Correspondence on "Sex steroid priming for growth hormone stimulation testing in children and adolescents with short stature: A systematic review".

Duncan et al. reviewed the response to growth hormone stimulation testing after priming in peripubertal children. The concern is that there is little research documenting the response to growth hormone treatment in patients with sex hormone primed growth hormone stimulation testing and those unprimed. The controversy about priming or not can be summarized as follows: if one wants to know if the production of growth hormone during puberty will be adequate in terms of peak growth hormone responses then stimulation with priming should be done.

Updated consensus guidelines on the management of Phelan-McDermid syndrome.

Phelan-McDermid syndrome (PMS) is a genetic condition caused by SHANK3 haploinsufficiency and characterized by a wide range of neurodevelopmental and systemic manifestations. The first practice parameters for assessment and monitoring in individuals with PMS were published in 2014; recently, knowledge about PMS has grown significantly based on data from longitudinal phenotyping studies and large-scale genotype-phenotype investigations. The objective of these updated clinical management guidelines was to: (1) reflect the latest in knowledge in PMS and (2) provide guidance for clinicians, researchers, and the general community. A taskforce was established with clinical experts in PMS and representatives from the parent community. Experts joined subgroups based on their areas of specialty, including genetics, neurology, neurodevelopment, gastroenterology, primary care, physiatry, nephrology, endocrinology, cardiology, gynecology, and dentistry. Taskforce members convened regularly between 2021 and 2022 and produced specialty-specific guidelines based on iterative feedback and discussion. Taskforce leaders then established consensus within their respective specialty group and harmonized the guidelines. The knowledge gained over the past decade allows for improved guidelines to assess and monitor individuals with PMS. Since there is limited evidence specific to PMS, intervention mostly follows general guidelines for treating individuals with developmental disorders. Significant evidence has been amassed to guide the management of comorbid neuropsychiatric conditions in PMS, albeit mainly from caregiver report and the experience of clinical experts. These updated consensus guidelines on the management of PMS represent an advance for the field and will improve care in the community. Several areas for future research are also highlighted and will contribute to subsequent updates with more refined and specific recommendations as new knowledge accumulates.

Brain injury in children with diabetic ketoacidosis: Review of the literature and a proposed pathophysiologic pathway for the development of cerebral edema.

Cerebral edema (CE) is a potentially devastating complication of diabetic ketoacidosis (DKA) that almost exclusively occurs in children. Since its first description in 1936, numerous risk factors have been identified; however, there continues to be uncertainty concerning the mechanisms that lead to its development. Currently, the most widely accepted hypothesis posits that CE occurs as a result of ischemia-reperfusion injury, with inflammation and impaired cerebrovascular autoregulation contributing to its pathogenesis. The role of specific aspects of DKA treatment in the development of CE continues to be controversial. This review critically examines the literature on the pathophysiology of CE and attempts to categorize the findings by types of brain injury that contribute to its development: cytotoxic, vasogenic, and osmotic. Utilizing this scheme, we propose a multifactorial pathway for the development of CE in patients with DKA.

Improving Outcomes for People with Type 1 Diabetes Through Collaboration: Summary of Type 1 Diabetes Exchange Quality Improvement Collaborative Studies.

Type 1 diabetes (T1D) management has evolved over the last decade. Innovations and groundbreaking research have paved the way for improved outcomes for people with T1D. One of the major T1D focused research network that has supported real-world research studies in the United States is the T1D Exchange Quality Improvement Collaborative (T1DX-QI) Network.T1DX-QI is a large multicenter network of 55 T1D clinics that uses quality improvement, health equity framework, and population health principles to improve outcomes for people with T1D. This article summarizes insights from T1DX-QI clinical and population health improvement studies.

Evolving growth hormone deficiency: proof of concept.

Introduction: We present the evolution of GHD in adolescent males with persistent growth failure, in whom the diagnosis was established after a second GH stimulation test (GST). Methods: We performed a retrospective chart review of children who presented for short stature (height less < 2SD for mean/mid-parental height) and/or growth failure (sustained growth velocity < 0 SD) to pediatric endocrinology at Mount Sinai Kravis Children's Hospital, New York and who had 2 GSTs. Data collected from electronic medical records were analyzed using SPSS v28.0. Results: Of 53 patients included, 42 were males. Average GH peak on initial GST was 15.48 ± 4.92 ng/ml, at 10.07 ± 2.65 years, mean height -1.68 ± 0.56SD(28% had <2SD), IGF-1 -1.00 ± 0.88SD. After 2.23 ± 1.22 years, at 12.04 ± 2.41years, height SDs decreased to -1.82 ± 0.63SD and IGF-1 was -1.08 ± 0.84SD. At repeat GST, average GH peak was 7.59 ± 2.12 ng/dL, with 36% ≤7 ng/dl and 32% in puberty. 12 males reached adult height of 0.08 ± 0.69 SD with a mean height gain of 1.83 ± 0.56SD(p<0.005), IGF-1 of -1.15 ± 0.81SD after 4.64 ± 1.4 years of GH. Conclusion: We offer evidence for Evolving Growth Hormone Deficiency (EGHD) through repeat GST in children with persistent growth slowdown, even with pubertal progression; emphasizing the need for careful longitudinal follow-up to make accurate diagnosis.

Acute Effects of Growth Hormone on the Cellular Immunologic Landscape in Pediatric Patients.

INTRODUCTION: Growth hormone (GH) and the immune system have multiple bidirectional interactions. Data about the acute effects of GH on the immune system are lacking. The objective of our study was to evaluate the acute effects of GH on the immune system using time-of-flight mass cytometry. METHODS: This was a prospective study of pediatric patients who were being evaluated for short stature and underwent a GH stimulation test at a tertiary care center. Blood samples for immunologic markers, i.e., complete blood count (CBC) and time of flight mass cytometry (CyTOF), were collected at baseline (T0) and over the course of three hours (T3) of the test. Differences in immune profiling in patients by timepoint (T0, T3) and GH response (growth hormone sufficient (GHS) versus growth hormone deficient (GHD)) were calculated using a two-way ANOVA test.  Results: A total of 54 patients (39 boys and 15 girls) aged five to 18 years were recruited. Twenty-two participants tested GHD (peak GH <10 ng/ml). The CyTOF analysis showed a significant increase from T0 to T3 in granulocyte percentage, monocyte count, and dendritic cell (DC) count; in contrast, a significant decrease was seen in T lymphocytes (helper and cytotoxic) and IgD+ B lymphocytes. The CBC analysis supported these findings: an increase in total white blood cell count, absolute neutrophil count, and neutrophil percentage; a decrease in absolute lymphocyte count, lymphocyte percentage, absolute eosinophil count, and absolute monocyte count. No significant differences were found between CBC/CyTOF measurements and GH status at either time. CONCLUSIONS: This study provides the first high-resolution map of acute changes in the immune system with GH stimulation. This implies a key role for GH in immunomodulatory function.

Characteristics of diabetes after pediatric liver transplant.

Studies of DALT in pediatric recipients describe incidence and risk factors, but diagnostic criteria varied. This study reports characteristics and course of pediatric DALT by established diabetes criteria. Retrospective chart review of pediatric LT recipients evaluated for hyperglycemia (1/1/1997-12/30/2009) and matched, non-diabetic controls. DALT: random blood glucose >11.1 mm, ≥ 2 times, with insulin treatment. DALT diagnosed in 8.0% (24/300) included 7/24 (29.2%) with severe hyperglycemia (>27.7 mm), ketoacidosis in 2/24 (8.3%). At diagnosis, age was ≥ 11 yr old in 22/24 (91.7%); body mass was lean (BMIz -0.2 ± 1.5). Mean blood glucose was 24.6 mm with negative diabetes autoantibodies (19/19) and elevated C-peptide (2.3 nm). DALT onset median 5.0 months included 29.1% >12 months. Insulin duration median 4.6 months included 41.7% >6 months. DALT resolved in 83.3% over 4.9 (0.9-9.1) yr. DALT differed from controls by increased preceding rejections, prednisolone dose, tacrolimus level, and triple immunosuppression (all p < 0.01). In conclusion, pediatric DALT occurred in non-obese adolescents with insulin resistance, distinct from diabetes types 1 or 2. DALT was associated with preceding rejection and increased immunosuppression. Blood glucose monitoring, especially during increased immunosuppression following LT, could allow early diagnosis and reduce morbidity.

Late-Onset Isolated Growth Hormone Deficiency.

Two male patients, who presented at 13.5 and 13.9 years of age with growth failure and short stature, were ultimately diagnosed with isolated growth hormone deficiency (GHD). Patient 1 was first evaluated when his height declined from -0.67 SD to -1.3 SD. He had a peak growth hormone (GH) concentration to GH stimulation test (GHST) of 16.9 ng/mL (16.9 µg/L) and remained untreated. As puberty advanced, his height decreased further to -1.65 SD. A second GHST while his serum testosterone was 79 ng/dL (2.74 nmol/L) had a peak GH of 5.4 ng/mL (5.4 µg/L), consistent with GHD. He was treated with GH for 4.8 years and reached adult height of 180.5 cm (0.57 SD), gaining 2.22 SDS. Patient 2, height -2.63 SD, had an unstimulated peak GH concentration of 19 ng/mL (19 µg/L). As puberty advanced, his height decreased further to -2.96 SD. Repeat peak GH concentration was 9.2 ng/mL (9.2 µg/L) when serum testosterone was 83.9 ng/dL (2.91 nmol/L). GH treatment resulted in rapid increase of height velocity from 1.8 cm/year to 11.3 cm/year in 6 months, consistent with GHD. Both patients demonstrate that GHD may develop over time and cannot be excluded by a single GHST. Longitudinal monitoring of children with poor growth as puberty progresses is essential to uncover GHD.

An Observational Crossover Study of People Using Real-Time Continuous Glucose Monitors Versus Self-Monitoring of Blood Glucose: Real-World Evidence Using EMR Data From More Than 12,000 People With Type 1 Diabetes.

BACKGROUND: We used real-world electronic health record (EHR) data to examine HbA1c levels among children and adults with type 1 diabetes (T1D) who are classified as continuous glucose monitor (CGM) users after T1D diagnosis and switch to self-monitoring of blood glucose (SMBG) during follow-up, versus people who opt for SMBG after T1D diagnosis and switch to CGM during follow-up visits. METHODS: We conducted an observational, case-crossover study using electronic medical record (EMR) data from the T1D Exchange Quality Improvement Collaborative. The primary outcome in this study was HbA1c. Baseline HbA1c levels were taken at the index date, corresponding to initial device classification, and compared with HbA1c value recorded at the clinic visit following device switch. RESULTS: Of all patients classified in the SMBG group, 7,706 switched to CGM use within the 5-year study time frame, and 5,123 of all initial CGM users switched to SMBG within the study time frame and were included in this analysis. At baseline, median (interquartile range [IQR]) HbA1c for SMBG use was 8.1 (2.4), whereas postcrossover to CGM use, there was a decline in median (IQR) levels to 7.7 (1.9) (P < .001). For baseline CGM users, median (IQR) HbA1c levels were 7.9 (2.0), and postcrossover to SMBG, median (IQR) HbA1c levels increased to 8.0 (2.9) (P < .001). CONCLUSION: We found that people who switched to CGM use had significantly improved HbA1c levels compared to those who switched to glucose monitoring with SMBG.

International Consensus Guideline on Small for Gestational Age: Etiology and Management From Infancy to Early Adulthood.

This International Consensus Guideline was developed by experts in the field of small for gestational age (SGA) of 10 pediatric endocrine societies worldwide. A consensus meeting was held and 1300 articles formed the basis for discussions. All experts voted about the strengths of the recommendations. The guideline gives new and clinically relevant insights into the etiology of short stature after SGA birth, including novel knowledge about (epi)genetic causes. Further, it presents long-term consequences of SGA birth and also reviews new treatment options, including treatment with gonadotropin-releasing hormone agonist (GnRHa) in addition to growth hormone (GH) treatment, as well as the metabolic and cardiovascular health of young adults born SGA after cessation of childhood GH treatment in comparison with appropriate control groups. To diagnose SGA, accurate anthropometry and use of national growth charts are recommended. Follow-up in early life is warranted and neurodevelopment evaluation in those at risk. Excessive postnatal weight gain should be avoided, as this is associated with an unfavorable cardiometabolic health profile in adulthood. Children born SGA with persistent short stature < -2.5 SDS at age 2 years or < -2 SDS at 3 to 4 years of age, should be referred for diagnostic workup. In case of dysmorphic features, major malformations, microcephaly, developmental delay, intellectual disability, and/or signs of skeletal dysplasia, genetic testing should be considered. Treatment with 0.033 to 0.067 mg GH/kg/day is recommended in case of persistent short stature at age of 3 to 4 years. Adding GnRHa treatment could be considered when short adult height is expected at pubertal onset. All young adults born SGA require counseling to adopt a healthy lifestyle.

Which obese youth are at increased risk for type 2 diabetes? Latent class analysis and comparison with diabetic youth.

PURPOSE: Most obese youth screened for diabetes have normal fasting glucose levels. Identification of youth with increased risk for type 2 diabetes (T2D) is needed within this large population to guide further management. METHODS: Retrospective chart review was performed for obese youth, 8-20 yr old, who met American Diabetes Association criteria for screening (OB) or had T2D (D). Measures included body mass index z-score (BMIz) and homeostasis model assessment of insulin resistance (HOMA-IR) by fasting plasma glucose (FPG) and insulin. Statistics compared OB with D and further examined OB by latent class analysis (LCA). RESULTS: Normal FPG was found in 91.5% of all obese youth (OBt n = 94) Comparison of OB with normal FPG (OBng; n = 86) and D (n = 44) was significant for family history of T2D (p = 0.008) without other associations. Evaluation of OBng by LCA showed three classes with increasing BMIz and HOMA-IR. Class 3 (32.5%; BMIz 2.66 ± 0.38; HOMA-IR 6.72 ± 2.29) differed from classes 1 and 2 (p < 0.05), and was associated with family history of T2D. CONCLUSION: Currently recommended screening of obese youth by FPG is normal in 91.5%, but lacks further information to detect increased risk for youth-onset T2D. Evaluation of obese youth by LCA identified one third (class 3) in whom the combination of higher levels of BMIz, HOMA-IR, and family history suggests the greatest risk for T2D and targets them for further evaluation and intensive preventative management.

Growth Hormone Stimulation Testing: To Test or Not to Test? That Is One of the Questions.

The evaluation of children with short stature includes monitoring over a prolonged period to establish a growth pattern as well as the exclusion of chronic medical conditions that affect growth. After a period of monitoring, evaluation, and screening, growth hormone stimulation testing is considered when the diagnosis of growth hormone deficiency (GHD) is entertained. Though flawed, growth hormone stimulation tests remain part of the comprehensive evaluation of growth and are essential for the diagnosis of growth hormone (GH) deficiency. Variables including testing length, growth hormone assay and diagnostic cut off affect results. Beyond the intrinsic issues of testing, results of GH stimulation testing can be influenced by patient characteristics. Various factors including age, gender, puberty, nutritional status and body weight modulate the secretion of GH.

Identifying and addressing disparities in the evaluation and treatment of children with growth hormone deficiency.

Health disparities are a significant cause of concern globally and in the United States. Disparities have been additionally highlighted throughout the ongoing COVID-19 pandemic during which populations of color have been the most affected by the disease. Social determinants of health, race, ethnicity, and gender have all contributed to disparate outcomes and disparities spanning all age groups. Multiple socio-ecological factors contribute to disparities and different strategies have been proposed. The purpose of this paper is to provide an overview of disparities in pediatric treatment and outcomes, with a focus on children with endocrine disorders.

Fasting Serum IGFBP-1 as a Marker of Insulin Resistance in Diverse School Age Groups.

Introduction: The known markers of insulin resistance in obese children are well studied. However, they require serial measurements and complicated calculations. The objective is to study IGFBP-1 and its relation with other known risk measures. Materials and Methods: The study included 98 New York City school students of diverse ethnic/racial backgrounds (57 males and 41 females), 11-15 years of age. Subjects were enrolled in a cross-sectional study, and anthropometric measures were collected. They underwent fasting intravenous glucose tolerance tests (IVGTT), and glucose, insulin, lipids, IGFBP-1, adiponectin and inflammatory markers were collected. Results: The subjects were stratified into 3 groups based upon the BMI Z-score. Out of all the subjects, 65.3% were in the group with a BMI Z-score <1 SDS, 16.3% subjects were in the group with a BMI Z-score of 1 to 2 SDS, and 18.4% of the subjects were in the group with a BMI Z-score of more than 2 SDS. The group with a BMI Z-score of more than 2 SDS had increased waist circumference (WC), body fat, increased fasting insulin, and triglycerides (TG). This group had decreased levels of adiponectin and HDL and low IGFBP-1 as compared to the group with BMI <1 SDS. The group with a BMI Z-score of 1 to 2 SDS had a decreased level of IGFBP-1 as compared to the group with a BMI Z-score less than 1 SDS. IGFBP-1 inversely correlated with age, WC, BMI, body fat, TG, and insulin levels. IGFBP-1 positively correlated with adiponectin and HDL levels. Conclusion: IGFBP-1 in children can identify the presence of insulin resistance in the group with BMI 1 to 2 SDS, even before the known markers of insulin resistance such as elevated triglycerides and even before decreased HDL and adiponectin levels are identified.

Trends in Type 1 Diabetic Ketoacidosis During COVID-19 Surges at 7 US Centers: Highest Burden on non-Hispanic Black Patients.

CONTEXT: The impact of the COVID-19 pandemic on individuals with type 1 diabetes remains poorly defined. OBJECTIVE: We examined United States trends in diabetic ketoacidosis (DKA) among individuals with type 1 diabetes (T1D) during the COVID-19 pandemic at 7 large US medical centers and factors associated with these trends. METHODS: We compared DKA events among children and adults with T1D during COVID-19 surge 1 (March-May 2020) and COVID-19 surge 2 (August-October 2020) to the same periods in 2019. Analysis was performed using descriptive statistics and chi-square tests. RESULTS: We found no difference in the absolute number of T1D patients experiencing DKA in 2019 vs 2020. However, a higher proportion of non-Hispanic Black (NHB) individuals experienced DKA in 2019 than non-Hispanic White (NHW) individuals (44.6% vs 16.0%; P < .001), and this disparity persisted during the COVID-19 pandemic (48.6% vs 18.6%; P < .001). DKA was less common among patients on continuous glucose monitor (CGM) or insulin pump in 2020 compared to 2019 (CGM: 13.2% vs 15.0%, P < .001; insulin pump: 8.0% vs 10.6%, P < .001). In contrast to annual DKA totals, a higher proportion of patients had DKA during COVID-19 surges 1 and 2 compared to the same months in 2019 (surge 1: 7.1% vs 5.4%, P < .001; surge 2: 6.6% vs 5.7%, P = .001). CONCLUSION: DKA frequency increased among T1D patients during COVID-19 surges with highest frequency among NHB patients. DKA was less common among patients using CGM or insulin pumps. These findings highlight the urgent need for improved strategies to prevent DKA among patients with T1D-not only under pandemic conditions, but under all conditions-especially among populations most affected by health inequities.

Pelvic ultrasonography in the evaluation of central precocious puberty: comparison with leuprolide stimulation test.

OBJECTIVE: To compare the ovarian and uterine structure demonstrated sonographically with baseline and leuprolide-stimulated luteinizing hormone (LH) and estradiol values in females with suspected precocious puberty. STUDY DESIGN: Retrospective chart review. Fifty females (age 3.1 to 9.5 years) underwent stimulation testing with leuprolide (20 µg/kg) and pelvic ultrasonography. Subjects were grouped as (1) prepubertal (baseline and stimulated LH and estradiol in prepubertal range); (2) early pubertal (baseline LH and estradiol in prepubertal range but stimulated LH or estradiol in pubertal range); and (3) pubertal (baseline and stimulated LH or estradiol in pubertal range). Sonographic data were compared with baseline and leuprolide-stimulated LH and estradiol. RESULTS: Baseline and stimulated LH and stimulated estradiol significantly correlated with ovarian and uterine volumes. Ovarian and uterine volumes were significantly higher in females in the pubertal group than in females in the prepubertal group. No significant differences were noted in the ovarian or uterine dimensions between the prepubertal and early pubertal groups. There was significant overlap in ovarian and uterine volumes among females in all three groups. CONCLUSION: Contrary to leuprolide stimulation, pelvic ultrasonography alone cannot distinguish between prepubertal females and those in the early stages of puberty.

Growth failure: 'idiopathic' only after a detailed diagnostic evaluation.

The terms 'idiopathic short stature' (ISS) and 'small for gestational age' (SGA) were first used in the 1970s and 1980s. ISS described non-syndromic short children with undefined aetiology who did not have growth hormone (GH) deficiency, chromosomal defects, chronic illness, dysmorphic features or low birth weight. Despite originating in the pre-molecular era, ISS is still used as a diagnostic label today. The term 'SGA' was adopted by paediatric endocrinologists to describe children born with low birth weight and/or length, some of whom may experience lack of catch-up growth and present with short stature. GH treatment was approved by the FDA for short children born SGA in 2001, and by the EMA in 2003, and for the treatment of ISS in the US, but not Europe, in 2003. These approvals strengthened the terms 'SGA' and 'ISS' as clinical entities. While clinical and hormonal diagnostic techniques remain important, it is the emergence of genetic investigations that have led to numerous molecular discoveries in both ISS and SGA subjects. The primary message of this article is that the labels ISS and SGA are not definitive diagnoses. We propose that the three disciplines of clinical evaluation, hormonal investigation and genetic sequencing should have equal status in the hierarchy of short stature assessments and should complement each other to identify the true pathogenesis in poorly growing patients.

Graves disease in infancy: a patient presentation and literature review.

SUMMARY: We describe a case of an infant who presented with clinical features of hyperthyroidism. The child was found to be tachycardic, hypertensive and diaphoretic, she was noted to have poor weight gain and difficulty in sleeping. The child was admitted to the pediatric intensive care unit for care. She was found to have biochemical evidence of hyperthyroidism with positive thyroid stimulating immunoglobulin. She responded well to methimazole and propranolol and had a remarkable recovery. She is the youngest patient to be diagnosed with Graves disease in the English literature, at 12 months of life. LEARNING POINTS: Hyperthyroidism must always be considered even at very young age, for patient presenting with poor weight gain and hyperdynamic state. Autoimmune diseases are becoming more common in infancy. Craniosynostosis and increased height for age are well-documented consequences of untreated hyperthyroidism in developing children.

Clinical findings influencing time to menarche post gonadotropin-releasing hormone agonist therapy in central precocious puberty.

PURPOSE: This study aimed to evaluate the time interval to menarche after gonadotropin-releasing hormone agonist (GnRHa) treatment in females with central precocious puberty (CPP) and to identify factors contributing to timing of menarche. METHODS: We retrospectively reviewed medical records of 39 females with CPP who reached menarche after GnRHa treatment (leuprolide or histrelin). CPP diagnostic criteria were breast development at <8 years old, measurable pubertal luteinizing hormone and/or estradiol concentrations, and bone age advancement. Indications to treat were advanced bone age and psychosocial concerns. Descriptive summaries were reported as frequency and proportion for categorical variables and mean and standard deviation for continuous measures. Linear regression models were developed to evaluate the associations of clinical factors with the time interval to menarche. RESULTS: Mean age was 9.4±1.6 years at treatment onset, and treatment duration was 2.2±1.4 years. Menarche occurred at 12.6±1.1 years, which was 1.04±0.5 years after treatment discontinuation. This was negatively associated with Tanner stage of breast development and bone age at treatment onset and change in bone age during treatment. No association was seen between time interval to menarche and treatment duration, medication, or body mass index. CONCLUSION: We found the average time interval to menarche after GnRHa treatment in our population of female patients with CPP to be 1.04±0.5 years; this is in agreement with other reports. Tanner stage of breast development, bone age at treatment onset, and change in bone age were negatively associated with time interval to menarche. These data provide clinical correlates that assist providers during anticipatory guidance of patients with CPP after GnRHa treatment.