Understanding Behavior in Phelan-McDermid Syndrome.

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 Behavioral data showed high levels of withdrawn behavior and attention problems.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

The phenotypic spectrum of proximal 6q deletions based on a large cohort derived from social media and literature reports.

Proximal 6q (6q11-q15) deletions are extremely rare and little is known about their phenotypic consequences. Since parents and caregivers now use social media to seek information on rare disorders, the Chromosome 6 Project has successfully collaborated with a Facebook group to collect data on individuals worldwide. Here we describe a cohort of 20 newly identified individuals and 25 literature cases with a proximal 6q deletion. Microarray results and phenotype data were reported directly by parents via a multilingual online questionnaire. This led to phenotype descriptions for five subregions of proximal 6q deletions; comparing the subgroups revealed that 6q11q14.1 deletions presented less severe clinical characteristics than 6q14.2q15 deletions. Gastroesophageal reflux, tracheo/laryngo/bronchomalacia, congenital heart defects, cerebral defects, seizures, and vision and respiratory problems were predominant in those with 6q14.2q15 deletions. Problems related to connective tissue (hypermobility, hernias and foot deformities) were predominantly seen in deletions including the COL12A1 gene (6q13). Congenital heart defects could be linked to deletions of MAP3K7 (6q15) or TBX18 (6q14.3). We further discuss the role of ten genes known or assumed to be related to developmental delay and/or autism (BAI3, RIMS1, KCNQ5, HTR1B, PHIP, SYNCRIP, HTR1E, ZNF292, AKIRIN2 and EPHA7). The most influential gene on the neurodevelopmental phenotype seems to be SYNCRIP (6q14.3), while deletions that include more than two of these genes led to more severe developmental delay. We demonstrate that approaching individuals via social media and collecting data directly from parents is a successful strategy, resulting in better information to counsel families.

How reliable and valid is the teacher version of the Strengths and Difficulties Questionnaire in primary school children?

INTRODUCTION: The Strengths and Difficulties Questionnaire (SDQ) is validated for parents, but not yet for teachers in a broad age range of children. We conducted a cross-sectional study with 4-10 years old school children to investigate if the SDQ-T can be used instead of the validated but lengthy Teacher's Report Form (TRF) to acquire information about emotional and behavioral problems in the school community. METHODS: Teachers of 453 children from primary schools were approached. Teachers of 394 children (response rate 86.9%) with a mean age of 7.1 years filled in the SDQ-T (n = 387), the TRF (n = 349) or both (n = 342). We assessed reliability by calculating internal consistency and concurrent validity (using correlation coefficients, sensitivity, specificity) of the SDQ-T compared with the TRF. RESULTS: Internal consistency of the SDQ-T Total Difficulties Score (SDQ-T TDS; Cronbach α = 0.80), hyperactivity/ inattention- (α = 0.86) and prosocial behavior (α = 0.81) was very good. Concurrent validity demonstrated a strong correlation of all subscales of the SDQ-T with the corresponding scale on the TRF (range 0.54-0.73), except for peer problems (0.46). Using a SDQ-T TDS cut-off score > 14, the SDQ-T had a good sensitivity (90%) and specificity (94%). DISCUSSION: The good reliability, validity and brevity of the SDQ-T make it an easily applicable questionnaire for obtaining information about emotional and behavioral problems from teachers in primary school children.

Is there an effect of intranasal insulin on development and behaviour in Phelan-McDermid syndrome? A randomized, double-blind, placebo-controlled trial.

Phelan-McDermid syndrome (PMS) or 22q13.3 deletion syndrome is a rare neurodevelopmental disorder with at least 60 children and 35 adults diagnosed in the Netherlands. Clinical features are moderate to severe intellectual disability and behavioural problems in the autism spectrum. Other researchers had observed a beneficial effect of intranasal insulin on development and behaviour in a pilot study in six children with PMS. To validate this effect, we conducted a randomized, double-blind, placebo-controlled clinical trial using a stepped-wedge design. From March 2013 to June 2015, 25 children aged 1-16 years with a molecularly confirmed 22q13.3 deletion including the SHANK3 gene participated in the clinical trial for a period of 18 months. Starting 6 months before the trial, children were systematically assessed for cognitive, language and motor development and for adaptive, social and emotional behaviour every 6 months. The second, third and fourth assessments were followed by daily nose sprays containing either intranasal insulin or intranasal placebo for a 6-month period. A fifth assessment was done directly after the end of the trial. Intranasal insulin did not cause serious adverse events. It increased the level of developmental functioning by 0.4-1.4 months per 6-month period, but the effect was not statistically significant in this small group. We found a stronger effect of intranasal insulin, being significant for cognition and social skills, for children older than 3 years, who usually show a decrease of developmental growth. However, clinical trials in larger study populations are required to prove the therapeutic effect of intranasal insulin in PMS.

Developmental phenotype in Phelan-McDermid (22q13.3 deletion) syndrome: a systematic and prospective study in 34 children.

BACKGROUND: Phelan-McDermid syndrome (PMS) or 22q13.3 deletion syndrome is characterized by global developmental delay, cognitive deficits, and behaviour in the autism spectrum. Knowledge about developmental and behavioural characteristics of this rare chromosomal disorder is still limited despite a rapid growing number of diagnoses. Our aim was to study a new and relatively large cohort to further characterize the developmental phenotype of children with PMS. METHODS: We performed a descriptive study of children with a 22q13.3 deletion including SHANK3, aged 8 to 178 months, who were systematically (n = 34) and longitudinally (n = 29) assessed with standardized instruments: Bayley Scales of Infant and Toddler Development, third edition; Wechsler Preschool and Primary Scale of Intelligence, third edition; and Vineland Screener for Social and Adaptive Behavior. RESULTS: Maximal developmental functioning ranged from 34 to 52 months depending on the developmental domain. In general, children performed poorest in the domain of language and best on the domain of motor (young children) or cognitive development (older children). At the individual level, 25 % scored better for receptive and 18 % for expressive language, whereas 22 % scored better for fine and 33 % for gross motor function. Developmental quotients were higher in younger children and decreased with age for all developmental domains, with 38 % of the children showing no improvement of cognitive developmental functioning. Almost all children (33/34) had significant deficits in adaptive behaviour. Children with very small deletions, covering only the SHANK3, ACR, and RABL2B genes, had a more favourable developmental phenotype. CONCLUSIONS: Cognitive, motor, and especially language development were significantly impaired in all children with PMS but also highly variable and unpredictable. In addition, deficits in adaptive behaviour further hampered their cognitive development. Therefore, cognitive and behavioural characteristics should be evaluated and followed in each child with PMS to adapt supportive and therapeutic strategies to individual needs. Further research evaluating the relationship between deletion characteristics and the developmental phenotype is warranted to improve counselling of parents.

Identification of emotional and behavioral problems by teachers in children with developmental coordination disorder in the school community.

Current evidence on the co-occurrence of Developmental Coordination Disorder (DCD) and psychosocial problems mainly concerns parent-reported information, but rarely includes teacher information. The aim of this study was (1) to investigate the teachers' identification of emotional and behavioral problems in children with DCD and (2) to examine the performance of the teacher version of the Strengths and Difficulties Questionnaire (SDQ-T) compared with the Teacher Report Form (TRF) in children with DCD. We assessed primary school children (202 boys, 200 girls, range 4-10.8 years, mean age 7.2 years) for DCD following the DSM IV-TR criteria. Emotional and behavioral problems were measured with the TRF (n=327) and the SDQ-T (n=361). DCD was established in 23 (5.7%) children, 16 boys and 7 girls (mean age 7.0 years). Children with DCD had a higher proportion of clinical scores on both the TRF Total Problem Scale (TRF TPS) and SDQ-T Total Difficulties Score (SDQ-T TDS). Children with DCD had increased odds on the TRF domains Thought (odds ratio, OR: 5.39), Externalizing (OR: 4.12) and Internalizing (OR: 4.42) problems, and on all SDQ-T-domains and Total Difficulties score (OR: 7.30). In the DCD group the SDQ-T TDS correlated strongly (Spearman's rho 0.80) with the TRF TPS and demonstrated a moderate agreement (Cohen's Kappa 0.53). In conclusion, teachers identified significantly more emotional and behavioral problems in children with DCD compared with their peers. The SDQ-T showed moderate agreement with the TRF in identifying emotional and behavioral problems in children with DCD.

Developmental coordination disorder in children with specific language impairment: co-morbidity and impact on quality of life.

Co-morbidity of Developmental Coordination Disorder (DCD) in children with specific language impairment (SLI) and the impact of DCD on quality-of-life (QOL) was investigated in 65 5-8 year old children with SLI (43 boys, age 6.8±0.8; 22 girls, age 6.6±0.8). The prevalence of DCD was assessed using DSM-IV-TR criteria (American Psychiatric Association (APA), 2000) operationally defined in the clinical practice guideline (CPG): movement ABC scores below 15th percentile, scores on DCDQ and/or MOQ-T below 15th percentile, absence of medical condition according to paediatric-neurological exam. Quality of life (QOL) was measured with the TNO-AZL-Child-Quality-Of-Life (TACQOL) Questionnaire filled out by parents for the SLI group with and without DCD, and compared to a reference group (N=572; age 6.9±0.9). The TACQOL covers 7 QOL domains: physical, motor, cognitive and social functioning, autonomy, positive and negative moods. Prevalence of DCD in children with SLI was 32.3%. In children with SLI, mean QOL scores were significantly lower in the autonomy, cognitive, social and positive moods domains compared to the reference group. Children with SLI and DCD differed from children with SLI without DCD by significantly lower mean overall-, motor-, autonomy-, and cognitive domain-QOL scores. Clinicians should be aware that about one third of children with SLI can also be diagnosed with DCD. Assessment of QOL is warranted in order to assess which domains are affected in children with SLI with or without DCD.

Validity and reliability of the Movement Assessment Battery for Children-2 Checklist for children with and without motor impairments.

AIM: The aim of this study was to investigate the validity and reliability of the Movement Assessment Battery for Children-2 Checklist (MABC-2). METHOD: Teachers completed the Checklist for 383 children (age range 5-8y; mean age 6y 9mo; 190 males; 193 females) and the parents of 130 of these children completed the Developmental Disorder Coordination Questionnaire 2007 (DCDQ'07). All children were assessed with the MABC-2 Test. The internal consistency of the 30 items of the Checklist was determined to measure reliability. Construct validity was investigated using factor analysis and discriminative validity was assessed by comparing the scores of children with and without movement difficulties. Concurrent validity was measured by calculating correlations between the Checklist, Test, and the DCDQ'07. Incremental validity was assessed to determine whether the Checklist was a better predictor of motor impairment than the DCDQ'07. Sensitivity and specificity were investigated using the MABC-2 Test as reference standard (cut-off 15th centile). RESULTS: The Checklist items measure the same construct. Six factors were obtained after factor analysis. This implies that a broad range of functional activities can be assessed with the Checklist, which renders the Checklist useful for assessing criterion B of the diagnostic criteria for DCD. The mean Checklist scores for children with and without motor impairments significantly differed (p<0.001). The scores for the Checklist/Test and DCDQ'07 were significantly correlated (r(S) =-0.38 and p<0.001, and r(S) =-0.36 and p<0.001, respectively). The Checklist better predicted motor impairment than the DCDQ'07. Overall, the sensitivity was low (41%) and the specificity was acceptable (88%). INTERPRETATION: The Checklist meets standards for validity and reliability.

An interstitial duplication of chromosome 13q31.3q32.1 further delineates the critical region for postaxial polydactyly type A2.

Postaxial polydactyly type A2 (PAP-A2; OMIM 602085) is a common feature seen in patients with a partial duplication of the long arm of chromosome 13. Dose dependency has been shown for digital malformations in this region, deletions resulting in oligodactyly and duplications in polydactyly. We aimed to narrow down the critical region for PAP-A2 in order to identify candidate genes. We performed chromosomal analysis, FISH and array-CGH in a patient with an interstitial duplication of chromosome 13q31.3q32.1 and a mild phenotype including postaxial polydactyly. The duplicated region spanned 5.59 Mb (89.67-95.25 Mb) and contained eleven known genes, including GPC5 and GPC6. GPC5 and GPC6 show homology with GPC3 and GPC4, genes involved in Simpson-Golabi-Behmel syndrome, an overgrowth syndrome in which also polydactyly can occur. Mouse studies have shown expression of both GPC5 and GPC6 in developing limbs. Therefore, we propose that GPC5 and GPC6 are the most likely candidate genes for PAP-A2.

Effects of methylphenidate on quality of life in children with both developmental coordination disorder and ADHD.

Measurement of health-related quality of life (HRQOL) in attention-deficit-hyperactivity disorder (ADHD) gives a more complete picture of day-to-day functioning and treatment effects than behavioural rating alone. The aim of this pilot study was to investigate the impact of the combined diagnoses of developmental coordination disorder (DCD) and ADHD on HRQOL, and the effectiveness of methylphenidate (MPH) on HRQOL. HRQOL was established using the Dutch-Child-AZL-TNO-Quality-of-Life (DUX-25) and the TNO-AZL-Child-Quality-of-Life (TACQOL) questionnaires, completed by children and parents. HRQOL of these children was compared with that of 23 age- and sex-matched healthy controls. Twenty-three children (21 males, two females; mean age 8 y 6 mo, [SD 3 mo] range 7 y-10 y 8 mo) with ADHD/DCD entered a 4-week, open-label MPH study, after MPH-sensitivity was established, in a double-blind, placebo-controlled trial. In these children's self- and proxy reports, impact of both DCD and ADHD was reflected in lower general well-being (self and proxy report p=0.001) due to lower functioning in motor (selfp=0.026; proxy 0.001), autonomic (self p<0.001; proxy p=0.047), cognitive (self p=0.001; proxy p=0.01), and social (self and proxy p<0.001) domains. HRQOL scores improved in 18 children receiving MPH (p=0.001) versus controls. The ADHD /DCD group also demonstrated a significant improvement in ADHD symptoms (p<0.001) and motor functioning (p<0.001). Additional motor therapy will still be needed in about half of the children with ADHD/DCD receiving MPH, within multimodal treatment including educational and psychosocial assistance.

Validity of the motor observation questionnaire for teachers as a screening instrument for children at risk for developmental coordination disorder.

This study investigates validity of the Motor Observation Questionnaire for Teachers (MOQ-T) in 182 children aged 5-10years, 91 children referred for motor problems to a rehabilitation center and 91 comparison children. Performance on the MOQ-T was compared to performance on the Movement Assessment Battery for Children (M-ABC) and the Developmental Coordination Disorder Questionnaire (DCD-Q). Significant correlations were obtained between the MOQ-T and the DCD-Q (r=-.63), and the MOQ-T and the M-ABC (r=.57). The MOQ-T discriminated between children at risk for DCD and comparison children. Sensitivity of the MOQ-T was 80.5%, specificity 62% with the M-ABC as 'gold standard'. These results support the validity of the MOQ-T as a screening instrument for identification of children at risk for DCD.