Volume 36, Issue 10

Artificial Intelligence (AI) is integrating itself throughout the medical community. AI’s ability to analyze complex patterns and interpret large amounts of data will have considerable impact on all areas of medicine, including pediatric endocrinology. In this paper, we review and update the current studies of AI in pediatric endocrinology. Specific topics that are addressed include: diabetes management, bone growth, metabolism, obesity, and puberty. Becoming knowledgeable and comfortable with AI will assist pediatric endocrinologists, the goal of the paper.

We aimed to explore the associations of neonatal hypocalcemia with neonatal vitamin D deficiency and maternal vitamin D deficiency. A comprehensive systematic literature search using PubMed and web of science was performed for relevant articles from inception to February 17th, 2023. We used odds ratio (OR) and 95 % confidence interval (CI) as effect sizes for our meta-analysis. Publication bias was evaluated using funnel plot, Begg’s test, and Egger regression test. All the statistical analyses were performed using Stata 14.0. A total of 11 studies were included and analyzed, including 452 newborns with hypocalcemia and 2,599 newborns with normal serum calcium level. Our research results revealed that vitamin D deficiency in newborns may be related to the higher prevalence of hypocalcemia (OR: 2.87, 95 % CI: 1.17–7.04). In addition, maternal vitamin D deficiency might also be a risk factor for neonatal hypocalcemia (OR: 7.83, 95 % CI: 3.62–16.92). There was a significant correlation between vitamin D deficiency and neonatal hypocalcemia.This meta-analysis indicates that newborns with vitamin D deficiency have a higher risk of hypocalcemia, and maternal vitamin D level play a crucial role in this association. Vitamin D supplementation may have a positive effect in reducing the prevalence of neonatal hypocalcemia.

Objectives To investigate the prevalence of thyroid autoimmunity and related thyroid disorders among children and adolescents with type 1 diabetes in Jordan. Methods In a retrospective study, thyroid stimulating hormone and thyroid hormone (Free T4) levels were measured in 684 children with type 1 diabetes who presented to Jordan University Hospital between January 2012 and February 2021. Anti-thyroid peroxidase (TPOAb) and anti-thyroglobulin (TGAb) antibodies were measured in 526 and 438 subjects with type 1 diabetes, respectively. Results 681 children were included in the study (52.4 % females, average current age 14.3 years, average age at diagnosis 8.0 years, and average diabetes duration 6.2 years). Of the whole group, 18 children (2.6 %) were diagnosed with subclinical hypothyroidism and 31 children (4.4 %) had overt hypothyroidism. Of those who were tested for TPOAb and TGAb, 22.6 and 23.1 % were positive respectively. Predictors for developing hypothyroidism were female sex and positive antibodies to glutamic acid decarboxylase. Conclusions Screening for associated thyroid autoimmunity in children and adolescents with type one diabetes from Jordan is advised with a special focus on females and those with positive antibodies to glutamic acid decarboxylase.

Objectives We aimed to assess the efficacy of oral use of oral desamino-D-arginine-8-vasopressin lyophilisate (OLD) in children with central diabetes insipidus (CDI). Methods Clinical, laboratory, and imaging characteristics of twenty-five children with CDI treated with OLD were evaluated. Results Fourteen boys and eleven girls with a mean age of 52.37 months were evaluated. These children (mean weight and height at admission, 26.81 ± 14.8 kg vs. 92.52 ± 30 cm) presented with failure to thrive, irritability, prolonged fever, polyuria and hypernatremia (mean sodium level, 143.12 ± 8.6 mEq/L). At the time of hypernatremia, mean serum and urine osmolality were 298.2 ± 18 mOsm/kg and 160.20 ± 8.7 mOsm/kg, respectively. ADH levels were undetectable (<0.5 pmol/L) at admission in all cases. Oral administration of desmopressin lyophilisate (120 µg/tablet) was initiated at a dose of 5 μg/kg/day in two divided doses together with controlled water intake to avoid hyponatremia. Serum sodium levels normalised in a mean duration of 15.2 ± 16.4 h with a mean decline rate of 0.12 ± 0.04 mEq/L/h. Nine children needed rehospitalization because of hypernatremia due to non-compliance. Four episode of hyponatremia was observed. Weight gain and growth were normal during the mean follow-up duration of 37.79 ± 48.2 months. Conclusions Administration of OLD was practical and safe in the treatment of CDI in children with CNS malformations in this small retrospective series.

Objectives Children with classical congenital adrenal hyperplasia (CAH) require glucocorticoid (GC) substitution due to impaired cortisol synthesis. To avoid over- or undertreatment, one has to consider auxology as well as biochemical parameters for adrenal derived steroids like androstenedione (A4) and 17-hydroxyprogesterone (17-OHP). There are no established reference values for A4 and 17-OHP in CAH. Methods We performed a retrospective study in 53 prepubertal patients with CAH. Datasets of patients were included if the plasma A4 values of the respective clinical visit were under the limit of quantification. Related 17-OHP values were extracted as well as height/length, weight, dose of hydrocortisone, HC regimen, bone age and stages of pubertal development. Results Median hydrocortisone doses were in most observations within the recommended reference ranges. Hydrocortisone has a significant negative influence on 17-OHP values and HSDS. Age has a positive significant influence on 17-OHP, BMI-SDS, and HSDS. Median height standard-deviation-score (HSDS) was beneath 0 at all times, but showed an increasing trend in both sexes. Median body mass index standard-deviation-score (BMI-SDS) was above 0 at all times and showed an increasing trend as well. Conclusions With guideline-compliant doses of hydrocortisone, suppression of A4 at the respective time of day is possible in prepubertal children. Although HC has a significant negative influence on HSDS, increasing values for HSDS and HC are observed with increasing age. Thus, A4 suppression at the respective time point does not hinder regular growth. An increase in body mass index can already be observed as early as in prepuberty.

Objectives The aim of the current study was to evaluate the safety and efficacy of initiation protocol for MiniMed ™ 780G system among an Egyptian cohort of young people living with type 1 diabetes (T1D). Methods A prospective single-arm study including 72 participants with T1D. Five days of structured education and training were provided to all users and continuous glucose monitoring (CGM) was initiated on the first day of the training. Users initiated the pump initially in manual mode, with suspend before low feature, for 3 days before shifting to Auto Mode. Results The mean HbA 1c decreased from 8.72 ± 2.01 % to 6.7 ± 0.4 % (p<0.01). Time in range (70–180 mg/dL) substantially improved from 55.24 % ± 10.35 to 81.7 % ± 5.12 % after spending 84 days in auto mode (p<0.001) with 2.03 % of the time spent below 70 mg/dL. Regarding AHCL compatibility, users spent at least 90 % of time in auto mode. Conclusions Young people with T1D successfully initiated the AHCL system, using a tailored structured on-boarding protocol. Structured stepwise initiation protocol and onboarding steps are important prerequisite for participants’ adherence and engagement with the system. Patient education together with optimized pump settings are important predictors of glycemic outcomes.

Objectives This cross-sectional study examined the relationship between problem-solving skills, glucose regulation, and disease management in children with type 1 diabetes mellitus (T1DM) as well as the role of depression in this association. Methods The participants (n=54) were recruited from a diabetes camp. Problem-solving inventory (PSI), Beck depression inventory (BDI), and diabetes self-management profile (DSMP) were administered as tests. Forty-six participants who have been diagnosed with T1DM for at least a year and completed the survey were included in the analyses. Participants were categorized into high and low depression groups based on the median split. Student’s t-test was used to detect demographic differences in groups. Linear regression models were used to examine the association between PSI, HbA 1c , and DSMP. Regressions for PSI and DSMP were repeated in low and high-depression groups. Results Of the 46 participants with T1DM, 52 % were female, with a mean age of 13.96 ± 1.94 (range 10–17). Avoidant and monitoring style of problem solving as well as the total score of PSI significantly predicted HbA 1c levels. Impulsive and avoidant style of problem solving, problem-solving confidence, and total scores of PSI significantly predicted DSMP (p<0.05). The high depression group had a significantly higher DSMP score than the low depression group (p=0.001), with no difference in HbA 1c levels (p=0.968). When the DSMP regressions were repeated, no significant associations were seen in the low depression group. Avoidant style of problem solving, problem-solving confidence, and the total score of PSI significantly predicted DSMP in the high depression group (p<0.005). Conclusions Problem solving-skills are essential in children with T1DM for a successful disease management. Depression modulates the association between the problem-solving and self-management profile.

Objectives Type 1 diabetes (T1D) causes psychological distress, negatively impacting normal childhood activities. Depression, anxiety disorders, and eating problems are commonly observed in this population. Methods The study population consisted of 40 adolescents (22 females and 18 males) who had been diagnosed with T1D and 41 healthy adolescents (21 females and 20 males). The aim of this study was to compare adolescents with T1D to healthy controls in terms of depression, anxiety, and eating problems and subsequently examine the T1D group in relation to the risk of diabetes-specific eating disorders. Eating Attitudes Test (EAT-40), Revised Children’s Anxiety and Depression Scale (RCADS), and Diabetes Eating Problem Survey – Revised (DEPS-R) scales were used to compare the case and control groups. Results The case group exhibited significantly higher scores in EAT-40 total score, RCADS parent form major depressive disorder (MDD), social anxiety disorder (SAD), generalized anxiety disorder (GAD), panic disorder (PD), total anxiety score, total scale scores, RCADS child form MDD, PD, and total scale scores compared to the control group. Individuals at high risk of diabetes-specific eating disorder within the case group demonstrated significantly higher RCADS (child and parent form) MDD scores and RCADS parent form separation anxiety (SA) and total scale scores. Binary logistic regression analysis revealed that the RCADS parent form total scale score could predict DEPS-R. Conclusions Routine screening of children and adolescents diagnosed with T1D for depression, anxiety, and eating disorder risk may facilitate early detection of possible psychopathologies, allowing for early intervention to address factors that may disrupt treatment adherence. Further longitudinal studies with larger samples are needed to investigate psychopathologies, particularly eating disorders, in children and adolescents with T1D.

Objectives Genotype–phenotype correlation in congenital adrenal hyperplasia (CAH) caused by 21-hydroxylase deficiency ranges from 45 to 97 %. We performed massively parallel sequencing of CYP21A2 on stored newborn bloodspot samples to catalogue the genotypes present in our patients with CAH and enable genotype–phenotype comparison. Methods Participants ≤15 years old with clinically diagnosed CAH were recruited from The Sydney Children’s Hospitals Network. Phenotype was classified from clinical and biochemical details in the medical record as salt wasting (SW), simple virilising (SV), non-classic (NC) or an intermediate phenotype (SW/SV; SV/NC). Amplicon-based sequencing for CYP21A2 was performed on stored newborn bloodspot samples by the New South Wales Newborn Bloodspot Screening Laboratory on MiSeq™Dx (Illumina, California). Available genetic test results were also obtained from the medical records. Results Samples from 67 participants (43 % female, age 0.3–15 years) were sequenced, including 9 sibships. SW phenotype was present in 33/67 participants (49 %), SV in 9 (13 %) and NC in 16 (24 %). Intermediate phenotypes included SW/SV in seven participants (10 %) and SV/NC in two (3 %). Variants were identified in 90/116 alleles (78 %). A complete genotype was available in 47/67 participants (70 %). The most common genotype was homozygous c.293-13A/C>G (I2G) in 7/47 participants (15 %). Genotype correlated with the most commonly reported phenotype in 36/44 cases (82 %). Correlation was higher in SW and NC phenotypes. Conclusions This study uses genetic testing of newborn bloodspots to identify and characterise the genotypes present in an ethnically diverse Australian population with CAH. It further strengthens our knowledge of genotype–phenotype correlations in CAH.

Objectives Autosomal dominant hypocalcemia (ADH) is characterized by hypocalcemia and hyperphosphatemia secondary to hypoparathyroidism. It is classified as type 1, caused by gain-of-function mutations of the calcium-sensing receptor (CASR), and type 2, caused by activating mutations in GNA11 , which is a crucial mediator of CASR signaling. What is new? We report a rare pediatric case of ADH type 2. Case presentation The patient was a 15-year-old girl with short stature. Blood tests demonstrated hypocalcemia and hyperphosphatemia without elevated parathyroid hormone levels. Brain computed tomography revealed calcification in the bilateral basal ganglia. Genetic testing revealed the rare GNA11 mutation, c.1023C>G (p.Phe341Leu). The patient was diagnosed with ADH type 2. She had experienced numbness and tetany in her hands for several years, which improved with alfacalcidol therapy. Conclusions Our patient is the third female and first pediatric reported case of a variant mutation in the GNA11 gene (ADH type 2), c.1023C>G (p.Phe341Leu).

Objectives Severe and very severe hypertriglyceridemia although rare within the pediatric population occur more often among oncology patients, secondary to chemotherapeutic agents. Currently there exists minimal literature to guide management of severe hypertriglyceridemia among pediatric patients. Very-low-fat dietary restriction should be considered over nil per os (NPO) for initial management of severe hypertriglyceridemia in stable pediatric patients. Pediatricians caring for oncology patients must consider chylomicronemia as a potential etiology for presenting symptoms. Pediatric severe hypertriglyceridemia management guidelines are needed as pediatricians must currently rely on anecdotal experiences for management decisions. Case presentation Three children receiving treatment for acute lymphoblastic leukemia required hospitalization for very severe hypertriglyceridemia. Management varied among the cases but included: NPO or very-low-fat diet, insulin, intravenous fluids, fibrates, and omega-3 fatty acids. Conclusions These cases suggest that pediatric severe hypertriglyceridemia management, in the absence of pancreatitis should allow a very-low-fat diet initially rather than NPO followed by pharmacologic therapies.

Objectives TANGO2 deficiency is a rare inborn error of metabolism, with distinct clinical features. The clinical presentations of TANGO2 deficiency are developmental delay, speech difficulties, intellectual disability, non-life-threatening paroxysmal neurologic episodes (TANGO2 spells), acute metabolic crises, cardiac crises, seizures and hypothyroidism. Patients may die in acute metabolic crises. Here we report our experience in the management of an acute metabolic crisis in TANGO2 deficiency. Case presentation A 9-year-old patient diagnosed with TANGO2 deficiency was admitted with fever, fatigue, unable to walk. In follow up, encephalopathy, rhabdomyolysis and arrhythmia were detected. Vitamin B-complex was started. Our patient’s mental status and rhabdomyolysis improved dramatically, and cardiac crises ended without Torsades de pointes, ventricular tachycardia and/or fibrillation or myocardial dysfunction. Conclusions With this report, we aimed to show the effectiveness of vitamin B-complex in the management of acute metabolic crises.

Objectives PAX4 (Paired box 4), a transcription factor crucial in pancreatic beta cell development and function, is a rare cause of maturity-onset diabetes of the young (MODY). What is new? A novel PAX4 variant is verified by family segregation study to be likely pathogenic. A child below 10 years of age diagnosed to have PAX4-MODY, differing from previously reported paediatric cases diagnosed in adolescence. Case presentation A child with diabetes diagnosed at age 8 years, harbored a PAX4 variant, c.890G>A (p.Gly297Asp), initially classified as variant of uncertain significance. Eleven family members (7 adults and 4 children) with and without diabetes across 3 generations were genotyped. The variant co-segregated with diabetes or prediabetes across 3 generations of the family. The variant is reclassified as likely pathogenic according to standard guidelines. Conclusions Genetic testing is essential to confirm PAX4-MODY as the presentation is variable even within the same family. PAX4 mutation needs to be considered in MODY genetic testing in Asian patients.

Objectives Over the past 3 years, coronavirus disease 2019 with its worldwide spread has profoundly marked public health, therefore anti-COVID-19 vaccinations have been developed to prevent the dissemination of the disease. To date, 71 cases of Graves’ disease (GD) after vaccination against SARS-Cov-2 were described in the adult population. Our goal is to present the first case in the paediatric population. Case presentation We present the first case of a 16-year-old adolescent girl who developed GD 6–7 weeks after the second dose anti-COVID-19 mRNA vaccine. Therapy with methimazole and propranolol was started, achieving normal thyroid function and negativity of thyroid autoantibodies at the time of therapy discontinuation after 8 months. Conclusions This case shows that the development of GD after COVID-19 mRNA vaccination can occur also in the adolescent population. Nevertheless, the small number of cases of GD described so far, after many millions of vaccinations, makes it impossible to determine whether this is simple a coincidence or a cause. Further epidemiological data on the incidence of GD in the vaccination period compared to the previous period will be able to clearly define this question.