bluuebunny/crossref_metadata_2025 huggingface dataset:
Association Between Hyperinsulinemia and Helicobacter Pylori Infection
Authors: Hayes Dorado Juan Pablo
Published: May 2021

Introduction: The association between Helicobacter pylori infection and hyperinsulinemia and insulin resistance has been described. Objective: To investigate the frequency of hyperinsulinemia and insulin resistance in adolescents with Helicobacter pylori infection. Materials and Methods: Prospective, observational and analytical study. Adolescents with Helicobacter pylori infection; July 2019 - June 2020 period. Exclusion criteria: Obesity, hypothyroidism, hepatopathy, nephropathy, collagen disease, corticotherapy, use of proton pump inhibitors and H2 antihistamines. Variables: Antibodies against Helicobacter pylori; fasting plasma glucose and insulinemia, 2-hour plasma glucose and insulinemia after oral glucose tolerance test (OGTT); determination of the insulin resistance index by the Homeostasis Model Assessment (HOMA-IR). Two groups of patients: Those with Helicobacter pylori infection and the other of uninfected adolescents. Results: Patients attended: 34; studied: 19; excluded: 15. Group of non-infected: 20. The HOMA-IR value was 2.5 + -0.8 in adolescents with Helicobacter pylori infection and 1.8 + -0.6 (p = 0.02) in uninfected patients. Conclusions:The values of insulinemia and HOMA-IR were higher in the group of adolescents with Helicobacter pylori infection, compared to those evidenced in the group of uninfected.
Hyperglycemic Emergencies in Minority Children and Adolescents With Diabetes Mellitus
Authors: Badran Ahmed , Thakkar Amruta , Galetaki Despoina , Miller Assia , Umpaichitra Vatcharapan , Bargman Renee , Chin Vivian L
Published: May 2021

Introduction: Hyperglycemic emergencies in children with diabetes traditionally include diabetic ketoacidosis (DKA) predominantly associated with T1DM, whereas hyperosmolar hyperglycemic state (HHS) that is associated with relative insulin deficiency in T2DM, rarely occurs (2%). There have been increasing reports of mixed DKA-HHS affecting up to 27%. The purpose of this study is to identify clinical features, risk factors, complications and outcomes among minority children presenting with hyperglycemic emergencies at our center. Methods: This is a retrospective chart review of children and adolescents (ages 1-21 years) admitted for hyperglycemic emergencies including DKA [defined as glucose >200 mg/dL, metabolic acidosis (pH <7.3 or serum bicarbonate <15 mmol/L) and ketonemia (ß-hydroxybuyrate ≥3 mmol/L) or moderate to large ketonuria], or HHS [defined as glucose >600 mg/dL, effective serum osmolality >320 mOsm/kg, venous pH >7.25 or arterial pH >7.30 or serum bicarbonate >15 mmol/L, absent to mild ketonemia] or mixed DKA-HHS between 2004 and 2019. Descriptive statistics, chi-squared analysis and t-tests were used. Results: Of 322 patients, 92% were African American with mean age 13.6 ± 3.5 years, 39% males, consisting of 266 (83%) with DKA, 52 (16%) mixed DKA-HHS, and 4 (1%) HHS. Ninety-eight of the DKA and DKA-HHS groups had T1DM. All 4 patients with HHS had T2DM. Compared to the DKA group, the mixed DKA-HHS group required higher IV fluids rates (p<0.0001), 4.3-fold greater odds of acute kidney injury (AKI, mean serum creatinine of 1.6 mg/dl vs 1.1 mg/dl; ref 0.5-1.0 mg/dL) and 3.3-fold greater odds of developing altered mental status (AMS). Risk factors such as insulin adherence, and precipitating factors like infection or stress were not different between both groups (p=0.06). There was no significant difference in insulin rates or time to resolution (p=0.4) in both groups. Among the HHS group, 50% presented with AMS and AKI (mean Cr 1.1 mg/dl ± 0.31) due to severe dehydration and required higher IV fluids rates (≥2 x maintenance). Creatinine kinase in 2 patients were slightly elevated (mean 1643 units/L, ± 77; ref 39-309). Insulin drip at 0.05 u/kg/hour was started in all 4 patients. None had venous thrombosis, rhabdomyolysis, cerebral edema, or death. Average time of resolution was 10 ±1.63 hours. Conclusion: In this study, 16% of patients with hyperglycemic emergencies presented with mixed DKA-HHS which was associated with more complications compared to the DKA group. Serum osmolality should be calculated and checked at diagnosis. Identification of hyperosmolality whether with or without DKA in the emergency setting is important because treatment should be focused on the degree of dehydration (usually moderate to severe) and other complications such as AKI and mental status changes.
Insulin Basal Dose Is Associated With Better Metabolic Control in Type 1 Diabetes Children and Adolescents
Authors: Arellano-Llamas Abril , Mejía-Carmona Luz Elena , Rojas-Zacarias Alicia , Ochoa-Romero Oscar , Díaz-Rodríguez Irene
Published: May 2021

Basal insulin dose in type 1 diabetes has been established empirically, since 2011 all guidelines suggest insulin basal dose less than 50% of total insulin dose in the pediatric population. However, in real life, basal dose indication has not changed in all patients in the basal-bolus treatment scheme. Objective: To measure how the physician indicates in real-life basal insulin dose in pediatric patients with type 1 diabetes in the basal-bolus scheme, and correlate this dose with metabolic control measured by glycated hemoglobin. Methods. This was a retrospective study, subjects include pediatric T1D (2 to 16 years, non-obese, using insulin more than 0.3 UI/Kg/d), more than 1 year of diagnostic, none of them in ketoacidosis, attended during 2019. The protocol was revised and accepted in the institution. Data were analyzed with Kruskal-Wallis, U Mann Withney, Pearson correlation test. Results: There were 141 subjects, male (51%), median age 13.3 years (3.6-15.9), median evolution time since diagnosis 8 years (1-14), pre-pubertal (Tanner stage 1, 22%), total daily dose 1.02 UI/Kg/d (0.3-2.19 UI/Kg/d). Basal insulin was glargine 50.4%, and NPH 49.6%, prandial insulin was lispro 66.7%, and regular human 29.8%. Children using 50% or less basal insulin of total insulin dose was 40.4%. The basal dose was 38% of total insulin dose in children less than 6 years, and 59% in children older than 6 years. (p=0.033). Glycated hemoglobin was less than 7.5% in 12.8%. The persons with glycated hemoglobin less than 7.5% used less basal insulin 0.38 u/kg/d, than those with higher glycated hemoglobin 0.57 U/kg/d (p=0.02) with no impact in total insulin dose (0.86 vs 1.05 UI/Kg/d, p=0.129). The correlation of the percentage of insulin basal dose and glycated hemoglobin was 0.279, p=0.001, meaning, more basal insulin, worse diabetes control. Conclusion: Lower basal insulin dose percentage from total daily dose is associated with better metabolic control in children treated with the basal-bolus scheme. There is high clinical inertia in the indication of basal insulin in older children.
Insulin Growth Factor 1 Predicts Central Precocious Puberty in Girls 6 to 8 Years-Old: A Retrospective Study
Authors: Escagedo Patricia Diaz , Deal Cheri L , Dwyer Andrew , Hauschild Michael
Published: May 2021

Background: Central precocious puberty (CPP) in females is characterized by thelarche before 8 years of age. Evidence of reproductive axis activation confirms the diagnosis (basal serum LH ≥ 0.3 IU/L or luteinizing hormone-releasing hormone (LHRH)-stimulated LH ≥ 5 IU/L. Stimulation testing is the diagnostic gold standard but is time-consuming and costly. Serum levels of insulin-like growth factor-1 (IGF-1) and insulin-like growth factor-binding protein 3 (IGFBP-3) are increased in girls with CPP. Objective: To assess the utility of serum IGF-1 and IGFBP-3 in identifying CPP in girls aged 6 to 8 years old. Methods: The study was a single-center retrospective study. Girls with confirmed CPP (n=44) and isolated premature adrenarche/thelarche (PA/PT, n=16) had baseline biochemical profiling and LHRH stimulation testing. Serum IGF-1 and IGFBP-3 results were converted to standard deviation scores (SDS). Correlations were calculated and receiver operating characteristic curves were plotted. Results: Girls with CPP had higher basal and peak LH, IGF-1 SDS, and growth velocity (p<0.05). IGF-1 SDS correlated positively with basal and peak LH (p<0.05). IGF-1 SDS (1.75-2.15) differentiated CPP and PA/PT with 89% sensitivity and 56% specificity (basal LH) and 94% specificity and 55% sensitivity (peak LH). IGFBP-3 SDS did not differ between groups or by CPP parameters. Conclusions: In clinical practice, IGF-1 SDS may be an additional tool for identifying CPP in girls aged 6 to 8 years-old when baseline clinical and laboratory diagnostic criteria are inconclusive, possibly avoiding more invasive procedures.
Investigating Insulin Resistance in Pediatric Cardiomyopathy - A Pilot Study
Authors: Mak Daniel , Ryan Kaitlin A , Han Joan C
Published: May 2021

Children with cardiomyopathy are a vulnerable population and understanding the factors that contribute to cardiac dysfunction are of great importance. At the biochemical level, energy utilization by cardiomyocytes during stress may provide insight into the progression of cardiomyopathy. There is a large body of literature that describes insulin resistance in adults with cardiomyopathy (1,2). Extensive literature on the topic in adult individuals exists however investigation in the pediatric population is sparse. The pathophysiology of disease in children and adolescents is unique. To study the role of insulin resistance in pediatric cardiomyopathy, we measured the homeostasis model assessment-estimated insulin resistance (HOMA-IR) at baseline in pre-pubertal patients (age 13-18 years old; mean 16 years old; n = 8) with either hypertrophic cardiomyopathy (HCM) or dilated cardiomyopathy (DCM). In patients with HCM, greater insulin resistance was positively correlated with greater left ventricular (LV) septal thickness (r = 0.55; p = 0.33; n = 5) and LV posterior wall thickness (r = 0.7; p = 0.19; n = 5) during diastole. As expected, insulin resistance was strongly correlated with BMI (r = 0.84; p = 0.08; n = 5) though greater BMI was not as strongly associated with LV septal thickness (r = 0.59; p = 0.3; n = 5) or posterior wall thickness (r = 0.59; p = 0.3; n = 5). In patients with DCM, insulin resistance was positively correlated with LV end diastolic volume (r = 0.59; p = 0.59; n = 3). Interestingly, there was an observed inverse association between insulin resistance and BMI in DCM (r = -0.85; p = 0.34; n =3). Though our sample population is limited, thus affecting statistical significance, results showed that there was a trend towards greater insulin resistance in patients with poorer cardiac measurements. These findings are consistent with adult literature and the proposition that cardiac dysfunction is an insulin resistant state.

References: (1) Riehle C, Abel ED. Insulin Signaling and Heart Failure. Circulation research. 2016;118(7):1151-1169. (2) Shah A, Shannon RP. Insulin resistance in dilated cardiomyopathy. Reviews in cardiovascular medicine. 2003;4 Suppl 6:S50-57
6-Month Subcutaneous Leuprolide Acetate Effectively Suppresses Clinical Signs of Puberty in Children With Central Precocious Puberty
Authors: Eugster Erica A , Atkinson Stuart , Boldt-Houle Deborah , Miller Bradley Scott
Published: May 2021

Objective: Gonadotropin-releasing hormone (GnRH) agonists, such as intramuscular leuprolide acetate, triptorelin and the subcutaneous histrelin implant, are standard treatment for central precocious puberty (CPP). Implants require surgery and sometimes anesthesia, while frequent intramuscular injections can be painful. A shift to longer acting-formulations and subcutaneous injections has been proposed for the treatment of CPP. Therapies with convenient administration, prolonged duration of action and favorable safety profile may be beneficial, improving patient adherence. 87% of subjects achieved stimulated LH suppression to <4 IU/L by Week (W) 24 in a Phase III trial evaluating the efficacy and safety of the first6-month subcutaneous injectable in situ gel leuprolide acetate for CPP. We present secondary analyses of bone age (BA) advancement, weight, BMI, and pubertal maturation from this trial.

Methods: 62 children (60 girls, 2 boys) with CPP (naïve to treatment) received 2 doses of 45 mg subcutaneous leuprolide acetate at 24-week intervals, constituting the intent-to-treat population. Radiographs of the left hand and wrist were used to determine BA using the Greulich and Pyle method. BA was assessed by a blinded central reader. Rate of BA advancement was determined by the ratio of BA to chronological age (CA, BA/CA). Pubertal maturation was categorized with the Tanner staging system using breast development, external genitalia, and pubic hair. Safety outcomes were measured.

Results: Mean age at onset of treatment was 7.5 ± 0.9 (SD) (range 4-9) years. BA/CA consistently declined throughout treatment, from 1.4 ± 0.2 at baseline, to 1.3 ± 0.1 at W24 and 1.3 ± 0.1 at W48. Although mean weight increased 8.7% from screening to W24 (34.8 kg vs 37.7 kg) and 16.9% from screening to W48 (40.4 kg), mean BMI remained stable throughout the study. The proportion of girls with early breast Tanner stage development (stage 1 and 2) increased from 9% at baseline to 37% at W48. The proportion of girls with late breast Tanner stage development (stage 4 and 5) decreased from 18% at baseline to 5% at W48. Both boys regressed from Tanner stage 3 to stage 2 for external genitalia development by W48. Tanner staging for pubic hair development remained stable for approximately 80% and decreased for 7% of children by W48. 52/53 treatment emergent adverse events were mild or moderate.

Conclusions: 6-month 45 mg subcutaneous leuprolide acetate is a promising treatment for CPP. It effectively suppressed LH, suppressed clinical signs of pubertal maturation and demonstrated a good safety profile. It also has the beneficial features of subcutaneous administration, small injection volumeand twice a year dosing. This may be a welcome addition to the armamentarium given the proposed shift in CPP therapies towards longer-acting formulations and subcutaneous injections.
A Clinical Experience of Pubertal Induction in Female Patients With Congenital Hypogonadotropic Hypogonadism (CHH) From an Endo-ERN Referral Center
Authors: Federici Silvia , Cangiano Biagio , Goggi Giovanni , Persani Luca , Bonomi Marco
Published: May 2021

Female congenital hypogonadotropic hypogonadism (CHH) is a rare condition, with a strong genetic background, characterized by absent or incomplete pubertal development, for which inductive treatment with sex-hormone is required. Although the available data, mostly coming from studies in patients with Turner syndrome, indicate transdermal estradiol (TDE) as the first-choice formulation, no internationally validated therapeutic schemes are currently available. Furthermore, data on CHH patients are certainly lacking and there is no standard of care for pubertal induction in this specific population. The aim of our work was the retrospective analysis of the data from a collection of case reports of pubertal induction in CHH patients referred to our Center. Six patients underwent induction with transdermal estradiol (TDE) at the starting dose of 0.1µg/kg/day (night-time for the first 4-6 months), increased every 4-6 months up to the adult dose, for a mean period of 2.86 ± 0.45 ys. Micronized progesterone (200 mcg) was introduced at reaching of 50µg dose or if breakthrough bleeding occurred. Treatment was monitored through clinical and anthropometric evaluations at each dose modification. The average age of induction was 17.25 ± 1.41 ys, with each bone age> 13 ys. Three out of six patients already had a Tanner B2 stage at diagnosis. The mean times of pubertal advancement were respectively 1.3 ± 0.46 ys for the achievement of B3, 2.13 ± 0.29 ys for the B4 and 2.35 ± 0.77 ys for menarche; all the patients reached an adult breast conformation (B5) in 2.81 ± 0.28 ys. These data are consistent with physiological pubertal progress. All of them achieved adequate uterine development (medium longitudinal diameter 72.2 ± 3.37mm), except one patient with suboptimal development (54mm). The final height (FH) was adequate in all patients, with SDS FH +1.6 (-0.43 - +3.38), in spite of an average growth of 4.11 cm (2.5-6) ​​during the induction period and a growth rate > 2cm/year only in 50% of patients. No side effects were reported, and individual compliance and satisfaction were quite high. This clinical experience suggests that the adopted regimen, consistent with current literature, guarantees excellent efficacy and safety. However, further studies are needed to identify the optimal treatment in adolescents with CHH, taking into account their higher age at the start of induction, the modest impact on growth and final stature, to focus on the specific clinical objectives in these patients
FSH Stimulated Inhibin B in Disorders of Puberty
Authors: Chaudhary Shakun , Walia Rama , Bhansali Anil , Dayal Devi , Sachdeva Naresh , Singh Tulika
Published: May 2021

Background: Predicting puberty is a clinical challenge. Available tests include basal gonadotropins, GnRH and GnRH analogue stimulation test, hCG stimulation test and basal inhibin B(INHB). Unlike GnRH and GnRH analogue stimulated LH, no study has investigated for possibility of rapidly releasable pool of inhibin B from gonads so far. Therefore, in quest of a better diagnostic test present study was undertaken to explore stimulability of inhibin B and if found stimulable, potential role of FSH stimulated inhibin B(FSH-INHB) as marker of entry into puberty. Methods: A total of forty-two subjects fulfilling eligibility criteria were enrolled into this prospective interventional study. Study cohort was divided into Cohort A (Healthy children in puberty; n=26) and Cohort B (Patients of hypogonadotropic hypogonadism; n=16). All participants were subjected to FSH stimulation test and GnRHa stimulation test as per study protocol. Data was analysed for male and female separately. Results: Mean delta change between INHB and FSH-INHB in cohort A (Male; n=18) was 188.8 pg/ml (p value-0.002) while in cohort B(Male; n=8) was 16.64 pg/ml (p value-0.076). Mean delta change in cohort A(Female; n=8) was 1065 pg/ml (p value- 0.023) while in cohort B (Female; n=8) was 9.8 pg/ml (p value-0.128). On ROC analysis, INHB of 68.88 pg/ml in male had 94.4 % sensitivity and 87.5% specificity while 51.47 pg/ml in female had 75% sensitivity and 100% specificity for entry into puberty. Cut off for FSH-INHB were 116.14 pg/ml and 116.50 pg/ml for male and female respectively (100% sensitivity/100% specificity).

Conclusion: Inhibin B was stimulable in both male and female after entry into puberty, highlighting the presence of rapidly releasable pool in ovaries and testes. FSH stimulated inhibin B may emerge as promising tool for entry into puberty.
Molecular Clues From Testis Involve NHLH2, a DNA Binding Transcription Factor That Controls the Onset of Mini-Puberty via Its Neuronal Activity, in Curative GnRH Treatment of Cryptorchidism Dependent Infertility
Authors: Hadziselimovic Faruk
Published: May 2021

Introduction: GnRHa treatment following surgery to correct cryptorchidism restores mini-puberty via endocrinological and transcriptional effects and prevents adult infertility in most cases. A large group of genes are important for central hypogonadotropic hypogonadism in mammals, including many that are transcribed both in brain and testis. However, the expression of these genes in prepubertal gonads has not been systematically studied and little is known about the effect of hormone therapy on their testicular and neuronal expression levels. Here, we interpret histological sections, data on hormone levels and RNA profiling data from adult normal testis in comparison to pre-pubertal low infertility risk (LIR) and high infertility risk (HIR) patients randomized for treatment with surgery in combination with GnRHa or only surgery. Major Results: We organize 31 target genes relevant for hypogonadotropic hypogonadism and cryptorchidism into five classes depending on their expression levels in HIR versus LIR samples and their response to GnRHa treatment. Only the mRNA encoding the DNA binding transcription factor NHLH2 is decreased in HIR as compared to LIR samples, increased after GnRHa treatment, and expressed in both brain and testis. GnRHa treatment of cryptorchidism that restores mini-puberty and rescues adult fertility increases NHLH2 mRNA levels in testis from HIR patients. Conclusion: This phenomenon may reflect a broader effect of hormone treatment on gene expression in both testicular and central nervous tissues, which could explain why the hypothalamus-pituitary-testicular axis is permanently restored by the administration of GnRHa.
Diagnosis of Childhood and Adolescent Growth Hormone Deficiency Using Transcriptomic Data
Authors: Garner Terence , Stevens Adam , Whatmore Andrew James , Clayton Peter Ellis , Murray Philip G
Published: May 2021

Background: We have shown that gene expression (GE) data have promise as a novel tool to aid in the diagnosis of childhood growth hormone deficiency (GHD)1. Our previous study compared GE data in children with GHD to healthy control children of normal stature. The aim of this study was to assess the utility of GE data in the diagnosis of GHD in childhood and adolescence using non-GHD short stature children as a control group.

Methods: GE data were obtained from patients undergoing growth hormone stimulation testing via a sample of blood taken at the start of the test. Arginine and glucagon stimulation tests with a cut-off for peak GH of <7mcg/L (IDS iSYS assay) were used for the diagnosis of GHD. GE was assessed in peripheral blood mononuclear cells via RNA-seq using the Illumina HiSeq 4000 platform. Data were taken for the 271 genes whose expression was utilised in our previous study. The synthetic minority oversampling technique was used to balance the dataset and a random forest algorithm applied to predict GHD status. Boruta was used to assess which of the genes were contributing to the predictive capacity.

Results: Twenty-four patients were recruited to the study, with eight subsequently diagnosed with GHD. Of the eight patients diagnosed with GHD, three had two stimulation tests and five had one stimulation test with anterior pituitary hypoplasia (in addition one patient had an arachnoid cyst and another a thin stalk). Median (range) peak GH was 2.5 (0.1 - 5) mcg/L in the GHD group and 11.0 (7.4 - 31) mcg/L in the non-GHD group.

There were no significant differences in gender, age, auxology (height SDS, weight SDS, BMI SDS) or biochemistry (IGF-I or IGFBP-3 SDS) between the GHD and non-GHD subjects. 82 of the 271 genes used in our previous study were above the threshold of detection for RNA-seq in this study. A random forest algorithm using these 82 genes gave an AUC of 0.97 (95% CI 0.93 - 1.0) for the diagnosis of GHD. Boruta was able to identify 65/82 genes with predictive capacity greater than permuted data within the dataset. Using a gene ontology approach the top fifty biological processes generated 16 clusters by affinity propagation which included regulation of TORC1 signalling and inositol phosphate metabolism.

Conclusion: This study demonstrates highly accurate diagnosis of childhood GHD using a combination of GE data and random forest analysis and validates the findings of our original study.

1Murray etal (2018) JCI Insight 3(7): e93247
Long-Term Growth Hormone Therapy Does Not Advance Skeletal Maturation in Children and Adolescents
Authors: Nwosu Benjamin Udoka , Parajuli Sadichchha , Jasmin Gabrielle , Lee Austin F
Published: May 2021

Context: There is no consensus on the effect of recombinant human growth hormone (rhGH) therapy on skeletal maturation in children despite the current practice of annual monitoring of skeletal maturation with bone age in children on rhGH therapy. Aims: To investigate the effects of long-term rhGH therapy on skeletal age in children and explore the accuracy of bone age predicted adult height (BAPAH) at different ages based on 13 years of longitudinal data. Methods: A retrospective longitudinal study of 71 subjects aged 2-18 years, mean 9.9 ± 3.8y, treated with rhGH for non-syndromic short stature for a duration of 2-14y, mean, 5.5 ± 2.6y. Subjects with syndromic short stature and systemic illnesses such as renal failure were excluded. Results: Bone age minus chronological age (BA-CA) did not differ significantly between baseline and the end of rhGH therapy (-1.05 ± 1.42 vs -0.69 ± 1.63, p=0.09). Piece-wise regression however showed a quantifiable catch-up phenomenon in BA of 1.6 months per year of rhGH therapy in the first 6.5y, 95%CI 0.023 - 0.229, p=0.017, that plateaued thereafter, β=0.015, 95% CI -0.191-0.221, p=0.88. There was no relationship between BAPAH z score – height z score and the duration of rhGH therapy, p=0.68. BAPAH overestimated final adult height in younger subjects but became more precise in older subjects (p<0.0001). Conclusion: Long-term rhGH therapy demonstrated an initial catch-up phenomenon in skeletal maturation in the first 6.5y that plateaued thereafter with no overall significant advancement in bone age. These findings are reassuring and do not support the practice of yearly monitoring of skeletal maturation with bone age in children on rhGH therapy, especially in younger subjects where BAPAH is imprecise.
Pharmacokinetics and Pharmacodynamics of Macimorelin Acetate (AEZS-130) in Paediatric Patients With Suspected Growth Hormone Deficiency (GHD)
Authors: Csákváry Violetta , Muzsnai Agota , Raduk Dmitri , Chaychenko Tetyana , Damholt Birgitte Bentz , Kelepouris Nicky , Teifel Michael , Ammer Nicola
Published: May 2021

Growth hormone deficiency (GHD) in children is a rare, aetiologically diverse condition that results in growth failure and short stature. Inadequate response to two different growth hormone stimulation tests (GHST) is required for the diagnosis of GHD. Macimorelin acetate, a potent, orally administered growth hormone (GH) secretagogue, is approved by the FDA and EMA for the diagnosis of adult GHD. Study AEZS-130-P01 is the first of two studies to investigate macimorelin acetate as a diagnostic test in children with suspected GHD.

This was an open-label, group comparison, dose escalation trial to investigate the safety, tolerability, pharmacokinetics and pharmacodynamics of single-dose 0.25, 0.5 and 1 mg/kg oral macimorelin acetate in paediatric subjects with suspected GHD. The macimorelin GHST was administered between two standard GHST, conducted as per local clinical practice, with a recovery period of 7-28 days between tests. Blood samples were collected pre-dose (±15 min) and 15, 30, 45, 60, 90, 120 and 360 minutes after macimorelin acetate intake.

Overall, 24 paediatric subjects (8 per cohort [C1, C2, C3]) were included in the pharmacokinetic/pharmacodynamic (PK/PD) analysis. Five males and 3 females were observed in C1 and C2, 7 males and 1 female in C3. In all three cohorts, at least 3 subjects represented Tanner stages I or II. All 24 subjects (100%) were white, with a median age of 9.8, 9.0 and 10.5 years (range 4-15 years) and a median body-mass index of 16.1 kg/m2 (12.4-21.4 kg/m2) at screening. Overall, 88 adverse events were reported, many related to the standard GHST; none were considered related to the macimorelin test. Maximum plasma concentrations for macimorelin were mainly observed between 30-45 min. The mean Cmax values were 3.46, 8.13 and 12.87 ng/ml for C1, C2, and C3, respectively. The AUCs increased with dose; the mean AUC0-6 values were 6.69, 18.02 and 30.92 h*ng/mL. The mean elimination half-lives were 1.22, 1.61 and 1.71 h, respectively. PK and PD profiles for all three cohorts were comparable, with peak GH levels mainly observed within 30-60 min following macimorelin intake.

Macimorelin acetate was safe and well tolerated in all dosing cohorts. A dose-dependent increase in macimorelin Cmax and AUC in children and adolescents correlated well with data from adult subjects. A robust dose-proportional GH response was also achieved. PD results showed that GH response was comparable in all dose groups, with a slight shift to earlier tmax at higher macimorelin doses.
Phase 3 Study Evaluating Once Weekly Somatrogon Compared to Daily Genotropin in Japanese Patients With Pediatric Growth Hormone Deficiency (pGHD)
Authors: Horikawa Reiko , Tanaka Toshiaki , Hasegawa Yukihiro , Yorifuji Tohru , Ng David , Rosenfeld Ron G , Hoshino Yuko , Okayama Akifumi , Shima Daisuke , Gomez Roy , Pastrak Aleksandra , Castellanos Orlando
Published: May 2021

Objectives: Somatrogon is a long-acting recombinant human growth hormone consisting of the amino acid sequence of human growth hormone and three copies of the carboxy-terminal peptide of human chorionic gonadotropin. Somatrogon is being developed as a once weekly treatment for children with pGHD. A Phase 3 trial was designed to compare the efficacy and safety of somatrogon administered once weekly with Genotropin administered once daily in Japanese patients with pGHD (ClinicalTrials. gov: NCT03874013).

Methods: 44 Japanese pGHD patients (age 3-11 years) were randomized in a 1:1 ratio to receive either once weekly somatrogon (0.66 mg/kg/week) or once daily Genotropin (0.025 mg/kg/day) subcutaneously for 12 months. Somatrogon-treated patients had a pharmacokinetic assessment in the first 6 weeks with dose escalation occurring in 3 steps, at 0.25, 0.48, and 0.66 mg/kg/week, for 2 weeks at each dose. For the remaining 46 weeks, patients in the somatrogon treatment group continued to receive somatrogon at a dose of 0.66 mg/kg/week. The primary endpoint of the study was annualized height velocity (HV) at 12 months.

Results: Baseline characteristics were balanced and comparable between the two treatment groups. The least square means of HV at month 12 were 9.65 cm/year in the somatrogon group (n=22) and 7.87 cm/year in the Genotropin group (n=22), with a point estimate treatment difference of 1.79 cm/year (95% confidence interval: 0.97, 2.60) in favour of somatrogon. The point estimate was greater than the pre-established mean treatment difference of -1.8 cm/year, which was the non-inferiority margin met in the global Phase 3 study (n=224) with somatrogon (0.66 mg/kg/week) and Genotropin (0.034mg/kg/day) (ClinicalTrials. gov: NCT02968004). Most of the adverse events were mild to moderate in severity and somatrogon was generally well-tolerated with no notable difference in safety between the two treatment groups. Injection site pain was more common in the somatrogon group (somatrogon: 72.7%, Genotropin: 13.6%).

Conclusions: The Japanese Phase 3 trial in patients with pGHD demonstrated that once weekly somatrogon was comparable to daily Genotropin. The annual HV after 12 months of treatment was higher in the somatrogon group than the Genotropin group. Somatrogon administration was generally well tolerated in patients with pGHD. The results of this Japanese Phase 3 study are consistent with the results previously reported from the global Phase 3 study that met its primary endpoint of noninferiority to daily Genotropin.
A Novel Case of Hyperinsulinemic Hypoglycemia in a Neonate With SARS-CoV-2 Infection
Authors: Paulo Remberto , Bowlby Deborah A , Matlock Kristal Anne
Published: May 2021

The Case: An 8 days old male, born at 40 wks, 2.8 kg (SGA) presented to local ED with lethargy, decreased PO intake and urine output, respiratory distress. No fever, URI sx, vomiting/diarrhea. His dad had URI symptoms and fever a week prior. He was found to have T=95.5F, glucose <10 mg/dL, improved to 125 after D10 boluses x2; and required supplemental O2 due to desats/cyanosis. CXR showed bilateral hazy opacities. Sepsis rule out was initiated, patient admitted to the PICU, started on antibiotics and dextrose. Patient became more alert over the next 3 days, but could not be weaned off from IV dextrose/continuous feeds, GIR up to 15 mg/kg/min. He was transferred to our institution. Critical sample at BG of 45 mg/dl showed high insulin level (6.9 uU/ml) and C-peptide (1.25 ng/dl); low beta-OH butyrate <0.2 mmol/L; and free fatty acids (0.25 mmol/L); all suggestive of hyerperinsulinemic hypoglycemia (HH). Cortisol and GH robust at 10.5 mcg/dl and 7.13 ng/ml. Nasopharyngeal swab for SARS-CoV-2 RT-PCR positive. Dad’s swab also positive. Mom was asymptomatic and not tested. ID was consulted, recommended supportive management and close observation. Pt was started on Diazoxide 10mg/kg/day divided q8h, and hydrochlorothiazide (HCT) 5mg/day. Patient’s status gradually improved - BG stabilized, feeds were compressed, IV fluids and O2 supplementation weaned off, and was discharged after 8 days with average BG in the 70-80’s range. Diazoxide and HCT were successfully weaned off in the following 3 mos. To this day patient remains well, no recurrence of hypoglycemia.

Discussion/Conclusion: There is a dearth of information on SARS-CoV-2 infection in newborns. The few studies available show favorable outcomes in this population, with typical mild-moderate respiratory symptoms and fever, while some newborns are asymptomatic. Our patient required oxygen tx and developed HH requiring Diazoxide therapy. To our knowledge, this is the first reported case of HH in the newborn with SARS-CoV-2 infection. Hyerperinsulinism is the most common cause of hypoglycemia in infants. These newborns are at risk of developing significant neurologic morbidity, which can be dose dependent. Prompt diagnosis and aggressive management are important to reduce such risk. Perinatal stress is likely the underlying mechanism leading to HH in newborns with SARS-CoV-2 infection. Patient is also SGA. Both perinatal stress and SGA can lead to inappropriately elevated insulin levels and resultant hypoglycemia. HH in both of these conditions is effectively managed by Diazoxide. Our case illustrates that although most newborns do well with SARS-CoV-2 infection, a high index of suspicion for HH should be maintained in such newborns, particularly in those with at least one other risk factor for HH such as SGA. More studies are needed to elucidate underlying pathology and tease out actual incidence of hypoglycemia in neonates with SARS-CoV-2 infection.
A Pediatric Patient With Noonan Syndrome and Late Onset Unilateral Lymphedema
Authors: Burdea Liliana , Aguirre Roxana L
Published: May 2021

Introduction: Noonan syndrome is a common autosomal dominant disorder with a prevalence of 1 in 1000-2500 births. The lymphatic disorders in Noonan syndrome are rare and usually bilateral. We present a 14-year-old male with Noonan syndrome and late-onset unilateral lower extremity lymphedema.

Case presentation: A 14-year-old male with Noonan syndrome due to a pathogenic mutation in the RIT1 gene (c.265T>C p.Tyro89His) presented to emergency room due to progressive swelling of the right lower extremity. No history of recent trauma or injury. He had a history of small mid-muscular ventricular septal defect (VSD), chylothorax with right-sided pleural effusions during infancy, sensorineural hearing loss with bilateral hearing aids, and undescended testes status post-surgery. He had been on growth hormone (GH) therapy since age 12 years with good adherence and no reported side effects. In the emergency room, initial laboratory evaluation and Doppler ultrasound ruled out deep venous thrombosis. Physical exam was remarkable for edema of the right lower extremity, warm to touch, with erythema, not painful. Due to initial concerns for cellulitis, the patient was treated with antibiotics. Erythema improved but not the edema. Cardiac evaluation including echocardiogram with stable, unchanged VSD was unremarkable. Patient underwent additional workup notable for an albumin level of 4.4g/dl (3.4-5.0), Immunoglobulin (Ig) A 53 mg/dl (66-436), IgG 788 mg/dl (791-1643), IgM 82 mg/dl (43-279) and a stool alpha antitrypsin level of 0.65 mg/g (0.0-0.5) ruling out protein-losing enteropathy (PLE). Growth hormone was held initially and restarted after 2 months due to clinical improvement, but just for one week due to worsening swelling. Lymphoscintigraphy of lower extremities showed an asymmetry between the right and left leg in the transit, suggesting a mild lymphatic abnormality in the right leg. There was a significant improvement in terms of his lymphedema with physical therapy and compressive stocking after 6 months. He has been off growth hormone therapy since then. Discussion: Patients with Noonan syndrome may develop lymphedema and PLE, although findings are usually bilateral. Interestingly our patient has unilateral lymphedema that has been improving with compression stocks and physical therapy. Our patient was on GH therapy for 2 years before he developed lymphedema and although growth hormone causes water retention, we would not expect a selective involvement as in our patient. Based on his history of chylothorax we decided to perform a Lymphoscintigraphy that confirmed an abnormality in the lymphatic system of the right lower extremity. The effect of GH once restarting pointed it was a precipitating factor instead of the cause. Late-onset lymphedema is an uncommon presentation but should be a diagnosis that we have to keep in mind when patients with Noonan syndrome are presenting with edema.
A Pediatric Patient With Papillary Thyroid Carcinoma With Local and Distant Metastases
Authors: Burdea Liliana , Jo Inha , Mantis Stelios
Published: May 2021

Introduction: Thyroid cancer is less common among children than adults, but the incidence has been increasing, especially in adolescents. Papillary thyroid carcinoma (PTC) is the most common type of thyroid cancer in pediatric patients representing more than 90% of all cases. Children with PTC are likely to present with regional lymph node metastases, but distant metastases are rare. We present a 12-year-old female patient who presented with a neck mass found to be PTC with neck and pulmonary metastases. Case Presentation: A 12-year-old girl previously healthy presented to her primary doctor with a neck mass for several months. The patient had no other complaints, and the physical exam was notable for a palpable right anterior neck mass measuring 3x4cm. Thyroid studies were remarkable for a thyroid-stimulating hormone (TSH) of 2.13 uIU/mL (0.350-4.94) and negative antithyroid antibodies. Initial neck ultrasound (US) showed a multilobulated right thyroid nodule with macrocalcifications. Fine needle aspiration (FNA) of the nodule revealed PTC. Patient underwent neck and chest computed tomography (CT) preoperatively, notable for cervical lymph nodes involvement and multiple bilateral lung nodes less than 1cm each. She underwent neck exploration and total thyroidectomy and was started on thyroid hormone replacement therapy afterwards. Pathology of the specimen revealed PTC with extension into the perithyroidal soft tissue and two out of five lymph nodes with metastatic PTC. She underwent I-123 whole-body scan (WBS) eight weeks later, followed by I-131 therapy. Interestingly, the pulmonary nodes did not demonstrate any uptake on the WBS before or after receiving I-131 therapy. Patient continues with no pulmonary symptoms and her thyroglobulin (Tg) level continues to be low. She underwent extensive workup that ruled out infections and other malignancy causing the pulmonary nodes. The most recent chest CT, six months after I-131 therapy, showed a slight decrease in the pulmonary nodes. She underwent repeat WBS, 10 months after I-131, notable for minimal uptake in the lungs. The patient is currently euthyroid on thyroid hormone replacement therapy, and she is undergoing surveillance with laboratory studies every three months, neck US and chest CT every six months. Conclusion: In children with PTC, the pulmonary metastases usually demonstrate radioactive iodine uptake, making them responsive to I-131 treatment. Even though the pulmonary nodes were not iodine avid for our patient based on the WBS, it seems like they are responding to the first dose of I-131 as they have decreased in size. Pulmonary metastases in children have different behavior than in adults, and studies have shown that clinical response to I-131 therapy may take several years to show a reduction in the size of nodes. Therefore, careful consideration should be made before giving another dose of I-131 to this group of patients.
Approaching High-Metabolic Risk Youth During a Pandemic: Severe Presentations of New Onset Type 2 Diabetes
Authors: Long Nathaniel , Eichner Natalie Z M , Benavides-Vasquez Jorge , Saenz Lina Paola Huerta
Published: May 2021

Background: Delays in timely medical care due to the restrictions imposed by the COVID-19 pandemic have worsened patient outcomes with different disease conditions. Youth with obesity, insulin resistance, and dysglycemia are increasingly presenting with HHS and/or DKA, leading to increased morbidity and mortality. Case Descriptions:Case 1: A 17-year-old Hispanic female with history of obesity, insulin resistance, and hyperglycemia reported polyuria, polydipsia, and polyphagia for 2 months. The day of admission, EMS was called because patient was found unresponsive at home and required advanced CPR. At arrival to the ED, the patient was awake and responsive. She had acanthosis nigricans and abdominal striae. Initial labs showed elevated plasma glucose (1,256 mg/dL), sodium (153 mmol/L), bicarbonate (9 mmol/L), anion gap (35 mmol/L), phosphorus (7.5 mg/dL; N=3-4.8), lactate (4 mmol/L; N=0.5-2), BHB (11.4 mmol/L; N=0-0.3), venous pH (7.09), BUN (24 mg/dL), creatinine (1.63 mg/dL), and HbA1c (14.3%). She was admitted for DKA, hyperosmolarity, AKI, and metabolic encephalopathy. After IVF resuscitation, insulin drip at 0.05 U/kg/h was started. She recovered from DKA, AKI and hyperosmolarity after 5 days. T1D antibody tests were negative. C-peptide was low (0.7 ng/mL; N=0.8-3.5), and TSH was low (0.38 uIU/mL) with normal free T4 (0.88 mg/dL). Case 2: A 13-year-old Hispanic female with history of asthma, morbid obesity, premature adrenarche, and prediabetes started presenting polydipsia and polyuria 2 months before admission. One day before admission, she presented drowsiness, abdominal pain, and polyuria. Initial labs at the ED included glucose (792 mg/dL), bicarbonate (10.4 mmol/L), anion gap (28 mmol/L), venous CO2 (10.4 mmol/L; N=21-31), BHB (>22.5 mmol/L), sodium (153 mmol/L), BUN (29 mg/dL), and creatinine (1.37 mg/dL), consistent with DKA, hyperosmolarity, and AKI. Physical exam showed severe obesity, acanthosis nigricans, and hypertension. IV fluids and insulin drip at 0.075 U/kg/h were started. DKA and AKI resolved after 4 days. Labs showed negative T1D antibodies, normal C-peptide (1.2 ng/mL), HgA1C (>14%), microalbuminuria (16.22 mg/dL; N<2 mg/dL), elevated total cholesterol (230 mg/dL) and triglycerides (550 mg/dL). Both youth were negative for SARS-CoV2 and had been engaging in unhealthy lifestyle choices, such as sedentarism and excessive sugary drink intake, exacerbated by COVID-19-related lockdowns and school closures. There were delays in seeking medical care associated to fear of COVID-19.

Conclusion: In the current context of a pandemic, it would be helpful to plan close evaluation and timely therapeutic interventions for youth with well-known high-metabolic risks to prevent hospitalizations, severe presentations of T2D and associated morbidity and/or mortality.
Exogenous Cushing’s Syndrome, Hypogonadism and Diabetes Secondary to Megestrol Acetate
Authors: Baby Merilyn , Murthy Deepa Badrinath , Litao Melissa Kaori , Shust Gail , Shah Bina Cherryl
Published: May 2021

Introduction: Megestrol acetate (MA) is a synthetic progestin that is often prescribed for anorexic patients with HIV due to its effects on weight gain and appetite stimulation. It can cause several endocrine/metabolic abnormalities. Chronic use of MA can cause exogenous Cushing’s Syndrome (ECS) and iatrogenic adrenal insufficiency (AI) due to its stronger affinity for the glucocorticoid receptor (GR). It can also cause gonadotropin suppression, diabetes and hyperprolactinemia. We present a case of a young woman with perinatal HIV/AIDS that developed ECS secondary to MA treatment in the setting of fatigue, rapid weight gain and irregular menses. Case: A 19 year old female with perinatal HIV/AIDS (CD4<200) was treated with MA (200mg/day for 5 months) for anorexia and weight loss. On exam she was pre-hypertensive (BP 138/62), obese (BMI 43.07, SDS +2.25; weight 114kg, SDS +2.34) with increased fat deposition over upper back and abdominal striae, excessive weight gain (21.5 kg in 5 months) suggestive of ECS. She had menarche at 13 years of age and had regular menses until starting MA, upon which she developed oligomenorrhea. A random serum cortisol level was <0.5ug/dl at 1pm with a low ACTH <1.5pg/ml and DHEAS of 13.4ug/dl. Her FSH was 3.4 mIU/L and LH 0.82 mIU/L, estradiol was <2pg/dl and total testosterone <2.5ng/dl consistent with secondary hypogonadism. Liver/kidney function, prolactin and lipid profile were normal. HbA1c increased from 5.3 to 6.4% in 8 months so she was started on metformin. ECS with AI, central hypogonadism and diabetes were all attributed to MA therapy. MA was discontinued gradually over two weeks. Stress dosing of glucocorticoids were advised as needed. Results: Gradual recovery of HPA axis was noted after discontinuation of MA. Two months after taper, serum ACTH level rose to 2.5pg/ml but AM cortisol level remained low at <0.5ug.dl. Her HPA axis showed partial recovery by 5 months with ACTH level of 53.2pg/ml and AM cortisol level of 5.5ug/dl. By 8 months after discontinuing MA therapy, AM cortisol was 9.3ug/dl, suggesting complete HPA axis recovery. Her HPG axis also normalized by 8 months with FSH 6.6 mIU/L and LH of 14.6 mIU/L, estradiol 32pg/dl with regular menses. Metformin was discontinued at 4 months due to hypoglycemia and HbA1C of 5.7%. Subsequently, euglycemia was achieved (HbA1C of 5.4%) within 9 months. BMI was stable (BMI 43.07, SDS +2.25; weight 114kg, SDS +2.34). Conclusion: Multiple endocrine abnormalities may occur due to MA therapy due to its affinity to bind with glucocorticoid and progesterone/androgen receptors. ECS and AI are known to occur with various forms of glucocorticoid use, but rarely can be seen with MA therapy. HPA axis, HPG axis and metabolic parameters should be evaluated and monitored carefully during MA therapy.