Precocious Puberty and GnRH analogs: Current treatment practices and perspectives amongst US pediatric endocrinologists.

INTRODUCTION: GnRHas are used for treatment of precocious puberty. Over the last decade, several new formulations have been approved. METHODS: The Drugs & Therapeutics subcommittee of the Pediatric Endocrine Society (PES) undertook a review to ascertain the current treatment options, prescribing behaviors, and practices of GnRHas among pediatric endocrinologists practicing within the United States. The survey consisted of four main subsections: 1. Description of clinical practice; 2. Self-assessment of knowledge base of pediatric and adult GnRHa formulations; 3. Current practice for treating CPP; and 4. Utilization of healthcare resources. RESULTS: There were 223 survey respondents. Pediatric endocrine practitioners were most familiar with the pediatric one-monthly preparation, the three-month preparation, and the histrelin implant (Supprelin®) (61.9%, 71.7%, and 34.5%, respectively), with lower familiarity for 24-week triptorelin intramuscular (Triptodur®) and 22.9% and six-month subcutaneous leuprolide (Fensolvi®). Only 23% of the respondents reported being extremely familiar with the availability of adult formulations, and 25% reported being completely unaware of cost differences between pediatric and adult GnRHa preparations. The implant was the most preferred therapy (44.4%), but in practice, respondents reported a higher percentage of patients were treated with 3-month preparation. While family preference/ease of treatment (87%) was the key determinant for using a particular GnRHa preparation, insurance coverage also played a significant role in the decision (65.5%). Responses regarding assessment for efficacy of treatment were inconsistent, as were practices and criteria for obtaining an MRI. CONCLUSIONS: The survey indicated there is more familiarity with older, shorter-acting GnRHas, which are prescribed in greater numbers than newer, longer-acting formulations. There is lack of consensus on the need for CNS imaging in girls presenting with CPP between 6-8 years of age and use of laboratory testing to monitor response to treatment. Insurance requirements regarding CNS imaging and laboratory monitoring are highly variable. Despite having similar constituents and bioavailability there are substantial cost differences between the pediatric and adult formulations and lack of evidence for safe use of these formulations in children. The survey-based analysis highlights the challenges faced by prescribers, while reflecting on areas where further research is needed to provide evidence-based practice guidelines for pediatric endocrinologists.

Pediatric Endocrine Society Statement on Considerations for Use of Teplizumab (Tzield™) in Clinical Practice.

Teplizumab (TzieldTM, Provention Bio), a monoclonal antibody directed at t-cell marker CD3, is the first medication approved by the FDA to delay progression from Stage 2 to Stage 3 type 1 diabetes (T1D). To date, the overwhelming majority of pediatric endocrinologists do not have experience using immunotherapeutics and seek guidance the use of teplizumab in clinical practice. To address this need, the Pediatric Endocrine Society (PES) Diabetes Special Interest Group (Diabetes SIG) and Drug and Therapeutics Committee assembled a task force to review clinical trial data and solicit expert recommendations on the approach to teplizumab infusions. We present considerations on all aspects of teplizumab administration, utilizing evidence where possible and providing a spectrum of expert opinions on unknown aspects. We discuss patient selection and prescreening, highlighting the safety and considerations for monitoring and treatment of side effects. We propose a schedule of events, a protocol for administration and discuss practice management aspects. We advocate for the need for further long-term systematic surveillance studies to continue evaluating the efficacy and safety of teplizumab.

Type 1 and Covid-19: Diagnosis, Clinical Care, and Health Outcomes during the Pandemic.

The coronavirus disease 2019 (COVID-19) pandemic disrupted health care, creating challenges for people with diabetes and health care systems. Diabetes was recognized as a risk factor for severe disease early in the pandemic. Subsequently, risk factors specific for people with type 1 diabetes were identified, including age, hemoglobin A1c level, and lack of continuous glucose monitoring . Telemedicine, especially when accompanied by diabetes data, allowed effective remote care delivery. However, pre-existing racial disparities in access to diabetes technology persisted and were associated with worse outcomes. Events of the COVID-19 pandemic underscore the importance of continuing to develop flexible and more equitable health care delivery systems.

Pharmacologic Weight Management in the Era of Adolescent Obesity.

CONTEXT: Pediatric obesity is a serious health problem in the United States. While lifestyle modification therapy with dietary changes and increased physical activity are integral for the prevention and treatment of mild to moderate obesity in youth, only a modest effect on sustained weight reduction is observed in children and young adults with severe obesity. This underscores the need for additional evidence-based interventions for children and adolescents with severe obesity, including pharmacotherapy, before considering invasive procedures such as bariatric surgery. EVIDENCE ACQUISITION: This publication focuses on recent advances in pharmacotherapy of obesity with an emphasis on medications approved for common and rarer monogenic forms of pediatric obesity. EVIDENCE SYNTHESIS: We review medications currently available in the United States, both those approved for weight reduction in children and "off-label" medications that have a broad safety margin. CONCLUSION: It is intended that this review will provide guidance for practicing clinicians and will encourage future exploration for successful pharmacotherapy and other interventions for obesity in youth.

Increase in newly diagnosed type 1 diabetes in youth during the COVID-19 pandemic in the United States: A multi-center analysis.

BACKGROUND: An increase in newly diagnosed type 1 diabetes (T1D) has been posited during the COVID-19 pandemic, but data are conflicting. We aimed to determine trends in newly diagnosed T1D and severity of presentation at diagnosis for pediatric and adolescent patients during COVID-19 (2020) as compared to the previous year (2019) in a multi-center analysis across the United States. METHODS: This retrospective study from seven centers in the T1D Exchange Quality Improvement Collaborative (T1DX-QI) included data on new onset T1D diagnosis and proportion in DKA at diagnosis from January 1 to December 31, 2020, compared to the prior year. Chi-square tests were used to compare differences in patient characteristics during the pandemic period compared to the prior year. RESULTS: Across seven sites, there were 1399 newly diagnosed T1D patients in 2020, compared to 1277 in 2019 (p = 0.007). A greater proportion of newly diagnosed patients presented in DKA in 2020 compared to 2019 (599/1399(42.8%) vs. 493/1277(38.6%), p = 0.02), with a higher proportion presenting with severe DKA (p = 0.01) as characterized by a pH <7.1 and/or bicarbonate of <5 mmol/L. Monthly data trends demonstrated a higher number of new T1D diagnoses over the spring and summer months (March to September) of 2020 compared to 2019 (p < 0.001). CONCLUSIONS: We found an increase in newly diagnosed T1D and a greater proportion presenting in DKA at diagnosis during the COVID-19 pandemic compared to the prior year. Future longitudinal studies are needed to confirm these findings with population level data and determine the long-term impact of COVID-19 on diabetes trends.

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.

Frequency and characterization of mutations in genes in a large cohort of patients referred to MODY registry.

OBJECTIVES: There have been few large-scale studies utilizing exome sequencing for genetically undiagnosed maturity onset diabetes of the young (MODY), a monogenic form of diabetes that is under-recognized. We describe a cohort of 160 individuals with suspected monogenic diabetes who were genetically assessed for mutations in genes known to cause MODY. METHODS: We used a tiered testing approach focusing initially on GCK and HNF1A and then expanding to exome sequencing for those individuals without identified mutations in GCK or HNF1A. The average age of onset of hyperglycemia or diabetes diagnosis was 19 years (median 14 years) with an average HbA1C of 7.1%. RESULTS: Sixty (37.5%) probands had heterozygous likely pathogenic/pathogenic variants in one of the MODY genes, 90% of which were in GCK or HNF1A. Less frequently, mutations were identified in PDX1, HNF4A, HNF1B, and KCNJ11. For those probands with available family members, 100% of the variants segregated with diabetes in the family. Cascade genetic testing in families identified 75 additional family members with a familial MODY mutation. CONCLUSIONS: Our study is one of the largest and most ethnically diverse studies using exome sequencing to assess MODY genes. Tiered testing is an effective strategy to genetically diagnose atypical diabetes, and familial cascade genetic testing identified on average one additional family member with monogenic diabetes for each mutation identified in a proband.

Hyponatremic Seizures and Adrenal Hypoplasia Congenita in a Neonate with Congenital Diaphragmatic Hernia.

Congenital diaphragmatic hernia (CDH) in neonates may occur as an isolated finding, in association with other anomalies, or as part of a genetic syndrome. We report the first case of an infant with CDH who presented with hyponatremic seizures due to adrenal hypoplasia congenita (AHC). The patient underwent repair of CDH defect. After an uncomplicated postoperative course while on discharge planning, he developed a seizure episode associated with severe hyponatremia and hyperkalemia. Extensive diagnostic workup revealed an NR0B1 gene variant confirming the diagnosis of X-linked AHC. The patient was eventually discharged home on hydrocortisone, fludrocortisone, and salt supplements. There are a few case reports of adrenal insufficiency in neonates with CDH, manifesting with symptoms before and immediately after reparative surgery. Clinical presentation of our patient was unique in manifesting as neonatal seizure secondary to severe hyponatremia after a stable postoperative phase. The patient's electrolytes and hemodynamic status remained stable before, during, and after surgery for CDH. This case underlines the importance of taking detailed family history and continued vigilance for signs and symptoms of adrenal insufficiency in infants with repaired CDH by pediatricians and intensivists.

Pubertal outcome in a female with virilizing adrenocortical carcinoma.

Adrenocortical tumors are neoplasms that rarely occur in pediatric patients. Adrenocortical carcinoma (ACC) is even more uncommon, and is an aggressive malignancy with 5-year survival of 55% in a registry series. There is a lack of information on long-term endocrine outcome in survivors. We describe a 10-year follow-up in a patient who presented at 3 years 5 months with a 1-year history of axillary odor and 6 months' history of pubic hair development with an increased clitoral size. Androgen levels were increased and a pelvic sonogram revealed a suprarenal mass of the left kidney. The tumor was successfully removed. At 6 years 11 months, androgen levels increased again. Workup for tumor recurrence was negative and the findings likely represented early adrenarche. The patient had menarche at an appropriate time and attained a height appropriate for her family.

Improved long-term glucose control in neonatal diabetes mellitus after early sulfonylurea allergy.

BACKGROUND: Activating mutations of the ABCC8 gene can lead to permanent neonatal diabetes mellitus (PNDM). Glucose variability in infants with NDM treated with insulin can be extreme. We report long-term glycemic control in a patient with PNDM on sulfonylurea therapy, despite initial allergic reaction. METHODS: A Chinese girl presented on the first day of life with persistent hyperglycemia. Despite treatment with various insulin regimens, hemoglobin (Hb)A1c (normal 4.8%-6.3%) increased from 5.0% at 14 days of age to a peak of 9.7% at 15 months of age. Her average insulin dose was 0.5 units/kg/day. Genetic analysis revealed two novel ABCC8 gene activating mutations encoding the beta-cell sulfonylurea-1 receptor of the ATP-sensitive potassium channel. At age 3 years 2 months, transition from insulin to the oral sulfonylurea glyburide was initiated. After 8 days, she developed urticaria, palmar erythema, and a diffuse maculopapular rash, which resolved when medication was discontinued. At age 3 years 11 months, glyburide was reintroduced at a very low dose and was increased with concomitant weaning of insulin over the following 6 months. RESULTS: Normoglycemia (HbA1c 5.6%) was achieved on glyburide without any further allergic reaction at the age of 4 years 5 months with improved metabolic control. For the next 3 years, HbA1c measurements, and glucose means and variability were significantly lower compared with values during insulin therapy. CONCLUSIONS: As compared with subcutaneous insulin, oral sulfonylureas improved long-term metabolic control in a patient with NDM caused by novel activating mutations in the ABCC8 gene. Desensitization permitted safe oral sulfonylurea therapy in our patient with NDM despite initial allergic reaction. Fewer episodes of hypoglycemia occurred on sulfonylurea than on insulin therapy, which is an advantage in a very young child.