A randomized clinical trial of the efficacy and safety of sitagliptin as initial oral therapy in youth with type 2 diabetes.

OBJECTIVE: To assess the efficacy and safety of DPP-4 inhibition with sitagliptin in youth with type 2 diabetes (T2D). STUDY DESIGN: This was a 54-week, double-blind, randomized, controlled clinical trial evaluating the safety and efficacy of DPP-4 inhibition with sitagliptin 100 mg once daily as initial oral therapy in youth with T2D. The 190 participants, aged 10-17 years, had HbA1c 6.5%-10% (7.0%-10% if on insulin). All were negative for pancreatic autoantibodies and overweight/obese at screening or diagnosis. The trial was placebo controlled for the first 20 weeks, after which metformin replaced placebo. The primary efficacy endpoint was change from baseline in HbA1c at Week 20. RESULTS: Treatment groups were well balanced at baseline (mean ± SD HbA1c = 7.5% ± 1.0, BMI percentile = 97.1% ± 6.8, age = 14.0 years ± 2.0 [57.4% <15], 60.5% female). At Week 20, least squares mean changes from baseline in HbA1c were -0.01% (sitagliptin) and 0.18% (placebo); between-group difference (95% CI) = -0.19% (-0.68, 0.30), p = 0.448. At Week 54, the changes in HbA1c were 0.45% (sitagliptin) and -0.11 (placebo/metformin). There were no notable between-group differences in the adverse event profiles through Week 54. CONCLUSIONS: DPP-4 inhibition with sitagliptin did not provide significant improvement in glycemic control. In this study, sitagliptin was generally well tolerated with a safety profile similar to that reported in adults. (ClinicalTrials.gov: NCT01485614; EudraCT: 2011-002528-42).

Efficacy and safety of the addition of sitagliptin to treatment of youth with type 2 diabetes and inadequate glycemic control on metformin without or with insulin.

OBJECTIVE: To assess the efficacy and safety of sitagliptin in youth with type 2 diabetes (T2D) inadequately controlled with metformin ± insulin. STUDY DESIGN: Data were pooled from two 54-week, double-blind, randomized, placebo-controlled studies of sitagliptin 100 mg daily or placebo added onto treatment of 10- to 17-year-old youth with T2D and inadequate glycemic control on metformin ± insulin. Participants (N = 220 randomized and treated) had HbA1c 6.5%-10% (7.0%-10% if on insulin), were overweight/obese at screening or diagnosis and negative for pancreatic autoantibodies. The primary endpoint was change from baseline in HbA1c at Week 20. RESULTS: Treatment groups were well balanced at baseline (mean HbA1c = 8.0%, BMI = 30.9 kg/m2 , age = 14.4 years [44.5% <15], 65.9% female). The dose of background metformin was >1500 mg/day for 71.8% of participants; 15.0% of participants were on insulin therapy. At Week 20, LS mean changes from baseline (95% CI) in HbA1c for sitagliptin/metformin and placebo/metformin were -0.58% (-0.94, -0.22) and -0.09% (-0.43, 0.26), respectively; difference = -0.49% (-0.90, -0.09), p = 0.018; at Week 54 the LS mean (95% CI) changes were 0.35% (-0.48, 1.19) and 0.73% (-0.08, 1.54), respectively. No meaningful differences between the adverse event profiles of the treatment groups emerged through Week 54. CONCLUSIONS: These results do not suggest that addition of sitagliptin to metformin provides durable improvement in glycemic control in youth with T2D. In this study, sitagliptin was generally well tolerated with a safety profile similar to that reported in adults. (ClinicalTrials.gov: NCT01472367, NCT01760447; EudraCT: 2011-002529-23/2014-003583-20, 2012-004035-23).

Improving vitamin D testing and supplementation in children with newly diagnosed cancer: A quality improvement initiative at Rady Children's Hospital San Diego.

BACKGROUND: Vitamin D deficiency and insufficiency have been associated with poorer health outcomes. Children with cancer are at high risk for vitamin D deficiency and insufficiency. At our institution, we identified high variability in vitamin D testing and supplementation in this population. Of those tested, 65% were vitamin D deficient/insufficient. We conducted a quality improvement (QI) initiative with aim to improve vitamin D testing and supplementation among children aged 2-18 years with newly diagnosed cancer to ≥80% over 6 months. METHODS: An inter-professional team reviewed baseline data, then developed and implemented interventions using Plan-Do-Study-Act (PDSA) cycles. Barriers were identified using QI tools, including lack of automated triggers for testing and inconsistent supplementation criteria and follow-up testing post supplementation. Interventions included an institutional vitamin D guideline, clinical decision-making tree for vitamin D deficiency, insufficiency and sufficiency, electronic medical record triggers, and automated testing options. RESULTS: Baseline: N = 26 patients, four (15%) had baseline vitamin D testing; two (8%) received appropriate supplementation. Postintervention: N = 33 patients; 32 (97%) had baseline vitamin D testing; 33 (100%) received appropriate supplementation and completed follow-up testing timely (6-8 weeks post supplementation). Change was sustained over 24 months. CONCLUSIONS: We achieved and sustained our aim for vitamin D testing and supplementation in children with newly diagnosed cancer through inter-professional collaboration of hematology/oncology, endocrinology, hospital medicine, pharmacy, nursing, and information technology. Future PDSA cycles will address patient compliance with vitamin D supplementation and impact on patients' vitamin D levels.

Sociodemographic and clinical characteristics associated with vitamin D status in newly diagnosed pediatric cancer patients.

Vitamin D deficiency and insufficiency are associated with serious sequelae in childhood cancer survivors. However, data on vitamin D deficiency in children with newly diagnosed cancer are scarce and the role of sociodemographic factors and vitamin D supplementation is largely unknown. We assessed vitamin D status and its socio-demographic and clinical correlates in 163 children with newly diagnosed cancer, using 25-hydroxy vitamin D (25(OH)D) concentrations and assessed longitudinal changes following vitamin D supplementation. Sixty-five percent of the patients with newly diagnosed cancer had low 25(OH)D concentrations. Fifty-two patients (32%) were vitamin D deficient (≤20 ng/mL 25(OH)D concentration), and 53(33%) were insufficient (21-29 ng/mL 25(OH)D concentration). Age over 10 (P = 0.019), Hispanic ethnicity (P = 0.002), and female sex (P = 0.008) were significantly associated with lower 25(OH)D concentration at diagnosis. Vitamin D supplementation resulted in significant increase in 25(OH)D concentrations (P < 0.001). However, following supplementation in the longitudinal analysis, this increase was less pronounced in Hispanic patients vs. non-Hispanic (P = 0.007), and in children with solid tumors vs. hematological malignancies (P = 0.003). Vitamin D deficiency and insufficiency are common in children with newly diagnosed cancer. Hispanic patients, females and older children were at higher risk for vitamin D deficiency and insufficiency. Although supplementation appeared to increase 25(OH)D concentrations over time, this increase was not as pronounced in certain subsets of patients. Prospective trials of the effects of vitamin D supplementation on bone health in children with newly diagnosed cancer are warranted, particularly in Hispanics and patients with solid tumors.

Non-alcoholic fatty liver disease in pediatric type 2 diabetes: Metabolic and histologic characteristics in 38 subjects.

BACKGROUND: Obesity and type 2 diabetes (T2D) is risk factors for non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH). In children with T2D and liver biopsies, we investigated correlations between NAFLD/NASH and transaminase activity, A1c, lipids, and histologic changes in repeat biopsies. METHODS: Liver histology of children with T2D was evaluated using the NASH CRN scoring system and NAFLD Activity Score (NAS). We included results ≤6 months from biopsy and A1c nearest biopsy. RESULTS: Thirty-eight subjects (21 females, 17 males, 63.2% Hispanic, 15.8% Caucasian) had T2D diagnosed at 13.4 ± 2.7 years, 78.9% using metformin and 50% on insulin. Histological diagnosis of NAFLD occurred at mean age 14.3 ± 2.3 years, notable for NASH in 61%. Steatosis grade was higher in children with NASH than those without (mean 2.6 ± 0.7 vs 2.1 ± 0.5 (P < 0.001). Stage 3 fibrosis was noted only in subjects with NASH (26%). ALT was higher in NASH vs those without (112 ± 56 vs 85 ± 112, P = 0.016). NAS correlated with A1c (r = 0.51, P < 0.01) and triglycerides (r = 0.5, P < 0.01), and inversely with high-density lipoprotein (HDL) (r = -0.42, P = 0.04). Males had lower HDL and higher triglycerides (P < 0.04). In eight subjects with repeat biopsies, NAS was equal (37.5%) or improved (62.5%), and steatosis decreased (68.1% to 32.8%, P = 0.027). CONCLUSIONS: In children with T2D and NAFLD, NASH is common. Having advanced fibrosis in 26% of NASH cases at this age is concerning. Better control of lipids, weight, and diabetes may help avoid worsening in NAS.

Chromosomal rearrangements in the 11p15 imprinted region: 17 new 11p15.5 duplications with associated phenotypes and putative functional consequences.

BACKGROUND: The 11p15 region contains two clusters of imprinted genes. Opposite genetic and epigenetic anomalies of this region result in two distinct growth disturbance syndromes: Beckwith-Wiedemann (BWS) and Silver-Russell syndromes (SRS). Cytogenetic rearrangements within this region represent less than 3% of SRS and BWS cases. Among these, 11p15 duplications were infrequently reported and interpretation of their pathogenic effects is complex. OBJECTIVES: To report cytogenetic and methylation analyses in a cohort of patients with SRS/BWS carrying 11p15 duplications and establish genotype/phenotype correlations. METHODS: From a cohort of patients with SRS/BWS with an abnormal methylation profile (using ASMM-RTQ-PCR), we used SNP-arrays to identify and map the 11p15 duplications. We report 19 new patients with SRS (n=9) and BWS (n=10) carrying de novo or familial 11p15 duplications, which completely or partially span either both telomeric and centromeric domains or only one domain. RESULTS: Large duplications involving one complete domain or both domains are associated with either SRS or BWS, depending on the parental origin of the duplication. Genotype-phenotype correlation studies of partial duplications within the telomeric domain demonstrate the prominent role of IGF2, rather than H19, in the control of growth. Furthermore, it highlights the role of CDKN1C within the centromeric domain and suggests that the expected overexpression of KCNQ1OT1 from the paternal allele (in partial paternal duplications, excluding CDKN1C) does not affect the expression of CDKN1C. CONCLUSIONS: The phenotype associated with 11p15 duplications depends on the size, genetic content, parental inheritance and imprinting status. Identification of these rare duplications is crucial for genetic counselling.

Low vitamin D level in pediatric patients with new onset type 1 diabetes is common, especially if in ketoacidosis.

BACKGROUND: Vitamin D deficiency (VDD) adversely affects bone health. US data on prevalence of VDD or vitamin D insufficiency (VDI) at diagnosis of type 1 diabetes (T1D) is lacking. Low serum 25-hydroxyvitamin D (25OHD) is speculated to increase the risk of developing T1D. OBJECTIVES: Assess the prevalence of pediatric VDD and VDI at diagnosis of T1D, and investigate correlations with demographic and clinical parameters. METHODS: We performed a retrospective Institutional Review Board (IRB)-approved chart review of all T1D cases diagnosed from January 2011 to August 2012, all having the same 25OHD assay performed at Quest Diagnostics. Definitions for VDD, VDI, and vitamin D sufficiency (VDS) were 25OHD levels (ng/mL) ≤ 20, 21-29, and ≥ 30, respectively. We termed 25OHD <30 ng/mL as Low-D. RESULTS: We identified 185 autoantibody positive T1D subjects (51% female) with 25OHD measured, 51% Caucasian, 25% Hispanic, 4% mixed-Hispanic, 4% African American, and 16% other/mixed race. Mean age 9.8 yr (0.9-18.6). Most had Low-D (58%), 40% VDI, 18% VDD, and 42% VDS. No gender or age differences among the 25OHD groups. Low-D was more common (p < 0.0001) in Hispanics (81%) vs Caucasians (44%), but VDD rates were similar. Low-D subjects were heavier than VDS (p = 0.018). All four with elevated celiac titers were VDS. Diabetic ketoacidosis was present in 33%, but more common (44%) in Low-D vs. VDS (18%) (p < 0.0001), and trended higher in VDD (61%) vs. VDI (36%). Seventy-seven percentage with DKA had Low-D. CONCLUSION: VDD and insufficiency are common, even in Caucasians, at onset of T1D in pediatrics, worse in those with DKA.

Lipoprotein particle concentrations in children and adults following Kawasaki disease.

OBJECTIVE: To test the hypothesis that children and adults with a history of Kawasaki disease (KD) are more likely to have abnormal lipoprotein particle profiles that could place them at increased risk for developing atherosclerosis later in life. STUDY DESIGN: Fasting serum samples were obtained from 192 children and 63 adults with history of KD and 90 age-similar healthy controls. Lipoprotein particle concentrations and sizes were measured by nuclear magnetic resonance spectroscopy (LipoScience Inc, Raleigh, North Carolina), and serum was assayed for total cholesterol (TC), triglycerides, and high-density lipoprotein (HDL) cholesterol (HDL-C). Low-density lipoprotein (LDL) cholesterol was estimated using the Friedewald formula. Data were analyzed in a least-square means model, with adjustment for age and sex and with the use of Holm correction for multiple comparisons. RESULTS: Compared with respective control groups, both adult and pediatric subjects with KD had significantly lower mean very low-density lipoprotein-chylomicron particles, intermediate-density lipoproteins, triglycerides, and TC concentrations. Pediatric subjects with KD had significantly lower LDL particle and LDL cholesterol concentrations and lower mean TC/HDL-C ratio (P < .001). In contrast, the adult subjects with KD had significantly lower HDL particle, small HDL particle, and HDL-C concentrations (P < .001), but HDL-C was within normal range. CONCLUSIONS: Nuclear magnetic resonance lipoprotein particle analysis suggests that pediatric and adult subjects with KD, regardless of their aneurysm status, are no more likely than age-similar, healthy controls to have lipid patterns associated with increased risk of atherosclerosis.

Extended Use of Histrelin Implant in Pediatric Patients.

Purpose: Histrelin implant (HI) is a gonadotropin-releasing hormone agonist (GnRHa) used in pediatrics to treat central precocious puberty (CPP) and for pubertal suppression in transgender/non-binary (TG/NB) youth with gender dysphoria. HI is designed for annual removal/replacement; however, effectiveness has been reported beyond 1 year. No previous study has assessed prolonged HI use in TG/NB youth. We hypothesize that HI is effective >12 months in TG/NB youth as described in children with CPP. Methods: This retrospective, two-center study included 49 subjects with 50 HI retained ≥17 months, in TG/NB (42) and CPP (7). Pubertal suppression was assessed biochemically and/or clinically (testicular/breast exams). Escape from pubertal suppression and HI removal is also characterized. Results: Most implants (42/50) maintained clinical/biochemical suppression for the duration of the study. The average use of a single HI was 37.5±13.6 months. Pubertal suppression escape occurred in eight subjects at average 30.4 months from placement: five had only biochemical; two clinical; and one both clinical and biochemical escape. After an average of 32.9 months, only 3/23 HI removed had adverse effects (HI broken, difficult removal). Conclusion: Extended use of HI in our TG/NB and CPP subjects was efficacious, resulting in sustained biochemical and clinical pubertal suppression in most. Suppression escape occurred at 15-65 months. Complications at HI removal were infrequent. Keeping HI for extended time would improve cost and morbidity, while maintaining efficacy and safety for most patients.

Crinecerfont, a CRF1 Receptor Antagonist, Lowers Adrenal Androgens in Adolescents With Congenital Adrenal Hyperplasia.

CONTEXT: Crinecerfont, a corticotropin-releasing factor type 1 receptor antagonist, has been shown to reduce elevated adrenal androgens and precursors in adults with congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21OHD), a rare autosomal recessive disorder characterized by cortisol deficiency and androgen excess due to elevated adrenocorticotropin. OBJECTIVE: To evaluate the safety, tolerability, and efficacy of crinecerfont in adolescents with 21OHD CAH. METHODS: This was an open-label, phase 2 study (NCT04045145) at 4 centers in the United States. Participants were males and females, 14 to 17 years of age, with classic 21OHD CAH. Crinecerfont was administered orally (50 mg twice daily) for 14 consecutive days with morning and evening meals. The main outcomes were change from baseline to day 14 in circulating concentrations of ACTH, 17-hydroxyprogesterone (17OHP), androstenedione, and testosterone. RESULTS: 8 participants (3 males, 5 females) were enrolled; median age was 15 years and 88% were Caucasian/White. After 14 days of crinecerfont, median percent reductions from baseline to day 14 were as follows: ACTH, -57%; 17OHP, -69%; and androstenedione, -58%. In female participants, 60% (3/5) had ≥50% reduction from baseline in testosterone. CONCLUSION: Adolescents with classic 21OHD CAH had substantial reductions in adrenal androgens and androgen precursors after 14 days of oral crinecerfont administration. These results are consistent with a study of crinecerfont in adults with classic 21OHD CAH.

Self-limiting hematuria following growth hormone provocative testing with arginine hydrochloride.

Evaluation of growth hormone (GH) deficiency often involves use of agents that stimulate GH secretion, such as clonidine, glucagon, insulin, levo-dopa or arginine hydrochloride. We present three pediatric cases of benign, macroscopic hematuria in children without pre-existing renal disease following GH stimulation testing with clonidine and arginine hydrochloride. In all cases hematuria resolved spontaneously within 3-4 days without any intervention. This suggests that careful observation in such cases is sufficient and additional costly evaluation may be avoided. Other than six anecdotal cases registered via on-line adverse event reporting system (AERS), this is the first published report to date of painless, macroscopic, self-limiting hematuria after arginine hydrochloride infusion.

Mutational analysis using next generation sequencing in pediatric thyroid cancer reveals BRAF and fusion oncogenes are common.

BACKGROUND: We previously described mutation rates of BRAFV600E, RAS, RET-PTC and PAX8-PPARγ in pediatric subjects with well-differentiated thyroid cancer (WDTC). We expanded the cohort adding next-generation sequencing (NGS) and assessed genotype-phenotype correlations. METHODS: Single-center retrospective cohort examining thyroidectomy tissue blocks from consecutive pediatric WDTC patients between 2001 and 2015. Tissues were analyzed at Quest Diagnostics for BRAF, RAS mutations, RET-PTC and PAX8-PPARγ, and additional fusions, using standalone and NGS tests. WDTC included papillary (PTC), follicular (FTC) and follicular-variant PTC (FVPTC). RESULTS: We genotyped 46 samples (36 females). Mean age at diagnosis was 14.7 years and the cohort comprised of mostly Hispanic (60.9%) and Caucasian (26.1%) patients. Mean follow-up was 3.5 years. Genetic alterations (GA) were noted in 69.6%, with BRAFV600E (n = 11), and RET-PTC (n = 8) detected only in PTC. GA were detected in 2/7 FTC (1 PAX8-PPARγ, 1 NRAS) and 6/10 FVPTC (3 PAX8-PPARγ, 1 STRN-ALK, 1 BRAFK601E, 1 NRAS). Patients with BRAFV600E were predominantly Hispanic (81.8%) and >15 years (81.8%), whereas 87.5% RET-PTC and 50% other-fusions occurred in patients ≤15 years (p = 0.044). Of the 29 PTC patients, 82.8% had GA: BRAFV600E (37.9%), RET-PTC (27.6%), 17.2% other fusion-oncogenes (2 -ALK, 3 -NTRK). Non-RET fusions had the highest vascular invasion (100%, p = 0.042 vs RET-PTC) and frequent lymphatic invasion (80%). GA were most common in PTC with cervical metastasis. CONCLUSIONS: BRAFV600E was the most common single mutation, especially in older and Hispanic adolescents. All fusions combined are more common than BRAFV600E. NGS reveals a genetic basis in most pediatric WDTC, which may have implications for the role of molecular testing and systemic therapy.

Subcutaneous Testosterone Is Effective and Safe as Gender-Affirming Hormone Therapy in Transmasculine and Gender-Diverse Adolescents and Young Adults: A Single Center's 8-Year Experience.

Purpose: To describe our Center's 8-year experience with subcutaneous testosterone (SC-T) as gender-affirming hormone therapy (GAHT) in transmasculine and gender-diverse (TM/GD) youth. Methods: An Institutional Review Board (IRB)-approved retrospective study for 119 TM/GD subjects who started SC-T at age 13-19 and received SC-T for >6 months between 2012 and 2020. Results: SC-T was typically started at 25-50 mg biweekly and dose was escalated at provider's discretion. Over 96% of subjects were on 100-320 mg monthly (divided weekly or biweekly) at last follow-up. There was an overall increase in mean total and free testosterone (T) over the dose range (p=0.003), with mean total and free T levels of 460 ng/dL and 92 pg/mL, respectively, at a monthly SC-T dose of 200 mg. For subjects on SC-T without additional menstrual suppression, 54% had cessation of menses at 140 mg monthly and 97% at 200 mg monthly. On average, menses stopped 4.7 (standard deviation 3.0) months after starting SC-T. There was a decrease in high-density lipoprotein and increase in hematocrit from baseline to follow-up. Body mass index Z-scores did not change significantly with treatment. Mild acne was common; severe acne and significant injection site reactions were uncommon. Sustained hypertension, transaminitis, and dyslipidemia were infrequent. Conclusions: SC-T is well tolerated and effective in reaching recommended T levels and stopping menses in TM/GD youth. Occurrence of serious adverse effects is low and inability to tolerate injections is very uncommon. SC-T is a safe and effective alternative to intramuscular testosterone in initiation and maintenance of GAHT in TM/GD youth.

Diagnostic utility of fine needle aspiration cytology in pediatric thyroid nodules based on Bethesda Classification.

OBJECTIVES: The Bethesda system for reporting cytopathology (TBSRTC) has been widely adopted in the management of thyroid nodules. Based on the limited pediatric data available, the implied malignancy risk for each of the categories may be significantly different in pediatrics vs. adults, especially in the indeterminate categories (Bethesda Class III or IV). We report the diagnostic utility of fine needle aspiration (FNA) biopsy at our institution based on the Bethesda system and the risk of malignancy in each category. METHODS: We retrospectively reviewed all patients who underwent a thyroid FNA at our tertiary pediatric hospital from 12/1/2002 to 11/30/2018. FNA results were classified according to TBSRTC. Patient demographics, cytology, histopathology, radiological and clinical follow-ups were examined. RESULTS: A total of 171 patients were included with 203 cytological samples. Average age at initial FNA was 14.7 years (range 6.9-18.6 years). The numbers of nodules reported for Bethesda categories I-VI were 29, 106, 22, 14, 6 and 26, respectively, and the rate of malignancy was: 13.8, 4.7, 22.7, 35.7, 83.3 and 100%, respectively. Use of ultrasound guidance reduced the non-diagnostic rate from 38.1 to 11.5%. Introduction of on-site adequacy testing further reduced the non-diagnostic rate to 6.5% since 2014. CONCLUSIONS: The risk of malignancy for thyroid nodules in this pediatric cohort is higher than reported in adults. However, rates described here are much closer to adult ranges than previously published pediatric cohorts. The addition of adequacy testing improved the non-diagnostic rate of FNA procedures performed with ultrasound guidance.

Tildacerfont in Adults With Classic Congenital Adrenal Hyperplasia: Results from Two Phase 2 Studies.

CONTEXT: Congenital adrenal hyperplasia due to 21-hydroxylase deficiency (21OHD) is typically treated with lifelong supraphysiologic doses of glucocorticoids (GCs). Tildacerfont, a corticotropin-releasing factor type-1 receptor antagonist, may reduce excess androgen production, allowing for GC dose reduction. OBJECTIVE: Assess tildacerfont safety and efficacy. DESIGN AND SETTING: Two Phase 2 open-label studies. PATIENTS: Adults with 21OHD. INTERVENTION: Oral tildacerfont 200 to 1000 mg once daily (QD) (n = 10) or 100 to 200 mg twice daily (n = 9 and 7) for 2 weeks (Study 1), and 400 mg QD (n = 11) for 12 weeks (Study 2). MAIN OUTCOME MEASURE: Efficacy was evaluated by changes from baseline at 8 am in adrenocorticotropic hormone (ACTH), 17-hydroxyprogesterone (17-OHP), and androstenedione (A4) according to baseline A4 ≤ 2× upper limit of normal (ULN) or A4 > 2× ULN. Safety was evaluated using adverse events (AEs) and laboratory assessments. RESULTS: In Study 1, evaluable participants with baseline A4 > 2× ULN (n = 11; 19-67 years, 55% female) had reductions from baseline in ACTH (-59.4% to -28.4%), 17-OHP (-38.3% to 0.3%), and A4 (-24.2% to -18.1%), with no clear dose response. In Study 2, participants with baseline A4 > 2× ULN (n = 5; 26-63 years, 40% female) had ~80% maximum mean reductions in biomarker levels. ACTH and A4 were normalized for 60% and 40%, respectively. In both studies, participants with baseline A4 ≤ 2× ULN maintained biomarker levels. AEs (in 53.6% of patients overall) included headache (7.1%) and upper respiratory tract infection (7.1%). CONCLUSIONS: For patients with 21OHD, up to 12 weeks of oral tildacerfont reduced or maintained key hormone biomarkers toward normal.

Rapid weight gain in children soon after diagnosis of type 1 diabetes: is there room for concern?

OBJECTIVE: To examine weight status in children at diagnosis (Dx) of type 1 diabetes and observe weight change post-Dx. RESEARCH DESIGN AND METHODS: Data on 136 subjects (76 M/60 F) with type 1 diabetes diagnosed in 1998-2001 at Children's Hospital San Diego was obtained from Institutional Review Board (IRB)-approved database. All patients received two daily insulin injections (NPH/Regular) and were examined at least twice, up to 7 months post-Dx. RESULTS: Average age at Dx (SD) was 9.02 yr (4.46)yr; 63.9% were Caucasian, 25% Mexican American (MA), 2.9% African American, 0.7% Asian, and 7.3% mixed. Diabetic ketoacidosis rate was more common in MA (44.1%) vs. Caucasians (20.9%) at Dx (p < 0.02). Average body mass index Z-score (BMI-Z) at Dx was -0.28 (39th percentile); 13.5% had BMI > or = 85th percentile, and 7.2% were obese. By 2 wk, and 15-41 d post-Dx, mean weight gain was 9% (5.9) and 12.8% (8), respectively. Mean A1C at Dx, 42-70 and 71-139 d later, was 11.4, 7.6, and 6.9%, respectively. Coinciding with improved glycemic control, by 10 wk, mean BMI-Z reached a plateau of 0.86 (80th percentile). On average, MA were heavier than Caucasians at Dx (p = 0.006), and remained heavier. By 71-139 d, 31.7% had BMI > or = 85th percentile and 15.9% were obese; 47.8% of 2- to 5-yr olds had BMI > or = 85th percentile vs. 22.6% nationally (p < 0.005) CONCLUSIONS: Despite the initial weight loss at Dx of type 1 diabetes, by 10-20 wk post-Dx, almost one third were overweight and obese, more so in MA. In light of the obesity epidemic, closer attention to overall caloric intake in children with new onset diabetes is prudent.

The utility of intact parathyroid hormone level in managing hypocalcemia after thyroidectomy in children.

INTRODUCTION: Hypocalcemia is a common complication after thyroidectomy. Intact parathyroid hormone (PTH) has been successfully used as a predictive indicator for hypocalcemia in adults during the postoperative period. We aim to demonstrate the utility of PTH in predicting and managing postoperative hypocalcemia following thyroidectomy in pediatrics. METHODS: The study is a retrospective case series including 38 patients up to 18 years of age who underwent total or completion thyroidectomy from 1/1/2010 to 12/31/2016 at a tertiary pediatric academic center. Patient demographics, pathology, postoperative PTH, serum calcium, and length of stay were analyzed. RESULTS: The median age was 14.3 years (range of 4.3-18.4 years) with 84.2% being female. Thyroid malignancy was noted in 25 patients, and 13 had benign pathology including 8 patients with multinodular goiter and 5 with Grave's disease. In this serie, 63.2% (24/38) developed hypocalcemia (serum calcium <8.5 mg/dL) postoperatively. The median PTH of 15.8 pg/mL in the hypocalcemic group was significantly lower than the median PTH of 41.6 pg/mL in the normocalcemic group (p < 0.001). Using a PTH threshold of 26 pg/mL, hypocalcemia was predicted with a sensitivity of 75%, and specificity of 100%. Six patients with calcium <7.5 mg/dL received teriparatide injections to avoid intravenous calcium replacement. The length of hospital stay for normocalcemic patients was 1.7 ±â€¯0.8 days vs. 2.9 ±â€¯1.4 days for hypocalcemic patients (p = 0.002). We found no correlation between the incidence of hypocalcemia and pathologic indication for surgery. Completion thyroidectomy was associated with a lower risk of hypocalcemia when compared to total thyroidectomy (p = 0.01) and neck dissections carried an increased risk of postoperative hypocalcemia (p = 0.04). CONCLUSION: Postoperative PTH level has an excellent specificity in predicting hypocalcemia in this pediatric cohort using a threshold of PTH ≤ 26 pg/mL. Those with PTH >26 pg/mL may avoid hypocalcemia by oral calcium replacement with outpatient follow-up. We did not identify a reliable PTH cutoff value above which pediatric patients may be safely discharged immediately following surgery. Adult guideline or pathways that advocate for outpatient thyroidectomy surgery based on normal PTH ≥10 pg/mL in the recovery room may not apply to children.

Diagnosis and treatment of a boy with IPEX syndrome presenting with diabetes in early infancy.

IPEX syndrome (Immune dysregulation, Polyendocrinopathy, X-linked) should be tested for in males under 6 months old presenting with diabetes, even without other IPEX features. Early diagnosis and bone marrow transplantation can improve outcomes.

Undescended retropharyngeal parathyroid adenoma with adjacent thymic tissue in a 13-year-old boy with primary hyperparathyroidism.

We describe a rare presentation of a symptomatic parathyroid adenoma located in an ectopic retropharyngeal position in a 13-year-old boy. Preoperative CT scan and MRI demonstrated the ectopic location of the parathyroid adenoma. The patient underwent successful parathyroidectomy with cure of his hyperparathyroidism. On pathologic exam, the specimen was made up of a parathyroid adenoma and adjacent thymic tissue, indicating that it was likely an undescended lower parathyroid gland arising from the third pharyngeal pouch. Ectopic retropharyngeal parathyroid adenomas are very rare and to our knowledge, none have been previously described in adolescents.

Neonatal diabetes mellitus due to a novel variant in the INS gene.

Neonatal diabetes mellitus (NDM) is a rare condition that presents with diabetes in the first few months of life. The treatment of NDM may differ depending on the genetic etiology, with numerous studies showing the benefit of sulfonylurea therapy in cases caused by mutations in KCNJ11 or ABCC8 Mutations in the insulin gene (INS) have also been identified as causes of NDM; these cases are generally best treated with insulin alone. We report a case of a female infant born small for gestational age (SGA) at late preterm diagnosed with NDM at 7 wk of life who was found by rapid whole-genome sequencing to harbor a novel de novo c.26C>G (p.Pro9Arg) variant in the INS gene. She presented with diabetic ketoacidosis, which responded to insulin therapy. She did not respond to empiric trial of sulfonylurea therapy early in her hospital course, and it was discontinued once a genetic diagnosis was made. Early genetic evaluation in patients presenting with NDM is essential to optimize therapeutic decision-making.