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James is a 7½-year-old boy born in Vietnam to a mother with mental illness. Little is known about his early history; he spent the first 6 months of his life in an orphanage, followed by foster care and a disrupted adoption. He moved to the U.S. at age 1½ and joined his current adoptive family at age 4 years. Shortly thereafter, James' psychiatric nurse practitioner diagnosed him with attention deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD). Pragmatic language and syntax deficits were also noted from an early age.James is now exhibiting anxiety, perseverative beliefs, and regression in his toileting. He began "talking to himself in his room" and using neologisms. A school-based evaluation resulted in educational diagnoses of ADHD and ASD based on social disconnectedness and invading others' personal space. James' parents felt "something else was going on" and sought a second opinion with a multidisciplinary team (consisting of a pediatric psychologist and a developmental pediatrician). Considering James' history, previous assessments, and their assessment battery (Behavior Assessment System for Children, Behavior Rating Inventory of Executive Function, and Autism Diagnostic Observation Schedule, and Rorschach Inkblot Test), the team characterized his current symptoms as an emerging psychotic disorder.Several consultations occurred over the next 9 months of the school term. First, clinicians in the psychiatry department confirmed symptoms of functional decline, cognitive disorganization, and hallucinations, which were attributed to post-traumatic stress rather than a psychotic disorder. Second, adding to the diagnostic uncertainty, when James started an atypical antipsychotic medication and was under good symptom control, the school team believed that ADHD-not psychosis-best accounted for his presentation. There was significant contention between the medical team and consulting school psychologist regarding the extent to which data from the parental history and Rorschach should be considered in formulating the patient's diagnosis.Two-and-a-half years later, James was weaned off risperidone to manage a new side effect of tics. He subsequently manifested significant paranoia with reactive aggression toward peers for imagined slights and insults that he could "swear he heard." A different school-contracted psychologist's re-evaluation corroborated the diagnosis of schizophrenia based on the several years of unfolding clinical observations. Acting from the supposition that early-onset psychosis was too rare and too stigmatizing a condition to apply to a "kid who's just having trouble paying attention," the first school psychologist remained adamant that ADHD and ASD were the most appropriate diagnoses, and James would be ill-served "pumped full of neuroleptics."He returns now to the original Developmental Behavioral Pediatric consulting team. What would you do to try to bridge this impasse?

BACKGROUND AND PURPOSE Immune system dysfunction and inflammatory dysregulation have been shown in several animal models of fragile X syndrome (FXS). However, the phenotypical implications of this dysregulation have not been systematically evaluated in a large patient cohort. METHODS Five thousand seven hundred thirty-six FXS patients from a nationwide health insurance database were identified and compared to 573 600 age- and sex-matched controls. The phenome-wide association studies codes of FXS patients and those without FXS were compared and the false discovery rate was controlled at 0.05 using the Benjamini-Hochberg procedure. RESULTS In addition to the commonly reported comorbidities of FXS, an over-representation of infectious diseases, including otitis media, cellulitis and abscess of fingers or toes, viral enteritis, candidiasis and pneumonia, was discovered. In addition, there was an under-representation of autoimmune disorders in FXS patients. CONCLUSIONS Our systematic comorbidity analyses identified immunologically-based phenotypes associated with FXS. Our findings align with previous observations of compromised immunity and phagocytic defects in animal models of FXS. These results suggest the importance of immune-related pathways in FXS patients and their relevance to the FMR1 gene.

Purpose: For neurodevelopmental disorders (NDDs), etiological evaluation can be a diagnostic odyssey involving numerous genetic tests, underscoring the need to develop a streamlined algorithm maximizing molecular diagnostic yield for this clinical indication. Our objective was to compare the yield of exome sequencing (ES) with that of chromosomal microarray (CMA), the current first-tier test for NDDs. Methods: We performed a PubMed scoping review and meta-analysis investigating the diagnostic yield of ES for NDDs as the basis of a consensus development conference. We defined NDD as global developmental delay, intellectual disability, and/or autism spectrum disorder. The consensus development conference included input from genetics professionals, pediatric neurologists, and developmental behavioral pediatricians. Results: After applying strict inclusion/exclusion criteria, we identified 30 articles with data on molecular diagnostic yield in individuals with isolated NDD, or NDD plus associated conditions (such as Rett-like features). Yield of ES was 36% overall, 31% for isolated NDD, and 53% for the NDD plus associated conditions. ES yield for NDDs is markedly greater than previous studies of CMA (15–20%). Conclusion: Our review demonstrates that ES consistently outperforms CMA for evaluation of unexplained NDDs. We propose a diagnostic algorithm placing ES at the beginning of the evaluation of unexplained NDDs.

Objective The objective of the present study is to examine the craniofacial development of patients with Down syndrome (DS) and compare them with a neurotypical population. Methods This study is a cross-sectional analysis of lateral cephalometric radiographs of participants with DS. The study population consisted of children and young adults with DS aged 3–25 years. Cephalometric data were summarized by age and sex. Raw and normalized z-scores were computed. One-sample t tests were used to test whether mean z-scores differed from zero. The demographic characteristics between those with or without lateral cephalograms among all study participants were compared by Fisher’s exact tests. Results The study sample comprised of 27 participants with DS. Study subjects demonstrated a class III skeletal pattern. This was more pronounced in the older age groups as compared to younger age groups. Subjects also had an increased proportionate lower anterior face height to total facial height compared to normative standards. Gonial angles, mandibular plane angles, and airway measurements increased with age. Conclusions Patients with Down syndrome present typically with class III skeletal pattern and long lower anterior facial heights. In patients with Down syndrome, comprehensive phase of orthodontic treatment may be best initiated following cessation of growth.

Neurodevelopmental disorders (NDDs) are a heterogeneous group of childhood-onset conditions caused by disrupted brain development, leading to developmental impairments such as autism spectrum disorder (ASD) and intellectual disability (ID). Various genetic conditions are associated with NDDs, including Rett syndrome (RTT), tuberous sclerosis complex (TSC), and fragile X syndrome (FXS). Increased biological understanding of such disorders has improved our knowledge of circuit dysfunction shared by NDDs, in addition to resulting in clinical trials targeting cognition and behavior. In this chapter, we will discuss strategies for translational medicine in the field of NDDs. We will explore challenges in translating animal model data to human interventional trials. We will highlight as examples RTT, TSC, and FXS, where the discovery of gene function and investigation of animal models have led to hypothesis testing in patients and potential future targeted treatments. From these three examples, we will provide overarching observations about the promises and pitfalls of translational neuroscience for NDDs as a whole.

The Down Syndrome Study Group (DSSG) was founded in 2012 as a voluntary, collaborative effort with the goal of supporting evidenced-based health care guidelines for individuals with Down syndrome (DS). Since then, 5 DS specialty clinics have collected prospective, longitudinal data on medical conditions that co-occur with DS. Data were entered by clinical staff or trained designees into the National Down Syndrome Patient Database, which we created using REDCap software. In our pilot year, we enrolled 663 participants across the U.S., ages 36 days to 70 years, from multiple racial and ethnic backgrounds. Here we report: (i) the demographic distribution of participants enrolled, (ii) a detailed account of our database infrastructure, and (iii) lessons learned during our pilot year to assist future researchers with similar goals for other patient populations.

In this chapter, we outline tips for gathering critical history and creating safety and trust during the assessment of a traumatized child with co-occurring neurodevelopmental disorders. Particular emphasis is placed on balancing the science and craft of child assessment, using psychometrically sound and precise tools while also being attuned and sensitive to a child’s readiness to disclose and managing possible distress and posttraumatic re-experiencing during an evaluation.

CASE Steven is an 11-year-old boy who was adopted from an orphanage in Eastern Europe 8 years ago, when he was 3 years old along with his biological sister who is 1 year older. You have cared for him in your practice since that time seeing them annually for well child care. His mother reports that the first 2 years after adoption were very difficult, and Steven has never really bonded with her or her husband. Currently, he is reported to steal possessions of family members and instigate arguments with his older sister and act defiantly. The parents have put locks on their bedroom door due to fears of violence, primarily by Steven's older sister. Steven's mother reports that she and her husband no longer attempt to "parent" the children and provide minimal supervision to avoid conflict. In school, Steven is reported to have symptoms of inattention and hyperactivity that improved with treatment with stimulant medication and some learning challenges, but otherwise he is described as a lovely boy who has good relationships with his teachers.They present to urgent care clinic when mom stated "We have had enough." That day both children were caught taking $10 from the mother's wallet. On further discussion, it was discovered that they had done this several times over the last month to buy ice cream for neighborhood friends to "welcome them" to the neighborhood. Steven's mother presents today stating that the family has exhausted therapy services and are experiencing financial hardship secondary to investing time and money into behavioral and psychiatric services for Steven and his sister. They want to dissolve the adoption and have the children removed from their home. They seek guidance on how to do this. What would be your initial approach with the parents?

Purpose: Williams-Beuren syndrome is among the most well-characterized microdeletion syndromes, caused by recurrent de novo microdeletions at 7q11.23 mediated by nonallelic homologous recombination between low copy repeats flanking this critical region. However, the clinical phenotype associated with reciprocal microduplication of this genomic region is less well described. We investigated the molecular, clinical, neurodevelopmental, and behavioral features of seven patients with dup(7)(q11.23), including two children who inherited the microduplication from one of their parents, to more fully characterize this emerging microduplication syndrome. Methods: Patients were identified by array-based comparative genomic hybridization. Clinical examinations were performed on seven affected probands, and detailed cognitive and behavioral evaluations were carried out on four of the affected probands. Results: Our findings confirm initial reports of speech delay seen in patients with dup(7)(q11.23) and further delineate and expand the phenotypic spectrum of this condition to include communication, social interactions, and repetitive interests that are often observed in individuals diagnosed with autism spectrum disorders. Conclusions: Array-based comparative genomic hybridization is a powerful means of detecting genomic imbalances and identifying molecular etiologies in the clinic setting, including genomic disorders such as Williams-Beuren syndrome and dup(7)(q11.23). We propose that dup(7)(q11.23) syndrome may be as frequent as Williams-Beuren syndrome and a previously unrecognized cause of language delay and behavioral abnormalities. Indeed, these individuals may first be referred for evaluation of autism, even if they do not ultimately meet diagnostic criteria for an autism spectrum disorder.

The Down Syndrome Study Group (DSSG) was founded in 2012 as a voluntary, collaborative effort with the goal of supporting evidenced-based health care guidelines for individuals with Down syndrome (DS). Since then, 5 DS specialty clinics have collected prospective, longitudinal data on medical conditions that co-occur with DS. Data were entered by clinical staff or trained designees into the National Down Syndrome Patient Database, which we created using REDCap software. In our pilot year, we enrolled 663 participants across the U.S., ages 36 days to 70 years, from multiple racial and ethnic backgrounds. Here we report: (i) the demographic distribution of participants enrolled, (ii) a detailed account of our database infrastructure, and (iii) lessons learned during our pilot year to assist future researchers with similar goals for other patient populations.

Introduction EARLY TRAUMA AND MENTAL HEALTH An Analysis of Early Developmental Trauma in Social Anxiety Disorder and Posttraumatic Stress Disorder Melanie Bishop, David Rosenstein, Susanne Bakelaar, and Soraya Seedat A School Based Study of Psychological Disturbance in Children Following the Omagh Bomb Maura McDermott, Michael Duffy, Andy Percy, Michael Fitzgerald, and Claire Cole Relationship between the COMT-Val158Met and BDNF-Val66Met Polymorphisms, Childhood Trauma and Psychotic Experiences in an Adolescent General Population Sample Hugh Ramsay, Ian Kelleher, Padraig Flannery, Mary C. Clarke, Fionnuala Lynch, Michelle Harley, Dearbhla Connor, Carol Fitzpatrick, Derek W. Morris, and Mary Cannon Childhood Maltreatment and Coping in Bipolar Disorder Ledo Daruy-Filho, Elisa Brietzke, Bruno Kluwe-Schiavon, Cristiane da Silva Fabres, and Rodrigo Grassi-Oliveira EARLY TRAUMA AND THE BRAIN A Preliminary Study of the Influence of Age of Onset and Childhood Trauma on Cortical Thickness in Major Depressive Disorder Natalia Jaworska, Frank P. MacMaster, Ismael Gaxiola, Filomeno Cortese, Bradley Goodyear, and Rajamannar Ramasubbu Childhood Emotional Maltreatment Severity Is Associated with Dorsal Medial Prefrontal Cortex Responsivity to Social Exclusion in Young Adults Anne-Laura van Harmelen, Kirsten Hauber, Bregtje Gunther Moor, Philip Spinhoven, Albert E. Boon, Eveline A. Crone, and Bernet M. Elzinga Reduced Cingulate Gyrus Volume Associated with Enhanced Cortisol Awakening Response in Young Healthy Adults Reporting Childhood Trauma Shaojia Lu, Weijia Gao, Zhaoguo Wei, Weiwei Wu, Mei Liao, Yuqiang Ding, Zhijun Zhang, and Lingjiang Li Childhood Maltreatment Is Associated with Larger Left Thalamic Gray Matter Volume in Adolescents with Generalized Anxiety Disorder Mei Liao, Fan Yang, Yan Zhang, Zhong He, Ming Song, Tianzi Jiang, Zexuan Li, Shaojia Lu, Weiwei Wu, Linyan Su, and Lingjiang Li Reduced Visual Cortex Gray Matter Volume and Thickness in Young Adults Who Witnessed Domestic Violence during Childhood Akemi Tomoda, Ann Polcari, Carl M. Anderson, and Martin H. Teicher EARLY TRAUMA AND PHYSICAL HEALTH Association between Adverse Childhood Experiences and Diagnosis of Cancer Monique J. Brown, Leroy R. Thacker, and Steven A. Cohen Childhood Adversity as a Risk for Cancer: Findings from the 1958 British Birth Cohort Study Michelle Kelly-Irving, Benoit Lepage, Dominique Dedieu, Rebecca Lacey, Noriko Cable, Melanie Bartley, David Blane, Pascale Grosclaude, Thierry Lang, and Cyrille Delpierre Adverse Childhood Experiences and the Cardiovascular Health of Children: A Cross-Sectional Study Chelsea Pretty, Deborah D. O'Leary, John Cairney, and Terrance J. Wade Impact of Early Psychosocial Factors (Childhood Socioeconomic Factors and Adversities) on Future Risk of Type 2 Diabetes, Metabolic Disturbances and Obesity: A Systematic Review Teresa Tamayo, Christian Herder, and Wolfgang Rathmann Early Life Adversity as a Risk Factor for Fibromyalgia in Later Life Lucie A. Low and Petra Schweinhardt INTERVENTIONS Listen Protect Connect for Traumatized Schoolchildren: A Pilot Study of Psychological First Aid Marizen Ramirez, Karisa Harland, Maisha Frederick, Rhoda Shepherd, Marleen Wong, and Joseph E. Cavanaugh

OBJECTIVES: The goals of this study were (1) to provide estimates of diagnostic stability for a sample of young children diagnosed with attention-deficit/hyperactivity disorder (ADHD) after undergoing comprehensive multidisciplinary assessments and (2) to identify baseline child and family characteristics that predict diagnostic stability over time. METHODS: Children aged 3 to 6 years, 11 months consecutively diagnosed with ADHD after multidisciplinary consultations at a tertiary care clinic between 2003 and 2008 were recontacted in 2012 and 2013 (N = 120). At follow-up, the primary outcome was the proportion of children who continued to meet diagnostic criteria for ADHD. To identify predictors of diagnostic stability, logistic regression models were used. In addition, a latent class model was used to independently classify subjects into distinct clusters. RESULTS: In this cohort, 70.4% of the children contacted at follow-up continued to meet diagnostic criteria for ADHD. Predictors of diagnostic stability included externalizing and internalizing symptoms at baseline, parental history of psychopathology, and family socioeconomic status. The latent class model independently identified 3 distinct profiles: (1) children who no longer met ADHD criteria; (2) children with persistent ADHD and high parental psychopathology; and (3) children with persistent ADHD and low family socioeconomic status. CONCLUSIONS: Young children who underwent comprehensive developmental and psychological assessments before receiving an ADHD diagnosis, had higher rates of diagnostic stability than in previous studies of community samples. Child and family factors that predict diagnostic stability have the potential to guide treatment planning for children diagnosed with ADHD before 7 years of age.