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Identifying children who are at-risk for developmental delay, so that these children can have access to interventions as early as possible, is an important and challenging problem in developmental research. This research aimed to identify latent subgroups of children with developmental delay, by modelling and clustering developmental milestones. The main objectives were to (a) create a developmental profile for each child by modelling milestone achievements, from birth to three years of age, across multiple domains of development, and (b) cluster the profiles to identify groups of children who show similar deviations from typical development. The ensemble methodology used in this research consisted of three components: (1) Bayesian sequential updating was used to model the achievement of milestones, which allows for updated predictions of development to be made in real time; (2) a measure was created that indicated how far away each child deviated from typical development for each functional domain, by calculating the area between each child's obtained sequence of posterior means and a sequence of posterior means representing typical development; and (3) Dirichlet process mixture modelling was used to cluster the obtained areas. The data used were 348 binary developmental milestone measurements, collected from birth to three years of age, from a small community sample of young children (N = 79). The model identified nine latent groups of children with similar features, ranging from no delays in all functional domains, to large delays in all domains. The performance of the Dirichlet process mixture model was validated with two simulation studies., Competing Interests: The authors have declared that no competing interests exist.

RASopathies are developmental diseases caused by mutations in rat sarcoma-mitogen-activated protein kinase pathway genes. These disorders, such as Noonan syndrome (NS) and NS-related disorders (NSRD), including cardio-facio-cutaneous (CFC) syndrome, Costello syndrome (CS), and NS with multiple lentigines (NSML; also known as LEOPARD syndrome), have a similar systemic phenotype. A wide spectrum of congenital heart disease and hypertrophic cardiomyopathy (HCMP) can exhibit major associated characteristics. A retrospective study was conducted at the Mackay Memorial Hospital, National Taiwan University Hospital, Buddhist Tzu-Chi General Hospital, Chang-Gung Memorial Hospital, Taichung Veterans General Hospital, and Chung Shan Medical University Hospital from January 2007 to December 2018. We reviewed the clinical records of 76 patients with a confirmed molecular diagnosis of RASopathies, including NS, CS, CFC syndrome, and NSML. We evaluated the demographic data and medical records with clinical phenotypes of cardiac structural anomalies using cross-sectional and color Doppler echocardiography, electrocardiographic findings, and follow-up data. A total of 47 (61.8%) patients had cardiac abnormalities. The prevalence of cardiac lesions according to each syndrome was 62.7, 50.0, 60.0, and 66.7% in patients with NS, CFC syndrome, CS, and NSML, respectively. An atrial septal defect was usually combined with other cardiac abnormalities, such as pulmonary stenosis (PS), HCMP, ventricular septal defect, or patent ductus arteriosus. Patients with NS most commonly showed PS. In patients with NSRD and cardiac abnormalities, HCMP (29.4%) was the most commonly observed cardiac lesion. PTPN11 was also the most frequently detected mutation in patients with NS and NSRD. Cardiac abnormalities were the most common symptoms observed in patients with RASopathies at the time of their first hospital visit. Performing precise analyses of genotype-cardiac phenotype correlations in a larger cohort will help us accurately diagnose RASopathy as soon as possible., (© 2019 Wiley Periodicals, Inc.)

Background: Chromosomal microarray analysis (CMA) is nowadays widely used in the diagnostic path of patients with clinical phenotypes. However, there is no ascertained evidence to date on how to assemble single/combined clinical categories of developmental phenotypic findings to improve the array-based detection rate., Methods: The Italian Society of Human Genetics coordinated a retrospective study which included CMA results of 5,110 Italian patients referred to 17 genetics laboratories for variable combined clinical phenotypes., Results: Non-polymorphic copy number variants (CNVs) were identified in 1512 patients (30%) and 615 (32%) present in 552 patients (11%) were classified as pathogenic. CNVs were analysed according to type, size, inheritance pattern, distribution among chromosomes, and association to known syndromes. In addition, the evaluation of the detection rate of clinical subgroups of patients allowed to associate dysmorphisms and/or congenital malformations combined with any other single clinical sign to an increased detection rate, whereas non-syndromic neurodevelopmental signs and non-syndromic congenital malformations to a decreased detection rate., Conclusions: Our retrospective study resulted in confirming the high detection rate of CMA and indicated new clinical markers useful to optimize their inclusion in the diagnostic and rehabilitative path of patients with developmental phenotypes., (© 2019 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals, Inc.)

Background: The field of intellectual and developmental disabilities (IDD) is currently experiencing a significant transformation that encompasses an integrated approach, especially regarding shared aspects such as a focus on the human and legal rights, the eligibility for services and supports, and an emphasis on individualized supports provided within inclusive community-based environments. Accompanying this transformation is the increased need of precision in both the operational definitions of IDD-related constructs, and the terminology used to describe the respective construct., Method: the specialized literature was revised, and previous works on the subject by the authors were updated., Results: This article provides psychologists with the current definition of intellectual disability, operational definitions of intellectual disability and developmental disabilities constructs and associated terminology, and the parameters of an integrated approach to disability., Conclusions: Implications for psychologists who are involved in diagnosis, classification, and planning supports for persons with intellectual or developmental disability are discussed.

Editorial of vol 31(3).

Chromosome 16 is one of the most gene-rich chromosomes of our genome, and 10% of its sequence consists of segmental duplications, which give instability and predisposition to rearrangement by the recurrent mechanism of non-allelic homologous recombination. Microarray technologies have allowed for the analysis of copy number variations (CNVs) that can contribute to the risk of developing complex diseases. By array comparative genomic hybridization (CGH) screening of 1476 patients, we detected 27 cases with CNVs on chromosome 16. We identified four smallest regions of overlapping (SROs): one at 16p13.11 was found in seven patients; one at 16p12.2 was found in four patients; two close SROs at 16p11.2 were found in twelve patients; finally, six patients were found with atypical rearrangements. Although phenotypic variability was observed, we identified a male bias for Childhood Apraxia of Speech associated to 16p11.2 microdeletions. We also reported an elevated frequency of second-site genomic alterations, supporting the model of the second hit to explain the clinical variability associated with CNV syndromes. Our goal was to contribute to the building of a chromosome 16 disease-map based on disease susceptibility regions. The role of the CNVs of chromosome 16 was increasingly made clear in the determination of developmental delay. We also found that in some cases a second-site CNV could explain the phenotypic heterogeneity by a simple additive effect or a pejorative synergistic effect.

Objective To assess the usefulness of the antenatal fetal neurodevelopmental test for the prediction of postnatal developmental disabilities. Methods Fetal behavior was assessed with Kurjak's antenatal neurodevelopmental test (KANET) using four-dimensional ultrasound between 28 and 38 weeks of gestation. A score range of 0-5 was characterized as abnormal, from 6 to 9 was considered borderline, and 10-16 was normal. After birth, follow-up was conducted for at least 2 years in all fetuses. Results There were 337 normal (95.47%) and 16 borderline (4.53%) cases among the 353 cases studied, whereas there was no abnormal case. Five cases with postnatal developmental disabilities (one case of Werdig-Hoffmann disease diagnosed just after delivery, one case of autism spectrum disorder diagnosed at 24 months, one case of Ullrich congenital muscular dystrophy diagnosed at 9 months and two cases of developmental disorders diagnosed at age 3 and 18 months) were noted among the 337 normal cases (1.48%), whereas three cases with developmental disabilities (one case of motor development delay diagnosed at 6 months, one case of Duchenne muscular dystrophy diagnosed at 18 months and one case of autism spectrum disorder diagnosed at age 30 months) were found among the 16 borderline cases (18.75%). There was a significant difference in the prevalence of postnatal developmental disabilities between the normal and borderline KANET groups (P<0.001). Conclusion Our results suggest that the KANET assessment may be a useful diagnostic modality for the prediction of postnatal developmental disabilities.

Nablus syndrome was first described by the late Ahmad Teebi in 2000, and 13 individuals have been reported to date. Nablus syndrome can be clinically diagnosed based on striking facial features, including tight glistening skin with reduced facial expression, blepharophimosis, telecanthus, bulky nasal tip, abnormal external ear architecture, upswept frontal hairline, and sparse eyebrows. However, the precise genetic etiology for this rare condition remains elusive. Comparative microarray analyses of individuals with Nablus syndrome (including two mother-son pairs) reveal an overlapping 8q22.1 microdeletion, with a minimal critical region of 1.84 Mb (94.43-96.27 Mb). Whereas this deletion is present in all affected individuals, 13 individuals without Nablus syndrome (including two mother-child pairs) also have the 8q22.1 microdeletion that partially or fully overlaps the minimal critical region. Thus, the 8q22.1 microdeletion is necessary but not sufficient to cause the clinical features characteristic of Nablus syndrome. We discuss possible explanations for Nablus syndrome, including one-locus, two-locus, epigenetic, and environmental mechanisms. We performed exome sequencing for five individuals with Nablus syndrome. Although we failed to identify any deleterious rare coding variants in the critical region that were shared between individuals, we did identify one common SNP in an intronic region that was shared. Clearly, unraveling the genetic mechanism(s) of Nablus syndrome will require additional investigation, including genomic and RNA sequencing of a larger cohort of affected individuals. If successful, it will provide important insights into fundamental concepts such as variable expressivity, incomplete penetrance, and complex disease relevant to both Mendelian and non-Mendelian disorders., (© 2018 Wiley Periodicals, Inc.)

Purpose of Review: We aim to further disentangle the jungle of terminology of epileptic encephalopathy and provide some insights into the current understanding about the aetiology and pathophysiology of this process. We cover also the key features of epilepsy syndromes of infancy and childhood which are considered at high risk of developing an epileptic encephalopathy., Recent Findings: The concept of 'epileptic encephalopathy' has progressively been elaborated by the International League Against Epilepsy according to growing clinical and laboratory evidence. It defines a process of neurological impairment caused by the epileptic activity itself and, therefore, potentially reversible with successful treatment, although to a variable extent. Epileptic activity interfering with neurogenesis, synaptogenesis, and normal network organization as well as triggering neuroinflammation are among the possible pathophysiological mechanisms leading to the neurological compromise. This differs from the newly introduced concept of 'developmental encephalopathy' which applies to where the epilepsy and developmental delay are both because of the underlying aetiology and aggressive antiepileptic treatment may not be helpful., Summary: The understanding and use of correct terminology is crucial in clinical practice enabling appropriate expectations of antiepileptic treatment. Further research is needed to elucidate underlying pathophysiological mechanisms, define clear outcome predictors, and find new treatment targets.

This study compared performances and motor delay classifications for the Test of Gross Motor Development-2nd edition (TGMD-2) and the Körperkoordinationstest Für Kinder (KTK) in a sample of 424 healthy children (47% girls) between 5 and 10 years of age. Low-to-moderate correlations (r range = 0.34-0.52) were found between assessments across age. In general, both boys and girls demonstrated higher raw scores across age groups. However, percentile scores indicated younger children outperformed older children, denoting a normative percentile-based decrease in motor competence (MC) in the older age groups. In total, the TGMD-2 and KTK classified 39.4% and 18.4% children, respectively, as demonstrating very low MC (percentile ≤5). In conclusion, the TGMD-2 classified significantly more children with motor delays than the KTK and the differences between children's motor skill classification levels by these assessments became greater as the age groups increased. Therefore, the TGMD-2 may demonstrate more susceptibility to sociocultural influences and be more influenced by cumulative motor experiences throughout childhood. Low-to-moderate correlations between assessments also suggest the TGMD-2 and KTK may measure different aspects of MC. As such, it may be important to use multiple assessments to comprehensively assess motor competence.

Objective: Early intervention (EI) programs under Part C of the Individuals with Disabilities Education Act serve a developmentally heterogeneous population of infants and toddlers with or at risk of developmental delays or disabilities. The aim of this study was to identify empirically distinct subgroups of children in EI so as to inform early prognosis and service planning., Methods: We applied mixture modeling to developmental assessment data from 1513 children who enrolled in a large, urban EI program between 2009 and 2013. The observed variables were children's EI-entry developmental quotients (DQs) in 5 domains (communication, cognitive, motor, adaptive, and personal-social) as assessed by the Battelle Developmental Inventory, Second Edition., Results: A 4-class model showed the best fit to the data, revealing subgroups with distinct developmental profiles. Children in the first subgroup showed a severe delay in communication with less severe delays in the other domains. Children in the second subgroup likewise showed a severe delay in communication, but with comparably severe delays in the cognitive and motor domains. Profiles for the third and fourth subgroups showed the same overall patterns as those for the first and second subgroups, respectively, but to a less severe degree. Developmental trajectories differed by subgroup., Conclusion: Consideration of subgroups based on children's developmental assessment scores provides insight into underlying commonalities among children with different presenting diagnoses on entry into EI. The subgroups also have clinical relevance in terms of both practitioners' and parents' understanding of children's likely service needs and developmental trajectories.

Infants with developmental delays must be detected early in their development to minimize the progression of motor and neurological impairments. Our objective is to quantify how sensorized toys in a natural play environment can promote infant-toy physical interactions. We created a hanging elephant toy, equipped with an inertial measurement unit (IMU), a pressure transducer, and multiple feedback sensors, to be a hand-grasping toy. We used a 3 DoF robotic model with inputs from the IMU to calculate multiple kinematic metrics and an equation to calculate haptic metrics from the pressure transducer. Six typical infants were tested in the gym set-up. Three infants interacted with the toy for more than half the trial time. The youngest infant exhibited the largest toy displacement with ΔD = 27.6 cm, while the oldest infant squeezed the toy with the largest mean pressure of 4.5 kPa. More data on on both typical and atypical infants needs to be collected. After testing atypical infants in the SmarToyGym set-up, we will be able to identify interaction metrics that differentiate atypical and typical infants.

Objective: This study aims to identify the scientific evidence on the risks and effects of exposure to environmental contaminants in children during sensitive developmental periods., Data Source: The search was performed in the Bireme database, using the terms: children's health, environmental exposure, health vulnerability, toxicity pathways and developmental disabilities in the LILACS, MEDLINE and SciELO systems., Data Synthesis: Children differ from adults in their unique physiological and behavioral characteristics and the potential exposure to risks caused by several threats in the environment. Exposure to toxic agents is analyzed through toxicokinetic processes in the several systems and organs during the sensitive phases of child development. The caused effects are reflected in the increased prevalence of congenital malformations, diarrhea, asthma, cancer, endocrine and neurological disorders, among others, with negative impacts throughout adult life., Conclusion: To identify the causes and understand the mechanisms involved in the genesis of these diseases is a challenge for science, as there is still a lack of knowledge on children's susceptibility to many environmental contaminants. Prevention policies and more research on child environmental health, improving the recording and surveillance of environmental risks to children's health, should be an ongoing priority in the public health field., (Copyright © 2016 Sociedade Brasileira de Pediatria. Published by Elsevier Editora Ltda. All rights reserved.)

The Diagnostic Classification of Mental Health and Developmental Disorders of Infancy and Early Childhood: Revised Edition (DC:0-5; ZERO TO THREE) is scheduled to be published in 2016. The articles in this section are selective reviews that have been undertaken as part of the process of refining and updating the nosology. They provide the rationales for new disorders, for disorders that had not been included previously in the Diagnostic Classification of Mental Health and Developmental Disorders of Infancy and Early Childhood: Revised Edition (DC:0-3R; ZERO TO THREE, 2005), and for changes in how certain types of disorders are conceptualized., (© 2016 Michigan Association for Infant Mental Health.)

Infant mental health is explicitly relational in its focus, and therefore a diagnostic classification system for early childhood disorders should include attention not only to within-the-child psychopathology but also between child and caregiver psychopathology. In this article, we begin by providing a review of previous efforts to introduce this approach that date back more than 30 years. Next, we introduce changes proposed in the Diagnostic Classification of Mental Health and Developmental Disorders of Infancy and Early Childhood DC:0-5 (ZERO TO THREE, in press). In a major change from previous attempts, the DC:0-5 includes an Axis I "Relationship Specific Disorder of Early Childhood." This disorder intends to capture disordered behavior that is limited to one caregiver relationship rather than cross contextually. An axial characterization is continued from the Diagnostic Classification of Mental Health and Developmental Disorders of Infancy and Early Childhood DC:0-3R (ZERO TO THREE, 2005), but two major changes are introduced. First, the DC:0-5 proposes to simplify ratings of relationship adaptation/maladaptation, and to expand what is rated so that in addition to characterizing the child's relationship with his or her primary caregiver, there also is a characterization of the network of family relationships in which the child develops. This includes coparenting relationships and the entire network of close relationships that impinge on the young child's development and adaptation., (© 2016 Michigan Association for Infant Mental Health.)

Objective: This study aims to identify functioning categories of the International Classification of Functionality, Disability and Health for Children and Youth covered by the Griffiths developmental scales and the Schedule of Growing Skills II (SGS-II), as well as to analyse levels of agreement between coders when assigning its items to the ICF-CY classification system., Methods: Items were linked to the ICF-CY following a content analysis procedure and the published linking rules. Agreement was calculated with Cohen's Kappa Coefficient., Results: All SGS items assess mostly Activities and Participation, alike most of the Griffiths' scales except for the Language and Eye-hand coordination scales, which assess mostly Body Functions. Consistently with previous studies, agreement levels between coders vary considerably, thus being highly dependent on the nature of the concept analysed., Conclusion: Although necessary from a capacity-driven approach to assessment, information collected with these instruments should be complemented with other assessments in order to cover all aspects of the child's life, in line with a systemic approach.

Introduction: The WHO has launched a common classification for disabilities in children, the International Classification of Functioning, Disability and Health, Child and Youth Version (ICF-CY). We wanted to determine whether cat-egories of the environmental (e) and the body functions (b) components of the classification could address environmental needs in children with different disorders and various disability severities., Methods: A set of 16 e categories and 47 b categories were selected and worded to best enable parents to describe children's everyday support needs and environmental influences through interviews in their own homes., Results: Of the 367 invited parents, 332 (90.5%) participated, providing data on children with spina bifida, spinal muscular atrophy, muscular disorders, cerebral palsy, visual impairments, hearing impairments, mental disability and disabilities following brain tumour treatment. The mean age of children across disabilities was 9.4 years (range: 1.0-15.9). The mean e code score was 35.7 (range: 4.0-64.0), and the mean b code score was 32.2 (range: 0.0-159.0). The most urgent needs as detected by qualifier 4 environmental categories scores were common among children with complex disorders and issues related to health professionals, legal services and health services., Conclusions: Parents understand the environmental and body function components in a meaningful manner and the codes seem to be valid. Special emphasis should be given to environmental issues for children with more complex disabilities. There was no correlation between the severity of a disability and environmental issues, indicating that each child's needs were basically met, irrespective of disability severity., Funding: partnership project § 16, 21, 31 administered by the Danish Health Authority., Trial Registration: not relevant.

Objective: The purpose of the study was to extend our understanding of the Kyoto Scale of Psychological Development (KSPD) by comparison with a parent-rated scale, the Kinder Infant Development Scale (KIDS)., Methods: The participants of this study were 229 children aged 0-4, who were referred to the Developmental Evaluation Center of the National Center for Child Health and Development, due to a suspected developmental disorder/delay. The participants were divided into subgroups, depending on age and overall DQ. For each group separately, correlation analyses were conducted between the Developmental Quotient (DQ) of each KSPD domain and DQ of each KIDS subscale., Results: For high DQ group, in all ages, the KSPD Postural-Motor (P-M) domain DQ demonstrated a high correlation with the KIDS Physical-Motor DQ, and at young ages, it was also found to be moderately or strongly associated with the KIDS Manipulation DQ. For high DQ group, the KSPD Cognitive-Adaptive (C-A) domain DQ was most consistently related to the KIDS Manipulation DQ, and was also moderately correlated with the KIDS Physical-Motor DQ, Receptive Language DQ, Social Relationship with Adults DQ, Discipline DQ, and Feeding DQ, depending on age. For high DQ group, the KSPD Language-Social (L-S) DQ most consistently showed a moderate or high correlation with the KIDS Receptive Language DQ and the Manipulation DQ, and also related to Physical-Motor DQ, Expressive Language DQ, Language Conception DQ, Social Relationship with Adults DQ, and Social Relationship with Children DQ for some age groups. The low DQ group demonstrated stronger relationships on many of the pairs of the DQ of a KSPD subdomain and the DQ of a KIDS subscale, regardless of the type of subdomains and subscales., Conclusions: For high DQ group, the KSPD P-M domain was consistently related to parent-reported physical/motor development, the C-A domain primarily reflected a child's fine motor skills and his/her ability to understand and follow verbal instructions provided by adults, while the L-S domain was associated with parent-reported language ability. For low DQ group, the effect of global delay increased overall correlations between each domain and subscale. Further studies are necessary to replicate the findings in a larger sample including typical children., (Copyright © 2015 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.)

In this article, I argue that the history and philosophy of autism need to account for two kinds of autism. Contemporary autism research and practice is structured, directed and connected by an 'ontological understanding of disease'. This implies that autism is understood as a disease like any other medical disease, existing independently of its particular manifestations in individual patients. In contrast, autism in the 1950s and 1960s was structured by a psychoanalytical framework and an 'individual understanding of disease'. This implied that autism was not a distinct disease but an idiosyncratic and meaningful response of the child to a disturbed development of the ego. These two kinds of autism are embedded in and reveal two very different 'styles of psychiatric thought'.

Cerebellar hypoplasia (CH) is one of the congenital abnormalities of the central nervous system and is seen in several diseases and syndromes. This study was conducted in order to examine methods for evaluating CH in fetus and neonate because CH has been diagnosed without any morphometric criteria at autopsy. We sampled 140 autopsied cases including nineteen trisomy 18 (T18), four non-T18 with presumed CH, and 117 control cases without any brain malformation. Statistical significance was present in the cerebellar weight and weight ratio of cerebellum per total brain between T18 and the control. The exponential regression models (ERM) showed that cerebral weight, cerebellar weight, and weight ratio of cerebellum per total brain increased gradually relative to gestational age in both T18 and the control. However, cerebellar weight and weight ratio of cerebellum per total brain of T18 showed growth delay with clear distinction between the two groups. The non-T18 with presumed CH showed similar results. Body weight, total brain, and gestational age should be considered totally when evaluating fetal and neonatal cerebellar development. Furthermore, the ERM results may be useful to evaluate the cerebellar development of fetus and neonate at autopsy., (© 2015 Japanese Society of Pathology and Wiley Publishing Asia Pty Ltd.)

Asymmetry in infants is a clinical condition in which abnormal body shape, posture or mobility is observed. It is characterized by diverse etiology, localization and severity. The most frequently noted kind is idiopathic asymmetry. Symptomatic asymmetry is less frequent and a variety of structural or systemic disorders underlie this disease. The dynamics of child development in the first year of life makes it necessary for clinicians to give an early diagnosis of asymmetry, which has a significant impact on the expected course of its development and intervention strategies. The aim of the study is to present the definitions, classification and differential diagnosis of asymmetry in infants.

Null hypothesis significance testing (NHST) dominates quantitative data analysis, but its use is controversial and has been heavily criticized. The American Psychological Association has advocated the reporting of effect sizes (ES), confidence intervals (CIs), and statistical power analysis to complement NHST results to provide a more comprehensive understanding of research findings. The aim of this paper is to carry out a sample survey of statistical reporting practices in two journals with the highest h5-index scores in the areas of developmental disability and rehabilitation. Using a checklist that includes critical recommendations by American Psychological Association, we examined 100 randomly selected articles out of 456 articles reporting inferential statistics in the year 2013 in the Journal of Autism and Developmental Disorders (JADD) and Research in Developmental Disabilities (RDD). The results showed that for both journals, ES were reported only half the time (JADD 59.3%; RDD 55.87%). These findings are similar to psychology journals, but are in stark contrast to ES reporting in educational journals (73%). Furthermore, a priori power and sample size determination (JADD 10%; RDD 6%), along with reporting and interpreting precision measures (CI: JADD 13.33%; RDD 16.67%), were the least reported metrics in these journals, but not dissimilar to journals in other disciplines. To advance the science in developmental disability and rehabilitation and to bridge the research-to-practice divide, reforms in statistical reporting, such as providing supplemental measures to NHST, are clearly needed.

Discovery of most autosomal recessive disease-associated genes has involved analysis of large, often consanguineous multiplex families or small cohorts of unrelated individuals with a well-defined clinical condition. Discovery of new dominant causes of rare, genetically heterogeneous developmental disorders has been revolutionized by exome analysis of large cohorts of phenotypically diverse parent-offspring trios. Here we analyzed 4,125 families with diverse, rare and genetically heterogeneous developmental disorders and identified four new autosomal recessive disorders. These four disorders were identified by integrating Mendelian filtering (selecting probands with rare, biallelic and putatively damaging variants in the same gene) with statistical assessments of (i) the likelihood of sampling the observed genotypes from the general population and (ii) the phenotypic similarity of patients with recessive variants in the same candidate gene. This new paradigm promises to catalyze the discovery of novel recessive disorders, especially those with less consistent or nonspecific clinical presentations and those caused predominantly by compound heterozygous genotypes.

Purpose: To evaluate the incidence of unprovoked seizures in children and the prevalence of related neurodevelopmental comorbidities at the time of the presumed first seizure and six months thereafter., Methods: The medical records of all children (0-18 years of age) seeking medical attention as the result of a first unprovoked seizure between September 1, 2001 and December 31, 2006, and registered in the population-based Stockholm Incidence Registry of Epilepsy (SIRE) were reviewed. Neurodevelopmental comorbidities were evaluated on the basis of the medical records from this first visit and from other healthcare during the following six months., Results: The incidence of unprovoked seizures was between 30 and 204/100,000 person years (n=766) in the different age groups. It was highest among the youngest children and lowest among the 18-year-olds with small gender differences. The most common neurodevelopment comorbidities were developmental delay (22%, CI: 19-25%), speech/language and learning difficulties (23%, CI: 20-26%) and intellectual disability (16%, CI: 13-18%). The types of neurodevelopmental comorbidity varied by age at the time of seizure onset, with cerebral palsy being more common among the 0-5-year-olds, attention deficits among the 6-16-year-olds, and autism and psychiatric diagnosis among the older children. An associated neurodevelopmental comorbidity was more common among those experiencing recurrent than single seizures during follow-up six months from the index seizure (42% versus 66%). In 68% (CI: 64-71%) of the children there was no known or suspected neurodevelopmental comorbidity., Conclusion: The incidence of unprovoked, non-febrile seizures among 0-18-year-olds included in the SIRE was 67/100,000 person-years. Neurodevelopmental comorbidities were common already at the time of onset of the seizure disorder, indicating that neither seizure treatment nor seizures were the underlying cause of other neurodevelopmental symptoms in these patients during the period studied., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Background: Cohen Syndrome (COH1) is a rare autosomal recessive disorder, principally identified by ocular, neural and muscular deficits. We identified three large consanguineous Pakistani families with intellectual disability and in some cases with autistic traits., Methods: Clinical assessments were performed in order to allow comparison of clinical features with other VPS13B mutations. Homozygosity mapping followed by whole exome sequencing and Sanger sequencing strategies were used to identify disease-related mutations., Results: We identified two novel homozygous deletion mutations in VPS13B, firstly a 1 bp deletion, NM&#95;017890.4:c.6879delT; p.Phe2293Leufs*24, and secondly a deletion of exons 37-40, which co-segregate with affected status. In addition to COH1-related traits, autistic features were reported in a number of family members, contrasting with the "friendly" demeanour often associated with COH1. The c.6879delT mutation is present in two families from different regions of the country, but both from the Baloch sub-ethnic group, and with a shared haplotype, indicating a founder effect among the Baloch population., Conclusion: We suspect that the c.6879delT mutation may be a common cause of COH1 and similar phenotypes among the Baloch population. Additionally, most of the individuals with the c.6879delT mutation in these two families also present with autistic like traits, and suggests that this variant may lead to a distinct autistic-like COH1 subgroup.

Purpose: Screens for developmental delay generally provide a set of norms for different age groups. Development varies continuously with age, however, and applying a single criterion for an age range will inevitably produce misclassifications. In this report, we estimate the resulting error rate for one example: the cognitive subscale of the Bayley Scales of Infant and Toddler Development (BSID-III)., Design: Data come from a general population sample of 594 children (305 male) aged 1 month to 42.5 months who received the BSID-III as part of a validation study. We used regression models to estimate the mean and variance of the cognitive subscale as a function of age. We then used these results to generate a dataset of one million simulated participants and compared their status before and after division into age groups. Finally, we applied broader age bands used in two other instruments and explored likely validity limitations when different instruments are compared., Results: When BSID-III age groups are used, 15% of cases are missed and 15% of apparent cases are false positives. Wider age groups produced error rates from 27% to 46%. Comparison of different age groups suggests that sensitivity in validation studies would be limited, under certain assumptions, to 70% or less., Implications: The use of age groups produces a large number of misclassifications. Although affected children will usually be close to the threshold, this may lead to misreferrals. Results may help to explain the poor measured agreement of development screens. Scoring methods that treat child age as continuous would improve instrument accuracy., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Within the new DSM-5, the currently differentiated subgroups of "Autistic Disorder" (299.0), "Asperger's Disorder" (299.80) and "Pervasive Developmental Disorder" (299.80) are replaced by the more general "Autism Spectrum Disorder". With regard to a patient-oriented and expedient advising therapy planning, however, the issue of an empirically reproducible and clinically feasible differentiation into subgroups must still be raised. Based on two Autism-rating-scales (ASDS and FSK), an exploratory two-step cluster analysis was conducted with N=103 children (age: 5-18) seen in our social-pediatric health care centre to examine potentially autistic symptoms. In the two-cluster solution of both rating scales, mainly the problems in social communication grouped the children into a cluster "with communication problems" (51 % and 41 %), and a cluster "without communication problems". Within the three-cluster solution of the ASDS, sensory hypersensitivity, cleaving to routines and social-communicative problems generated an "autistic" subgroup (22%). The children of the second cluster ("communication problems", 35%) were only described by social-communicative problems, and the third group did not show any problems (38%). In the three-cluster solution of the FSK, the "autistic cluster" of the two-cluster solution differentiated in a subgroup with mainly social-communicative problems (cluster 1) and a second subgroup described by restrictive, repetitive behavior. The different cluster solutions will be discussed with a view to the new DSM-5 diagnostic criteria, for following studies a further specification of some of the ASDS and FSK items could be helpful.

Purpose: Comprehensive description of functioning is important in providing early intervention services for infants with developmental delay/disabilities (DD). A code set of the International Classification of Functioning, Disability and Health: Children and Youth Version (ICF-CY) could facilitate the practical use of the ICF-CY in team evaluation. The purpose of this study was to derive an ICF-CY code set for infants under three years of age with early delay and disabilities (EDD Code Set) for initial team evaluation., Methods: The EDD Code Set based on the ICF-CY was developed on the basis of a Delphi survey of international professionals experienced in implementing the ICF-CY and professionals in early intervention service system in Taiwan., Results: Twenty-five professionals completed the Delphi survey. A total of 82 ICF-CY second-level categories were identified for the EDD Code Set, including 28 categories from the domain Activities and Participation, 29 from body functions, 10 from body structures and 15 from environmental factors., Conclusions: The EDD Code Set of 82 ICF-CY categories could be useful in multidisciplinary team evaluations to describe functioning of infants younger than three years of age with DD, in a holistic manner. Future validation of the EDD Code Set and examination of its clinical utility are needed., Implications for Rehabilitation: The EDD Code Set with 82 essential ICF-CY categories could be useful in the initial team evaluation as a common language to describe functioning of infants less than three years of age with developmental delay/disabilities, with a more holistic view. The EDD Code Set including essential categories in activities and participation, body functions, body structures and environmental factors could be used to create a functional profile for each infant with special needs and to clarify the interaction of child and environment accounting for the child's functioning.

Co-existence of attention-deficit/hyperactivity disorder, oppositional defiant disorder, tic disorders, developmental coordination disorder, language disorder, learning problems, and autism spectrum disorder and sharing of symptoms across disorders, contribute to the typical clinical presentation in child psychiatry as well as in developmental medicine. The acronym ESSENCE refers to Early Symptomatic Syndromes Eliciting Neurodevelopmental Clinical Examinations. Affected children are brought for clinical assessment because of impairing symptoms that raise concern before the age of about 5 years in general development, communication and language, social inter-relatedness, motor coordination, attention, activity, behaviour, mood, and/or sleep. Such children are usually in need of a range of expert assessments, but a holistic approach is rarely taken from the start. Major problems in at least one ESSENCE domain before 5 years of age predict poor mental health later in life. Expert ESSENCE centres for assessment, habilitation and treatment of these children are needed.

Cerebellar hypoplasia (CH) refers to a cerebellum with a reduced volume, and is a common, but non-specific neuroimaging finding. The etiological spectrum of CH is wide and includes both primary (malformative) and secondary (disruptive) conditions. Primary conditions include chromosomal aberrations (e.g., trisomy 13 and 18), metabolic disorders (e.g., molybdenum cofactor deficiency, Smith-Lemli-Opitz syndrome, and adenylosuccinase deficiency), genetic syndromes (e.g., Ritscher-Schinzel, Joubert, and CHARGE syndromes), and brain malformations (primary posterior fossa malformations e.g., Dandy-Walker malformation, pontine tegmental cap dysplasia and rhombencephalosynapsis, or global brain malformations such as tubulinopathies and α-dystroglycanopathies). Secondary (disruptive) conditions include prenatal infections (e.g., cytomegalovirus), exposure to teratogens, and extreme prematurity. The distinction between malformations and disruptions is important for pathogenesis and genetic counseling. Neuroimaging provides key information to categorize CH based on the pattern of involvement: unilateral CH, CH with mainly vermis involvement, global CH with involvement of both vermis and hemispheres, and pontocerebellar hypoplasia. The category of CH, associated neuroimaging findings and clinical features may suggest a specific disorder or help plan further investigations and interpret their results. Over the past decade, advances in neuroimaging and genetic testing have greatly improved clinical diagnosis, diagnostic testing, recurrence risk counseling, and information about prognosis for patients and their families. In the next decade, these advances will be translated into deeper understanding of these disorders and more specific treatments., (© 2014 Wiley Periodicals, Inc.)

Aim: The International Classification of Functioning Disability and Health, Child-Youth version (ICF-CY) provides a framework for describing and evaluating health, intervention outcomes, and needs assessment. It can, however, also serve as a system for classifying the focus of outcome studies and identification of gaps in current knowledge., Method: The paediatric arterial ischaemic stroke (AIS) population was targeted. Multiple databases were systematically searched for AIS outcome studies focussing on functioning or disability. Findings were rated using the ICF-CY framework., Results: Twenty-eight studies were identified. Most were cross-sectional and age range at assessment varied widely. Sixty-seven different standardized measures were used, predominantly evaluating body functions. The most common domains of activity and participation reported were learning and applying knowledge, general tasks and demands, and self-care skills. Health-related quality of life was measured in nine papers. Environmental factors were rarely evaluated., Interpretation: AIS outcome studies addressing the relationship between body structures and functions (e.g. brain lesion characteristics, neurological examination findings) and activities, participation, and quality of life have emerged in recent years. Comparison of findings across studies is complicated by design and tool selection. The relationship between components of activity limitation and participation restriction is rarely explored., (© 2013 Mac Keith Press.)

The classification of tic disorders has been revised in the new fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5). The previously expressed suggestion to categorize tic disorders within the "Anxiety and Obsessive Compulsive Disorders" was not implemented. The section "Disorders Usually First Diagnosed in Infancy, Childhood, or Adolescence" was revised and renamed as "Neurodevelopmental Disorders." Tic disorders are classified there as movement disorders. Most of the changes are distinct improvements from both a clinical and a scientific perspective. For example, by removing the adjective "stereotype," the definition of tics is more precise and unified. Also, the new time-oriented criteria are more practical in the clinical setting, e.g., the exclusion criterion of a tic-free interval more than 3 months given for chronic tic disorders has been deleted. The renamings from "Transient" to "Provisional Tic Disorder" as well as from "Chronic" to "Persistent Tic Disorder" are welcome changes from a clinical perspective. Overall, the revision of the criteria is an important step towards providing more clarity and feasibility. However, the revised classification of tic disorders is still based only on clinical experience and not on evidence. Future studies should show whether the revised and improved criteria truly provide the optimal classification.

Objectives: Perinatal asphyxia complicated by hypoxic ischemic brain injury remains a source of neurological lesions. A major aim of neonatologists is to evaluate the severity of neonatal encephalopathy (NE) and to evaluate prognosis. The purpose of this study was to determine the contribution of brain MRI compared to electroencephalogram (EEG) and clinical data in assessing patients' prognosis., Materials and Methods: Thirty newborns from the pediatric resuscitation unit at Rouen university hospital were enrolled in a retrospective study between January 2006 and December 2008, prior to introduction of hypothermia treatment. All 30 newborns had at least two anamnestic criteria of perinatal asphyxia, one brain MRI in the first 5 days of life and another after 7 days of life as well as an early EEG in the first 2 days of life. Then, the infants were seen in consultation to assess neurodevelopment., Results: This study showed a relation between NE stage and prognosis. During stage 1, prognosis was good, whereas stage 3 was associated with poor neurodevelopment outcome. Normal clinical examination before the 8th day of life was a good prognostic factor in this study. There was a relationship between severity of EEG after the 5th day of life and poor outcome. During stage 2, EEG patterns varied in severity, and brain MRI provided a better prognosis. Lesions of the basal ganglia and a decreased or absent signal of the posterior limb of the internal capsule were poor prognostic factors during brain MRI. These lesions were underestimated during standard MRI in the first days of life but were visible with diffusion sequences. Cognitive impairment affected 40% of surviving children, justifying extended pediatric follow-up., Conclusion: This study confirms the usefulness of brain MRI as a diagnostic tool in hypoxic ischemic encephalopathy in association with clinical data and EEG tracings., (Copyright © 2013 Elsevier Masson SAS. All rights reserved.)

Objective: The aim of the present school-based questionnaire was to analyze the sleep problems of children with developmental disorders, such as pervasive developmental disorder and attention deficit hyperactivity disorder., Methods: The sleep problems of 43 children with developmental disorders were compared with those of 372 healthy children (control group). All children attended one public elementary school in Kurume, Japan; thus, the study avoided the potential bias associated with hospital-based surveys (i.e. a high prevalence of sleep disturbance) and provided a more complete picture of the children's academic performance and family situation compared with a control group under identical conditions. Children's sleep problems were measured with the Japanese version of the Children's Sleep Habits Questionnaire (CSHQ)., Results: Children with developmental disorders had significantly higher total CSHQ scores, as well as mean scores on the parasomnias and sleep breathing subscales, than children in the control group. The total CSHQ score, bedtime resistance, sleep onset delay, and daytime sleepiness worsened with increasing age in children with developmental disorders; in contrast, these parameters were unchanged or became better with age in the control group. In children with developmental disorders, there was a significant association between a higher total CSHQ score and lower academic performance, but no such association was found in the control group. For both groups, children's sleep problems affected their parents' quality of sleep. There were no significant differences in physical, lifestyle, and sleep environmental factors, or in sleep/wake patterns, between the two groups., Conclusions: Children with developmental disorders have poor sleep quality, which may affect academic performance. It is important for physicians to be aware of age-related differences in sleep problems in children with developmental disorders. Further studies are needed to identify the association between sleep quality and school behavioral performance., (Copyright © 2012 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.)

Purpose: Environmental variables have been explored in studies of the development of young children with motor delays. Linking environmental variables to the International Classification of Functioning, Disability and Health - Children and Youth (ICF-CY), environmental factors (EFs) categories can provide a common language for documenting their contribution to developmental outcomes. This review of studies aimed to (1) link EFs for developmental outcomes in infants with or at risk for motor delays to ICF-CY categories and (2) synthesize the influences of EFs (with ICF-CY linkage) on developmental outcomes., Method: A systematic literature search was performed of multiple databases. After applying selection criteria, environmental variables in 28 articles were linked to ICF-CY categories and underwent qualitative synthesis., Results: Results indicated that physical environmental variables could be linked successfully to ICF-CY EFs categories, but not social environmental variables. Multiple environmental variables were associated with motor and other developmental outcomes., Conclusion: Difficulties in linking social factors to ICF-CY categories indicate that additional EFs codes may need to be considered in the ICF-CY revision processes. The review provides empirical data on relationships between EFs and developmental outcomes in children with or at risk for motor delay.

The purpose of this study was to determine the effectiveness of the Bayley Scales of Infant Development, Third Edition (Bayley-III) to track development and classify delays in low- and high-risk infants across the first two years of life. We assessed cognitive, language, and motor development in 24 low-risk full-term and 30 high-risk preterm infants via seven assessments performed between 3 and 24 months corrected age. The Bayley-III resulted in highly unstable delay classifications, low sensitivities, and poor positive predictive values across time. The results highlight that early intervention professionals, researchers, and policy makers should: (1) emphasize clinical opinion and prevalence of risk factors rather than standardized assessment findings when classifying delays and determining eligibility for services, and (2) develop more effective developmental assessments for infants and young children., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Neurodevelopmental disorders such as intellectual disability, autism spectrum disorder and schizophrenia lack precise boundaries in their clinical definitions, epidemiology, genetics and protein-protein interactomes. This calls into question the appropriateness of current categorical disease concepts. Recently, there has been a rising tide to reformulate neurodevelopmental nosological entities from biology upward. To facilitate this developing trend, we propose that identification of unique proteomic signatures that can be strongly associated with patient's risk alleles and proteome-interactome-guided exploration of patient genomes could define biological mechanisms necessary to reformulate disorder definitions.

Mental retardation affects about 2-3% of the population and is often associated with comorbidities. So far, more than 450 different medical conditions are known with mental retardation as a sign and it is assumed that there are many more yet to be defined. The diagnosis of the underlying entity allows for a few specific optimization of cognitive function, but usually improves the treatment of comorbidities. Furthermore, the detection of the underlying genetic defect allows the specification of the risk of recurrence and enables prenatal diagnosis for future pregnancies of persons at risk in the family. Recent findings suggest that especially in diseases that are associated with defective synaptic signal transduction may be targeted by specific drugs for improvement of cognitive performance in the near future.

This article provides the dentist with a background on disabilities, education, practice and provision of services related to statutory and regulatory requirements, particularly the Americans with Disabilities Act anrid the California Fair Employment and Housing Act.

Objective: Maltreatment, family violence, and disruption in primary caregiver attachment in childhood may constitute a developmental form of trauma that places children at risk for multiple psychiatric and medical diagnoses that often are refractory to well-established evidence-based mental health treatments. No integrative diagnosis exists to guide assessment and treatment for these children and adolescents. This study therefore assessed clinicians' ratings of the clinical utility of a proposed developmental trauma disorder diagnostic framework., Method: An Internet survey was conducted with an international convenience sample of 472 self-selected medical, mental health, counseling, child welfare, and education professionals. Respondents made quantitative ratings of the clinical significance of developmental trauma disorder, developmental trauma exposure, and symptom items and also posttraumatic stress disorder (PTSD) and other Axis I internalizing and externalizing disorder symptom items for 4 clinical vignettes. Ratings of the discriminability of each developmental trauma disorder item from PTSD, other anxiety disorders, affective disorders, and externalizing behavior disorders, and of each developmental trauma disorder item's amenability to existing evidence-based treatments for those disorders, also were obtained., Results: Respondents viewed developmental trauma disorder criteria as (1) comparable in clinical utility to criteria for PTSD and other psychiatric disorders; (2) discriminable from and not fully accounted for by other disorders; and (3) refractory to existing evidence-based psychotherapeutic treatments., Conclusions: The exposure and symptom criteria proposed for a developmental trauma disorder diagnosis warrant clinical dissemination and scientific field testing to determine their actual clinical utility in treating traumatized children with complex psychiatric presentations., (© Copyright 2013 Physicians Postgraduate Press, Inc.)

Reactive attachment disorder (RAD) is a severe disorder of social functioning. Previous research has shown that children with RAD may have poor cognitive and language abilities; however, findings mainly come from biased, institutionalised samples. This paper describes the characteristics of all children who were given a suspected or likely diagnosis of reactive attachment disorder in an epidemiological study of approximately 1,600 children investigating the prevalence of RAD in the general population. We found that children with RAD are more likely to have multiple comorbidities with other disorders, lower IQs than population norms, more disorganised attachment, more problem behaviours, and poorer social skills than would be found in the general population and therefore have a complex presentation than can be described as ESSENCE. We discuss the clinical and educational implications.

Brain maturation in 1-36 month old children suffering from congenital cardiopathologies was assessed after a study of psychomotor development. The Rogers' test (Rogers et al., Developmental programming for infants and young children. Volume 2. Early intervention developmental profile, Revised edition, ESL/ELT Michigan, Ann Arbor, 1981) was applied to 65 children, of whom 21 presented with simple cardiopathologies (CpS) and 22 with complex cardiopathologies (CpC). All children were matched by age, sex and socioeconomic status to 22 healthy children in a control group (C). Mean differences between the three groups were established by applying the Kruskal-Wallis test, and mean differences between the C and CpS/CpC groups were determined using the Mann-Whitney test. The proportion of cases evaluated as "low" in each group was calculated by applying the Rogers' test, and a test of proportion differences was applied between the C and CpS/CpC groups. CpS children performed similarly to the C, whereas CpC children scored significantly lower than C children on all variables. It is highly likely that the suboptimal psychomotor performance observed in CpC children was due to compromised hemodynamics and related to subclinical immaturity of cerebral development.