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Context The Kabi/Pfizer International Growth Database (KIGS) is a large, international database (1987-2012) of children treated with recombinant human growth hormone (rhGH) in real-world settings. Objective This work aimed to evaluate the safety and efficacy of rhGH from the full KIGS cohort. Methods Data were collected by investigators from children with growth disorders treated with rhGH (Genotropin [somatropin]; Pfizer). Safety was evaluated in all treated patients, and efficacy in those treated for 1 year or more. A subgroup included patients treated for 5 years or more (≥ 2 years prepubertal) who had reached near-adult height (NAH). Main outcomes included adverse events (AEs), serious AEs (SAEs), and height growth. Results The full KIGS cohort (N = 83 803 [58% male]) was treated for idiopathic GH deficiency (IGHD; 46.9%), organic GHD (10.0%), small for gestational age (SGA; 9.5%), Turner syndrome (TS; 9.2%), idiopathic short stature (ISS; 8.2%), and others (16.2%). Median rhGH treatment duration was 2.7 years and observation 3.1 years. SAEs occurred in 3.7% of patients and death in 0.4%. The most common SAEs were recurrence of craniopharyngioma (n = 151), neoplasm (n = 99), and cancer (n = 91); and scoliosis (n = 91). Median first-year delta height-SD score (SDS) (Prader) in prepubertal patients was 0.66 (IGHD), 0.55 (ISS), 0.58 (TS), and 0.71 (SGA). Median gains in NAH-SDS were 1.79 (IGHD), 1.37 (ISS), and 1.34 (SGA) for boys, and 2.07 (IGHD), 1.62 (ISS), 1.07 (TS), and 1.57 (SGA) for girls. Conclusion Data from KIGS, the largest and longest running international database of rhGH-treated children, show that rhGH is safe and increases short-term height gain and adult height across GHD and non-GHD conditions.

Context Prenatal exposures, including undernutrition, overnutrition, and parental diabetes, are recognized risk factors for future cardiometabolic disease. There are currently no data on effects of parental diabetes on disease progression or complications in youth-onset type 2 diabetes (T2D). Objective We analyzed effects of parental diabetes history on glycemic outcomes, β-cell function, and complications in a US cohort of youth-onset T2D. Methods Participants (N = 699) aged 10 to 17 years with T2D were enrolled at 15 US centers and followed for up to 12 years as part of the TODAY (Treatment Options for type 2 Diabetes in Adolescents and Youth) and TODAY2 follow-up studies. Information about diabetes diagnosis in biological mothers was available for 621 participants (never = 301; before or during pregnancy = 218; after pregnancy = 102) and in biological fathers for 519 (no diabetes = 352; paternal diabetes = 167). Results Maternal, but not paternal, diabetes was associated with loss of glycemic control over time, defined as glycated hemoglobin A1c greater than or equal to 8% for more than 6 months (P = .001). Similarly, maternal, but not paternal, diabetes was associated with increased risk of glomerular hyperfiltration (P = .01) and low heart rate variability (P = .006) after 12 years of follow-up. Effects were largely independent of age, sex, race/ethnicity, and household income. Maternal diabetes during vs after pregnancy had similar effects on outcomes. Conclusion Maternal diabetes, regardless of whether diagnosed during vs after pregnancy, is associated with worse glycemic control, glomerular hyperfiltration, and reduced heart rate variability in youth with T2D in TODAY. The strong associations of diabetes outcomes with maternal diabetes suggest a possible role for in utero programming.

Background Congenital adrenal hyperplasia (CAH) is a group of genetic disorders that affects the adrenal glands and is the most common cause of primary adrenal insufficiency in children. In the past few decades, magnetic resonance imaging (MRI) has been implemented to investigate how the brain may be affected by CAH. A systematic review was conducted to evaluate and synthesize the reported evidence of brain findings related to CAH using structural, functional, and diffusion-weighted MRI. Methods We searched bibliographical databases through July 2021 for brain MRI studies in individuals with CAH. Results Twenty-eight studies were identified, including 13 case reports or series, 10 studies that recruited and studied CAH patients vs unaffected controls, and 5 studies without a matched control group. Eleven studies used structural MRI to identify structural abnormalities or quantify brain volumes, whereas 3 studies implemented functional MRI to investigate brain activity, and 3 reported diffusion MRI findings to assess white matter microstructure. Some commonly reported findings across studies included cortical atrophy and differences in gray matter volumes, as well as white matter hyperintensities, altered white matter microstructure, and distinct patterns of emotion and reward-related brain activity. Conclusions These findings suggest differences in brain structure and function in patients with CAH. Limitations of these studies highlight the need for CAH neuroimaging studies to incorporate larger sample sizes and follow best study design and MRI analytic practices, as well as clarify potential neurologic effects seen across the lifespan and in relation to clinical and behavioral CAH phenotypes.

Background The association between gut dysfunction and body fat composition in youth living with perinatal human immunodeficiency virus infection (YPHIV) has not been investigated. Methods We included YPHIV aged 7–19 years from the Pediatric HIV/AIDS Cohort Study Adolescent Master Protocol with plasma available within 6 months of baseline whole-body dual energy x-ray absorptiometry (DXA) and HIV RNA ≤1000 copies/mL within 3 months of baseline DXA and a second DXA 2 years later. Plasma markers of bacterial translocation and gut barrier dysfunction (lipopolysaccharide binding protein [LBP], zonulin, and intestinal fatty acid binding protein [I-FABP]) were measured at baseline by enzyme-linked immunosorbent assay and log10 transformed. Adiposity outcomes included percentage total body, truncal, and extremity fat in kilograms from DXA. Linear regression models were fit using generalized estimating equations to assess associations of baseline gut markers (log10) on adiposity outcomes at baseline and 2 years, adjusted for demographic variables, current antiretroviral therapy exposure, and physical activity. Results Two hundred sixty-one youth were included; 128 had a second DXA. Median age at first DXA was 12 years (interquartile range, 10–14 years), 49% were female, and 69% were Black. After adjustment for potential confounders, log10 LBP was positively associated with percentage total body fat at baseline (β = 4.08, P Conclusions Despite viral suppression, gut damage and the resultant bacterial translocation are associated with body composition measures in YPHIV.

Background: Few weight management interventions target young children with obesity from low-income minority families. Objective: To conduct a nonrandomized, pragmatic, pilot study of an adapted, ev...

Context Congenital adrenal hyperplasia (CAH) is a genetic disorder that results in hormonal imbalances and decreased brain volumes in regions important for emotional processing. Objective To examine whether emotion perception differs between youth with CAH and control youth, and if these differences relate to brain volumes. Methods In this cross-sectional study of 27 youths with CAH (mean age = 12.63 years, 16 female) and 35 age- and sex-matched controls (mean age = 13.03 years, 20 female), each participant rated picture stimuli and completed a 3T structural brain scan. Valence and arousal ratings and reaction times of 61 affective images were assessed. Gray matter volumes were measured by MRI. Results Youth with CAH had lower valence ratings for negative (P = .007) and neutral (P = .019) images. Controls showed differences in reaction times and arousal ratings across stimuli conditions, but youth with CAH did not. Brain volumes of the right amygdala (P = .025) and left hippocampus (P = .002) were associated with valence ratings. Left rostral middle frontal (P < .001) and right medial orbitofrontal cortex (P = .002) volumes were negatively related to valence scores only in youth with CAH, whereas left medial orbitofrontal cortex (P < .001) volumes were associated with valence scores positively in youth with CAH and negatively in controls. Conclusion Findings suggest that youth with CAH perceive emotive stimuli as more unpleasant. Decreased brain volumes in the amygdala, hippocampus, and prefrontal cortex are associated with these measures of altered emotion perception in youth with CAH.

Introduction: Patients with classical congenital adrenal hyperplasia (CAH) have prenatal and postnatal hormonal imbalances. To characterize the ontogeny of reported brain and behavior changes in older children with CAH, we aimed to study brain structure in infants with CAH compared to healthy controls. Methods: We performed neuroimaging in 16 infants with classical CAH due to 21-hydroxylase deficiency [8 males, gestational age 38.2 ± 1.7 weeks, post-conceptional age (PCA) 42.2 ± 3.0 weeks] and 14 control infants (9 males, gestational age 38.5 ± 1.8 weeks, PCA 42.5 ± 2.4 weeks) utilizing 3-Tesla magnetic resonance imaging. Regional brain volumes were adjusted for PCA and sex, along with an additional adjustment for total brain volume (TBV), for group comparisons by regression analyses [mean, 95% confidence interval (CI)]. The degree to which each brain region was differentiated between CAH and control infants was examined by relaimpo analyses, adjusting for all other brain regions, PCA, and sex. Results: Infants with CAH had significantly smaller thalamic volumes [8606 mm3, 95% CI (8209, 9002)] compared to age-matched control infants [9215 mm3, 95% CI (8783, 9647); β = -609; p = 0.02], which remained smaller after further adjustment for TBV. Upon further adjustment for TBV, the temporal lobe was larger in infants with CAH [66817 mm3, CI (65957, 67677)] compared to controls [65616 mm3, CI (64680, 66551); β = 1202, p = 0.03]. The brain regions most differentiated between CAH vs controls were the thalamus (22%) and parietal lobe (10%). Conclusions: Infants with CAH exhibit smaller thalamic regions from early life, suggesting a prenatal influence on brain development in CAH. Thalamic emergence at 8-14 weeks makes the region particularly vulnerable to changes in the intrauterine environment, with potential implications for later maturing brain regions. These changes may take time to manifest, meriting longitudinal study through adolescence in CAH.

Infants and toddlers with classical congenital adrenal hyperplasia (CAH) are at high risk for morbidity/mortality arising from life-threatening adrenal crisis. Management of acute illnesses in CAH requires an understanding of factors leading to emergency department (ED) visits and hospitalizations in the first few years of life. We, therefore, examined adrenal crisis at pre-hospital and ED stages of illness in young children with CAH as they related to medical outcomes.Retrospective cohort study of 39 children with CAH due to 21-hydroxylase deficiency (0-4 years of age) and 27 age-matched controls.ED visit, acute illness symptoms (fever, vomiting, diarrhea) and other characteristics (hospitalizations, administration of stress-dose hydrocortisone, electrolyte abnormalities).CAH infants and toddlers had significantly higher rates of ED visits [0.50 (0.25-0.88) per person-year] than controls [0 (0-0) per person-year; P0.001]. Moreover, CAH children under 6 months old had significantly higher rates of ED visits compared to older ages. Only 50% (51/102) of illness-related ED visits in CAH children were preceded by administration of either oral (46/51) or intramuscular (11/51) stress-dosing by parents. 10.8% of ED visits resulted in hospital admission. Controlling for age and 17-hydroxyprogesterone at diagnosis, electrolyte abnormalities and administration of parenteral hydrocortisone in the ED significantly predicted hospital admission. Receiving a hydrocortisone injection prior to the ED was a significant predictor for having electrolyte abnormalities.Infants and toddlers with classical CAH are at high risk for acute illness and hospitalizations and often do not receive adequate stress-dosing prior to the ED. This article is protected by copyright. All rights reserved.

With the rapidly increasing incidence of type 2 diabetes mellitus (T2DM) in youth (as in adults), it is critical to recognize phenotypic markers that can help predict and potentially prevent its onset, and reduce the associated burden of the disease for patients, families, and society. In this review, we summarize the most recent literature characterizing growth, puberty, and body composition in youth at risk for or who have T2DM.There is an inverse, nonlinear relationship between birth weight and future risk of developing T2DM. Height seems to have an inverse correlation with risk for diabetes. Earlier onset of puberty in males and females is associated with the T2DM phenotype. While adiposity is a known correlate of T2DM, visceral adiposity as represented by waist circumference has emerged as one of the key determinants of T2DM in population-based studies globally. Thresholds for body mass index vary across ethnicities in predicting risk for T2DM, depending on genetic factors and fat-distribution profiles.Emerging links between T2DM and dysregulated parameters of growth and development highlight the importance of early recognition of modifiable risk factors and the creation of individualized screening protocols.http://links.lww.com/COE/A31.

The aim of this study was to compare long-term growth between HIV-exposed uninfected children (CHEU) born to women with perinatally acquired HIV (CHEU-PHIV) and CHEU born to women with nonperinatally acquired HIV (CHEU-NPHIV).A longitudinal analysis of anthropometric measurements from a U.S.-based multisite prospective cohort study enrolling CHEU and their mothers since April 2007.CHEU were evaluated for growth annually from birth through age 5 and again at age 7 years. Z-scores were calculated using U.S. growth references for weight (WTZ), height (HTZ), and weight-for-length or BMI-for-age (WLZ/BMIZ). Mid-upper arm circumference (MUACZ) and triceps skinfold thickness (TSFZ) Z-scores were obtained from ages 1 and 2, respectively, through age 7 years. Piecewise mixed-effects models, overall and stratified by race and sex, were fit to assess differential growth patterns across age by maternal PHIV status.One thousand four hundred fifty-four singleton infants (286 CHEU-PHIV and 1168 CHEU-NPHIV) were included. CHEU-PHIV had slower growth rates than CHEU-NPHIV for WTZ and WLZ/BMIZ at earlier ages and continued to have lower mean WTZ [-0.27, 95% confidence interval (95% CI): -0.50, -0.04] and WLZ/BMIZ (-0.39, 95% CI: -0.67, -0.11) through age 7. Among non-Black boys, CHEU-PHIV had slightly lower WTZ and WLZ/BMIZ at birth than CHEU-NPHIV and these growth deficits persisted through age 7 years.Compared with CHEU-NPHIV, CHEU-PHIV had diminished growth in early childhood with differences most pronounced among non-Black male children. Further longitudinal follow-up of CHEU-PHIV into young adulthood is needed to understand whether these early effects of maternal PHIV status on growth persist and have other health consequences.

Background The role of obesity on long-term metabolic complications remains poorly understood in youth living with perinatally-acquired HIV (YPHIV). Methods The PHACS Adolescent Master Protocol (AMP) study enrolled YPHIV from 2007-2009 across 15 U.S. sites, including Puerto Rico. We included YPHIV aged 7-19 yr with body composition data assessed by whole-body dual energy x-ray absorptiometry (DXA) at baseline and 2 years later. Metabolic outcomes included homeostatic assessment of insulin resistance (HOMA-IR) and non-high-density lipoprotein cholesterol (non-HDL-C). We fit linear regression models using generalized estimating equations to assess the association of % change in body and trunk fat over 2 yr with metabolic outcomes at years 2 and 3, adjusted for potential confounders (age, race: Black vs. non-Black, Tanner stage, sex, family history, CD4, viral load, and ART). Results 232 participants had a second DXA and either HOMA-IR or non-HDL-C measured at year 2. Participant characteristics at the first DXA were: median (Q1, Q3) age 12 yr (9, 14) 70% Black, CD4 count 714 cells/mm3; 70% with HIV RNA < 400 copies/mL; 72% on protease inhibitor-, 25% on non-nucleoside reserve transcriptase inhibitor-, and 3% on integrase strand transfer inhibitor-based ART. The median % increase from baseline in total body and trunk fat percentage at 2 yr was 5.41% and 4.47%, respectively. The figure shows distributions of HOMA-IR and non-HDL-C. In both unadjusted and adjusted analyses (Table), for every 1% increase in total body fat percentage from baseline to 2 years, we observed a 0.002 (95%CI -0.0, 0.005) higher log10 HOMA-IR at year 3, which equals ∼ a 0.5% higher HOMA-IR. For every 1% increase in total body and trunk fat percentage over 2 years, non-HDL-C (mg/dL) was 0.19 (95%CI 0.03, 0.35) higher and 0.65 (95%CI 0.12, 1.19) higher, respectively, in unadjusted models. Results were similar but slightly attenuated when we additionally adjusted for confounders including ART. Figure:HOMA-IR and non-HDL cholesterol at baseline, year 2, and year 3Table:Unadjusted and adjusted models assessing the association of percent change in body fat and trunk fat percentage with metabolic outcomes ¹Adjusted for age (years), sex (male vs female), race (Black vs non-Black), Tanner stage (2, 3, 4-5 vs 1), family history of diabetes or cardiovascular disease (yes, not known vs no), CD4 (≤350 vs >350 cells/mm³), and viral load (≥400 vs ²Adjusted for age (years), sex (male vs female), race (Black vs non-Black), Tanner stage (2, 3, 4-5 vs 1), family history of diabetes or cardiovascular disease (yes, not known vs no), CD4 (≤350 vs >350 cells/mm³), viral load (≥400 vs Conclusion Increases in adiposity over time may lead to downstream decreased insulin sensitivity and dyslipidemia in YPHIV. This is clinically significant, as even small increases in HOMA-IR have been associated with all-cause mortality in non-diabetic HIV-uninfected adults. Long-term follow-up is warranted. Disclosures Mitchell E. Geffner, MD, Adrenas: Advisor/Consultant|Adrenas: Honoraria|Ascendis: Advisor/Consultant|Ascendis: Honoraria|Aventria: Honoraria|Eton: Advisor/Consultant|Eton: Honoraria|ICON Clinical Research, LLC/Aeterna Zentaris: Advisor/Consultant|ICON Clinical Research, LLC/Aeterna Zentaris: Honoraria|McGraw-Hill: Royalties|Neurocrine Biosciences: Grant/Research Support|Novo Nordisk: Grant/Research Support|Nutritional Growth Solutions Ltd: Advisor/Consultant|Nutritional Growth Solutions Ltd: Honoraria|Pfizer, Inc.: Advisor/Consultant|Pfizer, Inc.: Honoraria|Spruce Biosciences: Grant/Research Support|UpToDate: Royalties Grace A. McComsey, MD, Gilead, Merck, ViiV, Janssen, Theratechnologies: Advisor/Consultant.

Background Few data exist on early-life metabolic perturbations in newborns with perinatal HIV and antiretroviral (ARV) exposure but uninfected (HEU) compared to those perinatally HIV unexposed and uninfected (HUU). Methods We enrolled pregnant persons with HIV (PWH) receiving tenofovir (TDF)/emtricitabine or lamivudine (XTC) plus dolutegravir (DTG) or efavirenz (EFV), and pregnant individuals without HIV, as well as their liveborn infants. Newborns were randomized to receive either zidovudine (AZT) or nevirapine (NVP) postnatal prophylaxis. Preprandial homeostasis model assessment for insulin resistance (HOMA-IR) was assessed at birth and 1 month. Linear mixed models were fit to assess the association between in utero HIV/ARV exposure and average HOMA-IR from birth to 1 month, adjusting for confounders. Results Of 450 newborns, 306 were HEU. HOMA-IR was higher in newborns HEU versus HUU after adjusting for confounders (mean difference of 0.068 in log HOMA-IR, P = .037). Among newborns HEU, HOMA-IR was not significantly different between TDF/XTC/DTG versus TDF/XTC/EFV in utero ARV exposure and between AZT versus NVP newborn postnatal prophylaxis arms. Conclusions Newborns HEU versus HUU had lower insulin sensitivity at birth and at 1 month of life, raising potential concern for obesity and other metabolic perturbations later in life for newborns HEU. Clinical Trials Registration NCT03088410.

BACKGROUND Early-life metabolic derangements in HIV-exposed uninfected (HEU) infants have been reported. METHODS Pregnant women with HIV and HIV-uninfected pregnant women were enrolled with their newborns in a US cohort from 2011 to 2015. We measured cord insulin, C-peptide, and metabolic cytokines of HEU and HIV-unexposed uninfected (HUU) newborns using ELISA and metabolites, lipid subspecies, and eicosanoids via liquid chromatography/mass spectrometry. Linear regression was employed to assess the association of intrauterine HIV/ART with insulin and C-peptide. Graphical lasso regression was used to identify differences between metabolite/lipid subspecies networks associated with C-peptide. RESULTS Of 118 infants, 56 were HEU, ART exposed. In adjusted analyses, mean cord insulin (β = 0.295, p = 0.03) and C-peptide (β = 0.522, p

Context Gray matter morphology in the prefrontal cortex and subcortical regions, including the hippocampus and amygdala, are affected in youth with classical congenital adrenal hyperplasia (CAH). It remains unclear if white matter connecting these aforementioned brain regions is compromised in youth with CAH. Objective To examine brain white matter microstructure in youth with CAH compared to controls. Design A cross-sectional sample of 23 youths with CAH due to 21-hydroxylase deficiency (12.9 ± 3.5 year; 61% female) and 33 healthy controls (13.1 ± 2.8 year; 61% female) with 3T multishell diffusion-weighted magnetic resonance brain scans. Main Outcome Measures Complementary modeling approaches, including diffusion tensor imaging (DTI) and neurite orientation dispersion and density imaging (NODDI), to examine in vivo white matter microstructure in six white matter tracts that innervate the prefrontal and subcortical regions. Results DTI showed CAH youth had lower fractional anisotropy in both the fornix and stria terminalis and higher mean diffusivity in the fornix compared to controls. NODDI modeling revealed that CAH youth have a significantly higher orientation dispersion index in the stria terminalis compared to controls. White matter microstructural integrity was associated with smaller hippocampal and amygdala volumes in CAH youth. Conclusions These patterns of microstructure reflect less restricted water diffusion likely due to less coherency in oriented microstructure. These results suggest that white matter microstructural integrity in the fornix and stria terminalis is compromised and may be an additional related brain phenotype alongside affected hippocampus and amygdala neurocircuitry in individuals with CAH.

The Treatment Options for type 2 Diabetes in Adolescents and Youth (TODAY) trial examined the effects of three treatment arms in a group of racially and ethnically diverse adolescents and youth with type 2 diabetes mellitus. TODAY2 was an observational follow-up study reporting outcomes and complications in these participants after having diabetes for approximately 13 years. Participant retention was essential to fulfill this objective. This report describes motivations and problems participants self-reported related to continuing in this study.The TODAY2 retention survey was administered to participants, mean age 27 years, 36% non-Hispanic Black, 18% non-Hispanic white, 39% Hispanic, 52% public and 35% private healthcare coverage, who completed the last study visit (63.8% of original TODAY cohort). The survey listed potential benefits and barriers to staying in the trial. Participants indicated agreement or disagreement with each statement using a four point Likert-type scale.More than 93% of survey responders agreed with benefits listed for staying in TODAY2. The most cited reason for staying in the study was related to the strong relationship that participants had with study staff. The common barriers to attending trial visits were: tending to other medical problems, fear of disappointing study staff, and school/work scheduling conflicts. Participants with public healthcare coverage were more likely to endorse benefits related to diabetes care (e.g. getting latest test results, staying motivated to care for my diabetes) and monetary compensation, whereas participants with poor glycemic control cited that a barrier to attending study visits was "fear of disappointing" study staff.In a racially and ethnically diverse population of youth-onset type 2 diabetes, benefits and barriers associated with long-term retention are described. These findings can be used to help inform future retention strategies for young adults in clinical trials.

Introduction: In the randomized “Toddler Turner” study, girls who received growth hormone (GH) starting at ages 9 months to 4 years (early-treated [ET] group) had marked catch-up growth and were 1.6 ± 0.6 SD taller than untreated (early-untreated [EUT]) control girls after 2 years. However, whether the early catch-up growth would result in greater near-adult height (NAH) was unknown. Therefore, this extension study examined the long-term effects of toddler-age GH treatment on height, pubertal development, and safety parameters. Methods: Toddler Turner study participants were invited to enroll in a 10-year observational extension study for annual assessments of growth, pubertal status, and safety during long-term GH treatment to NAH for both ET and EUT groups. Results: The ET group was taller than the EUT group at all time points from preschool to maturity and was significantly taller at the onset of puberty (p = 0.016), however, the difference was not significant at NAH. For the full cohort (ET + EUT combined, n = 50) mean (± SD) NAH was 151.2 ± 7.1 cm at age 15.0 ± 1.3 years. NAH standard deviation score (SDS) was within the normal range (>−2.0) for 76% of ET and 60% of EUT subjects (68% overall) and correlated strongly with height SDS at GH start (r = 0.78; p < 0.01), which in turn had a modest inverse correlation with age at GH start (i.e., height SDS declined with increasing age in untreated girls [r = −0.30; p = 0.016]). No new safety concerns arose. Conclusion: Although the ET group was taller throughout, height SDS at NAH was not significantly different between groups due to catch-down growth of ET girls during lapses in GH treatment after the Toddler study and similar long-term GH exposure overall. Early initiation of GH by age 6 years, followed by uninterrupted treatment during childhood, can prevent ongoing growth failure and enable attainment of height within the normal range during childhood, adolescence, and adulthood.

Mitochondrial dysfunction (MD) is linked to cardiometabolic complications, such as obesity and insulin resistance (IR), the frequencies of which are higher in adults living with HIV infection and receiving combination antiretroviral therapies (ARV). ARV-treated youth living with perinatally acquired HIV infection (YLPHIV) may be especially susceptible to IR due to long-term exposure to both factors. Medical histories, fasting blood chemistry panels, and mitochondrial function in banked peripheral blood mononuclear cells (PBMCs) were assessed in eligible YLPHIV from the Pediatric HIV/AIDS Cohort Study (PHACS)/Adolescent Master Protocol (AMP) Mitochondrial Determinants Component cohort, stratified by Homeostatic Model Assessment of IR (HOMA-IR) score: case (score ≥4, n = 39) or control (score

Adrenal insufficiency (AI) remains a significant cause of morbidity and mortality in children with 1 in 200 episodes of adrenal crisis resulting in death. The goal of this working group of the Pediatric Endocrine Society Drug and Therapeutics Committee was to raise awareness on the importance of early recognition of AI, to advocate for the availability of hydrocortisone sodium succinate (HSS) on emergency medical service (EMS) ambulances or allow EMS personnel to administer patient's HSS home supply to avoid delay in administration of life-saving stress dosing, and to provide guidance on the emergency management of children in adrenal crisis. Currently, hydrocortisone, or an equivalent synthetic glucocorticoid, is not available on most ambulances for emergency stress dose administration by EMS personnel to a child in adrenal crisis. At the same time, many States have regulations preventing the use of patient's home HSS supply to be used to treat acute adrenal crisis. In children with known AI, parents and care providers must be made familiar with the administration of maintenance and stress dose glucocorticoid therapy to prevent adrenal crises. Patients with known AI and their families should be provided an Adrenal Insufficiency Action Plan, including stress hydrocortisone dose (both oral and intramuscular/intravenous) to be provided immediately to EMS providers and triage personnel in urgent care and emergency departments. Advocacy efforts to increase the availability of stress dose HSS during EMS transport care and add HSS to weight-based dosing tapes are highly encouraged.

Introduction: Youth with classical congenital adrenal hyperplasia (CAH) have higher prevalence of cardiometabolic risk factors such as obesity, abdominal adiposity, and hypertension. Patients with CAH also exhibit an earlier adiposity rebound (AR) compared to normative populations. However, the predictive relationship between AR and cardiometabolic risk factors needs to be better understood. Methods: We performed a retrospective cohort study at a US tertiary pediatric center in youth with classical CAH due to 21-hydroxylase deficiency. AR was determined by cubic polynomial modeling. A subset of participants had fasting analytes, whole-body dual-energy X-ray absorptiometry, and magnetic resonance imaging as adolescents. Results: In 42 youth with CAH (45.2% female, 54.8% Hispanic, and 90.5% salt-wasting form), the average age at AR was 3.4 ± 1.3 years. AR differed by BMI-z, with youth with obesity having an earlier AR (2.8 ± 1.0 years) compared to lean youth (4.1 ± 1.3 years, p = 0.001). However, AR did not differ by either CAH form or sex. Earlier AR predicted higher BMI-z at 7 and 12 years of age. In addition, earlier AR predicted increased central obesity (as measured by waist circumference, subcutaneous adipose tissue, and trunk fat) and total body fat in adolescence. AR was negatively correlated with bone age, and its relationships with HDL and hypertension were trending towards significance. Conclusions: AR in youth with classical CAH could serve as a useful clinical marker to identify those patients who are at higher risk for developing cardiometabolic risk factors during childhood and adolescence.

Metabolic perturbations in HIV-exposed uninfected (HEU) obese youth may differ from those in the general obese pediatric population.Metabolic parameters of obese (body mass index Z-score95th percentile) HEU youth in the Pediatric HIV/AIDS Cohort Study (PHACS) Surveillance Monitoring of ART Toxicities (SMARTT) study were compared with a matched sample of obese youth from the US National Health and Nutrition Examination Survey (NHANES). We evaluated systolic and diastolic hypertension (blood pressure ≥90th percentile for age, sex, and height), total cholesterol200 mg/dL, high-density lipoprotein cholesterol35 mg/dL, low-density lipoprotein cholesterol130 mg/dL, triglycerides (TGs)150 mg/dL, and Homeostatic Model Assessment-Insulin Resistance4.0. Modified Poisson regression models were fit to quantify the prevalence ratio (PR) of each outcome comparing the 2 cohorts, adjusting for confounders.The blood pressure outcome analytic subgroup included 1096 participants (n = 304 HEU), the total cholesterol and high-density lipoprotein cholesterol subgroup 1301 participants (n = 385 HEU), and the low-density lipoprotein cholesterol, TG, and Homeostatic Model Assessment-Insulin Resistance subgroup 271 (n = 83 HEU). After adjustment, obese HEU youth had a higher prevalence of systolic and diastolic hypertension [PR = 3.34, 95% confidence interval (CI): 2.48 to 4.50; PR = 2.04, 95% CI: 1.18 to 3.52, respectively], but lower prevalence of insulin resistance (PR = 0.67, 95% CI: 0.54 to 0.85) and hypercholesterolemia (PR = 0.67, 95% CI: 0.44 to 1.01) compared with obese NHANES youth.In the United States, obese HEU youth seem to have an increased risk of hypertension, but lower risk of insulin resistance and hypercholesterolemia, compared with a general obese pediatric population. Monitoring for cardiovascular morbidity in adulthood may be warranted in HEU children.

Background Children with growth hormone deficiency (GHD) are treated with recombinant human growth hormone (rhGH), usually administered as a daily subcutaneous injection. Long-acting hGH (LAGH) treatments (approved and in development) have the potential to improve adherence and treatment outcomes. Somatrogon is a LAGH currently being developed as a once-weekly injectable treatment for GHD. The Pfizer Registry of Outcomes in Growth hormone RESearch (PROGRES) study was initiated to assess the long-term safety and effectiveness of Genotropin and other hGH formulations to treat GHD under routine clinical care. Goals & aims: The overall goal of the registry is to increase our understanding of hGH treatments as used in a real-world setting. Enrolling children treated with different daily hGH brands as well as somatrogon (if approved in a given geography) will enable comparison between daily and LAGH, and across daily hGH brands. The primary objectives of the study are to describe and compare the safety and effectiveness of daily and LAGH treatments in children. Secondary objectives include evaluating adherence to hGH treatments and the health-related quality of life (HRQoL) and treatment experience of patients receiving hGH treatments. Methods For this non-interventional, prospective, phase 4 cohort study, eligible patients (male or female at any age) from >20 countries are planned for inclusion, with the aim of targeting 667 patients across the daily hGH brands in each of the three geographic regions. Patients will be enrolled from September 2021 to October 2029, with data collection planned until October 2030. Study inclusion criteria include prescription of daily Genotropin or other approved hGH treatments for GHD and the provision of informed consent/assent. If somatrogon is approved by regulatory agencies, somatrogon-treated patients will also be eligible for inclusion. Patients participating in any interventional clinical trials at the time of enrollment will be excluded from the study. Patients will be followed until the end of the study, withdrawal of consent, death, switch to an excluded hGH, or loss to follow-up, whichever occurs first. In addition to demographic and clinical characteristics, information on hGH treatment brand, dose and start/end dates will be collected, along with reasons for switching or discontinuing treatment. Primary safety outcomes include adverse events (AEs), serious AEs, and AEs of special interest. Primary effectiveness outcomes include annual height velocity (HV) and change in HV standard deviation scores. Treatment adherence, compliance outcomes, HRQoL, and patient treatment experience will be assessed. Conclusions The findings from the PROGRES study will provide valuable insights into the use of somatrogon, Genotropin and other approved hGH treatments in real-world clinical practice, specifically with regard to the long-term safety and effectiveness of these treatments as well as treatment compliance and patient HRQoL. Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.

Youth with classical congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency exhibit an increased prevalence of obesity, early adiposity rebound, and increased abdominal adiposity compared to unaffected youth. Current obesity management in CAH largely focuses on lifestyle modifications. There is evidence that topiramate therapy is effective in reducing BMI, as well as visceral adipose tissue, in unaffected adolescents with exogenous obesity. However, little is known about the efficacy of topiramate in patients with classical CAH. We report a 17-year-old female with severe obesity and salt-wasting CAH due to 21-hydroxylase deficiency, who demonstrated reductions in BMI, as well as abdominal visceral and subcutaneous adipose tissue on topiramate therapy. The patient was diagnosed with classical CAH as a newborn with a 17-hydroxyprogesterone 11,000 ng/dL. She had a BMI > 95th percentile at 3 years old, followed by unremitting obesity. At 17 years old, she was started on topiramate to treat chronic migraines. Following three years of topiramate therapy, her BMI z-score decreased from +2.6 to +2.1. After four years of therapy, her waist circumference decreased from 110 to 101 cm, abdominal visceral adipose tissue decreased substantially by 34.2%, and abdominal subcutaneous adipose tissue decreased by 25.6%. Topiramate therapy was associated with effective weight loss and reduced central adiposity in an adolescent with classical CAH and severe obesity, without side effects. Further study is warranted regarding topiramate therapy in obese youth with classical CAH and increased central adiposity, who are at higher risk for significant morbidity.

OBJECTIVE We assessed differences in mitochondrial function between youth living with perinatal HIV (YPHIV) and youth perinatally HIV-exposed but uninfected (YPHEU). DESIGN Cross-sectional analysis. METHODS We measured lactate and pyruvate values, as well as mitochondrial Complex I and Complex IV activity in peripheral blood mononuclear cells. Logistic or linear regression models were fit, as appropriate, to assess the association between PHIV status and each mitochondrial parameter, adjusted for confounders. We introduced interaction terms to assess effect modification of PHIV status on the relationship between anthropometric factors and each mitochondrial parameter. Among YPHIV, similar regression models were fit to assess the relationship between HIV-associated factors and each mitochondrial outcome. RESULTS A total of 243 YPHIV and 118 YPHEU were compared. On average, YPHIV had higher lactate/pyruvate ratio (β: 7.511, 95% confidence interval [95% CI]: 0.402, 14.620) and Complex IV activity (β: 0.037, 95% CI: 0.002, 0.072) compared to YPHEU, adjusted for confounders. Among YPHIV, body mass index Z score (BMIZ) and Complex I activity were inversely associated, whereas, among YPHEU, there was a positive association (β for interaction: -0.048, P = 0.003). Among YPHIV, current (β: -0.789, 95% CI: -1.174, -0.404) and nadir CD4+% (β: -0.605, 95% CI: -1.086, -0.125) were inversely associated with lactate/pyruvate ratio; higher current (4.491, 95% CI: 0.754, 8.229) and peak (7.978, 95% CI: 1.499, 14.457) HIV RNA levels were positively associated with lactate/pyruvate ratio in adjusted models. CONCLUSIONS Mitochondrial function and substrate utilization appear perturbed in YPHIV compared to YPHEU. Increasing immunosuppression and viremia are associated with mitochondrial dysfunction among YPHIV.

Background: Prenatal exposures, including parental nutrition and diabetes (DM) status, are increasingly viewed as risk factors for future cardiometabolic health. There are currently no data on effects of parental DM on disease progression or complications in youth-onset T2D. Aims: To analyze effects of parental history of DM on glycemic outcomes and complications in the TODAY study. Methods: Participants (n=699) aged 10-14 yr with newly diagnosed T2D were enrolled at 14 U.S. centers and followed for up to 15 yr. Subjects had negative islet autoantibodies and BMI >= 85th %. Information about DM diagnosis in mothers of participants was available for 621 participants [Never (MN) =301; During pregnancy (MD) =218; After pregnancy (MA)=102)] and in biological fathers in 519 (No DM=352; Paternal DM=167). Results: Maternal, but not paternal, DM was associated with accelerated loss of glycemic control, defined as HbA1c >8% for over 6 months (p < 0.0001). Participants whose mothers had diabetes had 60% higher risk of loss of glycemic control [MD vs. MN hazard ratio (HR): 1.58 (1.28, 1.95), p < 0.0001; MA vs. MN HR: 1.57 (1.20, 2.04), p = 0.0009]. Similarly, maternal, but not paternal, diabetes was associated with glomerular hyperfiltration [MD vs. MN HR: 1.58 (1.18-2.1), p = 0.0021; MA vs. MN HR: 1.56 (1.08, 2.24), p = 0.0170;], diabetic retinopathy (MD: 50.0%; MA: 59.7%; MN: 41.8%, p=0.0439), and pulse wave velocity indices reflecting heart rate variability, including SD of normal R-R interval [(SDNN), MD: 42 ± 26 ms; MA: 41 ± 26 ms; MN: 54 ± 31 ms; p = 0.0005] and proportion of successive NN intervals greater than 50 ms [(pNN50%), MD: 14.1 ± 19.4; MA: 16.2 ± 21.5; MN: 21.9 ± 23.5; p = 0.0069], after 10 to 15 yr of follow-up. Associations were maintained after adjusting for multiple confounders. Conclusions: Maternal, but not paternal, diabetes is associated with adverse diabetes outcomes and accelerated onset of complications in their offspring with T2D in TODAY. Disclosure E. M. Isganaitis: None. M. A. Van name: None. R. Shah: None. S. Chernausek: None. R. M. Farrell: Stock/Shareholder; Self; Tandem Diabetes Care. M. Geffner: Advisory Panel; Self; Daiichi Sankyo, Novo Nordisk, Pfizer Inc., Consultant; Self; Gilead Sciences, Inc., Other Relationship; Self; Ascendis Pharma A/S, McGraw-Hill, UpToDate, Research Support; Self; Novo Nordisk. J. Keady: None. M. M. Kelsey: Other Relationship; Self; Boehringer Ingelheim (Canada) Ltd., Daiichi Sankyo, Janssen Pharmaceuticals, Inc., Merck Sharp & Dohme Corp. B. Tesfaldet: None. J. B. Tryggestad: None. Funding National Institute of Diabetes and Digestive and Kidney Diseases (U01DK61212, U01DK61230, U01DK61239, U01DK61242, U01DK61254)

BACKGROUND There are few data on the prevalence of gestational diabetes (GDM) in pregnant women living with HIV (WLHIV) in sub-Saharan Africa, particularly those using integrase strand transfer inhibitors such as dolutegravir (DTG). METHODS We prospectively enrolled pregnant WLHIV and pregnant women without HIV ≥18 years old in Gaborone, Botswana, excluding those with pre-existing diabetes. We screened for GDM using a 75 g oral glucose tolerance test (OGTT) performed at 24-28 weeks' gestation or at the earliest prenatal visit for those presenting after 28 weeks. Logistic regression models were fitted to assess the association between maternal HIV infection and GDM. Subgroup analyses were performed among WLHIV to assess the association between maternal antiretroviral therapy (ART) in pregnancy [DTG vs. efavirenz (EFV) with tenofovir/emtricitabine] and GDM. RESULTS Of 486 pregnant women, 66.5% were WLHIV, and they were older than women without HIV (median age 30 vs. 25 years, P

The second-to-fourth digit ratio (2D:4D) has been associated with sexual dimorphism, with a lower 2D:4D in males. A large body of research has relied on the 2D:4D as a proxy for prenatal androgen exposure, and includes reports of relationships between 2D:4D and a wide range of human traits. Here, we examine the validity of the 2D:4D proxy by studying the association between 2D:4D and classical Congenital Adrenal Hyperplasia (CAH) due to 21-hydroxylase deficiency, a condition characterized by excessive prenatal exposure to androgens during most of the gestational period. To this end, we retrospectively examine 513 serial radiographs of the left hand obtained clinically in 90 youth with classical CAH (45 female) and 70 control youth (31 female). Replicating previous reports, we observe associations of the 2D:4D with sex (lower 2D:4D in males) and age (increase of 2D:4D through development). However, we find no evidence for differences in 2D:4D between CAH and controls (full sample: β = −0.001 (−0.008, 0.006)]; females: β = −0.004 [−0.015, 0.007]; males: β = 0.001, [−0.008, 0.011]). Although our findings do not rule out a small association between the 2D:4D and CAH, they cast doubt on the usefulness of the 2D:4D as a biomarker for prenatal androgen exposure in behavioral research.

Early-life metabolic derangements in HIV-exposed uninfected (HEU) infants have been reported.Pregnant women with HIV and HIV-uninfected pregnant women were enrolled with their newborns in a US cohort from 2011 to 2015. We measured cord insulin, C-peptide, and metabolic cytokines of HEU and HIV-unexposed uninfected (HUU) newborns using ELISA and metabolites, lipid subspecies, and eicosanoids via liquid chromatography/mass spectrometry. Linear regression was employed to assess the association of intrauterine HIV/ART with insulin and C-peptide. Graphical lasso regression was used to identify differences between metabolite/lipid subspecies networks associated with C-peptide.Of 118 infants, 56 were HEU, ART exposed. In adjusted analyses, mean cord insulin (β = 0.295, p = 0.03) and C-peptide (β = 0.522, p 0.01) were significantly higher in HEU vs. HUU newborns. HEU neonates exhibited primarily positive associations between complex lipids and C-peptide, indicative of fuel storage, and augmented associations between cord eicosanoids and cytokines. HUU neonates exhibited negative associations with lipids and C-peptide indicative of increased fuel utilization.Higher cord insulin and C-peptide in HEU vs. HUU newborns as well as differences in cord metabolites, metabolic-related cytokines, and eicosanoids may reflect a propensity for fuel storage and an inflammatory milieu suggestive of fetal metabolic changes associated with in utero HIV/ART exposure.There is a paucity of studies assessing cord blood and neonatal metabolic health in HIV-exposed uninfected (HEU) newborns, an increasing population worldwide. Compared to HIV-unexposed uninfected (HUU) newborns, HEU newborns exhibit alterations in fuel homeostasis and an inflammatory milieu associated with in utero HIV/antiretroviral therapy (ART) exposure. The long-term implications of these neonatal findings are as yet unknown, but merit continued evaluation as this important and growing population ages into adulthood.

In individuals with intact thirst and adequate fluid intake, the identification of diabetes insipidus may be challenging due to normal serum sodium levels and normal serum osmolality. In such cases, a water deprivation test can prove critical in indirectly assessing the activity of anti-diuretic hormone within the body. Lack of urinary concentration in the context of dehydration is diagnostic of diabetes insipidus. Response to exogenous arginine vasopressin analogs can help distinguish central from nephrogenic diabetes insipidus.

Noonan syndrome is a common autosomal dominant disorder associated with an increased risk of malignancy. We report a 16-year-old female with Noonan syndrome (KRAS gene variant, Q22R) and diffuse-type tenosynovial giant cell tumor, a proliferative disorder that has been rarely reported in this population. These tumors may represent a complication of the dysregulated RAS/MAPK signaling pathway that underlies Noonan syndrome. They lack typical clinical features, causing misdiagnosis and delays in management, which could lead to osseous invasion requiring more complicated surgical procedures. Increased awareness of this association will improve the clinical outcomes of patients with Noonan syndrome who develop diffuse-type tenosynovial giant cell tumors.

This cross-sectional study evaluates the use of machine learning for prediction of congenital adrenal hyperplasia based on distinct facial morphologic features., Key Points Question Do patients with congenital adrenal hyperplasia (CAH) have distinct facial morphologic features that are distinguishable by deep learning? Findings In this cross-sectional study of 102 patients with CAH and 144 control participants, deep learning methods achieved a mean area under the receiver operating characteristic curve of 92% for predicting CAH from facial images. Facial features distinguished patients with CAH from controls, and analyses of facial regions found that the nose and upper face were most contributory. Meaning The findings suggest that facial morphologic features, as analyzed by deep neural network techniques, can be used as a phenotypic biomarker to predict CAH., Importance Congenital adrenal hyperplasia (CAH) is the most common primary adrenal insufficiency in children, involving excess androgens secondary to disrupted steroidogenesis as early as the seventh gestational week of life. Although structural brain abnormalities are seen in CAH, little is known about facial morphology. Objective To investigate differences in facial morphologic features between patients with CAH and control individuals with use of machine learning. Design, Setting, and Participants This cross-sectional study was performed at a pediatric tertiary center in Southern California, from November 2017 to December 2019. Patients younger than 30 years with a biochemical diagnosis of classical CAH due to 21-hydroxylase deficiency and otherwise healthy controls were recruited from the clinic, and face images were acquired. Additional controls were selected from public face image data sets. Main Outcomes and Measures The main outcome was prediction of CAH, as performed by machine learning (linear discriminant analysis, random forests, deep neural networks). Handcrafted features and learned representations were studied for CAH score prediction, and deformation analysis of facial landmarks and regionwise analyses were performed. A 6-fold cross-validation strategy was used to avoid overfitting and bias. Results The study included 102 patients with CAH (62 [60.8%] female; mean [SD] age, 11.6 [7.1] years) and 59 controls (30 [50.8%] female; mean [SD] age, 9.0 [5.2] years) from the clinic and 85 controls (48 [60%] female; age

Objective: The Treatment Options for type 2 Diabetes in Adolescents and Youth (TODAY) trial demonstrated that glycemic failure rates were significantly lower in youth randomized to metformin plus rosiglitazone treatment compared to metformin alone or metformin plus intensive lifestyle intervention. At end of study, rosiglitazone was permanently discontinued, and routine diabetes care resumed. Herein, we report post-intervention glycemic failure rates in TODAY participants over an additional 36 months of follow-up for the three original treatment arms and describe insulin sensitivity and beta-cell function outcomes. Research Design and Methods: A total of 699 participants were randomized during TODAY, of whom 572 enrolled in the TODAY2 observational follow-up. Glycemic failure was defined as HbA1c ≥8% over a 6-month period or inability to wean from temporary insulin therapy within 3 months after acute metabolic decompensation during TODAY or a sustained HbA1c ≥8% over two consecutive visits during TODAY2. Oral glucose tolerance tests were conducted and insulin sensitivity, insulinogenic index, and oral disposition index (oDI) were calculated. Results: During the 36 months of TODAY2, glycemic failure rates did not differ among participants by original treatment group assignment. Insulin sensitivity and beta-cell function deteriorated rapidly during the 36 months of TODAY2 routine diabetes care, but did not differ by treatment group assignment. Conclusions: The added benefit of preventing glycemic failure by using rosiglitazone as a second agent in youth-onset type 2 diabetes did not persist after its discontinuation. More work is needed to address this rapid progression to avoid long-term diabetes complications.

Context Classical congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency results in hormone imbalances present both prenatally and postnatally that may impact the developing brain. Objective To characterize gray matter morphology in the prefrontal cortex and subregion volumes of the amygdala and hippocampus in youth with CAH as compared to controls. Design A cross-sectional study of 27 CAH youth (16 female; 12.6 ± 3.4 years) and 35 typically developing, healthy controls (20 female; 13.0 ± 2.8 years) with 3-T magnetic resonance imaging scans. Brain volumes of interest included bilateral prefrontal cortex and 9 amygdala and 6 hippocampal subregions. Between-subject effects of group (CAH vs. control) and sex, and their interaction (group-by-sex) on brain volumes, were studied while controlling for intracranial volume (ICV) and group differences in body mass index and bone age. Results Congenital adrenal hyperplasia youth had smaller ICV and increased cerebrospinal fluid volume compared to controls. In fully-adjusted models, CAH youth had smaller bilateral superior and caudal middle frontal volumes, and smaller left lateral orbitofrontal volumes compared to controls. Medial temporal lobe analyses revealed that the left hippocampus was smaller in fully-adjusted models. Congenital adrenal hyperplasia youth also had significantly smaller lateral nucleus of the amygdala and hippocampal subiculum and CA1 subregions. Conclusions This study replicates previous findings of smaller medial temporal lobe volumes in CAH patients and suggests that the lateral nucleus of the amygdala, as well as subiculum and subfield CA1 of the hippocampus, are particularly affected within the medial temporal lobes in CAH youth.

Individuals with Turner syndrome (TS) have a higher morbidity and mortality compared to the general population. Diabetes and cardiovascular disease are the major contributors to this burden. Precursors to diabetes and cardiovascular disease make up what is known as metabolic syndrome, including abdominal obesity, hypertension, dyslipidemia, and elevated fasting glucose. These features of poor cardiometabolic health are also prevalent among women with TS. Youth with TS also exhibit many of these features, indicating that the pathogenesis of these cardiometabolic conditions may begin early in life. The etiology of the increased risk of cardiometabolic conditions in TS is likely multifactorial, involving genetics, epigenetics, hypogonadism, medical co-morbidities, medications, and lifestyle. Counseling for the increased risk of cardiometabolic diseases as well as efforts to prevent or lower this risk should be routinely provided in the care of all patients with TS. Clinical practice guidelines are now available to guide screening and treatment of cardiometabolic conditions in girls and women with TS.

OBJECTIVE. To identify risk factors for glycemic failure in youth with type 2 diabetes (T2D). METHODS. A retrospective review of HbA1c, anthropomorphic measures, medication records, and laboratory studies was performed using registry data from a dedicated pediatric type 2 diabetes clinic. Latent profile analysis (LPA) was performed to model longitudinal trajectory of HbA1c over five years. RESULTS. The registry includes 229 youth with T2D, of whom 80% self-identify as Latinx. The odds ratio (OR) for uncontrolled diabetes five years after diagnosis correlated with diagnostic HbA1c, with OR of 2.41 if HbA1c at diagnosis >8.5% (sensitivity 68%, specificity 54%, P=0.015). LPA modeling identified three HbA1c profiles: (A) mean HbA1c 9%, and (C) mean HbA1c of 12% at diagnosis, rapid decline to 6.4% by 4–6 months, and increase to 11% by 18 months. Our analysis of medication regimen showed that, amongst patients treated with metformin, the addition of multiple daily injections (MDI) did not improve HbA1c compared to those on basal insulin. Finally, weight loss over the first year after diagnosis correlated with improvement in HbA1c in both subjects prescribed metformin monotherapy, as well as insulin-containing regimen. CONCLUSION. Youth with T2D exhibit distinct HbA1c profiles. Patients with diagnostic HbA1c >8.5% are at high risk for glycemic failure, irrespective of short-term improvement in HbA1c. Weight management has the potential to improve short-term HbA1c outcome in youth with T2D. Additional studies are needed to determine the role of medication adherence on glycemic control.

The second-to-fourth digit ratio (2D:4D) has been associated with sexual dimorphism, with a lower 2D:4D in males. A large body of research has relied on the 2D:4D as a proxy for prenatal androgen exposure, and includes reports of relationships between 2D:4D and a wide range of human traits. Here, we examine the validity of the 2D:4D proxy by studying the association between 2D:4D and classical Congenital Adrenal Hyperplasia (CAH) due to 21-hydroxylase deficiency, a condition characterized by excessive prenatal exposure to androgens during most of the gestational period. To this end, we retrospectively examine serial radiographs of the left hand obtained clinically in 91 youth with classical CAH (49.5% female) and 70 control youth (44.3% female). Replicating previous reports, we observe associations of the 2D:4D with sex (lower 2D:4D in males), age (increase of 2D:4D through development) and ethnicity (lower 2D:4D in Hispanic individuals). However, we find no evidence for differences in 2D:4D between CAH and controls (full sample: □ = 0.0003 [-0.007, 0.008]; females: □ = −0.004 [-0.015, 0.007]; males: □ = 0.003, [-0.007, 0.013]). Although our findings do not rule out a small association between the 2D:4D and CAH, they cast doubt on the usefulness of the 2D:4D as a biomarker for prenatal androgen exposure in behavioral research.

Purpose: Classical Congenital Adrenal Hyperplasia (CAH) due to 21-hydroxylase deficiency affects 1:15,000 newborns and involves adrenal insufficiency and androgen excess. These hormone abnormalities are evident as early as 7 weeks’ gestation and persist throughout pregnancy. Structural brain abnormalities are also known to occur in CAH, with abnormalities of brain and facial structure occurring together in conditions such as fetal alcohol spectrum disorder and holoprosencephaly. As well, sex differences in facial morphology are well described in healthy individuals. Thus, we aimed to study facial features using artificial intelligence in CAH youth. Methods: We studied frontal images of the face in 57 youth with severe salt-wasting CAH (60% female; 9.4±5.5y), and 38 controls (47% female, 9.7±5.1y), acquired with an iPad v12.1. We included 32 additional controls (43% female; 4-19y) from a publicly available face image dataset (1). Applying deep learning techniques, we converted 2-D facial photos to mathematical descriptors in order to differentiate features between groups. For a given test image, our pipeline output was a predicted “CAH score” between [0,1]. Due to our small dataset, we employed K-fold cross validation to train and test our deep neural network. At each of the K-9 folds, 88% of data (468 control and 531 CAH images) were used to train the network, with the remaining data (55 control and 63 CAH images) used to test the trained network. Test results were validated in terms of area under the curve (AUC) of receiver operating characteristic curves (generated from predicted CAH scores of test subjects), to analyze true and false positive rates. Our pipeline automatically detected face-bounding boxes and 68 facial landmarks (dlib toolkit) which were then used to compute 27 Euclidean (linear) facial features (2,3). We performed between group analyses of features with t-tests. Results: The averaged AUC of nine folds was 0.83±0.14, representing strong predictive power as a proxy to correlating facial dysmorphology with CAH. Predicted CAH scores were different between control (0.24±0.33) and CAH (0.69±0.37; p

INTRODUCTIONTesticular adrenal rest tumors (TART) are a known consequence for males with classical congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency. TART are associated with potential infertility in adults. However, little is known about TART in very young males with CAH.OBJECTIVEWe assessed the prevalence of TART in newborn, infant, and toddler males with classical CAH via scrotal ultrasound.METHODSMales with CAH had scrotal ultrasounds during the first 4 years of life, evaluating testes for morphology, blood flow, and presence of TART. Newborn screen 17-hydroxyprogesterone (17-OHP) and serum 17-OHP at the time of ultrasound were recorded. Bone ages were considered very advanced if ≥ 2SD above chronological age.RESULTSThirty-one ultrasounds in 16 males were performed. An initial ultrasound was obtained in four newborns at diagnosis (6.8 ±2.1 days), six infants (2.2 ±0.9 months), and six toddlers (2.4 ±0.9 years). Eleven males had at least one repeat ultrasound. A large proportion (11/16) were in poor hormonal control with an elevated 17-OHP (325 ±298 nmol/L). One infant was in very poor hormonal control (17-OHP 447 nmol/L) at initial ultrasound, and two toddlers had advanced bone ages (+3.2 and +4.5 SD) representing exposure to postnatal androgens. However, no TART were detected in any subjects.CONCLUSIONSTART were not found in males up to 4 years of age with classical CAH despite settings with expected high ACTH drive. Further research into the occurrence of TART in CAH may elucidate factors which contribute to the detection and individual predisposition to TART.

Purpose: Youth with classical Congenital Adrenal Hyperplasia (CAH) due to 21-hydroxylase deficiency have an increased prevalence of obesity, abdominal adiposity, and fat mass compared to unaffected youth. As well, CAH youth in the United Kingdom (UK) have been found to have an earlier adiposity rebound (AR; rise in BMI corresponding to increased adipocyte size and number) at 1.7 years old, three years earlier than the general UK population. In unaffected youth, an earlier AR is predictive of obesity in adolescence. Our objective was to further understand the relationships between AR, weight status, and disease factors inherent to CAH in pediatric patients at our United States (US) center. Methods: In 45 youth with classical CAH, weight-for-length (kg/cm; if