Modeling gross motor developmental curves of extremely and very preterm infants using the AIMS home-video method.

BACKGROUND: Motor development is one of the first signals to identify whether an infant is developing well. For very preterm (VPT) infants without severe perinatal complications, little is known about their motor developmental curves. AIMS: Explore gross motor developmental curves from 3 until 18 months corrected age (CA) of VPT infants, and related factors. Explore whether separate profiles can be distinguished and compare these to profiles of Dutch term-born infants. STUDY DESIGN: Prospective cohort study with parents repeatedly recording their infant, using the Alberta Infant Motor Scale (AIMS) home-video method, from 3 to 18 months CA. SUBJECTS: Forty-two Dutch infants born ≤32.0 weeks gestational age and/or with a birthweight (BW) of <1500 g without severe perinatal complications. OUTCOME MEASURES: Gross motor development measured with the AIMS. RESULTS: In total 208 assessments were analyzed, with 27 infants ≥five assessments, 12 with

The AIMS home-video method: parental experiences and appraisal for use in neonatal follow-up clinics.

BACKGROUND: In The Netherlands, prematurely born infants and their parents are offered regular developmental check-ups in a hospital setting. In line with providing healthcare at distance, the use of video footage showing the infant's behavior and movements, taken by parents at home and assessed by professionals online, might be a fruitful future practice. The focus of this study was to gain insight into parental experiences with the Alberta Infant Motor Scale home-video method and their appraisal of its applicability for use in an outpatient neonatal follow-up clinic. METHOD: A qualitative descriptive study among parents of healthy extremely or very premature infants (GA 26.2-31.5 weeks) participating in a longitudinal study of motor development between 3-18 months corrected age. Ten semi-structured interviews were conducted and transcribed verbatim. Data was analyzed independently. Inductive content analysis was performed following the process of the AIMS home-video method. RESULTS: Parents appraised the AIMS home-video method as manageable and fun to do. Instructions, instruction film, and checklists were clear. Transferring the video footage from their phone to their computer and uploading it to the web portal was sometimes time-consuming. Parents gained a better awareness of their infant's motor development and found the provided feedback a confirmation of what they already thought about their infant's development and was reassuring that their child was doing well. First-time parents seemed more uncertain and had a greater need for information about (motor) development, but on the other hand, also had confidence in their child. All parents thought that home-videos can be an addition to follow-up visits, but cannot replace (all) visits. It may be an opportunity to reduce the frequency of hospital visits, while still having their infant monitored. CONCLUSION: Parents appraised the AIMS home-video method positively and are of the opinion that home-videos can be of added value in monitoring infants at risk in neonatal follow-up additional to hospital visits. In future research a user-friendly application and/or platform to exchange video footage safely between parents and professionals should be developed with all possible stakeholders involved and implementation should be explored.

Pathogenic neurofibromatosis type 1 (NF1) RNA splicing resolved by targeted RNAseq.

Neurofibromatosis type 1 (NF1) is caused by loss-of-function variants in the NF1 gene. Approximately 10% of these variants affect RNA splicing and are either missed by conventional DNA diagnostics or are misinterpreted by in silico splicing predictions. Therefore, a targeted RNAseq-based approach was designed to detect pathogenic RNA splicing and associated pathogenic DNA variants. For this method RNA was extracted from lymphocytes, followed by targeted RNAseq. Next, an in-house developed tool (QURNAs) was used to calculate the enrichment score (ERS) for each splicing event. This method was thoroughly tested using two different patient cohorts with known pathogenic splice-variants in NF1. In both cohorts all 56 normal reference transcript exon splice junctions, 24 previously described and 45 novel non-reference splicing events were detected. Additionally, all expected pathogenic splice-variants were detected. Eleven patients with NF1 symptoms were subsequently tested, three of which have a known NF1 DNA variant with a putative effect on RNA splicing. This effect could be confirmed for all 3. The other eight patients were previously without any molecular confirmation of their NF1-diagnosis. A deep-intronic pathogenic splice variant could now be identified for two of them (25%). These results suggest that targeted RNAseq can be successfully used to detect pathogenic RNA splicing variants in NF1.

Constitutional 2p16.3 deletion including MSH6 and FBXO11 in a boy with developmental delay and diffuse large B-cell lymphoma.

We describe a case of a boy with neurodevelopmental delay and a diffuse large B-cell lymphoma (DLBCL) in whom we discovered a germline de novo 2p16.3 deletion including MSH6 and part of the FBXO11 gene. A causative role for MSH6 in cancer development was excluded based on tumor characteristics. The constitutional FBXO11 deletion explains the neurodevelopmental delay in the patient. The FBXO11 protein is involved in BCL-6 ubiquitination and BCL-6 is required for the germinal center reaction resulting in B cell differentiation. Somatic loss of function alterations of FBXO11 result in BCL-6 overexpression which is a known driver in DLBCL. We therefore consider that a causative relationship between the germline FBXO11 deletion and the development of DLBCL in this boy is conceivable.

Recommendations on Surveillance for Differentiated Thyroid Carcinoma in Children with PTEN Hamartoma Tumor Syndrome.

BACKGROUND: PTEN hamartoma tumor syndrome (PHTS) represents a group of syndromes caused by a mutation in the PTEN gene. Children with a germline PTEN mutation have an increased risk of developing differentiated thyroid carcinoma (DTC). Several guidelines have focused on thyroid surveillance in these children, but studies substantiating these recommendations are lacking. OBJECTIVE: The present study intends to provide the available evidence for a thyroid carcinoma surveillance program in children with PHTS. METHODS: An extensive literature search was performed to identify all studies on DTC in pediatric PHTS patients. Two pediatric cases are presented to illustrate the pros and cons of thyroid carcinoma surveillance. Recommendations for other patient groups at risk for DTC were evaluated. Consensus within the study team on recommendations for children with PHTS was reached by balancing the incidence and behavior of DTC with the pros and cons of thyroid surveillance, and the different surveillance methods. RESULTS: In 5 cohort studies the incidence of DTC in childhood ranged from 4 to 12%. In total 57 cases of DTC and/or benign nodular disease in pediatric PHTS patients were identified, of which 27 had proven DTC, with a median age of 12 years (range 4-17). Follicular thyroid carcinoma (FTC) was diagnosed in 52% of the pediatric DTC patients. No evidence was found for a different clinical behavior of DTC in PHTS patients compared to sporadic DTC. CONCLUSIONS: Children with PHTS are at increased risk for developing DTC, with 4 years being the youngest age reported at presentation and FTC being overrepresented. DTC in pediatric PHTS patients does not seem to be more aggressive than sporadic DTC. RECOMMENDATIONS: Surveillance for DTC in pediatric PHTS patients seems justified, as early diagnosis may decrease morbidity. Consensus within the study team was reached to recommend surveillance from the age of 10 years onwards, since at that age the incidence of DTC seems to reach 5%. Surveillance for DTC should consist of yearly neck palpation and triennial thyroid ultrasound. Surveillance in children with PHTS should be performed in a center of excellence for pediatric thyroid disease or PHTS.

Renal cell carcinoma in young FH mutation carriers: case series and review of the literature.

Hereditary Leiomyomatosis and Renal Cell Cancer (HLRCC) is an autosomal dominant syndrome caused by heterozygous pathogenic germline variants in the fumarate hydratase (FH) gene. It is characterized by cutaneous and uterine leiomyomas and an increased risk of developing renal cell carcinoma (RCC), which is usually adult-onset. HLRCC-related RCC tends to be aggressive and can metastasize even when the primary tumor is small. Data on children and adolescents are scarce. Herein, we report two patients from unrelated Dutch families, with HLRCC-related RCC at the ages of 15 and 18 years, and a third patient with an FH mutation and complex renal cysts at the age of 13. Both RCC's were localized and successfully resected, and careful MRI surveillance was initiated to monitor the renal cysts. One of the patients with RCC subsequently developed an ovarian Leydig cell tumor. A review of the literature identified 10 previously reported cases of HLRCC-related RCC in patients aged younger than 20 years, five of them presenting with metastatic disease. These data emphasize the importance of recognizing HLRCC in young patients to enable early detection of RCC, albeit rare. They support the recommendations from the 2014 consensus guideline, in which genetic testing for FH mutations, and renal MRI surveillance, is advised for HLRCC family members from the age of 8-10 years onwards.

A home-video method to assess infant gross motor development: parent perspectives on feasibility.

BACKGROUND: Current use of smartphone cameras by parents create opportunities for longitudinal home-video-assessments to monitor infant development. We developed and validated a home-video method for parents, enabling Pediatric Physical Therapists to assess infants' gross motor development with the Alberta Infant Motor Scale (AIMS). The objective of the present study was to investigate the feasibility of this home-video method from the parents' perspective. METHODS: Parents of 59 typically developing infants (0-19 months) were recruited, 45 parents participated in the study. Information about dropout was collected. A sequential mixed methods design was used to examine feasibility, including questionnaires and semi-structured interviews. While the questionnaires inquired after the practical feasibility of the home-video method, the interviews also allowed parents to comment on their feelings and thoughts using the home-video method. RESULTS: Of 45 participating parents, 34 parents returned both questionnaires and eight parents agreed to an interview. Parent reported effort by the infants was very low: the home-video method is perceived as similar to the normal routine of playing. The parental effort level was acceptable. The main constraint parents reported was time planning. Parents noted it was sometimes difficult to find the right moment to record the infant's motor behavior, that is, when parents were both at home and their baby was in the appropriate state. Technical problems with the web portal, reported by 28% of the parents were also experienced as a constraint. Positive factors mentioned by parents were: the belief that the home videos are valuable for family use, receiving feedback from a professional, the moments of one-on-one attention and interaction with their babies. Moreover, the process of recording the home videos resulted in an increased parental awareness of, and insight into, the gross motor development of their infant. CONCLUSION: The AIMS home-video method is feasible for parents of typically developing children. Most constraints are of a practical nature that can be addressed in future applications. Future research is needed to show whether the home-video method is also applicable for parents with an infant at risk of motor development problems.

Co-creation of a digital tool for the empowerment of parents of children with physical disabilities.

PLAIN ENGLISH SUMMARY: Parents of children with physical disabilities do a lot to support their child in daily life. In doing this they are faced with many challenges. These parents have a wide range of unmet needs, especially for information, on different topics. It is sometimes hard for them to get the right information at the right moment, and to ask the right questions to physicians and other healthcare professionals. In order to develop a digital tool to help parents formulate questions and find information, we thought it would be crucial to work together in a process of co-creation with parents, researchers, IT-specialists and healthcare professionals. In close collaboration with them we developed a tool that aims to help parents ask questions, find information and take a more leading role in consultations with healthcare professionals, called the WWW-roadmap (WWW-wijzer in Dutch).In two groups of parents (one group with and one group without experience of using the tool), we will study the effects of using this tool, on consultations with physicians. We expect that using the tool will result in better empowerment, satisfaction and family-centred care. BACKGROUND: Parents of children with physical disabilities do much to support their child in daily life. In doing so, they are faced with many challenges. These parents have a wide range of unmet needs, especially for information, on various topics. Getting timely and reliable information is very difficult for parents, whereas being informed is a major requirement for the process of empowerment and shared decision-making. This paper describes the development of a digital tool to support parents in this process. During its development, working together with parents was crucial to address relevant topics and design a user-centred intervention. METHODS: In co-creation with parents, healthcare professionals, IT-professionals and researchers, a digital tool was developed, the 'WWW-roadmap' ['WWW-wijzer' in Dutch]. This digital tool aims to enable parents to explore their questions (What do I want to know?), help in their search for information (Where can I find the information I need), and refer to appropriate professionals (Who can assist me further?).During the process, we got extensive feedback from a parent panel consisting of parents of children with physical disabilities, enabling us to create the tool 'with' rather than 'for' them. This led to a user-friendly and problem-driven tool. DISCUSSION: The WWW-roadmap can function as a tool to help parents formulate their questions, search for information and thus prepare for consultations with healthcare professionals, and to facilitate parental empowerment and shared-decision making by parent and professional. Effects of using the WWW-roadmap on consultations with professionals will be studied in the future.

Childhood neuroendocrine tumours: a descriptive study revealing clues for genetic predisposition.

BACKGROUND: Neuroendocrine tumours (NETs) are rare in children and limited data are available. We aimed to specify tumour and patient characteristics and to investigate the role of genetic predisposition in the aetiology of paediatric NETs. METHODS: Using the Dutch Pathology Registry PALGA, we collected patient- and tumour data of paediatric NETs in the Netherlands between 1991 and 2013 (N=483). RESULTS: The incidence of paediatric NETs in the Netherlands is 5.40 per one million per year. The majority of NETs were appendiceal tumours (N=441;91.3%). Additional surgery in appendiceal NETs was indicated in 89 patients, but performed in only 27 of these patients. Four out of five patients with pancreatic NETs were diagnosed with Von Hippel-Lindau disease (N=2) and Multiple Endocrine Neoplasia type 1 (N=2). In one patient with an appendiceal NET Familial Adenomatous Polyposis was diagnosed. On the basis of second primary tumours or other additional diagnoses, involvement of genetic predisposition was suggestive in several others. CONCLUSIONS: We identified a significant number of patients with a confirmed or suspected tumour predisposition syndrome and show that paediatric pancreatic NETs in particular are associated with genetic syndromes. In addition, we conclude that treatment guidelines for appendiceal paediatric NETs need revision and improved implementation.

Germline activating TYK2 mutations in pediatric patients with two primary acute lymphoblastic leukemia occurrences.

The contribution of genetic predisposing factors to the development of pediatric acute lymphoblastic leukemia (ALL), the most frequently diagnosed cancer in childhood, has not been fully elucidated. Children presenting with multiple de novo leukemias are more likely to suffer from genetic predisposition. Here, we selected five of these patients and analyzed the mutational spectrum of normal and malignant tissues. In two patients, we identified germline mutations in TYK2, a member of the JAK tyrosine kinase family. These mutations were located in two adjacent codons of the pseudokinase domain (p.Pro760Leu and p.Gly761Val). In silico modeling revealed that both mutations affect the conformation of this autoregulatory domain. Consistent with this notion, both germline mutations promote TYK2 autophosphorylation and activate downstream STAT family members, which could be blocked with the JAK kinase inhibitor I. These data indicate that germline activating TYK2 mutations predispose to the development of ALL.

Information seeking by parents of children with physical disabilities: An exploratory qualitative study.

BACKGROUND: Evidence suggests that parents of children with disabilities feel that not all their information needs are being met, but it remains unclear how parents try to fill these information gaps. AIMS: The aim of this study is to describe how parents of children with physical disabilities search for and evaluate information. METHODS: Qualitative semi-structured interviews were conducted with 15 parents of children with a disability, aged 1.5-21 years. Data were analysed using thematic analysis. RESULTS: There was much variation in information needs between parents. Parents used different sources, depending on the type of information needed, the most important being healthcare professionals, peers, and websites. Peers played an important role in information provision and were the preferred source of experience-based knowledge and support. The Internet is a widely used medium to search for information and to access various sources. There was a general preference for closed Internet communities for peer contact. Information was commonly evaluated by comparing sources. CONCLUSIONS AND IMPLICATIONS: Parents use different sources for different information needs, and evaluate information by comparing them. Healthcare professionals and parents can support each other in locating and evaluating information including experience-based knowledge. Healthcare professionals should guide parents in their search for information and experience-based knowledge from peers.

Health risks for ataxia-telangiectasia mutated heterozygotes: a systematic review, meta-analysis and evidence-based guideline.

Ataxia-telangiectasia (AT) is an autosomal recessive neurodegenerative disorder with immunodeficiency and an increased risk of developing cancer, caused by mutations in the ataxia-telangiectasia mutated (ATM) gene. Logically, blood relatives may also carry a pathogenic ATM mutation. Female carriers of such a mutation have an increased risk of breast cancer. Other health risks for carriers are suspected but have never been studied systematically. Consequently, evidence-based guidelines for carriers are not available yet. We systematically analyzed all literature and found that ATM mutation carriers have a reduced life expectancy because of mortality from cancer and ischemic heart diseases (RR 1.7, 95% CI 1.2-2.4) and an increased risk of developing cancer (RR 1.5, 95% CI 0.9-2.4), in particular breast cancer (RRwomen 3.0, 95% CI 2.1-4.5), and cancers of the digestive tract. Associations between ATM heterozygosity and other health risks have been suggested, but clear evidence is lacking. Based on these results, we propose that all female carriers of 40-50 years of age and female ATM c.7271T>G mutation carriers from 25 years of age onwards be offered intensified surveillance programs for breast cancer. Furthermore, all carriers should be made aware of lifestyle factors that contribute to the development of cardiovascular diseases and diabetes.

What do parents need to enhance participation of their school-aged child with a physical disability? A cross-sectional study in the Netherlands.

BACKGROUND: The aim was to provide an overview of the number, domains and priority of needs as expressed by parents in supporting participation of their school-aged child with a physical disability. Additionally, this study investigated whether the number of needs within each domain is related to the child's gross motor function level, parent's perceived own general health, family socio-economic status and family type. METHOD: A cross-sectional study with a total of 146 participants (84.9% mothers) who completed a survey including the Family Needs Inventory - Paediatric Rehabilitation, the Gross Motor Function Classification System Family Report Questionnaire, the General Health Questionnaire and a demographic questionnaire. A need has been operationalized as 'a family's, parent's or other family member's expressed desire for information, services and supports related to their family'. Descriptive statistics and correlation analysis were applied. RESULTS: Parents (n = 146; response rate 27%) varied in the number of expressed needs (range 0-124; mean = 35.9; median = 30; SD = 25.6). Highest mean percentage scores were found for the domains 'Laws, regulations and fees' (36%), 'Leisure time' (35.6%) and 'Aids, adaptations, facilities and resources' (33.8%). Seven single needs were expressed by 50% or more of the parents. All domains of needs showed a positive correlation with perceived parental general health. The domains 'Laws, regulations and fees', 'Day care & school', 'Emotional and mental support' and 'Raising my child' correlated negatively with family socio-economic status; and child's gross motor function level correlated positively with the domains 'Aids, adaptations, facilities and resources', 'Practical support at home' and 'Leisure time'. CONCLUSIONS: As parents have a major influence on participation of children with a physical disability, meeting their individual needs should become an objective for service providers and policy makers. Family-centred service might be more effective by putting a greater emphasis on changing the environment.

Assessment of family needs in children with physical disabilities: development of a family needs inventory.

BACKGROUND: Valid tools to assess family needs for children with physical disabilities are needed to help tune paediatric rehabilitation care processes to individual needs of these families. To create such a family needs inventory, needs of families of children with a physical disability (age 0-18 years) were identified. We examined differences in the number and type of needs listed by families when asked for by means of an interview compared with using an inventory. METHODS: Forty-nine families of children with a wide variety of physical disabilities (mean age 7.7 years; SD 4.6) participated in semi-structured interviews, focusing on family needs. They also checked an inventory of 99 items (based on a previously conducted literature review), regarding their family needs. In addition, individual interviews with healthcare professionals, and panel meetings with healthcare professionals and parents were held to further identify relevant family needs for the inventory. RESULTS: The individual parent and healthcare professional interviews raised 41 needs that were not included in the original inventory of 99 items. Moreover, the panel meetings raised a further 49 needs. After restructuring and reformulating several items, a 187-item Family Needs Inventory - Paediatric Rehabilitation (FNI-PR) was created. The parent interviews revealed significantly less family needs (mean number of needs = 10.8; SD = 6.0) compared with using the inventory (mean number of needs = 31.7; SD = 19.7) (P < 0.0001). Most expressed family needs were related to both general and specific information concerning the child's development and treatment, aids and information about legislation and to rules relating to compensation of costs. CONCLUSION: Based on responses of parents and healthcare professionals the FNI-PR has been developed, a comprehensive inventory for family needs that can be used in paediatric rehabilitation. An inventory checked by parents resulted in more family needs than a single open-ended question. The inventory may facilitate the implementation of family-centred care.

Parents' experiences with physical and occupational therapy for their young child with cerebral palsy: a mixed studies review.

Understanding the experiences of parents with their child's intervention might help meet the needs of parents and, subsequently get them engaged in their child's intervention. As parents' early beliefs regarding their child's intervention has consequences for treatment participation, it is important to understand these parental perspectives. The aim of this mixed studies review was to give an overview of the experiences and related factors of parents of young children (0-5 years of age) with cerebral palsy in relation to the physical and/or occupational therapy of their child in a rehabilitation setting. The literature was searched systematically for qualitative and quantitative studies published between January 1990 and July 2011. Inclusion criteria were (1) the study population consisted of parents of children with cerebral palsy, with at least 25% of children under the age of five; (2) children had received physical and/or occupational therapy in a rehabilitation setting; and (3) the experiences of the parents with their child's therapy were addressed. Data were synthesized with the framework synthesis method resulting in a conceptual framework describing the factors that are related to the parents' experiences with their child's interventions. A total of 13 studies (eight qualitative and five quantitative) were included and evaluated. Parents expressed various aspects in context, process and outcomes when asked about their experiences with their child's intervention. They had different needs over time and needed time to build a collaborative relationship with their child's therapists. The proposed framework acknowledges the various aspects in context, process and outcomes that parents reported when asked about their experiences. Knowing this, the importance of the broader context of the child in a family should be acknowledged; realizing the impact that the demands of daily life, supports and resources provided to parents, attitudes in the community and culture have on parental experiences.

Do children participate in the activities they prefer? A comparison of children and youth with and without physical disabilities.

OBJECTIVE: To assess the discrepancy between the leisure activities children prefer and the leisure activities they actually participate in, for children with and without a physical disability, and to explore how in both groups this is related to age and gender. DESIGN: Cross-sectional comparison. SUBJECTS: Children with and without physical disabilities that were recruited from schools for special education and regular schools in the Netherlands. MAIN MEASURES: The Children's Assessment of Participation and Enjoyment (CAPE) and the Preferences for Activities of Children (PAC). A discrepancy score was calculated representing high preference but no participation in the activity in the past four months. RESULTS: A total of 141 children (6-18 years) with a physical disability (mean age 12.5, 43% girls, 57% boys) and 156 children without physical disabilities (mean age 11.5, 55% girls,45% boys) were included in the study. There was no significant difference in discrepancy scores between children with and without physical disabilities (informal activities 9.8 ± 5.0 vs. 9.8 ± 4.6, formal activities 6.4 ± 3.4 vs. 6.6 ± 2.8). Discrepancy between preference and performance varied by age and gender for children without disabilities but not for children with disabilities. CONCLUSIONS: Both groups are equally able to participate in the activities they prefer. Age and gender had a significant effect on the discrepancy scores for children and adolescents without physical disabilities but not for children with physical disabilities.

Noonan syndrome: comparing mutation-positive with mutation-negative dutch patients.

Noonan syndrome (NS) is an autosomal dominant disorder characterized by facial dysmorphisms, short stature and congenital heart defects. The disorder is genetically heterogeneous and shows clinical overlap with other RASopathies. These syndromes are caused by mutations in a variety of genes leading to dysregulation of the RAS-MAPK pathway: PTPN11, KRAS, SOS1, RAF1, CBL, SHOC2, NRAS, BRAF, MAP2K1, MAP2K2, HRAS, NF1 and SPRED1. In this study, we conduct a genotype-phenotype analysis of 33 patients with a clinical diagnosis of NS without a PTPN11 mutation. Mutation analysis of the genes involved in RASopathies was performed, except for NF1 and SPRED1. In 14 (42%) NS patients, a mutation was found, 7 (21%) had a mutation in SOS1, 3 (9%) in RAF1 and 1 (3%) in KRAS, MAP2K2, BRAF and SHOC2 each. The phenotype of these mutation-positive cases corresponded to that described in the literature. In the cases with a BRAF and MAP2K2 mutation, the diagnosis cardio-facio-cutaneous syndrome was made. The patient with the SHOC2 mutation had features compatible with 'Noonan-like syndrome with loose anagen hair'. Three major clinical features of NS - a typical face, short stature and a pulmonary valve stenosis - were less frequently present in the group without a mutation. Missense mutations in genes encoding proteins of the RAS-MAPK pathway cause NS. The 3 major clinical features of NS were less frequently present in the mutation-negative patients, which stresses the importance of the syndrome-specific symptoms of the face, heart and short stature in NS. However, all mutation-negative cases met the NS criteria, indicating that the involvement of novel genes is to be expected.