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Background: Autism spectrum disorder (ASD) is a highly heritable, genetically complex neurodevelopmental disorder. Genetic liability is often expressed among relatives through subclinical, genetically meaningful traits, or endophenotypes. Studies of parents of individuals with ASD suggest important differences from controls in language-related skills in particular, including evidence that such differences may emerge in childhood, that may serve as early markers of genetic liability to ASD. This study investigated whether developmental academic profiles may be evident among clinically unaffected siblings of individuals with ASD, and possibly constitute developmental endophenotypic markers of ASD genetic risk among relatives. Methods: Longitudinal, archival academic testing records were studied to characterize developmental profiles in the domains of language, reading, and math, among clinically unaffected siblings of individuals with ASD. Relationships were explored between siblings’ childhood academic profiles and subclinical ASD-related traits, and the familiality of such traits. Results: Results revealed relatively lower performance in language-related academic skills among siblings of individuals with ASD, mirroring patterns previously reported among parents. Relationships were detected between siblings’ academic performance patterns and subclinical ASD-related traits in themselves and their parents, and with symptom severity in their sibling with ASD. Language phenotypes were associated in mother-sibling dyads, and rigidity and math performance associated in father-child dyads. Limitations: Data from this study represent a relatively small and racially homogenous group of siblings of individuals with ASD, and as such, replication in a larger more diverse sample should be completed to increase generalizability. Conclusions: Distinctive profiles of academic development were evident in siblings in language-related skills, mirroring prior findings in parents, suggesting specific and subtle phenotypes that may represent early-emerging indicators of genetic liability to ASD and are measurable in first-degree relatives using standardized academic testing. Results also suggest differential intergenerational transmission of ASD-related traits between mothers and fathers.

OBJECTIVE Autism spectrum disorder (ASD) is a complex neurodevelopmental condition characterized by core deficits in social communication and restricted and repetitive behaviors and interests. Recent advances in clinical genetics have improved our understanding of genetic syndromes associated with ASD, which has helped clarify distinct etiologies of ASD and document syndrome-specific profiles of neurocognitive strengths and weaknesses. Pediatric neuropsychologists have the potential to be impactful members of the care team for children with genetic syndromes and their families. METHOD We provide a critical review of the current literature related to the neuropsychological profiles of children with four genetic syndromes associated with ASD, including Tuberous Sclerosis Complex (TSC), fragile X syndrome (FXS), 22q11.2 deletion syndrome, and Angelman syndrome. Recommendations for assessment, intervention, and future directions are provided. RESULTS There is vast heterogeneity in terms of the cognitive, language, and developmental abilities of these populations. The within- and across-syndrome variability characteristic of genetic syndromes should be carefully considered during clinical evaluations, including possible measurement limitations, presence of intellectual disability, and important qualitative differences in the ASD-phenotypes across groups. CONCLUSIONS Individuals with genetic disorders pose challenging diagnostic and assessment questions. Pediatric neuropsychologists with expertise in neurodevelopmental processes are well suited to address these questions and identify profiles of neurocognitive strengths and weaknesses, tailor individualized recommendations, and provide diagnostic clarification.

The FMR1 gene in its premutation (PM) state has been linked to a range of clinical and subclinical phenotypes among FMR1 PM carriers, including some subclinical traits associated with autism spectrum disorder (ASD). This study attempted to further characterize the phenotypic profile associated with the FMR1 PM by studying a battery of assessments examining clinical-behavioral traits, social-cognitive, and executive abilities in women carrying the FMR1 PM, and associations with FMR1-related variability. Participants included 152 female FMR1 PM carriers and 75 female controls who were similar in age and IQ, and screened for neuromotor impairments or signs of fragile X-associated tremor/ataxia syndrome. The phenotypic battery included assessments of ASD-related personality and language (i.e., pragmatic) traits, symptoms of anxiety and depression, four different social-cognitive tasks that tapped the ability to read internal states and emotions based on different cues (e.g., facial expressions, biological motion, and complex social scenes), and a measure of executive function. Results revealed a complex phenotypic profile among the PM carrier group, where subtle differences were observed in pragmatic language, executive function, and social-cognitive tasks that involved evaluating basic emotions and trustworthiness. The PM carrier group also showed elevated rates of ASD-related personality traits. In contrast, PM carriers performed similarly to controls on social-cognitive tasks that involved reliance on faces and biological motion. The PM group did not differ from controls on self-reported depression or anxiety symptoms. Using latent profile analysis, we observed three distinct subgroups of PM carriers who varied considerably in their performance across tasks. Among PM carriers, CGG repeat length was a significant predictor of pragmatic language violations. Results suggest a nuanced phenotypic profile characterized by subtle differences in select clinical-behavioral, social-cognitive, and executive abilities associated with the FMR1 PM in women.

Background The Pediatric Heart Network Collaborative Learning Study (PHN CLS) increased early extubation after infant tetralogy of Fallot (TOF) and coarctation repair overall at participating sites through implementing a clinical practice guideline (CPG). We evaluated variability across sites in CPG implementation and outcomes. Methods Patient characteristics and outcomes (time to extubation, length of stay [LOS]) were compared across sites, including pre-CPB to post-CPG changes. Semistructured interviews were analyzed to assess similarities and differences in implementation strategies across sites. Results A total of 322 patients were included (4 active sites, 1 model site). Patient characteristics were similar across active sites, whereas pre-CPG median time to extubation varied from 15.4 to 35.5 hours. All active sites had a significant post-CPG decline (p Conclusions All PHN CLS sites successfully reduced time to extubation. The magnitude of change varied and may be partly explained by different CPG implementation strategies. These data can guide CPG dissemination and design of future improvement projects.

Purpose Pragmatic language skills are often impaired above and beyond general language delays in individuals with neurodevelopmental disabilities. This study used a multimethod approach to language sample analysis to characterize syndrome- and sex-specific profiles across different neurodevelopmental disabilities and to examine the congruency of 2 analysis techniques. Method Pragmatic skills of young males and females with fragile X syndrome with autism spectrum disorder (FXS-ASD, n = 61) and without autism spectrum disorder (FXS-O, n = 40), Down syndrome (DS, n = 42), and typical development (TD, n = 37) and males with idiopathic autism spectrum disorder only (ASD-O, n = 29) were compared using variables obtained from a detailed hand-coding system contrasted with similar variables obtained automatically from the language analysis program Systematic Analysis of Language Transcripts (SALT). Results Noncontingent language and perseveration were characteristic of the pragmatic profiles of boys and girls with FXS-ASD and boys with ASD-O. Boys with ASD-O also initiated turns less often and were more nonresponsive than other groups, and girls with FXS-ASD were more nonresponsive than their male counterparts. Hand-coding and SALT methods were largely convergent with some exceptions. Conclusion Results suggest both similarities and differences in the pragmatic profiles observed across different neurodevelopmental disabilities, including idiopathic and FXS-associated cases of ASD, as well as an important sex difference in FXS-ASD. These findings and congruency between the 2 language sample analysis techniques together have important implications for assessment and intervention efforts.

Pragmatic language is a characteristic weakness in the language profile of individuals with fragile X syndrome (FXS), the most frequent inherited cause of intellectual disability and among the most common known genetic causes of autism spectrum disorder (ASD). However, pragmatic language profiles in FXS are known to be highly heterogeneous, and influenced by other cognitive factors, sex, and ASD status. In this chapter, we review pragmatic strengths and weaknesses across males and females with FXS, including comparisons with individuals with Down syndrome (another form of intellectual disability) as well as the impact of ASD status on pragmatics in FXS. We also consider the role of related underlying mechanisms (e.g. theory of mind, hyperarousal) that may importantly impact pragmatic language profiles, and discuss sex-specific differences. We conclude this chapter with directions for continued investigation and clinical considerations for assessment and intervention.

Background: Acute decompensated heart failure (ADHF) is a highly morbid condition among adults. Little is known about outcomes in children with ADHF. We analyzed the Pediatric Cardiac Critical Care Consortium registry to determine the epidemiology, contemporary treatments, and predictors of mortality in critically ill children with ADHF. Methods: Cardiac intensive care unit (CICU) patients ≤18 years of age meeting Pediatric Cardiac Critical Care Consortium criteria for ADHF were included. ADHF was defined as systolic or diastolic dysfunction requiring continuous vasoactive or diuretic infusion, respiratory support, or mechanical circulatory support. Demographics, diagnosis, therapies, complications, and mortality are described for the cohort. Predictors of CICU mortality were identified using logistic regression. Results: Among 26 294 consecutive admissions (23 centers), 1494 (6%) met criteria for analysis. Median age was 0.93 years (interquartile range, 0.1–9.3 years). Patients with congenital heart disease (CHD) comprised 57% of the cohort. Common therapies included the following: vasoactive infusions (88%), central venous catheters (86%), mechanical ventilation (59%), and high flow nasal cannula (46%). Common complications were arrhythmias (19%), cardiac arrest (10%), sepsis (7%), and acute renal failure requiring dialysis (3%). Median length of CICU stay was 7.9 days (interquartile range, 3–18 days) and the CICU readmission rate was 22%. Overall, CICU mortality was 15% although higher for patients with CHD versus non-CHD (19% versus 11%; P Conclusions: ADHF in children is characterized by comorbidities, high mortality rates, and frequent readmission, especially among patients with CHD. Opportunities exist to determine best practices around appropriate use of mechanical support, cardiac arrest prevention, and optimal heart transplantation candidacy to improve outcomes for these patients.

BackgroundAutism spectrum disorder (ASD) is a multifactorial, neurodevelopmental disorder that encompasses a complex and heterogeneous set of traits. Subclinical traits that mirror the core features of ASD, referred to as the broad autism phenotype (BAP) have been documented repeatedly in unaffected relatives and are believed to reflect underlying genetic liability to ASD. The BAP may help inform the etiology of ASD by allowing the stratification of families into more phenotypically and etiologically homogeneous subgroups. This study explored polygenic scores related to the BAP.MethodsPhenotypic and genotypic information were obtained from 2,614 trios from Simons Simplex Sample. Polygenic scores of ASD (ASD-PGS) were generated across the sample to determine the shared genetic overlap between the BAP and ASD. Maternal and Paternal ASD-PGS was explored in relation to BAP traits and their child ASD symptomatology.ResultsMaternal pragmatic language was related to child’s social communicative atypicalities. In fathers, rigid personality was related to increased repetitive behaviors in children. Maternal (but not paternal) ASD-PGS was related to the pragmatic language and rigid BAP domains.ConclusionsDomain- and sex-specific associations emerged between parent and child phenotypes. ASD-PGS associations emerged with BAP in mothers only, highlighting the potential for a female protective factor, and implicating the polygenic etiology of ASD-related phenotypes in the BAP.

Background Autism spectrum disorder (ASD) is a multifactorial neurodevelopmental disorder that encompasses a complex and heterogeneous set of traits. Subclinical traits that mirror the core features of ASD, referred to as the broad autism phenotype (BAP), have been documented repeatedly in unaffected relatives and are believed to reflect underlying genetic liability to ASD. The BAP may help inform the etiology of ASD by allowing the stratification of families into more phenotypically and etiologically homogeneous subgroups. This study explores polygenic scores related to the BAP. Methods Phenotypic and genotypic information were obtained from 2614 trios from the Simons Simplex Collection. Polygenic scores of ASD (ASD-PGSs) were generated across the sample to determine the shared genetic overlap between the BAP and ASD. Maternal and paternal ASD-PGSs were explored in relation to BAP traits and their child's ASD symptomatology. Results Maternal pragmatic language was related to child’s social communicative atypicalities. In fathers, rigid personality was related to increased repetitive behaviors in children. Maternal (but not paternal) ASD-PGSs were related to the pragmatic language and rigid BAP domains. Conclusions Associations emerged between parent and child phenotypes, with more associations emerging in mothers than in fathers. ASD-PGS associations emerged with BAP in mothers only, highlighting the potential for a female protective factor, and implicating the polygenic etiology of ASD-related phenotypes in the BAP.

This longitudinal study examined pragmatic language in boys and girls with Down syndrome (DS) at up to three time points, using parent report, standardized and direct assessments. We also explored relationships among theory of mind, executive function, nonverbal mental age, receptive and expressive vocabulary, grammatical complexity, and pragmatic competence. Controlling for cognitive and language abilities, children with DS demonstrated greater difficulty than younger typically developing controls on parent report and standardized assessments, but only girls with DS differed on direct assessments. Further, pragmatic skills of individuals with DS developed at a delayed rate relative to controls. Some sex-specific patterns of pragmatic impairments emerged. Theory of mind and executive function both correlated with pragmatic competence. Clinical and theoretical implications are discussed.

BACKGROUND. Postoperative length of stay (LOS) is an important quality metric and is known to vary widely across hospitals after congenital heart surgery. Whether this variability is explained by factors associated with the intensive care unit (ICU) or acute care unit (ACU) remains unclear. We evaluated the relationship between ICU and ACU LOS and the impact of ACU characteristics on postoperative LOS. METHODS. Hospitalizations for congenital heart surgery within the Pediatric Cardiac Critical Care Consortium (PC(4)) registry (August 2014 to February 2018) were included. Models were developed for ICU, ACU, and postoperative LOS by adjusting for differences in case-mix across hospitals. PC(4) hospitals participating in the Pediatric Acute Care Cardiology Collaborative (PAC(3)) were also surveyed on ACU organizational factors and practice patterns. RESULTS. Overall, 19,674 hospitalizations across 27 hospitals were included. There was significant variation in ICU and ACU LOS. Postperative LOS appeared to be most closely related to ICU LOS; 75% (6 of 8) of hospitals with shorter than expected postoperative LOS also had shorter than expected ICU LOS. A clear relationship between postoperative and ACU LOS was not observed. Hospitals with an ACU able to provide higher-acuity care as indexed according to the PAC(3) survey were more likely to have shorter postoperative LOS (P < .01). CONCLUSIONS. For hospitals that achieve shorter than expected postoperative LOS after congenital heart surgery, ICU LOS appears to be the primary driver. Higher-acuity resources in the ACU may be an important factor facilitating earlier transfer from the ICU. These data are key to informing quality improvement initiatives geared toward reducing postoperative LOS.

Prolonged pleural drainage is a common complication in patients after Fontan palliation and is associated with short- and long- term morbidities. Among many potential etiologies, prolonged drainage has an inflammatory component, but there are no descriptions of cytokines in Fontan pleural drainage to date. This study aimed to examine the inflammatory make-up of Fontan pleural drainage. This prospective age-range-matched cohort study recruited 25 patients undergoing Fontan procedure and 15 bi-ventricular patients undergoing cardiopulmonary bypass (CPB). Chest tube samples were taken on postoperative day (POD) 1–4, 7, and 10. Cytokines were measured using Bio-Plex Assays. Univariate comparisons were made in patient characteristics and cytokine levels. Median age was 3.7 y (IQR 2.8–3.9) for controls and 2.5 y (IQR 2.1–2.9) in Fontan patients (p = 0.02). Median drainage duration and daily volume was higher in Fontan patients (both p

Many hospitals aim to extubate children early after cardiac surgery, yet it remains unclear how this practice associates with extubation failure. We evaluated adjusted extubation failure rates and duration of postoperative mechanical ventilation across hospitals and assessed cardiac ICU organizational factors associated with extubation failure.Secondary analysis of the Pediatric Cardiac Critical Care Consortium clinical registry.Pediatric Cardiac Critical Care Consortium cardiac ICUs.Patients with qualifying index surgical procedures from August 2014 to June 2017.None.We modeled hospital-level adjusted extubation failure rates using multivariable logistic regression. A previously validated Pediatric Cardiac Critical Care Consortium model was used to calculate adjusted postoperative mechanical ventilation. Observed-to-expected ratios for both metrics were derived for each hospital to assess performance. Hierarchical logistic regression was used to assess the association between cardiac ICU factors and extubation failure. Overall, 16,052 surgical hospitalizations were analyzed. Predictors of extubation failure (p0.05 in final case-mix adjustment model) included younger age, underweight, greater surgical complexity, airway anomaly, chromosomal anomaly/syndrome, longer cardiopulmonary bypass time, and other preoperative comorbidities. Three hospitals were better-than-expected outliers for extubation failure (95% CI around observed-to-expected1), and three hospitals were worse-than-expected (95% CI around observed-to-expected1). Two hospitals were better-than-expected outliers for both extubation failure and postoperative mechanical ventilation, and three were worse-than-expected for both. No hospital was an outlier in opposite directions. Greater nursing hours per patient day and percent nursing staff with critical care certification were associated with lower odds of extubation failure. Cardiac ICU factors such as fewer inexperienced nurses, greater percent critical care trained attendings, cardiac ICU-dedicated respiratory therapists, and fewer patients per cardiac ICU attending were not associated with lower odds of extubation failure.We saw no evidence that hospitals trade higher extubation failure rates for shorter duration of postoperative mechanical ventilation after pediatric cardiac surgery. Increasing specialized cardiac ICU nursing hours per patient day may achieve better extubation outcomes and mitigate the impact of inexperienced nurses.

Autism spectrum disorder (ASD) and intellectual disability (ID) can be caused by mutations in a large number of genes. One example is SHANK3 on the terminal end of chromosome 22q. Loss of one functional copy of SHANK3 results in 22q13 deletion syndrome or Phelan-McDermid syndrome (PMS) and causes a monogenic form of ASD and/or ID with a frequency of 0.5% to 2% of cases. SHANK3 is the critical gene in this syndrome, and its loss results in disruption of synaptic function. With chromosomal microarray analyses now a standard of care in the assessment of ASD and developmental delay, and with the emergence of whole exome and whole genome sequencing in this context, identification of PMS in routine clinical settings will increase significantly. However, PMS remains a rare disorder, and the majority of physicians have never seen a case. While there is agreement about core deficits of PMS, there have been no established parameters to guide evaluation and medical monitoring of the syndrome. Evaluations must include a thorough history and physical and dysmorphology examination. Neurological deficits, including the presence of seizures and structural brain abnormalities should be assessed as well as motor deficits. Endocrine, renal, cardiac, and gastrointestinal problems all require assessment and monitoring in addition to the risk of recurring infections, dental and vision problems, and lymphedema. Finally, all patients should have cognitive, behavioral, and ASD evaluations. The objective of this paper is to address this gap in the literature and establish recommendations to assess the medical, genetic, and neurological features of PMS.

BACKGROUND:\ud SCN2A is a gene that codes for the alpha subunit of voltage-gated, type II sodium channels, and is highly expressed in the brain. Sodium channel disruptions, such as mutations in SCN2A, may play an important role in psychiatric disorders. Recently, de novo SCN2A mutations in autism spectrum disorder (ASD) have been identified. The current study characterizes a de novo splice site mutation in SCN2A that alters mRNA and protein products.\ud \ud CASE PRESENTATION:\ud We describe results from clinical and genetic characterizations of a seven-year-old boy with ASD. Psychiatric interview and gold standard autism diagnostic instruments (ADOS and ADI-R) were used to confirm ASD diagnosis, in addition to performing standardized cognitive and adaptive functioning assessments (Leiter-R and Vineland Adaptive Behavior Scale), and sensory reactivity assessments (Sensory Profile and Sensory Processing Scales). Genetic testing by whole exome sequencing revealed four de novo events, including a splice site mutation c.476 + 1G > A in SCN2A, a missense mutation (c.2263G > A) causing a p.V755I change in the TLE1 gene, and two synonymous mutations (c.2943A > G in the BUB1 gene, and c.1254 T > A in C10orf68 gene). The de novo SCN2A splice site mutation produced a stop codon 10 amino acids downstream, possibly resulting in a truncated protein and/or a nonsense-mediated mRNA decay. The participant met new DSM-5 criteria for ASD, presenting with social and communication impairment, repetitive behaviors, and sensory reactivity issues. The participant's adaptive and cognitive skills fell in the low range of functioning.\ud \ud CONCLUSION:\ud This report indicates that a splice site mutation in SCN2A might be contributing to the risk of ASD. Describing the specific phenotype associated with SCN2A mutations might help to reduce heterogeneity seen in ASD.

Background Phelan-McDermid syndrome (PMS), a neurodevelopmental disorder caused by deletion or mutation in the SHANK3 gene, is one of the more common single-locus causes of autism spectrum disorder (ASD). PMS is characterized by global developmental delay, hypotonia, delayed or absent speech, increased risk of seizures, and minor dysmorphic features. Impairments in language and communication are one of the most consistent characteristics of PMS. Although there is considerable overlap in the social communicative deficits associated with PMS and ASD, there is a dearth of data on underlying abnormalities at the level of neural systems in PMS. No controlled neuroimaging studies of PMS have been reported to date. The goal of this study was to examine the neural circuitry supporting the perception of auditory communicative signals in children with PMS as compared to idiopathic ASD (iASD). Methods Eleven children with PMS and nine comparison children with iASD were scanned using functional magnetic resonance imaging (fMRI) under light sedation. The fMRI paradigm was a previously validated passive auditory task, which presented communicative (e.g., speech, sounds of agreement, disgust) and non-communicative vocalizations (e.g., sneezing, coughing, yawning). Results Previous research has shown that the superior temporal gyrus (STG) responds selectively to communicative vocal signals in typically developing children and adults. Here, selective activity for communicative relative to non-communicative vocalizations was detected in the right STG in the PMS group, but not in the iASD group. The PMS group also showed preferential activity for communicative vocalizations in a range of other brain regions associated with social cognition, such as the medial prefrontal cortex (MPFC), insula, and inferior frontal gyrus. Interestingly, better orienting toward social sounds was positively correlated with selective activity in the STG and other “social brain” regions, including the MPFC, in the PMS group. Finally, selective MPFC activity for communicative sounds was associated with receptive language level in the PMS group and expressive language in the iASD group. Conclusions Despite shared behavioral features, children with PMS differed from children with iASD in their neural response to communicative vocal sounds and showed relative strengths in this area. Furthermore, the relationship between clinical characteristics and neural selectivity also differed between the two groups, suggesting that shared ASD features may partially reflect different neurofunctional abnormalities due to differing etiologies. Electronic supplementary material The online version of this article (doi:10.1186/s11689-016-9138-9) contains supplementary material, which is available to authorized users.

Phelan-McDermid syndrome (PMS), a neurodevelopmental disorder caused by deletion or mutation in the SHANK3 gene, is one of the more common single-locus causes of autism spectrum disorder (ASD). PMS is characterized by global developmental delay, hypotonia, delayed or absent speech, increased risk of seizures, and minor dysmorphic features. Impairments in language and communication are one of the most consistent characteristics of PMS. Although there is considerable overlap in the social communicative deficits associated with PMS and ASD, there is a dearth of data on underlying abnormalities at the level of neural systems in PMS. No controlled neuroimaging studies of PMS have been reported to date. The goal of this study was to examine the neural circuitry supporting the perception of auditory communicative signals in children with PMS as compared to idiopathic ASD (iASD).Eleven children with PMS and nine comparison children with iASD were scanned using functional magnetic resonance imaging (fMRI) under light sedation. The fMRI paradigm was a previously validated passive auditory task, which presented communicative (e.g., speech, sounds of agreement, disgust) and non-communicative vocalizations (e.g., sneezing, coughing, yawning).Previous research has shown that the superior temporal gyrus (STG) responds selectively to communicative vocal signals in typically developing children and adults. Here, selective activity for communicative relative to non-communicative vocalizations was detected in the right STG in the PMS group, but not in the iASD group. The PMS group also showed preferential activity for communicative vocalizations in a range of other brain regions associated with social cognition, such as the medial prefrontal cortex (MPFC), insula, and inferior frontal gyrus. Interestingly, better orienting toward social sounds was positively correlated with selective activity in the STG and other "social brain" regions, including the MPFC, in the PMS group. Finally, selective MPFC activity for communicative sounds was associated with receptive language level in the PMS group and expressive language in the iASD group.Despite shared behavioral features, children with PMS differed from children with iASD in their neural response to communicative vocal sounds and showed relative strengths in this area. Furthermore, the relationship between clinical characteristics and neural selectivity also differed between the two groups, suggesting that shared ASD features may partially reflect different neurofunctional abnormalities due to differing etiologies.

Background: Autism spectrum disorder (ASD) is now understood to have multiple genetic risk genes and one example is SHANK3. SHANK3 deletions and mutations disrupt synaptic function and result in Phelan-McDermid syndrome (PMS), which causes a monogenic form of ASD with a frequency of at least 0.5% of ASD cases. Recent evidence from preclinical studies with mouse and human neuronal models of SHANK3 deficiency suggest that insulin-like growth factor-1 (IGF-1) can reverse synaptic plasticity and motor learning deficits. The objective of this study was to pilot IGF-1 treatment in children with PMS to evaluate safety, tolerability, and efficacy for core deficits of ASD, including social impairment and restricted and repetitive behaviors. Methods: Nine children with PMS aged 5 to 15 were enrolled in a placebo-controlled, double-blind, crossover design study, with 3 months of treatment with IGF-1 and 3 months of placebo in random order, separated by a 4-week wash-out period. Results: Compared to the placebo phase, the IGF-1 phase was associated with significant improvement in both social impairment and restrictive behaviors, as measured by the Aberrant Behavior Checklist and the Repetitive Behavior Scale, respectively. IGF-1 was found to be well tolerated and there were no serious adverse events in any participants. Conclusions: This study establishes the feasibility of IGF-1 treatment in PMS and contributes pilot data from the first controlled treatment trial in the syndrome. Results also provide proof of concept to advance knowledge about developing targeted treatments for additional causes of ASD associated with impaired synaptic development and function.