INTRODUCTION: Ultra-rare mendelian osteolytic disorders caused by different length in-frame activating duplications within exon 1 of TNFRSF11A encoding receptor activator of nuclear factor-kappa B (RANK) comprise familial expansile osteolysis (FEO), expansile skeletal hyperphosphatasia (ESH), early-onset familial Paget's disease of bone (PDB2), juvenile Paget's disease 2 (JPD2), and panostotic expansile bone disease (PEBD). FEO typically presents with childhood-onset deafness followed by resorption of permanent dentition, and then appendicular bone pain, fractures, and deformities from progressive focal expansile osteolytic lesions emerging from a background of generalized high bone turnover. An 18-bp duplication in TNFRSF11A has been reported in all kindreds with FEO, whereas a 12-bp duplication was found in the young man with PEBD complicated by a massive jaw tumor. We report the clinical course and successful treatment with bisphosphonates of a girl with the 12-bp duplication yet a skeletal phenotype seemingly milder than PEBD.

CASE PRESENTATION AND DISCUSSION: This 10-year-old girl presented for dental and orthodontic treatment and was found to have progressive external tooth root resorption. Speech delay was identified at age 18 months, and audiological evaluation showed both conductive and sensorineural hearing loss subsequently treated with a cochlear implant at age 3 years. Biochemical studies indicated increased bone turnover with elevated urinary N-telopeptide levels and serum alkaline phosphatase in the upper normal range. Low lumbar spine bone mineral density (BMD) was revealed by dual-energy X-ray absorptiometry, but whole-body Technetium-99 m bone scintigraphy was normal. Genetic testing identified the identical de novo 12-bp duplication within exon 1 of TNFRSF11A harbored by the young man with PEBD and massive jaw tumor. Bisphosphonate treatment, initiated with one dose of intravenous zoledronic acid that caused prolonged hypocalcemia, then comprised weekly oral alendronate that decreased bone turnover markers and normalized her BMD.

CONCLUSION: Constitutive activation of RANK signaling should be considered a possible cause in any young person with rapid bone turnover, particularly in the context of early-onset deafness and/or root resorption of permanent teeth. Early diagnosis and anti-resorptive treatment, given judiciously to avoid sudden and prolonged hypocalcemia, may prevent further skeletal disease.

OBJECTIVE: Determine the optimal combination of digital health intervention component settings that increase average sleep duration by ≥30 minutes per weeknight.

METHODS: Optimization trial using a 2 factorial design. The trial included 2 week run-in, 7 week intervention, and 2 week follow-up periods. Typically developing children aged 9-12y, with weeknight sleep duration <8.5 hours were enrolled (N=97). All received sleep monitoring and performance feedback. The five candidate intervention components ( ) were: 1) sleep goal ( ); 2) screen time reduction messaging ( ); 3) daily routine establishing messaging ( ); 4) child-directed loss-framed financial incentive ( ); and 5) caregiver-directed loss-framed financial incentive ( ). The primary outcome was weeknight sleep duration (hours per night). The optimization criterion was: ≥30 minutes average increase in sleep duration on weeknights.

RESULTS: Average baseline sleep duration was 7.7 hours per night. The highest ranked combination included the core intervention plus the following intervention components: sleep goal (either setting was effective), caregiver-directed loss-framed incentive, messaging to reduce screen time, and messaging to establish daily routines. This combination increased weeknight sleep duration by an average of 39.6 (95% CI: 36.0, 43.1) minutes during the intervention period and by 33.2 (95% CI: 28.9, 37.4) minutes during the follow-up period.

CONCLUSIONS: Optimal combinations of digital health intervention component settings were identified that effectively increased weeknight sleep duration. This could be a valuable remote patient monitoring approach to treat insufficient sleep in the pediatric setting.

OBJECTIVES: To evaluate the relationships between adipose tissue distribution, insulin secretion and sensitivity, sleep-disordered breathing, and inflammation in obese adolescents.

METHODS: Cross-sectional study of 56 obese adolescents who underwent anthropometric measures, dual-energy X-ray absorptiometry, overnight polysomnography, oral glucose tolerance test (OGTT) and frequently sampled intravenous glucose tolerance test. Correlation and regression analyses were used to assess relationships between adiposity, insulin secretion and sensitivity, measures of sleep-disordered breathing (oxyhemoglobin nadir, SpO; apnea hypopnea index, AHI; arousal index, AI; maximum end-tidal CO; non-REM sleep duration), and inflammation (high-sensitivity C-reactive protein, hsCRP).

RESULTS: Subjects (55% female) were mean (SD) 14.4 (2.1) years, with BMI Z-score of 2.3 (0.4). AHI was >5 in 10 (18%) subjects and 1< AHI ≤5 in 22 (39%). Visceral adipose tissue area (VAT) was positively correlated with OGTT 1 and 2 h insulin and 1 h glucose, and hsCRP (r=0.3-0.5, p≤0.007 for each). VAT was negatively correlated with sensitivity to insulin (r=-0.4, p=0.005) and SpO nadir (r=-0.3, p=0.04) but not with other sleep measures. After adjustment for BMI-Z, sex, population ancestry, age, and sleep measures, VAT remained independently associated with insulin measures and 1 h glucose, but no other measures of glycemia. SAT was not associated with measures of glycemia or insulin resistance.

CONCLUSIONS: Among adolescents with obesity, visceral adiposity was associated with insulin resistance, SpO nadir, and inflammation. The independent association of visceral adiposity with insulin resistance highlights the potential role of VAT in obesity-related chronic disease.

<p><strong>BACKGROUND: </strong>Physical activity is a major component of treatment for adolescents with obesity and prediabetes or type 2 diabetes; however, sedentary behavior remains pervasive. An SMS text message-based intervention paired with financial incentives may be an effective way to promote physical activity in this population.</p>

<p><strong>OBJECTIVE: </strong>This study aims to obtain end-user feedback on SMS text message content and assess the acceptability of a planned SMS text messaging intervention with financial incentives to motivate youth with prediabetes or type 2 diabetes to increase physical activity.</p>

<p><strong>METHODS: </strong>Adolescents with overweight or obesity and prediabetes or type 2 diabetes who attended a large academic pediatric endocrinology clinic were recruited to participate in group interviews (2-4/group) via videoconferencing. Participants were asked to share their thoughts on the use of SMS text messages and financial incentives to remind and motivate them to be more physically active. They rated and provided feedback on specific messages to be used in clinical trials. Participants were also asked about their personal experience with rewards to motivate behavior change and their anticipated reactions to rewards provided for goal attainment (gain-framing) versus those provided and then taken away if a goal was not met (loss-framing). The interviews were conducted by 2 trained interviewers and a note-taker. Content analysis was used to explore themes.</p>

<p><strong>RESULTS: </strong>Group interviews were completed with 20 participants (11/20, 55% women; 15/20, 75% with type 2 diabetes; 5/20, 25% with prediabetes) with a mean age of 15 (SD 1; range 12-18) years and a mean BMI of 41 (SD 5) kg/m (all &gt;95th percentile for age and sex). Most participants were non-Hispanic Black (14/20, 70%) and 10% (2/20) were Hispanics. Participants frequently cited near-continuous smartphone use and agreed that SMS text messages would serve as good reminders to be physically active, but the consensus about the need for short messages was strong. Favorable content included references to what they were likely to be doing when messages were sent (eg, homework or watching television) and messages that were upbeat or informative. Specific physical activity suggestions were rated favorably. Attitudes toward financial incentives varied, with differing opinions about whether loss-framed incentives would be motivating or discouraging. Many participants highlighted the role of intrinsic, rather than extrinsic, motivation in achieving and sustaining behavior change.</p>

<p><strong>CONCLUSIONS: </strong>The engagement of adolescents with obesity and diabetes or prediabetes allowed for the refinement of SMS text messages for our planned intervention, with an emphasis on short, upbeat, relatable, and informative messages. Although an SMS text messaging intervention using financial incentives to motivate youth with prediabetes or type 2 diabetes to be more physically active is theoretically acceptable, the impact on actual activity levels in this population requires prospective evaluation in a clinical trial.</p>

<p><strong>BACKGROUND: </strong>Due to high rates of comorbidities and rapid progression, youth with type 2 diabetes may benefit from early and aggressive treatment. However, until 2019, the only approved medications for this population were metformin and insulin.</p>

<p><strong>OBJECTIVE: </strong>To investigate patterns and predictors of treatment escalation within 5 years of metformin monotherapy initiation for youth with type 2 diabetes in clinical practice.</p>

<p><strong>SUBJECTS: </strong>Commercially-insured patients with incident youth-onset (10-18 years) type 2 diabetes initially treated with metformin only. METHODS: Retrospective cohort study using a patient-level medical claims database with data from 2000 - 2020. Frequency and order of treatment escalation to insulin and non-insulin antihyperglycemics were determined and categorized by age at diagnosis. Cox proportional hazards regression was used to evaluate potential predictors of treatment escalation, including age, sex, race/ethnicity, comorbidities, complications, and metformin adherence (medication possession ratio ≥0.8).</p>

<p><strong>RESULTS: </strong>The cohort included 829 (66% female; median age at diagnosis 15 years; 19% Hispanic, 17% Black) patients, with median 2.9-year follow-up after metformin initiation. One-quarter underwent treatment escalation (n=207; 88 to insulin, 164 to non-insulin antihyperglycemic). Younger patients were more likely to have insulin prescribed prior to other antihyperglycemics. Age at diagnosis (HR 1.14, 95% CI 1.07-1.21), medication adherence (HR 4.10, 95% CI 2.96-5.67), Hispanic ethnicity (HR 1.83, 95% CI 1.28-2.61), and diabetes-related complications (HR 1.78, 95% CI 1.15-2.74) were positively associated with treatment escalation.</p>

<p><strong>CONCLUSIONS: </strong>In clinical practice, treatment escalation for pediatric type 2 diabetes differs with age. Off-label use of non-insulin antihyperglycemics occurs, most commonly among older adolescents. This article is protected by copyright. All rights reserved.</p>

<p><strong>OBJECTIVES: </strong>The objective of this study was to characterize gut microbiome profiles of infants with congenital hyperinsulinism (HI) who underwent near-total or partial pancreatectomy for hypoglycemia management, as compared with healthy controls.</p>

<p><strong>METHODS: </strong>A prospective observational cohort study was performed. Subjects were infants (0-6 months) with HI who underwent removal of pancreatic tissue for management of intractable hypoglycemia from February 2017 to February 2018 at the Children's Hospital of Philadelphia. Fecal samples were collected postoperatively, on full enteral nutrition. The gut microbiome of HI subjects was analyzed and compared with age-matched samples from healthy infants.</p>

<p><strong>RESULTS: </strong>Seven subjects with ≥50% pancreatectomy and 6 with &lt;50% pancreatectomy were included. α (within-sample) diversity was lowest among infants with ≥50% pancreatectomy (richness: false discovery rate, 0.003; Shannon index: false discovery rate, 0.01). β (between-sample) diversity (Bray-Curtis dissimilarity, P = 0.02; Jaccard distance, P = 0.001) differed across groups (≥ or &lt;50% pancreatectomy, controls). Bifidobacteria and Klebsiella species were least abundant among infants with ≥50% pancreatectomy but did not differ between infants with &lt;50% pancreatectomy and historical controls.</p>

<p><strong>CONCLUSIONS: </strong>Infants with HI who underwent ≥50% pancreatectomy differed from age-matched infants in gut microbiome profile, whereas those with &lt;50% pancreatectomy more closely resembled control profiles. The durability of this difference should be investigated.</p>

<p><strong>BACKGROUND: </strong>Risk-based screening for type 2 diabetes (T2D) in youth with overweight/obesity is recommended, but rates remain low in practice. Identification of factors impacting provider ordering and patient completion of testing may guide strategies to improve screening.</p>

<p><strong>OBJECTIVE: </strong>To evaluate predictors of hemoglobin A1c (A1c)-based T2D screening in pediatric primary care.</p>

<p><strong>METHODS: </strong>This retrospective cohort study included 10 to 18 year-old patients with overweight/obesity (body mass index [BMI] Z-score ≥1.04) followed in a large academic-affiliated pediatric primary care network, 2009 to 2018. Percentages of patients with ordered and completed A1c were determined, and multivariable Cox proportional hazards regression was used to evaluate independent predictors of screening.</p>

<p><strong>RESULTS: </strong>34 927 (48.0% female; 52.5% with BMI Z-score ≥1.64) youth followed for a median of 3.0 years were included. 21% (7457) of patients had screening ordered and 14% (4966) completed screening during follow-up. In multivariable regression, after controlling for race/ethnicity, BMI, family history of diabetes and age, males were significantly less likely to have ordered screening, but were equally or more likely to complete screening if ordered.</p>

<p><strong>CONCLUSIONS: </strong>Male adolescents were less likely to undergo A1c-based T2D screening due to differential ordering practices. The source of this differential practice should be pursued to avoid under-recognition of cardiometabolic risk in at-risk male youth.</p>

<p><strong>BACKGROUND: </strong>Prediabetes awareness in adults has been associated with improved weight management. Whether youth with prediabetes diagnosis experience similar improvements is unknown.</p>

<p><strong>OBJECTIVE: </strong>To investigate the association between prediabetes identification and body mass index trajectory in overweight and obese adolescents.</p>

<p><strong>SUBJECTS: </strong>Youth who were followed longitudinally in a large academic-affiliated primary care network and who were overweight/obese while 10-18 years old.</p>

<p><strong>METHODS: </strong>Retrospective cohort study. Subjects were categorized as "screened" if at least 1 hemoglobin A1c (HbA1c) result was available. Time series analysis was used to determine the difference in difference (DID) in body mass index Z-score (BMI-Z) slope before and after HbA1c between: 1) screened youth found to have prediabetes-range HbA1c (5.7-6.4%, 39-46 mmol/mol) versus normal HbA1c, and 2) screened versus age-matched unscreened obese youth.</p>

<p><strong>RESULTS: </strong>4,184 (55.6% female) screened subjects (median follow-up 9.7 years) were included. 637 (15.2%) had prediabetes-range HbA1c. Prediabetes was associated with a greater decrease in BMI-Z slope than normal HbA1c (DID: -0.023/year [95% CI: -0.042 to -0.004]). When compared to age-matched unscreened subjects (n=2,087), screened subjects (n=2,815) experienced a greater decrease in BMI-Z slope after HbA1c than unscreened subjects at a matched age (DID: -0.031/y [95% CI -0.042 to -0.021]).</p>

<p><strong>CONCLUSIONS: </strong>BMI-Z trajectory improved more among youth with prediabetes-range HbA1c but also stabilized in screened youth overall. Prospective studies are needed to identify provider- and patient-level drivers of this observation. This article is protected by copyright. All rights reserved.</p>

<p>Feeding problems are frequent in infants with congenital hyperinsulinism (HI) and may be exacerbated by continuous enteral nutrition (EN) used to maintain euglycemia. Our center's HI team uses dextrose solution given continuously via gastric tube (intrasgastric dextrose, IGD) for infants not fully responsive to conventional medical therapy or pancreatectomy. Here, we describe our practice as well as growth, feeding, and adverse events in infants with HI exposed to IGD.</p>

<p><strong>METHODS: </strong>This was a retrospective cohort of infants with HI treated with IGD from 2009-2017. Primary outcomes were weight-for-length and body mass index Z-scores (WFL-Z and BMI-Z) in the year following IGD initiation. Secondary outcomes included EN use and adverse events. We used multivariable regression to assess covariates of interest.</p>

<p><strong>RESULTS: </strong>We studied 32 subjects (13 female) with a median age at IGD initiation of 73 days (range 17-367); median follow-up was 11.2 months (range 5.0-14.2). WFL-Z did not change significantly over time (p &gt; 0.05). EN use decreased significantly over time, i.e., at 0 months: 72% (95% CI 53-85) vs. at 12 months 39% (95% CI 22-59). No potential adverse events led to discontinuation of IGD.</p>

<p><strong>CONCLUSIONS: </strong>Over a median follow-up of nearly 1 year, IGD was well-tolerated, with no change in WFL-Z or BMI-Z from baseline.</p>

<p><strong>PURPOSE OF REVIEW: </strong>Because the incidence of type 2 diabetes and prediabetes in children is rising, routine screening of those at risk is recommended. In 2010, the ADA made the recommendation to include hemoglobin A1c (HbA1c) as a diagnostic test for diabetes, in addition to the oral glucose tolerance test or fasting plasma glucose. Our objective was to assess the pediatric literature with regard to HbA1c test performance and discuss advantages and disadvantages of use of the test for diagnostic purposes.</p>

<p><strong>RECENT FINDINGS: </strong>HbA1c has a number of advantages, including elimination of the need for fasting, lower variability, assay standardization, and long-term association with future development of diabetes. It also has many drawbacks. It can be affected by a number of non-glycemic factors, including red blood cell turnover, hemoglobinopathies, medications, race, and age. In particular, it performs differently in children compared with adults, generally with lower sensitivity for prediabetes (as low as 0-5% in children vs 23-27% in adults) and lower area under the receiver operating characteristic curve (AUC) (0.53 vs 0.73 for prediabetes), and it has lower efficacy at a higher cost, compared with other tests of glycemia. Finally, HbA1c may perform very differently across diverse populations according to race/ethnicity; in Chinese populations, the proportion of individuals classified with prediabetes based on HbA1c predominates compared with IFG (77% for HbA1c vs 27.7% for IFG), whereas in US populations, it is the opposite (24.8% for HbA1c vs 80.1% for FPG). HbA1c is controversial because although it is convenient, it is not a true measure of glycemia. The interpretation of HbA1c results requires a nuanced understanding that many primary care physicians who are ordering the test in greater numbers do not possess. Alternative markers of glycemia may hold promise for the future but are not yet endorsed for use in practice. Further studies are needed to determine appropriate thresholds for screening tests and the long-term impact of screening and identification.</p>