Mono-allelic KCNB2 variants lead to a neurodevelopmental syndrome caused by altered channel inactivation.

Ion channels mediate voltage fluxes or action potentials that are central to the functioning of excitable cells such as neurons. The KCNB family of voltage-gated potassium channels (Kv) consists of two members (KCNB1 and KCNB2) encoded by KCNB1 and KCNB2, respectively. These channels are major contributors to delayed rectifier potassium currents arising from the neuronal soma which modulate overall excitability of neurons. In this study, we identified several mono-allelic pathogenic missense variants in KCNB2, in individuals with a neurodevelopmental syndrome with epilepsy and autism in some individuals. Recurrent dysmorphisms included a broad forehead, synophrys, and digital anomalies. Additionally, we selected three variants where genetic transmission has not been assessed, from two epilepsy studies, for inclusion in our experiments. We characterized channel properties of these variants by expressing them in oocytes of Xenopus laevis and conducting cut-open oocyte voltage clamp electrophysiology. Our datasets indicate no significant change in absolute conductance and conductance-voltage relationships of most disease variants as compared to wild type (WT), when expressed either alone or co-expressed with WT-KCNB2. However, variants c.1141A>G (p.Thr381Ala) and c.641C>T (p.Thr214Met) show complete abrogation of currents when expressed alone with the former exhibiting a left shift in activation midpoint when expressed alone or with WT-KCNB2. The variants we studied, nevertheless, show collective features of increased inactivation shifted to hyperpolarized potentials. We suggest that the effects of the variants on channel inactivation result in hyper-excitability of neurons, which contributes to disease manifestations.

Isolated neurological presentations of mevalonate kinase deficiency.

Mevalonate kinase (MK) deficiency is a rare autosomal recessive metabolic disorder caused by pathogenic variants in the MVK gene with a broad phenotypic spectrum including autoinflammation, developmental delay and ataxia. Typically, neurological symptoms are considered to be part of the severe end of the phenotypical spectrum and are reported to be in addition to the autoinflammatory symptoms. Here, we describe a patient with MK deficiency with severe neurological symptoms but without autoinflammation and we found several similar patients in the literature. Possibly, the non-inflammatory phenotype is related to a specific genotype: the MVK p.(His20Pro)/p.(Ala334Thr) variant. There is probably an underdetection of the neurological MK deficient phenotype without inflammatory symptoms as clinicians may not test for MK deficiency when patients present with only neurological symptoms. In conclusion, although rare, neurological symptoms without hyperinflammation might be more common than expected in MK deficiency. It seems relevant to consider MK deficiency in patients with psychomotor delay and ataxia, even if there are no inflammatory symptoms.

Clinical Reasoning: Pediatric Seizures of Unknown Cause.

We describe a neonate and a 14-month-old child presenting with seizures that were not (completely) controlled with antiepileptic medications. There were no signs of infection, and electrolytes and neuroimaging were normal. In the neonate, pyridoxine was administered followed by cessation of seizures, and a diagnosis of pyridoxine-dependent epilepsy (PDE-ALDH7A1, a neurometabolic disorder of lysine metabolism) was genetically confirmed. The 14-month-old child received a genetic diagnosis of PDE-ALDH7A1 after abnormalities in the metabolic investigations. Both children were treated with pyridoxine and adjunct lysine reduction therapy (LRT). Seizures were controlled completely, but both children are developmentally delayed. During her second pregnancy, the mother of the neonate was started on pyridoxine treatment because of the risk of PDE-ALDH7A1. After delivery, pyridoxine treatment was continued in the neonate, who did not show any clinical symptoms. Molecular analysis identified the familial variants consistent with the diagnosis of PDE-ALDH7A1. Adjunct LRT was initiated. This child has never experienced seizures, and development has been completely normal thus far (age 2.9 years), despite the shared genotype with their sibling with developmental delays (DDs). In conclusion, in neonates, infants, and children presenting with seizures of unknown origin with partial or no response to common antiepileptic medications, the diagnosis of PDE-ALDH7A1 or other pyridoxine-responsive genetic epilepsies should be considered, prompting a trial of pyridoxine as "diagnostic therapeuticum." The digital application Treatable-ID (treatable-id.org) can support clinicians in the early diagnosis of treatable conditions in patients presenting with DD/intellectual disability of unknown cause.

Treatable inherited metabolic disorders causing intellectual disability: 2021 review and digital app.

BACKGROUND: The Treatable ID App was created in 2012 as digital tool to improve early recognition and intervention for treatable inherited metabolic disorders (IMDs) presenting with global developmental delay and intellectual disability (collectively 'treatable IDs'). Our aim is to update the 2012 review on treatable IDs and App to capture the advances made in the identification of new IMDs along with increased pathophysiological insights catalyzing therapeutic development and implementation. METHODS: Two independent reviewers queried PubMed, OMIM and Orphanet databases to reassess all previously included disorders and therapies and to identify all reports on Treatable IDs published between 2012 and 2021. These were included if listed in the International Classification of IMDs (ICIMD) and presenting with ID as a major feature, and if published evidence for a therapeutic intervention improving ID primary and/or secondary outcomes is available. Data on clinical symptoms, diagnostic testing, treatment strategies, effects on outcomes, and evidence levels were extracted and evaluated by the reviewers and external experts. The generated knowledge was translated into a diagnostic algorithm and updated version of the App with novel features. RESULTS: Our review identified 116 treatable IDs (139 genes), of which 44 newly identified, belonging to 17 ICIMD categories. The most frequent therapeutic interventions were nutritional, pharmacological and vitamin and trace element supplementation. Evidence level varied from 1 to 3 (trials, cohort studies, case-control studies) for 19% and 4-5 (case-report, expert opinion) for 81% of treatments. Reported effects included improvement of clinical deterioration in 62%, neurological manifestations in 47% and development in 37%. CONCLUSION: The number of treatable IDs identified by our literature review increased by more than one-third in eight years. Although there has been much attention to gene-based and enzyme replacement therapy, the majority of effective treatments are nutritional, which are relatively affordable, widely available and (often) surprisingly effective. We present a diagnostic algorithm (adjustable to local resources and expertise) and the updated App to facilitate a swift and accurate workup, prioritizing treatable IDs. Our digital tool is freely available as Native and Web App (www.treatable-id.org) with several novel features. Our Treatable ID endeavor contributes to the Treatabolome and International Rare Diseases Research Consortium goals, enabling clinicians to deliver rapid evidence-based interventions to our rare disease patients.

Follow-up protocol was useful for children whose parents attended emergency departments after partner violence, substance abuse or a suicide attempt.

AIM: This was a one-year follow-up of families referred to support services after the parents visited the emergency department due to intimate partner violence, substance abuse or a suicide attempt. Its aim was to evaluate the well-being of any children. METHODS: Data on families identified a year earlier by the Amsterdam protocol were gathered from child protective services and parent and child self-reports in two Dutch regions from 2012-2015. RESULTS: We included 399 children (52%) boys with a median age of eight years (range 1-18) in the study using child protective services data. Of the 101 families who participated in the first measurement, 67 responded one year after the parent's emergency department visit. The results showed that 20% of the children had no or minor problems, voluntary support services were involved in 60% of cases and child protective services were involved in 20%. Compared to their first assessment a year earlier, the children's psychosocial problems had not increased, but this could have been an underestimation due to selective responses. CONCLUSION: The Amsterdam protocol was valuable in referring families to voluntary support services, but given the ongoing problems in some families, professionals need to carefully monitor whether support services are sufficiently effective.

Comparing policies for children of parents attending hospital emergency departments after intimate partner violence, substance abuse or suicide attempt.

To improve identification of child maltreatment, a new policy ('Hague protocol') was implemented in hospitals in The Netherlands, stating that adults attending the hospital emergency department after intimate partner violence, substance abuse or a suicide attempt should be asked whether they care for children. If so, these children are referred to the Reporting Center for Child Abuse and Neglect (RCCAN), for assessment and referrals to support services. An adapted, hospital-based version of this protocol ('Amsterdam protocol') was implemented in another region. Children are identified in the same manner, but, instead of a RCCAN referral, they are referred to the pediatric outpatient department for an assessment, including a physical examination, and referrals to services. We compared results of both protocols to assess how differences between the protocols affect the outcomes on implementation, detection of child maltreatment and referrals to services. Furthermore, we assessed social validity and results of a screening physical examination. We included 212 families from the Amsterdam protocol (cohort study with reports by pediatric staff and parents) and 565 families from the Hague protocol (study of RCCAN records and telephone interviews with parents). We found that the RCCAN identified more maltreatment than pediatric staff (98% versus at least 51%), but referrals to services were similar (82% versus 80% of the total sample) and parents were positive about both interventions. Physical examination revealed signs of maltreatment in 5%. We conclude that, despite the differences, both procedures can serve as suitable methods to identify and refer children at risk for maltreatment.

Paediatric femur fractures at the emergency department: accidental or not?

Only a small proportion of all paediatric fractures is caused by child abuse or neglect, especially in highly prevalent long bone fractures. It can be difficult to differentiate abusive fractures from non-abusive fractures. This article focuses on femoral fractures in young children. Based on three cases, this article presents a forensic evidence-based approach to differentiate between accidental and non-accidental causes of femoral fractures. We describe three cases of young children who were presented to the emergency department because of a suspected femur fracture. Although in all cases, the fracture had a similar location and appearance, the clinical history and developmental stage of the child led to three different conclusions. In the first two cases, an accidental mechanism was a plausible conclusion, although in the second case, neglect of parental supervision was the cause for concern. In the third case, a non-accidental injury was diagnosed and appropriate legal prosecution followed. Any doctor treating children should always be aware of the possibility of child abuse and neglect in children with injuries, especially in young and non-mobile children presenting with an unknown trauma mechanism. If a suspicion of child abuse or neglect arises, a thorough diagnostic work-up should be performed, including a full skeletal survey according to the guidelines of the Royal College of Radiologists and the Royal College of Paediatrics and Child Health. In order to make a good assessment, the radiologist reviewing the skeletal survey needs access to all relevant clinical and social information.

Data research on child abuse and neglect without informed consent? Balancing interests under Dutch law.

According to the Declaration of Helsinki, participation of human subjects in medical research is only acceptable if subjects have given their consent. But in child abuse and neglect, many studies use a design in which subjects do not actively participate. Data in these studies are gathered from sources such as medical records or Child Protective Services. As long as such data are used anonymously, this does not interfere with individual privacy rights. However, some research is only possible when carried out with personally identifiable data, which could potentially be misused. In this paper, we discuss in which situations and under which conditions personal data of children may be used for a study without obtaining consent. In doing so, we make use of two recent studies, performed in our hospital, in which we encountered this issue. Both studies involved collecting personal data. After careful consideration, we decided not to ask informed consent; instead, we arranged for specific safeguards to protect the subject's and their parents' privacy as well as possible. CONCLUSION: Altogether, we conclude that our approach fits within the Dutch legal framework and seems a reasonable solution in situations in which individual privacy rights are at odds with the public interest of child abuse and neglect research. We argue that, although, in principle, data research is only acceptable after informed consent is obtained, the law should allow that, under specific circumstances and safeguards, this requirement is put aside to make research in the field of child abuse and neglect possible. WHAT IS KNOWN: • In principle, data research is only acceptable after informed consent is obtained.• In practice, this is not always feasible. WHAT IS NEW: • Under specific circumstances and safeguards, the informed consent requirement can be put aside.

[Domestic violence in the accident and emergency department: don't forget the children]. / Huiselijk geweld op de SEH: denk aan de kindcheck.

In 2013, the Dutch Government mandated a new policy stating that all healthcare professionals caring for adults in difficult psychosocial situations should always investigate the safety of any children involved. We describe two cases of such 'child checks' in the accident and emergency department (A&E). Patient A, a 10-year-old girl, was referred to the outpatient paediatric department (OPD) after her mother had attended the A&E as a victim of domestic violence (DV). The child had witnessed DV on multiple occasions. The family were referred to voluntary social and psychiatric healthcare. Patient B, a 46 year-old woman, attended the A&E with serious injuries, and said she had tripped over. The A&E physician suspected that the injuries were caused by DV, and the mother and her 9-year-old daughter were referred to the OPD. However, the mother refused to attend, and the family was reported to the Youth Care Office. Because parents' psychosocial problems, such as DV, can seriously affect children, their safety should always be investigated by performing a 'child check'.

Screening methods to detect child maltreatment: high variability in Dutch emergency departments.

BACKGROUND: In the Netherlands, screening for child maltreatment is mandatory in all emergency departments but it is unclear which screening methods are being used. As a first step towards implementation of a universal screening method across all emergency departments, we assessed the currently used screening methods. OBJECTIVE: To provide an overview of the screening methods for child maltreatment across all emergency departments in the Netherlands and to assess their empirical substantiation. METHODS: We surveyed all emergency departments in the Netherlands using a questionnaire on screening methods. All screening checklists used in emergency departments were assembled and compared with the literature. RESULTS: 85 hospitals with an emergency department were approached, 80 of which completed the questionnaire and 77 provided copies of their screening checklists. All participating hospitals use a screening checklist, 41% a screening physical examination, 60% a screening based on parental risk factors and 3% a retrospective review of all charts. The empirical substantiation for these screening methods is largely lacking, and at least 73% of the hospitals use a checklist that has not been reported in the literature. CONCLUSIONS: Large variations in screening methods exist across emergency departments in the Netherlands, most of which are not based on empirical evidence.

Prevalence of child sexual abuse in pediatric patients with chronic abdominal pain.

BACKGROUND AND OBJECTIVES: A history of sexual abuse is to be found in approximately 40% of all adult patients with gastrointestinal complaints. Data on the prevalence of child sexual abuse (CSA) in children with chronic abdominal pain (CAP) are lacking. The objective of this systematic review is to determine the prevalence of CSA in pediatric patients with CAP. METHODS: We conducted a systematic literature search in the electronic databases MEDLINE, EMBASE, PsychInfo, and ERIC. Reference lists of relevant articles were scanned for additional citations. We selected case-control, cohort and cross-sectional studies investigating the prevalence of CSA in children with CAP, ages 0 to 18 years. Data were extracted from relevant studies, which were assessed for methodological quality by 2 independent reviewers. Prevalence of CSA was the main outcome measure. RESULTS: The literature search yielded a total of 269 articles. Only 2 studies met our inclusion criteria, reporting CSA in 2.1% and 8.0% of children (age range 4-21 years) with CAP. Both studies were conducted in small groups (n = 48 and n = 50) without control group(s) and did not use standardized or validated instruments for diagnosing CSA. CONCLUSIONS: According to existing data, the prevalence of a history of CSA in pediatric patients with CAP is lower than in adult patients; however, no well-designed studies have been conducted in children. Future research is required to determine a reliable prevalence of CSA in children with CAP.

New hospital-based policy for children whose parents present at the ER due to domestic violence, substance abuse and/or a suicide attempt.

Child maltreatment is a major social problem with many adverse consequences, and a substantial number of maltreated children are not identified by health care professionals. In 2010, in order to improve the identification of maltreated children in hospitals, a new hospital-based policy was developed in Amsterdam, The Netherlands. This policy was adapted from another policy that was developed in The Hague, the Netherlands, in 2007. In the new Amsterdam policy, all adults presenting at the emergency department due to domestic violence, substance abuse, and/or a suicide attempt are asked whether they have any children in their care. If this is the case, parents are urged to visit the outpatient pediatric department together with all of their children. During this visit, problems are evaluated and voluntary referrals can be arranged to different care organizations. If parents refuse to cooperate, their children are reported to the Dutch Child Abuse Counseling and Reporting Centre. The two aims of this study are to describe (1) characteristics of the identified families and (2) the referrals made to different voluntary and involuntary care organizations during the first 2 years after implementation of the policy. Data were collected from medical records. One hundred and six children from 60 households were included, of which 68 children because their mother was a victim of domestic violence. Referrals to care organizations were arranged for 99 children, of which 67 on a voluntary basis. The Amsterdam policy seems successful in arranging voluntary support for the majority of identified children.