance are quantifiable measures that may help to refine the motor phenotype in 16p11.2. The characterization of motor profile is useful to study the trajectories of locomotion performance of children with genetic variants and may provide insights into neural pathway dysfunction based on genotype/phenotype model., Methods: Thirty-six children (21 probands with 16p11.2 deletion and duplication mutation and 15 unaffected siblings), with a mean age of 8.5 years (range 3.2-15.4) and 55% male, were enrolled. Of the probands, 23% (n = 6) had a confirmed diagnosis of autism spectrum disorder (ASD) and were all male. Gait assessments included 6-min walk test (6MWT), 10-m walk/run test (10MWR), timed-up-and-go test (TUG), and spatio-temporal measurements of preferred- and fast-paced walking. The Pediatric Evaluation of Disability Inventory-Computer Adaptive Tests (PEDI-CAT), a caregiver-reported functional assessment, was administered. Measures of balance were calculated using percent time in double support and base of support. Analyses of the six children with ASD were described separately., Results: Thirty-six participants completed the protocol. Compared with sibling controls, probands had significantly lower scores on the 6MWT (p = 0.04), 10MWR (p = 0.01), and TUG (p = 0.005). Group differences were also identified in base of support (p = 0.003). Probands had significantly lower PEDI-CAT scores in all domains including the mobility scale (p < 0.001). Using age-matched subsamples, the ASD and non-ASD genetic variant groups had larger base of support compared to the controls. In the fast-paced condition, all participants increased their velocity, and there was a corresponding decrease in percent time in double support compared to the preferred-pace condition in all participants. Only the ASD group presented with upper limb arm/hand stereotypies., Conclusions: Children with 16p11.2, with and without ASD, present with balance impairment during locomotion activities. Probands performed worse on functional assessments, and quantitative measures revealed differences in base of support. These results highlight the importance of using precise measures to differentiate motor dysfunction in children with neurodevelopmental disorders.