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 T2D clinic. Latent profile analysis (LPA) was performed to model longitudinal trajectory of HbA1c over 5 years. Results The registry includes 229 youth with T2D, of whom 80% self-identify as Latinx. The odds ratio (OR) for uncontrolled diabetes 5 years after diagnosis correlated with diagnostic HbA1c, with OR of 2.41 if HbA1c at diagnosis >8.5% (sensitivity 68%, specificity 54%,P= .015). LPA modeling identified three HbA1c profiles: (a) mean HbA1c <8% throughout the 5 years, (b) persistent elevation of mean HbA1c >9%, and (c) mean HbA1c of 12% at diagnosis, rapid decline to 6.4% by 4 to 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 1 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.

Abstract 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 <2 yr) percentiles or BMI (kg/m2; if ≥2 yr) Z-scores were calculated every 6 months between the ages of 1 and 7 years, and at the patient’s last clinic visit. The cubic polynomial method was used to determine age at AR, located at the nadir before the second rise in the model. BMI-Z at the last clinic visit (12.6±3.8 yr) was used to classify final weight status as lean (Z<2) or obese (Z≥2). AR, and weight-for-length percentile at 1 yr, were analyzed for prediction of BMI-Z at 7 yr. Additionally, in a subset of 21 CAH youth enrolled in prior studies, total body fat and trunk fat (DXA), as well as abdominal subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT; single-slice CT or 3-T MRI at the level of the umbilicus) were cross-sectionally measured. Other CAH factors assessed in all youth included: glucocorticoid dose at AR, 17OHP at newborn diagnosis, and average bone age SD from clinical x-rays. Mann-Whitney U tests and Pearson correlations were used to assess group differences and associations. Simple linear regressions were used to predict childhood obesity and adolescent adiposity. Data are presented as mean±SD. Results: Age at AR for CAH youth was 3.1±1.4 yr, which is earlier than the normative US population (5.5 yr). Stratifying youth by weight status at their last clinic visit, age at AR was earlier in obese (2.5±1 yr, n=23) versus lean (3.7±1.6 yr, n=22; p<0.01) youth. AR strongly predicted BMI-Z at 7 yr (R= -0.65, β= -0.27, p<0.001) whereas weight-for-length percentile did not (R=0.22, p=0.14). AR was negatively correlated with total body fat (R= -0.58, p<0.01), trunk fat (R= -0.60, p<0.01), and abdominal SAT (R= -0.60, p<0.01), but not with VAT (R= -0.24, p=0.3). There were no associations between AR and glucocorticoid dose or newborn 17OHP. However, AR was negatively correlated with bone age SD (R= -0.37, p=0.05). Conclusion: Youth with CAH at our center exhibited an earlier AR by two years compared to the normative US population. This earlier AR was predictive of obesity in childhood, as well as increased total body fat and central adiposity in adolescence. Further study of disease-specific factors such as genotype in CAH are merited.

OBJECTIVE:In the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) study, metformin plus rosiglitazone (M + R) maintained glycemic control better than metformin alone (M) or metformin plus lifestyle (M + L) in youth with type 2 diabetes (T2D). We hypothesized that changes in visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) would explain the differential treatment effects on glycemia. RESEARCH DESIGN AND METHODS:In 626 youth ages 11-17 years with T2D duration <2 years, VAT and SAT were estimated by DXA at baseline and at 6 and 24 months. Changes from baseline were analyzed in linear mixed models. RESULTS:Baseline mean age was 13.9 years, 66.4% were female, 72.2% were Hispanic/non-Hispanic black, and 20.3% were non-Hispanic white (NHW). Mean BMI was 33.7 kg/m2. VAT increased more in M + R (13.1%) than M + L (3.9%, P = 0.0006) or M (6.5%, P = 0.0146). SAT also increased more in M + R (13.3%) than in M + L (5.4%, P < 0.0001) or M (6.4%, P = 0.0005), indicating no significant fat redistribution in M + R. In NHWs, VAT increased more in M + R than M (P = 0.0192) and M + L (P = 0.0482) but did not explain the race-ethnicity differences in treatment effects on glycemic control among treatment groups. VAT and SAT increases correlated with higher HbA1c, lower insulin sensitivity, and lower oral disposition index (all P < 0.05), but associations did not differ by treatment group. CONCLUSIONS:In contrast to the existing reports in adults with T2D, in TODAY, M + R resulted in the most VAT accumulation compared with M + L or M. Differential effects on depot-specific indirect measures of adiposity are unrelated to treatment effects in sustaining glycemic control. Additional studies are needed to understand the clinical markers of metabolic risk profile in youth with T2D on rosiglitazone.

Background: Disordered bone mineral metabolism and low vitamin D concentrations are associated with cardiovascular abnormalities; few studies have evaluated this relationship in HIV-infected youth. Setting: The Adolescent Master Protocol is a Pediatric HIV/AIDS Cohort Study network study conducted across 14 US sites. Methods: Among perinatally HIV-infected (PHIV) and perinatally HIV-exposed but uninfected (PHEU) youth enrolled in the Adolescent Master Protocol, we evaluated associations of vitamin D [measured as 25-hydroxy-vitamin D (25-OHD)], parathyroid hormone (PTH), calcium, phosphate, and fibroblast growth factor-23 (FGF-23) concentrations with echocardiographic measures of left ventricular (LV) structure, function, and concentrations of NT-proBNP, a biomarker of cardiac damage. Results: Among 485 participants (305 PHIV and 180 PHEU) with echocardiograms and bone mineralization measures, low 25-OHD (<20 ng/mL) was common among all participants (48% PHIV and 44% PHEU), but elevated PTH (>65 pg/mL) was identified more often among PHIV participants than PHEU participants (9% vs 3%, P = 0.02). After adjusting for HIV status and demographic covariates, both low 25-OHD and elevated PTH were associated with lower mean LV mass z-scores, whereas elevated PTH was associated with higher mean fractional shortening z-scores. Participants with low 25-OHD also had slightly higher mean LV endsystolic wall stress z-scores, but differences were more pronounced in PHEU participants than in PHIV participants. FGF-23 was inversely related to end-diastolic septal thickness, both overall and among PHIV participants. Conclusions: In this cohort of PHIV and PHEU youth, we observed associations of 25-OHD, PTH, and FGF-23 with both structural and functional cardiac parameters, supporting links between bone mineral metabolism and cardiac status.

• The theoretical BSA-based dose of 1.46 mg/d was derived from observed dose vs BSA data that best corresponded with an ideal body weight (BSA=1 m2) Methods • Previously, only a single study compared BSAvs weight-based GH dosing in girls with TS1 This analysis suggested that BSA-based dosing may decrease cumulative GH doses and treatment costs compared with weight-based dosing while providing at least equal adult-height gains • The ANSWER Program is a long-term, US-based, non-interventional study designed to collect information on the effectiveness and safety of Norditropin® GH This dataset may be useful in comparing BW-based and theoretical BSAbased dosing in different patient populations • From June 2002 to September 2016, 20,204 pediatric patients were enrolled in ANSWER by their treating physicians, including 1003 patients with TS Patient information was entered by participating physicians using a Web-based tool Introduction

Context Little is known about reproductive function in girls with youth-onset type 2 diabetes. Objectives To characterize girls with irregular menses and effects of glycemic treatments on menses and sex steroids in the Treatment Options for Type 2 Diabetes in Youth (TODAY) study. Design Differences in demographic, metabolic, and hormonal characteristics between regular- vs irregular-menses groups were tested; treatment group (metformin with or without rosiglitazone, metformin plus lifestyle) effect on menses and sex steroids over time in the study was assessed. This is a secondary analysis of TODAY data. Setting Multicenter study in an academic setting. Patients TODAY girls not receiving hormonal contraception and those at least 1-year postmenarche were included. Irregular menses was defined as three or fewer periods in the prior 6 months. Results Of eligible participants with serum measurement of sex steroids (n = 190; mean age, 14 years), 21% had irregular menses. Those with irregular vs regular menses had higher body mass index (BMI) (P = 0.001), aspartate aminotransferase (AST) (P = 0.001), free androgen index (P = 0.0003), and total testosterone (P = 0.01) and lower sex hormone-binding globulin (SHBG) (P = 0.004) and estradiol (P = 0.01). Differences remained after adjustment for BMI. There was no treatment group effect on menses or sex steroids at 12 or 24 months, and no association of sex steroids was seen with measures of insulin sensitivity or secretion. Conclusions Menstrual dysfunction is common in girls with recently diagnosed type 2 diabetes and associated with alterations in sex steroids, SHBG, and AST but not with alteration in insulin sensitivity or β-cell function and did not improve with 2 years of antihyperglycemic treatment.

Objective: In TODAY, metformin + rosiglitazone (M+R) was better in maintaining glycemic control than metformin alone (M) or metformin + lifestyle (M+L), but longitudinal differences in whole body adiposity were small and unrelated to treatment group. As excess visceral adipose tissue (VAT) and nonalcoholic fatty liver disease (NAFLD) are common in T2D, we hypothesized that changes in VAT, subcutaneous adipose tissue (SAT), and liver enzymes, as a marker of NAFLD, would be related to treatment effect. Methods: TODAY enrolled 699 youth 11-17 y/o with T2D <2 year. In 626 subjects, VAT and SAT (by DXA) and AST and ALT were measured at baseline (BL) and 24 mo. Changes from BL to 24 mo were analyzed in baseline-adjusted repeated measures models. Results: At BL, mean age was 13.9 year, 66.4% were female, 41.1% hispanic, 31.1% non-hispanic black, 20.3% non-hispanic white (NHW). Mean BMI was 33.7 kg/m2 and BMI z-score +2.2. 3.3% had ALT ≥1.5 upper limit of normal (ULN), suggestive of NAFLD, and 0.3% had AST ≥1.5 ULN. At 24 mo, BMI, BMI z-score, VAT, and SAT all increased. VAT increased most in M+R and least in M+L (14.2% vs. 3.1%, p<0.001). SAT increased more in M+R (15.7%) than M+L (6.9%, p<0.0001) or M (8.7%, p<0.001). At 24 mo, between-group differences in VAT:SAT ratio and AST were not significant, but ALT increased more in M+L than M+R (23.1% vs. 2.7%, p=0.015). Sex did not moderate treatment effects on VAT and SAT. Greater increases in VAT occurred in NHW in M+R than M (p<0.001) or M+L (p<0.001). VAT and SAT increases correlated with higher HbA1c (p<0.001), and lower insulin sensitivity (p<0.033), and c-peptide oral disposition index (p<0.038), but did not differ by treatment group. Conclusion: Unlike in adults, in youth in TODAY, VAT rise was greater in M+R than M+L. VAT and SAT changes were not related to treatment group differences in glycemic control. Increased VAT and SAT correlated with lower insulin sensitivity and secretion. In T2D youth, R may blunt the rise in ALT, but does not lower the VAT:SAT ratio. Disclosure R. Dhaliwal: None. J.A. Shepherd: None. L. El Ghormli: None. K.C. Copeland: Other Relationship; Self; Novo Nordisk Inc. M. Geffner: Other Relationship; Self; Daiichi Sankyo Company, Limited. J. Higgins: None. L.L. Levitsky: Consultant; Self; Eli Lilly and Company. K.J. Nadeau: None. R.S. Weinstock: Research Support; Self; Medtronic MiniMed, Inc., Mylan, Kowa Pharmaceuticals America, Inc., Diasome Pharmaceuticals, Inc., Calibra Medical, Dexcom, Inc., Ultradian Diagnostics LLC., JAEB Center For Health Research, JDRF, National Institute of Diabetes and Digestive and Kidney Diseases. N.H. White: None.

Congenital adrenal hyperplasia (CAH) is an inherited disorder of adrenal steroidogenesis often diagnosed in infancy. Gynecologists may encounter adult patients with CAH due to the clinical effects of increased androgens, e.g. hirsutism, clitoromegaly, oligomenorrhea, or, rarely, pelvic masses. This case report reviews the association of para-ovarian adrenal rest tumors with CAH, and the role of gynecologists in their evaluation and treatment. A 23-year-old woman with CAH (21-hydroxyase deficiency) untreated for the past 5 years presented with a pelvic mass and elevated serum testosterone (1433 ng/dL) and plasma ACTH (1117 pg/mL). Intraoperative findings revealed multiple retroperitoneal masses. Final pathology demonstrated adrenal rest tissue. Para-ovarian and ovarian adrenal rest tumors may present as a rare gynecologic manifestation in patients with untreated CAH.

Abstract Background: The aim of this study was to assess aromatase inhibitor (AI) efficacy in increasing predicted adult height (PAH) and to describe clinical and biochemical safety profiles of AI-treated boys. Methods: A retrospective chart review was conducted at an academic children’s hospital endocrinology clinic. Twenty-one boys with predicted short stature and/or rapidly advancing bone age, divided as Tanner stage (TS) I–III Group 1 (G1, n=9) and TS IV–V Group 2 (G2, n=12), were treated with AIs, either letrozole or anastrozole (mean duration, G1: 2.4 years and G2: 0.9 years). Primary outcomes included PAH, hormonal/biochemical analytes, and clinical data. Results: PAH did not significantly change in either group. Mean peak testosterone significantly increased from baseline to 650±458 ng/dL (p=0.008) in G1 and to 1156±302 ng/dL (p=0.002) in G2. Estradiol did not significantly change in either group. Compared to baseline, G2 showed increased mean FSH (p=0.002), LH (p=0.002), hematocrit (p=0.0001), body mass index (BMI) z-score (p=0.0005), and acne (p=0.01). Conclusions: AIs did not increase PAH, regardless of TS. Boys in late puberty had significant increases in testosterone, gonadotropins, hematocrit, acne, and BMI, but no reduction in estradiol. The potential consequences of these findings are concerning and require long-term study, especially if AIs are started in late puberty.

CONTEXT:Classical congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency can cause life-threatening adrenal crises as well as severe hypoglycemia, especially in very young children. Studies of CAH patients 4 years old or older have found abnormal morphology and function of the adrenal medulla and lower levels of epinephrine and glucose in response to stress than in controls. However, it is unknown whether such adrenomedullary abnormalities develop in utero and/or exist during the clinically high-risk period of infancy and early childhood.OBJECTIVE:The objective of the study was to characterize adrenomedullary function in infants with CAH by comparing their catecholamine levels with controls. Design/Settings: This was a prospective cross-sectional study in a pediatric tertiary care center.MAIN OUTCOME MEASURES:Plasma epinephrine and norepinephrine levels were measured by HPLC.RESULTS:Infants with CAH (n = 9, aged 9.6 ± 11.4 d) had significantly lower epinephrine levels than controls [n = 12, aged 7.2 ± 3.2 d: median 84 [(25th; 75th) 51; 87] vs 114.5 (86; 175.8) pg/mL, respectively (P = .02)]. Norepinephrine to epinephrine ratios were also significantly higher in CAH patients than controls (P = .01). The control infants had primary hypothyroidism, but pre- and posttreatment analyses revealed no confounding effects on catecholamine levels.CONCLUSIONS:This study demonstrates for the first time that infants with classical CAH due to 21-hydroxylase deficiency have significantly lower plasma epinephrine levels than controls, indicating that impaired adrenomedullary function may occur during fetal development and be present from birth. A longitudinal study of adrenomedullary function in CAH patients from infancy through early childhood is warranted.

Influences of prenatal androgen exposure on human sex-typical behavior have been established largely through studies of individuals with congenital adrenal hyperplasia (CAH). However, evidence that addresses the potential confounding influence of parental socialization is limited. Parental socialization and its relationship to sex-typical toy play and spatial ability were investigated in two samples involving 137 individuals with CAH and 107 healthy controls. Females with CAH showed more boy-typical toy play and better targeting performance than control females, but did not differ in mental rotations performance. Males with CAH showed worse mental rotations performance than control males, but did not differ in sex-typical toy play or targeting. Reported parental encouragement of girl-typical toy play correlated with girl-typical toy play in all four groups. Moreover, parents reported encouraging less girl-typical, and more boy-typical, toy play in females with CAH than in control females and this reported encouragement partially mediated the relationship between CAH status and sex-typical toy play. Other evidence suggests that the reported parental encouragement of sex-atypical toy play in girls with CAH may be a response to the girls’ preferences for boys’ toys. Nevertheless, this encouragement could further increase boy-typical behavior in girls with CAH. In contrast to the results for toy play, we found no differential parental socialization for spatial activities and little evidence linking parental socialization to spatial ability. Overall, evidence suggests that prenatal androgen exposure and parental socialization both contribute to sex-typical toy play.

CONTEXT:Little is known about the impact of childhood-onset GH deficiency (GHD), in particular the duration of GH cessation during the transition phase, on adult phenotype. OBJECTIVE:We investigated the association between the manifestations and management of GHD during childhood/adolescence and the clinical features of GHD in adulthood. DESIGN/SETTING/PATIENTS/INTERVENTION: Patients with reconfirmed childhood-onset GHD who resumed GH treatment as adults were identified from two sequential databases (n = 313). The cohort was followed up longitudinally from GH start in childhood to reinitiation of treatment in adulthood and 1 yr beyond. Analyses were performed in the total cohort and in subgroups of patients with idiopathic GHD (IGHD) and non-IGHD. The cohorts were stratified based on duration of GH cessation (short, < or = 2 yr; long, > 2 yr). MAIN OUTCOME MEASURES:Regimen of pediatric GH administration, duration of GH interruption, IGF-I sd score, lipid concentrations, and quality of life were measured. RESULTS:Mean duration of GH interruption was 4.4 yr. IGF-I sd score in adulthood was related to severity of childhood GHD. In non-IGHD patients, a longer duration of GH interruption was associated with a worse lipid profile (P < 0.0001). Non-IGHD patients who gained more height during childhood GH treatment reported better quality of life than those who gained less height (P < 0.05). CONCLUSIONS:Pediatricians should tailor GH treatment, not only for its beneficial effect on growth but also for future health in adulthood. In adults with reconfirmed GHD, particularly those with non-IGHD, early recommencement of GH should be considered.

Consideration of GH re-testing should be performed in all adolescents reaching the transition period (if not at start of puberty) who had been previously diagnosed with idiopathic, isolated GH deficiency. In the presence of multiple hormone deficiencies and/or clear-cut evidence of organic disease, persistence of severe GH deficiency is much more likely. Thus, GH deficiency may be "confirmed" by a low serum IGF-I concentration. During the transition period, the optimal time to reassess the integrity of the GH-IGF-I axis after prior GH treatment, the specific testing protocol to use, and the definition of GH deficiency all remain unknown. During the transition period, patients should have their GH dose lowered with (upward) adjustments made on the basis of age-and gender-adjusted serum IGF-I concentrations. GH treatment during the transition period has been shown in most, but not all, studies to be beneficial in preventing development of the features of the adult GH deficiency syndrome. It is important to remember that, during the transition period in teenagers with GH deficiency, there must be initiation of a careful plan for transfer of care to an intermist-endocrinologist with expertise in management of hypothalamic-pituitary disease in young adults.

Aromatase inhibitors (AIs) are a class of drugs that prevent conversion of androgens to estrogens, and that are approved in the United States as adjunctive treatment of estrogen receptor-positive breast cancer. Because ultimate fusion of the growth plates is estrogen-dependent in both boys and girls, AI administration may help to slow down epiphysial maturation and allow for greater height potential. Research trials in children with short stature have predominantly been done in Finland and Florida. Despite the apparent efficacy described by these groups, only ~110 children worldwide have been treated with AIs in research protocols (and usually concomitant with other growth-promoting agents) as of the end of 2008 (and none to final height). That said, many children are being treated with AI's in the United States outside of research protocols. Furthermore, little is known about the short- and long-term safety of AIs in children. Thus, it is imperative that there be well-designed, long-term studies of efficacy and safety of AI use in pediatric populations.