Glucose levels are not the same for everyone: a real-world big data study evaluating fasting serum glucose levels by sex and age among children.

OBJECTIVES: Understanding the normal range of laboratory values as pertained to different age groups and males or females is paramount in health care delivery. We aimed to assess the distribution of morning fasting serum glucose levels by age and sex in the general population of children using a large-scale population-based cohort. METHODS: A retrospective study with real-world de-identified data from a large, state mandated health fund in Israel among children aged 2-18 years old between 2006 and 2019. Age, sex, and BMI differences in mean glucose levels were evaluated. RESULTS: Study included 130,170 venous blood samples from 117,411 children, 53.3 % were female. After adjusting for age boys had higher fasting serum glucose levels than girls, with a mean of 89.21 ± 8.66 mg/dL vs. 87.59 ± 8.35 (p<0.001) [4.95 ± 0.48 mmol/L vs. 4.86 ± 0.46]. Compared to the 15 to 18 year-olds (88.49 ± 7.63 mg/dL) [4.92 ± 0.42 mmol/L], 2 to 5 year-olds had lower glucose levels (84.19 ± 10.65, [4.68 ± 0.59] (p<0.001)), 11 to 14 year-olds had higher glucose (90.40 ± 7.42 [5.02 ± 0.41], (p<0.001)) and 6 to 10 year-olds showed no difference (88.45 ± 8.25) [4.91 ± 0.46]. 33.0 % (n=42,991) had a BMI percentile record the same year as their glucose test result. There was a weak yet significant positive association between blood glucose levels and BMI. CONCLUSIONS: Our large cohort indicates that boys have slightly higher fasting serum glucose levels than girls, as do adolescents compared to younger children. This finding is important for the delivery of adequate health care, screening for illness and avoiding unnecessary investigations and tests.

Leukocytosis and C-Reactive Protein Levels as Indicators of Infection in Children With Diabetic Ketoacidosis.

BACKGROUND: Diabetic ketoacidosis (DKA) is one of the serious complications of type 1 diabetes mellitus and may be aggravated by infection. Diagnosing an infection in a patient with DKA is often complicated because of the overlap of symptoms and the presence of leukocytosis in both conditions. Reliable indicators for the diagnosis of bacterial infection in DKA may reduce unnecessary use of antibiotics and enable closer monitoring of patients at risk. METHODS: This is a retrospective study. The study cohort included 180 children and adolescents with type 1 diabetes mellitus who were admitted to the Pediatric Emergency Department at Shaare Zedek Medical Center and had blood test results. We compared white blood cell count, C-reactive protein (CRP) levels, blood glucose levels, pH, the degree of acidosis, and the incidence of infection in patients with and without DKA. RESULTS: The incidence of probable bacterial infection in the entire cohort was 13.9%: 15.7% in the DKA group and 7.5% in the non-DKA group ( P = 0.65). The incidence of leukocytosis was significantly higher in patients with DKA ( P = 0.0003), although this was not related to bacterial infection. The CRP levels were higher in the DKA group with infection than without infection, and this was statistically significant ( P = 0.008). CONCLUSIONS: Our findings suggest that leukocytosis in DKA is not a reliable indicator of concomitant bacterial infection. In contrast, CRP levels were not related to the DKA or degree of acidosis and were significantly higher in patients with infection within the DKA group, and are therefore a more reliable indicator of concomitant infection in these patients.

Stress Hyperglycemia in a Pediatric Emergency Department Setting and its Relationship to the Underlying Disease and Outcome.

BACKGROUND: Stress hyperglycemia (SH) is a common finding in patients in pediatric emergency departments (PED) and has been related to increased morbidity and mortality. OBJECTIVES: To assess the incidence of SH among children visiting the PED. To identify which diseases predispose patients to SH and whether they indicate a worse outcome. METHODS: Data were collected retrospectively from the medical records of all children aged 0-18 years who visited the PED during the years 2010-2014 and who had a glucose level of ≥ 150 mg/dl. Data collected included age, gender, weight, blood glucose level, presence or absence of a pre-existing or a new diagnosis of diabetes mellitus, and previous treatment with medications affecting blood glucose levels or with intravenous fluids containing dextrose. Data were collected regarding hospitalization, duration of hospitalization, discharge diagnosis, and survival status. RESULTS: The study population included 1245 children with SH, which comprised 2.6% of all patients whose blood glucose level was measured in the PED during the study period. The mean age of children with SH was 49 months; 709 (56.9%) were male. The mean blood glucose level was 184 mg/dl. The rate of hospitalization was 57.8%. The mean duration of hospital stay was 5.6 days and mortality rate was 0.96%. The majority were diagnosed with a respiratory illness. CONCLUSIONS: SH is a common phenomenon among children evaluated in the PED and is associated with a high incidence of hospitalization. It may serve as an additional clinical indicator of disease severity.

The inter - Test variability of growth hormone stimulation tests and factors affecting this variability.

OBJECTIVE: To evaluate the variability of growth hormone stimulation tests results and factors affecting it in short children suspected of having growth hormone deficiency. DESIGN: The cohort included patients with short stature suspected of having growth hormone deficiency, and who underwent a second stimulation test, after the first stimulation test was positive. Testing was done at a single center from May 2014 to October 2017. Patients' weight, height, age, sex, stimulating agents and test results were recorded. RESULTS: The study population comprised 200 patients, 108 males and 92 females, average age 9.2 years (2.2-16.6 years). The average peak growth hormone was 5.2 µg/L and 7.8 µg/L in the first and second tests respectively and the concordance rate was 56.5%. The probability of a second positive test was increased if the peak growth hormone level in the first test was below 5 µg/L. In the second test, Clonidine and Glucagon led to higher peak growth levels than Arginine with averages of 9.02, 9.97 and 6.88 µg/L respectively. Younger children and children with higher BMI SDS only had lower peaks of growth hormone in the second test. The effect of height SDS on peak growth hormone levels was equivocal. CONCLUSION: The reproducibility rate of GH simulation tests in our study was low. A few factors may affect the peak levels of growth hormone in the second test, the most prominent being the peak of growth hormone in the first test.

The novel founder homozygous V225M mutation in the HSD17B3 gene causes aberrant splicing and XY-DSD.

PURPOSE: Mutations in the gene HSD17B3 encoding the 17-beta hydroxysteroid dehydrogenase 3 enzyme cause testosterone insufficiency leading to XY disorders of sex development. In this study the clinical and molecular characteristics of three patients from consanguineous families are elucidated. METHODS: We identified three patients from two unrelated families with XY DSD and a novel homozygous HSD17B3:c. 673G>A mutation. The effect of the mutation on splicing was determined in RNA extracted from the testis of one patient. RESULTS: Three patients presented at ages 0.1, 8 and 0.7 years with ambiguous genitalia and an XY Karyotype. Endocrine workup showed normal cortisol and mineralocorticoid levels with a low testosterone/androstenedione ratio. Whole-exome sequencing, carried out in the first family, revealed a homozygous novel mutation in the HSD17B3 gene: c. 673G>A, p. V225M. The same mutation was found by Sanger sequencing in the third unrelated patient. Haplotype analysis of a 4 Mb region surrounding the HSD17B3 gene on chromosome 9 revealed that the mutation resides on the same allele in all three patients. The mutation, being the first nucleic acid on exon 10, affects splicing and causes exon 10 skipping in one of our patients' testes. CONCLUSION: The novel homozygous c. 673G>A, p. V225M mutation in the 17HSDB3 gene is likely a founder mutation and causes severe XY-DSD. It changes a conserved amino acid residue, and also alters 17HSDB3 gene transcription by causing skipping of exon 10, thereby contributing to an imbalance in the relevant protein isoforms and consequently, significant decreased 17HDSB3 enzymatic activity.

Primary Ovarian Insufficiency Nationwide Incidence Rate and Etiology Among Israeli Adolescents.

PURPOSE: The aim of the study was to estimate the current incidence and the distribution of etiologies of primary ovarian insufficiency (POI) in a nationwide study. The prevalence of POI in young adult women has recently increased, but the data cited for adolescents are more than three decades old. METHODS: Data regarding females aged <21 years diagnosed with POI during the years 2000-2016 were collected from all the pediatric endocrinology units in Israel. POI was defined by at least 4 months of amenorrhea in association with menopausal levels of follicle-stimulating hormone. Iatrogenic cases were excluded. RESULTS: For the 130 females aged <21 years included in the study, the distribution of POI etiologies was Turner syndrome/mosaicism in 56 (43%), idiopathic in 35 (27%), and other (developmental, genetic, metabolic, adrenal, and autoimmune) in 39 (30%) females. During the years 2009-2016, compared with 2000-2008, the incidence rate of new POI diagnoses per 100,000 person-years doubled (4.5 vs. 2.0; p value <.0001), and incidence rates of idiopathic and other etiologies increased by 2.6 (p value = .008) and 3.0 (p value = .002), respectively. In contrast, the incidence of Turner syndrome was constant (p value = .2). In the age group of 15-21 years, the current incidence of non-Turner POI in adolescents is one per 100,000 person-years. CONCLUSIONS: In this nationwide study, the incidence rate of POI in youth aged <21 years was one tenth of the rate that is commonly cited. A significant increase in the rate of POI in non-Turner females was observed over the last decade. Contributions of environmental and epigenetic factors should be studied.

The metabolic consequences of overweight in a cohort of children with type 1 diabetes.

Objective To estimate the prevalence of overweight and obesity among a cohort of children with type 1 diabetes mellitus (T1DM) and its metabolic consequences. Methods This was a cross-sectional study conducted in the Pediatric Diabetic Clinic at Shaare Zedek Medical Center and Clalit Health Care Services. Background information was taken from the patients' files. Anthropometric measures, blood pressure, waist and hip circumference (WC and HC), hemoglobin A1c (HbA1c) and lipid profile were recorded. The prevalence of metabolic derangements was compared between normal and overweight children. Results The study included 96 patients with type 1 diabetes, mean age 14.1 ± 3.7 years, mean diabetes duration 3.9 ± 3 and mean HbA1c level 8.1 ± 1.4% (65 mmol/mol). Thirty-seven percent of the study population were overweight and of them 11.5% were obese. In the overweight group, the high-density lipoprotein (HDL) levels were significantly lower and systolic blood pressure (SBP) and diastolic blood pressure (DBP) values were higher compared with normal weight participants. Multivariate analysis showed that BMI and age at study affected SBP and HDL levels, while age at study and HbA1c levels affected DBP. Female patients were significantly overweight compared to males and had higher low-density lipoprotein (LDL) and cholesterol levels. Waist-to-hip ratio, an indicator of central obesity, was abnormally high among overweight males and females. Conclusions In our cohort of children with type 1 diabetes, there were a significant number of overweight children, with a higher prevalence in females. Components of metabolic syndrome were more prevalent among overweight and obese diabetic individuals.

Early puberty in end stage renal failure and renal transplant recipients.

Background Delayed puberty and hypogonadism are common in children with chronic kidney disease and in renal transplant recipients, but precocious puberty has rarely been reported in these populations. We describe six girls with precocious and/or early-onset, rapidly progressive puberty before and following renal transplantation. Methods Of 112 children under the age of 18 years (67 boys, 45 girls) who received renal transplants between 2010 and 2018, six girls presented with precocious or rapidly progressive early puberty at ages 6-7/12, 7-2/12, 7-4/12, 8, 8-8/12 and 8-11/12 years. Clinical evaluation included measurements of height, weight, body mass index (BMI), Tanner staging and bone age assessment. Gonadotropin responses to intravenous gonadotropin releasing hormone (GnRH) or intramuscular triptorelin acetate were determined. Results Tanner breast stage 3 was noted at 2-6 years following renal transplantation in five girls, four with preserved kidney function. One girl began puberty before renal transplantation. Peak luteinizing hormone (LH) and follicular stimulating hormone (FSH) levels were 6.5, 20.2, 7.83, 19.1, 9 and 2.2 mIU/mL and 13, 8.3, 8.01, 7.5, 8.1 and 7.7 mIU/mL, respectively. Treatment with an intramuscular slow-release formulation of triptorelin acetate every 4 weeks slowed progression of breast development. Conclusions Although delayed puberty is more common in children with renal disease, precocious puberty can also be seen. Evaluation of growth and puberty by a pediatric endocrinologist should be part of the routine care for all children following kidney transplantation.

Octreotide-associated cholestasis and hepatitis in an infant with congenital hyperinsulinism.

Congenital hyperinsulinism (CHI) is the most common cause of prolonged hypoglycemia in the neonate. It is caused by several genetic mutations that interfere with the cascade of normal insulin secretion from pancreatic beta cells. Octreotide, a somatostatin analog, suppresses insulin secretion from pancreatic beta cells, and is an effective therapy used for both short and long term in the treatment of CHI. It is well tolerated in most patients; however, several adverse effects have been reported, most of them mild and transient. Impaired liver function has been described previously in few children. Here, we describe about a child with CHI treated with continuous intravenous octreotide who developed cholestasis and hepatitis after a short period of treatment. This combination of liver effects with a short duration of treatment has not been reported previously with octreotide use in this population.

Relative expression of a dominant mutated ABCC8 allele determines the clinical manifestation of congenital hyperinsulinism.

Congenital hyperinsulinism (CHI) is most commonly caused by mutations in the ß-cell ATP-sensitive K(+) (K(ATP)) channel genes. Severe CHI was diagnosed in a 1-day-old girl; the mother's cousin and sister had a similar phenotype. ABCC8 gene sequencing (leukocyte DNA) revealed a heterozygous, exon 37, six-base pair in-frame insertion mutation in the affected patient and aunt but also in her unaffected mother and grandfather. In expression studies using transfected COSm6 cells, mutant sulfonylurea receptor 1 (SUR1) protein was expressed on the cell surface but failed to respond to MgADP even in the heterozygous state. mRNA expression in lymphocytes determined by sequencing cDNA clones and quantifying 6FAM-labeled PCR products found that although the healthy mother predominantly expressed the normal transcript, her affected daughter, carrying the same mutant allele, primarily transcribed the mutant. The methylation pattern of the imprinting control region of chromosome 11p15.5 and ABCC8 promoter was similar for all family members. In conclusion, differences in transcript expression may determine the clinical phenotype of CHI in this maternally inherited dominant mutation. The use of peripheral lymphocytes as a peripheral window to the ß-cell transcription profile can serve in resolving ß-cell phenotypes. The severe, dominant-negative nature of the 1508insAS mutation suggests that it affects the functional stoichiometry of SUR1-regulated gating of K(ATP) channels.