Relationship of thyroid function with genetic subtypes and treatment with growth hormone in Prader-Willi syndrome.

Prader-Willi syndrome (PWS) is the most common genetic syndrome with obesity and results from loss of expression of paternally inherited genes on chromosome 15q11-q13 by a variety of mechanisms which include large deletions (70%-75%), maternal uniparental disomy (UPD) (20%-30%), and imprinting defects (2%-5%) or balanced translocations. Individuals often have a characteristic behavior disorder with mild intellectual disability, infantile hypotonia associated with poor sucking, short stature, and obesity. PWS is characterized by hypothalamic-pituitary axis dysfunction with growth hormone (GH) deficiency, hypogonadism, and several other hormonal deficiencies resulting in short stature, centrally driven excessive appetite (hyperphagia), central obesity, cryptorchidism, and decreased lean body mass. In this study, we determined and sought differences in the incidence of thyroid abnormalities among the common genetic subtypes in a cohort of 52 subjects with PWS because there was limited literature available. We also sought the effects of growth hormone (GH) treatment on the thyroid profile. Fifty-two subjects with a genetically confirmed diagnosis of PWS were included in this study at the University of California, Irvine. Blood samples for baseline thyroxine stimulating hormone (TSH) and free thyroxine (fT4) levels were obtained in the morning after an overnight fast for 8-12 h. Statistical analyses were performed with SPSS (SPSS Inc., 21.0). Mean values were analyzed by one-way ANOVA, and student's t-test and statistical significance were set at p < 0.05. The subjects included 26 males and 26 females with an age range of 3-38 years. There were 29 subjects with chromosome 15q11-q13 deletions and 23 with UPD; 28 were GH treated currently or in the past, and 24 never received GH. There was no significant difference in age or body mass index (BMI) (kg/m2) between GH-treated versus non-GH-treated groups. BMI was higher in the deletion group compared to the UPD group (p = 0.05). We identified two individuals who were clinically diagnosed and treated for hypothyroidism, one of whom was on GH supplements. We identified two additional individuals with subclinical hypothyroidism who were not on GH treatment, giving a frequency of 7.6% (4/52) in this cohort of patients. We did not find significant differences in thyroid function (TSH) in the deletion versus UPD groups. We found significant differences in thyroid function, however, between GH-treated and non-GH-treated groups. The mean TSH was lower (2.25 ± 1.17 uIU/M, range 0.03-4.92 uIU/M versus 2.80 ± 1.44 uIU/M, range 0.55-5.33 uIU/M respectively, p = 0.046), and the free T4 levels were significantly higher (1.13 ± 0.70 and 1.03 ± 0.11 ng/dL, respectively, p = 0.05) in the GH-treated individuals compared to non-GH-treated individuals. In this cohort of subjects with PWS, we identified two previously diagnosed individuals with hypothyroidism and two individuals with subclinical hypothyroidism (4/52, 7.6%), three of whom were not receiving GH treatment. We did not find any significant differences in thyroid function between molecular subtypes; however, we found that euthyroid status (lower TSH levels and higher free T4 levels) was significantly higher in individuals who were treated with GH compared to the untreated group. We recommend that individuals with PWS should be screened regularly for thyroid deficiency and start treatment early with GH in view of the potentially lower incidence of thyroid deficiency.

Training pediatric physicians and staff to obtain data from the electronic health record.

Electronic health records (EHRs) have provided physicians with user-friendly self-service reporting tools to extract patient data from the EHR. Despite such benefits, physician training on how to use these tools has been limited. At our institution, physicians were faced with prolonged wait time for EHR data extraction requests and were unaware of self-service reporting tool availability in the EHR. Our goal was to develop an EHR data reporting curriculum for physicians and staff and examine the effectiveness of such training. In 2019, physician informaticists developed two interactive sessions to train physicians and staff on self-service reporting tools (Epic® SlicerDicer and Reporting Workbench (RWB)) available in our tertiary children's hospital EHR. We assessed participants' knowledge, confidence, and tool utilization before, after, and 3-months post training via survey. Training sessions occurred between April and August 2021. Thirty-six participants completed the study, with 25 surveys collected immediately post and 22 surveys collected at 3-months post training. Data literacy knowledge pre-test average score improved from 62% to 93% (p < 0.05) immediately post-session and 74% at 3-months post assessment (p = 0.05). Regular tool utilization increased from 29% (RWB) and 34% (SlicerDicer) pre-session to 56% and 44% at 3-months post, respectively. Participants reported increased confidence in performing SlicerDicer model selection, criteria selection, and data visualization as well as RWB report navigation, report creation, report visualization, and describing report's benefits/limitations. Ultimately, physician and staff self-service reporting tools training were effective in increasing data literacy knowledge, tool utilization, and confidence.

Obesity and Outcomes of Kawasaki Disease and COVID-19-Related Multisystem Inflammatory Syndrome in Children.

Importance: Obesity may affect the clinical course of Kawasaki disease (KD) in children and multisystem inflammatory syndrome in children (MIS-C) associated with COVID-19. Objective: To compare the prevalence of obesity and associations with clinical outcomes in patients with KD or MIS-C. Design, Setting, and Participants: In this cohort study, analysis of International Kawasaki Disease Registry (IKDR) data on contemporaneous patients was conducted between January 1, 2020, and July 31, 2022 (42 sites, 8 countries). Patients with MIS-C (defined by Centers for Disease Control and Prevention criteria) and patients with KD (defined by American Heart Association criteria) were included. Patients with KD who had evidence of a recent COVID-19 infection or missing or unknown COVID-19 status were excluded. Main Outcomes and Measures: Patient demographic characteristics, clinical features, disease course, and outcome variables were collected from the IKDR data set. Using body mass index (BMI)/weight z score percentile equivalents, patient weight was categorized as normal weight (BMI <85th percentile), overweight (BMI ≥85th to <95th percentile), and obese (BMI ≥95th percentile). The association between adiposity category and clinical features and outcomes was determined separately for KD and MIS-C patient groups. Results: Of 1767 children, 338 with KD (median age, 2.5 [IQR, 1.2-5.0] years; 60.4% male) and 1429 with MIS-C (median age, 8.7 [IQR, 5.3-12.4] years; 61.4% male) were contemporaneously included in the study. For patients with MIS-C vs KD, the prevalence of overweight (17.1% vs 11.5%) and obesity (23.7% vs 11.5%) was significantly higher (P < .001), with significantly higher adiposity z scores, even after adjustment for age, sex, and race and ethnicity. For patients with KD, apart from intensive care unit admission rate, adiposity category was not associated with laboratory test features or outcomes. For patients with MIS-C, higher adiposity category was associated with worse laboratory test values and outcomes, including a greater likelihood of shock, intensive care unit admission and inotrope requirement, and increased inflammatory markers, creatinine levels, and alanine aminotransferase levels. Adiposity category was not associated with coronary artery abnormalities for either MIS-C or KD. Conclusions and Relevance: In this international cohort study, obesity was more prevalent for patients with MIS-C vs KD, and associated with more severe presentation, laboratory test features, and outcomes. These findings suggest that obesity as a comorbid factor should be considered at the clinical presentation in children with MIS-C.

Pharmacogenetics of childhood uncontrolled asthma.

INTRODUCTION: Asthma is a heterogeneous, multifactorial disease with multiple genetic and environmental risk factors playing a role in pathogenesis and therapeutic response. Understanding of pharmacogenetics can help with matching individualized treatments to specific genotypes of asthma to improve therapeutic outcomes especially in uncontrolled or severe asthma. AREAS COVERED: In this review, we outline novel information about biology, pathways, and mechanisms related to interindividual variability in drug response (corticosteroids, bronchodilators, leukotriene modifiers, and biologics) for childhood asthma. We discuss candidate gene, genome-wide association studies and newer omics studies including epigenomics, transcriptomics, proteomics, and metabolomics as well as integrative genomics and systems biology methods related to childhood asthma. The articles were obtained after a series of searches, last updated November 2022, using database PubMed/CINAHL DB. EXPERT OPINION: Implementation of pharmacogenetic algorithms can improve therapeutic targeting in children with asthma, particularly with severe or uncontrolled asthma who typically have challenges in clinical management and carry considerable financial burden. Future studies focusing on potential biomarkers both clinical and pharmacogenetic can help formulate a prognostic test for asthma treatment response that would represent true bench to bedside clinical implementation.

Geographic Variation in Acute Pediatric Mental Health Utilization.

OBJECTIVE: To identify locations with higher need for acute pediatric mental health (MH) interventions or services and describe these communities' socio-demographic characteristics. METHODS: This single-center retrospective study included patients 5 to 18 years old with an emergency department (ED) or hospital admission between 2017 and 2019 for a primary known MH diagnosis or symptoms. We extracted visit data from the electronic medical record, mapped patients to their home census tract, calculated normalized visit rates by census tract, and performed spatial analysis to identify nonrandom geographic clusters and outliers of high utilization. Census tract utilization rates were stratified into quartiles, and socioeconomic and demographic characteristics obtained from the US Census Bureau were compared using analysis of variance, chi-square tests, and multivariable analysis. RESULTS: There were 10,866 qualifying visits across 617 census tracts. ED and hospital admission rates ranged from 2.7 to 428.6 per 1000 children. High utilization clusters localized to neighborhoods with lower socioeconomic status (p < .05). Southern regions with high utilizers were more likely to have fewer children per neighborhood, higher rates of teen births, and lower socioeconomic status. Multivariate analysis showed regions with high utilizers had fewer children per neighborhood, lower median household income, and more families that lacked computer access. CONCLUSION: ED and hospital utilization for pediatric MH concerns varied significantly by neighborhood and demographics. Divergent social factors map onto these locations and are related to MH utilization. Leveraging geography can be a powerful tool in the development of targeted, culturally tailored interventions to decrease acute pediatric MH utilization and advance child MH equity.

A Multicenter Retrospective Study of Vancomycin Dosing by Weight Measures in Children.

OBJECTIVE: Vancomycin carries risks of treatment failure and emergent resistance with underexposure and renal toxicity with overexposure. Children with overweight or obesity may have altered pharmacokinetics. We aimed to examine how body weight metrics influence vancomycin serum concentrations and to evaluate alternative dosing strategies. METHODS: This was a multicenter retrospective cohort study across 3 large, academic hospitals. Patients aged 2 to 18 years old who received ≥3 doses of intravenous vancomycin were included. Weight metrics included total body weight, adjusted body weight, ideal body weight, body surface area, and allometric weight. Outcomes included vancomycin concentration and ratios of area under the curve (AUC) to minimum inhibitory concentration (MIC). Regression analyses were used to examine which body-weight identifier predicted outcomes. RESULTS: Of the 1099 children, 45% were girls, mean age was 9.0 (SD = 5.4) years, 14% had overweight, and 17% had obesity. Seventy-five percent of children had vancomycin concentrations in the subtherapeutic range by trough <10 µg/mL, and 63% had a ratio of AUC to MIC <400 µg-hr/mL. Three percent had a supratherapeutic initial trough >20 µg/mL or ratio of AUC to MIC >600 µg-hr/mL. Serum vancomycin concentrations were higher in children with overweight or obesity compared with children who were at a normal weight or underweight; the mean ratio of AUC to MIC also trended higher in the groups with overweight or obesity. CONCLUSIONS: Most children received vancomycin regimens that produced suboptimal trough levels. Children with overweight or obesity experienced higher vancomycin trough levels than children of normal weight despite receiving lower total body weight dosing. Using the ratio of AUC to MIC was a better measure of drug exposure.

Vancomycin Dosing in Children With Overweight or Obesity: A Systematic Review and Meta-analysis.

CONTEXT: Vancomycin is a medication with potential for significant harm with both overdosing and underdosing. Obesity may affect vancomycin pharmacokinetics and is increasingly common among children. OBJECTIVE: We aimed to determine if children with overweight or obesity have increased vancomycin trough concentrations with total body weight (TBW) dosing compared with children with normal weight. DATA SOURCES: We conducted a search of Medline and Medline In-Process & Other Non-Indexed Citations from 1952 (the year vancomycin was discovered) to November 2017. STUDY SELECTION: Search terms included vancomycin, body weight, and body composition terms and were limited to children. Studies were reviewed and screened by ≥2 reviewers. DATA EXTRACTION: The primary outcome was vancomycin level. Data were extracted by 2 reviewers. We performed quality assessment using the Newcastle-Ottawa quality assessment scale. RESULTS: We identified 271 records. After abstract and full-text screening, we identified 7 studies for full review. Six of the 7 studies used a matched case-control design, although there was significant variation in study methodology. Four of the 7 studies were included in a meta-analysis, which revealed a small but significant difference in vancomycin trough levels between children with normal weight and children with overweight or obesity when dosed by using TBW (N = 521; mean difference 2.2 U [95% confidence interval: 1.0-3.4]). CONCLUSIONS: High-quality data to guide vancomycin dosing in children with obesity are lacking. More studies evaluating dosing strategies in children with obesity are warranted because using TBW to dose vancomycin may lead to higher vancomycin concentrations and potential toxicity.

Impact of genetic subtypes of Prader-Willi syndrome with growth hormone therapy on intelligence and body mass index.

Prader-Willi syndrome (PWS) is a genomic imprinting disorder characterized by infantile hypotonia with a poor suck and failure to thrive, hypogenitalism/hypogonadism, behavior and cognitive problems, hormone deficiencies, hyperphagia, and obesity. The Stanford Binet and Wechsler (WAIS-R; WISC-III) intelligence (IQ) tests were administered on 103 individuals with PWS from two separate cohorts [University of California, Irvine (UCI) (N = 56) and Vanderbilt University (N = 47)] and clinical information obtained including growth hormone (GH) treatment, PWS molecular classes, weight and height. Significantly higher IQ scores (p < .02) were found representing the vocabulary section of the Stanford Binet test in the growth hormone (GH) treated group when compared with non-GH treatment in the pediatric-based UCI PWS cohort with a trend for stabilization of vocabulary IQ scores with age in the GH treated maternal disomy (UPD) 15 subject group. Significant differences (p = .05) were also found in the adult-based Vanderbilt PWS cohort with 15q11-q13 deletion subjects having lower Verbal IQ scores compared with UPD 15. No difference in body mass index was identified based on the PWS molecular class or genetic subtype. Medical care and response to treatment with growth hormone may influence intelligence impacted by PWS genetic subtypes and possibly age, but more studies are needed.

Psychological Impact of Predictive Genetic Testing in VCP Inclusion Body Myopathy, Paget Disease of Bone and Frontotemporal Dementia.

Inclusion Body Myopathy associated with Paget's disease of bone and Fronto-temporal Dementia, also known as multisystem proteinopathy is an autosomal dominant, late onset neurodegenerative disorder caused by mutations in Valosin containing protein (VCP) gene. This study aimed to assess uptake and decision making for predictive genetic testing and the impact on psychological well-being. Individuals who had participated in the gene discovery study with a 50 % a priori risk of inheriting VCP disease were sent a letter of invitation offering genetic counseling and testing and were also invited to participate in this psychosocial study. A total of 102 individuals received an invitation and 33 individuals participated in genetic counseling and testing (32.3 %) with 29 completing baseline questionnaires. Twenty completed the follow-up post-test Hospital Anxiety and Depression Scale questionnaire including 13 of the 18 who had tested positive. Mean risk perception at baseline was 50.1 %. Reasons for testing included planning for the future, relieving uncertainty, informing children and satisfying curiosity. At baseline, one quarter of the participants had high levels of anxiety. However, scores were normal one year following testing. In this small cohort, one third of individuals at 50 % risk chose pre-symptomatic testing. Although one quarter of those choosing testing had high anxiety at baseline, this was not evident at follow-up.

A case report comparing clinical, imaging and neuropsychological assessment findings in twins discordant for the VCP p.R155C mutation.

Inclusion body myopathy, Paget disease of bone and/or frontotemporal dementia is an autosomal dominant disease caused by mutations in the Valosin Containing Protein (VCP) gene. We compared clinical findings including MRI images and neuropsychological assessment data in affected and unaffected twin brothers aged 56 years from a family with the p.R155C VCP gene mutation. The affected twin presented with a 10 year history of progressive proximal muscle weakness, difficulty swallowing, gastroesophageal reflux, fecal incontinence, and peripheral neuropathy. Comprehensive neuropsychological testing revealed rapid cognitive decline in the absence of any behavioral changes in a span of 1 year. This case illustrates that frontotemporal dementia related cognitive impairment may precede behavioral changes in VCP disease as compared with predominance of behavioral impairment reported in previous studies. Our findings suggest that there is a need to establish VCP disease specific tools and normative rates of decline to detect pre-clinical cognitive impairment among affected individuals.

Early-onset Alzheimers and cortical vision impairment in a woman with valosin-containing protein disease associated with 2 APOE ε4/APOE ε4 genotype.

Hereditary inclusion body myopathy is a heterogeneous group of disorders characterized by rimmed vacuoles and by the presence of filamentous cytoplasmic and intranuclear inclusions. Inclusion body myopathy with Paget disease of bone and frontotemporal dementia is a progressive autosomal dominant disorder associated with a mutation in valosin-containing protein (VCP) with typical onset of symptoms in the 30s. APOE [Latin Small Letter Open E]4 is a major risk factor for late-onset Alzheimer disease, a progressive neurodegenerative disorder that affects memory, thinking, behavior, and emotion as a result of the excessive buildup and decreased clearance of ß-amyloid proteins resulting in the appearance of neuritic plaques and neurofibrillary tangles. In conclusion, we report a unique patient with an APOE [Latin Small Letter Open E]4/APOE [Latin Small Letter Open E]4 genotype and atypical VCP disease associated with early Alzheimer disease and severe vision impairment. Future studies will elucidate the interaction of VCP mutations and APOE [Latin Small Letter Open E]4 alleles in understanding common mechanisms in AD and VCP disease.

Effect of genetic subtypes and growth hormone treatment on bone mineral density in Prader-Willi syndrome.

UNLABELLED: Abstract Background: Currently, there is limited information on the effects of growth hormone and of the different genetic subtypes on bone mineral density (BMD) in Prader-Willi syndrome (PWS). METHODS: We evaluated BMD in 79 individuals with the common subtypes of PWS (48 with deletion and 27 with UPD) and the effect of growth hormone treatment (n=46) vs. no growth hormone treatment. RESULTS: Forty-four percent of the individuals studied had whole body, hip, or spine BMD <-1 standard deviation (SD) and 10% had a BMD <-2 SD. BMD Z-scores and total BMD (g/cm2) of the spine were significantly higher in the growth hormone group. With each year of growth hormone treatment, these values increased by a factor of 0.207 and 0.011 (p=0.006 and 0.032), respectively. Individuals with uniparental disomy revealed higher spine BMD compared with deletion subclass; however, the differences were not significant. CONCLUSION: This study emphasizes the importance of evaluating bone mineralization in individuals with PWS and the beneficial effects of prolonged treatment with growth hormone. There was a trend for a higher BMD in individuals with uniparental disomy.

Cytokine profiling in patients with VCP-associated disease.

Valosin containing protein (VCP) disease (also known as Inclusion Body Myopathy, Paget Disease of Bone and Frontotemporal Dementia [IBMPFD] syndrome) is caused by mutations in the gene encoding VCP classically affecting the muscle, bone and brain. Although the genetic cause has been identified, details regarding the pathogenesis of IBMPFD have not been fully determined. Muscle wasting observed in VCP disease is suggestive of cytokine imbalance. We hypothesized that dysfunctional protein homeostasis caused by VCP mutations leads to cytokine imbalances thereby contributing to the muscle wasting phenotype. Circulating levels of interleukin-4 (IL-4), interleukin-6 (IL-6), tumor necrosis factor alpha (TNF a) and epidermal growth factor (EGF) were measured in plasma of patients with VCP disease or controls. TNF a and EGF were significantly altered in VCP disease as compared to control. TNF a was up-regulated, consistent with a cachexia phenotype and EGF levels were increased. No significant differences were observed in IL-4 and IL-6. Cytokine imbalances may be associated with VCP disease and may play a contributory role in VCP myopathy. Further understanding of how VCP dysfunction leads to aberrant protein homeostasis and subsequent cytokine imbalances may also aid in the understanding of other proteinopathies and in the development of novel treatments.

Frequency of Prader-Willi syndrome in births conceived via assisted reproductive technology.

PURPOSE: Prader-Willi syndrome is an imprinting disorder characterized by typical facial, physical, and cognitive/behavioral features, resulting from lack of paternally expressed genes on chromosome 15q11.2-q13. Studies have suggested an increased risk of other imprinting disorders in children conceived by assisted reproductive techniques. This study was designed to determine the association between assisted reproductive technology and Prader-Willi syndrome. METHODS: Data on individuals with Prader-Willi syndrome were collected from three distinct sources and the proportion of assisted reproductive technology births analyzed. RESULTS: The proportions of assisted reproductive technology births in the Prader-Willi Syndrome Association (USA), Rare Diseases Clinical Research Network, and University of California, Irvine Medical Center populations were 1.0% (18/1,736), 1.0% (1/98), and 2.0% (1/50), respectively (overall 1.1%; population frequency for the United States was 1.0%). Of note, 2.4% (45/1,898) of participants were co-twins (11 born after assisted reproductive technology procedures); US twin frequency is 1.6% (P = 0.007). The proportion of individuals with maternal disomy 15/imprinting defects born after assisted reproductive technology was higher than that in the total sample, 55.6% (10/18) and 34.5% (431/1,250), respectively. CONCLUSION: This study found no association between assisted reproductive technology and Prader-Willi syndrome. There was an increased frequency of twinning. The number of individuals with maternal disomy 15/imprinting defect was nearly double in the assisted reproductive technology group as compared with the total Prader-Willi syndrome participants.