An update on clinical presentation and responses to therapy of patients with hereditary hypophosphatemic rickets with hypercalciuria (HHRH).

Pathogenic variants in solute carrier family 34, member 3 (SLC34A3), the gene encoding the sodium-dependent phosphate cotransporter 2c (NPT2c), cause hereditary hypophosphatemic rickets with hypercalciuria (HHRH). Here, we report a pooled analysis of clinical and laboratory records of 304 individuals from 145 kindreds, including 20 previously unreported HHRH kindreds, in which two novel SLC34A3 pathogenic variants were identified. Compound heterozygous/homozygous carriers show above 90% penetrance for kidney and bone phenotypes. The biochemical phenotype for heterozygous carriers is intermediate with decreased serum phosphate, tubular reabsorption of phosphate (TRP (%)), fibroblast growth factor 23, and intact parathyroid hormone, but increased serum 1,25-dihydroxy vitamin D, and urine calcium excretion causing idiopathic hypercalciuria in 38%, with bone phenotypes still observed in 23% of patients. Oral phosphate supplementation is the current standard of care, which typically normalizes serum phosphate. However, although in more than half of individuals this therapy achieves correction of hypophosphatemia it fails to resolve the other outcomes. The American College of Medical Genetics and Genomics score correlated with functional analysis of frequent SLC34A3 pathogenic variants in vitro and baseline disease severity. The number of mutant alleles and baseline TRP (%) were identified as predictors for kidney and bone phenotypes, baseline TRP (%) furthermore predicted response to therapy. Certain SLC34A3/NPT2c pathogenic variants can be identified with partial responses to therapy, whereas with some overlap, others present only with kidney phenotypes and a third group present only with bone phenotypes. Thus, our report highlights important novel clinical aspects of HHRH and heterozygous carriers, raises awareness to this rare group of disorders and can be a foundation for future studies urgently needed to guide therapy of HHRH.

Profiles of disordered eating behaviour in type 1 diabetes using the DEPS-R and behaviour and glycaemic outcomes in a real-life setting.

AIMS: The Diabetes Eating Problems Survey - Revised (DEPS-R) is commonly used to assess disordered eating behaviour (DEB) in individuals with type 1 diabetes and has advantages compared to other measures not specifically tailored to diabetes. A score ≥20 on the DEPS-R is used to indicate clinically significant DEB; however, it does not distinguish between eating disorder (ED) phenotypes necessary to guide treatment decisions, limiting clinical utility. METHODS: The current study used latent class analysis to identify distinct person-centred profiles of DEB in adults with type 1 diabetes using the DEPS-R. Analysis of Variance with Games Howell post-hoc comparisons was then conducted to examine the correspondence between the profiles and binge eating, insulin restriction and glycaemic control (HbA1c, mean blood glucose, and percent time spent in hyperglycaemia) during 3 days of assessment in a real-life setting. RESULTS: Latent class analysis indicated a 4-class solution, with patterns of item endorsement suggesting the following profiles: Bulimia, Binge Eating, Overeating and Low Pathology. Differences in binge eating, insulin restriction and glycaemic control were observed between profiles during 3 days of at-home assessment. The Bulimia profile was associated with highest HbA1c and 3-day mean blood glucose. CONCLUSIONS: There are common patterns of responses on the DEPS-R that appear to reflect different ED phenotypes. Profiles based on the DEPS-R corresponded with behaviour in the real-life setting as expected and were associated with different glycaemic outcomes. Results may have implications for the use of the DEPS-R in research and clinical settings.

Change in Body Mass Index in Youth in the First 5 Years After Type 1 Diabetes Mellitus Diagnosis.

OBJECTIVE: Examine body mass index (BMI) trajectories in American youth with type 1 diabetes (T1D) over the first 5 years following diagnosis. METHODS: Retrospective record review of BMI trajectories in youth with T1D diagnosed in 2015 to 2016. RESULTS: Near the time of diabetes diagnosis, 35.5% of youth had BMIs in the overweight/obesity range. These rates increased over time (P < .001), with 52.8% having overweight/obesity 5 years after diagnosis. Average age when BMI rose from healthy to overweight/obese or overweight to obese (rise group) was at 12.7 years, occurring 2.5 years after diagnosis. There were no differences between hemoglobin A1c, use of continuous glucose monitors, or use of insulin pumps between the rise group and those with healthy BMI throughout the study period. CONCLUSIONS: Alarmingly high rates of overweight/obesity in youth were observed within 5 years following T1D diagnosis. Awareness and further research are necessary to address this independent risk factor for morbidities.

Formative Development of a Weight Management Intervention for Adolescents with Type 1 Diabetes Mellitus and Obesity.

The prevalence of overweight and obesity in youth with type 1 diabetes mellitus (T1D) now exceeds that of youth without T1D. Comorbid T1D and excess adiposity are associated with multiple serious negative health outcomes. Unfortunately, youth with T1D are often excluded from and/or not referred to standard behavioral lifestyle interventions. This is often attributed to the complexities of managing T1D and an effort not to overburden persons who have T1D. Furthermore, standard behavioral weight management intervention recommendations can be perceived as contradicting T1D disease management (e.g., removing sugar-sweetened beverages from diet, energy balance with exercise, and caloric restriction). A weight management intervention specifically designed for youth with T1D is needed to provide treatment to youth with comorbid T1D and overweight/obesity. The current study interviewed adolescents with T1D and overweight/obesity (n = 12), their caregivers (n = 12), and pediatric endocrinologists (n = 9) to understand (a) whether they would be interested in a weight management intervention adapted for youth with T1D and (b) specific adaptations they would want and need. Five central themes emerged following applied thematic analysis: (1) program content, (2) programmatic messaging, (3) program structure, (4) social support, and (5) eating disorder risk. Results provide detailed recommendations for the adaptation of a behavioral weight management intervention for youth with T1D.

Increased Incidence and Severity of New Graves Disease Diagnoses in Youth During the COVID-19 Pandemic.

OBJECTIVE: Graves disease (GD), an autoimmune disease of the thyroid, is likely caused by a combination of genetic predisposition and environmental triggers. Recent data suggest that COVID-19 may be associated with the development of autoimmune disease. The aim of this study was to assess the incidence and characteristics of new GD diagnoses in youth prior to and during the COVID-19 pandemic. METHODS: We performed a retrospective chart review of all new GD diagnoses in patients aged 0 to 18 years diagnosed at a tertiary care pediatric hospital between January 1, 2018, and December 31, 2021. RESULTS: Over a 4-year period, 51 patients had been diagnosed with new-onset GD. We observed an increased incidence in new-onset GD during the pandemic compared with that in the 2 prior years (P = .01). During the pandemic period, heart rates (P = .03) as well as systolic (P = .005) and diastolic (P = .01) blood pressures were higher at initial evaluation, patients more frequently reported palpitations (P = .03) and tremors (P = .04), and an increased proportion of patients required beta-blockade treatment at diagnosis (P = .002). The percentage of patients requiring thionamide treatment and thionamide doses had been similar over time. CONCLUSION: We identified an increase in new-onset pediatric GD diagnoses during the COVID-19 pandemic. In addition, youths had increased severity of symptoms and more frequently required beta-blockade treatment at diagnosis. Further study of the relationship between COVID-19 and autoimmune thyroid disease is needed.

The Rising Incidence of Hyperinsulinemic Hypoglycemia: Connection With Maternal Health.

OBJECTIVE: Due to a perceived rise in hyperinsulinemic hypoglycemia (HH) cases over time, notably during the COVID-19 pandemic, institutional experiences between 2013 and 2021 were reviewed to evaluate trends, characteristics, and outcomes in children with HH. METHODS: Charts of all children diagnosed with HH during the study period and evaluated by Pediatric Endocrinology were reviewed. HH was defined per Pediatric Endocrine Society guidelines. Regression analysis compared rates of change in HH cases and maternal risk factors over time. RESULTS: The incidence of HH began to rise in April 2016 and became significant in March 2017 (P < .001), with a more rapid rate of rise during the first year of the COVID-19 pandemic (P < .001). Seventy-four children with HH were identified over 9 years; 43% (n = 32) were diagnosed in 2020-2021. Maternal hypertensive disorders demonstrated longitudinal association with hyperinsulinism cases (P < .001). CONCLUSION: While HH diagnoses were on the rise for much of the 9-year study period, nearly half of all infants were diagnosed during the COVID-19 pandemic in 2020 to 21. The trends in HH diagnoses correlated with maternal hypertensive disorders. More studies exploring the roles of maternal health, hypertension, and stress and development of HH in offspring are needed.

Screening and counseling for nicotine use in youth with diabetes.

OBJECTIVE: To assess current practice patterns and identify knowledge gaps among pediatric endocrinologists in the United States regarding screening and counseling for combustible tobacco and e-cigarette use in youth with diabetes. INTRODUCTION: Electronic cigarettes (e-cigarettes) are the most used tobacco product among adolescents and may be associated with an increased risk of progression to combustible cigarette smoking, cardiovascular disease, and stroke. Diabetes mellitus is a known risk factor for cardiovascular disease, and nicotine products can increase this risk. We sought to assess current practice patterns and identify knowledge gaps among pediatric endocrinologists in the United States regarding screening and counseling for combustible tobacco and e-cigarette use in youth with diabetes. RESEARCH DESIGN AND METHODS: We conducted an anonymous, online-based survey of Pediatric Endocrine Society members who provide care to youth with Type 1 or Type 2 diabetes. The survey collected information about provider demographics and smoking habits, knowledge and attitudes regarding screening and counseling for combustible tobacco and e-cigarette use, and current practice patterns. RESULTS: The survey was completed by 106 individuals of whom 64 reported providing care to youth with diabetes mellitus and ever asking about combustible tobacco or e-cigarette use. The majority of respondents were female, attending providers, and working in academic medical centers. None reported a history of formal training in e-cigarette counseling but recognized the harms of e-cigarette use. Nearly all (98%) who ever screen for nicotine use reported routinely screening for combustible tobacco use, while 18% never screen for e-cigarette use (p < 0.01). Over 80% of respondents reported feeling confident or very confident about discussing the harms of combustible tobacco, compared to 58% reporting the same confidence in discussing harms of e-cigarette use (p < 0.0001). Over 90% of respondents agreed that pediatric endocrinology providers should ask about nicotine use with over half agreeing that counseling reduces the risk of initiating nicotine product use, and 30% reported lack of change with counseling as a barrier to discussing nicotine use. Lack of visit time was the most reported barrier to discussing nicotine use. More providers cited lack of knowledge regarding e-cigarettes compared to combustible tobacco as a barrier to discussing its use. CONCLUSIONS: Pediatric endocrinology providers recognize the harms of e-cigarette use, but more frequently ask about combustible tobacco use compared to e-cigarette use. This may be related to lower reported confidence and provider knowledge in counseling about e-cigarette use. Increased utilization of existing resources and expanding opportunities for providers to learn more about e-cigarettes may increase provider confidence and comfort in screening and counseling.

Self-reported insulin pump prescribing practices in pediatric type 1 diabetes.

INTRODUCTION: Disadvantaged and minority youth with type 1 diabetes are less likely to be on insulin pump therapy compared to the majority population. Little is known about how pediatric endocrinology providers determine eligibility for insulin pump. We aimed to identify provider factors influencing the decision to initiate insulin pump therapy. METHODS: We conducted a survey of Pediatric Endocrine Society members who prescribe insulin pump therapy to pediatric patients with type 1 diabetes. The survey collected information about prescriber characteristics, use and adherence to guidelines, eligibility criteria, and objective and subjective factors that influence insulin pump prescription. RESULTS: The survey was completed by 192 individuals who met eligibility criteria (14.1% response rate). The majority of respondents were attending providers, and were white, non-Hispanic females. A minority of providers (22%) reported following written insulin pump guidelines, and many (70%) reported using personal guidelines to guide patient selection. Most providers had no objective eligibility criteria, aside from standard glucose monitoring. Providers identified patient lifestyle and increased risk of hypoglycemia, as well as patient and family factors such as motivation, realistic expectations of insulin pump use, ability to demonstrate carbohydrate counting, patient request, and ability to communicate as important in the decision to initiate insulin pump. CONCLUSION: Pediatric endocrinology providers place significant importance on subjective factors and utilize few objective criteria in determining eligibility for insulin pump. In the setting of the known disparities in insulin pump use, providers should utilize objective, consistent criteria to determine which patients are safe to initiate insulin pump.

FAMILY HISTORY OF DIABETES IS ASSOCIATED WITH INCREASED RISK OF RECURRENT DIABETIC KETOACIDOSIS IN PEDIATRIC PATIENTS.

Objective: To determine the relationship between family history of diabetes mellitus (DM) and diabetic ketoacidosis (DKA) recurrence in youth with established type 1 diabetes mellitus (T1DM). Methods: We performed a retrospective chart review of patients with DKA admitted to a pediatric hospital between January, 2009, and December, 2014. We compared patients with recurrent (≥2 admissions) and nonrecurrent DKA (1 admission) and investigated patient level factors, including family history, that may be associated with DKA recurrence in pediatric patients with established T1DM. Results: Of the 131 subjects in the study, 51 (39%) subjects were in the recurrence group. Age ≥15 years old, public health insurance, and family history of T1DM or type 2 diabetes mellitus were associated with recurrent DKA admissions in both univariable and multivariable analyses. Family history was associated with DKA recurrence, with an incidence rate ratio of 1.5 (95% confidence interval = 1.0 to 2.3; P = .03). The association was not explained by type of familial diabetes, first degree relative status, or whether the family member lived in the household. Conclusion: Recognition that a positive family history of DM may be associated with a higher risk for DKA recurrence in patients with established T1DM may allow for targeted education and focus on a previously unidentified population at increased risk for DKA. Understanding the mechanism underlying the effect of family history of diabetes on the rates of DKA in patients with established T1DM may allow for improved identification and education of patients who may be at risk for DKA recurrence. Abbreviations: CI = confidence interval; DKA = diabetic ketoacidosis; EHR = electronic health record; IBD = inflammatory bowel disease; IRR = incidence rate ratio; T1DM = type 1 diabetes mellitus; T2DM = type 2 diabetes mellitus.

PARTIAL HOSPITALIZATION: AN INTERVENTION FOR YOUTH WITH POORLY CONTROLLED DIABETES MELLITUS.

Objective: To examine the efficacy of an integrated medical/psychiatric partial hospitalization program (PHP) to improve glycemic control in youth with both diabetes mellitus and mental health disorders. Methods: This retrospective chart review is of patients admitted to a PHP between 2005-2015 with concerns about diabetes mellitus care. Clinical characteristics, laboratory data, diabetic ketoacidosis hospitalizations, and outpatient clinic visit frequency were collected from the year prior to the year after PHP admission. Results: A total of 43 individuals met inclusion criteria: 22 (51%) were female, 40 (93%) had type 1 diabetes, the mean age was 15.2 ± 2.3 years, and the mean diabetes mellitus duration was 4.6 ± 3.6 years. Of those individuals, 35 of these patients had hemoglobin A1c (HbA1c) data available at baseline, 6 months, and 1 year after PHP. The average HbA1c before PHP admission was 11.3 ± 2.3% (100.5 ± 25 mmol/mol), and decreased to 9.2 ± 1.3% (76.7 ± 14.8 mmol/mol) within 6 months of PHP admission (P<.001). The average HbA1c 1 year after PHP was 10.7 ± 1.7 % (93.3 ± 19.1 mmol/mol). Overall, 24 patients (68%) had lower HbA1c, and 75% of those with improvement maintained an HbA1c reduction of ≥1% (≥10 mmol/mol) at 1 year compared to before PHP. Conclusion: Most patients demonstrated improved glycemic control within 6 months of PHP admission, and many of those maintained a ≥1% (≥10 mmol/mol) reduction in HbA1c at 1 year following PHP admission. This program may represent a promising intervention that could serve as a model for intensive outpatient management of youth with poorly controlled diabetes mellitus. Abbreviations: ADA = American Diabetes Association; DKA = diabetic ketoacidosis; EMR = electronic medical record; HbA1c = hemoglobin A1c; ICD-9 = International Classification of Diseases, 9th revision; PHP = partial hospitalization program.

Nephrolithiasis: A complication of pediatric diabetic ketoacidosis.

OBJECTIVE: To determine the frequency of nephrolithiasis as a complication of diabetic ketoacidosis (DKA) in pediatrics. METHODS: We performed a retrospective chart review of patients with DKA admitted to a pediatric hospital between January 2009 and July 2016. We identified patients with nephrolithiasis during admission for DKA. RESULTS: We identified 395 episodes of DKA over 7.5 years. Nephrolithiasis developed as a complication of DKA in 3 of those admissions (0.8%). All three patients with nephrolithiasis were males with new onset type 1 diabetes, aged 11 to 16.5 years. They all developed symptoms of nephrolithiasis after transition to subcutaneous insulin. One patient had subsequent worsening acidosis that required an additional 24 hours of IV insulin administration. CONCLUSIONS: Nephrolithiasis is a rare complication of pediatric DKA, and should be considered in children with DKA who develop hematuria, flank pain, or suprapubic pain. Nephrolithiasis can increase insulin resistance due to increased pain and inflammation, so these patients should be monitored closely for recurrence of DKA. As patients with diabetes have increased risk of chronic kidney disease and nephrolithiasis can cause kidney injury, risk factors for nephrolithiasis should be identified and addressed to avoid subsequent kidney damage.

Pediatric Diabetic Ketoacidosis With Hyperosmolarity: Clinical Characteristics and Outcomes.

OBJECTIVE: Studies of hyperglycemic emergencies with hyperosmolality, including hyperglycemic hyperosmolar state (HHS) and "mixed presentation" with features of diabetic ketoacidosis (DKA) and HHS, are lacking in children. Objectives were to determine the incidence of DKA, HHS, and mixed presentation in a pediatric population, to characterize complications, and to assess accuracy of associated diagnosis codes. METHODS: Retrospective cohort study of 411 hyperglycemic emergencies in pediatric patients hospitalized between 2009 and 2014. Hyperglycemic emergency type was determined by biochemical criteria and compared to the associated diagnosis code. RESULTS: Hyperglycemic emergencies included: 333 DKA, 54 mixed presentation, and 3 HHS. Altered mental status occurred more frequently in hyperosmolar events ( P<.0001), and patients with hyperosmolarity had 3.7-fold greater odds of developing complications compared to those with DKA ( P = .0187). Of those with DKA, 98.5% were coded correctly. The majority (81.5%) of mixed DKA-HHS events were coded incorrectly. Events coded incorrectly had 3.1-fold greater odds of a complication ( P = .02). CONCLUSION: A mixed DKA-HHS presentation occurred in 13.8% of characterized hyperglycemic emergencies, whereas HHS remained a rare diagnosis (0.8%) in pediatrics. Hyperosmolar events had higher rates of complications. As treatment of hyperosmolarity differs from DKA, its recognition is essential for appropriate management. ABBREVIATIONS: AMS = altered mental status; DKA = diabetic ketoacidosis; EMR = electronic medical record; HHS = hyperglycemic hyperosmolar state; ICD-9 = International Classification of Diseases, Ninth Revision; ISPAD = International Society of Pediatric and Adolescent Diabetes; NODM = new-onset diabetes mellitus; T1DM = type 1 diabetes mellitus; T2DM = type 2 diabetes mellitus.