Psychosocial Burden of Childhood Sickle Cell Disease on Caregivers in Kenya.

OBJECTIVES: To characterize the types and magnitude of psychosocial burden present in caregivers who have a child with sickle cell disease (SCD) in Kenya and to identify predictors of caregiver psychosocial burden, including disease severity and financial hardship. METHODS: Primary caregivers (N = 103) of children aged 1-10 years diagnosed with SCD completed surveys assessing multiple domains of caregiver quality of life (QOL), adjustment to child illness, mental health, and financial hardship. Descriptive statistics characterize psychosocial burden, and linear models assess associations. RESULTS: On indicators of QOL, caregivers report multiple difficulties across most domains, including daily activities and physical, social, cognitive, and emotional well-being. Daily activities emerged as most burdensome. On indicators of parental adjustment to chronic illness, guilt and worry emerged as the greatest concern, followed by long-term uncertainty and unresolved sorrow and anger; relative to these, they reported higher levels of emotional resources. Financial hardship was high, as caregivers reported moderate to major financial losses due to the time spent caring for their child. General linear model analyses revealed that level of financial hardship was a significant predictor of all negative psychosocial outcomes. CONCLUSIONS: Results document that Kenyan caregivers of children with SCD experience difficulties across multiple domains of functioning and that financial difficulties are likely associated with psychosocial burden. Results can guide intervention development for caregivers of children with SCD in low-resource, global contexts.

De Novo Truncating Variants in ASXL2 Are Associated with a Unique and Recognizable Clinical Phenotype.

The ASXL genes (ASXL1, ASXL2, and ASXL3) participate in body patterning during embryogenesis and encode proteins involved in epigenetic regulation and assembly of transcription factors to specific genomic loci. Germline de novo truncating variants in ASXL1 and ASXL3 have been respectively implicated in causing Bohring-Opitz and Bainbridge-Ropers syndromes, which result in overlapping features of severe intellectual disability and dysmorphic features. ASXL2 has not yet been associated with a human Mendelian disorder. In this study, we performed whole-exome sequencing in six unrelated probands with developmental delay, macrocephaly, and dysmorphic features. All six had de novo truncating variants in ASXL2. A careful review enabled the recognition of a specific phenotype consisting of macrocephaly, prominent eyes, arched eyebrows, hypertelorism, a glabellar nevus flammeus, neonatal feeding difficulties, hypotonia, and developmental disabilities. Although overlapping features with Bohring-Opitz and Bainbridge-Ropers syndromes exist, features that distinguish the ASXL2-associated condition from ASXL1- and ASXL3-related disorders are macrocephaly, absence of growth retardation, and more variability in the degree of intellectual disabilities. We were also able to demonstrate with mRNA studies that these variants are likely to exert a dominant-negative effect, given that both alleles are expressed in blood and the mutated ASXL2 transcripts escape nonsense-mediated decay. In conclusion, de novo truncating variants in ASXL2 underlie a neurodevelopmental syndrome with a clinically recognizable phenotype. This report expands the germline disorders that are linked to the ASXL genes.

Hydroxycarbamide versus chronic transfusion for maintenance of transcranial doppler flow velocities in children with sickle cell anaemia-TCD With Transfusions Changing to Hydroxyurea (TWiTCH): a multicentre, open-label, phase 3, non-inferiority trial.

BACKGROUND: For children with sickle cell anaemia and high transcranial doppler (TCD) flow velocities, regular blood transfusions can effectively prevent primary stroke, but must be continued indefinitely. The efficacy of hydroxycarbamide (hydroxyurea) in this setting is unknown; we performed the TWiTCH trial to compare hydroxyurea with standard transfusions. METHODS: TWiTCH was a multicentre, phase 3, randomised, open-label, non-inferiority trial done at 26 paediatric hospitals and health centres in the USA and Canada. We enrolled children with sickle cell anaemia who were aged 4-16 years and had abnormal TCD flow velocities (≥ 200 cm/s) but no severe vasculopathy. After screening, eligible participants were randomly assigned 1:1 to continue standard transfusions (standard group) or hydroxycarbamide (alternative group). Randomisation was done at a central site, stratified by site with a block size of four, and an adaptive randomisation scheme was used to balance the covariates of baseline age and TCD velocity. The study was open-label, but TCD examinations were read centrally by observers masked to treatment assignment and previous TCD results. Participants assigned to standard treatment continued to receive monthly transfusions to maintain 30% sickle haemoglobin or lower, while those assigned to the alternative treatment started oral hydroxycarbamide at 20 mg/kg per day, which was escalated to each participant's maximum tolerated dose. The treatment period lasted 24 months from randomisation. The primary study endpoint was the 24 month TCD velocity calculated from a general linear mixed model, with the non-inferiority margin set at 15 cm/s. The primary analysis was done in the intention-to-treat population and safety was assessed in all patients who received at least one dose of assigned treatment. This study is registered with ClinicalTrials.gov, number NCT01425307. FINDINGS: Between Sept 20, 2011, and April 17, 2013, 159 patients consented and enrolled in TWiTCH. 121 participants passed screening and were then randomly assigned to treatment (61 to transfusions and 60 to hydroxycarbamide). At the first scheduled interim analysis, non-inferiority was shown and the sponsor terminated the study. Final model-based TCD velocities were 143 cm/s (95% CI 140-146) in children who received standard transfusions and 138 cm/s (135-142) in those who received hydroxycarbamide, with a difference of 4·54 (0·10-8·98). Non-inferiority (p=8·82 × 10(-16)) and post-hoc superiority (p=0·023) were met. Of 29 new neurological events adjudicated centrally by masked reviewers, no strokes were identified, but three transient ischaemic attacks occurred in each group. Magnetic resonance brain imaging and angiography (MRI and MRA) at exit showed no new cerebral infarcts in either treatment group, but worsened vasculopathy in one participant who received standard transfusions. 23 severe adverse events in nine (15%) patients were reported for hydroxycarbamide and ten serious adverse events in six (10%) patients were reported for standard transfusions. The most common serious adverse event in both groups was vaso-occlusive pain (11 events in five [8%] patients with hydroxycarbamide and three events in one [2%] patient for transfusions). INTERPRETATION: For high-risk children with sickle cell anaemia and abnormal TCD velocities who have received at least 1 year of transfusions, and have no MRA-defined severe vasculopathy, hydroxycarbamide treatment can substitute for chronic transfusions to maintain TCD velocities and help to prevent primary stroke. FUNDING: National Heart, Lung, and Blood Institute, National Institutes of Health.

Fatigue in Children With Sickle Cell Disease: Association With Neurocognitive and Social-Emotional Functioning and Quality of Life.

Children with sickle cell disease (SCD) report fatigue in addition to acute and chronic pain, which can decrease overall health-related quality of life (HRQL). The primary objective of the current study was to investigate the relationship between fatigue and HRQL. Given limited prior research, secondary objectives included investigation of associations between fatigue and functional outcomes, including child neurocognitive and social-emotional functioning. Children aged 8 to 16 years (N=32) and a caregiver completed measures of fatigue, HRQL, pain, and neurocognitive and social-emotional functioning. Controlling for pain and number of SCD-related hospitalizations, hierarchical linear regression models were used to determine the impact of child-reported and parent-reported fatigue on child HRQL. Correlational analyses were used to explore the relationship between fatigue and additional child outcomes. Data indicated that children with SCD experience clinically relevant levels of fatigue, which independently predicts lower HRQL. Fatigue was also associated with lower working memory, executive functioning, and higher levels of internalizing symptoms. Given its observed impact on HRQL and relationship to functional outcomes, fatigue may be an important target of clinical, home, or school interventions. This practice may attenuate the burden of fatigue in these patients, and in turn, help improve the quality of life of children living with SCD.

Sluggish cognitive tempo in survivors of pediatric brain tumors.

The presence of neurocognitive late effects in survivors of pediatric brain tumors is well established. However, there remains some debate about how best to conceptualize these deficits. Sluggish cognitive tempo (SCT) is a proposed conceptual framework that has been used to describe a subset of children with ADHD who exhibit a particular profile characterized by lethargy, day dreaming and staring, and poor organization. Previous work has suggested that survivors of leukemia exhibit a similar profile, but it has not yet been examined in survivors of pediatric brain tumors. A sample of 65 survivors of pediatric brain tumors, 25 survivors of leukemia and 50 community controls completed the Child Behavior Checklist, with four items used to measure SCT. Survivors completed additional measures of neurocognitive functioning. Survivors of brain tumors demonstrated significantly greater symptoms of SCT than survivors of leukemia or controls. SCT was associated with attention problems and working memory deficits and the presence of a VP-shunt. Results provided conditional support for the presence of SCT in survivors of brain tumors, with further research needed to determine the clinical utility of the framework.

Working memory training in survivors of pediatric cancer: a randomized pilot study.

OBJECTIVES: Survivors of pediatric brain tumors and acute lymphoblastic leukemia (ALL) are at increased risk for neurocognitive deficits, but few empirically supported treatment options exist. We examined the feasibility and preliminary efficacy of a home-based, computerized working memory training program, CogmedRM, with survivors of childhood cancer. METHODS: Survivors of brain tumors or ALL (n = 20) with identified deficits in attention and/or working memory were randomized to either the success-adapted computer intervention or a non-adaptive, active control condition. Specifically, children in the adaptive condition completed exercises that became more challenging with each correct trial, whereas those in the non-adaptive version trained with exercises that never increased in difficulty. All participants were asked to complete 25 training sessions at home, with weekly, phone-based coaching support. Brief assessments were completed pre-intervention and post-intervention; outcome measures included both performance-based and parent-report measures of working memory and attention. RESULTS: Eighty-five percent of survivors were compliant with the intervention, with no adverse events reported. After controlling for baseline intellectual functioning, survivors who completed the intervention program evidenced significant post-training improvements in their visual working memory and in parent-rated learning problems compared with those in the active control group. No differences in verbal working memory functioning were evident between groups, however. CONCLUSIONS: Home-based, computerized cognitive training demonstrates good feasibility and acceptability in our sample. Children with higher intellectual functioning at baseline appeared to benefit more from the training, although further study is needed to clarify the strength, scope, and particularly the generalizability of potential treatment effects.

How parents cope with their child's diagnosis and treatment of an embryonal tumor: results of a prospective and longitudinal study.

The current study reports longitudinal coping responses among parents of children diagnosed with an embryonal brain tumor. Patients (n = 219) were enrolled on a treatment protocol for a pediatric embryonal brain tumor. Their parents (n = 251) completed the Coping Response Inventory at time of their child's diagnosis and yearly thereafter, resulting in 502 observations. Outcomes were examined with patient and parent age at diagnosis, patient risk, parent gender and education as covariates. At the time of diagnosis, the highest observed coping method was seeking guidance with well above average scores (T = 61.6). Over time, younger parents were found to seek guidance at a significantly higher rate than older parents (P = .016) and the use of acceptance resignation and seeking alternative results by all parents significantly increased (P = .011 and P < .0001 respectively). The use of emotional discharge was also observed above average at time of diagnosis (T = 55.4) with younger fathers being more likely to exhibit emotional discharge than older fathers (P = .002). Differences in coping according to age of the patient and parent education level are also discussed. Results show a high need for guidance, and above average emotional discharge, especially among younger parents. It is imperative for the healthcare team to lead with accurate information so that these parents may make informed decisions about the care of their child. This need remains high years after diagnosis. Therefore it is critical to continue a consistent level of effective communication and support, even following treatment.

Gender differences in facial expression recognition in survivors of pediatric brain tumors.

OBJECTIVE: To examine the relation between gender, history of cranial radiation therapy (CRT) and facial expression recognition (FER) skill in survivors of pediatric brain tumors. METHODS: Fifty-three survivors (27 females) completed a measure of FER and an intelligence test. RESULTS: There was a significant interaction between gender and CRT on ability to interpret low-intensity facial expressions, such that females who had not had CRT made fewer errors than either females who had CRT or males. CONCLUSION: A history of CRT has a notable effect on FER skill in females: girls who received CRT performed significantly more poorly than girls who did not.

Adjustment of caregivers of pediatric patients with brain tumors: a cross-sectional analysis.

OBJECTIVE: The purpose of the study was to compare the psychological adjustment of caregivers of children with brain tumors who are on-treatment with caregivers of children who are off-treatment. METHODS: Data were collected from 90 participants: 47 (52.2%) caregivers of children undergoing active treatment (on-treatment) and 43 (47.8%) caregivers of children off-treatment on measures of global psychological distress and illness and caregiving related distress. RESULTS: Results revealed that the two groups differed significantly in their reported symptoms of general psychological distress, with the off-treatment caregivers reporting significantly lower levels of general distress. However, off-treatment caregivers continued to experience elevated levels of uncertainty and caregiving burden related to their child's illness. CONCLUSIONS: There is significant evidence suggesting that the burden of caring for a child with a brain tumor is ongoing, continuing well into the off-treatment period. These results also suggest that the psychosocial functioning of these caregivers is best assessed using measures designed specifically to evaluate illness-related psychosocial functioning (e.g. the Parent Experience of Child Illness, Impact on Family Scale).

Hydrocephalus as a possible additional contributor to cognitive outcome in survivors of pediatric medulloblastoma.

OBJECTIVES: The purpose of the study was to assess the relationship between shunted hydrocephalus and intellectual, memory and academic functioning in a group of survivors of pediatric medulloblastoma. METHODS: Data from measures of cognitive, memory, academic and visual-motor functioning were gathered retrospectively from 35 survivors. Of these survivors, 10 (28.6%) required ventriculoperitoneal-shunt placement for hydrocephalus posttumor resection. RESULTS: Results revealed that participants with shunted hydrocephalus demonstrated significantly lower IQs, lower nonverbal intellectual functioning, lower academic skills in writing and math, and impairments in visual-motor abilities when compared with those without shunt. CONCLUSIONS: These results highlight the need to explore other variables--in addition to radiation and chemotherapy--as risk factors for neurocognitive impairments in survivors. Furthermore, identification of physiological substrates underlying these deficits is needed.

Social functioning and facial expression recognition in survivors of pediatric brain tumors.

OBJECTIVE: To assess social functioning and facial expression recognition skill in survivors of pediatric brain tumors (BT) as compared to children with juvenile rheumatoid arthritis (JRA). METHODS: The social functioning of 51 survivors of BT and 31 children with JRA was assessed using a facial expression recognition task, questionnaire ratings of social functioning, and an IQ screener. RESULTS: After controlling for estimated IQ, survivors of BT made significantly more errors interpreting adult facial expressions as compared to children with JRA. Additionally, history of therapy and diagnosis age predicted performance on the child portion of the facial recognition task. Finally, survivors of BT demonstrated significantly impaired social functioning across multiple measures when compared to children with JRA. CONCLUSIONS: Survivors of pediatric BT showed significant deficits in social functioning as compared to an illness comparison group. Errors in facial expression recognition represent another method for evaluating deficits that contribute to social outcomes.

Further evidence for the involvement of EFL1 in a Shwachman-Diamond-like syndrome and expansion of the phenotypic features.

Recent evidence has implicated EFL1 in a phenotype overlapping Shwachman-Diamond syndrome (SDS), with the functional interplay between EFL1 and the previously known causative gene SBDS accounting for the similarity in clinical features. Relatively little is known about the phenotypes associated with pathogenic variants in the EFL1 gene, but the initial indication was that phenotypes may be more severe, when compared with SDS. We report a pediatric patient who presented with a metaphyseal dysplasia and was found to have biallelic variants in EFL1 on reanalysis of trio whole-exome sequencing data. The variant had not been initially reported because of the research laboratory's focus on de novo variants. Subsequent phenotyping revealed variability in her manifestations. Although her metaphyseal abnormalities were more severe than in the original reported cohort with EFL1 variants, the bone marrow abnormalities were generally mild, and there was equivocal evidence for pancreatic insufficiency. Despite the limited number of reported patients, variants in EFL1 appear to cause a broader spectrum of symptoms that overlap with those seen in SDS. Our report adds to the evidence of EFL1 being associated with an SDS-like phenotype and provides information adding to our understanding of the phenotypic variability of this disorder. Our report also highlights the value of exome data reanalysis when a diagnosis is not initially apparent.

[Formula: see text]Executive functioning and health-related quality of life in pediatric sickle cell disease.

Research consistently indicates that children with sickle cell disease (SCD) face multiple risk factors for neurocognitive impairment. Despite this, no empirical research to date has examined the impact of neurocognitive functioning on quality of life for this pediatric group. Thus, the current study aims to examine the relationship between executive functioning and quality of life in a sample of children with SCD and further explore psychosocial and family/caregiver resources as moderators of this relationship. A total of 45 children with SCD aged 8 to 16 years and their caregivers completed measures of quality of life, behavioral ratings of executive functioning, and psychosocial functioning. Hierarchical linear regression models were utilized to determine the impact of executive functioning on quality of life and further test the interaction effects of proposed moderating variables. Controlling for age, pain, and socioeconomic status (SES), executive functioning was found to significantly predict child- and parent-reported quality of life among youth with SCD. Psychosocial resources of the primary caregiver or family was not found to moderate the relationship between executive functioning and quality of life. These results provide the first empirical evidence that lower executive skills negatively predict quality of life for children with SCD, supporting clinical and research efforts which aim to establish efficacious interventions that target cognitive decrements within this pediatric population.

Posterior fossa syndrome and long-term neuropsychological outcomes among children treated for medulloblastoma on a multi-institutional, prospective study.

BACKGROUND: Patients treated for medulloblastoma who experience posterior fossa syndrome (PFS) demonstrate increased risk for neurocognitive impairment at one year post diagnosis. The aim of the study was to examine longitudinal trajectories of neuropsychological outcomes in patients who experienced PFS compared with patients who did not. METHODS: Participants were 36 patients (22 males) who experienced PFS and 36 comparison patients (21 males) who were matched on age at diagnosis and treatment exposure but did not experience PFS. All patients underwent serial evaluation of neurocognitive functioning spanning 1 to 5 years post diagnosis. RESULTS: The PFS group demonstrated lower estimated mean scores at 1, 3, and 5 years post diagnosis on measures of general intellectual ability, processing speed, broad attention, working memory, and spatial relations compared with the non-PFS group. The PFS group exhibited estimated mean scores that were at least one standard deviation below the mean for intellectual ability, processing speed, and broad attention across all time points and for working memory by 5 years post diagnosis. Processing speed was stable over time. Attention and working memory declined over time. Despite some change over time, caregiver ratings of executive function and behavior problem symptoms remained within the average range. CONCLUSION: Compared with patients who do not experience PFS, patients who experience PFS exhibit greater neurocognitive impairment, show little recovery over time, and decline further in some domains. Findings highlight the particularly high risk for long-term neurocognitive problems in patients who experience PFS and the need for close follow-up and intervention.

Benefit Finding in Maternal Caregivers of Pediatric Cancer Survivors: A Mixed Methods Approach.

OBJECTIVE: Benefit finding has been described as the identification of positive effects resulting from otherwise stressful experiences. In this mixed methods study, we examined the relations between qualitative themes related to benefit finding and quantitative measures of psychosocial adjustment and coping as reported by maternal caregivers of survivors of pediatric cancer. METHODS: Female caregivers of survivors of pediatric cancer (n = 40) completed a qualitative questionnaire about their experiences caring for their child, along with several quantitative measures. Qualitative questionnaires were coded for salient themes, including social support and personal growth. Correlation matrices evaluated associations between qualitative themes and quantitative measures of stress and coping. RESULTS: Identified benefits included social support and personal growth, as well as child-specific benefits. Total benefits reported were significantly positively correlated with availability of emotional resources. Coping methods were also associated, with accepting responsibility associated with fewer identified benefits. CONCLUSION: Despite the stress of their child's illness, many female caregivers of survivors of pediatric cancer reported finding benefits associated with their experience. Benefit finding in this sample was associated with better adjustment.

The potential utility of parent-reported attention screening in survivors of childhood cancer to identify those in need of comprehensive neuropsychological evaluation.

BACKGROUND: Survivors of childhood cancer are at risk for neuropsychological late effects, yet identifying those in need of evaluation and obtaining needed services can be challenging for the medical team. Finding time- and cost-effective screening measures that can be used to identify children in need of evaluation is a clinical priority. Our objective was to investigate the association between parent-rated attention problems and related neuropsychological impairments in childhood cancer survivors as a means of identifying those at high risk for difficulties. METHODS: Cognitive and psychosocial data of survivors who completed neuropsychological evaluations were retrospectively abstracted. Parents of 70 survivors of pediatric cancer (mean age, 11.6 years) completed the Conners Parent Rating Scale and the Child Behavior Checklist. Children also completed a measure of intellectual functioning. The 18 symptoms of inattention and hyperactivity were abstracted from the Conners questionnaire, and participants were classified according to whether or not they met attention deficit/hyperactivity disorder (ADHD) symptom criteria (≥6 inattentive symptoms). RESULTS: Survivors who met symptom criteria for ADHD (27%) demonstrated greater impairments in IQ and working memory, but not processing speed, than survivors who did not. Meeting ADHD symptom criteria was also associated with greater externalizing and social problems but not more internalizing symptoms. ADHD symptom screening was associated with low sensitivity (range = 26.3%-69.2%) but stronger specificity (range = 75.0%-82.7%) for neuropsychological difficulties. CONCLUSION: Parental ratings of attentional symptoms may be a useful way to screen survivors who may be in need of a full neuropsychological assessment.