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 Behavioral data showed high levels of withdrawn behavior and attention problems.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.

Difference or delay? A comparison of Bayley-III Cognition item scores of young children with and without developmental disabilities.

The "difference or delay paradigm" focuses on the question of whether children with developmental disabilities (DD) develop in a way that is only delayed, compared to typically developing children, or also qualitatively different. The current study aimed to examine whether qualitative differences exist in cognitive development of young children with and without DD on the basis of item scores on the Dutch Bayley-III Cognition scale. Differential item functioning was identified for 15 of the 91 items. The presence of DD was related to a higher number of Guttman errors, hinting at more deviation in the order of skill development. An interaction between group (i.e., with or without DD) and developmental quotient appeared to predict the number of Guttman errors. DD was related to a higher number of Guttman errors for the whole range of developmental quotients; children with DD with a small developmental quotient had the highest number. Combined, the results mean that qualitative differences in development are not to be excluded, especially in cases of severe developmental disabilities. When using the Bayley-III in daily practice, the possibility needs to be taken into account that the instruments' assumption of a fixed order in skill development does not hold.

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.

Low verbal assessment with the Bayley-III.

Recently, the authors have developed the Bayley-III-NL Low Verbal for developmental assessment of children with language impairment. The Low Verbal version consists of an accommodated cognition scale, and non-accommodated communication and motor scales. The purpose of the study was to evaluate the validity and added value of the Bayley-III-NL Low Verbal for children with a language impairment, in relation to the standard Bayley-III-NL for children without impairment. We administered the Bayley-III Low Verbal to 69 children with language impairment, and the standard Bayley-III-NL to 1132 children without impairments. We used an evaluation form for test administrators and interviews with developmental psychologists to evaluate the suitability of the Low Verbal version for the target group. We analyzed the test results using nonparametric item response theory (IRT) to investigate whether test results can be reasonably compared across the two groups. The results of the IRT analyses support the validity of the Bayley-III-NL Low Verbal: the test items do not suffer from differential item functioning (DIF) across the two groups, and thus measure the ability levels of interest in the same way. The results of the evaluation form and interviews confirm that the Bayley-III-NL Low Verbal has added value for testing children with a language impairment, especially for children up to 36 months old. It is also suitable for children with general developmental delay. We conclude that the Bayley-III-NL Low Verbal can validly assess the cognitive, language, and motor development of young children with a language impairment and is the preferred instrument for this target group.

The bilirubin albumin ratio in the management of hyperbilirubinemia in preterm infants to improve neurodevelopmental outcome: a randomized controlled trial--BARTrial.

BACKGROUND AND OBJECTIVE: High bilirubin/albumin (B/A) ratios increase the risk of bilirubin neurotoxicity. The B/A ratio may be a valuable measure, in addition to the total serum bilirubin (TSB), in the management of hyperbilirubinemia. We aimed to assess whether the additional use of B/A ratios in the management of hyperbilirubinemia in preterm infants improved neurodevelopmental outcome. METHODS: In a prospective, randomized controlled trial, 615 preterm infants of 32 weeks' gestation or less were randomly assigned to treatment based on either B/A ratio and TSB thresholds (consensus-based), whichever threshold was crossed first, or on the TSB thresholds only. The primary outcome was neurodevelopment at 18 to 24 months' corrected age as assessed with the Bayley Scales of Infant Development III by investigators unaware of treatment allocation. Secondary outcomes included complications of preterm birth and death. RESULTS: Composite motor (100 ± 13 vs. 101 ± 12) and cognitive (101 ± 12 vs. 101 ± 11) scores did not differ between the B/A ratio and TSB groups. Demographic characteristics, maximal TSB levels, B/A ratios, and other secondary outcomes were similar. The rates of death and/or severe neurodevelopmental impairment for the B/A ratio versus TSB groups were 15.4% versus 15.5% (P = 1.0) and 2.8% versus 1.4% (P = 0.62) for birth weights ≤ 1000 g and 1.8% versus 5.8% (P = 0.03) and 4.1% versus 2.0% (P = 0.26) for birth weights of >1000 g. CONCLUSIONS: The additional use of B/A ratio in the management of hyperbilirubinemia in preterm infants did not improve their neurodevelopmental outcome. TRIAL REGISTRATION: Controlled-Trials.com ISRCTN74465643.

Accommodating the Bayley-III for motor and/or visual impairment: a comparative pilot study.

PURPOSE: This study assessed the validity and usefulness of the Bayley Scales of Infant and Toddler Development, Third Edition (Bayley-III) Low Motor/Vision accommodated version. Accommodations are adaptations to minimize impairment bias, without altering what the test measures. Of the items, 66% have Low Motor accommodations like enlarged materials; 62% have Low Vision accommodations. METHODS: Using a within-subject design, we tested 19 children with the accommodated and standard Bayley-III, in a randomly counterbalanced order. The children had motor and/or visual impairment and a chronological age between 22 and 90 months. The test administrators completed an evaluation form. RESULTS: A subgroup of children benefited from the accommodations; 2 children obtained a large raw score difference. Test administrators considered the accommodations as practical, and advantageous for most children. CONCLUSION: The Low Motor/Vision accommodated version seems to validly assess the development of this population. Future, larger-scale research should study whether the accommodations improve the construct validity of the Bayley-III.

Validity and suitability of the Bayley-III Low Motor/Vision version: a comparative study among young children with and without motor and/or visual impairments.

The aim of the present study was to examine the validity of the Bayley-III Low Motor/Vision version, and its suitability for children with motor and/or visual impairment(s). This version contains accommodated items, that is, adaptations to minimize impairment bias, without altering what the test measures. We hypothesized that the accommodations would not affect the item scores of children without impairment, and that children with impairment(s) would benefit from the accommodations. We tested 41 children without impairment and 63 children with impairment with both the standard Bayley-III and the Low Motor/Vision versions, in randomly counterbalanced order. The test administrators filled in an evaluation form. Results showed that the accommodations did not affect the test scores of children without impairment and did improve the test scores of children with impairment on the Cognition scale, while no improvement was found for the other scales. The test administrators indicated that the vast majority of the children with impairment had been able to show their abilities on the test and that the accommodations were beneficial in 29 out of these 52 cases. For some children, the accommodated instrument appeared to be unsuitable because the impairment was too severe. The conclusion is that the accommodations improve the validity of the Bayley-III when used with children with mild to moderate motor and/or visual impairment, especially with regard to the Cognition scale.

Developmental trajectories from birth to school age in healthy term-born children.

OBJECTIVE: To determine the stability of the scores obtained on tests of motor development from birth until school age in healthy, term singletons and to determine if early motor scores are associated with more complex cognitive functions at school age, such as attention and memory. PATIENTS AND METHODS: This longitudinal, prospective cohort study included 77 infants. The motor development of these infants was assessed during the neonatal period with Prechtl's neurologic examination; in early infancy with Touwen's neurologic examination and general movement assessment; at toddler age with Hempel's neurologic examination and the Psychomotor Developmental Index from the Bayley Scales of Infant Development; and at school age with the Movement Assessment Battery for Children. Cognition was determined at toddler age with the Mental Developmental Index from the Bayley Scales of Infant Development; and at school age with an intelligence test and attention and memory tests. RESULTS: The mean absolute difference in standardized motor scores for all time points was 1.01 SD (95% confidence interval: 0.91-1.11). Only the explained proportions of variance of maternal socioeconomic status and verbal intelligence were significant for sustained attention and verbal memory (r(2) = 0.104, P = .030 and r(2) = 0.074, P = .027), respectively. The children's scores on early motor tests added little value for their motor and cognitive development at school age. CONCLUSIONS: In healthy children the stability of motor development from birth until school age is low. Maternal socioeconomic status and verbal intelligence rather than the infants' scores on early motor tests signified added value for complex cognitive functions at school age.