Kumar, Seema

SummaryObjectiveTo examine change in weight status following initiation of lisdexamfetamine in children with attention deficit hyperactivity disorder (ADHD) and overweight or obesity.Study DesignA retrospective chart review included children aged 2 to <18 years treated with lisdexamfetamine for ADHD. Body mass index (BMI) data for up to 2 years after initiation of lisdexamfetamine were analysed using linear mixed effects models with autoregressive‐1 correlation structure on time of follow‐up per patient.ResultsThe analysis included 330 children ≤18 years, median age 10 years (interquartile range 8.1–13) comprising 55 children with severe obesity, 88 with mild‐moderate obesity, 131 with overweight and 56 with healthy weight, 68% male and 32% female. At 2 years after initiation of lisdexamfetamine in the severe obesity group, the BMI Z‐score decreased by −0.41 (95% confidence intervals [CI] [−0.57, −0.25], p < 0.001) and BMI percent of the 95th percentile decreased by −11.2% (95% CI [−15.8 to −6.7], p < 0.001). In the mild–moderate obesity group, BMI Z‐score decreased by −0.44 (95% CI [−0.56, −0.31], p < 0.001) and BMI% of the 95th percentile decreased by −11.1% at 24 months (95% CI [−13.9 to −8.4], p < 0.001). In the mild–moderate obesity and overweight groups, younger children (ages 4–10) showed greater reduction in their BMI (p < 0.001 and p = 0.029, respectively).ConclusionReduction in BMI for age was noted for up to 2 years following initiation of lisdexamfetamine in children with ADHD and overweight and obesity. Further studies are warranted to study the weight loss effect of lisdexamfetamine in children with obesity.

Abstract Context Pituitary adenomas and cysts are rare in pediatric patients and improved understanding can guide management recommendations. Objective To report incidence, presentation, management, and outcomes in a pediatric population-based cohort with pituitary adenomas and cysts, and to explore the relationship between these lesions and brain magnetic resonance imaging (MRI) rates, as well as lesion size and headaches with disease progression. Methods In this retrospective cohort study of pediatric patients (≤18 years) with incident pituitary adenomas and cysts in Olmsted County, MN, from 1976 to 2021, 234 unique patients were identified using diagnostic codes through the Rochester Epidemiology Project, with 37 confirmed cases of pituitary adenoma or cyst included. Incidence rates were calculated using census data. Descriptive statistics were used for extracted clinical data. Results Incidence of pediatric adenomas and cysts was 2.29 cases per 100 000 person-years. Of the 37 cases, 68% were nonfunctioning adenomas or cysts, 27% were prolactinomas, and there was 1 each of growth hormone (GH)– and thyrotropin (TSH)-secreting adenomas. Median lesion diameter was 5.5 mm (IQR, 4.0-8.0). Median follow-up was 7.4 years (IQR, 4.5-15.4). Four patients had disease progression which stabilized with second-line therapy. Brain MRI rates did not correlate with lesion incidence. No clinically meaningful relationship was found between lesion size or headache and disease progression. Conclusion Pituitary adenomas and cysts are rare in pediatric patients. Most are small, nonfunctioning, and stable on long-term follow-up. Larger studies on small nonfunctioning pituitary lesions are needed to enhance understanding of their natural history and develop long-term management recommendations.

Abstract Context Variants in melanocortin 4 receptor (MC4R) pathway-related genes have been associated with obesity. The association of these variants with cardiometabolic parameters are not fully known. Objective We compared the severity of obesity and cardiometabolic risk markers in children with MC4R pathway-related clinically reported genetic variants relative to children without these variants. Methods A retrospective chart review was performed in children with obesity who underwent multigene panel testing for monogenic obesity. Results Data on a total of 104 children were examined, with 93 (89%) identified as White. Thirty-nine (37.5%) patients had clinically reported variants in the MC4R pathway, and the remaining 65 patients did not have reported MC4R pathway-related variants. Among the MC4R-related variants, PCSK1 risk alleles were most common, reported in 15 children (14%). The maximum body mass index percent of the 95th percentile was not different between groups (P = .116). Low-density lipoprotein cholesterol (LDL-C) was not different between groups (P = .132). However, subgroup analysis demonstrated higher LDL cholesterol in children with the PCSK1 c.661A&gt;G risk allele relative to those with MC4R-related variant of uncertain significance (P = .047), negative genetic testing (P = .012), and those with non-MC4R related variants (P = .048). The blood pressure, fasting glucose, hemoglobin A1C, total cholesterol, alanine transaminase, and high-density lipoprotein cholesterol were not different between groups. Conclusion Variants in the MC4R pathway-related genes were not associated with severity of obesity and cardiometabolic risk markers except for the c.661A&gt;G PCSK1 risk allele, which was associated with higher LDL-C levels.

SummaryObjectiveRising prevalence of obesity has led to increased rates of prediabetes and diabetes mellitus (DM) in children. This study compares rates of prediabetes and diabetes using two recommended screening tests (fasting plasma glucose [FPG] and haemoglobin A1c [HbA1c]).Study DesignData were collected prospectively from 37 multi‐component paediatric weight management programs in POWER (Paediatric Obesity Weight Evaluation Registry).ResultsFor this study, 3962 children with obesity without a known diagnosis of DM at presentation and for whom concurrent measurement of FPG and HbA1c were available were evaluated (median age 12.0 years [interquartile range, IQR 9.8, 14.6]; 48% males; median body mass index 95th percentile [%BMIp95] 134% [IQR 120, 151]). Notably, 10.7% had prediabetes based on FPG criteria (100–125 mg/dL), 18.6% had prediabetes based on HbA1c criteria (5.7%–6.4%), 0.9% had DM by FPG abnormality (≥126 mg/dL) and 1.1% had DM by HbA1c abnormality (≥6.5%). Discordance between the tests was observed for youth in both age groups (10–18 years [n = 2915] and age 2–9 years [n = 1047]).ConclusionThere is discordance between FPG and HbA1c for the diagnosis of prediabetes and DM in youth with obesity. Further studies are needed to understand the predictive capability of these tests for development of DM (in those diagnosed with prediabetes) and cardiometabolic risk.

Abstract Disclosure: M. Salama: None. S. Kumar: None. F. Pinto e Vairo: None. R. Hentz: None. Objective: The association between disrupted melanocortin 4 receptor (MC4R) pathway function and childhood obesity is well established. Several variants in MC4R pathway related genes have been implicated to influence cardiometabolic parameters including lipid metabolism and glucose homeostasis. We compared the cardiometabolic risk markers in children with obesity and MC4R related clinically reported genetic variants relative to children with obesity and no MC4R related genetic variants. Methods: This was a retrospective case-control study conducted by chart review of children (age &lt;18 years) with obesity who underwent a multi-gene panel testing for monogenic obesity between February 2020 and November 2022. Children were divided into two groups according to their genetic test results: The first group was of children with clinically reported variants (pathogenic, likely pathogenic, risk allele or variant of uncertain significance) within the MC4R pathway), and the second group was of children with no reported variants in the MC4R pathway (negative genetic testing or variants in non-MC4R related genes). Data on systolic and diastolic blood pressure percentiles, fasting lipid panel, fasting blood glucose, hemoglobin A1c and ALT were extracted. Tests for group differences were performed using the independent two-sample t-test, Wilcoxon rank-sum test, Chi-Square test, or Fisher’s exact test as appropriate for each variable type and test assumptions. Results: Data on a total of 91 children were reviewed. Mean age at testing was 11 years (SD: 4) and mean peak BMI% of the 95th percentile was 158 (SD: 28). 36 patients had clinically reported variants in the MC4R pathway, and 55 patients had no reported MC4R related variants. The blood pressure percentiles, fasting glucose, hemoglobin A1C, total cholesterol, high density lipoprotein cholesterol and low-density lipoprotein cholesterol were not different between both groups. Conclusion: In this pilot study, among children with obesity, variants in the MC4R pathway related genes were not associated with cardiometabolic risk markers. Larger studies are warranted to assess the correlation between MC4R pathway genes and cardiometabolic risk. Presentation: Friday, June 16, 2023

Abstract This mini-review aims to briefly summarize the pathophysiology of childhood obesity, type 2 diabetes mellitus (T2DM), and cardiovascular disease (CVD) risk in children and adolescents. Recent data on efficacy of lifestyle interventions, medications, and metabolic surgery for obesity, T2DM, and CVD risk factors are also reviewed. We conducted a PubMed search of English-language original and review articles relevant to childhood obesity, T2DM, and CVD risk factors, and biomarkers in children with an emphasis on recent publications. Childhood obesity arises from an intricate interaction between genetic, physiologic, environmental, and socioeconomic factors. The rise in the prevalence of childhood obesity is associated with the development of comorbidities including T2DM and CVD at an early age. A multipronged approach is central to the detection, monitoring, and management of childhood obesity and associated adverse metabolic consequences.

Abstract Interventions for adolescent weight management that are ready to use in clinical settings are needed to address the obesity epidemic and improve the health and wellbeing of affected adolescents. This report describes the systematic process our team followed to adapt an evidence-based intervention (EBI) for adolescent weight management from its randomized control trial protocol to a package for delivery in a group-based telehealth format within a medical center. The EBI adaptation was clinician initiated, prompted by identified practice needs, and involved collaboration of the clinical team with the EBI developer. The process was guided by the Reach, Effectiveness, Adoption, Implementation, Maintenance (RE-AIM) framework and followed key steps for adapting EBIs to new contexts. RE-AIM-aligned adaptations included telehealth delivery and broader inclusion criteria, separate clinical and research evaluation batteries, adaptations to fit the clinical practice, practical fidelity checklists to guide and record session delivery, and continuous quality improvement processes aimed to facilitate program longevity and family engagement. The process culminated in a package of adapted intervention materials deemed by stakeholders as appropriate to the practice and congruent with the EBI model. This report provides a much-needed practical demonstration of the translation of an EBI for adolescent weight management from research protocol to group telehealth delivery in a medical center. Key lessons include the value of clinician-researcher collaboration, the breadth of resources needed to adapt EBIs for real-world delivery, and the importance of considering delivery context in implementation and evaluation decisions, including defining inclusion criteria, staffing, and outcomes assessments.

The PAX1 gene plays an important role in the development of the parathyroid glands and the thymus. Mouse knockout models of PAX1, PAX3, and PAX9 have been found to have hypoplastic or absent parathyroid glands. To our knowledge, there are no reported cases of PAX1-associated hypoparathyroidism in humans. We present a case of hypoparathyroidism in a 23-month-old boy with a homozygous pathogenic variant in the PAX1 gene ( PAX1 NM_006192.5 c.463_465del variant), predicted to cause an in-frame deletion of asparagine at position 155 (p.Asn155del) of the PAX1 protein. The hypoparathyroidism was unmasked after the patient developed significant hypocalcemia while receiving GoLYTELY (polyethylene glycol 3350, sodium sulfate anhydrous, sodium bicarbonate, sodium chloride, potassium chloride) for bowel cleanout. The patient had mild and asymptomatic hypocalcemia prior to hospitalization. The patient was noted to have inappropriately normal parathyroid hormone (PTH) level at the time of documented hypocalcemia thereby suggesting a diagnosis of hypoparathyroidism. Plain language summary The first human case of hypoparathyroidism associated with a rare genetic disorder: a case report of PAX1 gene mutation The paired box ( PAX) gene family is important for embryo development. One subfamily, PAX1, is necessary for development of the spinal column, thymus (important for the immune system development), and parathyroid (helps regulate the amount of calcium in the body). We present the case of a 23-month-old boy with known PAX1 gene mutation who came in with episodes of vomiting and poor growth. His presentation was thought to be most likely related to constipation. He was started on bowel cleanout medication and intravenous fluids. However, his calcium that had been mildly low subsequently dropped to very low levels. The level of parathyroid hormone (which helps regulate calcium levels) was inappropriately normal, meaning that his body was unable to make more, and was consistent with hypoparathyroidism. He was treated with calcium supplements and vitamin D and calcium levels normalized. He continues to be on calcium and vitamin D and calcium levels have remained stable. Doctors should keep this complication in mind when treating patients with PAX1 gene mutation.

Abstract Background In the United States, rare disease (RD) is defined as a condition that affects fewer than 200,000 individuals. Collectively, RD affects an estimated 30 million Americans. A significant portion of RD has an underlying genetic cause; however, this may go undiagnosed. To better serve these patients, the Mayo Clinic Program for Rare and Undiagnosed Diseases (PRaUD) was created under the auspices of the Center for Individualized Medicine (CIM) aiming to integrate genomics into subspecialty practice including targeted genetic testing, research, and education. Methods Patients were identified by subspecialty healthcare providers from 11 clinical divisions/departments. Targeted multi-gene panels or custom exome/genome-based panels were utilized. To support the goals of PRaUD, a new clinical service model, the Genetic Testing and Counseling (GTAC) unit, was established to improve access and increase efficiency for genetic test facilitation. The GTAC unit includes genetic counselors, genetic counseling assistants, genetic nurses, and a medical geneticist. Patients receive abbreviated point-of-care genetic counseling and testing through a partnership with subspecialty providers. Results Implementation of PRaUD began in 2018 and GTAC unit launched in 2020 to support program expansion. Currently, 29 RD clinical indications are included in 11 specialty divisions/departments with over 142 referring providers. To date, 1,152 patients have been evaluated with an overall solve rate of 14.1% and as high as 66.7% depending on the phenotype. Noteworthy, 42.7% of the solved or likely solved patients underwent changes in medical management and outcome based on genetic test results. Conclusion Implementation of PRaUD and GTAC have enabled subspecialty practices advance expertise in RD where genetic counselors have not historically been embedded in practice. Democratizing access to genetic testing and counseling can broaden the reach of patients with RD and increase the diagnostic yield of such indications leading to better medical management as well as expanding research opportunities.