Behavioral Phenotyping Neurofibromatosis Type 1

Neurofibromatosis type 1 (NF1) is a genetic disorder leading to symptoms in the skin, bones, and nervous system, but also to an increased risk of benign and malignant tumors. NF1 leads to unpredictable and variable complications and a lower quality of life. Cognitive deficits and behavioral problems are among the most common complications of NF1 in children. Both physical and psychological characteristics are part of the so-called phenotype, belonging to the genetic makeup: the genotype of this disorder. This thesis focuses on the behavioral phenotype including the most frequent cognitive, motor, behavioral, emotional and social problems in NF1

Health-related quality of life of children with neurofibromatosis type 1:Analysis of proxy-rated PedsQL and CHQ questionnaires

This study aims to (1) investigate health-related quality of life (HRQoL) in children with Neurofibromatosis Type 1 (NF1) using the Pediatric Quality of Life inventory (PedsQL) and the Child Health Questionnaire (CHQ); and (2) compare the psychometric properties and content of these questionnaires in NF1 patients. PedsQL and CHQ proxy-reports were administered to parents/caregivers of 160 patients with NF1 aged 5–12 years. HRQoL scores were compared with Dutch population norms using independent t-tests. Psychometric properties (feasibility and reliability) were assessed by floor/ceiling effects and Cronbach's alpha coefficient. A principal component analysis (PCA) with varimax rotation was performed to identify the data's internal structure. By content mapping, we identified unique constructs of each questionnaire. Proxy-reported HRQoL was significantly lower on all PedsQL subscales for children aged 5–7 years, and on 4/6 subscales for children aged 8–12 years compared to norms. Significantly lower HRQoL was reported on 6/14 CHQ subscales (children 5–7 years) and 9/14 subscales (children 8–12 years). The PedsQL showed slightly better feasibility and reliability. The PCA identified two components, representing psychosocial and physical aspects of HRQoL, explaining 63% of total variance. Both questionnaires showed relevant loadings on both components. The CHQ subscales concerning parents and family were considered unique contributions. Proxy-reported HRQoL of children with NF1 is significantly lower compared to norms on multiple domains. Both questionnaires adequately measure HRQoL in children with NF1. However, the PedsQL has slightly better psychometric properties, while the CHQ covers a unique dimension of HRQoL associated with disease impact on parents and family.</p

Shared symptomatology between atopic dermatitis, ADHD and autism spectrum disorder:a protocol for a systematic scoping review

INTRODUCTION: Children with atopic dermatitis (AD) are more at risk for the neurodevelopmental disorders attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) with parallel increases in global prevalences. Children afflicted with these conditions appear to share similar problems in sensory modulation but investigational studies on the underlying aetiology are scarce. This scoping review aims to find knowledge gaps, collate hypotheses and to summarise available evidence on the shared pathophysiology of AD, ADHD and ASD in children. METHODS AND ANALYSIS: Our study will follow the methodological manual published by the Joanna Briggs Methodology for Scoping Reviews and will be reported in accordance with the Preferred Reporting Items for Systematic reviews and Meta-Analyses Extension for Scoping Reviews. The following electronic databases will be searched for studies focused on children with AD and symptoms of ADHD and/or ASD: Medline ALL via Ovid, Embase, Web of Science Core Collection and the Cochrane Central Register of Controlled Trials via Wiley. ETHICS AND DISSEMINATION: This review does not require ethics approval as it will not be conducted with human participants. We will only use published data. Our dissemination strategy includes peer review publication and conference reports.</p

Sensory processing in young children with visual impairments:Use and extension of the Sensory Profile

Background: Children with visual impairments (VI) are at risk for sensory processing difficulties. A widely used measure for sensory processing is the Sensory Profile (SP). However, the SP requires adaptation to accommodate for how children with VI experience sensory information. Aims: (1) To examine sensory processing patterns in young children with VI, (2) to develop VI-specific items to use in conjunction with the SP and to determine internal consistency and construct validity of these newly developed items, and (3) to examine the association between sensory processing and and emotional and behavioral problems. Methods: Twenty-six VI-specific items were added to the SP. The SP and these items were completed by caregivers of 90 children with VI between 3 and 8 years old. The Child Behavior Checklist (CBCL) was used to assess emotional and behavioral problems. Results: Three- to five-year-old children with VI have significantly more difficulties in three quadrants of the SP as compared to the norm group. Six- to eight-year-old children with VI have more difficulties in all quadrants. A reliable and valid VI-specific set of 15 items was established following psychometric evaluation. Age-related differences were found in the associations between the SP and CBCL. Conclusion: Although further validation is recommended, this evaluation of the VI-specific item set suggests it has the potential to be a useful measure for children with VI

Risk factors of impaired neuropsychological outcome in school-aged survivors of neonatal critical illness

__Objective__ Until now, long-term outcome studies have focused on general cognitive functioning and its risk factors following neonatal extracorporeal membrane oxygenation (ECMO) and/or congenital diaphragmatic hernia (CDH). However, it is currently unknown which neuropsychological domains are most affected in these patients, and which clinical variables can be used to predict specific neuropsychological problems. This study aimed to identify affected neuropsychological domains and its clinical determinants in survivors of neonatal ECMO and/or CDH. __Design__ Prospective follow-up study. __Setting__ Tertiary university hospital. __Patients__ Sixty-five eight-year-old survivors of neonatal ECMO and/or CDH. __Interventions__ None. __Measurements and Main Results__ Intelligence, attention, memory, executive functioning and visuospatial processing were evaluated

Everolimus for the treatment of refractory seizures associated with tuberous sclerosis complex (TSC): current perspectives

Up to 90% of patients with tuberous sclerosis complex (TSC) have epilepsy, and in over half of patients seizure control cannot be achieved by regular antiepileptic drugs. The underlying problem is mTOR hyperactivation due to loss of function of the TSC proteins. Treatment with everolimus, an mTOR inhibitor, has been shown to be of great benefit to TSC patients, both in reducing tumor growth and as a treatment for intractable epilepsy. Up to 40% of TSC patients with intractable epilepsy show a clinically relevant seizure response to everolimus. It has not yet fully lived up to its promise as a disease-modifying drug, however, as half of TSC patients with intractable epilepsy do not show a clinically relevant seizure frequency reduction. There is no evidence yet of a positive effect on the cognitive and neuropsychiatric deficits in TSC patients. In preclinical studies, mTOR inhibition can rescue abnormal neuronal migration and synapse formation that is caused by mTOR hyperactivation. These studies show a critical time window that suggests that mTOR inhibition may be most beneficial in young children. The trials done so far have not studied treatment in children under 2 years of age, although case series suggest that the safety profile is similar to that in older children. Further studies into the optimal time window, dosing schedules and possibly combination with other drugs may further improve the benefit of everolimus for TSC patients

Autism Symptoms in Children and Young Adults With Fragile X Syndrome, Angelman Syndrome, Tuberous Sclerosis Complex, and Neurofibromatosis Type 1:A Cross-Syndrome Comparison

Objective: The etiology of autism spectrum disorder (ASD) remains unclear, due to genetic heterogeneity and heterogeneity in symptoms across individuals. This study compares ASD symptomatology between monogenetic syndromes with a high ASD prevalence, in order to reveal syndrome specific vulnerabilities and to clarify how genetic variations affect ASD symptom presentation. Methods: We assessed ASD symptom severity in children and young adults (aged 0-28 years) with Fragile X Syndrome (FXS, n = 60), Angelman Syndrome (AS, n = 91), Neurofibromatosis Type 1 (NF1, n = 279) and Tuberous Sclerosis Complex (TSC, n = 110), using the Autism Diagnostic Observation Schedule and Social Responsiveness Scale. Assessments were part of routine clinical care at the ENCORE expertise center in Rotterdam, the Netherlands. First, we compared the syndrome groups on the ASD classification prevalence and ASD severity scores. Then, we compared individuals in our syndrome groups with an ASD classification to a non-syndromic ASD group (nsASD, n = 335), on both ASD severity scores and ASD symptom profiles. Severity scores were compared using MANCOVAs with IQ and gender as covariates. Results: Overall, ASD severity scores were highest for the FXS group and lowest for the NF1 group. Compared to nsASD, individuals with an ASD classification in our syndrome groups showed less problems on the instruments' social domains. We found a relative strength in the AS group on the social cognition, communication and motivation domains and a relative challenge in creativity; a relative strength of the NF1 group on the restricted interests and repetitive behavior scale; and a relative challenge in the FXS and TSC groups on the restricted interests and repetitive behavior domain. Conclusion: The syndrome-specific strengths and challenges we found provide a frame of reference to evaluate an individual's symptoms relative to the larger syndromic population and to guide treatment decisions. Our findings support the need for personalized care and a dimensional, symptom-based diagnostic approach, in contrast to a dichotomous ASD diagnosis used as a prerequisite for access to healthcare services. Similarities in ASD symptom profiles between AS and FXS, and between NF1 and TSC may reflect similarities in their neurobiology. Deep phenotyping studies are required to link neurobiological markers to ASD symptomatology

Autism Spectrum Disorder in an Unselected Cohort of Children with Neurofibromatosis Type 1 (NF1)

In a non-selected sample of children with Neurofibromatosis type 1 (NF1) the prevalence rate of autism spectrum disorder (ASD) and predictive value of an observational (ADOS)—and questionnaire-based screening instrument were assessed. Complete data was available for 128 children. The prevalence rate for clinical ASD was 10.9%, which is clearly higher than in the general population. This prevalence rate is presumably more accurate than in previous studies that examined children with NF1 with an ASD presumption or solely based on screening instruments. The combined observational- and screening based classifications demonstrated the highest positive predictive value for DSM-IV diagnosis, highlighting the importance of using both instruments in children with NF1

Prognostic Factors for Long-term Aesthetic Outcome of Infantile Haemangioma Treated with Beta-blockers

Parents of infants treated with beta-blockers for infantile haemangioma are often concerned about the long-term aesthetic outcome. This cross-sectional study assessed the influence on the long-term aesthetic outcome of characteristics of the infantile haemangioma, the beta-blocker treatment, and the infant. The study included 103 children aged 6-12 years, treated with beta-blockers (propranolol or atenolol) for infantile haemangioma during infancy (age at treatment initiation ≤1 year) for ≥6 months. Dermatologists and parents scored the Patient Observer Scar Assessment Scale, and the child scored a visual analogue scale. Dermatologists identified whether telangiectasia, fibrofatty tissue, and atrophic scar tissue were present. The long-term aesthetic outcome of infantile haemangioma was judged more negatively by dermatologists and parents in case of a superficial component, ulceration, older age at treatment initiation, higher cumulative dose, and/or shorter follow-up time. According to children, infantile haemangioma located on the head had better aesthetic outcome than infantile haemangioma located elsewhere. Close monitoring, particularly of infantile haemangioma with a superficial component, is essential for early initiation of treatment, and to prevent or treat ulceration. These outcome data can support parental counselling and guide treatment strategy.</p