Efficacy and Safety of Leuprolide Acetate 6-Month Depot for the Treatment of Central Precocious Puberty: A Phase 3 Study.

Context: Treatment options for central precocious puberty (CPP) are important for individualization of therapy. Objective: We evaluated the efficacy and safety of 6-month 45-mg leuprolide acetate (LA) depot with intramuscular administration. Methods: LA depot was administered at weeks 0 and 24 to treatment-naïve (n = 27) or previously treated (n = 18) children with CPP in a phase 3, multicenter, single-arm, open-label study (NCT03695237). Week 24 peak-stimulated luteinizing hormone (LH) suppression (<4 mIU/mL) was the primary outcome. Secondary/other outcomes included basal sex hormone suppression (girls, estradiol <20 pg/mL; boys, testosterone <30 ng/dL), suppression of physical signs, height velocity, bone age, patient/parent-reported outcomes, and adverse events. Results: All patients (age, 7.8 ± 1.27 years) received both scheduled study doses. At 24 weeks, 39/45 patients (86.7%) had LH suppressed. Six were counted as unsuppressed; 2 because of missing data, 3 with LH of 4.35-5.30 mIU/mL and 1 with LH of 21.07 mIU/mL. Through 48 weeks, LH, estradiol, and testosterone suppression was achieved in ≥86.7%, ≥97.4%, and 100%, respectively (as early as week 4 for LH and estradiol and week 12 for testosterone). Physical signs were suppressed at week 48 (girls, 90.2%; boys, 75.0%). Mean height velocity ranged 5.0 to 5.3 cm/year post-baseline in previously treated patients and declined from 10.1 to 6.5 cm/year at week 20 in treatment-naïve patients. Mean bone age advanced slower than chronological age. Patient/parent-reported outcomes remained stable. No new safety signals were identified. No adverse event led to treatment discontinuation. Conclusion: Six-month intramuscular LA depot demonstrated 48-week efficacy with a safety profile consistent with other GnRH agonist formulations.

An Early Case of Complete Androgen Insensitivity Syndrome.

Inguinal hernias are rare in female infants, and when present, there is an increased incidence of androgen insensitivity in these infants. We present a case of bilateral inguinal hernias in a 26-day-old full-term phenotypic female. On physical exam, the patient was found to have bilateral palpable inguinal masses which were suspected to be testicular tissue on ultrasound. Patient also had bilateral inguinal hernias, but otherwise there were no other concerning symptoms, and the remaining physical examination was overall unremarkable. Initial workup included a pelvic ultrasound that did not visualize a uterus or ovaries. In addition, genetic testing confirmed normal male genotype with 100% 46, on fluorescence in situ hybridization (FISH) and array comparative genomic hybridization (CGH) was negative and did not reveal any copy number changes. Molecular testing was consistent with a diagnosis of androgen insensitivity syndrome with hemizygous pathogenic variant in the androgen receptor (AR) gene (deletion of Exon 2 of AR gene Xq12). This case highlights the importance of a high clinical suspicion of complete androgen insensitivity syndrome (CAIS) in a phenotypic female infant with inguinal hernias. To our knowledge, this is one of the earliest diagnoses of CAIS in a phenotypically female infant.

Case report: 11-ketotestosterone may potentiate advanced bone age as seen in some cases of Wiedemann-Steiner Syndrome.

Context: Wiedemann-Steiner Syndrome (WSS) is a genetic disorder associated with an array of clinical phenotypes, including advanced bone age and short stature. 11-ketotestosterone (11KT) is a member of the group known as 11-oxygenated C19 androgens that are implicated in premature adrenarche. Case description: Case 1: The patient is a 3 year and 11-month-old female diagnosed with WSS due to deletion of KMT2A detected on CGH microarray. At two years and 11 months, imaging revealed an advanced bone age. We obtained an 11KT level on this patient. 11KT in case 1 was elevated at 26.3 ng/dL, while the normal reference range is 7.3-10.9 ng/dL and the reference interval for premature adrenarche is 12.3-22.9 ng/dL, The repeat 11KT at follow up (chronological age 4 years and 6 months) was still elevated at 33.8 ng/dL Case 2: A second child with WSS and a 5kb intragenic KMT2A deletion was evaluated at 11 months of age; his 11KT was 4.5 ng/dL. Conclusions: The elevated 11KT may indicate maturational changes related to increasing adrenal gland androgenic activation and may explain the advanced bone age seen in some patients with WSS. To our knowledge, this is the first case report that describes 11KT as a bioactive androgen potentially causing bone age advancement in WSS. Lack of elevation of 11KT in the second child who is an infant suggests increasing androgenic precursors and metabolites related to premature adrenarche may need to be longitudinally followed.

Diagnostic Test Accuracy of Urine C-peptide Creatinine Ratio for the Correct Identification of the Type of Diabetes: A Systematic Review.

Objective: To examine the accuracy of urine c-peptide creatinine ratio (UCPCR) for identifying the type of diabetes in appropriate clinical settings. Design: Systematic review of test accuracy studies on patients with different forms of diabetes. Data sources: Medline, Embase and Cochrane library databases from 1 January 2000 to 15 November 2020. Eligibility criteria: Studies reporting the use of UCPCR for diagnosing patients with type 1 diabetes mellitus (T1DM), type 2 diabetes mellitus (T2DM) and monogenic forms of diabetes (categorized as maturity-onset diabetes of the young [MODY]). Study selection and data synthesis: Two reviewers independently assessed articles for inclusion and assessed the methodological quality of the studies using the Quality Assessment of Diagnostic Accuracy Studies-2 tool, with input from a third reviewer to reach consensus when there was a dispute. Meta-analysis was performed with the studies reporting complete data to derive the pooled sensitivity, specificity and diagnostic odds ratio (DOR), and narrative synthesis only for those with incomplete data. Results: Nine studies with 4,488 patients were included in the qualitative synthesis, while only four of these (915 patients) had complete data and were included in the quantitative synthesis. All the studies had moderate risk of bias and applicability concerns. Meta-analysis of three studies (n=130) revealed sensitivity, specificity and DOR of 84.4% (95% confidence interval [CI] 68.1-93.2%), 91.6% (82.8-96.1%) and 59.9 (32.8-106.0), respectively, for diagnosing T1DM using a UCPCR cut-off of <0.2 nmol/mmol. For participants with T2DM (three studies; n=739), UCPCR >0.2 nmol/mmol was associated with sensitivity, specificity and DOR of 92.8% (84.2-96.9%), 81.6% (61.3-92.5%) and 56.9 (31.3-103.5), respectively. For patients with MODY in the appropriate clinical setting, a UCPCR cut-off of >0.2 nmol/mmol showed sensitivity, specificity and DOR of 85.2% (73.1-92.4%), 98.0% (92.4-99.5%) and 281.8 (57.5-1,379.7), respectively. Conclusions: Based on studies with moderate risk of bias and applicability concerns, UCPCR confers moderate to high sensitivity, specificity, and DOR for correctly identifying T1DM, T2DM and monogenic diabetes in appropriate clinical settings. Large multinational studies with multi-ethnic participation among different age groups are necessary before this test can be routinely used in clinical practice. Study registration: Protocol was registered as PROSPERO CRD42017060633.

Childhood Hypertriglyceridemia: Is It Time for a New Approach?

PURPOSE OF REVIEW: Hypertriglyceridemia (HTG) is widely prevalent in youth. There is an unmet need for effective medications in the management of HTG in youth. The purpose of this review is to summarize the approach to HTG in acute and chronic settings, and highlight emerging therapies targeted at specific genes, proteins, and enzymes to selectively alter triglyceride (TG) metabolism. RECENT FINDINGS: Genetic and lifestyle factors play a significant role in the pathophysiology of HTG. Severe elevation of TG poses a risk of acute pancreatitis, while mild-to-moderate HTG increases the risk for premature atherosclerotic cardiovascular disease (ASCVD) and, increasingly, has been linked with non-alcoholic fatty liver disease. Although a variety of therapeutic agents are in development, strict adherence to a heart healthy lifestyle, including dietary changes, remain the cornerstone of management for youth with HTG. In addition to lifestyle changes, pharmacological interventions, including fibrates, omega 3 fatty acids, and statins may be considered for management of moderate-to-severe HTG. In view of its association with premature cardiovascular disease (CVD), non-high-density-lipoprotein-C (non-HDL-C) is an important target for therapy in children with moderate HTG. Management of HTG is dependent on its etiology, concomitant symptoms, and degree of TG elevation. The last two decades have seen remarkable changes in drug development, specifically those that act through the lipoprotein lipase complex, including new targeted treatments such as inhibitors of apolipoprotein C3 and angiopoietin-like protein 3.

Novel therapeutic targets and agents for pediatric dyslipidemia.

Landmark studies have convincingly demonstrated that atherosclerosis begins in youth. While generally asymptomatic, an increasing number of youth with disorders of lipid and lipoprotein metabolism, such as familial hypercholesterolemia, are being identified through selective and universal screening. While a heart healthy lifestyle is the foundation of treatment for all youth with dyslipidemia, lipid-lowering therapy may be required by some to prevent morbidity and premature mortality, especially when initiated at a young age. When appropriate, use of statins has become standard of care for reducing low-density lipoprotein cholesterol, while fibrates may be beneficial in helping to lower triglycerides. Many therapeutic options commonly used in adults are not yet approved for use in youth less than 18 years of age. Although currently available lipid-lowering therapy is well tolerated and safe when administered to youth, response to treatment may vary and some conditions lack an efficient therapeutic option. Thus, newer agents are needed to aid in management. Many are in development and clinical trials in youth are currently in progress but will require FDA approval before becoming commercially available. Many utilize novel approaches to favorably alter lipid and lipoprotein metabolism. In the absence of long-term outcome data of youth who were treated beginning at an early age, clinical registries may prove to be useful in monitoring safety and efficacy and help to inform clinical decision-making. In this manuscript, we review currently available and novel therapeutic agents in development for the treatment of elevated cholesterol and triglycerides.

SARS-CoV-2 infection in hospitalized children with type 1 and type 2 diabetes.

CONTEXT: While diabetes is a risk factor for severe illness from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in adults, there is conflicting data surrounding the relationship between the virus and diabetic disease process in children. OBJECTIVE: This case series aims to illustrate an increase in the incidence of types 1 and 2 diabetes mellitus (T1DM, T2DM) between April - November 2020 at a large tertiary care children's hospital and examine the characteristics and adverse outcomes in these children. In addition, two children with significant complications from coronavirus disease 2019 (COVID-19) and diabetes are highlighted. METHODS: Hospitalized children with T1DM or T2DM and SARS-CoV-2 infection were identified, and electronic medical records were reviewed. RESULTS: We observed a 16.3% increased rate of new-onset T1DM and 205.3% increased rate of new-onset insulin-dependent T2DM between April and November 2020 when compared to the same observational time frame in 2019. Among children with new-onset T1DM, 56.9% presented with DKA in 2019 and 47.1% in 2018 compared to 64.3% in 2020, which was higher than the national average. Twenty-eight children were diagnosed with COVID-19 and diabetes during this time. The 2 described cases with significant complications from COVID-19 and DKA required large doses of intravenous insulin over a prolonged duration. CONCLUSION: This study highlights that the COVID-19 pandemic might have led to an increased rate of new-onset T1DM, T2DM, and DKA in children and adolescents compared to a similar time frame in the prior 2 years. The clinical phenotypes and outcomes in children with diabetes to COVID-19 infection may be distinct and therefore, future pediatric specific studies are needed to define the role of SARS-CoV-2.

Case Studies in Pediatric Lipid Disorders and Their Management.

CONTEXT: Identification of modifiable risk factors, including genetic and acquired disorders of lipid and lipoprotein metabolism, is increasingly recognized as an opportunity to prevent premature cardiovascular disease (CVD) in at-risk youth. Pediatric endocrinologists are at the forefront of this emerging public health concern and can be instrumental in beginning early interventions to prevent premature CVD-related events during adulthood. AIM: In this article, we use informative case presentations to provide practical approaches to the management of pediatric dyslipidemia. CASES: We present 3 scenarios that are commonly encountered in clinical practice: isolated elevation of low-density lipoprotein cholesterol (LDL-C), combined dyslipidemia, and severe hypertriglyceridemia. Treatment with statin is indicated when the LDL-C is ≥190 mg/dL (4.9 mmol/L) in children ≥10 years of age. For LDL-C levels between 130 and 189 mg/dL (3.4-4.89 mmol/L) despite dietary and lifestyle changes, the presence of additional risk factors and comorbid conditions would favor statin therapy. In the case of combined dyslipidemia, the primary treatment target is LDL-C ≤130 mg/dL (3.4 mmol/L) and the secondary target non-high-density lipoprotein cholesterol <145 mg/dL (3.7 mmol/L). If the triglyceride is ≥400 mg/dL (4.5 mmol/L), prescription omega-3 fatty acids and fibrates are considered. In the case of triglyceride >1000 mg/dL (11.3 mmol/L), dietary fat restriction remains the cornerstone of therapy, even though the landscape of medications is changing. CONCLUSION: Gene variants, acquired conditions, or both are responsible for dyslipidemia during childhood. Extreme elevations of triglycerides can lead to pancreatitis. Early identification and management of dyslipidemia and cardiovascular risk factors is extremely important.

Glycaemic control and outcomes in children with type 2 diabetes diagnosed at or before 10 years of age.

Background: Type 2 diabetes (T2DM) in children is considered rare before puberty. Objective: Describe the characteristics and outcomes of children with T2DM diagnosed at or before 10 years of age. Methods: Retrospective electronic medical record review of children diagnosed with T2DM at a University Children's Hospital over 12 years was conducted. Patient characteristics at diagnosis, 2-3-year follow-up, and 4-5-year follow-up were analysed as a whole and by age groups, 5-8 and 9-10 years. Results: There were 42 children ≤ 10 years with T2DM (5-8-year age group, n = 8 and 9-10-year age group, n = 34). There were 88.1% African American, 11.9% Caucasian, and 88.1% females. Body mass index (BMI) was ≥95th percentile in 95.2%. Average BMI z score was 2.5 ± 0.4 and higher in the 5-8-year age group (2.7 ± 0.5 vs 2.4 ± 0.4, P = .02). Average haemoglobin A1C at diagnosis was 10.5 ± 2.4%, and improvement was seen at 2-3 years, but subsequent worsening was noted at 4-5 years in both age groups. At 4-5 years after diagnosis, 93.9% required insulin for management of their hyperglycaemia, 21.2% had hypertension requiring treatment, 28.6% had low-density lipoprotein ≥130 mg/dL, and 28.6% had high-density lipoprotein <40 mg/dL. Conclusions: T2DM at or below 10 years of age disproportionately affected females and ethnic minorities and was associated with morbid obesity. The majority of these children did not achieve glycaemic control and required insulin for management of their hyperglycaemia after 4-5 years, indicating the need for increased awareness of T2DM and intensive treatment in this special group.

Association of Slipped Capital Femoral Epiphysis With Panhypopituitarism Due to Pituitary Macroadenoma: A Case Report.

Slipped capital femoral epiphysis (SCFE) commonly occurs in overweight or obese adolescents, but can also be associated with endocrine disorders including hypothyroidism, pituitary tumors, and growth hormone deficiency. In this article, we present a case of panhypopituitarism that initially presented with SCFE. A 16-year-old male presented with right SCFE. After a right hip open reduction and percutaneous pinning procedure, findings of skeletal maturity that lagged behind his chronologic age and a delayed Tanner stage resulted in a referral to an endocrine specialist. Endocrine laboratory evaluation identified elevated prolactin levels (1493 ng/mL), hypogonadotropic hypogonadism, and central adrenal insufficiency as evidenced by low morning cortisol level of 1.0 µg/dL. Magnetic resonance imaging revealed a large pituitary T2 isointense mass measuring 1.8 × 2.7 × 2.3 cm. The patient was diagnosed with panhypopituitarism due to a pituitary macroadenoma. Multidisciplinary collaboration for treatment of this patient consisted of oral cabergoline, oral levothyroxine, oral hydrocortisone therapy, intramuscular testosterone therapy, and a prophylactic closed reduction percutaneous pinning of the left hip due to high risk of also developing SCFE of the left hip. Panhypopituitarism should be considered as a diagnosis after atypical presentations of SCFE. In our case, an astute clinical assessment resulted in prompt endocrine referral and management of panhypopituitarism. Our report highlights the importance of multidisciplinary collaborations to guarantee early detection of endocrinopathies in patients with SCFE undergoing surgical interventions in order to avoid potential complications, such as adrenal crisis during surgery.

Dyslipidemia in Pediatric Type 2 Diabetes Mellitus.

PURPOSE OF REVIEW: Cardiovascular (CV) disease is a major cause of mortality in type 2 diabetes mellitus (T2D). Dyslipidemia is prevalent in children with T2D and is a known risk factor for CVD. In this review, we critically examine the epidemiology, pathophysiology, and recommendations for dyslipidemia management in pediatric T2D. RECENT FINDINGS: Dyslipidemia is multifactorial and related to poor glycemic control, insulin resistance, inflammation, and genetic susceptibility. Current guidelines recommend lipid screening after achieving glycemic control and annually thereafter. The desired lipid goals are low-density lipoprotein cholesterol (LDL-C) < 100 mg/dL, high-density lipoprotein cholesterol (HDL-C) > 35 mg/dL, and triglycerides (TG) < 150 mg/dL. If LDL-C remains > 130 mg/dL after 6 months, statins are recommended with a treatment goal of < 100 mg/dL. If fasting TG are > 400 mg/dL or non-fasting TG are > 1000 mg/dL, fibrates are recommended. Although abnormal levels of atherogenic TG-rich lipoproteins, apolipoprotein B, and non-HDL-C are commonly present in pediatric T2D, their measurement is not currently considered in risk assessment or management.

Osteopetrorickets Presenting with Failure to Thrive and Hypophosphatemia.

Osteopetrosis is a rare group of bone disorders characterized by defective osteoclast bone resorption causing high bone mineral density. A high bone mineral density in combination with defective skeletal mineralization results in a phenotype of osteopetrorickets. We present a rare presentation of infantile osteopetrorickets in an 8-week-old female who presented with failure to thrive, hypophosphatemia, anemia, and thrombocytopenia. A skeletal survey showed increased bone density with rachitic changes. She was found to have a homozygous T-cell immune regulator 1 (TCIRG1) pathogenic mutation consistent with osteopetrosis. This highlights the importance of a clinical suspicion of osteopetrosis with this symptom constellation.

Approach to Hypertriglyceridemia in the Pediatric Population.

Hypertriglyceridemia is increasingly identified in children and adolescents, owing to improved screening and higher prevalence of childhood obesity. Hypertriglyceridemia can result from either increased triglyceride (TG) production or reduced TG clearance. The etiologic origin can be primary (genetic) or secondary, but it is often multifactorial. Management is challenging because of the interplay of genetic and secondary causes and lack of evidence-based guidelines. Lifestyle changes and dietary interventions are most important, especially in hypertriglyceridemia associated with obesity. Dietary restriction of fat remains the mainstay of management in primary hypertriglyceridemia. When fasting TG concentration is increased above 500 mg/dL (5.65 mmol/L), fibrates may be used to prevent pancreatitis. Omega-3 fatty acids are often used as an adjunctive therapy. When the fasting TG concentration is less than 500 mg/dL (5.65 mmol/L) and if the non-high-density lipoprotein cholesterol level is above 145 mg/dL (3.76 mmol/L), statin treatment can be considered.

Unique sex- and age-dependent effects in protective pathways in acute kidney injury.

Sex and age influence susceptibility to acute kidney injury (AKI), with young females exhibiting lowest incidence. In these studies, we investigated mechanisms which may underlie the sex/age-based dissimilarities. Cisplatin (Cp)-induced AKI resulted in morphological evidence of injury in all groups. A minimal rise in plasma creatinine (PCr) was seen in Young Females, whereas in Aged Females, PCr rose precipitously. Relative to Young Males, Aged Males showed significantly, but temporally, comparably elevated PCr. Notably, Aged Females showed significantly greater mortality, whereas Young Females exhibited none. Tissue KIM-1 and plasma NGAL were significantly lower in Young Females than all others. IGFBP7 levels were modestly increased in both Young groups. IGFBP7 levels in Aged Females were significantly elevated at baseline relative to Aged Males, and increased linearly through day 3, when these levels were comparable in both Aged groups. Plasma cytokine levels similarly showed a pattern of protective effects preferentially in Young Females. Expression of the drug transporter MATE2 did not explain the sex/age distinctions. Heme oxygenase-1 (HO-1) levels (~28-kDa species) showed elevation at day 1 in all groups with highest levels seen in Young Males. Exclusively in Young Females, these levels returned to baseline on day 3, suggestive of a more efficient recovery. In aggregate, we demonstrate, for the first time, a distinctive pattern of response to AKI in Young Females relative to males which appears to be significantly altered in aging. These distinctions may offer novel targets to exploit therapeutically in both females and males in the treatment of AKI.

DIABETES AND PREDIABETES ARE SIGNIFICANTLY HIGHER IN MORBIDLY OBESE CHILDREN COMPARED WITH OBESE CHILDREN.

OBJECTIVE: The objective of this study was to examine the prevalence and characteristics of comorbidities in obese and morbidly obese children with a comparison between the 2 sets of children. METHODS: This was a retrospective electronic chart review of obese and morbidly obese children and adolescents as defined by body mass index. We evaluated medical history of comorbid conditions, medication use, and cardiovascular risk markers, including blood pressure, lipid profile, and glycosylated hemoglobin. RESULTS: There were 1,111 subjects (African American = 635; non-Hispanic white = 364; Hispanic = 36; others = 86), of which 274 were obese and 837 were morbidly obese children with a mean age of 12.7 ± 3.37 years. Morbidly obese children had a higher prevalence of prediabetes (19.5% of obese versus 27.3% of morbidly obese; P<.0001) and type 2 diabetes (39.8% of obese versus 52.4% of morbidly obese; P<.0001). Use of medications for treatment of asthma was significantly higher in the morbidly obese group compared with the obese group (21% versus 14%; P = .01). CONCLUSION: Morbidly obese children have a higher prevalence of diabetes, prediabetes, and use of asthma medications compared with obese children.

Distinct populations of label-retaining cells in the adult kidney are defined temporally and exhibit divergent regional distributions.

DNA label-retention, or retention of a thymidine analog, is a characteristic of slow cycling cells and has been used to identify stem cells in several organ systems. Recent findings have demonstrated inconsistent localization of label-retaining cells (LRCs) in the kidney. Differences in the dose and timing of administration of deoxyuridine, the length of the chase period, and the species of animal used have made understanding the distinctions between these findings difficult. In the present studies, we utilized a dual loading scheme in the same animal to demonstrate that the cells labeled at different ages identified independent populations of LRC that distributed globally in an anti-parallel manner in the kidney. Loading with a DNA label in neonates identified LRC more often in the papilla, while administering the DNA label in adult mice identified LRC prominently in the cortex and the outer medulla. Furthermore, the tissue compartment distribution (epithelial-endothelial-interstitial) as well as the specific distribution within the nephron epithelia differed for these populations. These findings highlighted the complexity of the dynamics of cell proliferation in the kidney throughout the postnatal and adult period and call attention to the confusion associated with the term "label-retaining cells" for different timings of the loading and chase periods. This study indicated that the results of previous studies should be viewed as nonoverlapping and that further studies are needed to ascertain the role of each of these populations in the steady-state maintenance and injury recovery of the kidney.