Premature pubarche in Prader-Willi syndrome: Risk factors and consequences.

OBJECTIVES: Children with Prader-Willi Syndrome (PWS) may develop premature pubarche (PP). We investigated the frequency of PP, and its potential precursors and sequelae, in PWS. DESIGN, PATIENTS AND MEASUREMENTS: A chart review of children with PWS treated at our institution between 1990 and 2021 was performed. PP was defined as Tanner stage 2 (TS2) pubic hair in girls <8 and boys <9 years old. Demographic, anthropometric, and laboratory data were collected to assess predisposing factors and consequences of PP in comparison to patients with PWS who had normal pubarche (NP). RESULTS: Analysis included 43 children with PWS, 23 (53.5%) with PP and 20 (46.5%) with NP. Median age at pubarche was 7.0 years in PP group and 10.0 years in NP group. Age at pubarche was not correlated with age of recombinant human growth hormone (rhGH) initiation, body mass index (BMI) z-score, or homeostasis model assessment of insulin resistance (HOMA-IR) at pubarche. BMI z-score at pubarche was modestly correlated with degree of pubarchal BA advancement (p = 0.033). Those with PP were more likely to have a lower high-density lipoprotein (HDL) (1.05 mmol/L vs. 1.41 mmol/L in the NP group, p = 0.041). The difference between target and final height did not differ between groups (p = 0.507). CONCLUSION: PP is common in PWS but does not compromise final height in comparison to the NP group. Obesity and insulin resistance were not associated with PP in children with PWS, contrary to what has been seen in obese children without PWS.

Progression of comorbidities in youth with overweight or obesity during the COVID-19 pandemic.

BACKGROUND: Childhood obesity rates have continued to increase with the COVID-19 pandemic. However, data are limited on the impact of increasing obesity on associated comorbidities. METHODS: We evaluated the progression of overweight- or obesity-associated comorbidities by investigating change in laboratory results pre-COVID-19 pandemic and post-COVID-19 pandemic onset in youth with overweight or obesity. We defined progression of comorbidities based on increase in category rather than absolute change in value. RESULTS: HbA1c progression was seen in 19%, and LDL cholesterol progression was seen in 26%, as defined by categories. HbA1c progression and LDL cholesterol progression were significantly correlated. HbA1c and LDL cholesterol progression were significantly associated with older age and Hispanics, respectively. CONCLUSION: The results indicate youths with overweight or obesity have experienced progression of comorbidities during the COVID-19 pandemic. This study emphasizes the importance of early detection of comorbidities among a high-risk pediatric population.

Genomic answers for children: Dynamic analyses of >1000 pediatric rare disease genomes.

PURPOSE: This study aimed to provide comprehensive diagnostic and candidate analyses in a pediatric rare disease cohort through the Genomic Answers for Kids program. METHODS: Extensive analyses of 960 families with suspected genetic disorders included short-read exome sequencing and short-read genome sequencing (srGS); PacBio HiFi long-read genome sequencing (HiFi-GS); variant calling for single nucleotide variants (SNV), structural variant (SV), and repeat variants; and machine-learning variant prioritization. Structured phenotypes, prioritized variants, and pedigrees were stored in PhenoTips database, with data sharing through controlled access the database of Genotypes and Phenotypes. RESULTS: Diagnostic rates ranged from 11% in patients with prior negative genetic testing to 34.5% in naive patients. Incorporating SVs from genome sequencing added up to 13% of new diagnoses in previously unsolved cases. HiFi-GS yielded increased discovery rate with >4-fold more rare coding SVs compared with srGS. Variants and genes of unknown significance remain the most common finding (58% of nondiagnostic cases). CONCLUSION: Computational prioritization is efficient for diagnostic SNVs. Thorough identification of non-SNVs remains challenging and is partly mitigated using HiFi-GS sequencing. Importantly, community research is supported by sharing real-time data to accelerate gene validation and by providing HiFi variant (SNV/SV) resources from >1000 human alleles to facilitate implementation of new sequencing platforms for rare disease diagnoses.

The Coronavirus Disease 2019 Pandemic is Associated with a Substantial Rise in Frequency and Severity of Presentation of Youth-Onset Type 2 Diabetes.

OBJECTIVES: To evaluate the frequency and severity of new cases of youth-onset type 2 diabetes in the US during the first year of the pandemic compared with the mean of the previous 2 years. STUDY DESIGN: Multicenter (n = 24 centers), hospital-based, retrospective chart review. Youth aged ≤21 years with newly diagnosed type 2 diabetes between March 2018 and February 2021, body mass index ≥85th percentile, and negative pancreatic autoantibodies were included. Demographic and clinical data, including case numbers and frequency of metabolic decompensation, were compared between groups. RESULTS: A total of 3113 youth (mean [SD] 14.4 [2.4] years, 50.5% female, 40.4% Hispanic, 32.7% Black, 14.5% non-Hispanic White) were assessed. New cases of type 2 diabetes increased by 77.2% in the year during the pandemic (n = 1463) compared with the mean of the previous 2 years, 2019 (n = 886) and 2018 (n = 765). The likelihood of presenting with metabolic decompensation and severe diabetic ketoacidosis also increased significantly during the pandemic. CONCLUSIONS: The burden of newly diagnosed youth-onset type 2 diabetes increased significantly during the coronavirus disease 2019 pandemic, resulting in enormous strain on pediatric diabetes health care providers, patients, and families. Whether the increase was caused by coronavirus disease 2019 infection, or just associated with environmental changes and stressors during the pandemic is unclear. Further studies are needed to determine whether this rise is limited to the US and whether it will persist over time.

Computed tomography-guided percutaneous cryoablation of hereditary adrenal pheochromocytoma in three patients.

OBJECTIVES: Pheochromocytomas (PHEO) are neuroendocrine tumors rarely diagnosed in children. We are reporting on the management challenges of three adolescent patients who present with hereditary PHEO. CASE PRESENTATION: The index patient and his male sibling presented with bilateral PHEO, while a third patient presented with a unilateral PHEO, all associated with von Hippel-Lindau (VHL) syndrome. The patients were treated with computed tomography (CT)-guided percutaneous cryoablation (CRA) of the adrenal lesions, with varying degrees of success. CONCLUSIONS: CT-guided percutaneous CRA of hereditary PHEO has not been reported in the pediatric population and may represent a novel treatment strategy that reduces the risk of intraprocedural complications and adrenal insufficiency (AI).

Relationship between youth cardiometabolic health and physical activity in medical records.

BACKGROUND: Thers is limited research examining modifiable cardiometabolic risk factors with a single-item health behavior question obtained during a clinic visit. Such information could support clinicians in identifying patients at risk for adverse cardiometabolic health. We investigated if children meeting physical activity or screen time recommendations, collected during clinic visits, have better cardiometabolic health than children not meeting recommendations. We hypothesized that children meeting either recommendation would have fewer cardiometabolic risk factors. METHODS AND FINDINGS: This cross-sectional study used data from electronic medical records (EMRs) between January 1, 2013 through December 30, 2017 from children (2-18 years) with a well child visits and data for ≥1 cardiometabolic risk factor (i.e., systolic and diastolic blood pressure, glycated hemoglobin, alanine transaminase, high-density and low-density lipoprotein, total cholesterol, and/or triglycerides). Physical activity and screen time were patient/caregiver-reported. Analyses included EMRs from 63,676 well child visits by 30,698 unique patients (49.3% female; 41.7% Black, 31.5% Hispanic). Models that included data from all visits indicated children meeting physical activity recommendations had reduced risk for abnormal blood pressure (odds ratio [OR] = 0.91, 95%CI 0.86, 0.97; p = 0.002), glycated hemoglobin (OR = 0.83, 95%CI 0.75, 0.91; p = 0.00006), alanine transaminase (OR = 0.85, 95%CI 0.79, 0.92; p = 0.00001), high-density lipoprotein (OR = 0.88, 95%CI 0.82, 0.95; p = 0.0009), and triglyceride values (OR = 0.89, 95%CI 0.83, 0.96; p = 0.002). Meeting screen time recommendations was not associated with abnormal cardiometabolic risk factors. CONCLUSION: Collecting information on reported adherence to meeting physical activity recommendations can provide clinicians with additional information to identify patients with a higher risk of adverse cardiometabolic health.

Recognizing Complications in Youth With Diabetes Admitted With Diabetic Ketoacidosis Versus Hyperglycemic Hyperosmolar State.

INTRODUCTION: We compare in-hospital complications in youth with isolated diabetic ketoacidosis (DKA) to youth with hyperosmolarity. METHOD: We reviewed medical records of youth (1-20 years) admitted over two years with DKA, hyperglycemic hyperosmolar state (HHS), and hyperosmolar DKA. We evaluated outcomes, including hospital length of stay, altered mental status (AMS), and acute kidney injury (AKI). RESULTS: Of 369 admissions, 334 had isolated DKA, 32 had hyperosmolar DKA, and three had isolated HHS. Hyperosmolar youth had longer length of stay, larger initial fluid boluses, more frequent pediatric intensive care unit admissions, and increased risk of AKI and AMS. The odds of AKI were positively associated with serum osmolality and negatively associated with new-onset diabetes mellitus (DM) compared with established DM. CONCLUSIONS: In youth with DM, hyperosmolarity increases acute complications compared with isolated DKA. Larger-scale studies are needed to identify ways to prevent acute complications in youth experiencing hyperglycemic emergencies.

Urea as safe treatment for hyponatremia due to syndrome of inappropriate antidiuretic hormone in infant with solitary central incisor and neurofibromatosis-1.

OBJECTIVES: Classic treatment for syndrome of inappropriate antidiuretic hormone (SIADH) is fluid restriction. However, this is not ideal for infants who need large fluid volumes to ensure adequate caloric intake for growth. The use of urea has not been thoroughly studied in children. CASE PRESENTATION: This infant had SIADH complicated by poor growth, solitary central incisor, and NF1. Following failed attempts to correct hyponatremia with fluid restriction and other therapeutics, urea normalized sodium levels and allowed liberalization of formula volumes, which resulted in improved weight gain. CONCLUSIONS: Urea is a safe, cost-effective, long-term treatment for SIADH in infants who are unable to fluid restrict due to caloric goals.

Management and outcomes in secondary diabetes among pediatric patients hospitalized with hemophagocytic lymphohistiocytosis.

OBJECTIVES: Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening disorder marked by massive cytokine release from macrophage and T-cell activation. Hallmarks include fever, splenomegaly, cytopenias, hypertriglyceridemia, hypofibrinogemia, and elevations in ferritin and soluble IL-2 receptor. Given the association of HLH with inflammation and glucocorticoid therapy, the development of hyperglycemia is not unexpected. Descriptions of the prevalence of secondary diabetes in youth diagnosed with HLH are lacking. METHODS: Retrospective review from 2010 through 2019 of hospitalized youth 0-21 years diagnosed with HLH. The primary outcome of interest was the development of secondary diabetes, defined as a serum glucose 200 mg/dL or higher necessitating insulin therapy. RESULTS: Of 28 patients with HLH, 36 % (n=10) developed secondary diabetes. The only risk factor associated with secondary diabetes was an infectious cause of HLH (60 % vs. 27.8 %, p 0.041). Intravenous regular insulin was used in 80 % of patients with a mean duration of 9.5 days (2-24 days). Most (70 %) needed insulin within 5 days of starting steroids. Stays in the ICU were longer (median 20 vs. 3 days, p 0.007) and intubation more likely (90 vs. 45 %, p 0.041) among those with secondary diabetes. Mortality was high (16-30 %) regardless of insulin use (p 0.634). CONCLUSIONS: One-third of hospitalized pediatric patients with HLH developed secondary diabetes requiring insulin therapy. Insulin is typically started within 5 days of initiating steroids, limited to IV infusions, and often is not needed by discharge. Secondary diabetes was associated with longer ICU stays and heightened risk of intubation.

Selective Venous Sampling Prompting Unilateral Oophorectomy in an Adolescent With PCOS and Markedly Elevated Testosterone.

BACKGROUND: For adolescents with suspected polycystic ovary syndrome (PCOS) and severely elevated testosterone concentrations, imaging is recommended to assess for neoplasm. Selective venous sampling (SVS) can be considered when imaging is nondiagnostic. CASE: An adolescent female treated for PCOS had a peak testosterone of 344 ng/dL (11.9 nmol/L). Imaging did not localize a mass. SVS implicated the right ovary as the source of hyperandrogenism. Following laparoscopic right oophorectomy, pathology excluded a neoplasm and confirmed PCOS. She subsequently had rapid and persistent improvement in her hyperandrogenism. SUMMARY AND CONCLUSION: Striking testosterone elevation can occur with adolescent PCOS. SVS is a tool for localizing the source of severe hyperandrogenism, yet unilaterality is not always diagnostic of a neoplasm. Unilateral oophorectomy could nonetheless be therapeutic for severe PCOS.

Considering metformin as a second-line treatment for children and adolescents with prediabetes.

Overweight and obesity affect approximately 1/3 of children in the United States and are risk factors for prediabetes and type 2 diabetes. Progression from prediabetes to diabetes carries substantial long-term health burdens, culminating in decreased life-expectancy. Earlier development of type 2 diabetes is associated with poorer prognoses, and children lose glycemic control more rapidly than adults. Metformin is approved by the USFDA for the treatment of type 2 diabetes in children, has limited toxicity, and may help prevent the development of type 2 diabetes. The more rapid disease progression in children and the safety of metformin suggests that initiation of metformin treatment to children with prediabetes who have not effectively responded to lifestyle changes may help prevent short- and long-term health damage resulting from prediabetic and diabetic dysglycemia.

Sleep Disorders in Children with Prader Willi Syndrome: Current Perspectives.

Children with Prader-Willi syndrome (PWS) face a multitude of potential health challenges including life-threatening obesity, endocrinopathies, behavioral and emotional dysregulation, developmental delays, and sleep disorders. In the current perspective piece, we provide a focused review of the condition's etiology and clinical findings, as well as a more in-depth discussion of sleep disorders frequently associated with PWS. In particular, we highlight and discuss difficult clinical scenarios frequently encountered by the pediatric sleep physician caring for this patient population, including diagnosis and treatment of complex sleep-related breathing disorders, considerations for sleep apnea surgery, the interplay between growth hormone and sleep apnea, diagnostic challenges in hypersomnia/narcolepsy, and current and emerging therapies for hypersomnia/narcolepsy. Overall, although there are many areas that need further research, sleep disorders remain a fruitful target for improving quality of life of children with PWS and their families.

Pediatric growth patterns in youth-onset type 2 diabetes mellitus: Implications for physiologically-based pharmacokinetic models.

An accurate understanding of the changes in height and weight of children with age is critical to the development of models predicting drug concentrations in children (i.e., physiologically-based pharmacokinetic models). However, curves describing the growth of a typical population of children may not accurately characterize growth of children with various conditions, such as obesity. Therefore, to develop height and weight versus age growth curves for youth who were diagnosed with type 2 diabetes, we extracted data from electronic medical records. Robust nonlinear models were parameterized to the equations describing height and weight versus age as defined by the Centers for Disease Control and Prevention (CDC). CDC z-scores were calculated using an internal program. The growth curves and z-scores were compared to CDC norms. Youth with type 2 diabetes were increasingly heavier than CDC norms from early childhood. Except for a period around puberty, youth with type 2 diabetes were, on average, shorter than CDC norms, resulting in shorter average adult height. Deviations in growth were apparent in youth who develop type 2 diabetes; such deviations may be expected for other conditions as well, and disease-specific growth curves should be considered during development of model-informed drug development for pediatric conditions.

Utilizing health information technology to improve the recognition and management of life-threatening adrenal crisis in the pediatric emergency department: medical alert identification in the 21st century.

Background Many barriers exist to the appropriate recognition and management of life-threatening adrenal crisis in the emergency department (ED). Clinical decision support (CDS) is a health information technology (IT) component that provides useful information to providers as healthcare is being delivered. We hypothesized that CDS incorporated into the electronic health record (EHR) could improve the recognition and management of adrenal crisis within the pediatric ED. Methods We retrospectively analyzed the impact of electronic CDS on the management of patients with known adrenal insufficiency (AI) presenting to two pediatric ED locations over a 19-month period with symptoms suggestive of adrenal crisis. Outcome variables assessed included the frequency of hydrocortisone (HC) administration, appropriateness of HC dosing, and timing to HC order placement and administration. Results A total of 145 encounters were reviewed. When the electronic CDS was in place at the time of the ED visit, patients were nearly 3 times as likely to receive HC (p = 0.002). Among those patients who received HC, the presence of the CDS increased the likelihood of an appropriate 50-mg/m2 dose of HC being given from 20 to 53% (p = 0.02). However, the CDS did not significantly reduce the time from ED arrival to HC order placement (p = 0.36) or administration (p = 0.59). Conclusions The use of innovative health IT strategies, such as the electronic CDS, can improve the recognition and management of adrenal crisis among patients with AI presenting to the pediatric ED.

Adherence With Multiple National Healthy Lifestyle Recommendations in a Large Pediatric Center Electronic Health Record and Reduced Risk of Obesity.

OBJECTIVE: To evaluate the utility of a routine assessment of lifestyle behaviors incorporated into the electronic health record (EHR) to quantify lifestyle practices and obesity risk at a pediatric primary care center. PATIENTS AND METHODS: Participants included 24,255 patients aged 2 to 18 years whose parent/caregiver completed a self-report lifestyle assessment during a well-child examination (January 1, 2013, through June 30, 2016). Cross-sectional analyses of age, race/ethnicity, body mass index, and lifestyle assessment responses were performed. Outcome measures included prevalence of patients meeting consensus recommendations for physical activity; screen time; and dairy, water, and fruit/vegetable consumption and the odds of obesity based on reported lifestyle behaviors. RESULTS: Prevalence of meeting recommendations for lifestyle behaviors was highest for physical activity (84%), followed by screen time (61%) and consumption of water (51%), dairy (27%), and fruits/vegetables (10%). Insufficient physical activity was the strongest predictor of obesity (odds ratio [OR], 1.65; 95% CI, 1.51-1.79), followed by excess screen time (OR, 1.36; 95% CI, 1.27-1.45). Disparities existed across ages, races/ethnicities, and sexes for multiple lifestyle habits. Youth who met 0 or 1 lifestyle recommendation were 1.45 to 1.71 times more likely to have obesity than those meeting all 5 recommendations. CONCLUSION: Healthy behaviors vary in prevalence, as does their association with obesity. This variation is partially explained by age, sex, and race/ethnicity. Meeting national recommendations for specific behaviors is negatively associated with obesity in a dose-dependent manner. These findings support the assessment of lifestyle behaviors in primary care as one component of multilevel initiatives to prevent childhood obesity.

Vague neuroglycopenic complaints camouflage diagnosis of adolescent insulinoma: a case report.

BACKGROUND: Insulinoma is a rare diagnosis in the general population with estimates of 1 in 250,000 people per year. Reports of these pancreatic islet cell tumors are even more unusual in children and adolescents. Chronic hypoglycemia due to an insulinoma often presents with neuroglycopenic symptoms that can easily be overlooked, especially in adolescents where nonspecific complaints are common. This may result in delayed diagnosis with prolonged periods of untreated hypoglycemia and associated complications. The rarity of pediatric insulinoma, vagueness of presenting symptoms, and challenge of tumor localization make insulinoma a true diagnostic quandary for clinicians. CASE PRESENTATION: In this report, we present a 15-year-old female who visited her primary care provider complaining of intermittent episodes of altered mental status including fatigue, irritability, and poor concentration. Her outpatient management included routine laboratory studies, drug screening, electroencephalogram (EEG), valproic acid initiation, CT scan of the abdomen, and endoscopic ultrasound with documentation of hypoglycemia, but otherwise inconclusive results. The patient was admitted to a tertiary children's hospital with severe refractory hypoglycemia 8 months after the initial evaluation. A serum critical sample was obtained and magnetic resonance imaging (MRI) of the abdomen performed which confirmed the presence of a pancreatic mass ultimately identified as an insulinoma. She went on to have surgical resection of her tumor resulting in complete resolution of her hypoglycemia and associated symptoms. CONCLUSION: Within this report we demonstrate the importance of being vigilant for fasting hypoglycemia secondary to insulinoma even when the patient presents with nonspecific symptoms such as fatigue, irritability, or problems with concentration. If these neuroglycopenic complaints are unnoticed or misdiagnosed, patients with a potentially curable disease are put at risk of neurologic injury, or even death, due to untreated severe hypoglycemia.

Association of HbA1c to BOLUS Scores Among Youths with Type 1 Diabetes.

BACKGROUND: Frequency of mealtime insulin bolusing (BOLUS) is a promising new objective assessment of adherence in youths with type 1 diabetes (T1D). As further confirmation of the validity of BOLUS, we compare the associations of glycated hemoglobin (HbA1c) values of T1D youths with the original scoring of BOLUS and two alternative scoring procedures: mean mealtime boluses within a 2-h meal window (2h-BOLUS) and total daily frequency of boluses (TOTAL-BOLUS). In addition, we assess HbA1c associations of these three procedures, including interaction terms for mealtime boluses plus correction boluses. SUBJECTS AND METHODS: Blood glucose meter data, insulin pump records, and HbA1c levels were collected from a combined clinical and research database for a random sample of 100 youths (mean age, 12.7 ± 4.6 years). Youths' pump records were scored using the published methodology and alternative procedures for evaluating insulin use. RESULTS: Youths' BOLUS, TOTAL-BOLUS, and mealtime boluses within a 2-h meal window (2h-BOLUS) scores are independently associated with youths' HbA1c level; all measures demonstrated stronger associations with youths' HbA1c than did frequency of glucose monitoring. The strongest association was between youths' BOLUS score and their HbA1c level. In multiple regression analyses, youths' BOLUS score better explains the variations in HbA1c levels than either youths' 2h-BOLUS or TOTAL-BOLUS scores. When combined with BOLUS in the same relationships, 2h-BOLUS and TOTAL-BOLUS were not found to have statistically significant coefficients. None of the bivariate relationships of HbA1c and interaction terms of mealtime and correction boluses was significant. CONCLUSIONS: The original method for calculating BOLUS appears superior to alternative scoring methods in its association with youths' HbA1c levels.